Doravirine (DOR) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with efficacy against some NNRTI resistant mutants. Although DOR resistance mutations are established for HIV-1 subtype B, it is less clear for non-B subtypes. This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others didn’t significantly impact DOR susceptibility. We observed agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y188L caused high-level resistance, in agreement with the predictions. These mutations are frequently observed in patients failing efavirenz or nevirapine-based first-line regimens. However, they are also observed in those failing a protease inhibitor-based second-line regimen, as we have observed in our database. Genotypic drug resistance testing is therefore vital prior to initiation on DOR-based treatment for those previously exposed to efavirenz or nevirapine.

Several studies with kaempferol (KP) and linearolactone (LL) have shown antiparasitic activities. However, the toxicity of treat-ments with both active principles is unknown. Therefore, this study aimed to evaluate the toxicological effects of treatments with KP and LL on the amoebic liver abscess (ALA) model in M. auratus administered intraperitoneally (i.p.). For this, ALA in-duction was carried out in male hamsters with 1.5 x105 E. histolytica trophozoites inoculated in the left hepatic lobe. The lesion evolved for four days and the i.p. of the treatments with KP (5 mg/kg body weight/day) and LL (10 mg/kg body weight/day) was carried out for four consecutive days. For histopathological evaluation, NMR studies, paraclinical analysis, and necropsy were performed. The results revealed that the inhibition of ALA by KP and LL were similar to that metronidazole (MTZ). Biochemical parameters revealed hepatic and renal alterations in all treatment groups, mainly for KP (AST and BUN). The lesions found in the organs were those that are directly linked to the pathology. In conclusion, KP and LL decrease ALA development but have few toxicological effects. Both compounds combined with MTZ could be therapeutic alternatives for amoebiasis caused by E. histolytica.

New antiviral agents are essential to improving treatment and control of SARS-CoV-2 infections that can lead to the disease COVID-19. Antimicrobial peptoids are sequence-specific oligo-N-substituted glycine peptidomimetics that emulate the structure and function of natural antimicrobial peptides but are resistant to proteases. We demonstrate antiviral activity of a new peptoid (TM9) against the coronavirus, murine hepatitis virus (MHV), as a closely related model for the structure and antiviral susceptibility profile of SARS-CoV-2. This peptoid mimics the human cathelicidin LL-37, which has also been shown to have antimicrobial and antiviral activity. In this study TM9 was effective against three murine coronavirus strains, demonstrating the therapeutic window is large enough to allow use of TM9 for treatment. All three isolates of MHV generated infection in mice after 15 min of exposure by aerosol using the Madison aerosol chamber and all three viral strains could be isolated from the lungs throughout the 5-day observation period post-infection, with the peak titers on day 2. MHV-A59 and MHV-A59-GFP were also isolated from liver, heart, spleen, olfactory bulbs, and brain. These data demonstrate that MHV serves as a valuable natural murine model of coronavirus pathogenesis in multiple organs, including the brain.

This study delves into the dynamic field of medical education research, emphasizing the integration of research training within medical curricula. It seeks to understand the impact of such integration on the competencies of future medical professionals. The primary aim is to systematically categorize and analyze the current trends and future directions in medical education research. This involves assessing the influence of research training on medical students' skills and the methodologies used in such research. Methods: The research employs an extensive bibliographic literature review across multiple databases. It classifies studies into categories like experiential or case studies, editorials, and original research articles. This classification is based on criteria such as geographical location, research objectives, theoretical frameworks, and methodologies. Results: Findings reveal a diverse landscape in medical education research, with a significant emphasis on research training. The research showcases varying methodologies and approaches used globally, highlighting the thematic focus and geographical distribution of these studies. Conclusion: Medical education research is a globally expansive and evolving field. It underscores the importance of continuous investigation, particularly focusing on integrating research elements at curricular levels and exploring innovative educational strategies. The study also points out potential gaps in research, especially in underrepresented regions, indicating directions for future research efforts.

Elizabethkingia anophelis is an opportunistic pathogen causing lifethreatening infections in humans, particularly in immunocompromised patients, neonates and elderly. Infections caused by this species are exceptionally challenging to treat due to its multiresistance to antimicrobials. We report a case of central line-associated bloodstream infection by E. anophelis in a 2.5-year-old girl with acute lymphoblastic leukemia successfully treated with a combination of piperacillin/tazobactam and amikacin. The literature was also reviewed on paediatric infections caused by E. anophelis. Accurate identification with MALDI-TOF, or using molecular techniques, is crucial because of varying susceptibilities among species. Early, accurate diagnosis and prompt effective treatment optimize outcomes.

Vaccine antigens must present the correct conformation of viral fusion glycoproteins to elicit effective immune responses. Virus-like particles (VLPs) serve as promising vaccine platforms because they mimic the membrane-embedded conformations of fusion glycoproteins on native viruses. Here, we employed SARS-CoV-2 VLPs (SMEN) presenting ancestral, Beta, or Omicron spikes to identify the variant that elicits potent and cross-protective immune responses in the highly sensitive K18-hACE2 mouse model. A combined intranasal and intramuscular administration regimen of the SMEN vaccine generated effective immune responses and was predominantly mediated by antibodies with minor contributions from T cells. Immunization with SMEN presenting an ancestral spike resulted in 100, 75, or 0% protection against ancestral, Delta or Beta VOC-induced mortality, respectively, whereas SMEN presenting the most divergent Omicron spike provided only limited protection (50%, 0%, and 25%) against ancestral, Delta, and Beta variants, respectively. By contrast, SMEN with a Beta spike offered 100% protection against the variants used in this study. Thus, the Beta variant not only overcame the immunity produced by other variants, but also elicited diverse and effective immune response. Our findings suggest that leveraging the Beta variant spike protein can enhance SARS-CoV-2 immunity, potentially leading to a more comprehensive vaccine against emerging variants.

Psoriasis is a chronic recurrent inflammatory autoimmune pathology, with a major genetic component and several interferences of immunological cells and their cytokines. The complex orchestration of psoriasis pathogenesis is related to the synergic effect of immune cells, polygenic alterations, the presence of autoantigens and several external factors. The major act of IL-23/IL-17 axis, strongly influencing the inflammatory pattern established during the disease activity, is visible as a continuous perpetuation of the pro-inflammatory response and keratinocyte activation and proliferation leading to the development of psoriatic lesions. Genome wide association studies (GWAS) along offered a better view of psoriasis pathogenic pathways, with approximately one third of psoriasis genetic impact on psoriasis development is associated to MHC region, with genetic loci located on chromosome 6. The most eloquent genetic factor of psoriasis, PSORS1, was identified in the MHC I site. Between the several factors involved in its complex etiology, dysbiosis, due to genetic or external stimulus, exhibiting less variety and the involvement of pathogenic bacteria, cand induce a burst of proinflammatory consequences, both cutaneous and gut microbiome being involved in psoriasis pathogenic process. A complex understanding of the major pathways that interplay in order to initiate and perpetuate psoriatic diseases and its associated comorbidities can help the current clinical practice by properly evaluating completely and individualized each patient and establish the proper therapeutic management.

Assessment of extreme events and climate change on reservoir inflow is important for water and power stressed countries. Projected climate is subject to uncertainties related to climate change scenarios and Global Circulation Models (GCMs’). Extreme climatic events will increase with the rise in temperature as mentioned in the AR5 of the IPCC. This paper discusses the consequences of climate change that include extreme events on discharge. Historical climatic and gauging data were collected from different stations within a watershed. The observed flow data was used for calibration and validation of SWAT model. Downscaling was performed on future GCMs’ temperature and precipitation data, and plausible extreme events were generated. Corrected climatic data was applied to project the influence of climate change. Results showed a large uncertainty in discharge using different GCMs’ and different emissions scenarios. The annual tendency of the GCMs’ is bi-vocal: six GCMs’ projected a rise in annual flow, while one GCM projected a decrease in flow. The change in average seasonal flow is more as compared to annual variations. Changes in winter and spring discharge are mostly positive, even with the decrease in precipitation. The changes in flows are generally negative for summer and autumn due to early snowmelt from an increase in temperature. The change in average seasonal flows under RCPs’ 4.5 and 8.5 are projected to vary from -29.1 to 130.7% and -49.4 to 171%, respectively. In the medium range (RCP 4.5) impact scenario, the uncertainty range of average runoff is relatively low. While in the high range (RCP 8.5) impact scenario, this range is significantly larger. RCP 8.5 covered a wide range of uncertainties, while RCP 4.5 covered a short range of possibilities. These outcomes suggest that it is important to consider the influence of climate change on water resources to frame appropriate guidelines for planning and management.

.Bacground: Sepsis remains a major health challenge worldwide, characterized by a dysre-gulated host response to infection, leading to high mortality and morbidity in intensive care units (ICUs). The Fibrosis 4 (FIB-4) index, originally developed to assess liver fibrosis in hepatitis C patients, has recently been explored for its potential prognostic value in sepsis patients. Method: This study retrospectively analyzed 309 sepsis patients admitted to the Internal Me-dicine and Anaesthesia ICUs between December 12, 2021, and December 15, 2023, to inves-tigate the relationship between FIB-4 levels, Acute Physiology and Chronic Health Evaluation (APACHE), and Sequential Organ Failure Assessment (SOFA) and clinical outcomes. Results: The study found that higher FIB-4 measurements were statistically significantly asso-ciated with increased 28-day mortality, with a cut-off value of 4.9 providing a sensitivity of 54.92% and specificity of 74.25%. Logistic regression analysis indicated that elevated Conclusion:FIB-4 levels were a significant predictor of early mortality, suggesting that the FIB-4 index could serve as a valuable prognostic tool in assessing the severity and prognosis of sepsis patients.

Bronchopulmonary dysplasia (BPD), also known as chronic lung disease, is the most common respiratory morbidity in preterm infants. "Old" or "Classic" BPD, as per the original description, is less common now. "New BPD," which presents with distinct clinical and pathological features, is more frequently observed in the current era of advanced neonatal care, where extremely premature infants are surviving due to medical advancements. The pathogenesis of BPD is complex and multifactorial and involves both genetic and environmental factors. This review provides an overview of the pathology of BPD and discusses the influence of several prenatal and postnatal factors on its pathogenesis, such as maternal factors, genetic susceptibility, ventilator-associated lung injury, oxygen toxicity, sepsis, patent ductus arteriosus (PDA), and nutritional deficiencies. This in-depth review draws on existing literature to explore these factors and their potential contribution to the development of BPD.

Introduction: The association of gene variants for interleukin 6(IL-6) (rs1800796), interleukin 10 (IL-10) (rs1800896) and tumor necrosis factorα (TNFα (rs1800629) with the occurrence of spontaneous preterm birth (PTB) was investigated to determine whether these genetic variants are a risk factor. Materials and methods: 199 blood samples from pregnant women who had given birth prematurely and 200 control blood samples were analyzed to determine single nucleotide polymor-phisms (SNPs) of genes for IL-6 (rs1800796), IL-10 (rs1800896) and TNFα (rs1800629). The control samples were samples from pregnant women with term delivery. Isolation of DNA was per-formed on mini-spin columns according to the manufacturer's protocol. The quality and purity of the isolated DNA were tested using a Qubit 3 fluorometer. Genotyping was performed with an ABI PRISM 7500 SDS using TaqMan SNP genotyping assays. The genotypes obtained were an-alyzed using the 7500 Software v2.3 package. Results: Carriers of the A/A genotype for the rs1800629 of the TNFα gene have 4.81 times greater chance of late-onset PTB compared to carriers of the G/G and A/G genotypes in the recessive inheritance model. The presence of the G/G genotype in the recessive inheritance model compared with the G/A and A/A genotypes for the rs1800896 of the IL-10 gene represents a potentially protective factor, with mothers in the term-birth group having an almost 2-fold lower odds of PTB in general and an almost 10-fold lower odds of early PTB. On the other hand, carriers of the A/G genotype of rs1800896 have a 1.54-fold higher chance of preterm birth in general and a 1.6-fold higher chance of late preterm birth in the super dominant inheritance model compared to the A/A and G/G genotypes in the group of mothers with PTB. In this study, no association was found between PTB and rs1800796 of the IL-6 gene. Conclusion: rs1800629 in mothers was associated with PTB. rs1800896 shows a potentially protective effect for the occurrence of PTB in this study. No association was found between PTB and rs1800796.

Dark pigmentation can be observed in various parts of the plant, ranging from foliage to petals to berries. The molecular basis of black pigmentation appears to vary among species, with anthocyanins playing a significant role, although specific anthocyanin types and their mechanisms differ. These findings suggest that the development of phenotypes is species-specific or varies between larger taxonomic groups; this is further supported by the polyphyletic nature of dark pigmentation. Additionally, several different regulatory mechanisms have been described for the occurrence of dark pigmentation. Firstly, the repression or knockout of the competing flavone biosynthesis has been shown to lead to darker pigmentation while another mechanism is based on the activation and upregulation of the anthocyanin biosynthesis genes in the presence of MYB transcription factors. Potential ecological functions of dark pigmentation were identified as the protection of the photosynthesis apparatus, camouflage against herbivores, and the attraction of pollinators. Promising industrial applications include microbial factories for the production of natural food colourants, induction of novel phenotypes for the ornamental plant industry and lastly the increase of anthocyanins within agriculturally relevant crops.

