A greenhouse dose-response study was conducted to determine the tolerance of three wild tomato accessions (TOM199, TOM198, TOM300) in comparison to a commercial cultivar (Better Boy) against the dicamba application at five rates (0, 70, 140, 210, and 280 g ae ha-1) at 14 and 28 days after treatment (DAT). Several physiological traits were evaluated at 0, 1, 3, 5, and 7 DAT. Wild accessions and cultivar were killed at all rates above 70 g ae ha-1 at 14 and 28 DAT, which is why differences between accessions and cultivar were only evident at 70 g ae ha-1. The GR50 (the herbicide rate that causes 50% reduction in dry weight) of Better Boy was 4.4 g ae ha-1 at 28 DAT, and this cultivar was approximately 11-fold more sensitive than wild accessions. At 7 DAT, the levels of H2O2 for wild accessions were lower than Better Boy up to 5 at 70 g ae ha-1 of dicamba. Furthermore, wild accessions showed lower herbicide absorption than Better Boy at all dicamba doses at 1, 3, and 7 DAT. All the three wild accessions expressed tolerance to the dicamba application at the dose of 70 g ae ha-1. At the same time, Better Boy and wild accessions were susceptible to dicamba application at rates of 140, 210, and 280 g ae ha-1.

Background: Partially hydrolyzed guar gum (PHGG) is a water-soluble, prebiotic fiber that is used in foods and supplements. The effects of PHGG and its role in gut health are still being studied. The purpose of this study was to evaluate changes in the gut microbiome composition of healthy individuals in response to low-dose PHGG supplementation compared with a low fiber diet. Methods: A randomized, double-blind, placebo-controlled crossover study was performed on 33 healthy subjects (17 male, 16 female). Each subject completed three 14-day treatment periods with a 2-week washout between each period. Treatments included supplementation with 3 g PHGG, 6 g PHGG, or placebo. During all periods, the participants followed a low fiber diet (<14 g/day). Stools were collected on days 0 and 14 of each period. Gut microbiome profiling was performed using 16S rRNA sequencing. Results: Supplementation of 3 g and 6 g PHGG significantly increased Verrucomicrobia on day 14 when compared to the placebo (p=0.0066 and p= 0.0068, respectively). On the genus level, Akkermansia was significantly increased on day 14 with both the 3 g and 6 g PHGG doses (p=0.0081 and p=0.0083). Faecalibacterium was significantly decreased on day 14 with 3 g PHGG (p=0.0054). Conclusion: Supplementing with low doses of PHGG has the potential to cause shifts in gut microbiome composition. By increasing beneficial microbes, PHGG can improve the microbiome composition of healthy individuals and may play a role in the treatment of inflammatory gastrointestinal diseases.

Objective: We report a case of acute pancytopenia and liver injury after concomitant administration of low-dose methotrexate (MTX), and high-dose esomeprazole and metamizole. Case summary: A 71-year-old patient with chronic systemic idiopathic erosive arthritis was admitted after a pelvic ring fracture. After hospital admission, she received MTX in addition to esomeprazole and metamizole. Subsequent laboratory tests revealed pancytopenia and elevated liver enzymes. The follow-up clinical examinations were unremarkable, with the exception of sub-febrile temperatures. Further investigations did not detect a definitive etiology. Due to the suspicion of methotrexate-induced hematotoxicity and hepatotoxicity, antagonizing therapy with calcium folinate was administered, after which the blood counts and liver parameters normalized. Discussion: Due to the administration of high-dose metamizole immediately before the administration of low-dose MTX, the pre-existing hematotoxic pharmacodynamic effect of MTX was acutely enhanced by that of metamizole, although folic acid was administered preemptively. In addition, the concomitant administration of high-dose esomeprazole and normal dose torasemide resulted in a pharmacokinetic interaction with MTX by decreasing its renal secretion and elimination, further enhancing the concentration-dependent hematotoxic and hepatotoxic side effects of MTX. Conclusions: The relatively high demand for analgesics in patients with chronic rheumatic diseases already being treated with MTX and proton pump inhibitors necessitates that clinicians consider drug-drug interactions as potential causes of adverse drug reactions after the administration of metamizole or nonsteroidal anti-inflammatory drugs. In this category of patients, it is strongly recommended to switch to analgesics of other classes.

The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a high rate of mortality in kidney transplant recipients (KTRs). The current vaccine strategy for KTRs seems to be unable to provide effective protection against coronavirus disease 2019 (COVID-19) [2] and the occurrence of severe COVID-19 in some vaccinated KTRs suggested a lack of immunity. We analized here the antibody response in a group of 32 kidney transplant recipients (KTR) followed at the Nephrology and Dialysis unit of the Hospital Pio XI of Desio, Italy, compared with a group of 23 healthy workers classified as Late responders (HCW-LR) (10 males age 27-62) and 13 females (age 46-64). We observed that the patients need additional vaccine boosters due to their immunocompromised status and therapy to protect them from infections related to viral variants, in accordance with the literature.

Little is known about the long-term durability of the induced immune response in subjects af-fected by obesity, particularly in those with an abdominal distribution of adipose tissue. We evaluated SARS-CoV-2-specific antibody response after BNT162b2 vaccine booster dose, com-paring individuals with abdominal obesity (AO) with those without, discerning between indi-viduals previously infected or not. IgG-TrimericS were measured in 511 subjects at baseline, 21 days after vaccine dose-1 and at one, three, six and nine months after dose-2 and at one and three months after booster dose. Nucleocapsid antibodies were assessed at baseline and at the end of the study to detect SARS-CoV-2 infection. To evaluate the three-months difference in absolute variation of IgG-TrmicericS levels from booster dose we used multivariable linear regression that showed interaction between AO and SARS-CoV-2 infection status (p=0.016). AO is associated with higher absolute IgG-TrimericS variation in prior infected individuals, regardless of possi-ble confounders and IgG-TrimericS levels at booster dose (p=0.0125). No interaction was evinced using BMI in the same regression model (p=0.418). The robust response in the development of antibodies after booster dose, observed in people with OA and previous infection, may support the recommendations to undergo the booster dose also in this population group.

Observe the synergistic effect and dose-effect relationship of Trimethoprim (TMP) on bactericidal activity with Flos Lonicerae in vitro. Microamount chessboard dilution method was conducted to determine the minimal inhibitory concentration (MIC) of Trimethoprim, Flos Lonicerae, as well as the combination of Trimethoprim and Flos Lonicerae separately against Staphylococcus aureus, Escherichia coli in vitro and Salmonella. The pour plate count method was used to determine the combined bactericidal activity of Flos Lonicerae combined with Different concentrations TMP. The results showed that the MIC values of the combination of Flos Lonicerae with TMP was much less than the MIC values of the independent use of Flos Lonicerae or TMP, The FIC values of the combination of Flos Lonicerae with TMP were between 0.5 and 1, there was additive effect between them. The bactericidal rates were fitted with least square method, the 95% confidence intervals of the optimal blending quantity about the combination of Flos Lonicerae with TMP on the test organisms were 231μg·mL^-1-249μg·mL^-1, 237μg·mL^-1-259μg·mL^-1, and 235 -259μg·mL^-1

Mesenchymal Stem Cells derived from bone marrow (hBM-MSCs) are utilized in tendon tissue‐engineering protocols while extra-embryonic cord-derived, including from Wharton’s Jelly (hWJ-MSC), are emerging as useful alternatives. To explore the tenogenic responsiveness of hBM-MSCs and hWJ-MSCs to hGDF-5 we supplemented each at doses of 1, 10, and 100 ng/mL and determined proliferation, morphology and time-dependent expression of tenogenic markers. We evaluated expression of Collagen types 1 (COL1A1) and 3 (COL3A1), Decorin (DCN), Scleraxis A (SCX-A), Tenascin-C (TNC) and Tenomodulin (TNMD) noting the earliest and largest increase with 100 ng/mL. With 100 ng/mL, hBM-MSCs showed upregulation of SCX-A (1.7-fold) at day 1, TNC (1.3-fold) and TNMD (12-fold) at Day 8. hWJ-MSCs, at the same dose, showed up-regulation of COL1A1 (3-fold), DCN (2.7-fold), SCX (3.8-fold) and TNC (2.3-fold) after 3 days of culture. hWJ-MSCs also showed larger proliferation rate and marked aggregation into a tubular shaped system at Day 7 (with 100 ng/mL of hGDF-5). Simultaneous to this we explored expression of pro-inflammatory (IL-6, TNF, IL-12A, IL-1β) and anti-inflammatory (IL-10, TGF-β1) cytokines across for both cell types. hBM-MSCs exhibited a better balance of pro-inflammatory and anti-inflammatory cytokines upregulating IL-1β (11-fold) and IL-10 (10-fold) at Day 8; hWJ-MSCs, had a slight expression of IL-12A (1.5-fold) but a greater up-regulation of IL-10 (2.5-fold). Collagen type I and tenomodulin proteins, detected by immunofluorescence, confirming the greater protein expression when 100 ng/mL were supplemented. In the same conditions, both cell types showed specific alignment and shape modification (fibroblast-like) with a Lenght/Width ratio increase at value higher than 1, suggesting their response in activating tenogenic commitment events, and they both potential use in 3D in vitro tissue engineering protocols.

With the rapid development of wind power generations, the inertial response of wind turbines (WTs) are widely concerned recently, which is important for grid frequency dynamic and stability. This paper recognizes and understands the inertial response of type-3 and type-4 WTs from the view of equivalent internal voltage, in analogy with typical synchronous generators (SGs). Due to the dynamic of the equivalent inertial voltage different from SGs, the electromechanical inertia of WTs is completely hidden. The rapid power control loop and synchronization control loop is the main reasons that the WT's inertial response is disenabled. On the basis of the equivalent internal voltage's dynamic, the existing inertia control method for WTs are reviewed and summarized as three approaches from the view of WT's control, i.e. optimizing the power control or synchronization control or both. At last, the main challenges and issues of these inertia controls are attempted to explain and address.

Background: BNT162b2 represents the authorized mRNA vaccine against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS–CoV–2) causing Covid–19. Methods: We conducted a prospective, single–center observational study with 273 employees of a medical facility to determine the efficacy and safety of the BNT162b2 third dose in relation to sex and BMI, and explore the possible determinants of neutralizing IgG and 25–hydroxy (25–OH) vitamin D levels. Results: At the median follow–up of 4.7 months, 38 of the participants had Covid–19 following vaccination. The incidence of adverse events (AEs) was significantly higher in females vs. males (p < 0.0108) and subjects with a high BMI of ≥ 30 kg/m2 vs. low BMI (p < 0.0117). The values of IgG were significantly enhanced in males vs. females (p < 0.0004), participants with high BMI vs. low BMI (p < 0.0003), a high number of ≥3 AEs vs. low number of AEs (p < 0.0003), and following infection with Covid–19 vs. without Covid–19 (p < 0.0005). Multivariate analysis (MVA) showed sex, BMI, number of AEs, and Covid-19 to be of predictive significance. On the contrary, 25–OH vitamin D concentrations in individuals with high vs. low BMI were significantly reduced (p < 0.0144) but this was not evident in MVA. Conclusions: This study confirmed the high efficacy of BNT162b2 in real–world scenario and revealed that its safety was affected by sex and BMI. Higher IgG levels suggesting better protection against infection were present in males, participants with high BMI, a high frequency of AEs, and those who overcame Covid-19 following vaccination.

Computed tomography (CT) is a widely employed imaging modality with diverse clinical applications in pediatric and adult populations, offering numerous advantages. Despite several alternatives to imaging modalities with ionising radiation, CT scans have demonstrated persistent global popularity, contributing to a substantial amount of effective radiation doses for patients. This exposure results in hazards, including stochastic effects that amplify the radiation-induced cancer risk proportionally to the radiation dose received. CT-related radiation comprises a substantial portion of cumulative effective doses within diagnostic radiology, specifically impacting younger patient cohorts undergoing repeated investigations for chronic diseases over time. Scientific literature over recent decades has explored various methods to mitigate radiation doses during medical imaging. One notable strategy involves implementing low-dose and ultralow-dose CT protocols, maintaining diagnostic efficacy in acute and non-acute medical and surgical conditions. Utilising innovative image reconstruction algorithms, such as iterative reconstruction and emerging deep-learning algorithms based on artificial intelligence, plays a pivotal role in achieving an approximately 80% reduction in patient radiation compared to standard doses. This review article discusses the significance of low-dose protocols across a spectrum of acute and chronic medical conditions affecting different body systems.

Elevated carbon dioxide (eCO₂) stimulates wheat grain yield, but simultaneously reduces protein (N) concentration. Also other essential nutrients are subject to change. This study is a comprehensive synthesis of wheat experiments with eCO₂, estimating effects on N, minerals (B, Ca, Cd, Fe, K, Mg, Mn, Na, P, S, Zn), and starch. Analysis was made by i) deriving response functions for the relative effect on element concentration in relation to CO₂ concentration, ii) meta-analysis to test the magnitude and significance of observed effects, and iii) relating CO₂ effects on minerals to effects on N and grain yield. Responses range from zero to strong negative effects of eCO₂ on mineral concentration, with largest reductions for the nutritionally important elements N, Fe, S, Zn and Mg. Together with the positive but small and non-significant effect on starch concentration, the large variation in effects suggests that CO₂-induced responses cannot be explained by a simple dilution model. To explain the observed pattern, uptake and transport mechanisms may have to be considered, along with the link of different elements to N uptake. Our study shows that eCO₂ has a significant effect on wheat grain stoichiometry, with implications for human nutrition in a world of rising CO₂.

Europium is one of the most reactive lanthanides and humans use it in many different applica-tions, but we still know little about its potential toxicity and cellular response to its exposure. Two strains of the eukaryotic microorganism model Tetrahymena thermophila adapted to high concentrations of two Eu(III) compounds (EuCl3 or Eu2O3) were obtained and compared to a control strain and cultures treated with both compounds. In this ciliate, EuCl3 is more toxic than Eu2O3. LC50 values show that this microorganism is more resistant to these Eu(III) compounds than other microorganisms. Oxidative stress originated mainly by Eu2O3 is minimized by overexpression of genes encoding important antioxidant enzymes. The overexpression of metallothionein genes under treatment with Eu(III) compounds supports the possibility that this lanthanide may interact with the -SH groups of the cysteine residues from metallothi-oneins and/or displace essential cations of these proteins during their homeostasis function. Both lipid metabolism (lipid droplets that fuse with europium-containing vacuoles) and au-tophagy are involved in the cellular response to europium stress. Bioaccumulation, together with a possible biomineralization to europium phosphate, seems to be the main mechanism of Eu(III) detoxification in these cells.

Rheumatoid arthritis (RA) is a chronic inflammatory disease. Despite new methods of diagnostics and treatment as well as extensive biological and immunosuppressive treatment, the etiology of RA is not fully understood. Moreover, the problem of diagnosis and treatment of RA patients is still current and affects a large group of patients. It is suggested that these ER-related features may impair adaptation to chronic stress, inferring the risk of rheumatoid arthritis. The main goal in this study was evaluation of changes in mRNA translation to determine chronic ER stress conditions in rheumatoid arthritis patients. The study group consist of 86 individuals including total 56 rheumatoid arthritis patients and 30 healthy controls. The expression level of mRNA form blood samples of RA patients as well as controls of the PERK-UPR associated genes: p-eIF2, BCL-2, PERK, ATF4, BAX were investigated by Real-Time qPCR. GAPDH expression was used as a standard control. Considering the median, the expression of PERK, BCL-2, p-eIF2, ATF4, BAX was found to be significantly increased in the blood of RA patients compared with the control group. The p-value for the PERK gene was 0.0000000036, the p-value for the BCL-2 gene was 0.000000014, the p-value for the p-eIF2 gene was 0.006948, the p-value for the ATF4 gene was 0.0000056 and the p-value for the BAX gene was 0.00019, respectively. Thus, it can be concluded that targeting of the components of the PERK-dependent UPR signaling pathway via small-molecule PERK inhibitors, may contribute to the development of novel, innovative treatment strategies against rheumatoid arthritis.

