In most Eukaryotes, ubiquitin either exists as free monoubiquitin or as a molecule that is covalently linked to other proteins. These two forms cycle between each other and due to the concerted antagonistic activity of ubiquitylating and deubiquitylating enzymes, an intracellular ubiquitin equilibrium is maintained that is essential for normal biological function. However, measuring the level and ratio of these forms of ubiquitin has been difficult and time consuming. In this paper, we have adapted a simple immunoblotting technique to monitor ubiquitin content and equilibrium dynamics in different developmental stages and tissues of Drosophila. Our data show that the level of total ubiquitin is distinct in different developmental stages, lowest at the larval-pupal transition and in three days old adult males, and highest in first instar larvae. Interestingly, the ratio of free mono-ubiquitin remains within 30-50% range of the total throughout larval development, but peaks to 70-80% at the larval-pupal and the pupal-adult transitions. It stays within the 70-80% range in adults. In developmentally and physiologically active tissues, the ratio of free ubiquitin is similarly high, most likely reflecting a high demand for ubiquitin availability. We also used this method to demonstrate the disruption of the finely tuned ubiquitin equilibrium by the abolition of proteasome function or the housekeeping deubiquitylase, Usp5. Our data support the notion that the ubiquitin equilibrium is regulated by tissue- and developmental stage-specific mechanisms.

Background: Ubiquitination is an important post-transcriptional modification crucial for maintaining cell homeostasis. As a deubiquitination enzyme, ubiquitin-specific protease 1 (USP1) is associated with tumor progression; however, its role in bladder cancer is unknown. This study was aimed to analyze USP1 expression and study its roles in bladder cancer. Methods: The web server GEPIA was used to analyze the USP1 expression. To explore USP1 function in bladder cancer, we constructed USP1-knockout cell lines in UMUC3 cells. A FLAG-USP1 (WT USP1) plasmid and a plasmid FLAG-USP1 C90S (catalytic-inactive mutant) used to overexpress USP1 in T24 cells. CCK8, colony formation, and transwell assays were used to assess cell viability, proliferation and migration. RNA sequencing (RNA-seq) and dual-luciferase reporter assays were performed to screen the pathway. Coimmunoprecipitation and immunofluorescence were used to explore the interaction between USP1 and c-MYC. Xenograft mouse model was used to study the role of USP1 in bladder cancer. Results: USP1 expression is upregulated in human bladder cancer cells and correlated with poor patient prognosis. USP1 overexpression promoted cell proliferation, clone formation, and migration; this was attenuated by genetic ablation of USP1. Furthermore, we observed that USP1- deficiency inhibited tumor formation in vivo. Mechanistically, the c-MYC pathway was remarkably activated compared with the other pathways. Furthermore, USP1 could directly interact with c-MYC. and increase c-MYC stability depending on the catalytic activity of USP1. Conclusions: Our results suggest that high expression of USP1 promotes bladder cancer progression by stabilizing c-MYC; hence, USP1 it may serve as a novel therapeutic target for treating bladder cancer.

The One Health approach often reaches classrooms through Environmental Education (EE), which aims to guide society's response to current crises (environmental, health, economic, values). However, traditional EE teaching has focused on isolated ecological concepts and standardized solutions, ignoring the multidimensional nature of EE and failing to integrate the interdependence between environmental, animal, and human health. Moreover, teacher training often neglects didactic content knowledge, preventing students from acquiring the systemic vision needed to address eco-social problems and create sustainable solutions aligned with the Sustainable Development Goals (SDGs). This limits teachers’ ability to influence students' concerns and behaviours. In this context, this study aims to reflect on the current state of the issue and propose strategies informed by Science Education research to improve EE teaching, enabling the integration of One Health dimensions through effective didactics to achieve Transformative Environmental Education (TEE). For this purpose, we begin by addressing the limitations identified in recent systematic reviews, shifting the paradigm towards a symbiosis of EE and Science Education through scientific practices. We then present practical examples showcasing successful EE initiatives that foster a deeper understanding of socio-environmental issues, encourage innovative solutions, and nurture engaged citizens from early education onwards. These proposals can support classroom practice and ongoing teacher self-development. Pedagogical strategies include tackling issues that require systemic and critical thinking by developing scientific and epistemic practices while raising awareness of environmental justice. Thus, this study advocates for a new vision of EE, integrating the One Health approach, which could be applied to develop new educational programs, including teacher training. This would lead to a new learning evaluation model and help identify key determinants that trigger pro-environmental behaviours.

Sudden cardiac arrest (SAC) is a leading cause of mortality. In recent years, though, many lives have been saved through the use of defibrillators by random bystanders. As a result, defibrillators have been popping up in various locations. In this work we propose a state mandate demanding the presence of a defibrillator at every pharmacy store and argue that it could greatly enhance and augment the impact of the defibrillator network. We support our claim via detailed calculations of the immediate (a defibrillator readily available) and partial (a defibrillator available at a reasonable distance) population coverage achievable by the implementation of our proposal, taking the Argolis area in Peloponnese Greece as a case study. Our findings indicate that, in addition to other benefits, the use of pharmacies to establish a defibrillator network could bring an eight-fold increase in the immediate population coverage of defibrillators and would provide immediate / partial access to a defibrillator to 18 / 24 incidents of SCA per year that would otherwise lead to death, potentially leading to the saving of numerous lives. Alternative scenaria are also discussed.

Advanced coatings are essential to modern technologies, as they optimise surface characteristics for different application scenarios. Transparent and self-cleaning coatings are increasingly used as protective coatings for various applications, such as foldable touchscreens, windows, and solar panels. Moreover, incorporating other functionalities such as high hardness, wear resistance, and flexibility into transparent and self-cleaning coatings is important for broadening the use cases. Although many kinds of multifunctional coatings have been developed, it is still difficult to embody several properties in one coating adequately, as some properties, such as hardness and flexibility, are inherently contrastive. This review first describes basic principles, including wetting ability, photocatalytic reactions, photo-induced hydrophilic phenomena, and the implication of self-cleaning. The desired properties of multifunctional coatings are then listed, and methods for evaluating different properties are used. Recent progress in various preparation methods for multifunctional coatings, including the sol-gel, dip/spin, and chemical vapour deposition (CVD) methods, are also presented. Magnetron sputtering (MS) technology is widely used in coating preparation. Compared with chemosynthesis and CVD, MS is time-saving, suitable for industrial production, and environmentally friendly. Coatings prepared by MS usually possess excellent mechanical properties. Thus, we highlight the current research status of MS technology in multifunctional coating preparation. Moreover, according to the multilayer design structure of coatings, their optical and mechanical properties and self-cleaning ability can be controlled by combining the characteristics of different materials. Finally, combining photocatalytic materials such as TiO2 with other materials through a multilayer structure to obtain a multifunctional coating with excellent overall properties is discussed.

. Protein cysteine S-glycosylation is a relatively rare and less well characterized post-translational modification (PTM). Creating reliable model proteins that carry this modification is challenging. The lack of available model or natural S-glycosylated proteins significantly hampers the development of MS-based methodologies for detecting protein cysteine S-glycosylation in real-world proteomic studies. There is also limited MS-sequencing data describing easier to create synthetic S-glycopeptides. Here, we present the results of an in-depth manual analysis of automatically annotated CID/HCD spectra for model S-glucopeptides. The CID spectra show a long series of y/b-fragment ions with retained S-glucosylation, regardless of the dominant m/z signals corresponding to neutral loss of 1,2-anhydroglucose from the precursor ions. In addition, the spectra show signals manifesting glucosyl transfer from the cysteine position onto Lys, Arg side chains, and a peptide N-terminus. Other spectral evidence indicates that the N-glucosylated initial products of transfer are converted into N-furanosylated (i.e., glycated) structures due to Amadori rearrangement. We discuss the peculiar transfer of the glucose oxocarbenium ion (Glc+) to positively charged guanidinium residue (ArgH+) and propose a mechanism for the gas-phase Amadori rearrangement involving a hydride ion shift.

Dipeptidyl peptidase 9 (DPP9) is a multifunctional intracellular protease with roles in tumour growth, inflammation and mitochondrial function. We developed a hepatocyte-specific DPP9 knockout mouse (DPP9-KO) to explore DPP9 in a mouse model of hepatocellular carcinoma (HCC). DPP9-KO mice were generated by crossing Albumin-Cre mice (Wt/Wt Cre+/+) with DPP9 floxed mice (Fl/Fl Cre-/-). Mice were treated with Diethylnitrosamine and Thioacetamide then an atherogenic High Fat Diet until 28 weeks of age. DPP9-KO mice had reduced liver and subcuta-neous adipose tissue mass and lower fasting plasma glucose, fewer small macroscopic liver nod-ules compared to DPP9-WT mice. However, there were no differences in the total number of mac-roscopic liver nodules, tumour burden, inflammation score and steatosis score. Consistent with the known ability of DPP9 to suppress NLRP1 activation, activated caspase-1 protein was ele-vated in DPP9-KO mouse liver. Additionally, Nfkbib, Cxcl10 and Ccl5 mRNA and protein levels of autophagy marker beclin1 and tumour suppressor p53 were increased. In conclusion, DPP9 de-pletion in hepatocytes may reduce liver cancer initiation, via mechanisms that may include in-creased autophagy and innate tumour suppression in this experimental model. Finally, the data supports DPP9 having a role in glucose regulation by the liver.

Visualizing geo-spatial data embedded into a three-dimensional terrain is challenging. The problem becomes even more complex when uncertainty information needs to be presented as well. This paper addresses the question of how to visually communicate all three aspects: the 3D terrain, the geo-spatial data, and the data-associated uncertainty. We argue that visualizing all aspects with a high degree of detail will likely exceed the visual budget. Therefore, we propose a visualization strategy based on prioritizing a selected aspect and presenting the remaining two with less detail. We discuss various design options that allow us to obtain differently prioritized visual representations. Our approach has been implemented as a tool for rapid visualization prototyping in the context of avionics applications. Practical solutions are described for a use case related to the visualization of 3D terrain and uncertain weather data.

The aim of this study is to characterize the compound extremes of rainfall and temperature in Côte d’Ivoire. For this purpose, we analyzed the outputs of fourteen (14) climate models from the CORDEX-Africa project. Results show an increase (approximately 4.3°C) of the surface temperature and a decrease (5,90 %) of the mean rainfall in the near (2036-2065) and far futures (2071-2100) over Côte d’Ivoire during January-February-March (JFM) period. The analysis of the compound extremes of wet/warm type highlights an increase in the frequency of this climatic hazard in the northern and central parts of the country during January-March (JFM) season in the near and far futures. The dry/warm mode will increase in the central and southern parts of the country during the near future and in the whole country during the far future. These increase in compound extremes could lead to an increase in droughts and natural disasters over the country and could have a negative impact on socio-economic activities, such as transportation and agricultural production. This work could provide decision support for political decision-makers in formulating future public policies for managing agricultural production, food security, and natural disasters.

Protein degradation is a biological phenomena essential for cellular homeostasis and survivor. Selective protein degradation is performed by the ubiquitination system which selectively target proteins that need to be eliminated and lead them to proteasome degradation. In this review, we focus on the ubiquitin-conjugating enzyme E2 O (UBE2O) and highlight the role of UBE2O in many biological and physiological process. We further discuss the UBE2O implications in various human diseases, particularly in leukemias and solid cancers and suggest how UBE2O targeting could be novel strategy in the treatment of different human neoplasia.

Green consumption has become a crucial academic and practical topic with the increasing environmental-protection awareness of scholars, industries and consumers. However, the growth in green purchasing may not reflect the concerns. This study aims to synthesize recent research, and points several causes of low purchases to green products in the consumer perspective, and provide a comprehensive understanding to the realistic consumer decision-making process. Through the scope of Consumer Buying Process framework, this study systematically reviewed 73 credible articles on green purchase behaviour published from 2010 to 2022. Main constructs and theories applied in selected literature is further discussed in each sector of the CBP framework. The study results showed the green purchase process may have a ‘loop tendency’ that falls into the circulation of construction of evaluation and adoption of those evaluation. Moreover, purchasing behaviour which performed by minority of the consumers may not be strong enough to form a valid social norm, and the current available still lacked power to fulfil consumer needs. The lack of research to impulsive purchasing behaviour, or the emotions of consumers are under-researched, thus how the emotional appraisals affect consumer green purchasing may require more research. With the modified consumer buying process framework, this study highlights the importance of creating memorable experience and build strong emotional communications with consumers. In addition, triggering the collective empathy is recommended to be an effective way of constructing consistent social norms thus enhance the green purchasing intention of consumers.

