Abstract: Endoglin (ENG) is a causative gene of type 1 hereditary hemorrhagic telangiectasia (HHT1). HHT1 patients have arteriovenous malformations (AVMs) in multiple organs, including the brain. In mice, Eng deletion induced by R26RCreER or SM22aCre leads to AVM development in the brain and other organs. We have reported that the severity of brain AVM in mice with activin receptor-like kinase 1 (Alk1, an HHT2 causative gene) mutation is correlated with the number of Alk1 negative endothelial cells (ECs). We hypothesized that increase of Eng negative ECs will enhance AVM severity. To increase EC Eng deletion, we used a codon improved cre (icre), which is more potent in recombination of floxed alleles than the wild type (WT) cre. R26RCreER;Eng^f/f mice that have Rosa promoter driving and tamoxifen (TM) inducible WT cre expression globally and PdgfbiCreER;Eng^f/f that have Pdgfb promoter driving and TM inducible icre expression in ECs were treated with 3 intra-peritoneal injections of TM (2.5 mg/25g of body weight) to delete Eng globally or in the ECs. AAV-VEGF was stereotactically injected into the brain to induce brain focal angiogenesis and brain AVM. We found that iCre caused more Eng deletion in the brain indicated by lower level of Eng proteins (p<0.001) and fewer Eng positive ECs (p=0.01) than mice with WT cre. Mice with iCre mediated Eng deletion have more abnormal vessels (p=0.02), CD68⁺ macrophages (p=0.002), and hemorrhage (p=0.04), and less vascular pericyte and smooth muscle coverage than mice with WT cre. In addition, arteriovenous shunts were detected in the intestines of icre mice, a phenotype that have not been detected in WT cre mice before. RNAseq analysis showed that 8 out of the 10 top upregulated pathways identified by Gene Ontology (GO) analysis are related to the inflammation. Therefore, increase of Eng deletion in ECs exacerbates AVM severity, which is associated with enhanced inflammation. Strategies that can reduce Eng negative ECs could be used to develop new therapies to reduce AVM severity for HHT1 patients.

Microbes found in soil can have a significant impact on the taste and quality of wine, also referred to as wine terroir. To date, wine terroir has been thought to be associated with physical and chemical characteristics of the soil. However, there is a fragmented understanding of the contribution of vineyard soil microbes to wine terroir. Additionally, vineyards can play an important role in carbon sequestration, since the promotion of healthy soil and microbial communities directly impact greenhouse gas emissions to the atmosphere. We review 24 studies that explore the role of soil microbial communities in vineyards and their influence on grapevine health, grape composition, and wine quality. Studies spanning 2015 to 2018 laid a foundation by exploring soil microbial biogeography in vineyards, vineyard management effects, and the reservoir function of soil microbes for grape-associated microbiota. On the other hand, studies spanning 2019 to 2023 appear to have a more specific and targeted approach, delving into the relationships between soil microbes and grape metabolites, the microbial distribution at different soil depths, and microbial influences on wine flavor and composition. Next, we identify research gaps and make recommendations for future work. Specifically, most of the studies utilize targeted sequencing (16S, 26S, ITS) which only reveals community composition. Utilizing high-throughput omics approaches such as shotgun sequencing (to infer function) and transcriptomics (for actual function) is vital to determine the specific mechanisms by which soil microbes influence grape chemistry. Going forward, understanding long-term effects of vineyard management practices and climate change on soil microbiology, grapevine trunk diseases, and the role of bacteriophages in vineyard soil and wine making would be a fruitful investigation. Overall, the studies presented shed light on the importance of soil microbiomes and their interactions with grapevines in shaping wine production. However, there are still many aspects of this complex ecosystem that require further exploration and understanding to support sustainable viticulture and enhance wine quality.

Many estuarine ecosystems and the fish communities that inhabit them have undergone substantial changes in the past several decades, largely due to multiple interacting stressors that are often of anthropogenic origin. Few are more impactful than droughts, which are predicted to increase in both frequency and severity with climate change. In this study, we examined over five decades of fish monitoring data from the San Francisco Estuary, California, U.S.A, to evaluate the resistance and resilience of fish communities to disturbance from prolonged drought events. High resistance was defined by the lack of decline in species occurrence from a wet to a subsequent drought period, while high resilience was defined by the increase in species occurrence from a drought to a subsequent wet period. We found some unifying themes connecting the multiple drought events over the fifty-year period. Pelagic fishes consistently declined during droughts (low resistance), but exhibit a considerable amount of resiliency and often rebound in the subsequent wet years. However, full recovery does not occur in all wet years following droughts, leading to permanently lower baseline numbers for some pelagic fishes over time. In contrast, littoral fishes seem to be more resistant to drought and may even increase in occurrence during dry years. Based on the consistent detrimental effects of drought on pelagic fishes within the San Francisco Estuary and the inability of these fish populations to recover in some years, we conclude that freshwater flow remains a crucial but not sufficient management tool for the conservation of estuarine biodiversity.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists throughout the world with over 65 million registered cases of survivors with post-COVID-19 sequelae, also known as LongCOVID-19 (LongC). LongC survivors exhibit various symptoms that span multiple organ systems, including the nervous system. To search for neurological biomarkers of LongC, we investigated the soluble proteins present in the plasma and the proteins associated with plasma neuronal-enriched extracellular vesicles (nEVs) in 33 LongC patients with neurological impairment (nLongC), 12 COVID-19 survivors without any LongC symptoms (Cov), and 28 pre-COVID-19 healthy controls (HC). COVID-19 positive participants were infected from 2020-2022, not hospitalized, and were vaccinated or unvaccinated before infection. IL-1b was significantly increased in both nLongC and Cov and IL-8 elevated in only nLongC. Both brain-derived neurotropic factor and cortisol were significantly elevated in nLongC and Cov compared to HC. nEVs from people with nLongC had significantly elevated protein markers of neuronal dysfunction, including amyloid beta 42, pTau181 and TDP-43. This study shows chronic peripheral inflammation with increased stress after COVID-19 infection. Additionally, differentially expressed nEV neurodegenerative proteins were identified in people recovering from COVID-19 regardless of persistent symptoms.

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a rare and inherited vascular disorder, characterized by the development of arteriovenous malformations (AVMs) in various organs and telangiectasia (small AVM) in the mucocutaneous. The majority of HHT patients have haploinsufficiency of genes involved in the transforming growth factor-beta (TGFβ) signaling pathway, including endoglin (ENG), activin receptor-like kinase 1 (ALK1, also known as ACVRL1), or SMAD4. Active angiogenesis is also required for telangiectasia and AVM development. Anti-angiogenic strategies have been tested in patients and animal models extensively. However, the exact mechanisms for telangiectasia and AVM development remain unclear. In this review, we discuss recent advances in identifying disease mechanisms, and potential therapeutic targets.

Monitoring is an essential component in ecosystem management and leveraging existing data sources for multiple species of interest can be one effective way to enhance information when making management decisions. Here we analyzed juvenile Chinook Salmon (Oncorhynchus tshawytscha) bycatch data that has been collected by the recently established Enhanced Delta Smelt Monitoring program (EDSM), a survey designed to estimate the abundance and distribution of the San Francisco Estuary’s (estuary) endangered Delta Smelt (Hypomesus transpacificus). Two key aspects of the EDSM program distinguish it from other fish surveys in the estuary: a stratified random sampling design and the spatial scale of its sampling effort. We integrated the EDSM dataset with other existing surveys in the estuary and used an occupancy model to assess detection probability differences across gear types. We saw no large-scale differences in size selectivity, and while detection probability varied among gear types, cumulative detection probability for EDSM was comparable to other surveys due to the program’s use of replicate tows. Based on our occupancy model and sampling effort in the estuary during spring of 2017 and 2018, we highlighted under-sampled regions that saw improvements in monitoring coverage due to EDSM. Our analysis also revealed that each sampling method has its own benefits and constraints. Although the use of random sites with replicates as conducted by EDSM can provide more statistically robust abundance estimates relative to traditional methods, the use of fixed stations and simple methods such as beach seine may provide a more cost-effective way of monitoring salmon occurrence in certain regions of the estuary. Stronger inference on salmon abundance and distribution can be made by leveraging the strengths of each survey’s method. Careful consideration of these trade-offs is crucial as the management agencies of the estuary continue to adapt and improve their monitoring programs.

Natural host defensins, also sometimes termed antimicrobial peptides, are evolutionarily conserved. They have been studied as antimicrobials, but some pharmaceutical properties, undesirable for clinical use, led to the development of synthetic molecules with constructed peptide arrangements and/or peptides not found in nature. The leading development currently is synthetic small molecule nonpeptide mimetics, whose physical properties capture the characteristics of the natural molecules, and share their biological attributes. We studied brilacidin, an arylamide of this type, for its activity in vitro against fungi (40 clinical isolates, 20 species) that the World Health Organization has highlighted as problem human pathogens. We find antifungal activity at low concentrations for many pathogens, which indicates further screening for activity, particularly in vivo, is justified to evaluate this compound, and other mimetics, as attractive leads for development of effective antifungal agents.

Coincident changes in abundance and behavior pose a challenge for interpreting abundance data from monitoring programs. In the San Francisco Estuary, long-term monitoring documented the declines of many species including the anadromous Longfin Smelt (Spirinchus thaleichthys). We identified seasonal patterns in reginal presence of Longfin Smelt through its life cycle using monitoring data and generalized additive modelling. We then investigated the year-to-year variability in the seasonal patterns of presence using functional data analysis (FDA). FDA separated the variability due to population size from variability due to differences in timing of presence. We found that Longfin Smelt have consistent seasonal distribution patterns and that two trawl types were needed to accurately describe those patterns. After accounting for variability due to year-class strength, shifts in the timing of presence were evident in three regions. The most variable period for the upstream regions Suisun Bay and West Delta was for age-0 fish in summer and for the downstream region Central Bay was for age-0 fish in late fall. This manifested as a delay in the typical fall re-occupation of upstream regions that comprise the study area for another monitoring study (Fall Midwater Trawl). Thus, a portion of the recent reductions in Fall Midwater Trawl abundance of Longfin Smelt resulted from changes in behavior rather than a decline in abundance. The presence of multiple monitoring surveys allowed analysis of distribution from one data set to aid interpretation of patterns in abundance from another monitoring survey. This study highlights how identifying portions of the life cycle with the most and least variability in distribution can help inform the types of management strategies that will be most effective. It also illustrates an analytical method that can be used to address the problem of confounded effects of abundance and behavior on patterns in monitoring data.

The early 2-factor (E2F) family of transcription factors, including E2F1-8, plays a critical role in apoptosis, metabolism, proliferation, and angiogenesis within glioblastoma (GBM). However, the specific functions of E2F transcription factors (E2Fs) and their impact on the malignancy of Bevacizumab (BVZ)-responsive GBM subtypes remain unclear. This study used data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to explore the impact of eight E2F family members on the clinical characteristics of BVZ-responsive GBM subtypes and possible mechanisms of recurrence after BVZ treatment.To predict the possibility of GBM patient survival and progression, we classified and comparedthe expression of E2Fs according to BVZ-responsive subtypes and employed a machine learning method-TreeBagger, one random forest algorithm. Multiple bioinformatics analyses have shown that the significant increased E2F8 post BVZ treatment may enhance the function of angiogenesis and stem cell proliferation, indicating one of the mechanisms of GBM recurrence after treatment. In addition, BVZ treatment in unresponsive GBM patients may potentially worsen disease progression. Our findings suggest that E2F family members play important roles in GBM malignancy and BVZ treatment response, highlighting their potential as prognostic biomarkers and therapeutic targets and recommending precise BVZ treatment for GBM patients.

Cumulus parameterization schemes model the subgrid-scale effects of moist convection, affecting the prognostic of cloud formation, rainfall, energy levels reaching the surface, and air quality. Working with a spatial resolution of 1 km, we studied the influence of cumulus parameterization schemes coded in the Weather Research &amp; Forecasting with Chemistry Version 3.2 (WRF-Chem 3.2) for atmospheric modeling in Cuenca, an Andean city of Southern Ecuador (2500 masl), during September 2014. For assessing the performance, we used meteorological records from the urban area and stations located mainly over the Cordillera, with heights above 3000 masl, and air quality records from the urban area. Firstly, we did not use any cumulus parameterization (0 No Cumulus). Then we considered four schemes: 1 Kain-Fritsch, 2 Betts-Miller-Janjic, 3 Grell-Devenyi, and 4 Grell-3 Ensemble. On average, the 0 No Cumulus option was better for modeling meteorological variables over the urban area, capturing 66.5% of records and being the best for precipitation (77.8%). However, 1 Kaint-Fritsch was better for temperature (78.7%) and 3 Grell-Devenyi for wind speed (77.0%) and wind direction (37.9%). All the options provided acceptable and comparable performances for modeling short-term and long-term air quality variables. The results suggested that using no cumulus scheme could be beneficial for holistically modeling meteorological and air quality variables in the urban area. However, all the options, including deactivating the cumulus scheme, overestimated the total amount of precipitation over the Cordillera, implying that its modeling needs to be improved, particularly for studies on water supply and hydrological management. New WRF-Chem versions and microphysics parameterization, the other component directly related to cloud and rainfall processes, must be assessed.

This work presents updated reconstructions of watershed runoff to San Francisco Estuary from tree-ring data to AD 903, coupled with models relating runoff to freshwater flow to the estuary and salinity intrusion. We characterize pre-development freshwater flow and salinity conditions in the estuary over the past millennium and compare this characterization with contemporary conditions to better understand the magnitude and seasonality of changes over this time. This work shows that the instrumented flow record spans the range of runoff patterns over the past millennium (averaged over five, ten, twenty and one hundred years), and thus serves as a reasonable basis for planning-level evaluations of historical hydrologic conditions in the estuary. Over annual timescales we show that, although median freshwater flow to the estuary has not changed significantly, it has been more variable over the past century compared to pre-development flow conditions. We further show that the contemporary period is generally associated with greater spring salinity intrusion and lesser summer-fall salinity intrusion relative to the pre-development period. Thus, salinity intrusion in summer and fall months was a common occurrence under pre-development conditions and has been moderated in the contemporary period due to the operations of upstream reservoirs, which were designed to hold winter and spring runoff for release in summer and fall. This work also confirms a dramatic decadal-scale hydrologic shift in the watershed from very wet to very dry conditions during the late 19th and early 20th centuries; while not unprecedented, these shifts have been seen only a few times in the past millennium. This shift resulted in an increase in salinity intrusion in the first three decades of the 20th century, as documented through early records. Population growth and extensive watershed modification during this period exacerbated this underlying hydrologic shift. Putting this shift in the context of other anthropogenic drivers is important in understanding the historical response of the estuary and in setting salinity targets for estuarine restoration. By characterizing the long-term behavior of San Francisco Estuary, this work supports decision-making in the State of California related to flow and salinity management for restoration of the estuarine ecosystem.