Background: External beam radiation therapy requires a sophisticated and laborious planning procedure. To improve the efficiency and quality of the planning procedure, machine learning predictions of the dose distributions have been introduced to speed up the planning procedure and to serve as quality assurance. The most recent dose prediction models are based on deep learning U-Nets that give good approximations of the dose in 3D almost instantly. It is our purpose to train a 3D dose prediction for glioblastoma VMAT treatment and test its robustness and sensitivity for the purpose of quality assurance of automatic contouring. Methods: From a cohort of 125 glioblastoma (GBM) patients, VMAT plans were created according to a clinical protocol. The initial model was trained on a concatenated 3D U-Net. A total of 60 cases were used for training, 15 for validation and 20 for testing. The prediction model was tested for sensitivity to dose changes according to realistic contour variations. Additionally, the model was tested for robustness by exposing it to a worst-case test set containing out-of-distribution cases.Results: The initially trained prediction model had a dose score of 0.94 Gy and a mean DVH score for all structures of 1.95 Gy. In terms of sensitivity, the model was able to predict the dose changes that occurred due to the contour variations with a mean error of 1.38 Gy.Conclusions: We obtained a 3D VMAT dose prediction model for GBM with limited data, providing good sensitivity to realistic contour variations. We tested and improved the model's robustness, by targeted updating the training set, making it a useful technique for dose awareness in the contouring evaluation and quality assurance.

Neuroinflammation, defined as inflammatory reactions mediated by cytokines, chemokines, reactive oxygen species, and secondary messengers in the central nervous system (CNS) including the brain and spinal cord is the basis of many neurological disorders. Recently, erythropoietin (EPO) has been considered and studied as a modulator of neuroinflammation. On this article minireview of pathophysiology of neuroinflammation and the neuroprotective effects of EPO is discussed and a case of subacute huge subdural hematoma with double mydriasis operated urgently, treated with low daily dose (vs high dose once or twice a month in the literature) of EPO and recovered fully and discharged home with good consciousness is reported. In addition, the probable unfavorable outcome of erythropoietin administration in patients with neuroinflammation in COVID-19 is considered.

In this work, two plasmonic structures with two different periodic nanostructures (nanodisk and nanostrip arrays) separated from the gold layer by an ultrathin dielectric Al2O3 layer are proposed, and their optical properties are simulated as 3-dimensional models using COMSOL Multiphysics software tool. The optical responses, such as the amplification of the electric field and the scattering, absorption and extinction cross sections of the two structures, are investigated and compared. The results show that both structures show strong field enhancement in their gap layer, and the structure with the periodic array of metal nanodisks shows stronger field enhancement and larger absorption, extinction, and scattering cross sections in its dipole resonance wavelength, which is defined as a bright plasmonic mode. In addition, some weaker resonant modes are observed for both structures and the reason for their generation is dis-cussed. The analysis of different possible modes in such structures is crucial for their application in various fields.

The aim of the present trial was to evaluate the growth performance of buffalo calves fed diets characterized by different forage/concentrate ratio with or without the Saccharomyces Cerevisiae supplementation (CBS 493.94, Yea-Sacc®). Twenty-four male buffalo calves (mean age 145.1 ± 16.1 days; mean weight 108.0 ± 18.7) were assigned randomly to 4 groups, homogeneous for age, fed four different diets: diet 1 F:C ratio 50:50; diet 2 F:C ratio 30:70; diet 3 F:C ratio 50:50 + Yea-Sacc® and diet 4 F:C ratio 30:70 + Yea-Sacc®. Buffalo calves were individually weighted before the start of the experiment and the data were used as a covariate, monthly until the end of the trial. Dry matter intake (DMI), daily weight gain (DWG) and feed conversion ratio (FCR) were calculated. The differences in diets’ composition significantly (p

Objective: The aim of this study was to optimize the fermentation process of Radix Ranunculi ternate via microbial fermentation and analyze the changes in the contents of the main components, the antioxidant and hypoglycemic capacities of the extract before and after fermentation. Methods: The solid-state fermentation process was optimized using single-factor tests and the response surface method, with the yield of the alcohol extract of R. ternate as an evaluation index. Results: The best fermentation process was optimized using solid-state endophytic fungus fermentation technology as follows: strain addition ratio of Chaetomium globosum/Fusarium equiseti =1:1, fermentation for 5 d, sieve size of 40 mesh, liquid/material ratio of 0.8:1 mL·g−1, fermentation temperature of 31 °C, and inoculation amount of 7.5%. Under the optimized conditions, the contents of the water-soluble extract and total polysaccharides decreased by 12.71% and 12.95%, respectively, in the fermentation, The contents of ethanol-soluble-extract, flavonoids, saponins, polyphenols, organic acids, and total amino acids of fermented R. ternate increased by 19.77%, 57.14%, 79.67%, 14.29%, 17.63% and 3.82%, respectively, and the scavenging rate for DPPH, ABTS+, ·OH free radicals and inhibitory rate for α-amylase also increased by 19.02%, 14.17%, 7.53% and 34.54%, respectively, compared with unfermented R. ternate. Conclusions: Solid-state fermentation opens new avenues for the development and application of R. ternate as natural antioxidant and hypoglycemic food.

In this study, the degradation characteristics of radio-frequency (RF) low-noise amplifier (LNA) based on silicon-germanium (SiGe) heterojunction bipolar transistors (HBTs) due to total ionizing dose (TID) are investigated. The small-signal equivalent model of a SiGe HBT is utilized to analyze circuit-level performance including the input and the output matching and noise figure (NF). As a target circuit, an LNA with a cascode common-emitter stage with emitter degeneration is studied and the equation of each performance parameter is derived. The RF LNA fabricated using commercial 350 nm SiGe technology was exposed to X-ray irradiation with the total dose up to 3 Mrad (SiO2). The experimental results exhibit that modeled device parameters estimate the degraded circuit performance. In addition, the relative impact of each parameter on the circuit metrics is revealed, which is expected from the derived design equations. The key device parameters for modeling TID-induced circuit degradations include the base resistance, the transconductance, and the base-to-emitter capacitance.

Previous studies investigated the effects of seed rates and seed recycling practices on the yield and yield related variables. However, higher yield does not always guarantee cost-efficiency. This study aimed at investigating the yield effects of plot-level seed rate along with the cost-benefit analysis of seed recycling practices. This study has introduced the dose-response model to the existing analytical methods used in analyzing the effect of different agrochemicals on crop yield. A multi-stage stratified sampling technique was used to select a total of 450 sample respondents. Data was gathered using a mix of data collection tools. Descriptive statistics along with the dose-response model have been applied for data analysis. Farmers of the study were found to be dissimilar in terms of their seed rate application. The dose-response analysis indicated that the highest average wheat yield has been associated with a seed rate of 50 kg ha-1 above what is recommended. The yield effect of seed recycling has also been assessed and a one-time seed recycling has caused a yield decline of 665 kg ha-1 as compared to the non-recycled seeds. The cost reduced by using recycled seed is by far lower than the economic gains associated with using unrecycled and fresh seeds. The cost-benefit analysis made clear that farmers can reduce their seed costs through seed recycling but their yields and net income can be best improved by using unrecycled CBWS. Thus, farmers must be encouraged to make use of unrecycled seed by establishing agricultural credit schemes geared towards seed procurement and seed price subsidy as key strategies to reduce economically wasteful seed recycling practices.

Wetland ecosystems in the Qinghai-Tibet Plateau are pivotal for global ecology and regional sustainability, contributing significantly to terrestrial ecosystems by regulating runoff, mitigating floods, and enhancing water quality. This study investigates the dynamic changes in wetland ecosystems within the Chaidamu Basin and their response to drought, aiming to foster sustainable wetland utilization in the Qinghai-Tibet Plateau. Using Landsat TM/ETM/OLI data on the Google Earth Engine platform, we employed a random forest method for annual long-term land cover classification. Meteorological drought conditions were assessed using SPEI3, SPEI6, SPEI9, and SPEI12, derived from monthly precipitation and evapotranspiration data. Pearson correlation analysis examined the relationship between wetland changes and various SPEI scales. The BFASAT method evaluated the impact of SPEI12 trends on wetlands, while cross-wavelet analysis explored teleconnections between SPEI12 and atmospheric circulation factors. Our findings revealed that the land cover dataset of the Chaidamu Basin (1990-2020) exhibited diverse categories with high classification accuracy (OA: 90.27%, Kappa: 88.34%). Wetlands, including lake, glacier, and marsh types, exhibited a noticeable increasing trend. Wetland expansion occurred during specific periods (1990-1997, 1998-2007, 2008-2020), featuring extensive conversions between wetland and other types, notably from other types to wetlands. Spatially, lake and marsh wetlands predominated in the low-latitude basin, while glacier wetlands were situated at higher altitudes. The study identified significant negative correlations between SPEI at various scales and total wetland area and types, with SPEI12 exhibiting the most substantial effect between September and December (r <-0.75) on wetlands. SPEI12 displayed a decreasing trend with non-stationarity and distinct breakpoints in 1996, 2002, and 2011, indicating heightened drought severity. Atmospheric circulation indices (ENSO, NAO, PDO, AO, WP) exhibited varying resonance with SPEI12, with NAO, PDO, AO, and WP demonstrating longer resonance times and pronounced responses.The continuous growth of wetlands amidst increasing aridification emphasizes the need for thoughtful wetland development to establish a sustainable "forest-lake-grass-field-river" ecological community. These findings underscore the significance of comprehending wetland changes and drought dynamics for effective ecological management in the Chaidamu Basin of the Qinghai-Tibet Plateau.

Sepsis is a major health problem and accounts for 20 per cent of deaths worldwide. It is the most expensive condition treated in United States hospitals at $27 billion per year or about $20,000 per patient. Treatment consisting largely of fluid resuscitation and antibiotics has only marginal impact. Mortality is about 27 per cent for hospitalized patients and about 42 per cent for patients in intensive care.There are two phases of sepsis – a hyper inflammatory phase and a subsequent hypo inflammatory phase.During the hyper inflammatory phase the metabolic rate increases associated with an increase in body temperature and a rapid escalation of immune system functioning including increased numbers of leucocytes and migration of those leucocytes to infected and damaged tissues and an increased supply and consumption of glucose to fuel this immune system.During the subsequent hypo inflammatory phase the metabolic rate declines and this is associated with a decrease in body temperature and a generalized decrease in the physiological activity of many organs including the immune system akin to hibernation. The activated immune system has priority for the available glucose over most other organs and physiological functions during such potentially life threatening circumstances. Thus adenosine triphosphate (ATP) production by mitochondria (the source of energy at the cellular level for the organism as a whole) also has a lower priority for the available glucose relative to the activated immune system. If glucose availability is threatened then mitochondrial production of ATP is partially or substantially suppressed in favor of glycolysis because glycolysis can rapidly produce large quantities of ATP that are necessary for immune cell function in infected, anaerobic, ischemic, or damaged tissues.However, glycolysis is only a temporary fix as it cannot produce the quantities of ATP necessary on an ongoing basis for the normal functioning of the healthy animal. Mitochondrial production of ATP must be recommenced for full recovery.It appears that the partial or substantial suppression of mitochondrial production of ATP by activation of the immune response becomes relatively fixated in some patients leading to a substantial ATP deficit. This is the fundamental issue of sepsis.This paper reviews the metabolism of glucose and insulin during sepsis and concludes that high dose insulin with mild hyper glycaemia in conjunction with the intravenous administration of thiamine, an inhibitor of the pyruvate dehydrogenase kinase enzymes, to re-establish physiological ATP production by mitochondria, administered early in the hypo metabolic (hypo inflammatory) phase of sepsis should significantly improve survival.

Celecoxib as adjuvant therapy has been shown in a small randomized trial for Covid-19 to prevent clinical deterioration and rapidly improve thoracic computerized axial tomography (CT-chest)¹. Multiple descriptive trials of high dose famotidine (both inpatient and outpatient) have demonstrated clinical response^2,3,4. We describe the rapid clinical responses after increasing the celecoxib dosage to 400mg bid with high dose famotidine 80mg qid in both a critical inpatient who on baseline required 40 liters per minute high flow nasal insufflation and an outpatient who declined admission but had critical Covid-19 biomarkers.

The domestic ducks (Anas platyrhynchos domesticus) are resistant to most of the highly pathogenic avian influenza virus (HPAIV) infections. In this study, we characterized the lung proteome and phosphoproteome of ducks infected with HPAI H5N1 virus (A/duck/India/02CA10/2011/Agartala) at 12 hr, 48 hr and 5 days post infection condition. Total 2082 proteins were differentially expressed and 320 phosphorylation sites mapping to 199 phosphopeptides corresponding to 129 proteins were identified. Functional annotation of proteome data analysis reveals activation of RIG-I-like receptor and Jak-STAT signaling pathways, that lead to induction of interferon stimulated genes (ISGs) expression. The pathway analysis of phosphoproteome datasets also confirms the activation of RIG I, Jak-STAT signaling, NF-kappa B signaling and MAPK signaling pathways in the lung tissues. The induction of ISGs proteins (STAT1, STAT3, STAT5B, STAT6, IFIT5 and PKR) establishes protective antiviral immune response in duck lung tissue. Further, the protein-protein interaction network analysis identified proteins like AKT1, STAT3, JAK2, RAC1, STAT1, PTPN11, RPS27A, NFKB1 and MAPK1 as main hub proteins that might play important roles in disease progression in ducks. Together, functional annotation of proteome and phosphoproteome datasets reveals the molecular basis of the disease progression and disease resistance mechanism in ducks infected with HPAI H5N1 virus.

Electrospun ultrathin fibers based on binary compositions of polylactide (PLA) and poly(ε-caprolactone) (PCL) with different ratios of polymer components from 0/100 to 100/0 wt. % were studied. Using a combination of thermal (DSC) and relaxation (EPR) measurements, the effect of biopolymers content on the characteristics of the crystal structure of PLA and PCL and the diffusive rotational mobility of the stable TEMPO radical in the amorphous regions of PLA/PCL compositions was shown. It was revealed that after PLA and PCL blending, significant changes in the degree of crystallinity of PLA, PCL segmental mobility, sorption capacity of the radical as well as activation energy of rotational diffusion in the amorphous regions of PLA/PCL composition are observed. The characteristic region of biopolymers’ composition from 50/50 to 30/70 % PLA/PCL blends ratio was found, where the inversion transition of PLA from dispersive medium to dispersive phase where an inversion transition is assumed when the continuous medium of the PLA transforms into a discrete phase. The performed studies made it possible for the first time to carry out a comprehensive analysis of the effect of the system component ratio on the structural and dynamic characteristics of the PLA/PCL film material at the molecular level.