Plastic pollution of the ocean is currently one of the most serious environmental threat. Analysis of observations in the Arctic ocean shows that microplastic particles have been found in Arctic snow cover, sea ice, water and sediments. Possible pathways and deposition locations of microplastics in the Arctic Ocean can be assessed based on 3D numerical modeling of thermohaline structure and water circulation, sea ice conditions and drift. The problem is that in addition to transport by currents, a number of other processes affect the state of microplastics. These include mechanical fragmentation, freezing into sea ice and release back into the water, biofouling, adsorption of contaminants and other factors. In this study, based on scenario calculations for a 5-year period, we analyzed the possible spread of microplastics brought by Siberian rivers to the Kara Sea shelf. The Lagrangian particle model used daily 3D numerical simulation data to simulate microplastic transport by ocean currents and by sea ice drift. The results of a series of scenario calculations show how the distribution of particles and their subsequent deposition depend on their type (density), size, processes of freezing into the ice and biofouling.

The study examines projected changes in dry- and wet-spell probabilities in West Africa using a Markov chain approach. Four simulations of regional climate models from the CORDEX-Africa program were used to analyze projected changes in intraseasonal variability. The results show an increase in the probability of having a dry day, a dry day preceding a wet day and a dry day preceding a dry day, and a decrease in the probability of wet days in the Sahel region under anthropogenic forcing scenarios RCP4.5 and RCP8.5. The decrease in wet days is stronger in the far future and under the RCP8.5 scenario (up to -30%). The study also finds that the probability of consecutive dry days (lasting at least 7 days and 10 days) is expected to increase in the Western Sahel, the Central Sahel, and the Sudanian Area under both scenarios, with stronger increases in the RCP8.5 scenario. In contrast, the decrease is expected over the Guinea Coast, with the changes more important under the RCP4.5. These changes in dry- and wet-spell probabilities are important for water management decisions and risk reduction in the energy and agricultural sectors. The study also highlights the need for decision-makers to implement mitigation and adaptation policies to minimize the adverse effects of climate change.

(1) The present study investigated the effect of orally administered Limosilactobacillus fermentum HY7302 (HY7302) on the relationship between ocular tissue and the microbiome in the corneal injured dry eye mice model. (2) 0.1% benzalkonium chloride (BAC) was applied to the ocular surface for 14 days to induce corneal injury in male Balb/c mice. During the BAC treatment period, HY7302 (1 × 108 CFU/kg/day or 1 × 109 CFU/kg/day) or omega-3 positive control (200 mg/kg/day) were administered orally (n = 8/group). To examine signaling pathways affected by HY7302 treatment, the in vitro effects of HY7302 on tight junctions and the inflammatory response were investigated in a mouse colon epithelial cell line, CMT-93. (3) BAC exposure decreased tear production, induced ocular inflammation and corneal epithelial detachment, and altered gut microbiota. However, oral administration of HY7302 restored tear secretion and decreased corneal epithelial detachment in BAC-treated corneal injury mice. Further, HY7302 alleviated corneal inflammation via modulation of matrix metalloproteinase-9 (MMP-9) expression and alterations in gut microbiota composition. (4) These findings suggest that the gut–eye axis interaction between gut microbiota and eye tissue affects disease severity in corneal injury, and that alteration of the microbiota by HY7302 could improve eye health by regulating the inflammatory response.

The selectivity in selective autophagy pathways is achieved via the selective autophagy receptors (SARs) – proteins that bind a ligand on the substrate to be degraded and the Atg8-family protein on the growing autophagic membrane, phagophore, effectively bridging them. In mammals, the most common ligand of SARs is ubiquitin, a small protein modifier that tags substrates for their preferential degradation by autophagy. Consequently, the most common SARs are the ubiquitin-binding SARs, such as SQSTM1/p62 (sequestosome 1). Surprisingly, there is only one SAR of this type in yeast – Cue5, which acts as a receptor for aggrephagy and proteaphagy – pathways that remove the ubiquitinated protein aggregates and proteasomes, respectively. However, recent studies described the ubiquitin-dependent autophagic pathways that do not require Cue5, e.g. stationary phase lipophagy for intracellular lipid droplets and nitrogen starvation-induced mitophagy for mitochondria. What is the role of ubiquitin in these pathways? Here, we propose that the ubiquitinated lipid droplets and mitochondria are recognized by the alternative ubiquitin-binding SARs. Our analysis identifies the proteins that could potentially fulfill this role in yeast. We think that matching of the ubiquitin-dependent (but Cue5-independent) autophagic pathways with the ubiquitin-and-Atg8-binding proteins enlisted here might uncover the novel ubiquitin-binding SARs in yeast.

Fusing data from many sources helps to achieve higher results of analysis. In this work, we present a new algorithm to fuse data from multiple cameras with data from multiple lidars. This algorithm was developed to increase the sensitivity and specificity of autonomous vehicle perception systems, where the most accurate sensors measuring the vehicle’s surroundings are cameras and lidar devices. Perception systems based on data from one type of sensor do not use complete information and have lower quality. The camera provides two-dimensional images; lidar produces three-dimensional point clouds. We developed a method for matching pixels on a pair of stereoscopic images using dynamic programming inspired by an algorithm to match sequences of amino acids used in bioinformatics. We improve the quality of the basic algorithm using additional data from edge detectors. We also improve the algorithm performance by reducing the size of matched pixels determined by available car speeds. We perform point cloud densification in the final step of our method, fusing lidar output data with stereovision output. We implemented our algorithm in C++ with Python API, and we provided the open-source library named Stereo PCD. This library very efficiently fuses data from multiple cameras and multiple lidars. In the article, we present the results of our approach to benchmark databases in terms of quality and performance. We compare our algorithm with other popular methods.

‘Inner mitochondrial membrane peptidase 2 like’ (IMMP2L) is a nuclear encoded mitochondrial peptidase that has been conserved through evolutionary history as has its target enzyme ‘mitochondrial glycerol phosphate dehydrogenase 2’ (GPD2). IMMP2L is known to cleave the mitochondrial transit peptide from GPD2 and another nuclear encoded mitochondrial respiratory related protein cytochrome C1 (CYC1). However, it is not known whether IMMP2L peptidase activates or alters the activity or respiratory related functions of GPD2 or CYC1. Previous investigations found compelling evidence of behavioural change in the Immp2lKD-/- KO mouse and in this study EchoMRI analysis found that many organs of the Immp2lKD-/- KO mouse were smaller and that the KO mouse had significantly less lean mass and overall body weight compared with wildtype littermates (p<0.05). Moreover, all of the organs analysed from the Immp2lKD-/- KO had lower relative levels of mitochondrial reactive oxygen species (mitoROS). The kidneys of the Immp2lKD-/- KO mouse displayed the greatest decrease in mitoROS levels that were over 50% less compared with wildtype litter mates. Mitochondrial respiration was also lower in the kidney of the Immp2lKD-/- KO mouse compared with other tissues when using succinate as the respiratory substrate, whereas respiration was similar to wildtype when glutamate was used as substrate. When glycerol-3-phosphate (G3P) was used as the substrate for Gpd2 we observed ~20% and ~7% respective decreases in respiration in female and male Immp2lKD-/- KO mice over time. Together these findings suggest that the respiratory related functions of mGpd2 and Cyc1 have been compromised to different degrees in different tissues in the Immp2lKD-/- KO mouse. Structural analyses using AlphaFold2-Multimer further predicted that the interaction between Cyc1 and mitochondrial encoded cytochrome b (Cyb) in Complex III had been altered as had the homodimeric structure of the mGpd2 enzyme within the inner mitochondrial membrane of the Immp2lKD-/- KO mouse. mGpd2 functions as an integral component of the glycerol phosphate shuttle (GPS) which positively regulates both mitochondrial respiration and glycolysis. Interestingly, we found that nonmitochondrial respiration (NMR) was also dramatically lowered in the Immp2lKD-/- KO mouse. Primary mouse embryonic fibroblast (MEF) cell lines derived from the Immp2lKD-/- KO mouse displayed a ~27% decrease in total respiration comprised of a ~50% decrease in NMR and a ~12% decrease in total mitochondrial respiration where the latter was consistent with the decreases in substrate specific mitochondrial respiration reported here. This study is the first to report the role of Immp2l in enhancing Gpd2 structure and function, mitochondrial respiration, nonmitochondrial respiration, organ size and homeostasis.

We evaluated the closure of idiopathic full-thickness macular holes (MHs) the day after surgery in minimizing the burden and maximizing patient outcomes. Herein, 25-gauge pars plana vitrectomy, internal limiting membrane peeling, and fluid-gas (20% sulfur hexafluoride) were performed for the treatment. Patients were instructed to remain in the facedown position until the confirmation of MH closure, and the position was discontinued in cases where the closure was confirmed. In total, 43 eyes of 43 patients, whose average age was 69.7±8.6 years, were enrolled in this study. We used swept-source (SS)-optical coherence tomography (OCT) for the confirmation of MH closure for gas-filled eyes and used spectral domain (SD)-OCT for the reconfirmation of MH closure after the gas volume was reduced to less than half of the vitreous cavity. MH closure was confirmed in 40 eyes (93%, the closure group) on the next day after surgery. The time from surgery to SS-OCT imaging was 24.7 hours. Although facedown positioning was terminated in cases where MH closure was confirmed, there were no cases in which the MH was re-opened afterward. The basal and minimum MH size was significantly larger in the non-closure group than that in the closure group (p = 0.027, p = 0.043, respectively). Therefore, checking with SS-OCT the day after surgery and terminating facedown positioning in cases where MH closure was confirmed would be a useful method, removing great burden for the elderly without sacrificing the MH closure rate.

In 2004, a significant portion of the spruce-dominated forests in the Tatra National Park (northern Slovakia) was destroyed by an exceptionally strong windstorm. Our study focused on the status of deadwood and its influence on post-disturbance forest regeneration 18 years after the destruction. Since some disturbed areas were salvaged and others were not, we could compare the situations between these two management approaches. In total, 40 research sites (20 salvaged and 20 unsalvaged) were measured, each represented by four satellite-like plots with a radius of 4 m. We measured the diameters of deadwood and its decay status (classes 1 – 5). At the same time, we recorded the sizes (stem base diameter and height) and species of young trees. The results showed that while salvage conditions and contact with soil stimulated deadwood decomposition, the diameter of logs was not a significant factor. The highest decay class (3.83) was found in deadwood on salvaged areas and attached to the soil, while the lowest decay class (3.10) was found in deadwood on unsalvaged areas and in the case of logs unattached to the soil. While carbon content (based on percentage of wood mass) did not change with decay class, wood density decreased sharply with decay class. Water moisture showed an increasing tendency with decay class. Moreover, our results showed that post-disturbance management influenced forest regeneration. Significantly higher tree diversity was observed in salvaged areas (5.40 species per plot) compared to unsalvaged areas (3.85 species per plot). While areas with logging were predominantly covered by broadleaved species, those without logging were typically dominated by Norway spruce (Picea abies L. Karst). We concluded that although salvage logging decreased the total carbon and water content in deadwood, it can stimulate tree species diversity. Thus, the currently prevailing opinion about the exclusively negative ecological effects of salvage logging should be accepted with caution, and local conditions must be considered before making broad judgments.

Aquaculture contributes to the sustainable development of food security, marine resource conservation, and economy. Shifting aquaculture feed from fish meal and oil to terrestrial plant-derivatives may result in cost savings. However, many carnivorous fish cannot be sustained on plant-derived materials, necessitating the need for the identification of important factors for farmed fish growth and to investigate whether components derived from terrestrial plants can be used in feed. Herein, we focused on the carnivorous fish leopard coral grouper (P. leopardus) to identify the essential growth factors and clarify their intake timing from feeds. Furthermore, we evaluated the functionality of starch, which are easily produced by terrestrial plants. Results reveal that carbohydrates, which are not considered essential for carnivorous fish, can be introduced as a major part of artificial diet. The development of artificial feed using starch offers the possibility of increasing the growth of carnivorous fish in aquaculture.