Exoskeleton technology has been shown to be useful for individuals with spinal cord injury (SCI), potentially facilitating their recovery of motor function and social reintegration. However, studies on the safety and usability of exoskeletons are limited. This study aimed to design a powered exoskeleton for SCI and evaluate its safety and usability. Ten healthy adults participated in this study. The prototype exoskeleton featured an adjustable frame, computer-controlled hip and knee joint actuators, and a gait-trigger sensor. The experimental actions included walking, standing, and sitting, with and without the prototype. Safety outcomes included adverse events, vital signs, numerical rating scale (NRS) scores for pain, discomfort, and fatigue, and prototype-human body clearance. Usability outcomes included donning and doffing times, subjective ratings, gait speed, stride length, and kinematic parameters of hip and knee joint angles. Safety outcomes showed no serious adverse events, stable vital signs, minimal NRS scores, and acceptable clearance. Usability outcomes showed high efficiency and received positive ratings. Kinematic parameters showed significant positive correlations between normal walking and walking with the prototype for both hip and knee joint angles, confirming its effectiveness in assisting walking. However, further device improvements and gait parameter tuning are necessary for future clinical application.

A Cu₂ZnSnS₄ (CZTS) film with a thickness of approximately 1.5 μm was fabricated on a Mo-coated glass substrate by annealing a CZTS precursor fabricated from nanoparticle ink. The chemical states of the elements in the CZTS thin film in the depth direction were studied to identify the presence of secondary phases, which are detrimental to the performance of solar cells containing CZTS. X-ray diffraction was unable to detect any secondary phases in CZTS because of their small relative amount. Instead, X-ray photoelectron spectroscopy (XPS), which is highly sensitive to chemical state, was conducted at different depths in the CZTS film to further check the presence of secondary phases. XPS analysis revealed peaks shift consistent with the presence of secondary phases. For the CZTS film annealed in a S atmosphere at 575 °C for 3 h, the film surface consisted of a secondary-phase layer composed of CuS, ZnS, and SnSx (x=1 or 2) originating from the decomposition of CZTS. At depths below 80 nm, the film was pure CZTS. Formation of MoS2 at the CZTS–Mo interface was confirmed by XPS analysis of Mo and S.

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

Despite decreasing anthropogenic mercury (Hg) emissions in Europe and the banning and restriction of many persistent organic pollutants (POPs) under the Stockholm Convention, Mediterranean marine mammals still have one of the highest body burdens of persistent pollutants in the world. Moreover, the Mediterranean basin is one of the most sensitive to climate change, with likely changes in the biogeochemical cycle and bioavailability of Hg, primary productivity, and the length and composition of pelagic food webs. The availability of food resources for marine mammals is also affected by widespread overfishing and the increasing number of alien species colonizing the basin. After reporting the most recent findings on the biogeochemical cycle of Hg in the Mediterranean Sea and the physico-chemical and bio-ecological factors determining its exceptional bioaccumulation in odontocetes, this review discusses possible future changes in the bioavailability of the metal. Recent ocean-atmosphere-land models predict that in mid-latitude seas, water warming (which in the Mediterranean is 20% faster than the global average) is likely to decrease the solubility of Hg and favor the escape of the metal to the atmosphere. However, the basin has been affected for thousands of years by natural and anthropogenic inputs of metals, and climate change with sea level rise (3.6 ± 0.3 mm year-1 in the last two decades) and the frequency of extreme weather events will likely remobilize large amount of legacy Hg from soils, riverine and coastal sediments. Moreover, possible changes in pelagic food webs and food availability could determine dietary shifts and lower growth rates in Mediterranean cetaceans, increasing their Hg body burden. Although adult marine mammals have evolved the ability to detoxify monomethylmercury (MMHg) and store the metal in the liver and other organs as insoluble Hg-Se crystals, in Mediterranean populations more exposed to the metal, this process can deplete the biological pool of Se, increasing their susceptibility to infectious diseases and autoimmune disorders. Mediterranean mammals are also among the most exposed in the world to legacy POPs, micro- and nanoplastics and contaminants of emerging interest. Concomitant exposure to these synthetic chemicals may pose a much more serious threat than the Se depletion. Unfortunately, as shown by literature data summarized in this review, the most exposed populations are those living in the NW basin, the main feeding and reproductive area for most Mediterranean cetaceans, declared a sanctuary for their protection since the 2002. Thus, while emphasizing the adoption of all available approaches to mitigate anthropogenic pressure with fishing and maritime traffic, it is recommended to direct future research efforts towards the assessment of possible biological effects, at individual and population level, of chronic and simultaneous exposure to Hg, legacy POPs, contaminants of emerging interest and microplastics.

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

The treatment of the bulky Rind-based dibromosilanes, (Rind)2SiBr2 (2) [Rind = 1,1,7,7-tetra-R1-3,3,5,5-tetra-R2-s-hydrindacen-4-yl: EMind (a: R1 = Et, R2 = Me) and Eind (b: R1 = R2 = Et)], with two equivalents of tBuLi in Et2O at low temperatures resulted in the formation of blue solutions derived from the diarylsilylenes, (Rind)2Si: (3). Upon warming the solutions above −20 °C, the blue color gradually faded, accompanying the decomposition of 3 and yielding the cyclic hydrosilanes (4) via intramolecular C−H bond insertion at the Si(II) center. The molecular structures of the bulky Eind-based 3b and 4b were confirmed by X-ray crystallography. Thus, at −20 °C, blue crystals were formed (Crystal-A), which were identified as mixed crystals of 3b and 4b. Additionally, colorless crystals of 4b as a singular component were isolated (Crystal-B), whose structure was also determined by an X-ray diffraction analysis. Although the isolation of 3 was difficult due to their thermally-labile nature, their structural characteristics and electronic properties were discussed based on the experimental findings complemented by computational results. We also examined the hydrolysis of 3b to afford the silanol, (Eind)2SiH(OH) (5b).

Interstitial lung disease (ILD) is one of the most serious extra-articular complications of rheu-matoid arthritis (RA), which increases the mortality of RA. Because the pathogenesis of RA-ILD remains poorly understood, appropriate therapeutic strategies and biomarkers have not yet been identified. Thus, the goal of this review was to summarize and analyze the reported data on the etiology and pathogenesis of RA-ILD. The incidence of RA-ILD increases with age, and is also generally higher in men than in women and in patients with specific genetic variations and eth-nicity. Lifestyle factors associated with an increased risk of RA-ILD include smoking and exposure to pollutants. The presence of an anti-cyclic citrullinated peptide antibody, high RA disease activity, and rheumatoid factor positivity also increase the risk of RA-ILD. We also explored the roles of biological processes (e.g., fibroblast–myofibroblast transition, epithelial–mesenchymal transition, and immunological processes), signaling pathways (e.g., JAK/STAT and PI3K/Akt), and the his-topathology of RA involved in RA-ILD pathogenesis based on published preclinical and clinical models of RA-ILD in animal and human studies.

While Retrieval-Augmented Generation (RAG) enhances Large Language Models (LLMs), it also presents challenges that can affect model accuracy and performance. Practical applications show that RAG can mask the intrinsic capabilities of LLMs. Firstly, LLMs may become overly dependent on external retrieval, underutilizing their own knowledge and inference abilities, which can reduce responsiveness. Secondly, RAG techniques might introduce irrelevant or low-quality information, adding noise to the LLM. This can disrupt the normal generation process, leading to inefficient and low-quality content, especially when dealing with complex problems. This paper proposes a RAG framework that uses reflective tags to control retrieval. This framework evaluates retrieved documents in parallel and incorporates the Chain of Thought (CoT) technique for step-by-step content generation. The model selects the highest quality and most accurate content for final generation. The main contributions include: 1) Reducing the hallucination problem by selectively utilizing high-scoring document, 2) Enhancing real-time performance through timely external database retrieval, and 3) Minimizing negative impacts by filtering out irrelevant or unreliable information through parallel content generation and reflective tagging. These advancements aim to optimize the integration of retrieval mechanisms with LLMs, ensuring high-quality and reliable outputs.

Esterquats constitute a unique group of quaternary ammonium salts (QASs) that contain an ester bond in the structure of the cation. Despite the numerous advantages of this class of compounds, only two mini-reviews discuss the subject of esterquats: the first one (2007) briefly summarizes their types, synthesis, and structural elements required for a beneficial environmental profile and only briefly covers their applications whereas the second one only reviews the stability of selected betaine-type esterquats in aqueous solutions. The rationale for writing this review is to critically reevaluate the relevant literature and provide others with a “state-of-the-art” snapshot of choline-type esterquats and betaine-type esterquats. Hence, the first part of this survey thoroughly summarizes the most important scientific reports demonstrating effective synthesis routes leading to the formation of both types of esterquats. In the second section, the susceptibility of esterquats to hydrolysis is explained, and the influence of various factors, such as the pH, the degree of salinity or the temperature of the solution, was subjected to thorough analysis that includes quantitative components. The next two sections refer to various aspects associated with the ecotoxicity of esterquats. Consequently, their biodegradation and toxic effects on microorganisms are extensively analyzed as crucial factors that can affect their commercialization. Then, the reported applications of esterquats are briefly discussed, including functionalization of macromolecules, such as cotton fabric as well as their successful utilization on a commercial scale. The last section demonstrates the most essential conclusions and reported drawbacks that allow us to elucidate future recommendations regarding the development of these promising chemicals.

In light of the critical and emerging global challenge posed by the increasing frequency and severity of heatwaves in recent decades, this study demonstrates a practical and robust workflow that bridges the gap in understanding how the effective integration of remote sensing data with ground-based observations can facilitate a comprehensive assessment of spatiotemporal heatwave patterns and trends in the central region of Thailand. This research transcends traditional methods, utilizing air temperature (Tair) and satellite-derived land surface temperature (LST) data from 1981 to 2019. Results exhibit that an analysis of Tair indicates increasing daytime heatwaves in peri-urban areas, with significant trends in heatwave number (HWN), heatwave frequency (HWF), and heatwave duration (HWD), heatwave amplitude (HWA) rises in urban settings while nighttime heatwaves significantly intensify in rural locales. Notably, LST trends reveal varied patterns, with peri-urban areas showing marked daytime increases in heatwave magnitude (HWM), HWA, and HWF. Correlation analysis (p=0.05) highlights strong daytime associations between Tair and LST in rural (HWN, HWF, HWD, r>0.90) and peri-urban (HWM, HWA, r>0.65) regions. Overall, this study advances approaches to the adaptable measurement and spatial-temporal pattern of heatwave-related risk areas, providing insights for decision-makers to develop sustainable practices and strategies for climate change adaptation.

The African continent has the highest prevalence of hypertension globally, with South Africa reporting the highest prevalence in Southern Africa. While the influence of genetic variability in the pathogenesis of hypertension is well described internationally, limited reports are available for African populations. This study aimed to assess the association of genetic variants and essential hypertension in a cohort of two ethnic South African population groups. Two hundred and seventy-seven hypertensive and one hundred and seventy-six normotensive individuals were genotyped for 79 variants. Genotyping was performed using the Illumina GoldenGate Assay and allele-specific polymerase chain reaction. The association of variants was assessed using the Fisher Exact test under the additive and allelic genetic models, while multivariate logistic regression was used to predict the development of hypertension. Five variants (CYP11B2 rs179998, AGT rs5051 and rs699, AGTR1 rs5186 and ACE rs4646994) were significantly associated with essential hypertension in the cohort under study. Furthermore, AGTR1 rs5186 and AGT rs699 were identified as risk factors for the development of hypertension in both ethnic groups. In two ethnic South African populations an association was observed between Renin-Angiotensin-Aldosterone System (RAAS) related genes and the development of hypertension.

Transition-metal-free synthesis of 4-pyrones via TfOH-promoted nucleophilic addition/cyclization of diynones and water has been developed. This transformation is simple, atom economical and environmentally benign, providing rapid and efficient access to substituted 4-pyrones.

Diabetes mellitus (DM) poses a significant challenge to global health, with its prevalence projected to rise dramatically by 2045. This narrative review explores the bidirectional relationship between periodontitis (PD) and type 1 diabetes mellitus (T1DM), focusing on cellular and molecular mechanisms derived by the interplay between oral microbiota and the host immune response. A comprehensive search of literature published between 2008 and 2023 was conducted to elucidate the association between these two diseases. Preclinical and clinical evidence suggests a bidirectional relationship, with individuals with T1DM exhibiting heightened susceptibility to periodontitis, and vice versa. The review includes recent findings from human clinical studies, revealing variations in oral microbiota composition in T1DM patients, including increases in certain pathogenic species such as Porphyromonas gingivalis, Prevotella intermedia, and Aggregatibacter actinomycetemcomitans, along with shifts in microbial diversity and abundance. Molecular mechanisms underlying this association involve oxidative stress and dysregulated host immune responses, mediated by inflammatory cytokines such as IL-6, IL-8, and MMPs. Furthermore, disruptions in bone turnover markers, such as RANKL and OPG, contribute to periodontal complications in T1DM patients. While preventive measures to manage periodontal complications in T1DM patients may improve overall health outcomes, further research is needed to understand the intricate interactions between oral microbiota, host response, periodontal disease, and systemic health in this population.