A typhoon-induced storm surge is considered one of the most severe coastal disasters in Taiwan. However, the combination of the storm surge and the astronomical tide called the storm tide can actually cause extreme flooding in coastal areas. This study implemented a two-dimensional hydrodynamic model to account for the interaction between tides and storm surges on the coast of Taiwan. The model was validated with observed water levels at Sauo Fish Port, Hualien Port, and Chenggong Fish Port under different historical typhoon events. The model results are in reasonable agreement with the measured data. The validated model was then used to evaluate the effects of the typhoon's intensity, bathymetric change, and the combination of the typhoon’s intensity and bathymetric change on the maximum storm tide and its distribution along the east coast of Taiwan. The results indicated that the maximum storm tide rises to 1.92 m under a typhoon with an intensity of a 100-year return period. The maximum storm tide increased from a baseline of 1.26 m to 2.63 m for a 90% bathymetric rise at Sauo Fish Port under the conditions of Typhoon Jangmi (2008). The combination of the intensity of a typhoon with a 100-year return period and a 90% bathymetric rise will result in a maximum storm tide exceeding 4 m, 2 m, and 3 m at Sauo Fish Port, Hualien Port, and Chenggong Fish Port, respectively. We also found that the distribution of the maximum storm tide on the east coast of Taiwan can expand significantly subject to the bathymetric rise.

Depression is the commonest mental disorder worldwide. Both antidepressants and psychotherapy are effective in treating depression, but response to these treatments is often incomplete. Yoga-based interventions (YBIs) have emerged as a promising adjunctive treatment for depression. Recent research has attempted to identify the biological mechanisms associated with the antidepressant actions of YBIs. In this scoping review, conducted according to the PRISMA-ScR guidelines, the PubMed and Scopus databases were searched to retrieve research on biomarkers of response to YBIs in patients with depression. Eleven studies were included in the review. Based on these studies, YBIs may improve depression through beneficial effects on systemic inflammation, stress axis regulation, cardiac autonomic functioning, and possibly reductions in oxidative stress-related cellular damage. Increases in brain-derived neurotrophic factor (BDNF) may represent a final common pathway upon which these processes converge. Though these results are theoretically plausible, they should be interpreted with caution due to certain methodological limitations in the existing research. Replication of these results and improvements in study methodology, and the evaluation of other biomarkers relevant to the pathophysiology of depression, could further elucidate the mechanism of action of YBIs in this disorder, and identify which patients would benefit most from this treatment approach.

In spite of prevalence gaps in several micronutrients supporting immune function, significance of their deficits/supplementation for efficacy of vaccines is underinvestigated. Thus, influence of supplementation combining vitamins C and D, zinc, selenium and manganese, and N-acetyl-cysteine on mouse IgG responses and underlying mechanisms to seasonal quadrivalent influenza vaccine (QIV) was investigated. QIV was given in two doses (28 days apart). The supplementation starting 5 days before the first injection increased the total serum IgG titre, through stimulation of germinal centre (GC) reaction in secondary lymphoid organs (SLOs), as indicated by increase in the frequency of GC B cells and follicular CD4+ T helper (Th) cells, and IL-21-producing Th cells. Additionally, the supplementation “optimized” IgG response following the second QIV injection by supporting more favorable (in respect to virus clearance) IgG2a response through favoring Th1 differentiation as indicating by Th1 (INF-γ) /Th2 (IL-4) signature cytokine level ratio upon QIV restimulation in SLO cell cultures. This most likely reflected partly their antioxidant action (as indicated by redox status analyses) on Th cell differentiation. Thus, the study forms solid base for further research aimed at repurposing use this safe and inexpensive micronutrient combination as an adjuvant for virus influenza vaccine.

Technological advancements in the Internet of Things (IoT), unmanned aerial vehicles (UAVs), and novel technological tools have transformed disaster management practices from localized approaches to a global framework. These innovations necessitate a unified understanding and application of diverse methodologies at an international level, ensuring they are accessible and operational across different sectors. This integration is crucial not only for technical personnel but also for medical teams, who play a pivotal role in disaster response and management. By fostering a comprehensive grasp of these methods, we can enhance coordination, efficiency, and effectiveness in addressing disasters on a global scale. The authors aimed to provide a comprehensive overview of emerging techniques that are driving shifts in strategic approaches and treatment technologies. Recognized as a domain of continuous research and development, this overview, by necessity, remains an incomplete snapshot of an evolving field. It highlights the dynamic nature of technological and strategic advancements, underscoring the importance of ongoing investigation and innovation to stay abreast of current trends and future directions. The article also highlights the importance of international collaboration beyond societal and national boundaries A single paragraph of about 200 words maximum. For research articles, abstracts should give a pertinent overview of the work. We strongly encourage authors to use the following style of structured abstracts, but without headings: (1) Background: Place the question addressed in a broad context and highlight the purpose of the study; (2) Methods: briefly describe the main methods or treatments applied; (3) Results: summarize the article’s main findings; (4) Conclusions: indicate the main conclusions or interpretations. The abstract should be an objective representation of the article and it must not contain results that are not presented and substantiated in the main text and should not exaggerate the main conclusions.

Oncolytic virotherapy is a promising immunotherapy approach for cancer treatment, utilizing viruses to preferentially infect and eliminate cancer cells while stimulating immune responses. In this review we synthesize current literature on the molecular circuits of immune sensing and response to oncolytic virotherapy; focusing on viral DNA or RNA sensing by infected cells, cytokine and danger-associated signal sensing by neighboring cells, and subsequent downstream activation of immune pathways. The sequential sense-and-response mechanisms involve the triggering of molecular sensors by viruses or infected cells to activate transcription factors and related genes for a breadth of immune responses. We describe how molecular signals induced in the tumor upon virotherapy can trigger diverse immune signaling pathways, activating both antigen-presenting cell-based innate and T cell-based adaptive immune responses. Insights into these complex mechanisms provide valuable knowledge for enhancing oncolytic virotherapy strategies.

This study was designed for the first time to improve phenolic yield and antioxidant activity of ultrasonic-assisted extraction from Acer truncatum leaves (ATL) using response surface methodology, and phenolic composition in ATL extracted under the optimized condition were characterized by UPLC-QTOF-MS/MS. Solvent and extraction time were selected based on preliminary experiments, and a four-factors-three-levels central composite design was conducted to optimize solvent concentration (X₁), material-to-liquid ratio (X₂), ultrasonic temperature (X₃) and power (X₄) for an optimal total phenol yield (Y₁) and DPPH• antioxidant activity (Y₂). The results showed that the optimal combination was ethanol: water (v:v) 66.21%, material-to-liquid ratio 1:15.31 g/mL, ultrasonic temperature 60 °C, power 267.30 W, and time 30 min with three extractions, giving a maximal total phenol yield of 7593.62 mg gallic acid equivalent /100 g d.w. and a maximal DPPH• antioxidant activity of 74241.61 μmol Trolox equivalent/100 g d.w.. Furthermore, 22 phenolics were first identified in ATL extract obtained under the optimized conditions, indicating that gallates, gallotannins, quercetin, myricetin and chlorogenic acid derivatives were the main phenolic composition in ATL. What’s more, a gallotannins pathway existing in ATL from gallic acid to penta-O-galloyl-glucoside was interpreted. All these results provided practical information aiming at full utilization of phenolics in ATL, together with fundamental knowledge for further research.

(1) Background: TNF inhibitors (TNFi) have revolutionized the treatment of rheumatoid arthritis (RA). However, 30-40 % of RA patients do not respond adequately to those biologics. In addition to neutralizing soluble TNF, TNFi have the ability to bind the transmembrane form of TNF, tmTNF. Importantly, tmTNF can act itself as a receptor that induces a “Reverse Signaling” (RS) in cells. We previously showed that certolizumab, a Fab’ TNFi, activates RS in human primary monocytes, at least in part through the transcription factor NRF2 that is known to regulate the expression of genes involved in anti-inflammatory response and oxidative stress. (2) Methods: Here, we have developed an assay for the prediction of clinical response of RA patients to TNF inhibitors. This assay is based on mRNA quantitation of CD36 activation and of 6 genes induced by NRF2 following tmTNF RS in fresh monocytes. (3) Results: We could predict the response to anti-TNF monoclonal antibodies (mAbs) with 93.3 % accuracy. However, our method was not suitable for the prediction of the response to TNF soluble receptor etanercept. (4) Conclusions: We have developed a rather simple, short-term, test that can be standardized. Predicting the response to TNF mAbs will help physicians offer the best available treatment and provide patients with personalized medicine.

Abstract: Brassinosteroids (BR) are essential plant hormones that play a crucial role in regulating plant growth and development, as well as their resistance to abiotic and biotic stresses, including pathogen infections. In the context of plant im-munity, BR influence various processes such as the expression of genes related to pathogen defense, the production of antimicrobial compounds, and the re-inforcement of the plant cell structure. The aim of work is understand the role of BR in plant defense against abiotic and biotic stresses. BR are involved in the regulation of metabolic processes, water economy, and photosynthesis, contributing to increased plant resistance to abiotic stresses. The study discusses various mechanisms of BR action on plant immunity, including the regulation of gene expression related to defense, activation of the plant defense system, in-teraction with other plant hormones, regulation of water and salt balance, and influence on photosynthetic processes. In the context of plant immunity, BR influence various processes, including the expression of genes related to pathogen defense, the production of antimicrobial compounds, and the reinforcement of the plant cell structure. Additionally, BR are involved in the regulation of metabolic processes, water economy, and photosynthesis, con-tributing to increased plant resistance to abiotic and biotic stresses. The paper emphasizes the importance of further research on the role and mechanisms of action of BR in plant immunity, which may contribute to the development of more effective strategies for the use of BR in agriculture, horticulture, and plant protection.

This paper addresses the analysis for the nonlinear vibration response of a rectangular tube with a flexible end and non-rigid acoustic boundaries. This is a further work of the linear structural acoustic problem in a well-known acoustic book. In fact, the acoustic boundaries of an enclosed space sometimes are non-rigid and the structural vibration responses are nonlinear. These two points are the focuses of this paper. The multi-level residue harmonic balance method is applied to this nonlinear structural acoustic problem. The results obtained from the multi-level residue harmonic balance method and numerical method are generally in good agreement. The effects of excitation magnitude, tube length, and phase shift parameter etc. are examined.

Background: The coronavirus disease-19 (COVID-19) has spread globally with more than 80,000 people infected, and nearly 3000 patients died. Currently, we are in an urgent need for effective treatment strategy to control the clinical deterioration of COVID-19 patients. Methods: The clinical data of 10 COVID-19 patients receiving short-term moderate-dose corticosteroid (160mg/d) plus immunoglobulin (20g/d) were studied in the North Yard of The First Hospital of Changsha, Hunan from January 17^th to February 27^th, 2020. Epidemiological, clinical, laboratory, radiological findings were analyzed. Results: After treatment with combination of low-dose corticosteroid (40-80mg/d) and immunoglobulin (10g/d), patients’ lymphocyte count (0.88±0.34 vs 0.59±0.18, P<0.05), oxygenation index including SPO₂ (94.90±2.51 vs 90.50±5.91, P<0.05) and PaO₂/FiO₂ (321.36±136.91 vs 129.30±64.97, P<0.05) were significantly lower than pre-treatment, and CT showed that the pulmonary lesion deteriorated in all patients. While after treatment of short-term moderate-dose corticosteroid plus immunoglobulin, patients’ APACHE Ⅱ score (9.10±6.15 vs 5.50±9.01, P<0.05), body temperature (37.59±1.16 vs 36.46±0.25, P<0.05), lymphocyte count (0.59±0.18 vs 1.36±0.51, P<0.05), Lactate dehydrogenase (419.24±251.31 vs 257.40±177.88, P<0.05), and C-reactive protein (49.94±26.21 vs 14.58±15.25, P<0.05) significantly improved compared with post-treatment with low-dose therapy. In addition, oxygenation index including SPO₂ (90.50±5.91 vs 97.50±1.18, P<0.05), PaO₂ (60.47±14.53 vs 99.07±34.31, P<0.05), and PaO₂/FiO₂ (129.30±64.97 vs 340.86±146.72, P<0.05) significant improved. Furthermore, CT showed that pulmonary lesions obviously improved in 7 patients. After systematic therapy, 4 out of 10 COVID-19 patients recovered and discharged. Conclusions: Short-term moderate-dose corticosteroid plus immunoglobulin is effective for reversing the continued deterioration of COVID-19 patients who failed to respond to the low-dose therapy. Funding: This work was supported by the Innovative Major Emergency Project Funding against the New Coronavirus Pneumonia in Hunan Province (Dr. Ji-Yang Liu, number 2020SK3014; Dr. Yuan-Lin Xie, number 2020SK3013).

Under the same seismic load, different local topography will have different effects, which is an important research field in seismic engineering. Hills are connected with valleys is a very typical terrain. Taking this terrain as an example, its response to the most destructive SH waves in the earthquake is studied. By simplifying and dividing the model, the wave functions satisfying the wave equation and boundary conditions in each region are constructed by using the complex function and moving coordinate method. The equations satisfying the boundary continuity conditions are established. With the help of calculation software, the numerical results are obtained. The influence of different parameters on ground motion is discussed.

Buckling defect will appear on the outer surface of the deformed ring during constrained ring rolling (CRR) of aluminum alloy thin wall conical ring with inner high ribs (AATWCRIHR), if the geometrical dimension of the ribs doesn't match the wall thickness. To avoid the buckling defect, a quantitative method for characterizing the degree of the buckling defect is proposed using the area of buckling profile. Then an orthogonal experimental scheme was designed taking the width of the middle rib, thickness of wall, and height of the middle rib as design variables and defining the area of buckling profile as optimization objective. Subsequently, a quadratic polynomial response surface model was established by combining the optimization algorithm with the finite element method (FEM), and the geometrical dimension of the middle ribs of the deformed AATWCRIHR is optimized. Also the optimal parameter combination to minimize the area of buckling profile is obtained and verified using FE simulation. Results show that the AATWCRIHR after optimization doesn’t generate the buckling defect during constrained ring rolling, and it is proved that the quantitative buckling defect representation method and the optimization design method based on the response surface model and the finite element simulation results are feasible for the constrained ring rolling process of the AATWCRIHR.

The calculation of effective doses is crucial in many medical and radiation fields, in order to ensure safety and compliance with regulatory limits. Traditionally, Monte Carlo codes using detailed human body computational phantoms have been used for such calculations. Monte Carlo dose calculations can be time-consuming and require expertise in different processes when building the computational phantom and dose calculations. This study employs various machine learning (ML) algorithms to predict the organ doses and effective dose conversion coefficients (DCCs) for different anthropomorphic phantoms. A comprehensive data set comprising neutron energy bins, organ labels, masses, and densities is compiled from Monte Carlo studies, and is used to train and evaluate the supervised ML models. This study includes a broad range of phantoms, including those from the International Commission of Radiation Protection (ICRP-110, ICRP-116 phantom), the Visible-Human Project (VIP-man phantom), and the Medical Internal Radiation Dose Committee (MIRD-Phantom), with row data prepared using numerical data and organ categorical labeled data. Extreme gradient boosting (XGB), gradient boosting (GB), and the random forest-based Extra Trees regressor are employed to assess the performance of the ML models against published ICRP neutron DCC values using the mean square error, mean absolute error, and R² metrics. The results demonstrate that the ML predictions significantly vary in lower energy ranges and vary less in higher neutron energy ranges, while showing good agreement with ICRP values at mid-range energies. Moreover, the categorical data models align closely with the reference doses, suggesting the potential of ML in predicting effective doses for custom phantoms based on regional populations, such as the Saudi voxel-based model. This study paves the way for efficient dose prediction using ML, particularly in scenarios requiring rapid results without extensive computational resources or expertise. The findings also indicate potential improvements in data representation and the inclusion of larger data sets to refine model accuracy and prevent overfitting. Thus, ML methods can serve as valuable techniques for the continued development of personalized dosimetry.