There are two generic approaches to curing any medical condition. The first treats every patient for all of the known possible causes that contribute to pathogenesis; the second individualizes potentially curative therapy by identifying in each separate patient only those components of pathogenesis that are actually operative, and treating those. This article adopts the second approach for formulating a cure of Alzheimer’s dementia (AD). Components of AD’s pathogenesis are, in alphabetical order: circadian rhythm disturbances, depression, diabetes and insulin resistance, dyslipidemia, hypertension, inflammation, metabolic syndrome, mitochondrial dysfunction, nutritional deficiencies, TGF-β deficiency, underweight, vascular abnormalities, and Wnt/β-catenin deficiency. For each component, data are described that show the degree by which its prevalence is more in the patients with mild cognitive impairment (MCI) who did not revert to having normal cognition than in those who did, because the former group is the pool of patients from among which future AD may develop. Addressing only those components that are present in a particular individual, is potentially a curative strategy. Published data indicate that curative therapy requires that the number of such components to address should be ≥3. Although structural brain changes cannot be directly addressed, the impaired neural tracts result from many of the reversible causal elements, so correcting them will benefit those tract

Background: During the pandemic, Emergency departments were overcrowded with critically ill patients and confronted ethical dilemmas to assign respiratory support to them due to scarce resources. Quick tools to evaluate patients at admission were needed; many scores were used but inaccurate to predict outcomes. The Rox Index is an easy and fast score that reflects the respiratory status in acute respiratory failure patients, this score could predict the outcome of covid 19 patients. Hypothesis: The 24-hour difference in the Rox Index discriminate accurately the mortality and needs for mechanical ventilation of patients with covid-19. Methods: Study design: Prospective analytic study. Population: 204 Patients admitted to the emergency department from May to August 2020. Data were collected from the clinical records. The Rox Index was calculated at admission and 24h later, the difference was used to establish the outcome, a logistic regression model adjusting for age, sex, presence of comorbidities and disease severity to build and perform ROC analysis. Results: Difference in respiratory ROX Index between admission and 24h is a good predictor for death AUC 0.92 and for mechanic ventilation AUC: 0.75. Each decrease in one unit of the difference at 24h had an Odds Ratio for death risk: 1.48 (95%CI: 1.31-1.67) and for mechanic ventilation: 1.16 (95%IC: 1.1-1.23). Conclusion: The 24-hour variation of Rox Index has good predictive value and allows healthcare professionals to identify which patients will benefit from invasive treatment, especially in low resource settings where emergency physicians deal with survival.

By reinterpreting the calibration of structural models, a reassessment of the importance of the input variables is undertaken. The analysis shows that volatility is the key parameter to any calibration exercise by several orders of magnitude. In order to maximize the sensitivity to volatility, a simple formulation of Merton’s model is proposed that employs deep out-of-the-money option implied volatilities. The methodology also eliminates the use of historic data to specify the default barrier thereby leading to a full risk neutral calibration. Subsequently, a new technique for identifying and hedging capital structure arbitrage opportunities is illustrated. The approach seeks to hedge the volatility risk, or vega, as opposed to the exposure from the underlying equity itself, or delta. The results question the efficacy of the common arbitrage strategy of only executing the delta hedge.

Hair cosmetics are in fashion. Numerous products are commonly used in combination. Frequent allergens are present in hair cosmetics, which, added to almost daily use, increase the risk of sensitization. Familiarity with the clinical distribution of the eczematous rash is necessary to seriously consider patch testing. There are haptens on the market, although not all of them. It is necessary to know how to patch your own products. When avoidance of the allergen cannot be possible, new treatments are being evaluated to combat allergic contact dermatitis, mainly of the occupational type. In this manuscript, a complete and practical review of the main allergens and contact sources of hair cosmetic origin has been carried out.

Many risk-modifying factors affect cancer incidence and mortality rates. We present an ecological study of incidence and/or mortality rates for cancers during 2007–2016 of 17 anatomical sites with respect to solar ultraviolet-B (UVB) doses and obesity prevalence. Solar UVB reduces cancer risk by producing vitamin D, which has many mechanisms to reduce risk of cancer incidence, progression, and metastasis. Obesity increases cancer risk through several mechanisms, including increased systemic inflammation. Data were averaged for 12 geographical regions. Solar UVB doses were significantly inversely correlated with mortality rates for five cancers for males and four for females. Obesity prevalence was directly correlated with mortality rates for three cancers for males and seven for females. The population attributable fraction of cancer mortality rates ascribed to low solar UVB dose was 0.03 for both males and females, whereas that for obesity prevalence was 0.05 for males and 0.08 for females. Thus, cancer mortality rates in France could be reduced through vitamin D supplementation and reducing the prevalence of obesity. Doing so also could reduce risk of other adverse health outcomes.

Obesity is a risk factor for the development of gestational diabetes mellitus (GDM). However, the most optimal type of nutritional intervention to prevent GDM in high-risk women is not clearly defined. This study investigates if nutritional treatment based on the Mediterranean diet (MedDiet) before 12th gestational week (GW) in women at high risk due to a body mass index (BMI)≥25kg/m2, reduces the rate of GDM and metabolic syndrome (MetS) at 3 years postpartum. We performed a post-hoc analysis of the San Carlos Gestational Prevention Study. A total of 735 women with BMI≥25kg/m2 were evaluated between 2015-2018, 246 in standard diet control group (CG) and 489 in MedDiet intervention group (IG). The rate of GDM was significantly lower in IG compared to CG (25.1%vs31.7%;p=0.037). Postnatal follow-up was completed by 141 women in CG (57%) and 312 women in IG (64%). At 3 years postpartum, we observed a reduction (relative risk 95% confidence interval) in the rates of impaired fasting glucose (IFG) (0.51 (0.28-0.92);p=0.019), obesity (0.51 (0.28-0.92),p=0.041), waist circumference (WC)≥89.5cm (0.54 (0.31-0.94);p=0.022) and MetS (0.56 (0.33-0.94);p=0.003). MedDiet reduces the rate of GDM and postpartum MetS in women with BMI)≥25kg/m2, suggesting that its implementation should be routinely recommended from the first GWs.

Elevated blood glucose levels, known as glycemia, play a significant role in sudden cardiac arrest, often resulting in sudden cardiac death, particularly among those with diabetes. Understanding this link has been a challenge for healthcare professionals, leading many research groups to investigate the relationship between blood glucose levels and cardiac electrical activity. Our hypothesis suggests that glucose-sensing mechanisms in cardiac tissue could clarify this connection. To explore this, we adapted a single-compartment, in-silico model of the human atrial node's action potential. We incorporated glucose-sensing mechanisms with voltage-gated sodium ion channels using ordinary differential equations. Parameters for the model were based on existing experimental studies to mimic the impact of glucose levels on atrial node action potential firing. Simulations using voltage clamp and current clamp techniques showed that elevated glucose levels decreased sodium ion channel currents, leading to a reduction in the sinoatrial node action potential frequency. In summary, our model provides a cellular-level understanding of how high glucose levels can lead to bradycardia and sudden cardiac death.

Gestational diabetes mellitus (GDM) pathophysiology comprises clinical and genetic factors. In fact, GDM has been associated with several single nucleotide polymorphisms (SNPs). This study aimed to build a prediction model of GDM combining clinical and genetic risk factors. A total of 1588 pregnant women from the San Carlos Cohort participated in the present study, 1069 (67.3%) Caucasian (CAU) and 519 (32.7%) Latin American (LAT), 255 (16.1%) with GDM. The incidence of GDM was similar in both groups (16.1% CAU and 16.0% LAT). Genotyping was performed by IPLEX Mass ARRAY PCR selecting 110 SNPs based on literature references. The SNPs showing the strongest likelihood of GDM development were the rs10830963, rs7651090 and rs1371614 in CAU and rs1387153 and the rs9368222 in LAT. Clinical variables including age, pre-pregnancy body mass index and fasting plasma glucose (FPG) at 12 gestational weeks predicted the risk of GDM (AUC 0.648, 95%CI 0.601-0.695 in CAU; AUC 0.688, 95%CI 0.628-9.748 in LAT) and adding the SNPs modestly improved prediction (AUC 0.722, 95%CI 0.680-0.764 in CAU; AUC 0.769, 95%CI 0.711-0.826 in LAT). In conclusion, adding genetic variants enhanced the prediction model of GDM risk in CAU and LAT pregnant women. An RCT is underway to demonstrate its usefulness

Elevated blood glucose levels, known as glycemia, play a significant role in sudden cardiac arrest, often resulting in sudden cardiac death, particularly among those with diabetes. Understanding the internal mechanisms has been a challenge for healthcare professionals, leading many research groups to investigate the relationship between blood glucose levels and cardiac electrical activity. Our hypothesis suggests that glucose-sensing biophysics mechanisms in cardiac tissue could clarify this connection. To explore this, we adapted a single-compartment, computational model of the human atrial node's action potential. We incorporated glucose-sensing mechanisms with voltage-gated sodium ion channels using ordinary differential equations. Parameters for the model were based on existing experimental studies to mimic the impact of glucose levels on atrial node action potential firing. Simulations using voltage clamp and current clamp techniques showed that elevated glucose levels decreased sodium ion channel currents, leading to a reduction in the sinoatrial node action potential frequency. In summary, our mathematical model provides a cellular-level understanding of how high glucose levels can lead to bradycardia and sudden cardiac death.

Prostate cancer is the second leading cause of death in males in America, with advanced prostate cancers exhibiting a 5-year survival rate of only 32%. Castration-resistance is often developed during the course of treatment, though its influences require further understanding. This study explores the human microbiome for its implications in castration-resistance and metastasis in prostate cancer. RNA sequencing data was downloaded for bone and soft tissue biopsies of patients with metastatic castration-resistant prostate cancer. These sequences were mapped to bacterial sequences to yield species-level abundance approximations. Numerous species were found to correlate to the expression of known markers of castration-resistance, including AR, PI3K, and AKT. Castration-resistance-associated signaling pathways were also enriched with these species, including PI3K-AKT signaling and endocrine resistance. For their implications in cancer aggression and metastasis, cancer stem cell markers were further explored for relation to these species. EGFR and SLC3A2 were widely downregulated with greater abundance of most species. Our results suggest that the microbiome is heavily associated with castration-resistance and stemness in prostate cancer. By considering the microbiome’s importance in these factors, we may better understand the highly aggressive and highly invasive nature of prostate cancer, allowing for needed improvement in the treatment of this disease.

The main sources of intrinsic noise in excitable cells at the microcircuit and network levels are the stochastic characteristics of ion channel gating and activation of the synaptic conductance. Studies using in vivo, in vitro, and in silico methods to examine the effects of synaptic background activity were not adequately investigated in non-neuronal excitatory cells, where neurotransmitter-based innervation also occurs. We created a mathematical model to replicate the background synaptic noise dynamics in a non-neuronal cell. We utilized the stochastic Ornstein-Uhlenbeck process to represent excitatory synaptic conductance, which was incorporated into a whole-cell model to produce spontaneous and evoked cellular electrical activities. The single-cell model includes many biophysically detailed ion channels represented by a set of ordinary differential equations in Hodgkin-Huxley and Markov formalisms. This paradigm effectively induced irregular spontaneous depolarizations (SDs) and spontaneous action potential (sAP) resembling in vitro-like electrical activity in the cells. The input resistance decreased by multiple factors, and the spontaneous action potential firing rate elevated. The potential to reach the action potential threshold is altered. Background synaptic activity can alter the input/output characteristics of non-neuronal excitatory cells. Suppressing these baseline activities would facilitate the discovery of new pharmaceutical targets for different clinical diseases.

Acute and chronic graft versus host disease (a/cGVHD) are major complications of allogeneic stem cell transplantation and a frequent cause of non relapse-mortality. The treatment of a/cGVHD consists of steroid administration at full dose. In the case of aGVHD, around 60 % of patients with grade III/IV fails to respond (steroid-resistant, SR), requiring a second line therapy. Extracorporeal photopheresis (ECP) represents a good option for second line treatment, leading to multiorgan response in several patients. Here, we have evaluated the performances of a cytofluorimetric quality control of the first ECP procedure in 29 patients with severe SR aGVHD who underwent ECP. The quality control represents a check control of in vitro cell apoptosis/death induction in collected and irradiated CD3+ cells by ECP. Our analysis shows that in more than 70 % quality controls a relevant apoptotosis/death of CD3+ cells was observed after cell irradiation, as compared to non-irradiated controls. Albeit observed in a small patients’ series, the occurrence of relevant in vitro effect after ECP relates to less procedures and/or to a better survival on ECP. Age, disease, gender, aGVHD grade and time from transplant to the first ECP had not impact on ECP efficacy in this patients’ series.

Relatives play an important role in mental health service users’ care. Interventions directed either at service users or their relatives may influence the other person as well. The project Activa’t per la salut mental (Get active for mental health) consisted of a series of four interventions addressed at people diagnosed with mental disorders and their relatives to help them in their recovery process, increasing their agency and quality of life. The objective of the present study is to evaluate the interaction of the participation of service users on their relatives’ outcomes and vice versa. The impact of the project was evaluated within an RCT. The treatment group had access to all the circuit interventions while the control group received treatment as usual and could only access one of the interventions. All participants were evaluated at baseline, six months, and twelve months after the end of the first intervention. Service users were evaluated with the Stages of recovery questionnaire, and relatives with the Family Burden Interview Schedule II and the Duke-UNC-11 questionnaires. The interaction between service users and their relatives was analysed by means of correlational analyses within the intervention group. Service users baseline characteristics influenced in the level of participation of relatives and vice versa. The results also indicated an interaction between service users’ recovery score changes on the change of care burden of relatives. Service users’ participation levels interacted with the decrease of relatives’ burden. These results can be extremely helpful in fostering interactive benefits in future projects addressing the wellbeing of mental health service users and their relatives. Future studies could use specific designs to explore the directionality of the causality of these effects.

The viewpoint and reaction of a country towards climate change are shaped by its political, cultural, and scientific backgrounds, in addition to the distinct characteristics of its evolving climate and the anticipated and actual consequences of the phenomenon in the times ahead. A region's climate has a significant impact on how water is managed and used, mostly in the primary sector (agroforestry systems, livestock, and agriculture), and both the distribution of ecosystem types and the amount and spreading of species on Earth. As a result, the environment and agricultural practices are affected by climate, so evaluating both distribution and evolution is extremely pertinent. Towards this aim, the climate distribution and evolution in the S. Francisco River basin (SFRB) is assessed in three periods (1970−2000, 1981−2022) in the past and 20412060 in the future from an ensemble of GCMs under two SSPs (Shared Socioeconomic Pathways), SSP2-4.5 and SSP5-8.5. The Köppen-Geiger (KG) climate classification system is analyzed, and climate change impacts are inferred for this watershed located in central-eastern Brazil, covering an area equivalent to 8% of the country. Results predict the disappearance of the hot-summer (Csa) and warm-summer (Csb) Mediterranean climates, and a reduction/increase in the tropical savanna with dry winter (Aw)/dry summer (As). A striking increase in the semi-arid hot (BSh-steppe) climate is predicted with a higher percentage (10%) under SSP5-8.5. The Source and the mouth of SFRB are projected to endure the major impacts of climate change that is followed by a predicted increase/decrease in temperature/precipitation. Future freshwater resource availability, and quality for human use will all be impacted. Consequences on ecosystems, agricultural and for the socioeconomic sectors within the SFRB might deepen the current contrasts between regions, urban and rural areas, and even between population groups, thus translating to a larger extent, the inequality that still characterizes Brazilian society. Maps depicting land use and cover changes in the São Francisco River basin from 1985 to 2022 highlight tendencies such as urbanization, agricultural expansion, deforestation, and changes in shrubland and water bodies. Urban areas fluctuated slightly, while cropland significantly increased from 33.57% to 45.45%, and forest areas decreased from 3.88% to 3.50%. Socioeconomic data reveals disparities among municipalities: 74.46% with medium Human Development Index (HDI), 0.59% with very high HDI, and 9.11% with low HDI. Most municipalities have a Gross Domestic Product (GDP) per capita below US$ 6,000. Population distribution maps show a predominance of small to medium-sized urban and rural communities, reflecting the basin's dispersed demographic and economic profile. To build routes towards a shared sustainable goal—namely, to adapt and reduce the expected climate change impacts in SFRB—it is imperative that integrated measures be conducted with the cooperation of stakeholders, local population, and decision-makers.