Preeclampsia is a complex pregnancy-related hypertensive disorder which poses significant risks for both maternal and fetal health. Preeclampsia affects 5-8% of the pregnancies in the United States, causing a significant public health and economic burden. Despite extensive research, the etiology and pathogenesis of preeclampsia remain elusive, but have been correlated with maternal conditions such as obesity. In the past decades, the incidence of preeclampsia increased along with the prevalence of obesity among women of reproductive age. Maternal obesity has been shown to negatively affect pregnancy in almost all aspects. However, the precise mechanisms by which obesity influences preeclampsia are unclear. Ankyrin repeat and SOCS Box Containing protein 4 (ASB4) is an E3 ubiquitin ligase that can promote the degradation of a wide range of target proteins. ASB4-null mice display a full spectrum of preeclampsia-like phenotypes during pregnancy including hypertension, proteinuria, and decreased litter size. Furthermore, maternal obesity induced by a high fat diet aggravates preeclampsia-like phenotypes in pregnant mice lacking ASB4. Variants in the ASB4 gene have been associated with obesity in humans, and a functional connection between the ASB4 gene and obesity has been established in mice. This review discusses the connections between preeclampsia, obesity, and ASB4.

A great deal of studies have assessed the expression of noncoding RNAs (ncRNAs) as well as their relevant molecular functions and biological mechanisms in the individuals of alcohol dependence. Alcohol dependence is one of the most prevalent neuropsychological disorders worldwide, and its pathogenesis is intricate and inadequately understood. There is considerable evidence demonstrating substantial links between multiple genetic factors and the development of alcohol dependence. Critical roles of ncRNAs have been emphasized in the pathophysiology of mental diseases including alcohol dependence. In the comprehension of ncRNAs action and their mechanisms of modification, they have emerged as therapeutic targets for a variety of psychiatric illness including alcohol dependence. Worth mentioning, dysregulated expression of ncRNAs has been regularly detected in individuals of alcohol dependence. An in-depth knowledge of roles of ncRNAs and m6A modification may be valuable for the development of a novel treatment against alcohol dependence. In general, a deeper comprehension of functional roles ncRNAs may make significant contributions to the precise diagnosis and/or actual treatment of alcohol dependence. Here in this review, we mostly focused on the up-to-date knowledge regarding alterations and/or modifications in the expression of ncRNAs in alcohol dependence, and then, presented their prospects for future research and therapeutic application with a novel concept of engram-system.

Traditional lime-based materials have considerable potential for use as components of green materials for plastering and finishing building surfaces in both new construction and historic heritage conservation. The paper presents the preliminary results of a research activity aimed at developing pre-packaged products based on Traditional Lime Putty (TLP) by partially replacing natural aggregates with Stone Waste Sludge (SWS), with a low rate of recovery from Apricena limestone production district in Apulia. The mineralogical and chemical analysis carried out by means XRD (X-Ray Diffraction), TG-DTA (Thermo Gravimetry-Differential Thermal Analysis) and hydrochloric acid attack test showed that the SWS consisted of 98.4 % CaCO3 by mass. The particle sizes measured by laser diffraction technique are below 22.5 μm for the 92% by mass of the sample. The high fineness of the stone waste was confirmed by the Blaine specific surface method equal to 9273.79 cm2/gr. The behavior of three fresh mixtures for prepacked coarse plaster, fine plaster, and finishing plaster with 12.90%, 17.94%, and 18.90 by mass of SWS, respectively, was evaluated by spreading test and applicability tests on a perforated ceramic slab. The finishing plaster has the highest consistency value of 235 mm, while the fine plaster and the coarse plaster have values of 205 mm and 155 mm, respectively. The coarse plaster is suitable for the use as base plaster (arriccio) or second layer rendering (tonachino) up to a thickness of approximately 1 cm. Both the fine plaster and finishing plasters can be used for the surfaces finishing with the application of layers of a few millimeters thick.

In this paper the one-to-one correspondences and equivalences between ideals, primals, filters and grills are introduced. It is shown the local functions and the topological spaces induced by them are the same. From this point of view, the topological properties with respect to one topology can be derived from topological properties valid in the corresponding topology.

Polycystic ovary syndrome (PCOS) is a complex disorder that impacts both the endocrine and metabolic systems. The gut microbiota plays a crucial role in in metabolism regulation and immune responses through its interaction with the external environment. This article explores the intricate interplay between intestinal flora and the pathogenesis of PCOS, focusing on the pivotal role of microbial metabolites, specifically short-chain fatty acids (SCFAs). SCFA levels in fecal and blood samples from women with PCOS (n=69) and healthy controls (n=18) were analyzed using Gas Chromatography-Mass Spectrometry (GC/MS) for precise measurement. The results revealed that women with PCOS exhibited a significant reduction in beneficial bacteria alongside a notable overgrowth of opportunistic microorganisms. An overproduction of acetic acid (AA) and valeric acid (VA) in fecal samples suggests a link between elevated SCFAs and the development of obesity and PCOS. Interestingly, AA in the bloodstream might offer a protective effect against PCOS by ameliorating key symptoms such as high body mass index (BMI), insulin resistance (IR), and chronic inflammation. This finding points to the potential therapeutic value of maintaining optimal AA levels in the blood. Although serum SCFA levels showed non-significant changes following metformin treatment, the normalization of AA in the gut underscores that metformin exerts a more pronounced effect locally within the gastrointestinal tract. This treatment also led to an increase in beneficial gut bacteria and a reduction in opportunistic pathogens, suggesting a restoration of gut microbial balance. Furthermore, the study identified the most effective model for predicting the success of metformin therapy, based on serum concentrations of butyric acid (BA) and VA, achieving a 91% accuracy rate, 100% sensitivity, and 80% specificity. These promising findings highlight the potential for developing targeted interventions and personalized treatments, ultimately improving clinical outcomes for women with PCOS.

A simple protocol for preparation of O-acylated enol form - (R/S)-ethyl-2-acetoxy-4-phenyl-4H-chromene-3-carboxylate 5 was presented. The compound was characterized by 1H-, 13C-and DEPT135 NMR spectra, including {1H,1H} COSY, {1H,13C} HSQC, {1H,13C} HMBC and 2D-NOESY spectra. The preferred regioselectivity for O-acylation of 3,4-dihydrocoumarin 5 in the presence of substituent in 4-th position in the chroman ring and accounting the steric hindrance of the ester group in 3-th place was confirmed.

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

Vaccination represents the historical milestone in medical sciences, which has been saving millions of lives. Nonetheless, continued outbreaks of emergent infectious diseases are swamping from every coast to every border all over the world. Modern vaccines are our most powerful arsenals to defend the public health of a global population ever since 1796. As unexpected, modern vaccination approaches have brought out all sorts of unwelcome pathogenic disorders to varying extents. Pathogenic viruses have also continued to evolve to defeat elaborate arsenals devised by human intelligence. In this review, we have covered a variety of vaccination approaches along with their sophisticated materials from the past to the most recent development. Furthermore, we discuss varied serious pathogenic outcomes elicited by contemporary vaccination programmes involving novel materials in real clinical trials. The complex immune mediators will be discussed in the context to tackle the complication of vaccine-induced pathogenesis. We will offer the insight into the intractable discrepancy of vaccine-associated pathology. The precision approach bestowed with evolutionary concepts will be considered as a feasible option to confront various issues of pathogenic complicacy.

Psoriasis is a lifelong, systemic, immune mediated inflammatory skin condition, affecting 1-3% of the world’s population, with an impact on quality of life similar to diseases like cancer or diabetes. Genetics are the single largest risk factor in psoriasis, with GWAS studies showing that many psoriasis risk genes lie along the IL23/Th17 axis. Potential psoriasis risk genes determined through GWAS can be annotated and characterised using functional genomics, allowing the identification of novel drug targets and the repurposing of existing drugs. The pathogenesis of psoriasis is complex and focusing on the IL23/Th17 axis can provide insight into key cell types, cytokines and intracellular signaling pathways involved. Examination of currently available biological treatments, time to relapse post drug withdrawal and rates of drug primary/secondary drug failure show the need for greater understanding of the underlying genetic mechanisms of psoriasis and how they can impact treatment. This could allow for patient stratification towards the treatment most likely reduce dis-ease burden for the longest period possible.

In an attempt to reuse fibrous textile waste and, at the same time, to address dye pollution in textile wastewater, waste cotton-based yarn was utilized as both a cheap and sustainable adsorbent and a precursor for carbon adsorbent production. Cotton and cotton/polyester yarn samples underwent thermal modification through carbonization followed by chemical activation with KOH. Various techniques including nitrogen adsorption-desorption isotherms, scanning electron microscopy, Fourier transform infrared spectroscopy, and surface charge determination were employed to analyze the morphological and surface properties of the cotton-based adsorbents. Adsorption properties were evaluated by testing the removal of selected cationic and anionic dyes from water. The impact of temperature, contact time, initial concentration, and pH of the adsorbate solution on adsorption was investigated, with experimental data analyzed using theoretical models. While carbonization alone did not significantly enhance adsorption properties, activated samples exhibited high efficacy in removing both cationic and anionic dyes from water. Despite the negative influence of the polyester component in the carbon precursor on the efficiency of activated samples in removing methyl orange, results indicated that activated cotton and cotton/polyester yarn could be used to prepare highly efficient adsorbents for the rapid removal of methylene blue from real wastewater samples.

Nowadays, animal breeders look for effective innovations to care animal health. Use of probiotics, postbiotics, parabiotics and the other beneficial natural substances are dominated. Mundticin-like substance EM 41/3 is thermo-stable bacteriocin (postbiotic) with a broad antimicrobial spectrum. In this study its effect in broiler rabbits was assessed. Rabbits represent food-derived animal and they are also suitable animal model. The parameters tested were analyzed by validated methods. Administration of MLS EM 41/3 produced by non-autochthonous strain Enterococcus mundtii EM 41/3 lead to significant increase of parameter immunity-phagocytic activity, while it did not influence microbiota composition. It also did not influence blood biochemistry and no oxidative stress was noted. Moreover, higher growth parameters were noted and also stimulated hydrolytic activity. Finally, no negative influence on rabbit meat quality was noted. Postbiotic MLS EM 41/3 administration in feeding strategy seems to be contributing fact for rabbit health status maintaining.

Periodontitis is a chronic inflammatory disease affecting the tissues that surround and support the teeth. In the U. S., approximately 65 million people are affected by this condition. Its occurrence is also associated with many important systemic diseases such as cardiovascular disease, rheumatoid arthritis, and Alzheimer’s disease. Among the most important etiologies of periodontitis is Porphyromonas gingivalis, a keystone bacterial pathogen. Keystone pathogens can orchestrate inflammatory disease by remodeling a normally benign microbiota causing imbalance between normal and pathogenic microbiota (dysbiosis). The important characteristics of P. gingivalis causing dysbiosis are its virulence factors that cause effective subversion of host defenses to its advantage [1], allowing other pathogens to grow. However, the mechanisms involving these processes are poorly understood. However, various microbial strategies target host sialoglycoproteins for immune dysregulation. In addition, the enzymes that break down sialoglycoproteins/sialoglycans are the “sialoglycoproteases”, resulting in exposed terminal sialic acid. This process could lead to pathogen-toll like receptor (TLR) interactions mediated through sialic acid receptor–ligand mechanisms. By assessing the function of P. gingivalis sialoglycoproteases, could pave the way to designing carbohydrate analogues and sialic acid mimetics to serve as drug targets.

4-(2-Methyloxazol-4-yl)benzenesulfonamide was synthesized by the reaction of 4-(2-bromoacetyl)benzenesulfonamide with an excess of acetamide. The obtained compound was evaluated as a potential inhibitor of human monoamine oxidase (MAO) A and B and was found to inhibit these enzymes with IC50 values of 3.47 μM for MAO-B and 43.3 μM for MAO-A. Thus, the new selective MAO-B inhibitor was identified, which may be used as the lead compound for development anti-Parkinson’s disease agents.

This study proposes an innovative pharmacovigilance approach, VIGI-4, leveraging ChatGPT Teams Pro version. Our method involves aggregating data from all phase 4 studies published in February 2024 to identify adverse reactions. These results are categorized by disease state alphabetically, demonstrating the method's capacity to generate structured and easily navigable outputs. The results section is tailored to exemplify the valuable, actionable insights attainable through our workflow. This research emphasizes the game-changing potential of integrating advanced technologies such as ChatGPT into pharmacovigilance, signaling a new era in safeguarding drug safety.

Alcoholic liver disease (ALD) is a major cause of chronic liver disease. This term covers a broad spectrum of liver lesions, from simple steatosis to alcoholic hepatitis and cirrhosis. The patho-genesis of ALD is multifactorial and not fully elucidated due to complex mechanisms related to direct ethanol toxicity with subsequent hepatic and systemic inflammation. The accumulation of pro-inflammatory cytokines and the reduction of anti-inflammatory cytokines promote the development and progression of ALD. To date, there are no targeted therapies to counteract disease progression and prevent acute liver failure. Corticosteroids reduce mortality by acting on the hepatic-systemic inflammation. On the other hand, several studies analyzed the effect of the inhibition of pro-inflammatory cytokines and the stimulation of anti-inflammatory cytokines as potential therapeutic targets in ALD. This narrative review aims to clarify the role of the cy-tokines in the pathogenesis and treatment of ALD.