Green leaf volatiles (GLVs) are important in giving grape a fresh and green aroma. But the changes in GLVs during the phenological development of grapevines are not well known. This study analysed the GLVs and transcription levels of associated biosynthetic genes in six grape species from the Loess Plateau region at five stages of maturation. Thirteen GLVs were detected, showing unique patterns for each grape type at various growth phases. The primary components in six grapes were (E)-2-Hexenal, (E)-2-Hexen-1-ol, and Hexanal. With the exception of Cabernet Franc in 2019, the overall GLV contents of the six types generally increased during growth and development, peaking or stabilizing at harvest. And Sauvignon Blanc, Cabernet Gernischt, and Cabernet Sauvignon exhibited higher total contents among the varieties. Correlation analysis revealed a strong positive correlation between the levels of Hexanal, 1-Hexanol, (E)-2-Hexen-1-ol, (Z)-3-Hexenyl acetate, Nonanal, and (E, E)-2,6-Nonadienal and the expression of VvHPL and VvAAT genes in the LOX-HPL pathway. Specifically, VvHPL emerges as a potential candidate gene responsible for species-specific differences in GLV compounds. Comprehending the changing patterns in the biosynthesis and accumulation of GLVs offers viticulturists and enologists the opportunity to devise targeted strategies for improving the aromatic profile of grapes and wines.

Adjunctive treatment of periodontitis lacks solutions allowing enough time for wound healing in the periodontal pockets by avoiding a fast re-colonization. Such a solution might be an antibiotic containing formulation with a controlled release over weeks. Here, a recently described minocycline containing approach is qualified for further clinical development by focusing on proof-of-concept, systemic burden, resistance development and degradation studies. Animal studies were done in two different (mouse-chamber, rat Porphyromonas gingivalis challenging) models, including effects on inflammation markers, bone loss and bone structure. Also, serum concentrations of minocycline after local application were determined by HPLC-MS/MS. The resistance status of bacterial clinical isolates against minocycline was investigated and the degradation of the formulation was characterized by laser scanning- and scanning electron microscopy. Animal studies clearly demonstrated the applicability of the new formulation in the investigated models. Inflammation markers decreased dosage dependent and reduced bone loss compared to non-treated group was observed. Thereby, the systemic burden of the antibiotic was neglectable. Minocycline is still effective against oral pathogens; resistance development was not seen. The biodegradable thread was first swollen and subsequently degraded over weeks. The results support the continued clinical development of this new formulation. A phase I clinical trial is planned to further evaluate its safety and efficacy.

Ubiquitin-Specific-peptidase 22 (Usp22) cleaves ubiquitin moieties from numerous proteins, in particular transcription factors. Recently, it was reported that Usp22 acts as negative regulator of interferon-dependent responses. In the current study, we investigated the role of Usp22 deficiency upon acute viral infection with lymphocytic choriomeningitis (LCMV) virus. We found that lack of Usp22 on bone marrow derived cells (Usp22 fl/fl Vav1-Cre mice) reduced induction of type I and II interferons. Limited type I interferon response did not influence virus replication. However, restricted expression of PD-L1 led to increased frequencies of functional virus-specific CD8+ T cells and rapid death of Usp22 deficient mice. CD8+ T cell depletion experiments revealed that accelerated CD8+ T cells were responsible for enhanced lethality in Usp22 deficient mice. In conclusion, we found that the lack of Usp22 generated a pathological CD8+ T cell response, which gave rise to severe disease in mice.

Monomeric Ubiquitin (Ub) is a 76-amino acid highly conserved protein found in eukaryotes. The first described biological activity of Ub in the 1970s was extracellular, but it quickly gained relevance due to its intracellular role, i.e., post-translational modification of intracellular proteins (ubiquitination) that regulate numerous eukaryotic cellular processes. In the following years, the extracellular role of Ub was relegated to the background, until a correlation between higher survival rate and increased serum Ub concentrations in patients with sepsis and burns was observed. Although the mechanism of action (MoA) of extracellular ubiquitin (eUb) is not yet well understood, further studies have shown that it may ameliorate the inflammatory response in tissue injury and multiple sclerosis diseases. These observations compounded with the high stability and low immunogenicity of eUb due to its high conservation in eukaryotes have made this small protein a relevant candidate for biotherapeutic development. Here, we review the in vitro and in vivo effects of eUb on immunologic, cardiovascular, and nervous systems, and discuss the potential MoAs of eUb as an anti-inflammatory, antimicrobial, cardio- and brain-protective agent.

This study investigated modifications in the ubiquitin proteasome system (UPS) in a mouse model of type 2 diabetes mellitus (T2DM) and their relationship to heart complications. db/db mice heart tissues were compared with WT mice tissues using RNA sequencing, qRT-PCR, and protein analysis to identify cardiac UPS modifications associated with diabetes. The findings unveiled a distinctive gene profile in the hearts of db/db mice with decreased levels of nppb mRNA and increased levels of Myh7, indicating potential cardiac dysfunction. mRNA levels of USP18 (deubiquitinating enzyme), psmb8, and psmb9 (proteasome β-subunits) were downregulated in db/db mice while mRNA levels of RNF167 (E3 ligase) were increased. Corresponding LMP2 and LMP7 proteins were downregulated in db/db mice, and RNF167 was elevated in Adult diabetic mice. Reduced expression of LMP2 and LMP7, along with increased RNF167 expression, may contribute to future cardiac deterioration commonly observed in diabetes. This study enhances our understanding of UPS imbalances in the hearts of diabetic mice and raises questions about the interplay between the UPS and other cellular processes, such as autophagy. Further exploration in this area could provide valuable insights into the mechanisms underlying diabetic heart complications and potential therapeutic targets.

Endolysin of bacteriophage T5 (EndoT5) is a Zn2+-dependent and Ca2+-activated L-alanyl-D-glutamate peptidase that hydrolyses peptidoglycans during the destruction of the cell wall of the phage host bacterium Escherichia coli. To elucidate the mechanism of calcium activation, the spatial solution structure of EndoT5 in a complex with two ions - catalytic Zn2+ and regulatory Ca2+ (EndoT5-Zn2+Ca2+, PDB ID: 8P3A) was determined by high-resolution NMR and deposited in the Protein Data Bank. We show that coordination of the Ca2+ ion fix the spatial position of polar amino acid residues D113, N115 and S117. As a result, the intramolecular mobility of extended protein loops (residues 40-70 and 111-132) is significantly reduced compared to the mobility of these loops in the structure of an enzyme containing only a catalytic a Zn2+ ion (EndoT5-Zn2+, PDB ID: 2MXZ). In the stabilized EF-like calcium-binding loop (residues 111-132), the number of van der Waals interactions with amino acid residues of the globular core of the protein increases. The binding of the Ca2+ ion is accompanied by the selection of the functional states of both extended loops of the enzyme (residues 40-70 and 111-132), because of which EndoT5-Zn2+Ca2+ acquires the structural integrity necessary for catalysis. Therefore, the mechanism of activation of L-alanyl-D-glutamate peptidase of bacteriophage T5 by Ca2+ ions involves stabilization of the enzyme molecule in a catalytically active “open” conformation. This work sheds light on the structural grounds of the ion-dependent functional proteoforms of this interesting protein.

Chloroplasts are ancient organelles responsible for photosynthesis and various biosynthetic functions essential to most life on Earth. Many of these functions require tightly controlled regulatory processes to maintain homeostasis at the protein level. One such regulatory mechanism is the ubiquitin-proteasome system whose fundamental role is increasingly emerging in chloroplasts. In particular, the role of E3 ubiquitin ligases as determinants in the ubiquitination and degradation of specific intra-chloroplast proteins. Here, we highlight recent advances in understanding the roles of plant E3 ubiquitin ligases in chloroplast function.

Compared to the general population, patients with inflammatory bowel disease (IBD) are less likely to be vaccinated, putting them at an increased risk of vaccine-preventable illnesses. This risk is further compounded by the immunosuppressive therapies commonly used in IBD management. Therefore, developing new treatments for IBD that maintain immune function is crucial, as successful management can lead to better vaccination outcomes and overall health for these patients. Here, we investigate the potential of recombinant banana lectin (rBanLec) as a supporting therapeutic measure to improve IBD control and possibly increase vaccination rates among IBD patients. By examining the therapeutic efficacy of rBanLec in a murine model of experimental colitis, we aim to lay the foundation for its application in improving vaccination outcomes. After inducing experimental colitis in C57BL/6 and BALB/c mice with 2,4,6-trinitrobenzene sulfonic acid, we treated animals orally with varying doses of rBanLec 0.1-10 µg/ml (0.01 – 1 µg/dose) during the course of the disease. We assessed the severity of colitis and rBanLec’s modulation of the immune response compared to control groups. rBanLec administration resulted in a dose-dependent reduction in colitis severity (less pronounced weight loss, less shortening of the colon) and an improved recovery profile, highlighting its therapeutic potential. Notably, rBanLec-treated mice exhibited significant modulation of the immune response, favoring anti-inflammatory pathways (primarily reduction in a local [TNFα]/[IL-10]) crucial for effective vaccination. Our findings suggest that rBanLec could mitigate the adverse effects of immunosuppressive therapy on vaccine responsiveness in IBD patients. By improving the underlying immune response, rBanLec may increase the efficacy of vaccinations, offering a dual benefit of disease management and prevention of vaccine-preventable illnesses. Further studies are required to translate these findings into clinical practice.

Epithelial ovarian cancer (EOC) has not significantly benefited from advances in immunotherapy, mainly because of the lack of well-defined actionable antigen targets. Using proteogenomic analyses of primary EOC tumors, we previously identified 91 aberrantly expressed tumor-specific antigens (TSAs) originating from unmutated genomic sequences. Most of these TSAs derive from non-exonic regions, and their expression results from cancer-specific epigenetic changes. The present study aimed to evaluate the immunogenicity of 48 TSAs selected according to two criteria: presentation by highly prevalent HLA allotypes and expression in a significant fraction of EOC tumors. Using targeted mass spectrometry analyses, we found that pulsing with synthetic TSA peptides leads to a high-level presentation on dendritic cells. TSA abundance correlated with the predicted binding affinity to the HLA allotype. We stimulated naïve CD8 T cells from healthy blood donors with TSA-pulsed dendritic cells and assessed their expansion with two assays: MHC-peptide tetramer staining and TCR Vβ CDR3 sequencing. We report that these TSAs can expand sizeable populations of CD8 T cells and, therefore, represent attractive targets for EOC immunotherapy.

Lysosomal degradation of tyrosinase, a pivotal enzyme in melanin synthesis, negatively impacts melanogenesis in melanocytes. Nevertheless, the precise molecular mechanisms by which lysosomes target tyrosinase have remained elusive. Here, we identify RING finger protein 152 (RNF152) as a membrane-associated ubiquitin ligase specifically targeting tyrosinase for the first time, utilizing AlphaScreen technology. We observed that modulating RNF152 levels in B16 cells, either via overexpression or siRNA knockdown, resulted in decreased or increased both tyrosinase and melanin levels, respectively. Notably, RNF152 and tyrosinase colocalized at the trans-Golgi network (TGN). However, upon treatment with lysosomal inhibitors, both proteins appeared in the lysosomes, indicating that tyrosinase undergoes RNF152-mediated lysosomal degradation. Through ubiquitination assays, we found the indispensable roles of both the RING and transmembrane (TM) domains of RNF152 in facilitating tyrosinase ubiquitination. In summary, our findings underscore RNF152 as a tyrosinase-specific ubiquitin ligase essential for regulating melanogenesis in melanocytes.

Multiple sclerosis is an autoinflammatory condition that results in damage of myelinated neurons in affected patients. While disease-modifying treatments have been successful in slowing the progression of relapsing remittent disease, most patients still progress to secondary progressive disease that is largely unresponsive to disease-modifying treatments. Similarly, there is currently no effective treatment for patients with primary progressive MS. Innate and adaptive immune cells in the CNS play a critical role in initiating an autoimmune attack and in maintaining the chronic inflammation that drives disease progression. In this review, we will focus on recent insights into the role of T cells with regulatory function in suppressing the progression of MS, and, more importantly, in promoting the remyelination and repair of MS lesions in the CNS. We will discuss the exciting opportunity to genetically reprogram regulatory T cells to achieve immune suppression and enhance repair locally at sites of tissue damage, while retaining a fully competent immune system outside the CNS. In the future, reprogramed regulatory T cells with defined specificity and function may provide life medicines that can persist in patients and achieve lasting disease suppression after one cycle of treatment.