Coccidioidomycosis (Valley Fever) is a disease caused by inhalation of Coccidioides spp. This neglected tropical disease of the Americas has substantial public health impact despite its geographic restriction to desert areas of the southwestern U.S., Mexico, Central and South America. The incidence of this infection in California and Arizona has been increasing over the past fifteen years. The burden of disease in outside the U.S. remains poorly understood. Several large cities are within the endemic region in the U.S. Coccidioidomycosis accounts for 25,000 hospital admissions per year in California. While most cases of coccidioidomycosis resolve spontaneously, up to 40% are severe enough to require anti-fungal treatment, and a significant number disseminate beyond the lungs. Disseminated infection, especially involving the meninges, is fatal without appropriate treatment. Infection with Coccidioides spp. is protective against a second infection, so vaccination seems biologically plausible. This review of efforts to develop a vaccine against coccidioidomycosis focuses on vaccine approaches and the difficulties in identifying protein antigen/adjuvant combinations that protect in experimental mouse models. Although the quest for a vaccine has not yet resulted in a clinically useful product, scientific efforts of vaccine development pave the way for future success.

Atopic dermatitis (AD) is a chronic inflammatory disorder presenting a dysregulated immune response and derangement of the epidermal barrier lipids. The Th2-type cytokines interleukin IL-4 and IL-13 play a prominent role in AD by activating the Janus Kinase/Signal Transduction and Activator of Transcription (JAK/STAT) intracellular signal axis. This study aimed to investigate the role of JAK/STAT in the lipid perturbations induced by Th2 signaling in 3D-epidermal equivalents. We used tofacitinib, a low-molecular-mass JAK inhibitor, to screen for the JAK/STAT-mediated deregulation of lipid metabolism. Th2 cytokines decreased the expression of elongases 1, 3, and 4, and serine-palmitoyl-transferase and increased that of sphingolipid delta(4)-desaturase, and carbonic anhydrase 2. Th2 cytokines inhibited the synthesis of palmitate and caused a depletion of triglycerides. This depletion was associated with altered PC profiles and fatty acid (FA) metabolism. Overall, the ceramide profiles were minimally affected. Except for most sphingolipids and very long chain FAs, the effects of Th2 on lipid pathways were reversed by co-treatment with tofacitinib. An increase in the mRNA levels of CPT1A and ACAT1, reduced by tofacitinib, suggests that Th2 cytokines promote FA beta-oxidation. In conclusion, pharmacological inhibition of JAK/STAT activation prevents the lipid disruption caused by halted homeostasis of FA metabolism.

Background: Atopic dermatitis is a chronic condition that significantly affects the daily life of those who suffer from it, requiring complex and personalized management with active participation of the patient in the management of their disease. Objective: to describe the design and development process of a mobile application, using the Design Thinking method, for the follow-up of patients with atopic dermatitis. Methods: User-centered design and prototype creation method, differentiating the phases of the empathize, define, idea, prototype, and test. A purposive snowball sampling was used to recruit patients with atopic dermatitis, family members, and health professionals. Three two-hour workshops were held, attended by 25 people. Results: the parameters to be monitored will include objective data (physical, behavioral, treatments, environmental, integration of daily routines) and subjective data (user experience). On the other hand, it will figure out behavior patterns, set up rewards, foster a feeling of community, and use notifications and a chatbot. Conclusion: The active integration of all stakeholders at each stage of the design and development of the digital solution has improved its relevance and acceptance, resulting in a tool that is expected to significantly improve the management of atopic dermatitis.

A fully automated bacteria whole genome sequencing (WGS) assay was evaluated to characterize Mycobacterium tuberculosis (MTB) and non-tuberculosis Mycobacterium (NTM) clinical isolates. Results generated were highly reproducible with 100% concordance in species and sub-lineage classification, and 92% concordance between antimicrobial resistance (AMR) genotypic and phenotypic profiles. These findings demonstrate that a fully automated WGS assay, with a short turnaround time of 24.5 hours, provides timely and valuable insights into MTB outbreak investigation while providing reliable genotypic AMR profiling consistent with traditional antimicrobial susceptibility tests (AST). This study establishes a favorable proposition in the adoption of an end-to-end fully automated WGS solutions for decentralized TB diagnostics, thereby aiding in WHO’s vision of tuberculosis eradication.

Enhanced electrical activity in detrusor smooth muscle (DSM) cells is a key factor in detrusor overactivity which causes overactive bladder pathological disorders. Transient receptor potential melastatin-4 (TRPM4) channels, calcium-activated cation channels, play a role in regulating DSM electrical activities. These channels likely contribute to depolarizing the DSM cell membrane, leading to bladder overactivity. Our research focuses on understanding TRPM4 channel function in mouse DSM cells using computational modeling. We aimed to create a detailed computational model of the TRPM4 channel based on existing electrophysiological data. We employed a modified Hodgkin-Huxley model with an incorporated TRP-like current to simulate action potential firing in response to current and synaptic stimulus inputs. Validation against experimental data showed close agreement with our simulations. Our model is the first to analyze the TRPM4 channel's role in DSM electrical activity, potentially revealing insights into bladder overactivity. In conclusion, TRPM4 channels are pivotal in regulating human DSM function and TRPM4 channel inhibitors could be promising targets for treating overactive bladder.

Cytomegalovirus (CMV) is the leading infectious cause of brain defects and neurological dysfunctions, including sensorineural hearing loss (SNHL). A targeted screening in neonates failing the hearing screen is currently recommended in Italy according to national guidelines. However, SNHL may not be present at birth; also, congenital CMV (cCMV) may manifest with subtle signs other than SNHL. Therefore, inclusion of additional criteria for cCMV screening appears clinically valuable. Starting January 2021, we have implemented an expanded targeted cCMV screening at our center, with testing in case of maternal CMV infection during pregnancy, inadequate antenatal care, maternal HIV infection or immunosuppression, birthweight and/or head circumference.

The effects of the climate crisis are affecting ecosystems at different scales and magnitudes. This paper focuses on a massive Mediterranean mussel die-off observed along the middle Italian Adriatic coast in the summer of 2022. We considered the possible environmental causes of this phenomenon and carried out a climatic analysis of the last decade. We performed field surveys in different locations along a 16 Km coastal stretch (from Martinsicuro (TE) on the South, to Grottammare (AP) on the North). The study area includes two marine Sites of Community Importance under the European Natura 2000 network. The mussels die-off has interested practically all the natural mussel-beds colonizing the study area. Mussels are sessile filter-feeding organisms inhabiting the intertidal zone, therefore, are highly exposed to variations in environmental conditions such as temperature and nutrient load. We discuss the possible causes of this die-off, proposing that high temperature and the scarce availability of food acted simultaneously as stress factors, generating local unsustainable living conditions for this species.

Bioelectrochemical systems (BES) encompass a group of biobased technologies capable of directly converting organic matter into electricity. In these systems, which are derived from conventional electrochemical systems, the ion exchange membrane represents a key element because of its influence on the economic feasibility and on the performance of BES. This study examines the impact of long-term operation of a BES on the mechanical, chemical and electrochemical properties of five different kind of cation exchange membranes (Nafion-117, CMI-7001, Zirfon UTP 500, FKE and FKB) through several techniques: (i) scanning electron microscopy (SEM) and atomic force microscopy (AFM) to assess the changes on the membranes surface, (ii) thermogravimetric analysis (TGA) to evaluate the structural stability of the membranes, and (iii) ion exchange capacity (IEC) to monitor any change in their electrochemical properties. Results confirmed that there is not an ideal membrane for BES. While Nafion and CMI-7000 exhibited the strongest chemical structure, they also underwent the highest fouling as revealed by a fast increase in surface roughness.

Background: Tibial shaft fractures are the most common of long bone fractures. The gold standard for management is locked intramedullary nailing. The freehand method under fluoroscopic monitoring is the most often utilized method for distal screw locking. Electromagnetic guidance-based distal screw locking methods have gained popularity recently. The study's objective is to evaluate the system using electromagnetic tracking data against the free-hand technique. Methods: Sixty-three patients who received intramedullary nailing for tibial shaft fractures at our institute between January 2018 and May 2022, were included in this study. Two groups of patients were distinguished: Group FH underwent freehand distal locking and intramedullary nailing, while Group SS underwent electromagnetically guided locking. Radiation exposure period, as well as dose area product, were noted and statistically compared. Results: In terms of dose area product, a mean value of 43.57±31.57 cGy/cm2 in group FH and a mean value of 27.62±11.20 cGy/cm2 in group SS (p &lt; 0.05) was assessed. Concerning the duration of surgery a mean value of 128.83±26.51 minutes was reported in group FH and a mean value of 126.42±48.31 minutes in group SS (p &gt; 0.05). Conclusions: This study confirms the use of electromagnetic-guided locking distal screws reduces the total time of exposure to ionizing radiation, with no difference in operating time.

Water scarcity is a key challenge to global development. In Brazil, the Sao Francisco River Basin (SFB) has experienced water scarcity problems because of decreasing streamflow and increasing demands from multiple sectors. However, the drivers of decreased streamflow, particularly the potential role of surface-groundwater interaction, have not been yet investigated. Here, we assess long-term trends in baseflow, quickflow, and streamflow of the SFB during 1980–2015 and constrain the most likely drivers of observed decreases through trend analysis of precipitation (P), evapotranspiration (ET), and terrestrial water storage change (TWS). We found that over 82% of the observed decrease in streamflow can be attributed to a significant decreasing baseflow trend (< -20 m3 s-1 y-1) along the SFR with spatial agreement between decreased baseflow, increased ET, and irrigated agricultural land. We also noted a decrease in TWS across the SFB with trends exceeding -20 mm y-1. Overall, our findings indicate that decreasing groundwater contributions (i.e., baseflow) is providing the observed reduction in total SFR flow. A lack of significant P trends indicates that only P variability likely has not caused the observed baseflow reduction, mainly in the Middle and Sub-middle SFB. Therefore, groundwater and surface withdrawals may be likely a driver of water scarcity over the SFB.

Artificial Intelligence (AI) and Machine Learning (ML) approaches that could learn from large data sources have been identified as useful tools to support clinicians in their decisional process; AI and ML implementations have had a rapid acceleration during the recent COVID-19 pandemic. However, many ML classifiers are “black box” to the final user, since their underlying reasoning process is often obscure. Additionally, the performance of such models suffer from poor generalization ability in presence of dataset shift. Here, we present a comparison between an explainable-by-design (“white box”) model (Bayesian Network (BN)) versus a black-box model (Random Forest), both studied with the aim to support clinicians of Policlinico San Matteo University Hospital in Pavia (Italy) during the triage of COVID-19 patients. Our aim is to evaluate whether the BN predictive performances are comparable with those of a widely used but less explainable ML model such as Random Forest and to test the generalization ability of the ML models across different waves of the pandemic.

Soot combustion experiments with 5%O2/He were conducted using model soot, and four distinct compositions of CexPr1-xO2-δ oxides were prepared, varying nominal cerium com-positions (x=0, 0.2, 0.3, and 1). The catalyst samples were comprehensively characterized using techniques such as XRD, Raman spectroscopy, HR-TEM, N2 adsorption at −196 °C, XPS, O2-TPD, H2-TPR, and work function measurements. The Pr-rich compositions, rang-ing from Ce0.3Pr0.7O2-δ to PrO2-δ, resulted in a significant increase in the total evolved O2 amounts and enhanced catalyst reducibility. However, a decrease in textural properties of the catalysts was noted, being particularly important for the pure praseodymia under the synthesis route conducted. The catalytic activity was investigated under two contact modes of mixing between soot and catalyst: loose and tight. The results revealed that the catalytic performance is associated with the surface contact in tight contact mode and with the combination of surface/subsurface/bulk oxygen mobility and the BET surface ar-ea in loose contact mode. Notably, the T10 and T50 parameters were achieved at much lower temperatures than the uncatalyzed soot combustion, even under loose contact conditions. Specifically, the 50% conversion was achieved at 511℃ and 538℃ for Ce0.3Pr0.7O2 and Ce0.2Pr0.8O2, respectively. While no direct correlation between catalytic activity and work function was observed a significant relationship emerges between work function values and the formation of oxy-gen vacancies, whatever the conditions used for these measurements. On the other hand, the ability to generate a high population of oxygen vacancies at low temperatures, rather than the direct activation of gas-phase O2, influences the catalytic performance of Pr-doped ceria catalysts, highlighting the importance of surface/subsurface oxygen vacancy generation, which was the parameter which showed better correlation with the catalytic activity, whatever the soot conversion value or the mode of contact considered.

Arsenic is naturally present in many geological formations around the world and is a major source of groundwater contamination. Bolivia is not exempt from this problem. Physical-chemical studies of water quality in deep and shallow wells have determined the presence of arsenic in some areas of the Bolivian Altiplano, valleys, and plains. In the Lake Poopó basin, water from shallow wells (up to 30 m) has arsenic concentrations that exceed the Bolivian drinking water standard and the WHO recommendation of 10 μg-As/l by up to 25 times. In peri-urban areas of Cochabamba, the arsenic content in groundwater is up to 113 μg-As/l. chronic exposure to arsenic is associated with neurological and dermatological problems and carcinogenic effects. To date, no measures have been taken to mitigate the arsenic problem for the rural population, who often rely on arsenic-contaminated water as their only source of drinking water. This contamination represents a serious threat to the health and economic well-being of the inhabitants and ecosystem in these areas. In this work, for arsenic removal, iron and iron oxide nanoparticles obtained from recycling metal chips by top-down and bottom-up technology have been used for arsenic adsorption in an experimental filter combined with other artisanal filtering materials in the form of layers. The results have shown that water contaminated with arsenic after passing through the filter reduces the concentration of total arsenic filtered from 83, 52 ppb to less than 5 ppb, less than the Bolivian standard 512 of 10 ppb for drinking water.

Ethical considerations regarding our treatment of animals have gained strength, leading to legislation and a societal focus across various disciplines. This is a subject of study within curricula related to agri-food sciences. The aim was to determine the perceptions of agronomy university students concerning animal welfare in livestock production systems. A survey was conducted to encompass various aspects, from participants' sociodemographic attributes to their attitudes and behaviors regarding animal welfare and the consumption of animal products. Statistical analysis, performed using R software, delved into the associations between participants' characteristics and their perspectives on the ethical, bioethical, and legal dimensions of animal welfare. Associations between demographic factors and ethical viewpoints among students were identified. Gender differences emerged in animal treatment perceptions, while rural and urban environments impacted perspectives on various animals. Bioethical considerations revealed distinctive disparities based on gender and education in concerns for animal welfare, value perceptions, evaluations of animal behaviors, and opinions on animal research. It is crucial to distinguish between animal welfare and ethical considerations arising from coexisting with sentient beings capable of experiencing suffering. Ethical theories provide a lens through which we perceive our obligations toward animals. The responsibility to ensure animal welfare is firmly rooted in recognizing that animals, like humans, experience pain and physical suffering. Consequently, actions causing unjustified suffering or mistreatment, particularly for entertainment purposes, are considered morally unacceptable.