This paper presents the PEnsemble 4 model, a sophisticated machine learning framework that integrates IoT-based environmental data to accurately forecast maize yield. With the projected significant growth in global maize demand over the next decade, the inherent risks posed by the crop’s dependence on weather conditions necessitate improved prediction capabilities. The PEnsemble 4 model, developed with high accuracy, incorporates comprehensive datasets encompassing soil attributes, nutrient composition, weather conditions, and UAV-captured vegetation imagery. By employing a combination of Huber and M estimates, the PEnsemble 4 model effectively analyzes temporal patterns in vegetation indices, specifically CIre and NDRE, which serve as reliable indicators of canopy density and plant height. In addition, this research significantly contributes to precision agriculture by offering an efficient and sustainable alternative to conventional farming practices through precise yield predictions. Notably, the PEnsemble 4 model enables earlier estimation, advancing the timeline for yield prediction from the conventional day 100 in the R6 stage to day 79 in the R2 stage. This improvement enhances decision-making processes in farming operations. The remarkable accuracy rate of 91% underscores the importance of adopting a multifaceted data approach that harnesses IoT-derived environmental insights. Additionally, the PEnsemble 4 model extends its benefits beyond yield prediction, facilitating the detection of water and crop stress, as well as disease monitoring in broader agricultural contexts. Ultimately, the PEnsemble 4 model establishes a new standard in maize yield prediction, revolutionizing crop management and protection through the synergistic utilization of IoT and machine learning technologies.

We define a spinor-Minkowski metric for SL(4,C). It is not a trivial generalization of the SL(2,C) metric and it involves the Minkowskian one. We define 4x4 version of the Pauli matrices and eight 4-component associated generalized eigenvectors that can be regarded as undotted covariant spinors. The 4-component spinors can be grouped into four categories. Each category transforms in its own way. The outer products of pairwise combinations of 4-component spinors can be associated with 4-vectors. Including the dotted covariant, undotted and dotted contravariant forms totally we have sixteen pairs of spinors. Eight of them live in the conjugate space which has no countepart in SL(2,C).

Antibiotic prescription is the first line of treating bacterial diseases. But it affects the composition and function of non-targeted intestinal microbiota. Antimicrobial resistance will be the cause for the death of millions of people worldwide. By considering collateral damage of antibiotics, searching an alternative antimicrobial agent will be a solution to minimize the problems. Probiotics, prebiotics and synbiotics are an alternative to antibiotics. Thanks to GIT microbes as they are responsible for metabolism, energy production, protection from pathogens and immunomodulation. So, it is appreciable if the gut microbiota modulated through consumption of probiotics, prebiotics and synbiotics. Probiotic effects are genus and species specific. To get good health benefit of probiotics, safety of probiotics should be assessed before using them. This is mandatory for prebiotics and synbiotic selection. So this review paper gives information about side effects of antibiotics on gut microbiota, description of probiotics, prebiotics and synbiotics as alternative to antibiotics in modulating GIT microbiota, techniques of assessing safety of probiotics and health benefits of probiotics, prebiotics and synbiotics with scientific evidence in clinical trial and some disagreement and challenges of using probiotics, prebiotics and synbiotics.

Most cervical cancer cases are a result of persistent high-risk Human papillomavirus (HPV) infections. Cervical cancer is prevalent in LMICs especially in SSA where it is second most prevalent cancer. In South Africa, it is the second most common cancer affecting women aged between 15 and 44 years. The host immune response has been shown as an important factor in controlling the progression or regression of high-risk HPV infection of the cervix to cervical cancer. The risk of cervical cancer is known to be influenced by the host's genetic diversity, particularly by immune response-regulating genes such as the Human Leukocyte Antigen (HLA) class I and II genes. HLA class I genes present viral peptides to CD8+ T cells which are restricted and pre-programmed for cytotoxic functions. There is very little known about the HLA genes of South African women and how these influence outcome of HPV infections. This review aims to understand the role and influence of HLA class I genes in HPV clearance, persistence, and CD8+ T cell mediated immunity in African women by examining existing literature in this area. Understanding this role can influence and inform therapeutic vaccine design that is population specific.

Gas and power networks are tightly coupled and interact with each other due to physically interconnected facilities. In an integrated gas and power network, a contingency observed in one system may cause iterative cascading failures, resulting in network wide disruptions. Therefore, understanding the impacts of the interactions in both systems is crucial for governments, system operators, regulators and operational planners, particularly, to ensure security of supply for the overall energy system. Although simulation has been widely used in the assessment of gas systems as well as power systems, there is a significant gap in simulation models that are able to address the coupling of both systems. In this paper, a simulation framework that models and simulates the gas and power network in an integrated manner is proposed. The framework consist of a transient model for the gas system and a steady state model for the power system based on AC-Optimal Power Flow. The gas and power system model are coupled through an interface which uses the coupling equations to establish the data exchange and coordination between the individual models. The bidirectional interlink between both systems considered in this studies are the fuel gas offtake of gas fired power plants for power generation and the power supply to LNG terminals and electric drivers installed in gas compressor stations and underground gas storage facilities. The simulation framework is implemented into an innovative simulation tool named SAInt (Scenario Analysis Interface for Energy Systems) and the capabilities of the tool are demonstrated by performing a contingency analysis for a real world example. Results indicate how a disruption triggered in one system propagates to the other system and affects the operation of critical facilities. In addition, the studies show the importance of using transient gas models for security of supply studies instead of successions of steady state models, where the time evolution of the line pack is not captured correctly.

Herein, two title compounds, N-Benzoyl-N’-4-cyanophenyl thiourea (I) and N-(4-nitrobenzoyl)-N’-4-cyanophenyl thiourea (II) were synthesized in high yield, via aroyl isocyanate and 4-aminobenzonitrile. The structure of the prepared compounds was characterized by elementary analysis and FT-IR, ¹H, ¹³C NMR spectroscopic methods. Cyclic voltammetric (CV) experiments were performed with glassy carbon electrode. The reduction potential values of different functional group such as nitro, cyano in title compounds were investigated using CV curves.

The DEAD-box RNA helicase DDX3X is a multifunctional protein involved in RNA metabolism and stress responses. In this study, we investigated the role of RG/RGG motifs in the dynamic process of liquid-liquid phase separation (LLPS) of DDX3X using cell-free assays and explored their potential link to cancer development through bioinformatic analysis. Our results demonstrate that the number, location, and composition of RG/RGG motifs significantly influence the ability of DDX3X to undergo phase separation and form self-aggregates. Mutational analysis revealed that the spacing between RG/RGG motifs and the number of glycine residues within each motif are critical factors in determining the extent of phase separation. Bioinformatic analysis of cancer genomic datasets uncovered a significant enrichment of DDX3X mutations in RG/RGG motifs across multiple cancer types, particularly in the N-terminal region of the protein. Furthermore, we found that DDX3X is co-expressed with the stress granule protein G3BP1 in several cancer types and can undergo co-phase separation with G3BP1 in a cell-free system, suggesting a potential functional interaction between these proteins in phase-separated structures. DDX3X and G3BP1 may interact through their RG/RGG domains and subsequently exert important cellular functions under stress situation. Collectively, our findings provide novel insights into the role of RG/RGG motifs in modulating DDX3X phase separation and their potential contribution to cancer pathogenesis.

To better understand the shape memory materials and self-healing materials, a new series of liquid-crystalline shape memory polyurethane (LC-SMPU) composites, named SMPU-OOBAm, were successfully prepared by incorporating 4-octyldecyloxybenzoic acid (OOBA) into the PEG-based SMPU. The effect of OOBA on the structure, morphology and properties has been carefully investigated. The results demonstrate that SMPU-OOBAm have liquid crystalline properties, triple-shape memory properties and self-healing properties. The incorporated OOBA promotes the crystallizability of both soft and hard segments of SMPU, and the crystallization rate of the hard segment of SMPU decreases when the OOBA-content increases. Additionally, the SMPU-OOBAm forms a two-phase separated structure (SMPU phase and OOBA phase), and it shows two-step modulus changes upon heating. Therefore, the SMPU-OOBAm shows triple-shape memory behavior, and the shape recovery ratio decreases with an increase in the OOBA content. Finally, SMPU-OOBAm shows self-healing properties. The new mechanism can be ascribed to the heating-induced “bleeding” of OOBA in the liquid crystalline state and the subsequent re-crystallization upon cooling. This successful combination of liquid crystalline properties, triple-shape memory properties and self-healing properties make the SMPU-OOBAm composites with many promise applications in smart optical devices, smart electronic devices and smart sensors.

Introduction The monitoring of cerebral perfusion in patients with brain damage is a major clinical challenge. Monitoring cerebral oxygenation (rSO2) by NIRS was introduced at the turn of the 1980s, and many clinicians believed it was a valuable method for assessing cerebral perfusion and subsequent measures to optimize cerebral flow. The main problem of NIRS usage is the presence of the intermediate structures-skin, skull, meninges, cerebrospinal fluid-and their influence on the outcome of the test. Therefore, it seems that NIRS assessment performed on a patient during brain death attempts, can give an idea of the magnitude of the influence of these intermediate structures on the monitoring result. Case We present a retrospective analysis of cerebral oxygenation measurements of a patient undergoing a brain death diagnostic procedure. A clinical situation where the cerebral blood flow is stopped can give an idea of the specificity of the method, particularly the impact of the influence of intermediate structures on the monitoring outcome. In this case, the NIRS result is increased by the oxygenation of the patient before the apnoea test. The influence of chromophores in the tissues surrounding the CNS, reflections and scattering of the light wave spectrum have a very significant effect on the final result of cerebral saturation measurement. Discussion The majority of research observations describing changes in cerebral perfusion or its optimisation may be burdened by the problem described, i.e. the significant influence of measured oxygenation from intermediate structures. The specificity of NIRS to assess cerebral perfusion requires careful analysis. The therapeutic implications of monitoring cerebral oxygenation with NIRS are of great importance and, from the example presented and the literature provided, the method should be used with caution. It has been shown that in a patient with brain death, the result of NIRS oxygenation measurements depends on the surrounding structures of the brain.

Treatment of the non-purified mixture of dinitro isomers obtained from the nitration of 1,4-dimethoxybenzene with piperidine, led to the isolation of novel but minor adduct, 1-(2,5-dimethoxy-4-nitrophenyl)piperidine (2b) in 15% yield. Yields of nucleophilic aromatic substitution adducts are high when using purified 1,4-dimethoxy-2,5-dinitrobenzene (1b) with piperidine and pyrrolidine to give 2b and 1-(2,5-dimethoxy-4-nitrophenyl)pyrrolidine (3b) in 76% and 82%, respectively.

Background: Ventilator-associated pneumonia (VAP) is among the most common healthcare-associated infections in Pediatric Intensive Care Units (PICUs). Because of the lack of a gold-standard diagnostic test, early diagnosis of VAP is challenging. We investigated whether bronchial biomarkers interleukin-4 (IL-4), plasminogen activator inhibitor-1 (PAI-1) and soluble receptor for advanced glycation end products (RAGE) could contribute in early VAP diagnosis through their fluctuation in time in critically ill pediatric patients. Methods: Bronchial secretions were collected from PICU patients with VAP on days 1 and 6. PAI-1, RAGE and IL-4 levels were measured by ELISA. Protein concentrations between high and low VAP suspicion patients were compared using unpaired Student’s t or Mann–Whitney U tests. Results: Twenty PICU patients, with median age 7.75yrs (range 0.5-15.3), mechanically ventilated for ≥48hrs with increased oxygenation requirements and VAP clinical/laboratory signs were enrolled. They were divided in VAP high-suspicion (n=12) or low-suspicion (n=8) groups based on Clinical Pulmonary Infection Score (cutoff:6). ΡΑΙ-1 και RAGE levels did not differ between high- or low-VAP suspicion groups the 1st or 6th days (p-value>0.05). IL-4 was not detected in bronchial secretions. Conclusion: Bronchial concentrations of IL-4, PAI-1 and RAGE in critically ill children are not correlated with high- or low-VAP suspicion.

In the intricate dance between viruses and host cells, RNA-binding proteins (RBPs) serve as crucial orchestrators of gene expression and cellular processes. We will delve into the riveting realm of viral hijacking, where viruses deftly exploit host RBPs to manipulate cellular machinery for their replication and pathogenesis. Through a masterstroke of molecular subterfuge, viruses co-opt RBPs involved in various facets of RNA metabolism - from transcription to degradation - to promote viral gene expression and evade host immune defenses. This manipulation leads to global alterations in cellular RNA metabolism, impacting essential host genes vital for immune responses and homeostasis.Unveiling this clandestine alliance between viruses and RBPs is not just a scientific pursuit, but a critical imperative for devising innovative antiviral strategies to disrupt these interactions. By unraveling the intricate interplay between viral proteins and host RBPs throughout the viral life cycle - from entry to assembly - researchers aim to identify vulnerabilities that can be targeted for therapeutic intervention. Strategies such as disrupting viral protein-RBP interactions hold promise for inhibiting viral replication and curbing pathogenesis, offering a beacon of hope in the battle against viral infections.Our manuscript elucidates the indispensable roles played by RBPs in viral replication, translation, and pathogenesis, shedding light on the molecular mechanisms driving viral success. Delving deeper, it explores how viruses intricately entwine with host RBPs, manipulating cellular signaling pathways to create a hospitable environment for viral spread. By dissecting these manipulative tactics, researchers uncover new targets for antiviral therapy, envisioning a future where tailored interventions disrupt viral-host RBP interactions with precision and efficacy.As the narrative unfolds, the therapeutic implications of targeting RBPs or their interactions with viral proteins emerge as a promising frontier in the fight against viral infections. From small molecule inhibitors to RNA-based therapeutics, innovative approaches are on the horizon, offering new avenues for combatting viral diseases. We set the stage for future research, beckoning researchers to delve deeper into the molecular intricacies of viral hijacking of RBPs and charting a course towards novel therapeutic interventions that promise to reshape the landscape of antiviral therapy.\Ultimately, it beckons the scientific community to embark on a voyage of discovery, unraveling the secrets of viral hijacking of RBPs and paving the way for transformative advances in antiviral therapeutics. The stage is set for a new chapter in the battle against viral infections, where knowledge becomes the sword and innovation the shield against the pernicious machinations of viral pathogens.