Cathepsin D (CatD; EC 3.4.23.5) family peptidases of parasitic organisms are regarded as potential drug targets as they play critical roles in the physiology and pathobiology of parasites. Previously, we characterized the biochemical features of cathepsin D isozyme 2 (CatD2) in the carcinogenic liver fluke Clonorchis sinensis (CsCatD2). In this study, we performed all-atomic molecular dynamics simulations by applying different systems for the ligand-free/bound forms under neutral and acidic conditions to investigate the pH-dependent structural alterations and associated functional changes in CsCatD2. CsCatD2 showed several distinctive characteristics as follows: 1) CsCatD2-inhibitor complex formed more hydrogen bonds; 2) acidic pH caused major conformational transitions from open to closed state in this enzyme; 3) neutral pH induced displacement of the N-terminal part to hinder the accessibility of the active site and open allosteric site of this enzyme; and 4) the flap dynamics metrics, including distance (d1), TriCα angles (θ1 and θ2), and dihedral angle (ϕ), account for the asymmetrical twisting motion of the active site of this enzyme. These findings provide an in-depth understanding of the pH-dependent structural dynamics of CsCatD2 and basic information for the rational design of an inhibitor as a drug targeting CsCatD2.

In the cone of positive quadratic forms C^{8 x 8}, it is shown that there exists in the neighbourhood of the quadratic form Q_{F_{22}} a large cluster of non-equivalent \Sigma_0-subcones of positive volume which are as well minimal as maximal.

Managing a portfolio whose value closely tracks an index by trading only in a subset of the index constituents involves an NP-hard optimisation problem. In the prior literature, it has been suggested to solve this problem using sequential Monte Carlo (SMC, a.k.a. particle filter) methods. However, this literature does not take transaction costs into account, although transaction costs are the primary motivation for attempting to replicate the index by trading in a subset, rather than the full set of index constituents. This paper extends the SMC approach to index tracking to allow for proportional transaction costs and implements this extended method on empirical data for a variety stock indices. In addition to providing a more practically useful tracking strategy by allowing for transaction costs, we find that including a penalty for transaction costs in the optimisation objective can actually lead to better tracking performance.

During the last few years, the world witnessed one of the worst calamities to humankind- the COVID-19 pandemic. We also witnessed the development of vaccines at an unprecedented pace against the SARS-CoV-2- the causative agent. India was among the hard-hit countries by COVID-19, developed its indigenous vaccine and implemented vaccines developed in other countries as well. Initially, the antibody level and the neutralizing antibody titer against the pathogen were considered as the correlates of immune protection from the disease. However, the long-term protection from the pathogen was provided by the immune memory cells viz. T and B memory cells and their ability to efficiently make recall responses. In this regard, globally the research studies focused mainly on the mRNA-based vaccines. The studies on immune memory response, particularly- the B cell memory response bestowed by the vaccines given to Indians is relatively obscure. We studied the level of RBD specific memory B cells in the peripheral circulation of the study participants and the ability of B cells to secrete antigen-specific antibodies among Indians vaccinated with Covaxin (BBV152), Covishield (AZD1222), Corbevax (BECOV2D) and Sputnik Light (Gam-COVID-Vac) as well as unvaccinated individuals. Our study revealed that Corbevax and Sputnik Light conferred better antibody-secreting cell (ASC) responses.

Oilseed plants of the Brassicaceae plant family are cultivated for food, feed and industrial purposes on large-scale in Europe. This review gives an overview of current market-oriented applications of new genomic techniques (NGTs) in relevant Brassicaceae oilseed crops based on a literature survey. In this respect, changes in oil quality, yield, growth and resistance to biotic and abiotic stress are goals in oilseed rape (B. napus) and camelina (C. sativa). Environmental risk assessment scenarios are developed for specific NGT applications in Brassicaceae oilseed crops with either a changed oil composition or with fitness related traits. In case of a changed oil composition an increase or decrease of polyunsaturated fatty acids (PUFA) demonstrates risks for health and survival of pollinators. In case of fitness related traits other risks were identified, i. e. an increased risk of spread and persistence of NGT plants. Furthermore, there are indications for potential disturbance of interactions with the environment, involving signalling pathways and reaction to stress conditions. It is shown that for a comprehensive risk assessment the technological potential of NGTs, the plants’ biology and the scale of releases have to be considered in combination. Therefore, the release of NGT plants into the environment for agricultural purposes will require risk assessment and monitoring of single traits as well as of combinatorial and long-term cumulative effects. In addition, risk management should develop concepts and measures to control and potentially restrict the scale of releases. This is especially relevant for NGT Brassicaceae in Europe which is a centre of diversity of this plant family.

Air pollution, climate change and global warming show direct linkage. Introduction - Background: Research in the field has proposed and demonstrated their link to increased allergenicity in plants, leading to increased allergic diseases. Allergen patterns are changing in response to climate change. Across Europe, up to 12% of the population suffers from allergic diseases (bronchial asthma and allergic rhinitis) caused by the pollen grains. The medical costs of these types of allergies are enormous and are increasing with the spread of common ragweed - Ambrosia artemisiifolia* in Europe. In practice, more and more patients are turning to allergists. Methods: Based on these data, the research aims to identify safety measures and specific legislation to control and eradicate common ragweed in the countries most affected by the spread of this plant in Europe, increase in population exposure in countries affected by the presence of common ragweed and the socio-economic impact of allergic rhinitis and bronchial asthma at European level.[1][2] Our database search did not reveal any other research that has addressed this topic to date. Results: This research identifies specific legislation to the countries most affected by the spread of this plant pollen grains at European level, changes in allergen patterns and monitoring/safety eradication measures decided by local authorities, and data on the spread of common ragweed over the last two decades, costs per treatment, increased allergic rhinitis and bronchial asthma morbidity in the most affected areas. Conclusions: At European level, there are no universally valid models for eradicating this weed. Various methods can be used to limit the spread of common ragweed and its pollen production (e.g. mowing once or twice a year of overgrown land, ploughing, chemical control, public information, etc.). Local and regional cooperation should be considered essential to promote phytosanitary & safety measures and exchange of information on methods to identify and manage the spread of common ragweed. Unified legislation at European level would help all affected countries; reduce morbidity from respiratory allergic diseases and the costs of treating these diseases.

The aim of the study is to develop a population pharmacokinetic (PopPK) model and to investigate the influence of CYP3A5/CYP3A4 and ABCB1 single nucleotide polymorphisms (SNPs) on the Tacrolimus PK parameters after LCP-Tac formulation in stable adult renal transplant patients. The model was developed using NONMEM v7.5, from full PK profiles from a clinical study (n=30) and trough concentrations (C0) from patient follow-up (n=68). The PK profile of the LCP-Tac formulation was best described by a two-compartment model with linear elimination, parameterised in elimination (CL/F) and distributional (CLD/F) clearances and central compartment (Vc/F) and peripheral compartment (Vp/F) distribution volumes. A time lagged first order absorption process was characterized using transit compartment models. According to the structural part of the base model, the LCP-Tac showed an absorption profile characterized by 2 transit compartments and a mean transit time of 3.02 hours. Inter-individual variability was associated with CL/F, Vc/F and Vp/F. Adding inter-occasion variability (IOV) on CL/F caused a statistically significant reduction in the model minimum objective function MOFV (p<0.001). Genetic polymorphism of CYP3A5 and cluster of CYP3A4/A5 SNPs statistically significantly influenced Tac CL/F. In conclusion a PopPK model was successfully developed for LCP-Tac formulation in stable renal transplant patients. CYP3A4/A5 SNPs as a combined cluster including three different phenotypes (high, intermediate, and poor metabolizers) was the most powerful covariate to describe part of inter-individual variability associated with apparent elimination clearance. Incorporating this covariate in the initial dose calculation and during the therapeutic drug monitoring (TDM) would probably optimize Tac exposure attainments.

Background: Youth experiencing homelessness (YEH) in East Asia Pacific (EAP) represent one of the most at-risk populations due to cultural and geographical factors. Effective mental health interventions, primarily researched in Western contexts, may not fully apply to YEH in EAP. Their lack of stable shelter, disrupted social networks, and limited access to mental health services elevate their susceptibility to adverse mental health, making urgent interventions essential to address their needs. Objective: To explore and provide systematic evidence on the types of mental health services and interventions for YEH in EAP and their impact on overall quality of life and wellbeing. Methods: Electronic databases(e.g., Medline, PsychInfo, PubMed, Scopus) were systematically searched(publication dates between 01/01/1990-13/05/2023), as well as additional online resources specific to homelessness. Articles were screened, and a critical appraisal assessed the quality of the included studies. Results: Eight studies with different interventions were identified in Indonesia(n = 2), Malaysia(n = 1), South Korea(n = 3), and The Philippines(n = 1). These were thematically clustered into six categories: art, cognitive behavioural therapy, life skills education, resilience enhancement, family strengthening and government interventions/services. Conclusion: This review highlights effective mental health interventions’ positive impact on YEH mental health outcomes and quality of life in EAP, stressing the urgent need to implement socio-culturally sensitive services. Future research should address knowledge gaps through comprehensive studies covering diverse EAP regions and populations, prioritising socio-culturally specific psychological measures.

Abstract: Acute coronary syndrome (ACS) represents the most severe manifestation of coronary artery disease (CAD), characterized by a particularly poor prognosis. Consequently, primary percutaneous coronary intervention (PPCI) is imperative in the event of acute ST-elevation myocardial infarction (STEMI). Interleukin-22 (IL-22) may be a new CAD biomarker because it signals and regulates immune and inflammatory responses. Objectives: To investigate the differences in circulating IL-22 levels between patients with STEMI undergoing PPCI and healthy controls; and to determine if these differences are associated with the culprit coronary artery, door-to-balloon time (DBT), final angiographic result, CAD classification, and the presence of diabetes mellitus (DM). Methods: A total of 280 participants were recruited, comprising 210 STEMI cases and 70 healthy controls. Participants underwent clinical and angiographic evaluation, and serum IL-22 levels were measured using enzyme-linked immunosorbent assay (ELISA). Data analysis was performed using the Mann-Whitney and Fisher’s tests, with a p < 0.05 significant. Results: Serum IL-22 levels were lower in cases (149.63, 84.99–294.56) than in controls (482.67, 344.33–641.00), p < 0.001. Lower IL-22 levels were associated with the right coronary artery (RCA) (144.57, 70.84–242.43; 146.00, 63.60–279.67; 191.71, 121.80–388.97), p = 0.033. IL-22 was lower with shorter DBT (≤ 60 minutes, 106.00, 49.60–171.71; > 60 minutes, 153.00, 88.86–313.60), p = 0.043. Conclusions: IL-22 levels were significantly lower in patients with STEMI compared to healthy controls.

Accurate diagnosis for the 400 million people with rare diseases is critical for healthcare decisions, prognosis, understanding disease mechanisms, and identification of treatments. Despite advances in genome sequencing, barriers such as high interpretation costs, diagnostic expertise, throughput associated delays, and uncertain variant classifications persist, with demand exceeding capacity. Many variant classification methods focus narrowly on specific consequences, leading to the use of complex integrative pipelines that often overlook transcript variability and lack prediction transparency. To overcome these limitations, we introduce DITTO. This transparent, transcript-aware machine-learning method demonstrates superior overall performance in accuracy, recall, and precision when compared to existing tools. DITTO is publicly available at https://github.com/uab-cgds-worthey/DITTO

Pulmonary hypertension (PH) is a serious condition linked to immune-system dysfunction. Myositis-specific/associated antibodies (MSA/MAA) play a role in idiopathic inflammatory myopathy (IIM) and interstitial lung disease (ILD), but their significance in PH remains unclear. We believe the presence of these antibodies, may be underestimated. This study analyzed adult PH patients without pre-existing IIM for MSA/MAA prevalence using a line-blot assay. We compared PH patients with and without ILD signs to a cohort clinically suspected of IIM/ILD (n=558). Our PH cohort (n=121) showed a significantly higher prevalence of overall weak positive MSA/MAAs and positive overlap syndrome-associated MAAs than the suspected IIM/ILD group (p

Oral squamous cell carcinoma (OSCC) is a highly prevalent and aggressive malignancy, with mortality rates that reach 60%, mainly due to an excessive diagnostic delay. MiRNAs, a class of crucial epigenetic gene-expression regulators, have emerged as potential diagnostic biomarkers, with >200 molecules reported to be dysregulated in OSCC. We had previously established an in silico methodology for the identification of the most disease-specific molecules by bridging genetics and epigenetics. Here, we identified the stage-specific miRNAs that govern the asymptomatic early stages of oral tumorigenesis by exploiting the reverse interplay between miRNA-levels and their target-genes’ expression. Incorporating gene expression data from our group’s experimental hamster model of sequential oral oncogenesis, we bioinformatically detected the miRNAs that simultaneously target/regulate >75% of the genes that are characteristically upregulated or downregulated in the consecutive stages of hyperplasia, dysplasia and early-invasion OSCC, while exhibiting the opposite expressional dysregulation in OSCC-derived tissue and/or saliva specimens. We found that all stages share the downregulation of miR-34a-5p, miR124-3p, and miR-125b-5p, while miR-1-3p is underexpressed in dysplasia and early-invasion. Malignant early-invasion stage is distinguished by the downregulation of miR-147a and the overexpression of miR-155-5p, miR-423-3p and miR-34a-5p. The identification of stage-specific miRNA molecules may facilitate their utilization as biomarkers for presymptomatic OSCC diagnosis.