The persistence of symptoms following COVID-19 infection represents a significant challenge in healthcare management. During the outbreak, tele-rehabilitation emerged as a new tool to support healthcare structures in providing rehabilitation services. This study assessed the effectiveness and the feasibility of a 3-week home-based motor and respiratory rehabilitation program for long COVID-19 individuals after traditional rehabilitation. Twenty-three patients completed the program and underwent functional tests at different time points (i.e. baseline, after hospital discharge, and after tele-rehabilitation). Motor function was evaluated using the instrumented Six-Minutes Walking Test (i6MWT), with monitored heart rate and oxygen saturation. Conversely, respiratory function was measured via forced vital capacity (FVC) and maximal voluntary ventilation (MVV) tests. Significant improvements (p &lt; 0.05) in motor and respiratory function were observed throughout the intervention, including an 18.3% increase in walked distance from the baseline. The findings suggest that a home-based tele-rehabilitation can enhance motor and respiratory function in post-COVID patients. Despite limitations such as sample size and lack of control group, the positive outcomes seem to support the feasibility of the proposed tele-rehabilitation program in managing long COVID symptoms and promoting functional recovery. Further research is needed to validate these findings and explore tele-rehabilitation’s potential in broader patient populations.

Background: Hashimoto’s thyroiditis (HT) is an autoimmune disease that progressively leads to thyroid gland destruction and hypothyroidism. Patients produce antibodies against two thyroid-specific antigens: thyroglobulin and thyroid peroxidase. As a result of the abnormal amount of thyroid hormone produced and its autoimmune etiology, patients with HT display a higher frequency of either autoimmune or non-autoimmune dermatological disorders. On ultrasound examination, HT can be detected by observing an enlarged thyroid gland with hypoechoic parenchymal regions or by observing a small gland indicating atrophy and diffusely heterogeneous parenchyma. Changes in the parenchymal vascularity can be observed as decreased or increased levels of vascularization. Objective: This study aimed to analyze the role of clinical data and ultrasound evaluation of patients with HT in suggesting an association with dermatological disorders. Patients and methods: Complete dermatological and endocrinological assessments as well as ultrasonography of the thyroid and lymphnodes were performed in HT patients. Results: The data obtained showed that a family history of thyroid disease, increased diameter of the inferior thyroid artery, and the presence of cervical lymphadenopathy were more frequent in the group of patients with dermatological diseases. Taken together, our results suggest the usefulness of ultrasound in determining a possible association between HT and dermatological disorders.

Climacteric fruits undergo a characteristic ripening process regulated by ethylene, a key plant hormone. Extending the shelf life of these fruits while preserving their postharvest quality poses a significant challenge for the food industry. This review provides a comprehensive overview of physiological and molecular strategies to delay ethylene-mediated ripening in climacteric fruits and their impact on shelf life, postharvest quality, sensory attributes, and volatile compounds. Additionally, it examines the role of ethylene in fruit ripening analysing various ethylene managing strategies including ethylene inhibitors, ethylene adsorbents and ethylene scavengers by catalytic oxidation The review concludes with future research directions including integrated strategies, environmental considerations and commercial applications for improving postharvest handling and fruit quality.

Abstract: Understanding the reliability and sensitivity of jump testing is essential to determine the neuromuscular progress of athletes and make informed decisions. This study aimed to assess the reliability and sensitivity of countermovement jump (CMJ) and drop jump (DJ) tests metrics in female volleyball players. Sixteen semi-professional female volleyball players participated in the study. Intrasession and intersession reliability of CMJ and DJ metrics were evaluated using a randomized cross-over design. Dual force platform was used to collect data, and several dependent variables were calculated using forward dynamics. Intraclass correlation coefficients (ICC), coefficients of variation (CV) and minimum difference (MD) were calculated. The third attempt presented the highest values for both test, and changes in jump strategy in DJ. CMJ is consistent across sessions, while DJ also shows intersession differences (p<0.05) in 11 out of 15 variables. Most CMJ variables exhibit excellent reliability while DJ variables have lower reliability and higher variability. Concentric and eccentric impulses for DJ showed excellent reliability. Most CMJ variables showed excellent reliability and variability, DJ had lower reliability, higher variability, and lower sensitivity. These findings provide valuable information when assessing athletes' performance and highlight the reliability, sensitivity, and variability in jump performance for CMJ and DJ tests.

The continuing mutability of the SARS-CoV-2 virus can result in failures of diagnostic assays. To address this, we describe a generalizable bioinformatics-to-biology pipeline developed for calibration and quality assurance of inactivated SARS-COV-2 variant panels provided to Radical Acceleration of Diagnostics programs (RADx)-radical program awardees. Heuristic genetic analysis based on variant-defining mutations demonstrated the lowest genetic variance in the Nucleocapsid protein (Np)- C-terminal domain (CTD) across all SARS-COV-2 variants. We then employed the Shannon entropy method on (Np) sequences collected from the major variants, verifying the CTD with lower entropy (less prone to mutations) than other Np regions. Polyclonal and monoclonal antibodies were raised against this target CTD antigen and used to develop an Enzyme-linked immunoassay (ELISA) test for SARS-CoV-2. Blinded Viral Quality Assurance (VQA) panels comprising of UV-inactivated SARS CoV-2 variants (XBB.1.5, BF.7, BA.1, B.1.617.2, and WA1) and distractor respiratory viruses (CoV 229E, CoV OC43, RSV A2, RSV B, IAV H1N1, and IBV) were assembled by the RADx-rad Diagnostics core and tested using the ELISA described here. The assay tested positive for all variants with high sensitivity (Limit of Detection: 1.72-8.78 ng/mL) and negative for the distractor virus panel. Epitope mapping for the monoclonal antibodies identified a twenty amino acid antigenic peptide on the Np-CTD that an in-silico program also predicted for the highest antigenicity. This work provides a template for a bioinformatics pipeline to select genetic regions with a low propensity for mutation (low Shannon entropy) to develop robust ‘pan-variant’ antigen-based assays for viruses prone to high mutational rates.

Darier disease (DD) is an autosomal dominant disorder due to mutation of ATP2A2 gene causing an isolated skin manifestation based on keratinocyte disconnection and apoptosis. Systemic manifestations of DD have not been demonstrated so far although a high incidence of neuropsychiatric syndromes suggest an involvement of central nervous system. A Novel ATP2A2 Gene Mutation c.118G>A, causing keratinocyte and cardiomyocyte disconnection in Darier disease, is reported. Their common pathologic pathway, still unreported, was documented by both skin and left ventricular endomyocardial biopsy because of cardiac dilatation and dysfunction appeared several decades after skin manifestations.Keratinocyte disconnection was paralleled by cardiomyocyte separation at lateral junction. Cardiomyocyte separation was associated to cell disarray, sarcoplasmic reticulum dilatation and increased myocyte apoptosis. Clinically, hyperkeratotic skin papules were associated to chest pain, severe muscle exhaustion and ventricular arrhythmias that improved following administration of aminophylline, a phosphodiesterase inhibitor enhancing SERCA2 protein phosphorylation.Specific mutations of ATP2A2 gene may cause cardiac involvement in patients with DD. Cardiac pathologic changes are similar to those documented in the skin including cardiomyocyte disconnection that promotes precordial pain and cardiac arrhythmias. Phosphodiesterase inhibitors, enhancing SERCA2 protein phosphorylation may substantially attenuate the symptoms.

Background : Newly generated cardiomyocytes (NGC) concur to recovery of human myocarditis. However, Methods: We retrospectively assessed NGC in 213 consecutive patients with endomyocardial biopsy denoting acute myocarditis, with normal coronaries and valves. Tissue samples were processed for histology (H&E), immunohistochemistry for the evaluation of inflammatory infiltrates, immunostaining for alpha-sarcomeric-actin, junctional connexin-43, Ki-67, phosphorylated STAT3 (p-STAT3) and Western Blot (WB) for HMGB1. Frozen samples were analyzed with polymerase chain reaction (PCR) for cardiotropic viruses. Controls included 20 normal surgical biopsies. Results: NGCs were defined as small myocytes (diameter < 10 µm) with nuclear positivity to Ki-67 and p-STAT3, positive immunostaining for cytoplasmic α-sarcomeric actin and connexin 43. Their number/mm2 in relation with age and pathway of integration were evaluated. NGCs crossed the membrane and grew integrated within the empty necrotic myocytes. NGC mean diameter was 6.6 ± 3.34 vs 22.5 ± 3.11 µm adult cells; their number, in comparable LVEF, was 86.3 ± 10.3/mm2 in patients between 10 and 40 years; 50.4 ±13.8/mm2 in those between 41 and 60; 15.1 ± 5.7/ mm2 in those between 61 and 80; control NGC mean diameter was 0.2± 0.2/mm2. PCR was positive for viral genomes in 16% of cases; NGCs were not statistically different in viral and non-viral myocarditis. WB analysis revealed a higher expression of HMGB1 in myocarditis compared to myocardial controls. Conclusions: NGCs are constantly recognizable in acute human myocarditis. Their number declines with age. Their integration within necrotic myocytes consents preservation of cardiac structure and function.

The present exploratory study tested the hypothesis that computerized cognitive training (CCT) in home telemonitoring may beneficially affect eyes-closed resting-state electroencephalographic (rsEEG) rhythms in Parkinson's disease patients with cognitive deficits (PDCD). A Eurasian database provided clinical-demographic-rsEEG datasets in 40 PDCD patients, 29 PD patients without cognitive deficits (PDNCD), 40 Alzheimer’s disease patients with cognitive deficits (ADCD), and 40 cognitively normal older adults (Healthy). Sixteen of the 40 PDCD patients completed a cross-over unsupervised CCT program of simple, serious video games (versus a sham program) consisting of 14 daily sessions of approximately 20 minutes each in the patients' homes. Compared to the Healthy, PDNCD, and ADCD groups, the PDCD group was characterized by greater diffuse rsEEG delta (about 2-4 Hz) and theta (about 4-7 Hz) source activity. The PDCD patients who underwent the CCT program showed an improvement in video game performance and a reduction in these delta-theta source activities after this program compared to the control condition. In conclusion, these results suggest that the 2-week CCT program in home telemonitoring may mitigate the abnormal “slowing” of rsEEG rhythms in PDCD patients, possibly enhancing the regulation of brain arousal and quiet vigilance.

In recent years, using pre-sprouted seedlings for sugarcane establishment has been developed in Brazil. Despite yielding promising results, the optimal irrigation management for this method during the Brazilian winter planting season has yet to be determined. Additionally, information regarding water demand and seedling behavior when subjected to different irrigation levels remains unclear. This study aimed to assess the response of pre-sprouted sugarcane seedlings to different irrigation levels during the winter in southeastern Brazil. Pre-sprouted sugarcane seedlings were subjected to different irrigation levels during the winter season in the region of Piracicaba, using a sprinkler irrigation system. Periodic evaluations were conducted, such as seedlings mortality rate, root size, root dry mass, number of sugarcane tillers sprouted per meter, total number of tillers, plant height, leaf area index, shoot dry mass, and total leaf chlorophyll index. The findings of this investigation indicate that a 10 mm irrigation level facilitated optimal fixation depth and achieved a 97.8% survival rate. Moreover, a correlation between seedling mortality rate and irrigation management was observed, emphasizing the critical role of irrigation in establishing and developing seedlings. Based on these findings, a 10 mm irrigation may represent the optimal irrigation strategy for pre-sprouted sugarcane seedlings in this scenario.

The implementation of sentinel lymph node (SLN) biopsy is changing the scenario in the surgical treatment of early-stage cervical cancer and the oncologic safety of replacing bilateral pelvic lymphadenectomy with SLN biopsy is currently under investigation. One of the undisputed values of SLN biopsy is its diagnostic accuracy in detecting low-volume metastases (LVM) via pathologic ultrastaging. In early-stage cervical cancer, the reported incidence of LVM ranges from 4 to 20%. The prognostic impact and the role of adjuvant treatment in patients with LVM is still unclear. Some non-prespecified analyses in prospective studies showed no impact on the oncologic outcomes compared to node-negative disease. However, the heterogeneity of the studies, the differences in the disease stage and the use of adjuvant treatment, and the concomitant pelvic lymphadenectomy (PLND) make any conclusion on this topic hard. Current guidelines suggest considering micrometastasis (MIC) as a node-positive disease, while isolated tumor cells (ITC) as a node-negative disease, with a low level of evidence. This review aims to highlight the unanswered questions about the definition, identification, prognostic and therapeutic role of LVM and underline the present and future challenges we are facing. We hope this review will guide further research, giving robust evidence on LVM and their impact on clinical practice.

Heart sounds and murmurprovidecrucial diagnosis information for valvular heart diseases (VHD). Phonocardiogram (PCG) combined with modern digital processing techniques, provides a complementary tool for clinicians. This article proposes a benchmark different time-frequency representations, which are spectogram, mel-spectogram and cochleagram for obtaining images, in addition to the use of two interpolation techniques to improve the quality of the images, which are Bicubic and Lanczos. Deep features are extracted from a pre-trained model called VGG16 and for feature reduction the Boruta algorithm is applied. To evaluate the models and obtain more precise results, nested cross-validation is used. The best results achieved in this study were for coclegram with 99.2% accuracy and mel-spectogram representation with the bicubic interpolation technique which reached 99.4% accuracy, both having support vector machine (SVM) as classifier 10 algorithm. Overall, this study highlights the potential of time-frequency representations of PCG 11 signals combined with modern digital processing techniques and machine learning algorithms for 12 accurate diagnosis of VHD.

The definition of patients with Special Needs (SN) is used in the literature to refer to individuals with mental and physical disorders for whom the usual perioperative pathways are not applicable due to lack of cooperation, regardless of age. Studies in the literature recognize the appropriateness of general anesthesia for performing day surgery dental care in this type of patient. The present retrospective, single-center, observational study involved 41 uncooperative patients aged between 3 and 17 undergoing dental surgery under general anesthesia. The main objective was to assess the possible incidence of difficult airway management, understood as difficulty ventilating and/or intubating the patient. A secondary objective was to highlight the influence of general anesthesia on patient outcomes by testing the incidence of perioperative complications. Tracheal intubation was successfully completed in all of the patients considered, and in no case did the patient have to be woken up because of difficulty in airway management. No perioperative complications attributable to anesthesia were found in any patients. From the present experience, it can be concluded that general anesthesia is a suitable option for performing dental care in pediatric subjects with special needs, and that although the peculiar peri-operative management of these patients might increase the risk of possible anesthesia-related side effects, no complications have been encountered in any case.