Reverse engineering is applied to identify optimum polymerization conditions for the synthesis of polymer with pre-defined properties. The proposed approach uses multi-objective optimization (MOO) and provides multiple candidate polymerization procedures to reach the targeted polymer property. The objectives for optimization include maximal similarity of molar mass distributions (MMD) compared to the target MMD, minimal reaction time, and maximal monomer conversion. The method is tested for vinyl acetate radical polymerizations and can be adopted to other monomers. The data for the optimization procedure is generated by an in-house developed kinetic Monte-Carlo (kMC) simulator for a selected recipe search space. The proposed reverse engineering algorithm comprises several steps: kMC simulations for the selected recipe search space to derive initial data, performing MOO for a targeted MMD, and identification of the Pareto optimal space. The last step uses a weighted sum optimization function to calculate the weighted score of each candidate polymerization conditions. To decrease the execution time clustering of the search space based on MMDs is applied. The performance of the proposed approach was tested for various target MMDs. The suggested MOO-based reverse engineering provides multiple recipe candidates depending on competing objectives.

Hydrological processes are complex to compute on hilly areas when compared to the plain areas. Most of the hydrological model do not take into account the critical rainfall-runoff generation processes such as subsurface storm flow, saturation excess flow, overland flow, return flow and pipe storage. The simulations of the above processes in the soil matrix requires detailed hillslope hydrological modelling. In present study, a hillslope experimental plot is designed to study the runoff generation processes on the plot scale. The setup is designed keeping in view the natural hillslope conditions prevailing in the north western Himalayas, India where high intensity storm event occurs frequently. Using the experimental data and the developed conceptual model, the overland flow and the subsurface flow through macropore dominated area has been estimated/analyzed on the pixel basis. Over the experimental hillslope plot, a rainfall simulator was installed to generate the rainfall intensity in the range of 15 to 150 mm/hr which represented the dominating rainfall intensity range in the region. Soil moisture sensors were also installed at 100 mm and 300 mm depth at different locations of the plot to observe soil moisture variations. It was found that once the soil is saturated, it remains in the field capacity for next 24-36 hours. Such antecedent moisture conditions are most favorable for the generation of rapid stormflow from hillslopes. Dye infiltration test was also performed on the undisturbed soil column to observe the macropore fraction variability over the vegetated hillslopes. The surface runoff predicted using the developed hillslope hydrological model compared well with the observed surface runoff under high intensity rainfall conditions.

Radiotherapy remains a cornerstone in cancer treatment, leveraging ionizing radiation to eradicate malignant cells. Its efficacy, however, is frequently challenged by the heterogeneous sensitivity of tumors and surrounding tissues to radiation. Therefore, understanding the molecular mechanisms underlying radiosensitivity is crucial for improving treatment outcomes. Among the myriad of molecular players involved, the tumor suppressor protein p53 stands out as a central regulator with significant implications for radiosensitivity. Known as the “guardian of the genome,” p53 plays a pivotal role in maintaining genomic stability and orchestrating cellular responses such as cell cycle arrest, DNA repair, apoptosis, and senescence in response to various stress signals, including radiation-induced DNA damage. Activation of p53 triggers the transcription of target genes involved in DNA repair pathways, such as p21, MDM2, and GADD45, facilitating the repair of radiation-induced DNA damage or the elimination of irreparably damaged cells. This, in turn, influences the overall radiosensitivity of tissues. Mutations in the TP53 gene, which encodes p53, are among the most frequent genetic alterations in human cancers. Loss or dysfunction of p53 can compromise the cellular response to radiation, leading to increased resistance to therapy and poorer clinical outcomes. Conversely, intact p53 function is associated with enhanced radiosensitivity due to its ability to promote cell cycle arrest and apoptosis in response to radiation-induced DNA damage. In conclusion, elucidating the molecular mechanisms by which p53 influences radiosensitivity is essential for advancing our understanding of radiation response in cancer cells and developing more effective therapeutic approaches in cancer treatment. This review provides a comprehensive overview of the multifaceted role of p53 in modulating cellular responses to radiation, emphasizing its influence on radiosensitivity.

Thoracic aortic aneurysm (TAA) has a prevalence of 0.16%-0.34% and an incidence of 7.6 per 100,000 person-years, accounting for 1%-2% of all deaths in Western countries. Currently, no effective pharmacological therapies have been identified to slow TAA development and prevent TAA rupture. Large TAAs are treated with open surgical repair and less invasive thoracic endovascular aortic repair, both of which have high perioperative mortality risk. Therefore, there is an urgent medical need to identify the cellular and molecular mechanisms underlying TAA development and rupture to develop new therapies. In this review, we summarize animal TAA models including recent developments in porcine and zebrafish models: porcine models can assess new therapeutic devices or intervention strategies in a large mammal and zebrafish models can employ large-scale small-molecule suppressor screening in microwells. The second part of the review covers current views of TAA pathogenesis, with a focus on the roles of the transforming growth factor-beta (TGFβ) pathway and the vascular smooth muscle cell (VSMC)-elastin-contractile unit. The last part discusses TAA treatment options as they emerge from recent preclinical studies.

The article describes how atherosclerosis and coronavirus disease 19 (COVID-19) may affect each other. The features of this comorbid pathogenesis at various levels (vascular, cellular and molecular) are considered. A bidirectional influence of these conditions is described: the presence of cardiovascular diseases affects different individual susceptibility to viral infection. In turn, SARS-CoV-2 can have a negative effect on the endothelium and cardiomyocytes, causing blood clotting, secretion of pro-inflammatory cytokines, and thus exacerbating the development of atherosclerosis. In addition to the established entry into cells via ACE2 принимая во внимание его влияние на, other mechanisms of SARS-CoV-2 entry are currently under investigation, for example, through CD147. Pathogenesis of comorbidity can be determined by the influence of the virus on various links which are meaningful for atherogenesis: generation of oxidized forms of LDL, launch of a cytokine storm, damage to the endothelial glycocalyx, and mitochondrial injury. The transformation of a stable plaque into an unstable one plays an important role in the pathogenesis of atherosclerosis complications and can be triggered by COVID-19. The impact of SARS-CoV-2 on large vessels such as aorta is more complex than previously thought considering its impact on vasa vasorum. Current information on the mutual influence of the medicines used in the treatment of atherosclerosis and acute COVID-19 is briefly summarized

Hearing loss in infancy leads to preventable speech, language, and cognitive developmental delay [1, 2]. Sensorineural hearing loss (SNHL) is caused by damages, problems, or issues related to the inner ear such as the cochlea with or without the auditory nerve; cranial nerve VIII, involvement. There are three anatomic areas which include the outer ear: composed of the auricle and external auditory canal and the middle ear: which includes the tympanic membrane, ossicles, and the middle ear space, the inner ear: composed of the cochlea, semi-circular canals, and internal auditory canals. The unique anatomical shape of the auricle catches the incoming sound waves to send them down the external auditory canal. Hearing risk assessment should be part of all health visits while regular hearing screening checks are done for all children from 4 to 21 years [1, 2]. Assessment of hearing loss includes history, physical examination and specific hearing assessment tests.

Biofilms are usually defined as surface-associated microbial communities, surrounded by an extracellular polymeric substance matrix. There are three major steps that are observed in biofilm formation: initial attachment events, microcolony formation and construction of mushroom-like structure with secretion of extracelluar polymeric substances. These substances can be considered a mechanism to protect the bacterial community from external insults.Biofilms, significantly increase the ability of the pathogen to evade both host defenses and antibiotics and they are being implicated in the pathogenesis and also clinical manifestation of several infections. They cause a variety of persistent infections, such as native valve endocarditis, osteomyelitis, dental caries, middle ear infections, ocular implant infections, urinary tract infections and cystic fibrosis. Established biofilms can tolerate antimicrobial agents at concentrations of 10–1000-times that needed to kill genetically equivalent planktonic bacteria, and are also resistant to phagocytosis, making biofilms extremely difficult to eradicate from living hosts. Consequently, biofilm-related infections that appear to respond to a therapeutic course of antibiotics may relapse weeks or even months later, making surgical removal and replacement of the infected tissue or medical device a frequent and unfortunate necessity.Several pathogens associated with chronic infections, including Pseudomonas aeruginosa in cystic fibrosis pneumonia, Haemophilus influenzae and Streptococcus pneumoniae in chronic otitis media and Enteropathogenic Escherichia coli in recurrent urinary tract infections, are linked to biofilm formation.

Biomaterials are the basis for the development of medicine because they allow safe contact with a living organism. The aim of this work was to produce innovative oxide layers with a porous microstructure on the surface of commercially pure titanium Grade 4 (CpTi G4), and to characterize their properties as drug carriers. Anodization of the CpTi G4 subjected to mechanical grinding and electrochemical polishing was carried out in a solution of 1M ethylene glycol with the addition of 40 g of ammonium fluoride at a voltage of 20 V for 2, 18, 24 and 48 hours at room temperature. It was found that the longer anodization time, the greater the number of pores formed on the CpTi G4 surface as revealed by FE-SEM method, and the greater the surface roughness determined in profilometric tests. As the anodizing time increases, the amount of the drug in the form of gentamicin sulfate incorporated into the resulting pores decreases. The most favorable drug release kinetics profile determined by UV-VIS absorption spectroscopy was found for the CpTi G4 anodized for 2 h making them the best choice when it comes to the drug carrier allowing full use of the therapeutic dose of the drug.

Spondyloarthritis comprises of a group of inflammatory diseases of the joints and spine with various clinical manifestations. The group includes ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthritis. The exact etiology and pathogenesis of spondyloarthritis are still unknown, but five hypotheses explaining the pathogenesis exist. These hypotheses suggest that spondyloarthritis is caused by arthritogenic peptides, an unfolded protein response, HLA-B27 homodimer formation, malfunctioning endoplasmic reticulum aminopeptidases, and, last but not least, gut inflammation and dysbiosis. Here we discuss the five hypotheses and the evidence supporting each. In all of these hypotheses, HLA-B27 plays a central role. It is likely that a combination of these hypotheses, with HLA-B27 taking center stage, will eventually explain the development of spondyloarthritis in predisposed individuals.

Polymer inclusion membranes (PIMs), which contained cellulose tri-acetate used as a polymer base, a plasticizer in the form of o-NPOE, and meso-tetra methyl tetrakis-[methyl-2-(4-acetlphenoxy)] calix[4]pyrrole (KP) used as a carrier, were prepared and tested for the effective purification of aqueous solutions of methylene blue dye. The scanning electron microscope (SEM), thermogravimetric analysis (TGA), and attenuated total reflection Fourier transform infrared (ATR-FTIR) were used to define the microstructure and surface of PIMs. Experimental results showed that with the increased concentration of methylene blue in an aqueous solution, the removal percentage also increased. Further observation also showed that the flux increased with the rise of the source phase pH values from 3 to 10. The carrier and plasticizer content in the membrane significantly influenced the membrane’s transport properties. The optimal composition of the membrane in per cent by weight was for KP: 74% plasticizer; 18% support; 8% carrier. It was shown that the membrane with optimal composition showed good reusability and enabled the easy and spontaneous separation of methylene blue from aqueous solutions.

An oxidation resistant coating on cemented tungsten carbides is characterised in this work. Cemented tungsten carbides (cWCs) are routinely used in mining and manufacturing but are also candidate materials for compact radiation shielding in fusion power generation. In both environments, cWCs will suffer significant degradation due to oxidation at relatively low temperatures. In a recent study, a Si-deposition coating method was demonstrated to improve the oxidation resistance of cWCs by up to a factor of 1,000. This work focusses on the growth kinetics, phase composition, and mechanical properties of these coatings. By combining quantitative X-ray diffraction, electron microscopy and nanoindentation, we show that the coating layer has a 20 % higher hardness than the substrate, which was explained on the basis of a previously-unknown presence of a fine distribution of very hard SiC laths. To interpret the coating stability, a coating growth map is developed. The map shows the structure is stable under a broad range of processing temperatures and composite compositions, demonstrating the potential application of these coatings in a variety of nuclear shielding cWCs.