Fowlpox virus (FPV) has been used as a vector for many years. To date, surprisingly, very little data exist on the persistence of fowlpox vaccines in chicken tissues, or what kind of immune cells respond to the vaccination at the site of inoculation. Although both humoral and cellular mediated immunity (CMI) play a part in overall immunity against FPV, little is known regarding the cell-mediated immune responses to FPV infection. The main aim of this paper was to measure persistence of the recombinant fowlpox vaccine in the skin tissues following vaccination. The results showed that the recombinant FPVs do not persist for long, and are cleared by 6 days post-vaccination (dpv). The response of immune cells (macrophages, B cells, CD4+ and CD8+ T cells) that infiltrating the site of vaccination was estimated.

Zero-dose children, or children who have not received any routine vaccination, are a priority population for global health policy makers as these children are at high risk of mortality from vaccine-preventable illnesses. We conducted a narrative review to identify potential interventions, both within and outside of the health sector, to reach zero-dose children. We reviewed peer-reviewed and grey literature and identified 59 relevant resources. Additionally, we interviewed six key informants to enhance synthesis of our findings. Data were organized into three priority settings: (1) urban slums, (2) remote or rural communities, and (3) conflict settings. We found that zero-dose children in the three-priority settings face differing barriers to vaccina-tion and, therefore, require context-specific interventions, such as leveraging slum health commit-tees for urban slums or integrating with existing humanitarian response services for conflict set-tings. Three predominant themes emerged for grouping the various interventions: (1) community engagement, (2) health systems strengthening and integration, and (3) technological innovations. The barriers to reaching zero-dose children are multifaceted and nuanced to each setting, there-fore, no one intervention is enough. Technological interventions especially must be coupled with community engagement and health systems strengthening efforts. Evaluations of the suggested interventions are needed to guide scale up, as the evidence-base around these interventions is rel-atively small.

Purpose: Novel coronavirus disease (COVID-19) is the current global concern. Radiotherapy (RT), commonly employed in cancer management, has been considered one of the potential treatments for COVID-19 pneumonia. Here, we present the final report of the pilot trial evaluating the efficacy and safety of low-dose whole-lung irradiation (LD-WLI) in patients with COVID-19 pneumonia. Methods and Materials: We enrolled patients with moderate COVID-19 pneumonia who were older than 60 years. Participants were treated with LD-WLI in a single fraction of 0.5 or 1.0Gy along with the national protocol of COVID-19. The primary endpoints were improvement of SpO₂, the number of hospital/ICU stay days, and the number of intubations after RT and the secondary endpoints were alterations of the c-reactive peptide, interleukin-6, ferritin, procalcitonin, and D-dimer. The response rate (RR) was defined as a rise in SpO₂ upon RT with rising or constant trend in the next two days, and clinical recovery (CR) included patients who were discharged from the hospital or acquired SpO₂ ≥93% on room air. Results: Between 21 May 2020 and 2 July 2020, ten patients were enrolled. The median age was 75 years, 80% were male, and 80% had comorbidities. The first five patients received a single 0.5Gy-WLI, and others received 1.0Gy. Patients were followed for 2-14 days (median 5.5 days). Following one day, nine patients experienced an improvement in SpO₂. Five patients were discharged (median 6^th day, range 2^nd-14^th day), and four patients died (median 7^th day, range 3^rd-10^th day). Overall, the RR and CR were 60.0% and 55.5%, respectively. The RR and CR rates of 0.5- and 1.0Gy group were 80% vs 40% and 75% vs 40%, respectively. No acute radiation-induced toxicity was recorded. Conclusions: LD-WLI with a single 0.5Gy fraction seems to be a more appropriate dose to warrant further evaluation in a large-scale, randomized trial.

The predatory mirids Macrolophus pygmaeus Ramber and Nesidiocoris tenuis Reuter (Heteroptera: Miridae) are used for the biological control of Tuta absoluta Meyrick (Lep.: Gelechiidae) and other pests in tomato greenhouses. The functional response of 1 (young) and 10 (old) days old adult females and males of M. pygmaeus and N. tenuis on eggs of T. absoluta, was determined on tomato at two temperatures (20° and 25°C) and LD 16:8 and found to be Type II. M. pygmaeus females exhibited higher predation efficiency, than males at both tested temperatures. Young M. pygmaeus females had a higher efficiency than old ones, whereas males had a low efficiency irrespective of age. The predation efficiency of N. tenuis was high (but lower than M. pygmaeus) in both young females and males, although old females had a higher efficiency than the respective males. Our results show that the two predatory species have different functional response characteristics to their prey depending mainly on sex and age which may affect their role as biological control agents.

Factors responsible of species distribution were intensively investigated in the past, including response at different spatial scales. The aim of the present research is to review the most relevant factors explaining chironomid species distribution focusing to factors operating at different spatial scales, such as latitude, longitude, altitude, water temperature, dissolved oxygen, nutrients acting at regional, country, water basin extension. Data including chironomid species abundances from different lentic and lotic waters from Italy and other surrounding countries were analyzed with different multivariate methods: partial canonical correspondence analysis and multiple discriminant analysis. Spatial analysis included univariate Moran’I correlograms, multivariate Mantel correlograms and Moran’s Eigenvectors Maps (MEM) calculation. The results confirmed previous conclusions, that is habitat type including different running waters reaches (kryal, krenal, rhthral, potamal) and different lake types is the most significant factor in separating chironomid assemblages and spatial factors act only as indirect influencers..

Human influenza A viruses (IAVs) cause global pandemics and epidemics, which remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral outbreaks, new treatments are urgently needed. Developing new virus control modalities requires better understanding of virus-host interactions. Here we describe how IAV infection triggers cellular apoptosis, and how this process can be exploited towards development of new therapeutics, which might be more effective than the currently available anti-influenza drugs.

Vitamin D deficiency and insufficiency are highly prevalent in CKD affecting over 80% of hemodialysis (HD) patients and require therapeutic intervention. Nephrological societies suggest the administration of cholecalciferol according to the guidelines for the general population. The aim of the observational study was to evaluate the efficacy and safety of the therapy with a high dose of cholecalciferol in HD patients with 25(OH)D deficiency and insufficiency to reach the target serum 25(OH)D level &gt; 30 ng/mL. 22 patients (16 M), with an average age of 72.5 ± 13.03 years and 25(OH)D concentration of 13.05 (9.00–17.90) ng/mL were administered cholecalciferol at a therapeutic dose of 70,000 IU/week (20,000 IU + 20,000 IU + 30,000 IU, immediately after each dialysis session). All patients achieved the target value &gt;30 ng/mL, with a mean time of 2.86 ± 1.87 weeks. In the first week, the target level of 25(OH)D (100%) was reached by 2 patients (9.09%), in the second week – by 15 patients (68.18%), in the fourth week – by 18 patients (81.18%) and in the ninth week by all 22 patients (100%). A significant increase in 1,25(OH)2D levels was observed during the study, however, only 2 patients (9.09%) achieved a concentration of 1,25(OH)2D above 25 ng/mL – the lower limit of the reference range. The intact PTH concentrations remained unchanged during the observation period. No episodes of hypercalcemia, and one new episode of hyperphosphatemia were observed. In conclusion, our study showed that the administration of a high therapeutic dose of cholecalciferol allowed for a quick, effective, and safe leveling of 25(OH)D concentration in HD patients.

ABSTRACT Objectives: Typical Diagnostic Reference Levels (DRL) in terms of Computed Tomography Dose Index (CTDI) and patient dose in terms of Effective Dose (ED ) and Size Specific Dose Estimate (SSDE) were estimated in Computed Tomography (CT) guided biopsy procedures. Materials and Methods: A total of 226 CT biopsy procedures - Iliac bone, liver, lung, mediastinum and para-aortic tissue - were retrospectively analyzed and Typical DRL extracted based on ICRP 135 instructions. Results: For helical mode acquisitions, DRLs in terms of CTDIvol were 9.7 mGy for Iliac bone, 8.9 mGy for liver, 8.8 mGy for lung, 7.9 mGy for mediastinal mass and 9 mGy for para-aortic lymph nodes biopsy procedures. For biopsy acquisitions, DRL values were 7.3 mGy, 7.7 mGy, 5.6 mGy, 5.6 mGy and 7.4 mGy respectively. Also, SSDE median values ranged from 7.6 mGy to 10 mGy for biopsy acquisitions and 11,3 mGy to 12,6 mGy for helical acquisitions, as well as the median values for effective dose ranged from 1.6 mSv to 5,7 mSv for biopsy scans and 3.9 to 9.3 mSv for helical scans. Conclusions: The use of DLR as an optimization tool for CT-guided biopsy procedures revealed that helical scans across the entire anatomical region greatly affect radiation dose compared to biopsy acquisitions.

This commentary is focused on radioactive contaminations in the Urals, where the consequences were more severe in the long term than those after the Chernobyl accident. The difference is that the latter was a technogenic catastrophe, but the former - a radioactive contamination tolerated since 70 years with several accidents in between. In earlier publications of Russian researchers no cancer frequency elevation was reported after exposures below 0.5 Sv or generally in the populations exposed to low doses. Later on, the same scientists started to claim similar relative risks for cancer and other diseases among exposed people in the Urals and in atomic bomb survivors from Hiroshima and Nagasaki. Apparently, an unofficial directive has been behind this ideological shift noticed around the year 2005. Trimming of statistics has been not unusual in the former Soviet Union. Potential motives included fostering radiophobia, stirring anti-nuclear protests in other countries and strangulation of nuclear energy aimed at the boosting of fossil fuel prices. Recent publications claiming cardiovascular risks after low-dose low-rate exposures and recommending more stringent standards of radiological protection are discussed here in some detail. Such recommendations for dose rates compatible with the natural radiation background are obviously nonsensical.

Acetamiprid is a broad-spectrum neonicotinoid insecticide used in agriculture to control aphids. While recent studies have documented resistance to acetamiprid in several aphid species, the underlying mechanisms are still not fully understood. In this study, we analyzed the transcriptome and metatranscriptome of a laboratory strain of the pea aphid, Acyrthosiphon pisum (Harris, 1776), with reduced susceptibility to acetamiprid after nine generations of exposure to identify candidate genes and the microbiome involved in the adaptation process. Sequencing of the transcriptome of both selected (RS) and non-selected (SS) strains allowed the identification of 14858 genes and 4938 new transcripts. Most of the differentially expressed genes were associated with catalytic activities and metabolic pathways involving carbon and fatty acids. Specifically, the alcohol-forming fatty acyl-CoA reductase (FAR) and acyl-CoA synthetase (ACSF2), both involved in the synthesis of epidermal wax layer components, were significantly upregulated in RS, suggesting that adaptation to acetamiprid involves the synthesis of a thicker protective layer. Metatranscriptomic analysis revealed subtle shifts in the microbiome of RS. These results contribute to a deeper understanding of acetamiprid adaptation by the pea aphid and provide new insights for aphid control strategies.

To date, radiation adaptation response has been reported as a low-dose related phenomenon and has been associated with radiation hormesis. Well-known cancers are caused by non-radiation active reactants, in addition to radiation. A model of suppression for radiation-specific cancers was previously reported, but the model did not target radiation-nonspecific cancers. In this paper, we describe kinetic models of radiation-induced suppressors for general radiation non-specific cancers, estimating the dose that induces the maximum hormesis effect while satisfying the condition that the risk is approximately proportional to dose above 100 mSv. It was found that the radiation hormesis effect is maximal at about 20 mSv when the rate constant for generation is the same as the rate constant for decomposition. When the two rate constants are different, the dose at which the radiation hormesis effect is maximized depends on both rate constants, but the dose increases as the two rate constants approach each other, reaching a maximum of about 20 mSv. This conclusion may lead to the discovery of unknown cancer suppressors at low doses and the development of cancer suppression methods in the future.

Patients with lean NAFLD make up an increasing subset of liver diseases. The association between lean NAFLD and feutin-A, which serves as a hepatokine and adipokine, has never been examined. Our study aimed to explore the association of serum fetuin-A among lean and nonlean patients. The study comprised 606 adults from the community, stratified into lean or nonlean (BMI </≥ 24 kg/m2) and NAFLD or non-NAFLD (scoring of ultrasonographic fatty liver indicator, US-FLI ≥ 2/<2). Multivariate logistic regression analyses were performed to estimate the odds ratio of having NAFLD among the tertiles of fetuin-A after adjustment. The least square means were computed by general linear models to estimate marginal means of the serum fetuin-A concentrations in relation to the NAFLD groups. The OR of having NAFLD for the highest versus the lowest tertile of fetuin-A was 2.62 (95% CI: 1.72-3.98; P for trend<0.001). Stratifying by BMI, the OR of having lean NAFLD for the highest versus the lowest tertile of fetuin-A was 2.09 (95% CI: 1.09-3.98; P for trend 0.026), while nonlean NAFLD had no significant association with the fetuin-A gradient after adjustments. Fetuin-A was positively associated with lean NAFLD after adjusting for central obesity and insulin resistance.

The orexin/hypocretin neuropeptide family has emerged as a focal point of neuroscientific research following the discovery that this family plays a crucial role in a variety of physiological and behavioral processes. These neuropeptides serve as powerful neuromodulators, intricately shaping autonomic, endocrine, and behavioral responses across species. Notably, they serve as master regulators of vigilance and stress responses; however, their role in complex processes such as food intake, metabolism, and thermoregulation warrant further investigation. This narrative review provides a journey through the evolution of our understanding of the orexin system, from its initial discovery to the promising progress made in developing orexin derivatives. It goes beyond conventional boundaries, striving to synthesize the multifaceted activities of orexins. Special emphasis is placed on domains such as stress response, fear, anxiety, and learning, in which the authors contributed to the literature with original publications. This article demonstrates the orchestrating role of the orexins in several intricate and integrative physiological processes. It also overviews the advancement of orexin pharmacology, which has already yielded some promising successes, particularly in the treatment of sleep disorders. This interdisciplinary approach to studying neuropeptides unveils their significance as vital connectors between transient functional changes and lasting structural adaptations. Ultimately, it advances our understanding of the intricate physiological and behavioral contributions of the orexin/hypocretin neuropeptide family.