We describe an interesting case report about a patient with hemophilia A with severe chronic elbow arthropathy who underwent multiple surgical because of his condition. We collected all the clinical and imaging findings, and we compared the decision-making flow chart and the surgery performed with the most recent indications, treatments and complications reported in the literature. The aim of this case report is to show how usually the hemophilic patient even if young usually comes to our attention from the beginning with complex and advance musculoskeletal disease. Elbow hemophilic arthropathy is a complex disease and the management in these patients could be more difficult than others because of the higher risk of complications rate after all surgical procedures, for this reason it’s very important to treat these patients in hub centers with expertise in well-coordinated multidisciplinary teams. The path from diagnosis to surgical treatment of hemophilic elbow arthropathy can be a risky one, as it happened in this case.

Colorectal cancer is the third most diagnosed cancer in males and in females, representing 8% of estimated new cases and the third cause of cancer-related death in both sexes, accounting for 9% of cancer deaths in men and 8% in women. About 20% of patients diagnosed with CRC present metastatic disease. Although lung metachronous or synchronous metastatic spread without other involved sites has been reported in only a small proportion of patients, considering that this tumor is frequently diagnosed, the clinical approach to CRC pulmonary metastases represents a major issue for thoracic surgeons and CRC oncologists. Among patients diagnosed with pulmonary metastases from CRC, about 9 – 12% are eligible for local treatments with radical intent, including surgical resection, SBRT and ablation therapy. Due to the lack of randomized controlled trials among different local strategies, there is no definitive evidence about the optimal approach, although surgical resection is considered the most effective therapeutic option in this clinical scenario. Oncological achievement of primary radical resection, the biology of primary tumor and metastatic sites, disease free interval and or progression free survival are independent prognostic factors which make it possible to define a cohort of patients which might significantly benefit from pulmonary metastasectomy.

Heart failure (HF) is a syndrome characterized by signs and symptoms resulting from structural or functional cardiac abnormalities, confirmed by elevated natriuretic peptides or evidence of congestion. HF patients are classified according to left ventricular ejection fraction (LVEF). Worsening HF (WHF) is associated with increased short- and long-term mortality, re-hospitalization, and healthcare costs. Standard treatment of HF includes angioten-sin-converting enzyme inhibitors, angiotensin receptor-neprilysin inhibitors, mineralocorti-coid-receptor antagonists, beta-blockers, and sodium-glucose co-transporter 2 inhibitors. To manage systolic HF by reducing mortality and hospitalizations in patients experiencing WHF, treatment with vericiguat, a direct stimulator of soluble guanylate cyclase (sGC), is indicated. This drug acts by stimulating sGC enzymes, part of the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) signaling pathway, regulating the cardiovascular system by catalyzing cGMP synthesis in response to NO. cGMP acts as a second messenger, triggering various cellular effects. Deficiencies in cGMP production, often due to low NO availability, are implicated in cardiovascular diseases. Vericiguat stimulates sGC directly, bypassing the need for a functional NO-sGC-cGMP axis, thus preventing myocardial and vascular dysfunction associated with de-creased sGC activity in heart failure. Approved by the FDA in 2021, vericiguat administration should be considered, in addition to the four pillars of HFrEF therapy, in symptomatic patients with LVEF < 45% following a worsening event. Cardiac rehabilitation represents an ideal setting where there is more time to implement therapy with vericiguat and incorporate a greater num-ber of medications for the management of these patients. This review covers vericiguat's metab-olism, molecular mechanisms, and drug-drug interactions.

There is a case about a system comprising two queues of M/M(a)/1/K with a due date with FCFS service policy in each queue. Using the methods of simulation and mathematical analysis, the solution diagrams were illustrated for the fixed due date Ɵ=1 second at the phase of due date up to the commencement of the service, limited capacity K₁=5 and K₂=4, for both scenarios of different service management rate resulted. For the analytical solution, first, a SAN model from the system was created in the Mobius tool. For simulation, a java discrete systems simulation code was used. Adjustment of the initial values, selection of the scenarios for service rate, the number of the consumers in the simulation, etc. were all carried out in the simulation code.

Water conflicts have been a significant issue in Brazil, especially in the Sao Francisco River basin. Subseasonal forecasts, up to a 60-day forecast range, can provide information to support decision-makers in managing water resources in the river basin, especially before drought events. Predictability in the subseasonal forecasts range is a research topic as this range contains mixed dependence on weather and seasonal phenomena. Numerical models may inherit this mixed dependence on their skills. The objective of this paper is to evaluate the Eta Model simulations to reproduce the drought events between the years 2011 and 2016. Two sets of 60-day simulations were produced; one started in September (SO) and the other in January (JF) each year. These months were chosen to evaluate the model skill to reproduce the onset and the middle of the rainy seasons in Central Brazil, where the Upper Sao Francisco River is located. The SO simulations reproduced the observed spatial distribution of precipitation but underestimated the amounts. Precipitation errors exhibit large variability across the subbasins. The JF simulations also reproduced the observed precipitation distribution but overestimated it in the Upper and Lower subbasins. The JF simulations better captured the interannual variability of precipitation. The 60-day simulations were discretized in six 10-day accumulations to assess the intra-monthly variability. They showed that simulations can capture the onset of the rainy season and the small amounts of the rainy months that occurred in these severe drought years.

Background: Clinical trails have revealed that patients with depression generally accompanied with learning and memory impairment, which critically impact on individual’s health and development. Danggui-Shaoyao-San (DSS), a famous Chinese complex prescription, significantly overcame depression and relieved cognitive disorder based on previous research and publication. However, its effectsand potential mechanism against chronic restraint stress (CRS) remained unknown. Methods: CRS animal model was established and mice were divided to six groups while they were oral administrated with Danggui-Shaoyao-San at doses of 1.25, 2.5 and 5 g/kg for 14 days. Emotional and cognitive performances were detected by behavior tests, meanwhile neural plasticity and its molecular mechanism were examined by Dil staining, western blot and immunofluorescence. Results: DSS treatment dose-dependently improved locomotion ability in open filed test, overcame depression behavior in forced swimming test and elevated plus maze test, enhanced learning and memory ability in Morris water maze test. CRS decreased number of total spines and mushroom spines, while DSS treatment dose-dependently restored these by Dil staining. Expression of BDNF and GluR1 were significantly down-regulated in CRS group, which were significantly normalized by DSS. Conclusions: DSS treatment dose-dependently reversed CRS-induced cognitive impairments by inducing structural remodeling of neurons.

Antiviral peptides (AVPs) represent a promising strategy for addressing the global challenge of viral infections and their growing resistance to traditional drugs. Lab-based AVP discovery methods are resource-intensive, highlighting the need for efficient computational alternatives. In this study, we developed five non-trained but supervised Multi-Query Similarity Search Models (MQSSMs) integrated into the StarPep toolbox. Rigorous testing and validation across diverse AVP datasets confirmed the models' robustness and reliability. The top-performing model, M13+, demonstrated impressive results with an accuracy of 0.969 and a Matthew’s correlation coeffi-cient of 0.71. To assess their competitiveness, the top five models were benchmarked against 14 publicly available machine learning and deep learning AVP predictors. The MQSSMs outper-formed these predictors, highlighting their efficiency in terms of resource demand and public ac-cessibility. Another significant achievement of this study is the creation of the most comprehensive dataset of antiviral sequences to date.

Background: Chronic pelvic pain is a debilitating condition affecting quality of life. Endometriosis is one of the leading causes of CPP, but recent studies highlighted the role of interstitial cystitis/bladder pain syndrome (IC/PBS) in causing CPP. Only some studies addressed the coexistence between these two conditions, which seems more frequent than what is supposed, leading to diagnostic delays and unnecessary surgeries. This systematic review aimed to evaluate the estimate of the coexistence of endometriosis and IC/PBS. Methods: We performed a systematic review of the literature indexed on PubMed, Scopus, ISI Web of Science, and Cochrane using a combination of keywords and text words represented by “painful bladder syndrome”, “endometriosis”, “interstitial cystitis”, “bladder pain syndrome”. We performed a meta-analysis of the results. Results: Meta-analysis shows that the coexistence of endometriosis and IC/PBS in women with CPP ranges between 15,5-78,3%, which is higher than the prevalence of IC/PBS in the general population. Conclusions: Women with CPP need a multidisciplinary approach and a referral to centers with specific expertise. In cases of endometriosis unresponsive to treatment, other reasons for CPP need to be ruled out, above all in women not responsive to treatment.

Although Eulerian approaches are standard in computational acoustics, they are less effective for certain classes of problems like bubble acoustics and combustion noise. A different approach for solving acoustic problems is to compute with individual particles following particle motion. In this paper, a Lagrangian approach to model sound propagation in moving fluid is presented and implemented numerically, using three meshfree methods to solve the Lagrangian acoustic perturbation equations (LAPE) in the time domain. The LAPE split the fluid dynamic equations into a set of hydrodynamic equations for the motion of fluid particles and perturbation equations for the acoustic quantities corresponding to each fluid particle. Then, three meshfree methods, the smoothed particle hydrodynamics (SPH) method, the corrective smoothed particle (CSP) method, and the generalized finite difference (GFD) method, are introduced to solve the LAPE and the linearized LAPE (LLAPE). The SPH and CSP methods are widely used meshfree methods, while the GFD method based on the Taylor series expansion can be easily extended to higher orders. Applications to modeling sound propagation in steady or unsteady fluids in motion are outlined, treating a number of different cases in one and two space dimensions. A comparison of the LAPE and the LLAPE using the three meshfree methods is also presented. The Lagrangian approach shows good agreement with exact solutions. The comparison indicates that the CSP and GFD method exhibit convergence in cases with different background flow. The GFD method is more accurate, while the CSP method can handle higher Courant numbers.

Introduction. Psoriatic disease (PsD), encompassing psoriasis, psoriatic arthritis, inflammatory bowel disease, and uveitis, presents a significant burden due to its chronic and diverse inflammatory nature, affecting various clinical domains including skin, joints, and internal organs. Psoriasis, affecting up to 3% of the global population, not only poses physical challenges but also profoundly impacts patients' psychological well-being, ranking among the most debilitating chronic conditions. Furthermore, PsD exhibits a spectrum of manifestations ranging from skin lesions like plaque psoriasis to systemic complications such as cardiovascular comorbidities, necessitating comprehensive assessment and management strategies. The increasing understanding of the aetiopathogenic mechanisms of these immune-mediated diseases and of the proinflammatory intracellular signalling pathways involved in Psoriatic disease (PsD) has facilitated the identification and development of new small molecules capable of inhibiting JAK proteins, emerging as effective treatment options for rheumatic and dermatological manifestations JAK inhibitors act rapidly, within a few days, with a striking beneficial class effect on pain. The oral formulation they share makes them a well-tolerated class of drugs, with a clear advantage over FAME in terms of convenience of administration, improving therapeutic compliance. Material and method. This observational, retrospective study conducted in a single-centre dermatology-rheumatology consultation of a second-level hospital in Granada, Spain, focused on patients diagnosed with Psoriatic Arthritis (PsA) over the last two years, who initiated treatment with Tofacitinib or Upadacitinib due to DMARD failure, excluding those with major contraindications to JAK inhibitors. Results: This study analyzed data from 32 patients diagnosed with Psoriatic Arthritis (PsA), focusing on their demographics, disease characteristics, and treatment history. The majority of patients (75%) initiated treatment with Tofacitinib, while the remainder started with Upadacitinib. The mean age of the patients differed between the two treatment groups. All patients met the CASPAR criteria for PsA diagnosis, with predominantly peripheral joint involvement. The average time from PsA diagnosis to initiation of JAKinhib treatment was 6.5 years, slightly longer for Upadacitinib users. Most patients presented with cutaneous psoriasis, and a minority exhibited radiographic erosions. Before JAKinhib therapy, all patients had previously received DMARDs. A subset of patients received concomitant DMARD therapy, predominantly methotrexate. Additionally, a proportion of patients were on low-dose corticosteroids. Baseline CRP and ESR levels were indicative of systemic inflammation. Disease activity measures at baseline indicated moderate disease activity, with a substantial proportion of patients having mild psoriasis involvement. Upadacitinib recipients with psoriasis primarily exhibited mild involvement. This study provides valuable insights into the characteristics and treatment patterns of PsA patients initiating JAKinhib therapy. Discusion. In this study, the efficacy, safety, and real-world outcomes of Janus kinase inhibitors (JAKinhibs) in the treatment of Psoriatic Arthritis (PsA) were assessed and compared with findings from pivotal randomized controlled trials (RCTs). Both Tofacitinib and Upadacitinib demonstrated significant efficacy in PsA patients refractory to DMARDs and TNF inhibitors, with rapid improvement in joint and skin activity indices. Although patients in this cohort exhibited younger age, higher female prevalence, and shorter disease duration compared to those in RCTs, treatment responses were comparable or even superior. Notably, despite fewer concurrent DMARDs and a higher proportion of patients receiving monotherapy, JAKinhibs maintained a favorable safety profile, with a low frequency of mild adverse events leading to treatment discontinuation. These findings emphasize the robust efficacy and tolerability of JAKinhibs in real-world clinical settings, supporting their role as effective therapeutic options for PsA patients.

Glassy carbon (GC) microelectrodes have been successfully used for detection of electroactive neurotransmitters such as dopamine and serotonin through voltammetry. However, non-electroactive neurotransmitters such as glutamate, lactate, and gamma-aminobutyric acid (GABA) are inherently unsuitable for detection through voltammetry techniques without functionalizing the surface of the microelectrodes. To that end, we present here the immobilization of L-glutamate oxidase (GluOx) enzyme on the surface of GC microelectrodes to enable catalysis of chemical reaction between L-glutamate, oxygen, and water to produce H2O2, an electroactive byproduct that is readily detectable through voltammetry. This immobilization of GluOx on the surface of bare GC microelectrodes and the subsequent catalytic reduction of H2O2 through fast scan cyclic voltammetry (FSCV) helped demonstrate indirect in vitro detection of glutamate, a non-electroactive molecule, at concentrations as low as 10 nM. The functionalized microelectrodes formed part of 4-channel arrays of microelectrodes (30 m x 60 m) on a 1.6 cm long neural probe supported on a flexible polymer, with potential for in vivo applications. The type and strength of the bond between the GC microelectrode surface and its functional groups on one hand, and glutamate and the immobilized functionalization matrix on the other hand, were investigated through molecular dynamics (MD) modeling and Fourier Transform Infrared Spectroscopy (FTIR). Both MD modeling and FTIR demonstrated the presence of several covalent bonds in the form of C-O (carbon-oxygen polar covalent bond), C=O (carbonyl), C-H (alkenyl), N-H (hydrogen bond), C-N (carbon-nitrogen single bond), and C≡N (triple carbon nitrogen bond). Further, penetration tests on agarose hydrogel model confirmed that the probes are mechanically robust with their penetrating forces being much lower than the fracture force of the probe material.