Nonlinear single unit activity (SUA) characteristics are the useful measures to reveal the information processing and transfer features associated with Parkinson’s disease (PD) in the basal ganglia. Most of the state-of-the-art approaches to compute such parameters in continuous and discrete forms are strongly dependent on SUA recording length, noise level and input parameters. Due to the specificity of SUA data collection (mainly short recordings with relatively low signal-to-noise ratio) new techniques to evaluate neuronal nonlinear properties are needed. We have developed an encoding technique based on a mean interspike interval (ISI) value to calculate spike train discrete nonlinear features. The approach to compute mutual information (MI) of isolated neurons with its unstructured activity was also proposed. The proposed technique of SUA nonlinear features evaluation slightly depends on spike train length, has low correlations with other SUA characteristics (firing rate, coefficient of ISI variance and asymmetry index). The derived entropy measure in the subthalamic nucleus has significant positive correlation with PD severity. The proposed approach provides nonlinear features that are slightly dependent on investigated sample size and independent on input parameters. Also, the developed mean ISI based measures reflect the more complex nature of oscillatory activity in the basal ganglia, than it was thought previously. Moreover, MI, unlike entropy, takes into account the position of the spike train elements, which allows us to investigate the amount of information retained after the occurrence of temporary failures. The developed approach may be useful in describing nonlinear features of basal ganglia activity contributing to PD pathophysiology probably associated with impaired information transfer in movement disorders.

Solar radiation is the main energy source for mankind and an accurate data of solar radiation levels for a particular location is vital for the optimum operation of solar energy transducers such as photovoltaic cells and solar thermal collectors. In this work, we show that there is a linear relationship between recorded monthly average temperatures and solar radiation in Swaziland. The correlation can be utilized to develop two mathematical models for the estimation of solar radiation: one from the measured monthly average temperatures and the other based on the square-root of the difference between measured maximum and minimum monthly average temperatures. Both models fit the data well and can be applied to estimate solar radiation in other parts of the region.

Abiotic stress is responsible for significant reduction in crop plant productivity worldwide. Ultraviolet (UV) radiation is a natural component of sunlight and a permanent environmental stimulus. This study investigated the distinct responses of young wheat and einkorn plants to excessive UV-B radiation (180 min at λmax 312 nm) following foliar pretreatment with 1 µM synthetic cytokinin 4PU-30. Results demonstrated that UV radiation significantly amplified hydrogen peroxide levels in both wheat and einkorn, with einkorn exhibiting more pronounced increase compared to wheat. This elevation indicated the induction of oxidative stress by UV radiation in the two genotypes. Intensified antioxidant enzyme activities and increased accumulation of typical stress markers and non-enzyme protectants were evidenced. Transcriptional activity of genes encoding key antioxidant enzymes was also investigated aiming to elucidate the genetic regulation of the antioxidant systems in both wheat and einkorn seedlings. Our results suggested a role for POX1 and POX7 genes in the UV-B tolerance of the two wheat species as well as a cytokinin stimulated UV-B stress response in einkorn mediated through upregulation of the tau subfamily gene GSTU6. Based on these findings it could be concluded that 4PU-30 had the potential of alleviating oxidative stress by attenuating the symptoms of superfluous UV-B illumination in the two examined plant species.

The 5-hydroxymethylfurfural (HMF) is a six-carbon heterocyclic organic compound with two substituents an aldehyde group and an alcohol group. It is formed from saccharides as a result of two reactions: the Maillard reaction and the caramelization of saccharides. It has both a negative and a positive effect on the human body, which makes it, even more, an attractive research object. The objective of the study was to determine HMF content in honey samples available on the Polish market using three varied methods and compare the results obtained. The methodology used included: two spectrophotometric methods (by White and Winkler) and the HMF determination method based on the LC-MS/MS technique developed uniquely for this study. The determined HMF content in all tested honey samples did not exceed the applicable standard. All results are within the scope of the European Council Directive 2001/110/EC of 20 December 2001, i.e. they do not exceed HMF content in honey, which is 40 mg/kg.

The increasing emergence of multidrug resistant (MDR) pathogens causes difficult-to-treat infections, with long-term hospitalizations and high incidence of death, thus representing a global public health problem. To manage MDR bacteria bugs, new antimicrobial strategies are necessary, and their introduction in practice is a daily challenge for scientists in the field. An extensively studied approach to treat MDR infections consists in inducing high levels of reactive oxygen species (ROS) by several methods. Although further clinical investigations are mandatory on the possible toxic effects of ROS to mammalian cells, clinical evaluations are extremely promising, and their topical use to treat infected wounds and ulcers, also in presence of biofilm, is already clinically approved. Biochar (BC) is a carbonaceous material obtained by pyrolysis of different vegetable and animal biomass feedstocks, at 200−1000 °C in limited presence of O2. Recently, it has been demonstrated that BC capability of removing organic and inorganic xenobiotics is mainly due to the presence of persistent free radicals (PFRs), which can activate oxygen, H2O2 or persulfate in the presence or not of transition metals by electron transfer thus generating ROS, which in turn degrade pollutants by advanced oxidation processes (AOPs). In this context, the antibacterial effects of BC containing PFRs have been demonstrated by some authors against Escherichia coli and Staphylococcus aureus, thus giving birth to our idea of the possible use of BC-derived PFRs as a novel method capable of inducing ROS generation for antimicrobial oxidative therapy. Here, the general aspects concerning ROS physiological and pathological production and regulation, and the mechanism by which they could exert antimicrobial effects have been reviewed. The methods currently adopted to induce ROS production for antimicrobial oxidative therapy have been discussed. Finally, for the first time, BC-related PFRs have been proposed as a new source of ROS for antimicrobial therapy via AOPs.

Molecular-scale density fluctuations at equilibrium produce cavities in a liquid and can be analyzed to shed light on the statistics of the number of molecules occupying observation volumes of increasing radius. An information theory approach led to the conclusion that these probabilities should follow a Gaussian distribution function. This prediction has been confirmed by computer simulations in different liquid models if the size of the observation volume is not large. The reversible work of cavity creation is exactly linked to the probability of finding zero molecules in a given observation volume. The Gaussian formula for the latter probability is scrutinized to arrive at the enthalpy and entropy changes associated with cavity creation. The reversible work of cavity creation has a purely entropic origin due to the solvent-excluded volume effect produced by the inaccessibility of a given region of the configurational space. The consequent structural reorganization of liquid molecules leads to exactly compensating enthalpy and entropy changes. These results are in line with those obtained in a direct statistical mechanical study by Lee.

The reactivity of 3,5-di-(pyridin-4-yl)-1,2,4-thiadiazole (L1) with 1,4-diiodotetrafluorobenzene (1,4-DITFB) was explored and the halogen-bonded 1:1 co-crystal (1) was successfully isolated and structurally characterized.

This article has been studied the synthesis of a new derivative of the known alkaloid cytisine contained in the seeds of plants of Cytisus laburnum L. and Thermopsis lanceolata R.Br., both of the Lugiminosae family. The new compound has been obtained from two biologically active compounds such as isoxazole and cytisine. It has been demonstrated that the reaction led to the single-stage method under very mild conditions to obtain some 4-[(3,5-dimethyl-1,2-oxazole-4-yl)sulfonyl]amides. This class of compounds is promising to obtain the new biologically active compounds. This article has examined in detail a structure with using the 1H and 13C NMR and two-dimensional NMR spectroscopy of COSY (1H-1H), HMQC (1H-13C) and NMVS (1H-13C). As a result, the homo- and heteronuclear spin-spin couplings should be established. The X-ray diffraction analysis has determined the spatial structure of a new derivative based on cytisine alkaloid. Thus, its hemorheological activity has been studied.

Paratuberculosis, or Johne's disease, caused by Mycobacterium avium subsp. paratuberculosis (MAP), is a chronic granulomatous enteritis affecting both domestic and wild ruminants. The agent was also found in wild mammals such as wild boar (Sus scrofa), however, the role of wild mammals in the epidemiology of MAP is unclear. During the research period, 941 free-ranging wild boar (S. scrofa) legally hunted in two locations in the Centre-eastern region of Portugal were examined. Ninety-seven wild boar exhibited one or more gross lesions and were tested for the presence of Mycobacterium avium subsp. paratuberculosis using acid-fast staining, mycobacterial culture, poly-merase chain reaction (PCR), and histopathological examination. Forty-five animals (46.4%, 95% CI: 36.5-56.3%) were identified as infected, as indicated by positive results in culture and/or PCR. The findings revealed that the most significant risk factor was being a juvenile compared to year-lings and adults (OR = 10.2, 95% CI: 2.2-48.0). Based on our results, 37.9% (n = 11) of the infected animals were considered suitable for human consumption. Our findings offer novel insights into mycobacterial infections in wild boar populations in Portugal and suggest that wild boar could be a source of human infection if zoonotic potential is considered.

Analysis of liquid biopsy samples can reveal a wealth of molecular as well as cellular entities circulating in various body fluids. These entities include circulating tumor cells, circulating cell-free and tumor DNA, RNA, and proteins. Detection and characterization of this genetic and proteomic material can provide crucial information on tumor characteristics, including its heterogeneity, biology, tumor progression, staging, associated gene mutations and the course of therapy. The increased use of liquid biopsy in clinical oncology offers in non-invasive manner easier tumor sampling and continuous monitoring of the disease evolution through repetitive sampling from cancer patients. The continuous monitoring offered by this method is highly relevant to the assessment of a given therapeutic regime and early detection of markers associated with possible drug resistance, which may develop in the course of the therapy. The use of proteomic approaches, including mass spectrometry-based proteomics for the analysis of biofluids extends for over three decades, yet only in the last few years such methods have found their way to clinical oncology. The non-invasive nature of liquid biopsy and the simple procedures for sample collection made this approach far more attractive than the traditional and well-established tissue biopsy. Such preference becomes more practical in the analysis of solid tumors, particularly in pediatric population. In this review we discuss some works on the emerging role of liquid biopsy analyses in clinical oncology, and how such use allows a better understanding of diagnosis, prognosis, disease evolution and response to therapy of various forms of cancer. We also discuss the role of MS-based methods in the characterization of post-translational modifications of proteins circulating in liquid biopsies.

This review provides information on acne transcriptomics allowing deeper insights into acne pathogenesis and isotretinoin´s mode of action. Puberty-induced insulin-like growth factor 1 (IGF-1), insulin and androgen signaling activate the kinase AKT and mechanistic target of rapamycin complex 1 (mTORC1). Western diet (hyperglycemic carbohydrates, milk/dairy products) as well co-stimulate AKT/mTORC1 signaling. AKT-mediated phosphorylation of nuclear FoxO1 and FoxO3 results in their extrusion into the cytoplasm, a critical switch, which enhances the transactivation of lipogenic and proinflammatory transcription factors including androgen receptor (AR), sterol regulatory element-binding transcription factor 1 (SREBF1), peroxisome proliferator-activated receptor γ (PPARγ), and signal transducer and activator of transcription 3 (STAT3) but reduces FoxO1-dependent expression of GATA binding protein 6 (GATA6), the key transcription factor of infundibular keratinocyte homeostasis. AKT-mediated phosphorylation of the p53-binding protein MDM2 promotes the degradation of p53. In contrast, isotretinoin enhances the expression of p53, FoxO1 and FoxO3 in sebaceous glands of acne patients. Overexpression of these proapoptotic transcription factors explains isotretinoin´s desired sebum-suppressive effect via induction of sebocyte apoptosis but also its adverse effects including teratogenicity (neural crest cell apoptosis), reduced ovarian reserve (granulosa cell apoptosis), risk of depression (apoptosis of hypothalamic neurons), VLDL hyperlipidemia, intracranial hypertension and dry skin.

Abstract: The glucocorticoid receptor (GR), including both alternative spliced isoforms (GRa and GRb), has been implicated in the development of primary open-angle glaucoma (POAG) and iatrogenic glucocorticoid-induced glaucoma (GIG). POAG is the most common form of glaucoma, which is the leading cause of irreversible vision loss and blindness in the world. Glucocorticoids (GCs) are commonly used therapeutically for ocular and numerous other diseases/conditions. One serious side effect of prolonged GC therapy is the development of iatrogenic secondary ocular hypertension (OHT) and OAG (i.e. GC-induced glaucoma (GIG)) that clinically and pathologically mimics POAG. GC-induced OHT is caused by pathogenic damage to the trabecular meshwork (TM), a tissue involved in regulating aqueous humor outflow and intraocular pressure. TM cells derived from POAG eyes (GTM cells) have lower expression of GRb, a dominant negative regulator of GC activity, compared to TM cells from age-matched control eyes. Therefore, GTM cells have a greater pathogenic response to GCs. Almost all POAG patients develop GC-OHT when treated with GCs, in contrast to a GC responder rate of 40% in the normal population. Increased expression of GRb can block GC-induced pathogenic changes in TM cells and reverse GC-OHT in mice. Endogenous expression of GRb in the TM may relate to differences in the development of GC-OHT among the normal population. A number of studies have suggested increased levels of endogenous cortisol in POAG patients as well as differences in cortisol metabolism, suggesting that GCs may be involved in the development of POAG. Additional studies are warranted to better understand the molecular mechanisms involved in POAG and GIG in order to develop new disease modifying therapies to better treat these two sight threatening forms of glaucoma.

The recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread so rapidly and severely affected the people of almost every country in the world. The highly contagious nature of this virus makes it difficult to take control of the present pandemic situation. With no specific treatment available, the coronavirus disease 2019 (COVID-19) presents a threat to people of all ages including the elderly people and people with other medical complications as a vulnerable group to this disease. Better understanding of viral pathogenesis, appropriate preventive measures, early diagnosis and supportive treatments of the infected patients are now the general solutions to fight against this viral transmission. But, as an emerging disease, most about it remains still poorly understood. This article holds an overview on the origin and structure, pathogenesis, diagnosis and possible therapeutic options for the causative agent, SARS-CoV-2 and disease, COVID-19. However, few therapeutic options, laboratory experiments and other strategies proposed here need to be further clinically tested.