Access to travel information is crucial for blind and partially sighted (BPS) people in travel planning. However, finding relevant information can be complex and challenging due to the unavailability of appropriate information and accessible information sources. To investigate this issue, a mixed-method study consisting of semi-structured interviews and co-design workshops was conducted to identify the needs of BPS people and the barriers BPS people experience due to the lack of access to such information. The findings provide insights into the information-seeking process and highlight the role of experience-sharing in cultivating a sense of agency, contribution, and interdependence. We contribute an accessible tourism ecosystem based on our findings to motivate research on technologies to support inclusive leisure travel for BPS people and to inform the design of inclusive tourism services.

Previous high throughput screening studies indicated trans-eQTLs tend to be tissue specific. In this study, I probed if this feature can be used to identify tissue-specific gene regulatory networks. eQTL data (P<5e-8) for 16,259 genes were identified and their summary association statistics were obtained from the eQTLGene database. Next, eQTLs that display both cis and trans regulatory effects were selected and the association between their corresponding genes were examined using Mendelian randomization. A total of 169 genes that exerted trans-regulatory impacts on 692 genes were identified. 90% of the genes (N=749) aggregated into a gene regulatory network significantly enriched in hemo-immune processes. The robustness of finding was confirmed through simulation. The identified network displayed the scale-free topology. This provided the reason to examine the association of the network’s hub genes with the phenome. The outcome of analyses revealed GSDMB and ORMDL3 impact several disorders of immune origin and ALDH2 overexpression contributes to obesity. This study reports trans-eQTLs can be used to identify tissue-specific gene regulatory networks and describes a workflow to achieve this purpose. The network identified in this study showed scale-free topology indicating the hub genes of a GRN could be targeted to prevent disease outcomes.

Biallelic pathogenic variants in CLPP, encoding mitochondrial matrix peptidase ClpP cause a rare autosomal recessive condition, Perrault syndrome type 3 (PRLTS3). It is characterized by primary ovarian insufficiency and early sensorineural hearing loss, often associated with progressive neurological deficits. Mouse models showed that accumulations of (i) its main protein interactor, the substrate-selecting AAA+ ATPase ClpX, (ii) mitoribosomes, and (iii) mtDNA nucleoids are main cellular consequences of ClpP absence. However, the sequence of these events and their validity in human remain unclear. Here, we studied global proteome profiles to define ClpP substrates among mitochondrial ClpX interactors, which accumulated consistently in ClpP-null mouse embryonal fibroblasts and brain. Validation work included novel ClpP-mutant patient fibroblast proteomics. ClpX co-accumulated in mitochondria with POLDIP2 as nucleoid component, LRPPRC as mitochondrial poly(A) mRNA granule element, GFM1 (in mouse also GRSF1) as tRNA processing factors. Only in mouse, accumulated ClpX, GFM1 and GRSF1 appeared in nuclear fractions. Mitoribosomal accumulation was minor. Consistent accumulations in murine and human fibroblasts also affected multimerizing factors not known as ClpX interactors, namely OAT, ASS1, ACADVL, STOM, PRDX3, PC, MUT, ALDH2, PMPCB, UQCRC2 and ACADSB, but the impact on downstream metabolites was marginal. Our data demonstrate the primary impact of ClpXP on the assembly of proteins with nucleic acids, and show nucleoid enlargement in human as a key consequence.

Aims: In late December 2019, early reports predicted the onset of a potential Coronavirus outbreak in china, given the estimate of a reproduction number for the 2019 Novel Coronavirus (COVID-19). Because of high ability of transmission and widespread prevalence, the mortality of COVID-19 infection is growing fast worldwide. Absent of an anti-COVID-19 has put scientists on the urge to repurpose already approved therapeutics or to find new active compounds against coronavirus. Here in this study, a set of computational approaches were performed in order to repurpose antivirals for dual inhibition of the frontier proteases involved in virus replication, papain-like protease (PLpro; corresponding to nsp3) and a main protease (Mpro), 3C‑like protease (3CLpro; corresponding to nsp5). Materials and Methods: In this regard, a rational virtual screening procedure including exhaustive docking techniques was performed for a database of 160 antiviral agents over 3CLpro and PLpro active sites of SARS-CoV-2. The compounds binding energies and interaction modes over 3CLpro and PLpro active sites were analyzed and ranked with the aid of free Gibbs binding energy. The most potent compounds, based on our filtering process, are then proposed as dual inhibitors of SARSC-CoV-2 proteases. Key findings: Accordingly, seven antiviral agents including two FDA approved (Nelfinavir, Valaganciclovir) and five investigational compounds (Merimepodib, Inarigivir, Remdesivir, Taribavirine and TAS106-106) are proposed as potential dual inhibitors of the enzymes necessary for RNA replication in which Remdesivir as well as Inagrivir have the highest binding affinity for both of the active sites. Significance: The mentioned drug proposed to inhibit both PLpro and 3CLpro enzymes with the aim of finding dual inhibitors of SARSC-CoV-2 proteases.

The main purpose of the study was to study the effects of a specific rowing ergometer training program on the athletic performance of young adolescents (n=56; 11.73 ± 1.4 years old) com-pared to a workout based on general strength training. Eight-week training program was im-plemented, with four sessions per week and two-hours per session. Sample was divided in two groups: a control group (CG) that performed circuit training with exercises aimed at building general strength and an experimental group (EG) who focused on specifically training on a rowing ergometer (rowing machine). The data obtained in a rowing meter test over the compe-tition distance were analyzed to obtain the average power attained (W) at the beginning of the training, at the middle (4 weeks), at the end of the training (8 weeks) and one year after the ex-perimentation. The results show that, although both forms of training improve the average W obtained in both categories, the EG subjects (+29.94W) obtained better averages in all phases of the study compared to the CG (+5.88W). Furthermore, this increase was greater in male rowers (+ 34.06W) than in female rowers (+24.54W). These results reveal that a specific rower rowing ergometer training program has a significant effect than a general strength program and these effects can even be observed a year after the intervention.

SMAD ubiquitination regulatory factor 1 (Smurf1) is a Nedd4 family E3 ubiquitin ligase that regulates cell motility, polarity and TGFβ signaling. Smurf1 contains an N-terminal protein kinase C conserved 2 (C2) domain that targets cell membranes and is required for interactions with membrane-localized substrates such as RhoA. Here we investigated the lipid-binding mechanism of Smurf1 C2, revealing a general affinity for anionic membranes in addition to a selective affinity for phosphoinositides (PIPs). We found that Smurf1 C2 localizes not only to the plasma membrane but also to negatively charged intracellular sites, acting as an anionic charge sensor and selective PIP-binding domain. Site-directed mutagenesis combined with docking/molecular dynamics simulations revealed that the Smurf1 C2 domain loop region primarily interacts with PIPs and cell membranes, as opposed to the β-surface cationic patch employed by other C2 domains. By depleting PIPs from the inner leaflet of the plasma membrane, we found that PIP binding is necessary for plasma membrane localization. Finally, we used a Smurf1 cellular ubiquitination assay to show that the amount of ubiquitin at the plasma membrane interface depends on the lipid-binding properties of Smurf1. This study shows the mechanism by which Smurf1 C2 targets membrane-based substrates and reveals a novel interaction based on PI(4,5)P2 and PIP3 selectivity.

Despite saltmarshes being considered as nature-based solutions (NbS) towards climate change mitigation, India’s saltmarsh ecosystems are least studied. This study quantifies the seasonal variation in carbon stocks mono-specific saltmarsh species (Porteresia coarctata) and its potential to play an important role in India’s climate change mitigation plans. Seasonal (pre-and post-monsoon) sampling of P. coarctata surface water, biomass and 30 cm sediment core was collected across four locations on the east coast of India to quantify sediment dry bulk density (DBD), organic matter (OM%), organic carbon (Corg%), Corg stocks of sediment and biomass, total carbon (C%) and nitrogen (N%) and stable isotopes of δ13C and δ15N. In general, the sediment DBD, OM and Corg of P. coarctata meadows was higher in post-monsoon and was influenced by salinity and pH changes. Isotope (δ¹³C) modelling of various sediment C sources suggested, particulate organic matter (POM) contribution was highest (0.04-0.79%) followed by P. coarctata (0.01–052%) and other macrophytes across our study locations. The seasonal variation of δ¹³C showed increased contribution of marine derived particulate and dissolved organic matter into P. coarctata meadows in post-monsoon season. Heavier δ¹⁵N values were observed in post-monsoon season suggesting anthropogenic input, that was utilized by P. coarctata to increase its above and below-ground biomass and shoot density. The combined ecosystem (30 cm sediment + biomass) Corg stocks of P. coarctata was 1.7-fold higher in post-monsoon (4021.20± 917 Mg C) compared to pre-monsoon (2297.36 ±647 Mg C) season among the four locations with a sediment Corg contribution >70%. Based on the International Panel for Climate Change Tier II assessment the P. coarctata meadows (443 ha) can help in avoiding the pre and post-monsoon emissions of 8431.34 and 14757.84 Mg CO₂ respectively. The combined price of the total CO₂ equivalent stored in P. coarctata meadows in pre- and post-monsoon is US$ 14.50 and US$ 25.38 million respectively. Further studies quantifying the NbS potential of P. coarctata mono-specific and mixed meadows of India’s coast is needed along with integration of saltmarsh ecosystems into India’s National Action Plan on Climate Change.

Recycling information can be complex and often confusing which may subsequently reduce the participations in any waste recycling schemes. As a result, this research explored the roles as well as the importance of a holistic approach in designing recycling information using 15 expert-based in-depth interviews. The rationale was to offer a better understanding of what constitutes waste, recycling, and how recycling information should be designed and presented to make recycling more attractive/convenient. Based on the research participants’ perceptions with supports from the existing studies, this research sub-categorised recycling information into three different themes, termed the “WWW” of recycling information components. As a result, these components (or attributes) were extensively described (using findings of semi-structured interviews) to elicit pragmatic guidance for practitioners, policy-makers, and other stakeholders in designing structured communication or information strategies that may simplify and subsequently increase waste-recycling practices. The policy implications of holistic information in enhancing recycling are further discussed.

The hospital indoor environment plays a significant role in shaping the microbial exposures that humans encounter. Resistance to antibiotics is one of the mechanisms employed by bacteria to develop resilience against stress in indoor environments. The extensive usage of antibiotics has been a key factor in driving changes in the ecological function of antibiotic resistance genes (ARGs) and their acquisition by pathogenic bacteria. By integrating the 16S rRNA Illumina sequencing and high throughput-qPCR approaches with water and air dust samples across seven departments at Peking University Shenzhen Hospital, China, this study yielded intriguing findings regarding the department-specific variation, transmission, and correlation of bacteria, ARGs and MGEs within the hospital indoor environment. One notable observation was that the seasonal variation played a vital role in shaping the bacterial composition in the overall hospital indoor environment across seven studied departments. Nevertheless, a similar significant seasonal impact was only observed in the blood test room and emergency departments, rather than in the other five departments. Another intriguing finding was the correlation between ARGs and MGEs abundance. This correlation was evident in the overall hospital indoor environment, which was conversely not found in the emergency, pneumology and gynecology departments. Additionally, while there was no significant relationship that occurred between bacterial communities and ARGs/MGEs within the hospital, the gynecology department demonstrated a close link between bacterial communities and the presence of ARGs/MGEs. Notably, the gynecology department also stood out as an important source of bacteria and ARGs/MGEs for other departments. This study underscores the need for careful surveillance and monitoring of antibiotic resistance, particularly in Legionella spp. in man-made water systems. The findings also show the importance of monitoring and understanding the genetic elements such as Tp614 involved in gene transfer and recombination, as well as their impact on antimicrobial treatment efficacy.