Air quality is a topic of growing relevance on the global agenda. Two key indicators of air quali-ty, nitrogen dioxide (NO2) and carbon monoxide (CO), represent significant hazards to human health and the environment putting the sustainability of natural resources at risk. Therefore, it is imperative to regularly monitor and reduce atmospheric pollutant concentrations to mitigate their harmful consequences. This study presents an analysis of NO2 total and CO emissions in Argentina, utilizing remote sensing data. The research aims to determine the spatiotemporal distribution of NO2 and CO emissions in Argentina from 2019 to 2021. Subsequently, it seeks to establish the influence of land uses and land cover on the emission of NO2 and CO through dif-ferent climatic, anthropic, and natural indicators. The study was carried out in Argentina during the period 2019-2021, where random points were placed for the different land covers with a total of 800 points surveyed. The year with the highest CO concentration (mol/m-2) was 2020. The values were highest for tree covers and herbaceous wetland coverage in the northern part of the country. For total NO2, the highest concentrations were reached during the years 2020 and 2021. Regarding its distribution, throughout the evaluated period, the highest concentrations of total NO2 were found in the built-up and cropland coverages, with the capital of the country and the northern region of the Buenos Aires province being the most affected areas. In addition, the concentration of CO was influenced by climatic variables (atmospheric pressure, wind speed, maximum environment temperature, Palmer index), natural (height, humidity, NDVI), and ur-ban variables (distances to mining extraction, airports, power plants, urban index) for the differ-ent uses and land covers. Finally, the concentrations of total NO2 were influenced by climatic variables (Palmer index and wind speed), natural (height and NDVI), and urban variables (dis-tance to airports, power plants, industries, service stations, and open dumpsites) for the differ-ent uses and land cover. This study contributes to sustainable environmental management, ena-bling the formulation of effective strategies for mitigating emissions and promoting the long-term health and well-being of communities.

Mercury has a strong environmental impact since both its organic and inorganic forms are toxic and it represents a pollutant of global concern. Liquid Hg is highly volatile and it can be released during natural and anthropogenic processes in the hydrosphere, biosphere and atmosphere. In this study the distribution of Gaseous Elemental Mercury (GEM) and the total and leached mercury concentrations on paints, plasters, roof tiles, concretes, metals, dust and wood structures were determined in the main buildings and structures of the former Hg-mining area of Abbadia San Salvatore (Siena, Central Italy). The mining complex (divided into 7 units) covers a surface of about 65 ha and contains mining structures and managers and workers buildings. In this work, nine surveys of GEM measurements were carried out from July 2011 to August 2015 for the buildings and structures located in the units 2, 3 and 6. Moreover, detailed measurements were performed in February, April, July, September and December 2016 in the edifices and mining structures of Unit 6. GEM concentrations showed a strong variability in terms of space and time mostly depending on the distance from the building hosting driers, furnaces and condensers and ambient temperature, respectively. In the Unit 2 surveys carried out in the hotter period (from June to September) showed GEM concentrations up to 27,500 ng m⁻³, while in the Unit 6 they were on average much higher and occasionally they saturated the GEM measurement device (>50,000 ng m⁻³). Concentrations of total (in mg kg⁻¹) and leached (in μg L⁻¹) mercury measured in different building materials (up to 46,580 mg kg⁻¹ and 4,470 mg L⁻¹ for total and leached mercury, respectively) showed for the same type of material highly variable values in dependence on the edifice or mining structure from which they were collected. The results obtained in this study are of relevant interest for the operational cleanings to be carried out during the reclamation activities.

As the world’s population age, Cognitive Frailty (CF) is becoming one of the most serious health problems and elucidating its biological mechanisms along with prevention and treatments becomes increasingly important also considering the associated health costs. This pilot study aims to investigate the potential cognitive and neuropsychological effects of a 5-week treatment with a therapy based on the regenerative properties of ozone (O3) in a cohort of patients stratified according to CF. We also study the potential effects of O3 on blood-based biomarkers indicative of specific biological systems that may be altered in CF. Seventy-five older persons have been recruited and randomly assigned to receive the active treatment (150cc of oxygen-O2-O3 mixture at the concentration of 30ug of O3 per cc of O2) or O2, or the placebo (air) for 5 weeks. The primary endpoint is a change in the scores of clinical scales from baseline (T0) to weeks 3 (T3), 9 (T9), 15 (T15) after treatment. The secondary endpoint is a change in biomarkers levels resulting from transcriptomics, proteomics and metabolomic patterns at the same times. This study will evaluate whether an intervention with the O2-O3 therapy could have potential cognitive, neuropsychological and biological effects on CF.

Over the last decade, the prevalence of health issues has increased by approximately 29.1%, putting a substantial strain on healthcare services. This has accelerated the integration of machine learning in healthcare, particularly following the COVID-19 pandemic. The utilization of machine learning in healthcare has grown significantly, however many present approaches are unsuitable for real-world implementation due to high memory footprints and lack of interpretability. We introduce DeClEx, a pipeline designed to address these issues. DeClEx ensures that data mirrors real-world settings by incorporating gaussian noise and blur and employing autoencoders to learn intermediate feature representations. Subsequently, our convolutional neural network, paired with spatial attention, provides comparable accuracy to state of the art pre-trained models while achieving threefold improvement in training speed. Furthermore, we provide interpretable results using explainable AI techniques. We integrate denoising and deblurring, classification and explainability in a single pipeline called DeClEx.

Opuntia ficus-indica has always interacted with many phytophagous insects at its center of origin; two of them are Dactylopius coccus and D. opuntiae. D. coccus, or true cochineal, is produced to extract carminic acid, and D. opuntiae or wild cochineal is a key invasive pest of O. ficus-indica in more than 20 countries around the world. Despite the economic and environmental relevance of this cactus and, D. opuntiae and D. coccus, there are few studies that have explored volatile organic compounds (VOCs) derived from the plant-insect interaction. The aim of this work was to determine VOCs of D. coccus and D. opuntiae feeding on cultivars suitable for their development and to identify different VOCs in cladodes infested by each Dactylopius species. Volatiles were identified through their essential oils, which were obtained by hydrodistillation. A total of 66 VOCs from both Dactylopius species were identified, and 125 from the Esmeralda and Rojo Pelón cultivars infested by D. coccus and D. opuntiae, respectively, were determined. Differential VOCs production due to infestation by each Dactylopius species was also found. Some changes in methyl salicylate, terpenes such as linalool or the alcohol p-vinylguaiacol were related to Dactylopius feeding on cladodes of their respective cultivars. Changes in these VOCs and their probable role in plant defense mechanisms should receive more attention because this knowledge could improve D. coccus rearing, or to its inclusion in breeding programs for D. opuntiae control in regions where it is a key pest of O. ficus-indica.

Background: C-reactive protein (CRP) is a predictive biomarker of colorectal surgery (CRS) complications but has not been evaluated by comparing patients undergoing CRS with intracorporeal anastomosis (IA) or extracorporeal anastomosis (EA). Therefore, we aimed to describe postoperative CRP values between two groups of patients who underwent laparoscopic right hemicolectomy for right-side colon cancer with IA or EA. Methods: We retrospectively reviewed the data of patients affected by right-side colon cancers who underwent laparoscopic right-hemicolectomy with ileo-colic IA or EA between January 2016 and December 2022. Results: A total of 340 patients underwent laparoscopic right hemicolectomy. EA was performed in 238 (70%) and IA in 102 (30%) cases. Patients with IA showed significantly higher values of CRP in the second, third and fourth postoperative days (15.2 mg/dL vs 9.5 mg/dL p=

Climate change in the coming decades could intensify extreme events such as severe droughts. Combined with the possible increase of water demands, these changes exert a large pressure on the water systems. In order to confirm this assumption, a set of scenarios was proposed in this study to consider the combined impact of climate changes and the increase in water demand on the main multiple-use reservoirs of São Francisco River, Brazil. For this purpose, five CMIP6 climate models were used considering two greenhouse gas emissions scenarios: the SSP2-4.5 and SSP5-8.5. The naturalized and withdraw streamflows were estimated to the adopted reser-voirs considering all existing, new and projected demands. The conjunction of scenarios indicat-ed an increase in Potential Evapotranspiration, a possible significant reduction in water availa-bility, a growth in water demand mainly for irrigation and a substantial reduction in the perfor-mance of the evaluated reservoirs.

Objective: To use the ancient and modern medical record cloud platform (V2.3.5) to organize and explore the medication patterns of the "Three Causes, Extremity, and One Disease Syndrome Formula" by Chen Wuxuan, and to summarize its therapeutic ideas. Method: Collect and organize the "San Yin Si Tian Fang" in the "San Yin Ji Yi Zheng Fang Lun", and use the modern medical record cloud platform (V2.3.5) to conduct medication frequency statistical analysis, cluster analysis, and complex network analysis. As a result, a total of 16 Chinese herbal medicines were collected in the "Three Causes, Extreme and One Disease Syndrome Formula", involving 75 traditional Chinese medicines. Statistical analysis showed that roasted licorice was the most commonly used, followed by Pinellia ternata, papaya, ginger, and Poria cocos; Medications mainly include warm drugs, sweet and pungent flavors, as well as drugs that promote lung and spleen meridians. Cluster analysis can divide the above-mentioned traditional Chinese medicine into two groups, with specific grouping as follows. Group 1: ginger, white peony, aconite, papaya, and achyranthes bidentata; Group 2: roasted licorice, poria cocos, dried ginger, pinellia ternata, and green peel. Conclusion: The characteristics of the 16 prescriptions are biased towards Xin Gan Wen, emphasizing the regulation of the spleen and stomach, which may be related to the common use of prescription by doctors in the Song Dynasty and the tendency towards warm and dry medication.

Transcription is carried out in most eukaryotes by three multimeric complexes (RNA polymerases I, II and III). However, plants contain two additional RNA polymerases (IV and V), which have evolved from RNA polymerase II. RNA polymerases II, IV and V contain both common and specific subunits that may specialize some of their functions. In this study, we conducted a search for the genes that putatively code for the specific subunits of RNA polymerases IV and V, as well as the corresponding of RNA polymerase II in olive. Based on the homology with the genes of Arabidopsis thaliana, we identified 13 genes that putatively code for the specific subunits of polymerases IV and V, and 16 genes that code for the corresponding specific subunits of polymerase II in olive. The transcriptomic analysis by RNA-Seq revealed that the expression of the RNA polymerases IV and V genes was induced during the initial stages of fruit development. Given that RNA polymerases IV and V are involved in the transcription of long non-coding RNAs, we investigated their expression and observed relevant changes in the expression of this type of RNAs. Particularly, the expression of the intergenic and intronic long non-coding RNAs tended to increase in the early steps of fruit development, suggesting their potential role in this process. The positive correlation between the expression of RNA polymerases IV and V subunits and the expression of non-coding RNAs supports the hypothesis that RNA polymerases IV and V may play a role in fruit development throughout the synthesis of this type of RNAs.

Mesenteric ischemia diagnosis is challenging with an overall mortality in up to 50% of cases despite advances in treatment. The main problem that affects the outcome is the delayed diagnosis because of non-specific clinical presentation. Multi Detector CT Angiography (MDCTA) is the first line investigation for the suspected diagnosis of vascular abdominal pathologies and is the diagnostic test of choice in suspected mesenteric bowel ischemia. MDCTA can accurately detect the presence of arterial and venous thrombosis, determine the extension and the gastrointestinal tract involved, and provide detailed information determining the subtype and the stage progression of the diseases helping clinicians and surgeons for the proper management. CT can differentiate forms that are still susceptible to pharmacological or interventional treatment (NOM= non-operative management) from advanced disease with transmural necrosis in which a surgical approach is required. Knowledge of CT imaging patterns and corresponding vascular pathways is mandatory in Emergency settings to reach a prompt and accurate diagnosis. The aims of this paper are 1. to provide technical information about the optimal CTA protocol; 2. To empathize the CTA arterial and venous supply to gastrointestinal tract and relative ischemic pattern; 3. To describe vascular, bowel and extraintestinal CT findings for the diagnosis of acute mesenteric ischemia.

Background: The incidence of prostate cancer (PC) has been risen annually. Despite the diagnosis is made mainly with non-metastatic PC, mortality is explained by the metastatic disease (mPC). Without a doubt there is an intermediate scenario in which patients have no mPC but will have initiated a metastatic cascade through an epithelial-mesenchymal transition. There is indeed a need for more and better tools to predict what patients will progress in the future to non-localized clinical disease or already have micrometastatic disease, and therefore, will clinically progress after primary treatment. Biomarkers for predicting mPC are still under development; there are few studies and not much evidence of their usefulness. Summary: This review is focused on tissue-based genomic biomarkers (TBGB) for predicting metastatic disease. We developed four main research questions that will attempt to answer according to the current evidence. Why is important to predict metastatic disease? Which tests are available to predict metastatic disease? What impact should there be on clinical guidelines and clinical practice in predicting metastatic disease? What are current prostate cancer treatments? Key Messages: Knowing useful predict tools could help determine which patients may need multimodal or adjuvant treatment even with a localized disease, and in consequence, what patients do not need more than a single modality of treatment. The importance of predicting metastasis is fundamental, given that once metastasis is diagnosed, the quality of life (QoL) and survival drop dramatically.

Background: The coexistence of HIV infection and latent tuberculosis infection (LTBI) presents a significant public health concern due to the increased risk of tuberculosis (TB) reactivation and progression to active disease. The multicenter observational cohort study, TUBHIVIT, conducted in Italy from 2017 to 2023, aimed to assess the prevalence of LTBI among people living with HIV (PLHIV) and their outcomes following LTBI screening and therapy initiation. Methods: We performed a prospective study in 5 referral centers for HIV care in Italy. PLHIV who consented to participate underwent QuantiFERON-TB Gold Plus and clinical, microbiological, and radiological assessments to exclude subclinical tuberculosis, as opportune. PLHIV diagnosed with LTBI that started chemoprophylaxis were followed until the ending of therapy. Results: A total of 1105 PLHIV were screened for LTBI using the QuantiFERON-TB Gold Plus test, revealing a prevalence of 3.4% of positive results (38/1105). Non-Italy-born individuals exhibited a significantly higher likelihood of testing positive. Thirty-one were diagnosed with LTBI, 1 showed active subclinical TB, 6 were lost to follow-up before discriminating between latent and active TB. Among PLHIV diagnosed with LTBI, 83.9% (26/31) started chemoprophylaxis. Most individuals received 6-9 months of isoniazid-based therapy. Of the 26 PLHIV commencing chemoprophylaxis, 18 (69.2%) completed the therapy, while 3 discontinued it and 5 were still on treatment at the time of the analysis. Adverse events were observed in two cases, while in one case the patient refused to continue the treatment.

Objective. To evaluate serum neuronal and inflammatory biomarkers in asphyctic newborns treated with hypothermia alone or hypothermia plus melatonin, and whether biomarkers correlate with neurodevelopmental outcomes. Design. This is a pilot multicentre, randomised, controlled, double blind clinical trial. Neuronal glial fibrillary acidic protein (GFAP), granulocyte-macrophage colony-stimulating factor (GM-CSF), and inflammatory cytokines (interleukin (IL)-1, IL-2, IL-7 and IL-13) were measured in serum samples at hospital admission (T0), 24 hours (T1), 72 hours (T2) and 7-10 days of age (T3). Neurodevelopmental outcomes (Bayley Scales of Infant and Toddler Development-III scales, Gross Motor Function Classification System (GMFCS) and the Tardieu scale) were performed at 6 and 18 months. Setting: Level 3 neonatal intensive care unit. Patients and interventions: 25 newborns were recruited. The treated patients received a daily dose of intravenous melatonin, 5 mg per kg body weight, for 3 days. Results. After adjusting the data for severity, in the group treated with melatonin, there is a decrease in plasma levels of GM-CSF, IL-2 and IL-13 at T1 compared to placebo, as well as, at T2, in GM-CSF concentrations, as well as IL-7 and IL-13 at T3. Evolutionarily, we found a significant decrease in GM-CSF concentrations in the treatment group compared to placebo, with no differences for the rest of the biomarkers. It is noteworthy that the sustained decrease in GM-CSF and inflammatory cytokines IL-2, IL-7 and IL-13 correlated with better neurodevelopmental outcomes at 6 and 18 months. Conclusions. In neonates with hypoxic-ischemic encephalopathy, the addition of iv melatonin to hypothermia therapy affects the plasma concentration of biomarkers in the first week of life, with a high correlation with long-term neurological prognosis.