For marine vessels, a propeller shaft system, also known as a propulsion shaft system, is an essential changer in engine torque and propeller thrust. The propeller shaft system is subjected to transverse, longitudinal, and torsional excitations during operation. These sources of excitations originate from alternating thrust generated by the propeller, operation of a propeller in a stern flow field which is non-uniform in time and space, misalignment of components such as shafts, bearings, and keyholes in the assembly, excitations in the form of rotational motion, and the whirling motion of the shafts. These dynamic excitations posed a challenging issue for the integrity and reliability of a marine vehicle. Thus, it is crucial to analyze the dynamic response of the propulsion shaft system. The dynamic analysis of the propulsion shaft system is typically conducted using numerical /analytical models. At present, Finite Element Model (FEM) as a numerical model plays a vital role in analyzing the dynamic response of the structure. The computed response and the modal parameters from the FE model are reliable only if accurate boundary conditions, such as stiffness, can be imposed on the model. However, the numerical FE model deviates from the experimental results because of uncertainties in the stiffness values of the bearings and other connectors. This paper uses the Response Surface Optimization (RSO) technique to estimate the unknown stiffness of the bearings used in the propulsion shaft system. The experimental model of the propeller shaft system is constructed from the steady-state response of the system using the step sine excitation. The natural frequencies and the amplitude of vibrations in the FE model are updated using the parametric RSO technique. The updated model shows that the difference in natural frequencies and vibration amplitude is less than 10% between the optimized and experimental models. Propeller Shaft, Vibrations, Optimization, Response Surface

Hyper-radiosensitivity (HRS) is the increased sensitivity to low doses of ionizing radiation observed in most cell lines. We previously demonstrated that HRS is permanently abolished in cells irradiated at a low dose rate (LDR), in a mechanism dependent on transforming growth factor β3 (TGF-β3). In this study, we aimed to elucidate the activation and receptor binding of TGF-β3 in this mechanism. T-47D cells were pre-treated with inhibitors of potential receptors and activators of TGF-β3, along with addition of small extracellular vesicles (sEVs) from LDR primed cells, before their radiosensitivity was assessed by the clonogenic assay. The protein content of sEVs from LDR primed cells was analyzed with mass spectrometry. Our results show that sEVs contain TGF-β3 regardless of priming status, but only sEVs from LDR primed cells remove HRS in reporter cells. Inhibition of the matrix metalloproteinase (MMP) family prevents removal of HRS, suggesting an MMP-dependent activation of TGF-β3 in the LDR primed cells. We demonstrate a functional interaction between TGF-β3 and activin receptor like kinase 1 (ALK1), by showing that TGF-β3 removes HRS through ALK1 binding, independent of ALK5 and TGF-βRII. These results are an important contribution to a more comprehensive understanding of the mechanism behind TGF-β3 mediated removal of HRS.

Objectives. Optimal treatment strategy for ischemic stroke in patients presenting with tandem occlusions the internal carotid artery remains controversial. Several studies have demonstrated better clinical outcomes after eptifibatide, which is a short half-life antiplatelet agent. This retrospective analysis was focused at safety and efficacy of administration of low-dose eptifibatide in stroke patients with tandem lesions. Methods. We evaluated results of endovascular treatment in 148 stroke patients with tandem lesions. Patients in whom balloon angioplasty alone resulted in satisfactory cerebral flow did not receive eptifibatide (33 patients); others received this drug together with stent implantation (115 patients). Eptifibatide was given in as intravenous bolus 180 g/kg, and then in modified low dose of 1 g/kg/min for 24 hours. Results. There were no statistically significant differences between both groups regarding 30-day mortality, frequency of thrombotic events and hemorrhagic complications. Analysis of clinical status at 30-day follow-up revealed that administration of eptifibatide was associated with statistically significant better outcome: a higher rate of either no neurological symptoms or only mild symptoms (4 NIHSS points maximally). Conclusions. Administration of eptifibatide in stroke patients presenting with tandem lesions is relatively safe. Moreover, treatment with this drug can improve clinical outcomes in these challenging patients.

We compared the functional and morphologic effects in the loading dose between patients with treatment-naïve neovascular age-related macular degeneration treated with either intravitreal aflibercept (IVA) or intravitreal faricimab (IVF) injection in clinical settings. This retrospective study included 30 eyes from 28 patients who started IVA treatment between June and September 2022 and 30 eyes from 29 patients who started IVF treatment between October 2022 and March 2023. The mean best corrected visual acuity (BCVA) significantly improved from pre-treatment after loading dose in the IVA group (from 0.46 ± 0.46 to 0.36 ± 0.37, p=0.0047) and not in the IVF group (from 0.46 ± 0.41 to 0.44 ± 0.45, p=0.60). The mean central retinal thickness (CRT) significantly improved in both groups. The proportion of eyes with residual exudative change was greater in the IVF group than in the IVA group at 2 months after the first treatment. (p=0.026) We further analyzed the patients who obtained complete resolution of exudative changes after the loading dose. The IVA group had a significant improvement in BCVA, whereas the IVF group did not p=0.0047 and 0.20, respectively) Although IVA and IVF significantly improved the CRT, the BCVA improved significantly in IVA group and not in IVF group.

Ecdysterone is a phytosteroid widely discussed for its various pharmacological, growth-promoting and anabolic effects mediated by activation of estrogen receptor beta (ERbeta). Performance-enhancement in sports was demonstrated recently, and ecdysterone was consequently included in the Monitoring Program to detect potential patterns of misuse in sport. Only few studies on the pharmacokinetics of ecdysterone in humans have been reported so far. In this study, post-administration urines in twelve volunteers (single dose of 50 mg of ecdysterone) were analyzed using dilute-and-inject liquid chromatography-tandem mass spectrometry. Identification and quantitation of ecdysterone and of two metabolites, 14-deoxy ecdysterone and 14-deoxy poststerone was achieved. Ecdysterone was the most abundant analyte present in post-administration urines, detected for more than 2 days with a maximum concentration (Cmax) in the 2.8-8.5 h urines (Cmax = 4.4-30.0 µg/mL). The metabolites 14-deoxy ecdysterone and 14-deoxy poststerone were detected later reaching the maximum concentrations at 8.5-39.5 h (Cmax = 0.1-6.0 µg/mL) and 23.3-41.3 h (Cmax = 0.1-1.5 µg/mL), respectively. Cumulative urinary excretion yielded average values of 18%, 2.3% and 1.5% for ecdysterone, 14-deoxy ecdysterone and 14-deoxy poststerone, respectively. Ecdysterone and 14-deoxy ecdysterone were excreted following first order kinetics with half-lives calculated with three hours, while pharmacokinetics of 14-deoxy poststerone needs further evaluation.

While there is a coordinated effort around reaching zero dose children and closing existing equity gaps in immunization delivery, it’s important that there is agreement and clarity around how ‘zero dose status’ is defined and what is gained and lost by using different indicators for zero dose status. There are two popular approaches used in research, program design, and advocacy to define zero dose status: one uses a single vaccine to serve as a proxy for zero dose status, while another uses a subset of vaccines to identify children who have missed all routine vaccines. We provide a global analysis utilizing the most recent publicly available DHS and MICS data to compare the number, proportion, and profile of children 12 to 23 months who are ‘penta-zero dose’ (have not received the pentavalent vaccine), ‘truly’ zero dose (have not received the BCG, polio, pentavalent, and measles vaccines), and ‘misclassified’ zero dose children (those who are penta-zero dose but have received at least one other vaccine). Our analysis includes 194,829 observations from 82 low- and middle-income countries. Globally, 14.2% of children are penta-zero dose and 7.5% are truly zero dose, suggesting that 46.5% of penta-zero dose children have had at least one contact with the immunization system. While there are similarities in the profile of children that are penta-zero dose and truly zero dose, there are key differences between the proportion of key characteristics among truly zero dose and misclassified zero dose children, including access to maternal and child health services. By understanding the extent of connection zero dose children may have with the health and immunization system and contrasting it with how much the use of a more feasible definition of zero dose may underestimate the level of vulnerability in the zero dose population, we provide insights that can help immunization programs design strategies that better target the most disadvantaged populations. If the vulnerability profiles of the truly zero dose children are qualitatively different from that of the penta zero dose children, then failing to distinguish the truly zero dose populations, and how to optimally reach them, may lead to the development of misguided or inefficient strategies for vaccinating the most disadvantaged population of children.

Aim: To investigate the effects of intensive physical exercise on retinal microvascular regulation in healthy volunteers by the adaptive optics retinal camera measurement. Methods: We included healthy volunteers (11 men and 14 women) aged 20.6± 0.9. Heart rate (HR) and systolic and diastolic blood pressure (SBP, DBP) were recorded before and after a submaximal physical exertion of continuously riding a training ergometer. The superior temporal retinal artery measurements were captured using the adaptive optics (AO) camera rtx1TM (Imagine Eyes, Orsay, France) without pupil dilatation. We compared measures of vessel diameter (VD), lumen diameter (LD), two walls (Wall 1, 2), wall-to-lumen ratio (WLR), and wall cross-sectional analysis (WCSA) before and immediately after the cessation of exercise. Results: Cardiovascular parameters: After exercise, SBP, DBP and HR changed significantly from 130.2±13.2 to 159.7±15.6 mm Hg, 81.2±6.3 to 77.1±8.2 mm Hg and 80.8±16.1 to 175.0±6.2 bpm, respectively (p < 0.002). Retinal microcirculation analysis: Before the exercise, the mean LD was 96.0±6.8, VD 118.5±8.3, WLR 0.234±0.02, WCSA 3802.8±577.6. The mean LD and Wall 1 did not change significantly after exercise but slightly decreased. The VD, Wall 2, WLR and WCSA decreased significantly (p

An increase in Spodoptera species was reported in Bt soybean fields expressing Cry1Ac insecticidal proteins in Brazil, requiring additional management with chemical insecticides. Here, we evaluated the dose effects of flubendiamide and thiodicarb on Spodoptera cosmioides (Walker, 1858), Spodoptera eridania (Stoll, 1782), Spodoptera albula (Walker, 1857) and Spodoptera frugiperda (J. E. Smith, 1797) (Lepidoptera: Noctuidae) that survived on MON 87751 × MON 87708 × MON 87701 × MON 89788, expressing Cry1A.105, Cry2Ab2 and Cry1Ac; MON 87701 × MON 89788 soybean, expressing Cry1Ac; and non-Bt soybean. On unsprayed Cry1A.105/Cry2Ab2/Cry1Ac soybean, only S. frugiperda showed ~60% mortality after 10 d, whereas S. cosmioides, S. eridania and S. albula showed >81% mortality. Surviving larvae of all species on this Bt soybean showed &gt;80% mortality when exposed to the field label dose of flubendiamide (70 mL/ha) or thiodicarb (400 g/ha) or at 50% of these doses. In contrast, all four species had <25% and <19% mortality on Cry1Ac and non-Bt soybean, respectively. Surviving S. cosmioides, S. eridania and S. albula on these soybean types presented >83% mortality post-exposure to both dose levels of flubendiamide and thiodicarb. Some S. frugiperda larvae surviving on Cry1Ac and non-Bt soybean sprayed with a 50% dose of either insecticide developed into adults. However, L1 larvae developing on Cry1Ac soybean leaves sprayed with flubendiamide and L2 larvae on this soybean sprayed with thiodicarb had a prolonged immature stage, and females lower fecundity, which are likely to impact its population growth on soybean.

Herpesviruses usurp cellular stress responses to avoid immune detection while simultaneously promoting viral replication and spread. The unfolded protein response (UPR) is an evolutionarily conserved stress response that is activated when the protein load in the ER saturates its chaperone folding capacity causing an accrual of misfolded proteins. Through translational and transcriptional reprogramming, the UPR aims to restore protein homeostasis; however, if this fails the cell undergoes apoptosis. It is commonly thought that many enveloped viruses, including herpesviruses, may activate the UPR due to saturation of the ER with nascent glycoproteins and thus these viruses may have evolved mechanisms to evade the potentially negative effects of UPR signaling. Over the past fifteen years there has been considerable effort to provide evidence that different viruses may reprogram the UPR to promote viral replication. Here we provide an overview of the molecular events of UPR activation, signaling and transcriptional outputs, and highlight key findings that demonstrate that the UPR is an important cellular stress response that herpesviruses have hijacked to facilitate persistent infection.

Flotation of small particles is one of the global challenges facing the mineral raw materials processing industry. Large amounts of non-ferrous and rare metals are lost in the flotation tailings in the form of mineral particles below 15 µm in size as a result of the low effectiveness of their capture by coarse bubbles generated in conventional flotation machines. The method of combined microflotation, which is being developed in recent years, uses not only coarse but also microbubbles (MB) produced in the stand-alone generator of air-in-water microdispersion, which serves as the flotation carriers. Depending on the dose of MB, the effect of their application may be both positive, but also negative. The theoretical analysis of various mechanisms of particle transfer onto the surface of coarse bubbles and further into the froth layer allowed to obtain the formula for the optimal MB dose f=2dddpρp, where dd is MB size; dp and ρp respectively are the size and the density of particles. Experiments performed on the copper ore flotation tailings at the Atalaya Mining (Spain) and Chaarat Kapan (Armenia) concentrators showed that, besides the optimal MB dose in the range of 1-3 ml/g, there is another optimal MB dose in the range of 10-20 ml/g, where the copper recovery increases by several percent compared to the reference test (f= 0). In the area between the optimal MB doses, the deep minimum in copper recovery is observed, which value is by several percent lower compared to the value in the reference test.

The present study aimed to examine the stereoselective pharmacokinetics of racemic ketamine in dogs at low dose. Secondary aims were to identify associated behavioural side effects and propose a ketamine infusion rate. The study was conducted on nine intact male beagles, with each dog undergoing two treatments (BOL and INF). For treatment BOL, a single intravenous bolus of 1 mg/kg racemic ketamine was administered over 2 minutes. The treatment INF involved an initial bolus of 0.5 mg/kg given over 1 minute, followed by an infusion at 0.01 mg/kg/min for 1 hour. Blood samples were collected from the left cephalic vein for pharmacokinetic analysis. The median R/S enantiomer ratio of ketamine remained close to 1 throughout the study. However, levels of S-norketamine were significantly higher than those of R-norketamine across all time points. Based on the collected data, the infusion rate predicted to achieve a steady state racemic ketamine plasma concentration of 150 ng/mL was 1.7 mg/kg/h. Furthermore, employing ROC curve analysis, a racemic ketamine plasma concentration of 102 ng/mL was defined as the cut-off value, correlating with the occurrence of undesirable behavioural patterns.

The total ionizing dose (TID) effect significantly impacts the electrical parameters of fully depleted silicon on insulator (FDSOI) devices and even invalidates the on-off function of devices. At present, most of the irradiation research on the circuit level is focused on the single event effect, and the research on the total ionizing dose effect is very little. Therefore, this study mainly analyzes the influence of TID effects on a CMOS inverter circuit based on 22 nm FDSOI transistors. First, we constructed and calibrated an N-type FDSOI metal-oxide semiconductor (NMOS) structure and P-type FDSOI metal-oxide semiconductor (PMOS) structure. The transfer characteristics and trapped charge distribution of these devices were studied under different irradiation doses. Next, we studied the TID effect on an inverter circuit composed of these two MOS transistors. The simulation results show that when the radiation dose is 400 krad (Si), the logic threshold drift of the inverter is approximately 0.052 V. These results help further investigate the impact on integrated circuits in the irradiation environment.

Background: In Transcranial Direct Current Stimulation (tDCS) the injected current gets distributed across the brain areas. The motive is to stimulate the target region-of-interest (ROI), while minimizing the current in non-target ROIs. For this purpose, determining the appropriate current-dose for an individual is difficult. Aim: To introduce Dose-Target-Determination-Index (DTDI) to quantify the focality of tDCS and examine the dose-focality relationship in three different populations. Method: Here, we extended our previous toolbox i-SATA to the MNI reference space. After a tDCS montage is simulated for a current-dose, the i-SATA(MNI) computes the average (over voxels) current density for every region in the brain. DTDI is the ratio of average current density at target ROI to the ROI with maximum value (peak region). Ideally target ROI should be the peak region, so DTDI shall range from 0 to 1. Higher the value, the better the dose. We estimated the variation of DTDI within and across individuals using T1-weighted brain images of 45 males and females distributed equally across three age groups- (a) Young adults (20 ≥ x ˂ 40 years), (b) Mid adults (40 ≥ x ˂ 60 years), and (c) Older adults (60 ≥ x ˂ 80 years). DTDI’s were evaluated for the frontal montage with electrodes at F3 and right supra-orbital for three current doses 1mA, 2mA, and 3mA with the target ROI at left middle frontal gyrus. Result: As the dose is incremented, DTDI may show (a) increase, (b) decrease, and (c) no change across the individuals. The focality decreases with age and the decline is stronger in males. Higher current dose at older age can enhance the focality of stimulation. Conclusion: DTDI provides information on which tDCS current dose will optimize the focality of stimulation. DTDI recommended dose should be prioritised based on the age (> 40 years) and sex (especially males) of an individual. The toolbox i-SATA(MNI) is freely available.