The leather industry is one of the most polluting industries in the world due to the large amounts of waste following the raw hides processing, but also due to the high content of chemicals present in their composition. The main problem of chromium-tanned leather solid waste is related to their storage, because of the ability of chromium to leach in soil or water, and also owing to the high ability of trivalent chromium to oxidize to its toxic form, hexavalent chromium. The purpose of this study is to present the latest methods for extracting trivalent chromium from the composition of solid leather wastes. The extraction methods identified in the present study are based on acid/basic/enzymatic hydrolysis and substitution with the help of organic chelators (organic acids and organic acid salts). In addition, the study includes a comparative analysis between the advantages and disadvantages of each identified extraction method. At the same time, the study also presentes alternative chromium extraction methods based on the combination of conventional extraction methods and ultrasound-assisted extraction.

The global increase in population has placed significant pressure on food security, leading to the emergence of aquaculture as a vital source of aquatic foods. However, rising costs and the limited availability of fishmeal in aquafeeds have spurred the search for alternative protein sources. While plant-based ingredients have been integrated into commercial aquafeeds, they come with challenges, including low protein content, palatability issues, and the presence of antinutritional factors. In this context, fish silage, derived from fish waste and discarded fish, stands out as a promising alternative technology due to its cost-effectiveness and sustainability attributes. The production of fish silage involves the addition of organic/inorganic acids or lactic acid bacteria to homogenized fish waste. This process yields a valuable mixture rich in peptides, free amino acids, and partially hydrolyzed proteins, offering significant nutritional benefits for animal diets. Beyond its nutritional advantages, fish silage contributes to environmental sustainability by reducing the impact of waste disposal and enhancing the value of fish waste. The objective of this review is to promote sustainable practices in the aquaculture industry in response to the increasing demand for high-quality feed nutrients. To achieve this, it includes an analysis of research results related to silage technology, an appraisal of the advantages and disadvantages of using fish silage as a feed additive, and a focus on emerging trends in this field.

Acute lower respiratory tract infection is a major health problem that affects more than 15% of the total population of Saudi Arabia each year. Epidemiological studies conducted over the last three decades have indicated that viruses are responsible for the majority of these infections. The epidemiology of respiratory viruses in Saudi Arabia is believed to be affected mainly by the presence and mobility of large numbers of foreign workers and the gathering of millions of Muslims in Mecca during the Hajj and Umrah seasons. Knowledge concerning the epidemiology, circulation pattern, and evolutionary kinetics of respiratory viruses in Saudi Arabia are scant, with the available literature being inconsistent. After reviewing the available data on epidemiology and evolution of respiratory viruses, this study examines the effect of varying vaccination rates across different age groups during the 2019/2020 influenza season in Saudi Arabia. Utilizing an age-structured SEIR (Susceptible–Exposed–Infectious–Recovered) model, it develops customized vaccination policies by considering age-specific incidence rates. This pioneering research segments the population into five age groups—infants and school-aged children, junior and older youth, young adults and adults, middle-aged, and seniors—across five regional areas in Saudi Arabis: Eastern, Central, Northern, Western, and Southern. A contact matrix, compiled from multiple sources, is used to delineate the dynamics of influenza transmission. The study undertakes a thorough comparison of three distinct vaccination scenarios: no vaccination, national vaccination, and optimized vaccine allocation policy, under various potential pandemic situations. It examines their impact on vaccination campaigns in terms of the total number of infections, mortality, and morbidity rates. The results emphasize the crucial impact of population demographics on disease transmission and vaccine distribution. According to the findings, the optimized vaccination scenario proved to be the most effective strategy in all scenarios.

In 2018, Iran witnessed approximately 21,000 fatalities resulting from road accidents, ranking it as the fifth leading cause of death across all age groups. These incidents carry substantial economic and social burden for the nation, claiming more than 5% of its GDP. Human behavior emerges as a significant contributing factor to high-risk driving offenses. It has been proposed that by influencing general deterrence, a rigorous defense can be established against such violations. Various theories posit that by reinforcing or diminishing influential factors, general deterrence perception can be molded, presenting a potential avenue for an effective deterrent against traffic infractions. This study examines deterrence perceptions prevailing among the public in Iran regarding the enforcement of traffic laws. Employing Structural Equation Modeling (SEM), we delve into the intricate relationships between variables, allowing for a comprehensive exploration of the factors influencing general deterrence. The study draws on the data derived from a survey comprising 548 questionnaires for modeling purposes. An innovative concept, private sector enforcement, is introduced and incorporated into the questioning and modeling process. The findings reveal that socioeconomic status (p-value&lt;0.01), police enforcement (p-value&lt;0.05), private sector enforcement (p-value&lt;0.05), specific deterrence (p-value&lt;0.01), and the use of technology (p-value&lt;0.01) have direct and indirect impacts on the general deterrence perception of drivers.

High-Rise buildings with their particular features can affects on surrounding environment and makes new microclimates. In the windy conditions, the spaces that are between building blocks changes to passages and affects on the wind velocity, intensity and it’s other parameters.The importance of this effect is different in each level of building height. The Pedestrian-Level is the lowest and one of important areas. Markets, playgrounds and pedestrian access had located in this area and any unwanted microclimate changes like high velocity and turbulence in this level can makes discomfort and dangerous condition for residents. So this research tries to consider the pedestrian- level wind comfort in some High-Rise building complexes arrangement that had located in Tehran district 22 with Computational Fluid Dynamics (CFD) modeling and reaching to a suitable arrangement pattern. It had collected the required data through field study and librarian databases and then compared them with standard guidelines and analyzed them by comparative comparison method. As a result a linear arrangement that placed crossover to wind direction for providing wind comfort and preventing wind danger is been suggested in this region.

Geranylgeranyl acetone (GGA) protects against various types of cell damages by upregulating heat shock proteins. We investigated whether GGA protect neuronal cells from cell death induced by oxidative stress. Glutamate exposure was lethal to HT-22 cells which comprise a neuronal line derived from mouse hippocampus. This configuration is often used as a model for hippocampus neurodegeneration in vitro. In the present study, GGA protected HT-22 cells from glutamate-induced oxidative stress. GGA pretreatment did not induce Hsps. Moreover, reactive oxygen species increased to the same extent in both GGA-pretreated and untreated cells exposed to glutamate. In contrast, glutamate exposure and GGA pretreatment increased mitochondrial membrane potential. However, increases in intracellular Ca2+ concentration were inhibited by GGA pretreatment. In addition, the increase of phosphorylated ERKs by the glutamate exposure was inhibited by GGA pretreatment. These findings suggest that GGA protects HT-22 cells from glutamate-provoked cell death without Hsp induction and that the mitochondrial calcium buffering capacity plays an important role in this protective effect.

Metal nanoframes have gained tremendous attention in the domain of modern research and development due to their distinctive 3D spatial structure, efficient physiochemical properties, and comparatively good activity. Different strategies have been implicated by the researchers to design nano frame of varying chemical nature and shapes. Most of the synthetic protocols being adopted to design a nano framee, mainly consist of two main steps, nucleation and growth of solid particles and secondly excavation of the interiors. In this context, many synthetic methods are overviewed. To show their unprecedented performance or activity, a few applications in catalytic, biomedical, theranostic, SERS, sensing of different materials, reduction of CO2, etc are also discussed.

The melanoma differentiation-associated protein 5 (MDA5; encoded by the IFIH1 gene) mediates the activation of the interferon pathway in response to viral infection. This protein is also upregulated in autoimmune diseases and psoriasis skin lesions. IFIH1 gene variants that increased the MDA5 activity have been associated with increased risk for immune mediated diseases, including psoriasis. Our aim was to determine the association between three IFIH1 variants (rs35337543, intron8 +1G>C; rs35744605, Glu627Stop; and rs1990760, Ala946Thr) and the main clinical findings in a cohort of Spanish patients with psoriatic disease (N=572; 77% early-onset). Early-onset psoriasis (EOPs) had a significant higher frequency of severe disease and Cw6+. Carriers of the 946Thr variant were more common in EOPs (p<0.001), and the effect was more pronounced among Cw6-negatives. This variant was also associated with an increased risk of psoriatic arthritis (PsA) independently of other factors (OR=1.62, 95%CI=1.11-2.37). The rs3533754 and rs35744605 have been reported as risk factors for viral infection and protective for autoimmune diseases, but we did not find significant differences between the two onset age or PsA groups. However, due to the reduced frequency of the two variants (<0.02) the size of our cohort was too low to conclude a significant effect. In conclusion, the common IFIH1 rs1990760 T allele that has been linked to increased gene expression was significantly more frequent in EOPs patients. This variant was also an independent risk factor for PsA in our cohort. This risk allele was in linkage disequilibrium with other variants previously associated with the risk of psoriasis and PsA. Our study reinforces the widely reported role of IFIH1 gene variants on psoriatic disease and other immune mediated diseases.

CO2 emission activity of xylotrophic fungi response to an increase in temperature in the range of 10-30 °C on the example of pure dikaryotic cultures of Fomes fomentarius s. str., F. inzengae, Fomitopsis betulina, F. pinicola, Phellinus igniarius was analyzed. Emission activity was assessed by the difference in CO2 concentration in 0.5-liter exposure chambers with Petri dishes with mycelium growing on agar at the beginning of exposure and an hour later using a Gasmet DX-4030 FTIR spectrometer (Gasmet Technologies Oy, Finland), error measurements ±50 ppm. Specific (μg CO2/cm2/h) and total (μg CO2/h) emission activity and its relationship with temperature and size (area) of the mycelium were assessed. It has been shown that in the range of 10-30 °C, the specific and total CO2 emission activity of the mycelium is closely and positively related to temperature. Specific emission, which is an indicator of the respiratory activity of the mycelium, does not depend on its size; its only driver is temperature, the relationship with which is linear: an increase in temperature by 10 °C causes an increase in the specific emission activity of the mycelium by 1.7 times. The total CO2 emission activity, which is an indicator of the total amount of CO2 emitted, is directly proportional to the specific emission activity and the size of the mycelium. In the range of 10-30 °C, an increase in temperature causes an almost equal increase in both the specific emission activity of the mycelium (Q10 1.7) and its growth (Q10 1.5) and causes an exponential increase in the total emission of CO2. This must be taken into account when predicting CO2 emissions from woody debris under climate change, as it could potentially contribute to accelerating climate change.

Yaba monkey tumor virus (YMTV) and Tanapox virus (TPV) are members of the Yatapoxvirus genus and can infect humans and other primates. Despite the threat posed by yatapoxviruses, the factors determining their host range are poorly understood. In this study, we analyzed the ability of YMTV and TPV orthologs of vaccinia virus K3 (called 012 in YMTV and TPV), which share 75% amino acid identity with one another, to inhibit PKR from 15 different primate species. We first used a luciferase-based reporter, and found that YMTV and TPV K3 orthologs inhibited PKR in a species-specific manner and showed distinct PKR inhibition profiles. TPV 012 inhibited PKR from 11 primates, including human, substantially better than YMTV 012. In contrast, both K3 orthologs inhibited the other four primate PKRs comparably well. Using YMTV 012 and TPV 012 hybrids, we mapped the region responsible for the differential PKR inhibition to the C- terminus of the K3 orthologs. Next, we generated chimeric vaccinia virus strains to investigate whether TPV K3 and YMTV K3 orthologs could rescue replication of a vaccinia virus strain that lacks PKR inhibitors K3L and E3L. Virus replication in primate-derived cells generally correlated with the patterns observed in the luciferase-based assay. Together, these observations demonstrate that yatapoxvirus K3 orthologs have distinct PKR inhibition profiles and inhibit PKR in a species-specific manner, which may contribute to the differential susceptibility of primate species to yatapoxvirus infections.