Hydrogen gas is seeping from the sedimentary basin of São Franciso, Brazil. The seepages of H₂ are accompanied by helium whose isotopes reveal a strong crustal signature. Geophysical data indicates that this intra-cratonic basin is characterized by i) a relatively high geothermal gradient, ii) deep faults delineating a horst and graben structure and affecting the entire sedimentary sequence, iii) an archean to paleoproterozoïc basements enriched in radiogenic elements and displaying mafic and ultramafic units, and iv) a possible karstic reservoir located 400 m below the surface. The high geothermal gradient could be due to a thin lithosphere enriched in radiogenic elements, which can also contribute to a massive radiolysis process of water at depth, releasing an important amount of H₂. Alternatively, ultramafic rocks that may have generated H₂ during their serpentinization are also documented in the basement. The seismic profiles show that the faults seen at the surface are deeply rooted in the basement, and can drain deep fluids to shallow depths in a short time scale. The carbonate reservoirs within the Bambuí group which forms the main part of the sedimentary layers are crossed by the fault system and represent good candidates for temporary H₂ accumulation zones. The formation by chemical dissolution of sinkholes located at 400 m depth might explain the presence of sub-circular depressions seen at the surface. These sinkholes might control the migration of gas from temporary storage reservoirs in the upper layer of the Bambuí formation to the surface. The very high fluxes of H₂ escaping out of these structures which have been recently documented are, however, in disagreement with the newly developed H₂ production model in the Precambrian continental crust. They either question the validity of these models or the measurement methodology.

In many of the current software applications, numerous vulnerabilities may be present.1 Attackers attempt to exploit existing vulnerabilities that lead to security breaches, unauthorized entry,2 data theft, or incapacitation of a computer system. Rather than addressing software or hardware3 vulnerabilities at a later stage, it is better to address them immediately. DevSecOps, when utilized4 in application development, tackles these vulnerabilities at an early stage. AIBughunter is a tool5 that addresses this problem in software and was developed by the ASWM research group to predict,6 classify, and repair software vulnerabilities. AIBughunter integrates LineVul to find vulnerable7 code lines and returns information about the type of vulnerability and its severity to developers.8 It also includes a tool, VulRepair, which detects and repairs vulnerabilities. VulRepair currently9 predicts patches for vulnerable functions at 44%. In order to become truly effective, this number 10 needs to be increased. This study examines VulRepair to see whether the 44% Perfect Prediction 11 can be increased. VulRepair is a T5 based model that uses Natural Language and Programming 12 Languages for pre-training along with Byte Pair Encoding. It outperforms other existing models, 13 such as VRepair and CodeBERT. However, the hyperparameters may not be optimized due to the 14 development of new optimizers. We review a Deep Neural Network (DNN) optimizer developed by 15 Google in 2023. This optimizer called Evolved Sign Momentum (LION) is available in PyTorch. We 16 applied this optimizer to VulRepair and tested its influence on hyperparameters. After adjusting the 17 hyperparameters, we obtained a 56% Perfect Prediction, which exceeds the value of the VulRepair 18 report of 44%. This means that VulRepair can repair more vulnerabilities and avoid more attacks. As 19 far as we know, our approach of utilizing an alternative to AdamW, the standard optimizer, has not 20 been previously applied to enhance VulRepair and similar models. 21

Background: Cleft lip and palate can affect the development of the maxilla, which may create a midfacial deficiency as well as an interference of the facial growth pattern and dentofacial esthetics. Objective: Estimate the chronological age of complete fusion of the spheno-occipital synchondrosis in cleft lip and/or palate patient´s and a control group, using cone beam computed tomography images. Methods: In this retrospective study, 125 patients were enrolled (cleft lip and/or palate group (n=91); control group (n=34)). Age comparison was made with Chi-square test and a Kaplan-Meyer analysis determined the median time to reach complete fusion of the spheno-occipital synchondrosis (p&lt;0.05). Results: The experimental group showed statistically significant differences in the median time for complete ossification between males and females (p=0.019). No statistically significant differences were found in the control group between males and females (p=0.104). The median time for complete ossification of the spheno-occipital synchondrosis was, for males, 15.0 years in both groups; for females, it was 14.0 years in the experimental group and 13.0 years in the control group. Conclusions: The present study showed no differences in the ossification of the spheno-occipital synchondrosis between individuals with and without cleft lip and/or palate.

PVC items are environmentally friendly as, unlike polyolefins, they are mainly based on chlorine, one of the most abundant elements on earth. However, in the eco-design context, articles' durability plays the crucial role, contributing to the enhancement of their sustainability. In this framework the research on additives capable of increasing the weatherability of outdoor articles is essential. The theory section of the paper reviews the mechanisms of weathering leading to PVC degradation that undermine the durability of items such as window frames or roller shutters. The weathering of PVC items is a complex phenomenon involving photo-chemical and secondary chemical reactions, that yields the formation of conjugated polyene sequences underskin in absence of oxygen and carbonyls in the surface. Here the chain scission of the polymer backbone occurs, bringing the disintegration of the surface of the item and causing the typical discoloration called chalking, especially evident in dark-colored articles. In the experimental section of the paper the effect of different acid scavengers on the item weathering has been studied with natural outdoor and two accelerated exposures, xenon-arc and Q-UV testing devices. Results confirm that some acid scavengers are efficient in preventing chalking, but some are ineffective or even detrimental. Thus, the PVC formulations of durable articles upon weathering still depend on a complex choice of the appropriate ingredients, and several outdoor and indoor accelerated weathering tests are needed to predict the articles' lifetime.

The study aimed to evaluate implant success and bone height variations after transcrestal sinus floor elevation (tSFE) using the osseodensification technique (OD) combined with beta-tricalcium phosphate (β-TCP), as bone graft material and simultaneous implant placement. Thirteen patients requiring the placement of one implant in the upper posterior maxilla, with a residual bone height of

We analyze the humoral and B-cell mediated immunogenic response induced by GP5 lineal epitopes from porcine reproductive and respiratory syndrome virus (PRRSV) to explore the role of this protein in the protective response. For inoculation, pigs aged twenty-one days were allocated into six groups (seven pigs per group): control (PBS), vehicle (carrier), vaccinated (Ingelvac-PRRSV, MLV®), non-vaccinated and naturally infected, GP5-B and GP5-B3. Subsequently blood samples were collected and analyzed. Cytokine were measured by ProcartaPlex kit. Peptide-specific IgGs and cross-reactivity against peptides were analyzed by ELISA and B-cell subpopulations were analyzed by flow cytometry. At 2 days post-immunization (dpi), the GP5-B3 peptide increased the serum concentrations of cytokines associated to activate adaptive cellular immunity (IL-1β and IL-12). The concentration of IgGs anti-GP5-B increased in both cases at 21 and 42 dpi, while IgGs anti-GP5-B3 increased at 21 dpi and remained at the same level until 42 dpi. Also, antibody-forming/Plasma B cells (CD2+/CD21-) and primed B cells (CD2-/CD21+) from immunized pigs showed an increase at 42 dpi. Conversely the naïve B cells from immunized pigs decreased compared with the controls. Importantly, Both GP5-B and GP5-B3 peptides exhibited immunoreactivity against serum antibodies from vaccinated group, as well as non-vaccinated and naturally infected group. In conclusion, GP5-B and GP5-B3 peptides elicited immunogenicity mediated by antigen specific IgG´s and B-cell activation.

Circulating tumor cells (CTC) have shown to be prognostic in advanced colorectal cancer (advCRC), but their value for predicting response to treatment or as a source of molecular data is debated. We compared CellSearch® (Janssen Diagnostics, LLC) and IsoFlux^TM (Fluxion Biosciences Inc, South San Francisco, CA) systems for the enumeration of CTC in patients with newly diagnosed advCRC (group 1; n=34). Using castPCR^TM we studied KRAS status in CTC isolated with IsoFlux^TM and compared it with that of the primary tumor in patients from group 1 and in KRAS wild-type (KRAS^WT) patients with progressive disease (group 2; n=22). Median number of CTC detected with CellSearch® (groups 1 and 2) was 1 (range: 0-78) and with IsoFlux^TM (group 1) was 8 (range: 0-419), showing a modest correlation (r=0.345, P=0.036), which improved if lung metastases (r=0.805, P=0.016) or if lung and liver metastases were present (r=0.812, P=0.05). A Bland-Altman plot showed that the higher the number of CTC detected the larger the difference between both methods in favor of IsoFlux^TM. After a median follow-up since CTC collection of 16 months (range: 1-30) CellSearch® ≥ 3 CTC (HR 2.77, 95% CI 0.77-9.95) and IsoFlux^TM ≥ 11 CTC (HR 4.14, 95% CI 1.05-16.19) were established as the best cutoff points for predicting survival. Using castPCR^TM we found KRAS mutations in CTC in 4 out of 8 patients from group 1 and in 2 out of 3 patients from group 2. None of these mutations were found in the primary tumor using standard methods, possibly reflecting intratumor heterogeneity or treatment selection pressure. We conclude that IsoFlux^TM is more efficient than CellSearch® in the isolation of CTC in patients with advCRC, achieving, in a majority of cases, the established minimum of CTC for castPCR^TM-based genetic analyses.

Wind turbines are a solution for sustainable energy, significantly reducing carbon emissions and fostering a circular economy for more cost-effective and cleaner power generation, in line with worldwide environmental aspirations. In this context, this research aims to explore a novel Two-Stage Twisted Blade micro-Vertical Axis Wind Turbine ($\mu$-VAWT) alternative inspired by the Savonius Rotor (SR). This investigation utilizes the $\kappa-\omega$ SST turbulence model to explore the power coefficient ($C_P$) and torque coefficient ($C_T$), finding $C_P$ values ranging from 0.02 to 0.04 across the turbine by altering the free stream velocity ($V$). $C_T$ analysis further delves into four specific sections, highlighting areas of particular interest. These results are validated by examining velocity contours, pressure contours, and streamlines in four horizontal sections, demonstrating that the proposed turbine model exhibits minimal torque fluctuation. Moreover, the analysis of vertical wind streamlines illustrates very low interference with various wind turbine proposals, underscoring the turbine's efficiency and potential for integration into diverse wind energy projects.

Coastal environments are complex systems that are influenced by a combination of natural processes and human activities. Scientific interest in the effects of coastal erosion/accretion and climatic change-related processes greatly increased in recent decades due to the growing human development along coastal areas. This paper investigates the state and evolution of beach-dune systems for the 1977-2001 and 2001-2019 periods of the Mediterranean coast of Andalusia (Spain) using two different proxies: the dune toe line, which was used to track foredunes evolution, and the high-water line, which was used to assess shoreline evolution. Results showed a general erosional behavior of the studied beach-dune systems and identified cases where the main trend was altered through human interventions. In the 1977-2001 period, 54% of foredunes showed erosion, 24% accretion and 22% stability while and 34% of shorelines showed erosion, 40% accretion and 34% stability. In the 2001-2019 period, 42% of foredunes showed erosion, 28% accretion and 30% stability, and 40% of shorelines showed erosion, 34% accretion and 26% stability. Combining the evolution classes of each proxy (dune toe/shoreline) allows the behavior of both shoreline proxies to be assed together and provides insights additional to those derive from the use of a single proxy. In this regard, Erosion/Erosion (EE) was the most frequent behavior, with 25% and 27% in the first and second periods respectively, and Accretion/Accretion (AA), with 17% in both periods. Erosion of foredunes combined with stability or accretion of the shoreline (ES and EA) were the most common pairings in the first period, while stability of dunes combined with accretion of the shoreline (SA) and Stability/Stability (SS) dominated in the second period. The results obtained provide additional insights on the nature and drivers of coastal change that aid local coastal managers and administrations in understanding erosion processes. The method can be applied at other areas around the world where a similar data base is available.

The Ni-laterite deposit at the San Felipe plateau, located 30 km northwest of Camagüey, in cen-tral Cuba, is the best example of a clay-type deposit in the Caribbean region. San Felipe resulted from weathering of mantle peridotites of the Cretaceous Camagüey ophiolites. In this study, a geochemical and mineralogical characterization of two profiles (83 and 84) from the San Felipe deposit has been performed by XRF, ICP-MS, quantitative XRPD, oriented aggregate mount XRD, SEM, FE-SEM and EMPA. Core 83 with a length of 23 m, and drilled in the central part of the plateau, presents a notable concentration of cryptocrystalline quartz fragments and a rather poor content in NiO, averaging 0.87% wt. Core 84, which is 12 m long, and drilled at the border of the plateau, lacks silica fragments and presents a higher NiO content, averaging 1.79 %wt. The smectite structural formulae reveal that they evolve from trioctahedral to dioctahedral towards the top of the laterite profiles. Quantitative XRD analyses indicate that smectite is a dominant Ni bearing phase, accompanied by serpentine and minor chlorite. Serpentine, as smectite, is en-riched in the less soluble elements Fe3+, Al and Ni towards the top of the profiles. Core 83 seems to have been affected by collapses, replenishments, whereas core 84 may have remained undis-turbed.

The conserved cyanobacterial protein PipX is part of a complex interaction network with regulators involved in essential processes that include metabolic homeostasis or ribosome assembly. Because PipX interactions depend on the relative levels of their different partners and of the effector molecules binding to them, in vivo studies are required to understand the physiological significance and contribution of environmental factors to regulation of PipX complexes. Here we have used the NanoBiT complementation system to analyse regulation of complex formation in Synechococcus elongatus between PipX and each of its two best characterized partners, PII and NtcA. Our results confirm previous in vitro analysis on regulation of PipX-PII and PipX-NtcA complexes by 2-oxoglutarate and on regulation of PipX-PII by the ATP/ADP ratio, showing the disruption of PipX-NtcA complexes by increased levels of ADP-bound PII in Synechococcus elongatus. The demonstration of a positive role of PII on PipX-NtcA complexes under the initial response to nitrogen starvation or the impact of a PipX point mutation on the activity of PipX-PII and PipX-NtcA reporters are further indications of the sensitivity of the system. This study reveals additional regulatory complexities in the PipX interaction network, opening the way to future research in cyanobacteria.