This article aims to analyze household energy data to predict electricity self-sufficiency and identify the key features that impact it. For this purpose, we use SHAP (Shapley Additive Explanations), LightGBM (Light Gradient Boosting Machine), and a correlation heatmap-based framework to analyze 12 months of energy and questionnaire survey data collected from over 200 smart houses in Kitakyushu, Japan. We use the SHAP summary plot to identify the impact-wise order of key features influencing the electricity self-sufficiency rate (ESSR). Using SHAP, we demonstrated that key features are; housing types, average monthly electricity bill, floor heating, electric capacity, number of washing and drying machines, fee plans, occupation of household head, total floor area, average monthly gas bill, cooking equipment, etc. Furthermore, we adopted the LightGBM classifier with $\ell^1$ regularization to extract the most significant features and predict the electricity self-sufficiency rate of households. This LightGBM-based model can also predict the electricity self-sufficiency rate of households that did not participate in the questionnaire survey. A heat map is also used to analyze the correlation among household variables. The findings discussed in this article offer valuable insights for energy policymakers to achieve the targets of energy self-sufficient houses.

Synergistic effects between reactions, reagents and catalysts can lead to minor heats of reaction and occur as an inherent result of multi-component reactions (MCRs) and their extensions. They enable syntheses to be performed at a low energy level and the number of synthesis steps to be drastically reduced in comparison with ‘classical’ two-component reactions. The very high potential for variability, diversity and complexity of MCRs additionally generates an extremely diverse range of products, thus bringing us closer to the aim of being able to produce tailor-made and extremely low-priced materials, drugs and libraries.

Postprandial glucose levels between 4 and 7.9 hours (PPG4–7.9h) correlate with mortality from various diseases including hypertension, diabetes, cardiovascular disease, and cancer. This study aimed to assess if predicted PPG4–7.9h could diagnose diabetes. Two groups of participants were involved: Group 1 (4420 participants) had actual PPG4–7.9h, while Group 2 (8422 participants) lacked this measure but had all the diabetes diagnostic measures. Group 1 underwent multiple linear regression to predict PPG4–7.9h using 30 predictors, achieving accuracy within 11.1 mg/dL in 80% of the participants. Group 2 had PPG4–7.9h predicted using this model. Receiver operating characteristic curve analysis showed that predicted PPG4–7.9h could diagnose diabetes with an accuracy of 87.3% in Group 2, with a sensitivity of 75.1% and specificity of 84.1% at the optimal cutoff of 102.5 mg/dL. Simulation on 10,000 random samples from Group 2 revealed that 175 participants may be needed to investigate PPG4–7.9h as a diabetes diagnostic marker with a power of at least 80%. In conclusion, predicted PPG4–7.9h appears to be a promising diagnostic indicator for diabetes. Future studies seeking to ascertain its definitive diagnostic value might require a minimum sample size of 175 participants.

Pueraria mirifica (PM), a plant whose dried and powdered tuberous roots are now widely used in rejuvenating preparations to promote youthfulness in both men and women, may have major estrogenic influence. In this study, we investigated modifying effects of PM at various doses on mammary and endometrial carcinogenesis in female Donryu rats. Firstly, PM administered to ovariectomized animals at doses of 0.03%, 0.3%, and 3% in a phytoestrogen-low diet for 2 weeks caused significant increase in uterus weight. Secondly, a 4 week PM application to non-operated rats at a dose of 3% after 7,12-dimethylbenz[a]anthracene (DMBA) initiation resulted in significant elevation of cell proliferation in the mammary glands. In a third experiment, postpubertal administration of 0.3% (200 mg/kg body weight (b.w.)/day) PM to 5-week-old non-operated animals for 36 weeks following initiation of mammary and endometrial carcinogenesis with DMBA and N-ethyl-N′-nitro-N-nitrosoguanidine (ENNG), respectively, resulted in significant increase of mammary adenocarcinoma incidence. A significant increase of endometrial atypical hyperplasia multiplicity was also observed. Furthermore, PM at doses of 0.3% and, more pronouncedly, of 1% induced dilatation, hemorrhage and inflammation of the uterine wall. In conclusion, postpubertal long-term PM administration to Donryu rats exerts estrogenic effects in the mammary gland and uterus, and at a dose of 200 mg/kg b.w./day was found to promote mammary carcinogenesis initiated by DMBA.

Hydrogen gas (H2) has attracted attention as a next-generation clean energy source. Its efficient and safe preparation and utilization are crucial in both industry and organic chemistry. In this study, a Pt/CB-catalyzed MW-mediated continuous-flow hydrogenation reaction was developed using methylcyclohexane (MCH) as the reducing agent (hydrogen carrier). Alkynes, alkenes, nitro groups, benzyl esters, and aromatic chlorides were chemoselectively hydrogenated using Pt/CB under MW-assisted continuous-flow conditions. This methodology represents a safe and energy-efficient hydrogenation process, as it eliminates the need for an external hydrogen gas supply or heating jackets as a heat medium. Further application of MW-mediated continuous-flow hydrogenation reactions is a viable method for the efficient generation and utilization of sustainable energy.

The importance of contact with nature for human health was confirmed by numerous research. One of the sometimes neglected fields is the landscape design of hospital premises. This study focuses on the perception and preferences of prospective patients regarding the hospital site design. The methodology included anonymous survey with images and lists of adjectives. The online questionnaire was distributed using e-mails and social media from 4th May to 8th July 2024. The objective was to include all age groups. The results confirm previous studies and demonstrate the importance of landscape architecture design of hospital premises for the well-being of patients. The findings may inform the design of hospital sites.

Acute Respiratory Distress Syndrome (ARDS) is a severe lung condition with a high mortality rate for which there are no effective therapeutics. The failure of the alveolar-capillary barrier, composed of lung endothelial (EC) and alveolar epithelial (AEC) cells, is a critical factor leading to excessive inflammation and edema characteristics of acute lung injury (ALI). Phosphodiesterases (PDE) are enzymes well-recognized for their roles in regulating endothelial permeability and inflammation. Although PDE inhibitors are used as therapeutics for inflammatory diseases like COPD (chronic obstructive pulmonary disease), their efficacy in treating ARDS has not yet been established. In this study, we investigate the effects of ensifentrine, an FDA-approved novel dual PDE 3/4 inhibitor, on lung endothelial and epithelial dysfunction caused by methicillin-resistant S. aureus (MRSA), a pathogen involved in bacterial ARDS. Human primary lung endothelial cells and alveolar epithelial cell lines (A549 and immortalized AEC) were treated with heat-killed MRSA, and their responses were assessed in the presence or absence of ensifentrine. Ensifentrine given either pre- or post exposure attenuated MRSA-induced increased lung endothelial permeability. VE-cadherin junctions, which serve to stabilize the EC barrier, were disrupted by MRSA; however, ensifentrine effectively prevented this disruption. Pre-treatment with ensifentrine protected against MRSA-induced EC pro-inflammatory signaling by inhibiting the expression of VCAM-1, ICAM-1, and by reducing the IL-6 release. In AEC, MRSA caused upregulation of ICAM-1, activation of NF-kB and production of IL-8, all of which were inhibited by ensifentrine. These results indicate that dual inhibition of phosphodiesterases 3 and 4 by ensifentrine is barrier protective and attenuates MRSA-induced inflammation in both lung endothelial and epithelial cells. The PDE3/4 inhibitor ensifentrine may represent a promising novel strategy for the treatment of ALI.

Stage IV grade C localized periodontitis (pre-puberal localized aggressive periodontitis/LPP), an extremely rare form of periodontal disease, occurs in otherwise healthy individuals (no signs of dental plaque/calculus) due a hyper-aggressive auto-immune response to high periodontopathic bacteria levels. Methods: A 4-year-old Caucasian girl with unusual high mobility of temporary lower left canine and localized gingival inflammation was misrecognized by multiple clinicians (initially diagnosed with hypophosphatasia, genetic and metabolic disorders, all turning negative), over a period of 4-6 month, despite initial radiographs showing clear pathognomonic signs. LPP diagnostic was made by the last clinician, but by now the tooth was lost. Similar inflammation signs appeared around the lower temporary right canine. X-ray examination showed similar bone and periodontal loss as previously seen, while periodontopathic bacteria tested highly positive. The patient received both mechanical cleaning and ten days systemic antibiotic treatment (Augmentin and Metronidazole). Results: Two months after, inflammation signs disappeared, with periodontal regeneration radiologically present, and only small periodontopathic bacteria precursors concentrations. Conclusions: Despite initial periodontal loss, an adequate treatment can keep under control an LPP disease. Moreover, bone and periodontal regeneration appears if periodontopathic bacteria scores are kept lower, showing the importance of fast adequate diagnostic and treatment.

In this paper we suggest a first ever construction of fractional integral and differential operators based on signed measures including a vector-valued case. The study focuses on constructing the fractional power of the Riemann-Stieltjes integral with a signed measure, using semigroup theory. The main result is a theorem that provides the exact form of a semigroup for the Riemann-Stieltjes integral with a measure having a countable number of extrema. The article provides examples of semigroups based on integral operators with signed measures and discusses the fractional powers of differential operators with partial derivatives.

The study of precipitation amount at different time scales constitutes an important issue in climate research and risk assessment. When dealing with daily totals, a frequent but sometimes underestimated problem is at what time the observation day begins. The choice of different starting times may lead to incompatibility between stations and incorrect identification of extreme events. In this work, the problem of temporal misalignment between precipitation datasets characterized by different starting time of the observation day is analyzed. The most widely used adjustment methods (1day and uniform shift) and two methods based on reanalysis (NOAA and ERA5) are evaluated in terms of temporal alignment, precipitation statistics and percentile distributions. As test series, the precipitation amount collected from 9 a.m. local time (09 LT) on the previous day to 09 LT on the target day (9-9 datasets) of the Padua and nearby stations in the period 1993-2022 have been selected. Results show that the reanalysis-based methods, in particular ERA5, outperform the others in temporal alignment, regardless the station. But, for the periods in which reanalysis data are not available, “1day” method, which shifts the daily amount back one calendar day, and “unif” method, which distributes uniformly the daily total from a 2-day moving window surrounding the target date, can be considered valid alternatives. On the other side, concerning the precipitation statistics, the reanalysis-based methods are not the best option, as they increase the precipitation frequency and reduce the mean value over wet days, NOAA much more than ERA5. Nevertheless, the uniform method provides a larger deviation from the original daily series. The use of the series of a station nearby the target one, which is mandatory in case of missing data, gives similar or better results than applying any adjustment method to the 9-9 series. General conclusions can hardly be drawn as they depend on the method and station. For the Padua dataset, the analysis was repeated at monthly and seasonal resolution. In general, the adjustment series show the most relevant changes in the precipitation statistics in summer and less temporal alignment with the original series in summer and autumn, the two seasons mainly affected by heavy rains in Padua. Finally, the percentiles distribution, analyzed for all the methods and stations, indicates that any adjustment method underestimates the percentile values, except ERA5. Only Legnaro, the station most correlated with Padua, gives results like ERA5.

New dimers of selected dipyridothiazines with an m-xylene linker have been designed, synthesized and characterized. Their structure was identified using 1H and 13C NMR as well as 2D NMR techniques (COSY, ROESY, HSQC and HMBC experiments) and HR MS spectrometry. The compounds were subjected to preliminary in silico biological profile tests using the Way2Drug server and analysis of the probable cytotoxic effect on various cancer cell lines. Preliminary in vitro cytotoxicity tests were performed against normal cell lines (HaCaT) and five cancer cell lines (SW480, SW620, MDA-MB-231, A-549, LN-229) showing moderate activity. An analysis of the structure-activity relationship was performed.

Stroke represents one of the neurological diseases most responsible for death and permanent disability in the world. Different factors, such as thrombus, emboli and atherosclerosis, take part in the intricate pathophysiology of stroke. Comprehending the molecular processes involved in this mechanism is crucial to developing new, specific and efficient treatments. Some common mechanisms are excitotoxicity and calcium overload, oxidative stress, and neuroinflammation. Furthermore, non-coding RNAs (ncRNAs) are critical in pathophysiology and recovery after cerebral ischaemia. ncRNAs, particularly microRNAs, and the long non-coding RNAs (lncRNAs) are essential for angiogenesis and neuroprotection, and they have been suggested to be therapeutic, diagnostic and prognostic tools in cerebrovascular diseases, including stroke. This review summarizes the intricate molecular mechanisms underlying ischemic and hemorrhagic stroke and delves into the function of miRNAs in the development of brain damage. Furthermore, we will analyze new perspectives on treatment based on molecular mechanisms in addition to traditional stroke therapies.