There is a growing recognition of the need to incorporate sustainability considerations early-on in the product development (PD) process (PDP). As part of a case study at an engineering consultancy firm, this paper identifies considerations that influence the integration of sustainable design practices into real-world PD practices. This is informed by the first author getting embedded in the firm as an intern, and closely observing the PD workflow across various projects, conducting interviews and group discussions with a wide range of practitioners, and iteratively designing and testing various potential interventions. From literature and observation, we find that designers and engineers often struggle to identify and apply the right sustainable design methods and tools (SDMTs) to tackle the environmental impacts associated with their products. Through a human-centered design process, we co-created a reusable, modular framework of practices that aids the selection of relevant strategies, based on the environmental hotspots, stage of the PD process, and the client’s sustainability priorities. The paper further presents insights related to the framework’s real-world application and impacts in the firm, based on results of longitudinal engagement with the firm.

F-box protein is a key protein of the SCF E3 ubiquitin ligase complex, responsible for substrate recognition and degradation through specific interactions. Previous studies have shown that F-box proteins play crucial roles in Cryptococcus sexual reproduction. However, the molecular mechanism by which F-box proteins regulate sexual reproduction in C. neoformans is unclear. In the study, we discovered the AICAR transformylase/IMP cyclohydrolase Ade16 as a substrate of Fbp1. Through protein interaction, protein stability, and in vivo ubiquitination experiments, we demonstrated that Ade16 is a substrate for Fbp1. To examine the role of ADE16 in C. neoformans, we constructed the iADE16 strains and ADE16OE strains to analyze the function of Ade16. Our results revealed that the iADE16 strains had a smaller capsule and showed growth defects under NaCl, while the ADE16OE strains were sensitive to SDS but not to Congo red, which is consistent with the stress phenotype of the fbp1Δ strains, indicating that the intracellular protein expression level after ADE16 overexpression was similar to that after FBP1 deletion. Interestingly, although iADE16 strains can produce basidiospores normally, ADE16OE strains can produce mating mycelia but not basidiospores after mating, which is consistent with the fbp1Δmutant strains, suggesting that Fbp1 is likely to regulate the sexual reproduction of C. neoformans through the modulation of Ade16. Fungal nuclei development assay showed that the nuclei of the ADE16OE strains failed to fuse in the bilateral mating, indicating that Ade16 plays a crucial role in the regulation of meiosis during mating. In summary, our findings have revealed a new determinant factor involved in fungal development related to the post-translational regulation of AICAR transformylase/IMP cyclohydrolase.

The stress-inducible heat shock protein 70 (Hsp70), which functions as a molecular chaperone and is frequently overexpressed in different cancer cell types, is presented on the cell surface of tumor cells and is actively released into the circulation in free and extracellular lipid vesicle-associated forms. Since the exact pathomechanism of endometriosis has not yet been elucidated but has been associated with the development of endometrial and ovarian cancer, we asked whether extracellular Hsp70 and circulating endometriotic cells (CECs) reflects the presence and development of endometriosis. Therefore, circulating levels of free and lipid microvesicle-associated Hsp70 were measured using the Hsp70-exo ELISA, and the presence of circulating CECs in the peripheral blood of patients with endometriosis was determined using membrane Hsp70 (mHsp70) and EpCAM monoclonal antibody (mAb)-based bead isolation approaches. Isolated CECs were further characterized by immunofluorescence using reagents directed against cytokeratin (epithelial), CD45 (leukocyte), CD105/CD44 (mesenchymal-stemness) and by comparative RNA analysis. Similar to the situation in patients with cancer, levels of circulating Hsp70 were elevated in the blood of patients with histologically proven endometriosis compared to a healthy control cohort, with the highest Hsp70 level in a patient with lymph node endometriosis. Moreover, CECs could be isolated using the cmHsp70.1 mAb- and to a lesser extent EpCAM mAb-based bead approaches in all patients with endometriosis. The longevity in cell culture and the expression of cytokeratin, CD105 and CD44, together with differentially expressed genes related to EMT reveals similarities of mHsp70 expressing CECs with circulating tumor cells (CTCs) and suggest a mesenchymal-stemness origin. These findings may support the involvement of mHsp70 positive, stem cell-like cells in the development of endometriotic lesions. In summary, elevated levels of Hsp70 in the blood and CECs could serve as liquid biopsy markers for endometriosis and help to elucidate the underlying pathomechanism of the disease.

Objective: Diabetes is associated with increased cardiovascular and cerebrovascular disease-related mortality. We investigated the association between carotid intima-media thickness (CIMT) with clusterin (CLU), amylin, secreted frizzled-related protein-4 (SFRP-4), total and active glucagon-like peptide-1 (GLP-1) levels, and dipeptidyl peptidase-4 (DPP-4) in type 2 diabetes mellitus (T2DM) individuals with or without coronary artery disease (CAD). Methods: This study consisted of four groups in Medicine Hospital between April- October, 2017: Control group (mean ages: 50.3 ± 10.7 years, 20 females and 15 males), diabetic group (DM) (mean ages: 53.9 ± 11.1, 14 females and 23 males), CAD group (mean ages: 62.6 ± 11.8, 17 females and 17 males) and CAD+ DM group: (mean ages: 62.6 ± 11.8 years, 18 females and 18 males). Results: Both CAD and CAD+DM groups have higher CIMT levels than controls. CAD+DM group have also significantly higher CIMT levels than DM group. Left external carotid artery (ECA) was only found different in DM group from controls. When compared with controls, DM, CAD groups have low DPP-4 and GLP-1_total concentration. Control group have significantly lower SFRP-4 levels than DM, CAD and CAD+DM (p<0.001) groups. Serum GLP-1_total levels were found to be significantly low in CAD+DM group when compared to control group. Conclusion: DPP-4 and SFRP-4 levels are predictive marker for atherosclerosis in diabetes, correlates well with HOMA-IR particularly in diabetes. CIMT has the potential to be a clinically useful predictor of vascular risk in diabetic patients with CAD. Large cohorts and at-risk populations are needed to confirm the predictive value of these findings.

In this study, we investigate how dataset composition influences the performance and bias of age estimation models across different ethnic groups. We utilized pre-trained Convolutional Neural Networks (CNNs) such as VGG19, fine-tuning them on two datasets: UTKFace and APPA-REAL. UTKFace comprises 23,705 samples (12,391 males, 11,314 females) including 10,078 White, 4,526 Black, and 3,434 Asian individuals. APPA-REAL consists of 7,591 samples (3,818 males, 3,773 females) with 6,686 White, 231 Black, and 674 Asian individuals. We adjusted dataset composition by oversampling minority groups and reducing samples from the majority group to evaluate effects on model performance, measured using Mean Absolute Error (MAE) and standard deviation. Our findings demonstrate that oversampling alone does not guarantee equitable performance across ethnicities; reducing samples from the majority group often resulted in more balanced performance, evidenced by lower MAE standard deviations. These results underscore the importance of a nuanced approach to achieve fairness, including combining various sampling techniques. This study emphasizes the critical need for tailored dataset compositions to mitigate bias and suggests exploring more refined data processing methods and algorithmic adjustments for enhanced model fairness and accuracy in facial recognition technologies.

Parkinson's disease is a neurodegenerative disorder resulting from progressive damage to specific brain regions. Key symptoms encompass involuntary movements (tremor), slowness of movements (bradykinesia), and muscle rigidity. Although the precise cause remains uncertain, a combination of genetic and environmental factors is believed to contribute to its development. This study focuses on the interaction of the E3 ubiquitin-protein ligase parkin with natural compounds. Docking investigations revealed that Amentoflavone exhibited an excellent binding energy score of approximately -10 kcal/mol. The E3 ubiquitin-protein ligase parkin displayed a robust binding affinity with docked amentoflavone, evident from a high binding energy of -10 kcal/mol. Nonetheless, additional biological studies are crucial not only to validate its potential efficacy against Parkinson's and assess safety in terms of toxicity but also to perform further computational analyses confirming these preliminary assessments.

Sick leave is influenced by various modifiable lifestyle factors and sex differences. This study examines the impact of body mass index, fruit and vegetable consumption, physical activity, smoking, and alcohol consumption on sick leave among Serbia's working population, focusing on sex differences. Data from the 2019 National Health Survey of Serbia were analyzed, focusing on a representative sample of 4,652 individuals aged 18-65. Chi-square tests and logistic regression models assessed the relationships between lifestyle factors and sick leave, adjusting for sociodemographic, work-related, and health-related variables. Among respondents, 15.8% reported sick leave in the past 12 months, with higher rates among women in both, short-term (13.9% vs. 10.6%) and long-term sick leave (3.4% vs. 2.2%). For men, obesity (OR = 2.6), poor dietary habits (fruit OR = 2.1; vegetables OR = 2.8), smoking (OR = 1.9), and risky alcohol consumption (OR = 4.1) significantly increase the likelihood of sick leave. In women, smoking (OR = 1.8) and risky alcohol consumption (OR = 3.1) are major predictors, while BMI and physical activity show less impact. Fruit and vegetable consumption and physical activity have inconsistent effects on sick leave, indicating the need for further research. This study identifies obesity, poor dietary habits, smoking, and alcohol consumption as key predictors of sick leave in men. In women, smoking and risky alcohol consumption are major predictors. Smoking is a risk factor for both sexes, while risky alcohol consumption emerges as a prominent predictor and is a significant predictor overall. These findings highlight the need for targeted public health interventions to address these lifestyle factors and reduce sick leave rates. Further research is needed to clarify the roles of dietary habits and physical activity in influencing sick leave.

Corona viruses hijack human enzymes to assembly sugar coat on Spike glycoproteins. The mechanism that human antibodies may uncover the antigenic viral peptide epitopes hidden by sugar coat are unknown. In this study, we analyzed recombinant SARS-CoV-2 Spike protein secreted from BTI-Tn-5B1-4 cells, by trypsin and chymotrypsin digestion followed by mass spectrometry analysis. We acquired MS/MS spectrums for glycopeptides of all 22 predicted N-glycosylated sites. We further analyzed the surface accessibility of Spike proteins according to Cryo-EM and homolog-modeled structures, and available antibodies that bind to SARS-CoV-1. The results showed that all 22 N-glycosylated sites of SARS-CoV-2 are modified by high-mannose type of N-glycans. MS/MS fragmentation clearly established the glycopeptide identities. Electron densities of glycans cover most of the Spike receptor binding domain of SARS-CoV-2, except YQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQ, similar to a region FSPDGKPCTPPALNCYWPLNDYGFYTTTGIGYQ in SARS-CoV-1. Other surface-exposed domains included those located on Central Helix, between amino acids 967 and 1016 of SARS-CoV-1, and 985 to 1034 of SARS-CoV-2 Spike protein. As the majority of antibody paratopes bind to peptide portion with or without sugar modification, we propose a snake-catcher model that a minimal length of peptide is first clamped by a paratope, and the binding is either strengthened by sugars close to peptide, or not interfered by sugar modification.

The study aimed to analyze thoracic and lumbar erector spinae muscle activations during 3D elongation exercises in individuals with adolescent idiopathic scoliosis (AIS). Participants included 24 adolescents, meeting specific criteria such as a Cobb angle between 10° and 20°, and not having undergone surgical or brace treatments. EMG data were collected to evaluate muscle activations. The study found no significant interaction between exercise type and the side of the curve, but a significant main effect of exercise type on muscle activation, irrespective of Cobb angle. Different exercise types significantly affected muscle activity, with the highest activations in the TheraBand exercise, followed by manual and without equipment conditions. This suggests that exercise type significantly impacts muscle engagement in AIS patients, providing valuable insights for targeted exercise program design. The study, however, focused on short-term muscle activation, not long-term Cobb angle progression, pointing to the need for further research in this area.

To cope the high glycemic variability (GV) is crucial in the management of multiple daily insulin (MDI) in diabetes. We compared the effect of low dose metformin 750mg/d adding vildagliptin 100mg/d (DPP4+LMET) or the high dose metformin 1500mg/d (HMET), in type 2 diabetes (T2D) with MDI, evaluating GV by continuous glucose monitoring (CGM). Single center, open-label, 12 weeks - 2 period crossover design. Twenty T2D with inadequately controlled (7.0% <HbA1c ≦9.0%) with MDI + LMET were enrolled. Primary endpoints were GV and hypoglycemia derived from CGM performed after each 12 weeks treatment periods. There was no significant difference in HbA1c, body weight changes, total daily dose of insulin. DPP4+LMET compared to the HMET, significantly reduced the calculated GV value, mean (7.15±1.3 vs 7.82±1.6, p<0.05), standard deviation (1.78±0.55 vs 2.27±1.11, p=0.03), continuous overlapping net glycemic action (6.44±1.28 vs 7.12±1.69, p<0.05), J-Index (26.7±11.0 vs 34.9±19.8, p<0.05), high blood glucose index (3.01±1.96 vs. 6.73±4.85, p=0.02), and mean amplitude of glycemic excursions (4.53±1.35 vs 5.50±2.34, p=0.03). The GV metrics with hypoglycemia and nocturnal hypoglycemia were not significantly different. DPP4+LMET decreased GV associated with hyperglycemia. Adding DPP4 inhibitor to the lower dose of metformin is an alternative approach to the stable GV in MDI.