We propose that a dietary reduction of Lipopolysaccharide (LPS) could reduce risk and slow the progression of cognitive decline and Alzheimer’s disease. LPS is a component of the highly inflammatory cell membrane of Gram-negative bacteria. The highest dietary sources of LPS are processed meat and dairy products, which can sharply raise plasma LPS within one to two hours. The LPS in these foods is packaged into chylomicrons, which enter the bloodstream. Smaller amounts of LPS from colonic microbiota do not account for the sharp postprandial increase of plasma LPS. Once in the bloodstream, LPS can trigger the release of inflammatory cytokines within three hours. LPS can increase cytokines via LPS binding protein and cluster of differentiation-14, triggering toll-like receptor-4, and activating nuclear factor kappa-B. Nuclear factor kappa-B can increase cytokine levels, including interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha. LPS and inflammatory cytokines are higher in Alzheimer’s disease, both in plasma and in the central nervous system. These cytokines can enter the brain via active transport and induce microglial activation and inflammatory damage in the brain, including loss of synapses and neurons. Elevated brain inflammation from dietary LPS can contribute to cognitive impairment and increased risk of dementia.

Objective: To analyse the association between maternal risk factors such as age, body mass index (BMI) and cigarette smoking, with perinatal outcomes. Materials and Methods: This a retrospective analysis from prospectively collected data performed at Hospital Universitario de Torrejón (Madrid, Spain), between September 2017 and December 2019. All pregnant women with singleton pregnancies and non-malformed live fetuses attending their routine ultrasound examination at 11+0 to 13+6 weeks' gestation were invited to participate. Association between preeclampsia, preterm birth, gestational diabetes mellitus (GDM), small for gestational age (SGA) or fetal growth restricted (FGR) neonates and type of delivery according to maternal age, BMI, and cigarrete smoking was studied. Logistic mixed models were used to analyze the data. Results: 1921 patients were included in the analysis. Women of 40 years old had a significantly higher risk of having GDM (Odds Ratio (OR) 1.61, 95% Confidence Interval (CI) 1.08 to 2.36), and SGA neonates (OR 1.54, 95% CI 1.00 to 2.37). Women with a BMI &lt;18 had an increased rate of birth SGA and FGR neonates (OR 3.28, 95% CI 1.51 to 7.05, and OR 3.73, 95% CI 1.54 to 8.37, respectively), whereas women with a BMI ≥35 had a higher risk of GDM (OR 3.10, 95% CI 1.95 to 4.89). Smoking increased the risk of having SGA and FGR neonates (OR 1.83, 95% CI 1.36 to 2.46, and OR 1.91, 95% CI 1.29 to 2.78). Conclusions: Advanced maternal age, low or high BMI, and smoking status are significant risk factors for pregnancy complications. Both clinicians and society should concentrate their efforts on addressing these factors to enhance reproductive health.

Larrea tridentata is an endemic plant from the Mexican highlands used in traditional medicine to treat hypertension and kidney stones, among many ailments. This study evaluated a vasorelaxant compound: 5- Hydroxy-2-(4-hydroxy-3-methoxyphenyl)-6,7,8-trimethoxy-4H-1-benzopyran-4-one (also known as 8-Methoxycirsilineol: 8-M) which we purified from an extract of this plant. Mesenteric artery rings were isolated from male guinea pigs for isometric force measurements. Freshly isolated smooth muscle cells from mesenteric artery were used for ionic current measurement for calcium and potassium. 10 μM 8-M completely relaxed vascular rings contracted with phenylephrine in a dose-dependent fashion with an EC50 = 4.26 ± 1.16 10-6 M and 4.56 ± 1.64 10-6 M for endothelium intact and endothelium-free tissue, respectively. The relaxant effect of 8-M was not affected by maximal doses of nifedipine, verapamil or iberiotoxin. Nevertheless, the relaxant effect was partially abolished by addition of 10 mM Tetraethylammonium (TEA). In accordance to this, calcium currents evoked by depolarization were not affected by 8-M, whereas TEA-sensitive potassium currents, were increased upon its addition. Vasorelaxation due to 8-M is partly due to activation of KV currents in an endothelium independent mode.

The aim of this work was to describe the physiological limitations induced under drought conditions in young sweet orange trees, including the crop capability to recuperate its physiological status once re-watering, and after a water withholding. The trial was conducted during two consecutive months (July and August) in two-years old sweet orange trees. Three irrigation treatments were arranged: A full irrigation treatment; (FI); a low-frequency deficit-irrigation treatment (LFDI); and a sustained-deficit irrigation (SDI) treatment. The obtained results showed that for Stem values below -1.5 MPa, significant decreases in gas exchange rates, evidencing diffusive limitations to drought stress. Additionally, there was evidence of increased osmolyte synthesis, compatible as a defensive response to prevent oxidative damage. Likewise, the isohydric behaviour observed also resulted in significant decreases in gs even for moderate stress situations. In addition, it was observed that in the LFDI treatment, the stress levels reached caused a significant increase in the levels of Pro and MDA, which were not equal to those detected in FI during the recovery periods, which leads us to assume that potential values below -1.8 MPa would be causing significant oxidative damage with no capacity for subsequent recovery, and probably affecting the final yield.

The acoustic environment in learning spaces significantly influences learning effectiveness and occupant well-being. Recent studies have shown that a series of architectural factors within physical learning environments can impact students' educational experiences. This research delves into the relationship between architectural characteristics and the perceived acoustic environment among 467 primary students in 19 learning spaces across 9 schools in Chile. The survey comprises a student questionnaire, a checklist evaluating space characteristics, and acoustic measurements of indoor noise levels during occupied conditions. Examined topics include Indoor Environmental Quality (IEQ) comfort perception, noise annoyance, hearing ability, and acoustic preference. Architectural characteristics considered encompass flexible and acoustic space design parameters. The results indicated that noise discomfort was a common issue, especially in traditional learning spaces without acoustic treatment. The type of learning space (traditional or flexible settings) has a greater impact on acoustic perception particularly concerning noise discomfort and acoustic preference. However, poorly acoustic spaces lacking absorbing materials or exhibiting lower spatial density (m2 per student) contribute to increased indoor noise levels affecting noise annoyance caused by children's talking inside. The study emphasizes the importance of considering both architectural design and acoustic conditioning for optimizing the acoustic experience in educational spaces.

Understanding and measuring rock characteristics is crucial for scientific and practical applications. This study investigates stone quarries in Morelia, Michoacán, Mexico, evaluating ten quarries (both volcanic and crushed) using diverse analytical methods. Physical properties such as density were measured alongside mechanical tests like uniaxial compressive strength and ultrasonic pulse velocity. Results demonstrate that crushed materials exhibit superior physical and mechanical properties compared to volcanic stones. Advanced techniques including high-magnification scanning electron microscopy and X-ray fluorescence provided insights into surface morphology and elemental composition. Additionally, a novel finite element model was constructed, leveraging dynamic modulus of elasticity (Ed) derived from ultrasonic pulse velocity and maximum load data from uniaxial compressive strength tests. This model facilitated the classification of quarries based on their engineering characteristics. The findings underscore the model’s potential applicability to quarry assessments globally, offering valuable insights into optimizing stone resource utilization and enhancing structural integrity in construction projects.

LLMs are a compressed repository of a vast corpus of valuable information on which they are trained. Therefore, this work hypothesizes that LLMs such as Llama, Orca, Falcon, and Mistral can be used for misinformation detection by making them cross-check new information with the repository on which they are trained. Accordingly, this paper describes the findings from the investigation of the abilities of LLMs in detecting misinformation on multiple datasets. The results are interpreted using explainable AI techniques such as LIME, SHAP, and Integrated Gradients. The LLMs themselves are also asked to explain their classification. These complementary approaches aid in better understanding the inner workings of misinformation detection using LLMs and lead to conclusions about their effectiveness at the task.

Over the last two decades, a considerable amount of equipment has been acquired (spreaders, seeders, sprayers, among others) to respond to the challenges of Precision Agriculture (PA) concept. Most of this equipment has been purchased at a high cost. However, many of them, despite still being functional and equipped with sensors, actuators, and electronic processing units capable of adjusting to variations in speed, have become obsolete in terms of communication, and incompatible with new monitoring and control systems based on the “Isobus” protocol. This work aims to present a solution for updating the control system (“Ferticontrol”) of a “Vicon RS-EDW” spreader with variable rate application (VRA), making it compatible with the “InCommand” system from “Ag Leader”. The solution includes low-cost “Arduino” and “Raspberry Pi” microcontrollers and open-source software. The development shows that it is possible to implement a solution that is accessible to farmers in general. It also provides a niche business opportunity for young researchers to set up small technology-based enterprises associated with universities and research centers. These partnerships guarantee permanent innovation and represent a decisive step towards modern, technological, competitive, and sustainable agriculture.

Yeast two-hybrid approaches, which are based on fusion proteins that must co-localise to the nucleus to reconstitute the transcriptional activity of GAL4 have greatly contributed to understand the nitrogen interaction network of cyanobacteria, whose main hubs are the trimeric PII and the monomeric PipX regulators. The bacterial two-hybrid system, based on the reconstitution in the E. coli cytoplasm of the adenylate cyclase of Bordetella pertussis, should provide a relatively faster and presumably more physiological assay for cyanobacterial proteins than the yeast system. Here we use the bacterial two-hybrid system to gain additional insights into the cyanobacterial PipX interaction network while simultaneously assessing the advantages and limitations of the two most popular two-hybrid systems. Comprehensive mutational analysis of PipX and bacterial two-hybrid assays were performed to compare outcomes between yeast and bacterial systems. We detected interactions previously recorded in the yeast two-hybrid system as negative as well as a “false positive”, the self-interaction of PipX, which is rather an indirect interaction dependent on PII homologs from the E. coli host, a result confirmed by Western analysis with relevant PipX variants. This is, to our knowledge, the first report of the molecular basis of a false positive in the bacterial two-hybrid system.

Antimicrobial resistance has been stated to be a global health problem. In Chile, the use of antibiotics should be declared by medical prescription, however, it is unknown what happens to the drugs once the treatment ends. One possibility is that these end up being disposed of in the trash or down the drain. In both scenarios, antibiotics could accumulate in the environment, stimulating the emergence of antimicrobial resistance mechanisms and their transfer between microorganisms. Unfortunately, sometimes wastewater ends up in bodies of water, due to the dragging of elements by rain, or by the presence of illegal water discharges. In this work, we use shotgun metagenomics to elucidate the functional and microbial composition of biohazard elements in the bay of Puerto Varas City, Chile. As expected, we found a high diversity in microbial communities, with bacterial elements described as human or animal pathogens. Also, we detect a diverse repertory of virulence and antibiotic-resistant genes (ARGs), related with macrolides, beta-lactams, and tetracyclines resistance, which are consistent with the families of antibiotics most used in Chile. Similar ARGs were identified in DNA mobile elements. In addition, we tested the AMR ability in 20 bacterial strains recovered from the Llanquihue lake. This is the first report of the presence of genomic elements that could constitute a health problem for the people who live around the Llanquihue Lake of Chile, considering the importance of the interconnection between environmental, animal, and human health, a concept known as One Health.

MicroRNAs, short non-protein coding RNAs, are overexpressed in GCTs. Circulating levels of germ cell tumor (GCT)- associated miRNAs, such as miR-371a-3p, can be utilized as efficient and cost-effective alternatives in diagnosing and managing patients presenting with GCTs. This quality of miRNAs has demonstrated favorable performance characteristics as a reliable blood-based biomarker with high diagnostic accuracy compared to current serum tumor markers (STMs) including α-fetoprotein (AFP), beta human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH). The conventional STMs exhibit limited specificity and sensitivity. Potential clinical implications of miRNAs include impact on de-escalating or intensifying treatment, detecting recurrence at earlier stages, and lessening the necessity of cross-sectional imaging or invasive tissue biopsy for non-teratomatous GCTs. Here we also highlight the outstanding issues that must be addressed prior to clinical implementation. Standards for measuring circulating miRNAs and determining ideal cutoff values are essential for integration into current clinical guidelines.

Solid-state fermentation (SSF) is the bioprocess where microorganisms are cultivated in the absence of free water under control conditions. Lactic acid can be produced by fermenting grape stalks with Rhizopus oryzae in SSF. During the microorganism growth, the temperature and water content of the solid bed fluctuate, leading to areas of either dry or excessive moisture in the solid substrate. Therefore, it's crucial to control the supply of water to the matrix. In this work, we obtain lactic acid through SSF of grape stalks using Rhizopus oryzae NCIM 1299. The SSF was conducted at a fixed temperature of 35 °C, with three constant relative humidity levels: 50, 65, and 80 %RH. Mathematical models, including the Logistic and First Order Plus Dead Time models for fungal biomass growth and the Luedeking and Piret with Delay Time model for lactic acid production, were adjusted to kinetic curves. Growth kinetic parameters (Xmax, μmax, Tp, T0, Yp/x and td) were determined for all conditions. These kinetic parameters were then correlated with relative humidity using a second-degree polynomial relationship. We observed a decrease in Xmax with increasing %RH, while the value of Yp/x increased at higher %RH. Finally, the optimal variable relative humidity profile was obtained by applying the Dynamic Optimization Technique, resulting in a 15.30% increase in lactic acid production.

Marine renewable energy technologies have a great potential in supplying clean electricity to millions of people across the globe, if technical and economic conditions are in right. So far, ocean energy projects are commonly started by SMEs or educational institutions with limited budgets. Therefore, any effort to reduce expenses is of great value. One of the areas involving substantial expenses are the inevitable seabed inspection prior to deployment of marine renewable energy device. Detailed seabed inspections can also reduce the risk of associated with deployment of structures on uneven seabed, especially marine renewable energy devices with gravity foundations. By reducing the costs and risks of such surveys prior and during the installation phases, the feasibility of marine renewable energy projects can be more favoured and competitive. In this perspective, this study proposes a cost and time effective technique for seabed surveys. The proposed technique involves the use of high precision and inexpensive sonar systems and underwater optical cameras integrated into a versatile and compact subsea monitoring platform. It also involves simple and practical data acquisition and processing protocols that do not requires hi expertise for operation. The results obtained showed that high resolution bathymetric maps and detailed seabed inspections imagery can be acquired. This study concludes that a simple and inexpensive subsea monitoring platform comprising a multibeam, dual beam and video cameras can be effective for high resolution seabed inspection and bathymetric measurements for marine energy applications.

Study of alterations in Osteoarthritis (OA) of Glypicans 1 to 6 (GPCs) and Notum in plasma, bone marrow mesenchymal stromal cells (BM-MSCs) and osteoblasts. Plasma levels of GPCs and Notum were measured of 25 patients and 24 healthy subjects. In addition, BM-MSCs from eight OA patients and eight healthy donors were cultured during 21 days with culture me-dium and osteogenic medium. Protein and gene expression levels of GPCs and Notum were de-termined by ELISA and qPCR at 0, 7 ,14 and 21 days. GPC5 and Notum have been found de-creased in OA patients’ plasma. OA BM-MSCs showed downexpression of GPC6 and upregula-tion of Notum. A decrease in GPC5 and Notum proteins and an increase in GPC3 were found. During osteogenic differentiation, elevated GPC2, 4, 5, 6 and Notum mRNA levels and decreased GPC3 were observed in OA. Furthermore, the protein levels of GPC2, GPC5 and Notum de-creased and GPC3 increased. Glypicans and Notum are altered in BM-MSCs and during osteo-genic differentiation from patients with OA. Furthermore, GPC5 and Notum can be proposed as new biomarkers of the pathology. The alterations found indicate that Notum could be a prom-ising therapeutic strategy for Osteoarthritis.