The information about the BCoV receptors, co/receptors that might be involved in the BCoV entry to the host cells is inconceivable. In addition to that, the roles of other host cell proteases, such as Furin and TMPRSS2, have not yet been well studied during BCoV replication. The current study’s main objectives are to identify some novel BCoV receptors and host cell proteases that might fine-tune the BCoV replication, tissue tropism, and molecular pathogenesis. We used a combination of some in silico prediction, molecular docking, and gene expression profile tools to predict some new BCoV receptors out of some known other coronavirus receptors and some host cell enzymes that are potentially involved in BCoV replication. To achieve these goals, we applied the in-silico prediction tools to check the potential interactions between eh BCoV/S glycoprotein and some known coronaviruses receptors (ACE2, APN1, NPR1, CECAM-1, AXL, and DPP4). We also established some potential models for the interaction between the BCoV/S and some common host cell proteases proved to play important roles in other coronavirus replication cycle (Furin, TMPRRS2, and Cathepsin-L). To confirm our prediction models, we assessed the gene expression profiles of these potential receptors and proteases in some bovine cell lines infected with BCoV using the next generation sequencing and the qRT-PCR assay. Our results show that the NPR1, AXL1 and the ACE2 have the strongest and firm binding affinities to the BCoV-S protein. Our prediction models and gene expression profiles show the potential bindings of the Furin and TMPRSS2 to the BCoV-S polybasic cleavage site (RRSRR|A). Notably, high expression of the host cell Furin was observed in response to both BCoV/Ent and BCoV/Resp infection, whereas TMPRSS2 expression was upregulated in the case of the BCoV/Ent infection, positioning Furin as a common receptor for different BCoV isolates. Further research is needed to study the roles of these top-ranked receptors and host cell proteases in molecular pathogenesis, and tissue tropism.

Background: Histone deacetylases (HDACs) are implicated in carcinogenesis, and HDAC inhibitors (HDACis) are explored as a therapeutic tool in several tumors. The aim of this study was to evaluate the clinical significance of HDAC -2, -4, and -5 expression in epithelial ovarian carcinoma (EOC). Methods: HDAC-2, -4, and -5 immunohistochemical expression was examined in 92 EOC tissue specimens and was correlated with clinicopathological characteristics. Results: HDAC-2 was the most frequently (94.4%) expressed isoform, being marginally higher in serous tumors compared with other types (p=0,08). HDAC-5 was the less frequently expressed (28.1%), being positively associated with HDAC-4. HDAC-4 positivity was associated with lower FIGO-stage (p=0,045) and T-category (p=0.,043) and the absence of lymph node (p=0,05) or distant metastasis (p=0,09) in serous carcinomas. HDAC-2 positivity was correlated with absence of lymph node metastasis in serous tumors (p=0,045). On the contrary, HDAC-5 nuclear positivity was correlated with lymph node metastasis in the entire cohort (p=0,048). HDAC-4 positivity was marginally associated with favorable prognosis in serous carcinomas in univariate survival analysis (p=0,086), a correlation which was not significant in multivariate analysis. Conclusion: These findings suggest a differential expression of HDAC-2, -4 and -5, providing evidence for a potential role in the pathobiology of EOC.

C. albicans Dfg5 and Dcw1 are homologous cell wall alpha-1,6-mannosidases with important functions. Our past studies have shown that Dfg5 and Dcw1 function in cell wall biogenesis via cross-linking of glycoproteins into the cell wall, thus playing a key role in cell wall integrity. Additionally, Dfg5 and Dcw1 are required for hyphal morphogenesis. However, the exact functions of Dfg5 and Dcw1 in cell wall integrity, hyphal morphogenesis, and pathogenesis were not known. In this study, we determined the relation of Dfg5 and Dcw1 with Hog1 MAPK, that plays a key role in cell wall integrity via regulation of chitin synthesis in C. albicans. Additionally, we also determined the effect of dfg5 and dcw1 mutations on gene expression of transcriptional regulators of hyphal morphogenesis. Furthermore, we determined the effects of dfg5 and dcw1 mutations on pathogenesis in a mouse model of oral candidiasis. Our results demonstrate that dfg5 and dcw1 mutations, as well as hog1 knock-out mutation result in dysregulation of chitin synthesis resulting in a cell separation defect. The heterozygous and conditional mutations of dfg5 and dcw1 result in decreased levels of Cst20, a positive regulator of hyphal morphogenesis. However, mutations of dfg5 and dcw1 mutations resulted in increased levels of all the five negative regulators of hyphal morphogenesis – Tup1, Nrg1, Mig1, Rbf1 and Rfg1. However, Tup1 levels were significantly higher than other negative regulators indicating that Dfg5 and Dcw1 function in hyphal morphogenesis by repression of Tup1. Finally, dfg5 and dcw1 mutations affected the ability of C. albicans to cause oral candidiasis in mice. Thus, cell wall glycosidases, Dfg5 and Dcw1, are required for virulence and pathogenesis and represent novel drug targets.

Leukemia cutis (LC) is defined as leukemic infiltration of the epidermis, the dermis, and the subcutaneous tissue. Leukemia cutis may follow or occur simultaneously with the diagnosis of systemic leukemia. However, cutaneous lesions are occasionally diagnosed as the primary manifestation of leukemia. Leukemic skin infiltrations demonstrate considerable variation regarding number of changes, distribution, and morphology. The highest incidence of LC is observed in chronic lymphocytic leukemia, monocytic and myelomonocytic acute myeloid leukemia, and in T-cell lineage leukemia. Although the pathogenic mechanism of the invasion of leukemic cells into the skin is not well understood, chemokine receptors and adhesion molecules as well as genetic characteristics of leukemia are thought to play a role. Leukemic skin lesions may be localized or disseminated and may occur alone or in combination on any site of the skin, most frequently in the trunk and extremities. The most common clinical presentations of leukemia cutis are papules, nodules, macules, plaques, and ulcers. In most patients, complete or partial resolution of cutaneous infiltrations occurs simultaneously with hematologic remission. However, in patients with resistant disease or recurrent skin infiltration, local radiotherapy can be used. This review presents recent data on the pathogenesis, diagnosis and treatment of leukemic skin involvement in different types of leukemia

Barrett’s esophagus (BE) is a premalignant lesion for esophageal adenocarcinoma (EAC). Development of Barrett’s esophagus is caused by biliary reflux that provokes intensive mutagenesis in stem cells of epithelium in distal esophagus and gastro-esophageal junction. Other possible cell origins of Barrett’s esophagus include stem cells of mucosal esophageal glands and their ducts, of stomach, residual embryonic cells and circulating bone marrow stem cells. Classic conception of healing of caustic lesion was replaced by idea of cytokine storm that forms inflammatory microenvironment for phenotypic shift toward intestinal metaplasia of distal esophagus. The review summarizes contemporary concepts of BE and EAC pathogenesis.

According to global data, there is a male reproductive potential decrease. Pathogenesis of male infertility often is associated with autoimmunity towards sperm antigens essential for fertilization. Antisperm autoantibodies (ASAs) have immobilizing and cytotoxic properties, impairing spermatogenesis, causing sperm agglutination, altering spermatozoa motility and acrosomal reaction, thus preventing ovum fertilization. Infertility diagnosis requires mandatory check for the ASAs. The concept of blood-testis barrier currently is re-formulated with emphasis of informational paracrine and juxtacrine effects, rather than simple anatomical separation. Aetiology of male infertility includes both autoimmune and non-autoimmune diseases, but equally develops through autoimmune links of pathogenesis. Varicocele commonly leads to infertility due to testicular ischemic damage, venous stasis, local hyperthermia, and hypoandrogenism. However, varicocelectomy can alter blood-testis barrier facilitating ASAs production as well. There are contradictory data on the role of ASAs in pathogenesis of varicocele-related infertility. Infection and inflammation both promote ASAs production due to “danger concept” mechanisms and because of antigen mimicry. Systemic pro-autoimmune influences like hyperprolactinemia, hypoandrogenism and hypothyroidism also facilitate ASAs production. Diagnostic value of various ASAs was not yet clearly attributed, and their cut-levels not agreed neither in sera nor in ejaculate. The assessment of the autoimmunity role in pathogenesis of male infertility is ambiguous.

The biogeography of inflammation in ulcerative colitis (UC) suggests a proximal to distal concentration gradient of a toxin. Hydrogen sulfide (H2S) has long been considered one such toxin candidate, and dietary sulfur along with the abundance of sulfate reducing bacteria (SRB) were considered the primary determinants of H2S production and clinical course of UC. The metabolic milieu in the lumen of the colon, however, is the result of a multitude of factors beyond dietary sulfur intake and SRB abundance. Here we present an updated formulation of the H2S toxin hypothesis for UC pathogenesis, which strives to incorporate the interdependency of diet composition and the metabolic activity of the entire colon microbial community. Specifically, we suggest that the increasing severity of inflammation along the proximal-to-distal axis in UC is due to dilution of beneficial factors, concentration of toxic factors, and changing detoxification capacity of the host, all of which are intimately linked to the nutrient flow from the diet.

Access to medical care is a global issue. Technology-aided approaches have been applied in addressing this. Interventions have however not focused on medical diagnosis as a fully automated procedure and available applications employ mainly text-based inputs rather than conversation in natural language. We explored the utility of ontology-based chatbot technology for the design of intelligent agents for medical diagnosis through a systematic review of the most recent related literature. English articles published in 2011-2016 returned 233 hits which yielded 11 relevant articles after a 3-stage screening. Findings showed that the creation of expert systems had been the focus of many the studies which utilize the physician-system-patient framework with system training based mostly on expert knowledge for designing web- or mobile phone-based applications that serve assistive purposes. Findings further indicated gaps in the design and evaluation of more effective systems deployable as standalone applications, for example, on an embodied robotic system. The need for technology supporting the physical examination part of diagnosis, connection to data sources on patients’ vitals and medical history are also indicated in addition to the need for more qualitative work on natural language-based interaction. The system should be one that is continuously learning. Future works should also be directed towards the building of more robust knowledge base as well as evaluation of theory-based diagnostic methodological options

Autoimmune bullous diseases (AIBDs) are a group of conditions marked by the formation of blisters and erosions on the skin and mucous membranes. Knowing that, most of the AIBDs are severe and resistant to treatment, we decided to look upon the nutritional aspect as a light for the future for both - patients and clinicians. In this review, we would like to summarize the evidence of the role of nutrition in pathogenesis and treatment of the following AIBDs: i) pemphigus, ii) bullous pemphigoid and mucous membrane pemphigoid, iii) dermatitis herpetiformis, and iv) epidermolysis bullosa aqusita.

This paper investigates pseudo-polymorphism in 2-pyridylmethoxy derivatives of p-tert-butylcalix[4]arene (PyC4), p-tert-butyldihomooxa-calix[4]arenes (PyHOC4), and p-tert-butylhexahomotrioxacalix[3]arenes (PyHO3C3), presenting 11 crystal structures with 15 crystallographically independent molecules. The macrocycle of PyC4 is smaller and less flexible with respect to those of PyHOC4 and PyHO3C3 and in solution, the cone conformation of these three molecules exhibit different point symmetries: C4, Cs and C3, respectively. A correlation is observed between the macrocycle's structural rigidity and the number of pseudo-polymorphs formed. The more rigid PyC4 displays a higher number (6) of pseudo-polymorphs compared to PyHOC4 and PyHO3C3, which exhibit a smaller number of crystalline forms (3 and 2, respectively). The X-ray structures obtained show that the conformation of the macrorings is primarily influenced by the presence of an acetonitrile guest molecule within the cavity, with limited impact from crystal packing and intermolecular cocrystallized solvent molecules. Notably, both calix[4]arene derivatives produce host-guest complex with acetonitrile, while the most flexible and less aromatic PyHO3C3 do not give crystals with acetonitrile as guest. Intertwined 1D and 2D solvent channel networks were observed in the PyHOC4-hexane and in the PyHO3C3-H2O-MeOH crystal structures, respectively, while the other pseudopolymorphs of PyHOC4 and PyHO3C3 and all PyC4 crystal forms exhibit a closely packed crystal structures without open channels.

Treatment of neurological disease is hampered by the lack of validated specific and sensitive biomarkers, resulting in delayed diagnosis and nonspecific disease modifying therapies. For example, in ALS the lack of a sensitive and specific biomarker impedes the ability to administer a treatment prior to or at the onset of motor neuron dysfunction. Although viral or other infectious etiologies have been proposed as a contributing factor to neurodegeneration, it can be argued that these are casual and not causal associations. In the case of ALS, evidence for direct causality would require in vivo validation of specific nucleotide sequences of microbial origin which are known to be neuroinvasive with tropism for motor neurons, such as polio and non-polio. Several viral enteropathogens recapitulate the pathological events in sporadic ALS, including the ability to cleave TDP-43 resulting in accumulation of misfolded proteins in the cytoplasm. This review provides supporting evidence that motor neuron disease is causally related to specific enteroviruses and argues that prospective validation is imperative for effective prevention and treatment.

GPT-4 was released in March 2023 to wide acclaim, marking a very substantial improvement across the board over GPT-3.5 (OpenAI's previously best model, which had powered the initial release of ChatGPT). Despite the genuinely impressive improvement, however, there are good reasons to be highly skeptical of GPT-4's ability to reason. This position paper discusses the nature of reasoning; criticizes the current formulation of reasoning problems in the NLP community and the way in which the reasoning performance of LLMs is currently evaluated; introduces a collection of 21 diverse reasoning problems; and performs a detailed qualitative analysis of GPT-4's performance on these problems. Based on the results of this analysis, the paper argues that, despite the occasional flashes of analytical brilliance, GPT-4 at present is utterly incapable of reasoning.