Synergy of radiation and immune system is currently receiving significant attention in oncology as numerous studies have shown that cancer irradiation can induce strong antitumor immune responses. It remains unclear, however, what are the best radiation fractionation protocols to maximize the therapeutic benefits of this synergy. Here, we present a novel mathematical model that can be used to predict and dissect the complexity of the immune-mediated response at multiple tumor sites after applying focal irradiation and systemic immunotherapy. We successfully calibrate the proposed framework with published experimental data, in which two tumors were grown in mice at two spatially separated sites from which only one was irradiated using various radiation fractionation protocols with and without concurrent systemic immunotherapy. The proposed model is calibrated to fit the temporal dynamics of tumor volume at both sites and can predict changes in immune infiltration in the non-irradiated tumors. The model was then used to investigate additional radiation fractionation protocols. Model simulations suggest that the optimal radiation doses per fraction to maximize antitumor immunity are between 10-13 Gy, at least for the experimental setting used for model calibration. This work provides the framework for evaluating radiation fractionation protocols for radiation-induced immune-mediated systemic antitumor responses.

This letter introduces a frequency response characteristic (FRC) curve and its application in high renewable power systems. In addition, the letter presents a method for fast frequency response assessment and frequency nadir prediction without performing dynamic simulations using detailed models. The proposed FRC curve and fast frequency response assessment method are useful for operators to understand frequency response performance of high renewable systems in real time.

Deep learning image reconstruction (DLIR) algorithms employs convolutional neural networks (CNNs) for CT image reconstruction to produce CT images with a very low noise level, even at low radiation dose. The aim of this study was to assess whether the DLIR algorithm reduces the CT effective dose (ED) and im-proves CT image quality in comparison with filtered back projection (FBP) and iterative reconstruction (IR) algorithms in intensive care unit (ICU) patients. We identified all consecutive patients referred to the ICU of a single hospital who underwent at least two consecutive chest and/or abdominal contrast-enhanced CT scans within a time period of 30 days using DLIR and subsequently FBP or IR algorithm (Advanced Mod-eled Iterative Reconstruction model-based algorithm [ADMIRE], or Adaptive Iterative Dose Reduction 3D [AIDR 3D]) for CT image reconstruction. The radiation ED, noise level, and signal-to-noise ratio (SNR) were compared between the different CT scanners. The non-parametric Wilcoxon test was used for statistical comparison. Statistical significance was set at p < 0.05. A total of 83 patients (mean age, 59 ± 15 years [standard deviation]; 56 men) were included. DLIR vs FBP reduced ED (18.45 ± 13.16 mSv vs 22.06 ± 9.55 mSv, P < 0.05), while DLIR vs FBP and vs ADMIRE and AIDR 3D IR algorithms reduced image noise (8.45 ± 3.24 vs 14.85 ± 2.73 vs 14.77 ± 32.77 and 11.17 ± 32.77\, P < 0.05) and increased SNR (11.53 ± 9.28 vs 3.99 ± 1.23 vs 5.84 ± 2.74 and 3.58 ± 2.74, P < 0.05). CT scanners employing DLIR reduced radiation ED and im-proved SNR compared to CT scanners using FBP, whereas CT scanners using DLIR improved SNR com-pared to CT scanners using FBP or IR algorithms in ICU patients.

Glioblastoma multiforme (GBM), the most prevalent primary malignant brain tumor in adults, exhibits a dismal 6.9% five-year survival rate post-diagnosis. Thymoquinone (TQ), the most abundant bioactive compound in Nigella Sativa, has been extensively researched for its anti-cancer properties across various human cancers. Yet, its specific anticancer mechanisms and pathways in glioblastoma remain to be elucidated. In this study, we assessed the impact of different TQ concentrations on the viability of A172 cells using WST-8 and Toluidine blue assays, followed by RNA sequencing (RNA-seq) to identify differentially expressed genes (DEGs). We confirmed their expression levels through quantitative RT-PCR and performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses for these DEGs. RNA-seq revealed no significant gene expression changes at 2.5 µM and 5 µM TQ concentrations. However, at 25 µM and 50 µM, TQ significantly reduced cell viability in a dose-dependent manner. We identified 1548 DEGs at 25 µM TQ (684 upregulated, 864 downregulated) and 2797 DEGs at 50 µM TQ (1528 upregulated, 1269 downregulated), with 1202 DEGs common to both concentrations. TQ inhibited key pathways such as PI3K-Akt signaling, calcium signaling, focal adhesion, and ECM-receptor interaction in A172 cells. It downregulated several potential oncogenes (e.g., AEBP1, MIAT) and genes linked to GBM proliferation and migration (e.g., SOCS2, HCP5), while modulating Wnt signaling and upregulating tumor suppressor genes (e.g., SPRY4, BEX2). TQ also affected p53 downstream targets, maintaining p53 levels. This study elucidates the anticancer mechanisms of TQ in A172 GBM cells, underscoring its effects on multiple signaling pathways and positioning TQ as a promising candidate for innovative glioblastoma treatment strategies.

After 2010, the source model of the microSelectron HDR Afterloader System was slightly modified from the previous model. Granero et al. named the modified source model “mHDR-v2r (revised model mHDR-v2)” and the previous model “mHDR-v2”. They concluded that the dosimetric differences arising from the dimensional changes between the mHDR-v2 and mHDR-v2r designs were negligible at almost all locations (within 0.5 % for r ≥ 0.25 cm), the two-dimensional anisotropy function difference between the two sources is found 2.1 % at r = 1.0 cm when compared with the results of the other experimental group. To confirm this difference, we performed a full Monte Carlo simulation without the energy fluence approximation. This is useful near the radiation source where charged-particle equilibrium does not hold. The two-dimensional anisotropy function of the TG-43U1 dataset showed a few percent difference between the mHDR-v2r and mHDR-v2 sources. There was no agreement in the immediate vicinity from the source (0.10 cm and 0.25 cm), when compared to Granero et al. in mHDR-v2r sources. The differences in these two-dimensional anisotropy functions were identified.

The effects of tyrosine on plasma response and cognition in aging are unknown. We assessed the dose-dependent response to tyrosine administration in older adults in both plasma tyrosine concentrations and working memory performance. In this double blind randomized cross-over trial 17 older adults (aged 60-75 years) received a single administration of 100, 150 or 200 mg/kg body weight of tyrosine. For comparison, 17 young adults (aged 18-35 years) received a dose of 150 mg/kg body weight of tyrosine. Tyrosine plasma concentrations were determined before and 90, 120, 150, 180, 210 and 240 minutes after tyrosine intake. Working memory was assessed using the N-back task at 90 minutes after tyrosine administration. Older adults showed a dose-dependent increase in plasma tyrosine concentrations (p<.001), and the plasma response was higher than for young adults with the same dose (p<.001). Load-dependent working memory performance decreased with higher doses of tyrosine (p=.048), especially in older adults with greater dose-dependent plasma tyrosine responses (p=.035). Our results show an age-related increase in plasma tyrosine response, which was associated with a dose-dependent decline in cognitive functioning in older adults.

The physiological process of iodine uptake in the thyroid is used for 131I treatment of thyroid diseases. Children are more sensitive to radiation compared to adults and may react differently to 131I exposure. The aims of this study were to evaluate the effects on thyroid protein expression in young and adult rats one year after 131I injection, and identify potential biomarkers related to 131I exposure, absorbed dose, and age. Twelve Sprague Dawley Rats (young and adults) were i.v. injected with 50 kBq or 500 kBq 131I and were killed twelve months later. Twelve untreated rats were used as age-matched controls. Quantitative proteomics, statistical analysis and evaluation of biological effects was performed. The effects of irradiation were most prominent in young rats. Protein biomarker candidates were proposed related to age, absorbed dose, thyroid function and cancer and a panel was proposed for 131I exposure. In conclusion, the proteome of rat thyroid was differentially regulated twelve months after low-intermediate dose exposure to 131I in both young and adult rats. Several biomarker candidates are proposed for 131I exposure, age, and many of them are known to be related to thyroid function or thyroid cancer. Further research on human samples are needed for validation.

Vaccination has proven to be one of the most effective strategies against the COVID 19 pandemic. Several studies have evaluated and confirmed its effectiveness in different populations, particularly in reducing severe outcomes such as hospitalization and death. However, the potential of vaccination to protect against infection itself has been overlooked. The aim of this study was to determine the effectiveness of the booster dose in a sample of Colombian patients during the fourth wave of COVID-19 pandemic, which was associated with the emergence and predominance of the Omicron variant. A cross-sectional study was conducted on individuals who underwent RT-PCR testing for COVID-19 detection in a dedicated laboratory in Bogotá, Colombia, between December 30th 2021 and February 7th 2022. A total of 1,468 subjects were included in the study. The comparison between fully vaccinated individuals with a booster dose and those without the booster dose revealed a 28% reduction in the odds of infection (OR = 0.719 CI 0.531 - 0.971). Age (OR = 1,009 CI 1,001 - 1,018) and low economic status (OR= 1,812 CI 1,416- 2,319) were associated with an increased risk of infection.These findings suggest the need for booster vaccination in the general population to improve the prevention rates of SARS-CoV-2 infection and mitigate severe outcomes.

Introduction The outcome of radiotherapy (RT) for prostate cancer (PCA) depends on the delivered dose. While the evidence for dose-escalated RT up to 80 Gy is well established, there have been only few studies examining dose escalation above 80 Gy. We initiated the presented study to assess the safety of dose escalation up to 84 Gy. Patients and methods In our retrospective analysis, we included patients who received dose-escalated RT for PCA at our institution between 2016 and 2021. We evaluated acute genitourinary (GU) and gastrointestinal (GI) toxicity as well as late GU and GI toxicity. Results A total of 86 patients could be evaluated, of whom 24 patients had received 80 Gy and 62 patients had received 84 Gy (35 without pelvis- and 27 with pelvis-radiotherapy). Regarding acute toxicities, no adverse events > grade 2 occurred. 12.5% of patients treated with 80Gy, in 25.7% of patients treated with 84 Gy excluding pelvis, and in 51.9% of patients treated with 84Gy including pelvis suffered from Grade 2 GU acute toxicity (80 Gy versus 84 Gy: p=0.186; with pelvis versus without pelvis: p=0.032). Grade 2 GI toxicity occurred in 12.5% of patients irradiated with 80Gy, in 14.3% of patients treated with 84 Gy excluding pelvis, and in 12.9% of patients treated with 84Gy including pelvis (80 Gy versus 84 Gy: p=0.582; with pelvis versus without pelvis: p=0.510).GU late toxicity of grade ≥ 2 occurred in 4.2% of patients treated with 80 Gy, in 7.1% of patients treated with 84 Gy excluding pelvic RT, and in 18.2% of patients treated with 84 Gy including pelvic RT (logrank-test p=0.237). 8.3% of patients treated with 80 Gy, in 3.6% of patients treated with Gy excluding pelvic RT, and in 0% of patients treated with 84 Gy including pelvic RT suffered from GI late toxicity of grade ≥ 2(logrank-test p=0.358). Conclusion We were able to show that dose-escalated RT in PCA up to 84 Gy is feasible and safe without asubstantial increase in toxicity. Further follow up is needed to assess survival.

Over a century ago, low-dose-rate (LDR) brachytherapy was introduced to treat prostate cancer (PCa). Since then, it has been widely applied worldwide, including in East Asia. LDR brachythera-py has been performed in 88 institutes in Japan. Beneficial clinical outcomes of LDR brachytherapy for intermediate-to-high-risk PCa have been demonstrated in large clinical trials. These clinical outcomes were achieved through advances in methods, such as urological precise needle puncture and seed placement, and the quantitative decision-making regarding radiological parameters by radiation oncologists. Combined use of LDR brachytherapy with other therapeutical modalities, such as external beam radiation and androgen deprivation therapy, for clinical risk classification of PCa has led to better anticancer treatment efficacy. In this study, we summarized basic LDR brachytherapy findings that should remain unchanged and be passed down in urology depart-ments. We also discussed the applications of LDR brachytherapy for PCa in various clinical settings, including focal and salvage therapies. In addition, we highlighted technologies associated with brachytherapy that are under development.

The severe acquired respiratory coronavirus–2 (SARS–CoV-2) infection has initiated both acute and chronic COVID–19 disease between 2020 and 2022, currently evolving with other homologous prior coronavirus strains of the Nidoviridae order, which encompasses other prevalent alpha/ beta coronaviruses, but also the Middle East Respiratory Syndrome (MERS-CoV) and SARS-CoV-1, with recent SARS–CoV–2 variants, increasing demands for effective immunogens and therapeutic approaches that will reduce global disease burden and further infection from SARS–CoV-2 affected individuals that may experience post acute sequelae (PASC) or “Long COVID”. Following a worldwide programme of prophylactic vaccination, there is still a dilemma in the efforts to find prophylactic and early therapeutic approaches that would treat novel SARS-CoV-2 variants and prevent future epidemics or pandemics within host human and animal populations, where zoonotic or cross species transfer naturally occurs. Concerns about viral immune escape intersect at a specific point; a gained evolutionary ability of several viruses to co–infect and compete against previous scientific advances since 1796 that remain undetected or asymptomatic during the early stages of infection progressing to symptomatic and severe disease through capping of the 5' end of DNA and RNA genomes respectively, which is performed by the activated viral 2’ - O - Methyltransferase (MTase) enzyme, which is a complex of two viral non-structural proteins (NSPs) joined together through an activation process (NSP10/16). Moreover, it was discovered that certain polymorphic viruses translate NSP1, which prevents the activation of various Pattern Recognition Receptors (PRRs), directly silences important interferon-stimulated genes (ISGs), is signalled in a paracrine manner to neighbouring cells, and that induces the apoptosis of host cells, inducing an effect of “trace erase” effect and making the viral infection as immunologically “invisible” as possible during the initial, key stages of viral replication and distribution, all such mechanisms occurring independently of the viruses in cause. Other viral NSPs share a role with NSP1 in directly suppressing the activation of PRRs and ISGs, and all such viral proteins help the virus in its process of self-camouflaging against first- and second-line immunity, thereby often severely impacting the quality of the produced adaptive immune responses. The outcome of all such phenomena is the sharp decrease in the host Type I and Type III interferons' (IFNs) rate of synthesis by the host cells, that would usually occur and affect homeostatic cellular pathways, resulting in further viral replication and induced apoptosis. Nonetheless, effects of microbial immune evasion during the development of other viral or carcinogenic pathologies are not widely known. In short, polymorphic viruses developed a proportionate evolutionary response against developed adaptive immune responses, by currently relying on gaps mostly situated in the natural immune system in their process of molecular self-camouflaging. Scientists developed numerous approaches of early treatment that generally showed good success rates and fewer risks of adverse events, and the still early present stages of COVID-19 research should also be taken into consideration whilst filtering for the most appropriate solutions. For example, the administration of recombinant human interferons I and III into the nasal mucosa cellular layer, as key mediators of anti–viral activity, can simulate intracellular infection and stimulate cellular activity in a timely manner, training the innate and adaptive immune system cells to develop and appropriately stimulate an adequate immune response through B and T cells. Another example could involve the treatment of natural and adaptive lymphocytes with a low dose of IFNs I and possibly III, prior to their insertion into the host lymphatic system, possibly alongside additional recruitment of plasmacytoid dendritic cells (pDCs) as further interferon “factories”, all with the purpose of early infection management. It might be that focusing on directly offering the immune system the information about the genetics and protein structure of the pathogen, rather than training its first-line mechanisms to develop faster, excessively increases its specificity, making it reach a level that brings the virus the opportunity to evolve and escape previously-developed host immune mechanisms. It is until the scientific community realises this potentially crucial aspect that large proportions of the world population will probably continue to face serious epidemics and pandemics of respiratory diseases over the coming several decades, evidenced with dengue fever and more recently, monkeypox and possibly avian flu. Of note, it has been indicated that IFN I and / or III display significant immunising, early therapeutic and clinical disease onset-attenuating effects for many other microbial evoked diseases, as well as for a number of oncological diseases.

A new treatment option for cluster headache (CH) prevention is needed. Monoclonal antibodies (mABs) against calcitonin gene-related peptide (CGRP) ligands are used as a preventative treatment for migraine. Considering the CGRP’s role in the CH attack’s ignition and upkeep, fremanezumab and galcanezumab have been evaluated for CH preventative treatment. However, only high-dose (300 mg) galcanezumab was proven for episodic CH prevention. We herein report 3 cases of migraine and comorbid CH with previous failures of preventive treatments. The 2 cases were treated with fremanezumab and the one with non-high-dose galcanezumab. All 3 cases showed good results not only on migraine but also on CH attacks. Our report suggested the efficacy of CGRP-mABs for CH prevention. Our cases differed from the cases in the phase 3 trials of CGRP-mABs for CH prevention in the following 2 points. First, the patients had both migraine and comorbid CH. Second, the combined use of CGRP-mABs with preventative drugs for CH, such as verapamil and/or prednisolone, was performed. Future accumulation of real-world data may prove the efficacy of CGRP-mABs for CH prevention.

Coronavirus 2019 (COVID-19) is an infectious disease that is becoming a pandemic. Hydroxychloroquine in combination with azythromycin are among drugs currently in use to eradicate COVID-19. Despite concerns due to its potential cardiac toxicity, hydroxychloroquine is widely accepted in mild and moderate COVID-19 pneumonia. In this case report, we report a case of a young Indonesian adult male with suspected COVID-19 pneumonia who received hydroxychloroquine and azythromycin therapies and during 24 hour experienced deterioration of atrioventricular block.

The demographic profile of patients transitioning from chronic kidney disease to renal replacement therapy is changing, with a higher prevalence of aging patients with multiple comorbidities such as diabetes mellitus and heart failure. Cardiovascular disease remains the leading cause of mortality in this population, exacerbated by the cardiovascular stress imposed by the HD procedure. The first year after transitioning to hemodialysis is associated with increased risks of hospitalization and mortality, particularly within the first 90–120 days, with greater vulnerability observed among the elderly. This review, based on data from clinics of Fresenius Medical Care Europe, Middle East, and Africa NephroCare, aims to optimize hemodialysis procedures to reduce mortality risk in stable incident and prevalent patients. It addresses critical aspects such as treatment duration, frequency, choice of dialysis membrane, dialysate composition, blood and dialysate flow rates, electrolyte composition, temperature control, target weight management, dialysis adequacy, and additional protocols, with a focus on mitigating prevalent intradialytic complications, particularly intradialytic hypotension prevention.

Interferons were the original prototype cytokine system discovered in 20th-century research. As the name implies, they were originally thought to be synthesised and secreted between cells. Thanks to technological advances, the processes involved in protein secretion can be explained comparatively more clearly at both the genetic and biochemical levels. The discovery of interferon (IFN) occurred when genetic research was still in its infancy. Franklin and Wilkins discovered the structure and function of deoxyribonucleic acid (DNA) at the same time as Crick and Watson; however, Isaacs and Lindemann, two scientists, described the first IFN in 1957. Mutations can be caused by inherent genetic protein synthesis and during infection as well as within IFN regulation pathways affecting cell proliferation. This remains central to host cell IFN synthesis and effects through IFN protein receptor subunits defined by 6 protein domains. Type II IFN is key to immune cell function secreted by a variety of immune cells, mainly natural killer (NK) as well as T cells. Single–stranded and/or double–stranded RNA/DNA viruses, as well as bacterial infections (e.g., Escherichia coli) and fungal infections (e.g., Aspergillus), also affect IFN regulation. Pathogenic proteins utilise intra/extracellular proteins that sense foreign antigens like Toll–like Receptors (TLRs), affected by mutations within the human cellular IFN transduction pathways. Since the discovery of the third IFN type in 2003, when immune cell phenotypes were further characterised, questions remain about the immunological mechanisms contributing to the regulation of the innate and adaptive host immune system. Alterations in the synthesis of type I/II/III host IFNs can differentially and beneficially alter homeostatic cellular pathways in pathological disease, with type I IFN being synthesised in cancer as well as by homeostatic cells. Therefore, considered here are the overall IFN molecular, cell regulatory mechanisms in the context of immune cell research developments.

This study addresses the challenge of assessing the carcinogenic potential of hazardous chemical mixtures, such as PFAS, which are known to contribute significantly to cancer development. Here, we propose a novel framework called HNNMixCancer that utilizes a Hybrid Neural Network (HNN) integrated into a machine-learning framework. This framework incorporates a mathematical model to simulate chemical mixtures and enables the creation of classification models for binary and multiclass classification and regression. Through extensive experimentation, we demonstrate that our HNN model outperforms other methodologies, including Random Forest, Bootstrap Aggregating, Adaptive Boosting, Support Vector Regressor, Gradient Boosting, Kernel Ridge, Decision Tree with AdaBoost, and KNeighbors, achieving a superior accuracy of 92.7% in binary classification. To address the limited availability of experimental data and enrich the training data, we generate an assumption-based virtual library of chemical mixtures using a known carcinogenic and non-carcinogenic single chemical for all the classification models. Remarkably, in this case, all methods achieve accuracies exceeding 98% for binary classification. In external validation tests, our HNN method achieves the highest accuracy of 80.5%. Furthermore, in multiclass classification, the HNN demonstrates an overall accuracy of 96.3%, outperforming RF, Bagging, and AdaBoost, which achieved 91.4%, 91.7%, and 80.2%, respectively. In regression models, HNN, RF, SVR, GB, KR, DT with AdaBoost, and KN achieve average R2 values of 0.96, 0.90, 0.77, 0.94, 0.96, 0.96, and 0.97, respectively, showcasing their effectiveness in predicting the concentration at which a chemical mixture becomes carcinogenic. Our method exhibits exceptional predictive power in prioritizing carcinogenic chemical mixtures, even when relying on assumption-based mixtures. This capability is particularly valuable for toxicology studies that lack experimental data on the carcinogenicity and toxicity of chemical mixtures. To our knowledge, this study introduces the first method for predicting the carcinogenic potential of chemical mixtures. The HNNMixCancer framework offers a novel alternative for dose-dependent carcinogen prediction. Ongoing efforts involve implementing the HNN method to predict mixture toxicity and expanding the application of HNNMixCancer to include multi-mixtures.

The major stress-inducible Hsp70 (HSPA1A) is overexpressed in the cytosol of many highly aggressive tumor cells including glioblastoma multiforme and presented on their plasma membrane. Depending on its intracellular or membrane localization, Hsp70 either promotes tumor growth or serves as a target for NK cells. The kinetics of the membrane Hsp70 (mHsp70) density on human glioma cells (U87) was studied after different irradiation doses to define the optimal therapeutic window for Hsp70-targeting NK cells. To maintain the cells in the exponential growth phase during a cultivation period of 7 days different initial cell counts were seeded. Although cytosolic Hsp70 levels remained unchanged on days 4 and 7 after a sublethal irradiation with 2 Gy, 4 Gy and 6 Gy, a dose of 2 Gy resulted in an upregulated mHsp70 density in U87 cells which peaks on day 4 and starts to decline on day 7. Higher radiation doses (4 Gy, 6 Gy) resulted in an earlier and more rapid onset of the mHsp70 expression on days 2 and 1, respectively, followed by a decline on day 5. Membrane Hsp70 levels are higher in G2/M than in G1, however, an irradiation-induced cell cycle arrest on days 4 and 7, was not associated with an increase in the mHsp70 density. Extracellular Hsp70 concentrations increased significantly compared to sham (0 Gy) irradiated cells on days 4 and 7 but not on day 1. Functionally, elevated mHsp70 densities were associated with a significantly better lysis by Hsp70-targeting NK cells. In summary, the kinetics of changes in the mHsp70 density upon irradiation on tumor cells is time- and dose-dependent.

Dermal penetration is considered to mainly occur via passive diffusion. Therefore, a high concentration gradient of dissolved active ingredient between formulation and skin is needed to achieve an effective dermal penetration. The concentration gradient between formulation and skin can be changed by changing the amount of dissolved active ingredient in the formulation. In case of poorly soluble active ingredients this can be achieved by using nanosized drug material instead of larger sized material. The smaller size and the resulting larger surface increase the kinetic solubility and thus increase the concentration gradient of dissolved active ingredient between formulation and skin, which then results in an increased dermal penetration. In this study we demonstrated that the concentration gradient between formulation and skin can also be influenced by the number of particles being present in the formulation and by the dose (volume of formulation) applied to the skin. Particles of undissolved active ingredient are known to act as a reservoir by releasing dissolved molecules in the liquid phase of the formulation. It could now be demonstrated that the particles - once the liquid in which they are dispersed evaporates - can connect to the skin via an aqueous meniscus. The aqueous meniscus contains dissolved active ingredient and therefore creates a small local spot with a locally high concentration gradient and improved dermal penetration. Therefore, the dermal penetration can be increased with formulations that contain high amounts of particles. This can be achieved by applying formulations with high numbers of particles and/or by applying larger volumes of particle containing formulations to the skin.

Folic acid, one of the 13 essential vitamins, plays an important role in cardiovascular development. Mutations in folic acid synthesis gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is significantly associated with the occurrence of congenital heart disease. However, the mechanisms underlying the regulation of cardiac development by mthfr gene are poorly understood. Here, we exposed zebrafish embryos to excessive folate or folate metabolism inhibitors. And we established a knock-out mutant of mthfr gene in zebrafish by using CRISPR/Cas9. The zebrafish embryos of insufficient or excessive folic acid, and mthfr-/- mutant all gave rise to early pericardial edema and cardiac defect at 3 days after fertilization(dpf). Furthermore, the folic acid treated embryos showed abnormal movement at 5dpf. The expression levels of cardiac marker genes hand2, gata4 and nppa changed in the abnormality of folate metabolism embryos and mthfr-/- mutant, and there is evidence that they are related to the change of methylation level caused by the change of folate metabolism. In conclusion, our study provides a novel model for the in-depth study of MTHFR gene and folate metabolism. And our results reveal that folic acid has a dose-dependent biphasic effect on early cardiac development.

Critical care of neonates involves substantial usage of antibiotics and exposure to multidrug resistant (MDR) nosocomial pathogens. These pathogens are often exposed to sub-MIC doses of antibiotics which might result in a range of physiological effects. Therefore, to understand the outcome of sub-inhibitory dosage of antibiotics on Staphylococcus populations, nasal swab specimens were collected from 34 neonates admitted to the Sick Newborn Care Unit between 2017-2018, a total of 41 non-repetitive isolates were included in this study. Staphylococcus haemolyticus was the prevalent species (58.54%) with high non-susceptibility to cefotaxime (CTX) (79.16%), gentamicin (87.50%), and meropenem (54.17%). Biofilm forming abilities of S. haemolyticus isolates in the presence of sub-optimal CTX (30μg/mL), the predominantly prescribed β-lactam antibiotic, were then determined by crystal violet assays and extracellular DNA (eDNA) quantitation. CTX was found to significantly enhance biofilm production among the non-susceptible isolates (p-valueWilcoxin test- 0.000008) with increase in eDNA levels (p-valueWilcoxin test- 0.000004). Additionally, no changes in non-susceptibility were observed among populations of two MDR isolates, JNM56C1 and JNM60C2 after >500 generations of growth in the absence of antibiotic selection in vitro. These findings demonstrate that sub-MIC concentration of CTX induces biofilm formation and short-term non-exposure to antibiotics does not alter non-susceptibility among S. haemolyticus isolates.

A novel coronavirus strain (severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first appeared in December 2019 and can cause acute respiratory distress syndrome and death. However, there are only limited therapy choices and no vaccine for SARS-CoV-2 is currently available. Here we report about a case of a SARS-CoV-2 caused pneumonia successfully treated with thalidomide. Thalidomide is an immunomodulatory and anti-inflammatory agent and was combined with a low-dose glucocorticoid. We suggest, that the effects of thalidomide might be related to regulating immunity, inhibiting the inflammatory cytokine surge, alleviating anxiety to reduce oxygen consumption, relieving vomit and lung exudation.

This report covers the analysis of Intrusion Detection Systems nowadays. Therefore, it focuses on the IDS classification, which includes not only a well-known explanation of Network/Host-Based IDS type but also cloud-based solutions. The paper explores ways of intrusion detection, providing examples of the best detecting tools (OSSEC, Snort or Bro (ZEEK)). Another aspect covered in this report is the juxtaposition of three systems: IDS, IPS and IRS and their response. Finally, there will be presented Intrusion Detection Systems' evasion techniques and challenges, followed by critical conclusions.

We aimed to directly compare the cost-effectiveness of the NELSON and NLST screening protocols, two trials influencing lung cancer screening implementation internationally. A decision-analytic model analyzing the cost-effectiveness of the NELSON protocols was manipulated to reflect the protocols of the NLST, while maintaining features specific to the Hungarian healthcare setting. In the NELSON protocol, there are three possible outcomes to the initial round of screening: positive, negative, or indeterminate, indicating an uncertain degree of suspicion for lung cancer. This pro-tocol differs from the NLST protocol, in which the only possible screening outcomes are positive or negative, with no indeterminate option. The NLST pathway for smokers aged 55-74 resulted in a 43 € increase in total average lifetime costs compared to the Hungarian screening pathway and re-sulted in a lifetime gain of 0.006 QALYs. The incremental costs and QALYs yield an ICER of 7875 €/QALY. Our results demonstrate that assigning any suspicious LDCT screen as a positive result (NLST protocol) rather than indeterminate (NELSON protocol) can yield a slight QALY gain that is worth the additional use of resources according to Hungary’s willingness to pay threshold. Our study provides insight on the cost-effectiveness, advantages, and disadvantages of various LDCT screening protocols for lung cancer and can assist other countries as they implement their screening programs.

This mini-review explores the comparative efficacy, safety, and clinical outcomes of high-dose proton pump inhibitor (PPI) intravenous infusion versus oral acid pump inhibitor therapy following endoscopic treatment for bleeding peptic ulcers. Recent evidence suggests that intravenous PPIs can significantly reduce the rebleeding rates within the critical first 72 hours post-intervention, with a noted rebleeding rate of 6% compared to 14% in patients receiving oral Vonoprazan (VPZ) therapy. Additionally, the rapid onset of action associated with intravenous administration leads to faster stabilization of vital signs and a reduced need for subsequent blood transfusions. Safety profiles for both intravenous and oral VPZ were favourable, with minimal adverse effects, the most common being transient headaches.However, the findings from our single-centre study with a moderate sample size prompt consideration of more extensive, multicentre trials to enhance the generalizability of the results. Current limitations include potential biases, short-term focus, missing data issues, and a need for long-term outcome data, necessitating further research. Future studies should also explore the cost-effectiveness of intravenous versus oral VPZ and the impact on patient quality of life and long-term mortality rates.This review underscores the importance of tailored PPI therapy in managing bleeding peptic ulcers post-endoscopy. It suggests a potentially pivotal role for intravenous PPIs in high-risk patient groups, advocating for a shift towards more aggressive and immediate care protocols in specific clinical settings.

This study assessed the performance of low-dose CT lung scans across various acquisition parameters and examined the impact of iterative reconstruction (IR) algorithms on image quality for lung cancer screening. The performance of multi-slice CT scanners was assessed by using a Catphan 600 phantom, specifically within the CTP404 test module that contains materials like Teflon, Delrin, Acrylic, Polystyrene, LDPE, PMP, Air, and water. Three protocols were selected and categorized into standard, low dose, and ultra-low dose. The standard protocol featured a tube voltage of 100 kVp for single-detector CT, a pitch of 0.75, detector collimation of 0.60 mm, and a gantry rotation time of 0.33 seconds, with 5 mm slice thickness. Images were reconstructed using standard kernels like B80f and 170f, combined with either FBP or various IR algorithms. Findings indicated that the noise power spectrum (NPS) peak value (HU2mm2) increased with higher IR levels, with FBP showing the highest peak. Additionally, NPS spatial frequency diminished as IR levels rose. Optimizing contrast and spatial resolution for both background and regions of interest involved adjusting the target transfer function (TTF) and contrast-to-noise ratio (CNR), crucial for protocol optimization. Proper adjustment of IR levels is vital, as higher levels can alter image texture and affect NPS spatial frequency. The results of this study showed that the use of IR algorithms in low-dose CT lung scans significantly improved image quality, particularly in terms of noise reduction and spatial resolution. However, the choice of acquisition parameters also played a crucial

Our hypothesis that controlled ozone applications interfere into the redox balance of the biological organism (first published in 1998 with a preclinical trial on protecting the liver from CCl4 intoxication), has been verified over the last 2 decades in reactive oxygen species (ROS)-induced mitochondrial pathologies, such as rheumatoid arthritis, osteoarthritis, aging processes, diabetes-2 and in prevention of intoxications. Low-dose ozone acts as a redox bioregulator: The restoration of the disturbed redox balance is comprehensible in a number of preclinical and clinical studies by a remarkable increase of the antioxidant repair markers, here mainly shown as glutathione increase and a reduction in oxidative stress markers, mainly malondialdehyde. The mechanism of action is shown, relevant data are displayed, evaluated and comprehensively discussed: The repair side of the equilibrium increases by 21% up to 140% compared to the non-ozone treated groups and depending on the indication; the stress markers are simultaneously reduced, the redox system regains its balance.

This retrospective study aimed to evaluate the impact of radiation dose on the outcomes of stereotactic radiosurgery (SRS) for benign meningiomas and determine an optimal dosing strategy for balancing tumor control and treatment-related toxicity. Clinical data of 147 patients with 164 lesions treated between 2014 and 2022 were reviewed. Primary outcomes included progression-free survival (PFS), local control rate (LCR), and radiation-induced toxicity, with secondary outcomes focusing on LCR and radiation-induced peritumoral edema (PTE) in two dose groups (≥14 Gy and &lt;14 Gy). Results revealed a median follow-up duration of 47 months, with 1-year, 2-year, and 5-year PFS rates of 99.3%, 96.7%, and 93.8% respectively, and an overall LCR of 95.1%. Radiation-induced toxicity was observed in 24.5% of patients, primarily presenting mild symptoms. Notably, no significant difference in LCR was found between the two dose groups (P = 0.628), while Group 2 (&lt;14 Gy) exhibited significantly lower PTE (P = 0.039). The study concludes that SRS with a radiation dose &lt;14 Gy demonstrates comparable tumor control with reduced toxicity, advocating for consideration of such dosing to achieve a balance between therapeutic efficacy and safety.

Background: Computed tomography examinations have produced high radiation doses to patients, especially the CT brain. This study aimed to optimize the radiation dose and image quality in adult CT brain protocol. Materials and Methods: Images were acquired by Catphan 700 phantom. Radiation doses were recorded as CTDIvol and dose length product (DLP). CT brain protocols were optimized by varying parameters such as kVp, mAs, signal-to-noise ratio (SNR) level, and Clearview iterative reconstruction (IR). Image quality were also evaluataion by The AutoQA Plus software. Results: CT Number accuracy and linearity had a robust positive correlation with the linear attenuation coefficient (µ) and showed more inaccurate CT numbers when using 80 kVp. MTF showed a higher value in 100 and 120 kVp protocols, while high contrast spatial resolution showed a higher value in 80 and 100 kVp protocols. Low contrast detectability and CNR tended to increase when using high mAs, SNR and Clearview IR protocol. Noise decreased when using a high radiation dose and a high percentage of Clearview IR. CTDIvol and DLP were increased with increasing kVp, mAs, and SNR levels, while the increasing percentage of Clearview did not affect the radiation dose. Conclusion: Optimized protocols, including radiation dose and image quality, should be evaluated to preserve diagnostic capability. The recommended parameter settings include kVp set between 100-120 kVp, mAs ranging from 200-300 mAs, SNR level within the range of 0.7-1.0, and an iterative reconstruction value of 30% Clearview to 60% or higher.

The best form of prevention against human infection through bacteria, viruses and other parasites is ozone disinfection of wastewater and drinking water as a highly effective, well-known method. As a therapeutic measure, various preclinical studies showed promising results, which are being revisited and reconsidered in times of pandemics and led to interesting results in recent clinical trials and reports, as presented by the example of protective measures against covid-19 in particularly vulnerable clinical personnel. In patients with rheumatoid arthritis, repeated ozone treatments have led to new findings in the "immunomodulation" through ozone. The more effective immune response is discussed as the response of innate immune memory and opens interesting aspects for complementary treatment of autoimmune diseases.

Local anaesthetic agents suppress action potentials in excitable tissues by blocking voltage-gated sodium channels. In doing so they inhibit the depolarisation of nociceptive nerve fibres and so prevent the transmission of pain impulses. UK legislation allows HCPC-registered Podiatrists with POM-A annotation access to six local anaesthetic drugs and two of these with the addition of adrenaline. The use of local anaesthetia has transformed the treatment of nail pathology by Podiatrists. In the UK, the drug of choice in podiatric practice is 3% mepivacaine hydrochloride: it is a good choice of drug for digital anaesthesia. This paper will review the chemistry, pharmacology and dose calculation of mepivacaine, and challenge some of the orthodoxy over the rigid calculation of maximum safe dosages.

Background: Rituximab is a monoclonal antibody widely used in the treatment of inflammatory and autoimmune disorders. Despite reports of its effectiveness in the treatment of demyelinating diseases of central nervous system (DDCNS), it is not yet approved for use in these disorders. The aim of this study was to investigate the effectiveness and safety of low dose rituximab in three different subgroups of DDCNS including relapsing-remitting multiple sclerosis (RRMS), secondary-progressive multiple sclerosis (SPMS) and neuromyelitis-optica-spectrum disorders (NMOSD).Methods: In a prospective cohort study, we monitored expanded-disability-status-scale (EDSS), relapses (new attacks) and serum-IgG levels to assess effectiveness and drug-adverse-events for safety in patients with RRMS, SPMS and NMOSD. These patients were candidates to receive rituximab according to our common practice protocol. We switched patients to rituximab if there was poor response to first line therapies. We follow a low dose protocol in our center (500 mg twice, two weeks apart, repeating every six months) and these patients treated in a 4-year period were assessed retrospectively for evaluation of our protocol’s safety and effectiveness. Results: 99 patients (42 RRMS, 43 SPMS and 14 NMOSD) received rituximab for a range of 12 to 40 months period. New attacks occurred in 8 RRMS (19%), 10 SPMS (23%) and 1 NMOSD (7%) patients. EDSS decreased in RRMS and NMOSD cases. Serum-IgG levels decremented in SPMS and NMOSD patients. Drug-adverse-events happened in two cases.Conclusion: In this study, low dose rituximab showed substantial effectiveness in preventing disease progression with a considerably good safety profile.

A single dose of psilocybin, a psychedelic and serotonin 2A receptor (5-HT2AR) agonist, may be associated with antidepressant effects. The mechanism behind its antidepressive action is unknown but could be linked to increased synaptogenesis and down-regulation of cerebral 5-HT2AR. Here, we investigate if a single psychedelic dose of psilocybin changes synaptic vesicle protein 2A (SV2A) and 5-HT2AR density in the pig brain. Twenty-four awake pigs received either 0.08 mg/kg psilocybin or saline intravenously. Twelve pigs (n=6/intervention) were euthanized one day post-injection, while the remaining twelve pigs were euthanized seven days post-injection (n=6/intervention). We performed autoradiography on hippocampus and prefrontal cortex (PFC) sections with [3H]UCB-J (SV2A), [3H]MDL100907 (5-HT2AR antagonist) and [3H]Cimbi-36 (5-HT2AR agonist). One day post psilocybin injection, we observed 4.4% higher hippocampal SV2A density and lowered hippocampal and PFC 5-HT2AR density (-15.21% to -50.19%). These differences were statistically significant in the hippocampus for all radioligands and in PFC for [3H]Cimbi-36 only. Seven days post-intervention, there was still significantly higher SV2A density in hippocampus (+9.24%) and PFC (+6.1%) whereas there were no longer any differences in 5-HT2AR density. Our findings suggest that psilocybin’s antidepressive actions are linked to increased persistent synaptogenesis and possibly also to an acute decrease in 5-HT2AR density.

Self-report measurement is frequently used in human sports to assess training adaptations [1, 2]. This is a technique novel to the equestrian sport. The aim of this study was to describe how elite event riders of Germany evaluate their own fitness as well as that of their horses for the entire duration of an eventing season. Additionally, correlations with possible influencing external factors such as type of training or duration of grazing were also investigated. Short online questionnaires were used to allow eight riders to describe the training of their horses. Five criteria (general performance, ability to concentrate, general state of mind, general muscular condition and emotional wellbeing) were used to assess both, their horse's, as well as their own wellbeing. A 1-10 rating scale was used to score each criterion resulting in an average of 38 points out of 50 (maximum wellbeing) for horse (Std. dev. 0.55) and rider (Std. dev. 0.65) respectively. A total of 120 questionnaires were analysed. A correlation could be demonstrated (Spearman's correlation coefficient = 0.5) between rider and horse score, whereby it only became a linear correlation above 30 points. In addition, the horse score correlates positively with its success at competitions. While the horses were rated similarly throughout the season, the riders’ perceived welfare was higher in the middle of the season compared with the beginning and end of the season. Regularly turned-out horses resulted in higher horse scores (Linear mixed model, p=0,04, n=120). It can be concluded that the self-report measurement of fatigue and wellbeing can be a useful tool for trainers and riders to better determine the horse’s fatigue and recovery. It should be noted that external factors influence both, rider and horse assessment.

Firocoxib is a non-steroidal anti-inflammatory drug specifically formulated for veterinary medicine and selectively acts on inhibiting the cyclooxygenase 2 enzyme(COX-2). This study aimed to evaluate the possible adverse effects of administering oral therapeutic firocoxib on gastric mucosa, hematological parameters, coagulation cascade, and hepatic and renal biochemistry in healthy horses. Nine clinically healthy Arabian horses, approximately nine years old, received 0.1mg/kg of oral firocoxib for 14 days. Before beginning treatment, a gastroscopic examination was conducted, and venous blood samples were obtained for laboratory tests on D0. Follow-up blood samples and gastroscopic examinations were taken on D7 and D14 after starting treatment and one week after completing treatment on D21. No changes were found in the gastroscopic and hematological tests. Additionally, coagulation and serum biochemistry levels remain between normal values for this particular species. However, the increased activated partial thromboplastin time (aPTT) and prothrombin time (PT) indicate reduced blood coagulation capacity, which contradicts the expected effect of treatment with selective COX-2 inhibitors, as these drugs theoretically promote coagulation. Administering Firocoxib to horses is safe as it does not cause any significant adverse reactions. Therefore, it is a suitable option for managing inflammatory conditions in these animals.

Water stress (WS) and heat stress (HS) have a negative effect on soybean plant growth and crop productivity. During WS, soybean plants opt for survival through ion homeostasis and the conformations of proteins are disconcerted as plant cells lose water while HS leads to difficulties in flowering and fruiting. Some of these changes include oxidative stress leading to the destruction of photosynthetic apparatus, macromolecules within cells and the onset of complex signaling cascades. Changes in the physiological characteristics, proteome, and certain metabolites investigated on molecular and cellular functions were studied in two soybean cultivars exposed to different heat and water stress conditions independently and in combination. Leaf protein composition was studied using 2-DE and complemented with MALDI TOF mass spectrometry. While two cultivars displayed genetic variation in response to water and heat stress, thirty-nine proteins were significantly altered in their relative abundance in response to WS, HS and combined WS+HS in both cultivars; a majority of them involved in metabolism, response to heat and photosynthesis showing significant cross-tolerance mechanisms. Functional analysis revealing a majority of heat responsive-proteins were more abundant during HS and combined stress (WS+HS) whereas these proteins were low to WS in cultivar PI 471938 and heat shock proteins were in low abundance to water, heat and combined stresses in cultivar R95-1705. Most protein abundances were not correlated with their expression at mRNA levels in PI cultivar, however, in cultivar R 95, the expression levels of transcript follow their relative abundance in proteins. Our systems bioinformatics analyses revealed that MED37C, a probable mediator of RNA polymerase transcription II protein showed potential interacting partners in Arabidopsis and our studies signifies the marked impact of this protein in PI cultivar. Elevated activities in antioxidant enzymes indicate that the PI-371938 cultivar has the ability to restore the oxidation levels and sustain the plant during the stress. Our study hypothesizes the plant’s development of cross-stress tolerance which will help foster the ongoing ventures in genetic modifications in stress tolerance.

Resistance evolution during exposure to non-lethal levels of antibiotics is influenced by various stress responses of bacteria which are known to affect growth rate. Here, we aim to disentangle how the interplay between resistance development and associated fitness costs is affected by stress responses. We performed de novo resistance evolution of wild-type strains and single-gene knockout strains in stress response pathways using four different antibiotics. Throughout resistance development, the increase in minimum inhibitory concentration (MIC) is accompanied by a gradual decrease in growth rate, most pronounced with amoxicillin or kanamycin. By measuring biomass yield on glucose and whole-genome sequences at intermediate and final timepoints, we identified two patterns of how the stress responses affect the correlation between MIC and growth rate. First, single-gene knockout E. coli strains associated with reactive oxygen species (ROS) acquire resistance faster and mutations related to antibiotic permeability and pumping out occur earlier. This increases the metabolic burden of resistant bacteria. Second, the ΔrelA knockout strain which has reduced (p)ppGpp synthesis, is restricted in its stringent response, leading to diminished growth rates. The ROS-related mutagenesis and the stringent response are vulnerabilities within the fitness of resistant strains that can possibly be targeted to prevent development of resistance.