Clinical, pathological, and imaging evidence in multiple sclerosis (MS) shows that inflammation starts early and progresses with age. B cells play a central role in this process, contributing to cytokine production, defective regulatory functions, and abnormal immunoglobulin production, even in the central nervous system. Anti-CD20 (aCD20) therapies, which deplete CD20+ B cells, are effective for both relapsing-remitting (RR) and progressive-relapsing (PR) MS. While effective against MS symptoms and lesions detectable by magnetic resonance imaging, aCD20 therapies can reduce the immune response to COVID-19 vaccination. By using high-parameter flow cytometry, we examined the antigen-specific (Ag+) immune response six months post-third COVID-19 mRNA-vaccination in MS patients with RR and PR forms on aCD20 therapy. Despite lower Ag+ B cell responses and lower levels of anti-SARS-CoV2, both total and neutralizing antibodies, RR and PR patients developed strong Ag+ T cell responses. We observed similar percentages and numbers of Ag+ CD4+ T cells and high proportion of Ag+ CD8+ T cells, with slight differences in T cell phenotype and functionality, that however suggested the presence of differences in immune responses driven by age and disease severity.

We evaluated the potential of using fish species and functional traits as indicators of land use impacts to fish assemblages. We used environmental data collected at multiple spatial scales (local, reach, and upstream catchment) for 19 tributary and main stem sites in the Nolichucky River watershed in Tennessee. Canonical correspondence analyses showed that temperature, elevation, specific conductivity, sediment yield, impervious surfaces, and row crop cover at the catchment scale were strongly associated with fish assemblage structure, as well as forest cover from all three spatial scales. Blocked indicator species analysis, with stream size as the block, showed that significantly strong indicators of the least-impacted riparian land use condition (≥60% forest cover) were Saffron Shiner (Notropis rubricroceus), Rainbow Trout (Oncorhyncus mykiss), Longnose Dace (Rhynichthys cataractae), Creek Chub (Semotilus atromaculatus), and Mottled Sculpin (Cottus bairdi). Traits indicative of the least-impacted sites were the herbivorous trophic guild, mean female age-at-maturity, longevity, rock-gravel spawners, montane geology and pelagic swimmers. Specific conductivity was strongly related to multiple catchment-scale land use variables, and was a strong local-scale influence on fish assemblage structure. Our results show promise for using a relatively common but endemic southern Appalachian fish species, the Saffron Shiner, as an indicator for land-use related impacts to these streams.

Uterine tube extracellular matrix is a key component that regulates tubal tissue physiology, and it has a region-specific structural distribution, which are directly associated to their functions. Considering this, application of biological matrices in culture systems is an interesting strategy to develop biomimetic tubal microenvironments and enhance their complexity. However, there are no established protocols to produce tubal biological matrices that consider the organ morphophysiology for such applications. Therefore, this study aimed to establish region-specific protocols to obtain decellularized scaffolds derived from porcine infundibulum, ampulla, and isthmus to provide suitable sources of biomaterials for tissue-engineering approaches. Porcine uterine tubes were decellularized in solutions of 0.1% SDS and 0.5% Triton X-100. Decellularization efficiency was evaluated by DAPI staining and DNA quantification. We analyzed ECM composition and structure by optical and scanning electronic microscopy, FTIR and Raman spectroscopy. DNA and DAPI assays validated the decellularization, presenting significative reduction of cellular content. Structural and spectroscopy analyses revealed that produced scaffolds remained well structured and with ECM composition preserved. YS and HEK293 cells were used to attest cytocompatibility, allowing cell survival and successful interaction with the scaffolds. These results suggest that such matrices are applicable for future biotechnological approaches in the reproductive field.

Ubiquitin binding domains (UBDs) are modular elements that bind non-covalently to ubiquitin and act as downstream effectors and amplifiers of the ubiquitination signal. With few exceptions, UBDs recognize the hydrophobic path centered on Ile44 (Leu-8, Ile-44, Val-70). Nevertheless, a variety of different orientations, which can be attributed to specific contacts between each UBD and surface residues surrounding the hydrophobic patch, specify how each class of UBD recognizes ubiquitin. Here, we describe the structure of a novel ubiquitin-binding domain that we identified in NEDD4 binding protein 1 (N4BP1). By performing protein sequence analysis, mutagenesis and NMR spectroscopy of the ¹⁵N isotopically labelled protein, we demonstrate that a Phe-Pro motif in N4BP1 recognizes the canonical hydrophobic patch of ubiquitin. This recognition mode resembles the molecular mechanism evolved in the CUE (Coupling of ubiquitin conjugation to ER degradation) domain family, where an invariant proline, usually following a phenylalanine, is required for binding to ubiquitin. Interestingly, the UBD of N4BP1 is evolutionary related to CUBAN (Cullin binding domain associating with NEDD8) (40% identity and 47% similarity), a protein module that also recognizes the ubiquitin-like NEDD8, which is the closest relative of ubiquitin (58% identity and 80% similarity). By performing circular dichroism and ¹⁵N NMR chemical shift perturbation of N4BP1 in complex with ubiquitin, we demonstrate that the UBD of N4BP1 lacks the NEDD8 binding properties observed in CUBAN and it recognizes the Ile44-centered patch of ubiquitin through a dedicated binding site, which share some of the features observed in the CUE domain family. Moreover, we show that, in addition to mediating the interaction with ubiquitin and ubiquitinated substrates, both the CUBAN and the UBD of N4BP1 are poly-ubiquitinated in cells. This modification is dependent on the presence of a functional domain. We believe that the structural and functional characterization of this novel UBD will allow a deeper understanding of the molecular mechanisms governing N4BP1 function, while at the same time providing a valuable tool for clarifying how the discrimination between ubiquitin and the highly related NEDD8 is achieved.

Population-based data on hematologic malignancies (HM) are rare in Greece regarding adults (≥18 years old). The aim of this study was the assessment of the burden of these malignant neoplasms (MN) for adults in Crete. The study assessed temporal trends of incidence and mortality, depicted their spatial distribution and extracted net-survival curves of patients. Population-data on these MN were obtained from the database of the Cancer Registry of Crete, for a 22 year time period (1/1/1992-31/12/2013). All HM were classified into four main groups of diseases: (1) Hodgkin’s lymphoma (HL); (2) Non-Hodgkin’s lymphomas (NHLs); (3) Multiple myeloma (MM); and (4) All chronic and acute leukemias. Annual, gender-specific, age standardized incidence and mortality rates were estimated (ASIR/100.000/year; ASMR/100.000/year). A total of 3,380 newly diagnosed cases were included in the final analyses; All ASIRs/100,000 increased significantly throughout the study period presenting differences in their geographical distribution of rates among municipalities of Crete. ASIRs for NHLs, HL, MM, leukemias and for all 4 MN were 13.1, 2.6, 4.7, 11.7 and 32.1, respectively, in 2013. Five-year net-survival for patients diagnosed with NHLs, HL, MM and leukemias were: 82%, 85%, 52% and 56%, respectively. This first research article studying a long period of time for adults in Greece generates hypotheses on the existence of risk factors that may partly explain this variation of rates.

The paper explores the features of numerical simulation to analyze the dynamic behavior of drives controlled by pulse-width modulators. Modern motor control systems widely use pulse width modulation. Effective numerical modeling of such systems has specific features because the models employed are continuous-event and have hybrid behavior due to the presence of nonlinear links with discontinuities of the first kind. Therefore, it is essential to have special integration methods with variable steps, which should be factored in when developing the model. The paper shows how these problems are solved when modeling an electric drive with a DC motor in the SimInTech software.

Toxic advanced glycation end-products (TAGE), formed by glyceraldehyde (GA) as an intermediate in the non-enzymatic reaction with intracellular proteins, are highly cytotoxic and have been implicated in the pathogenesis of various diseases. However, the mechanisms underlying the degradation and removal of TAGE remain largely unknown. In the present study, we identified the checkpoint kinase-1 (CHK1) mutant, d270KD, which was rapidly degraded intracellularly by GA, and showed that its degradation was mainly mediated by the ubiquitin-proteasome pathway. The high-molecular-weight complexes formed by the GA stimulation of d270KD were abundant in the RIPA-insoluble fraction, which also contained high levels of TAGE. The knockdown of p62/SQSTM1 reduced the amount of high-molecular-weight complexes in the RIPA-insoluble fraction, indicating its involvement in the formation of TAGE aggregates. The present results suggest that the ubiquitin-proteasome pathway and p62 play a role in the degradation and aggregation of intracellular TAGE formed by GA. This study provides new insights into the mechanisms underlying TAGE metabolism and may lead to the development of novel therapeutic strategies for diseases associated with TAGE accumulation.

Pd-Pt catalysts supported on carbon preheated to 1600°C have been reinvestigated in CHFCl2 hydrodechlorination. An additionally adopted catalyst oxidation at 350-400°C produced an order of magnitude increase in the catalytic activity of Pd/C. This increase is not caused by changes in metal dispersion or possible decontamination of the Pd surface from superficial carbon, but rather by unlocking the active surface, originally inaccessible in metal particles tightly packed in the pores of carbon. Burning carbon from the pore walls attached to the metal changes the pore structure, providing easier access for the reactants to the entire palladium surface. As upon calcination the performance of the rest of the Pd-Pt/C catalysts changes less than for Pd/C, the relation between the turnover frequency and alloy composition does not confirm the Pd-Pt synergy invoked in our previous work. The use of even higher-preheated carbon (1800°C), completely free of micropores, results in a Pd/C catalyst that does not need to be oxidized to achieve high activity and excellent selectivity up to CH2F2 (>90%).

The changing epidemiology of Staphylococcus aureus has created several gaps in its population structure and emergence of strains. Two global shifts in the aftermath of the past methicil-lin-resistant S. aureus (MRSA) pandemic are: a rise in healthcare-associated infections and evolu-tion of cutaneous and soft tissue infections with high morbidities and mortalities. Furthermore, bitter lessons from COVID-19 showed S. aureus necrotizing-pneumonia and skin conditions ag-gravating Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and Monkeypox manifestations. Limited data and paucity of high-quality evidence exist for many key clinical questions. Using clinical microbiology, molecular characterization, hospital data on age and in-fection sites, and antibiograms, we have investigated S. aureus infection patterns. We showed that age-specific distribution in both intensive care unit (ICU) and non-ICU revealed highest infection rates (94.7%) in senior-patients >50 years; most were MRSA (81.99%). However, specific distribu-tions of geriatric MRSA and MSSA rates were 46.5% and 4.6% in ICU and 35.48% and 8.065% in non-ICU, respectively. Intriguingly, age groups 0-20 years showed uniquely similar MRSA pat-terns in ICU and non-ICU patients (13.9%, 9.7%, respectively) and MSSA in ICU (11.6%). In age groups 20-50 years, MRSA were 2-fold in non-ICU (35%) than ICU (18.6%). Interestingly, highly significant association was found between infection-site and age-groups (P-value .000). Skin in-fections remained higher in all ages; pediatrics 32.14%, adults 56%, and seniors 25% while res-piratory infections were lower in pediatrics (14.3%) and adult 17%), and highest in seniors (38%). Blood and “other” sites in pediatrics recorded (28.6%; 25%, respectively), slightly lower in adults (18.6%; 8.6%) and seniors (14%); 22.8%), respectively. Further, significant association existed between infection-site and MRSA (Chi-Square Test, P-value .002). The common cutaneous infec-tions across all age-groups and the significant association of MRSA to geriatric-respiratory infec-tions have a high potential for skin-carriage as reservoir for endogenous infection. The similar frequencies of both lineages in youth in all settings imply MSSA-carriage as potential evolutionary origins for MRSA. These findings have important clinical implications for strategic planning in patient management and S. aureus control particularly in age-specific infections and vigilance for potential viral coinfections.

In the realm of artificial intelligence, knowledge graphs have become a fascinating area of research. Relationships between entities are depicted through a structural framework in knowledge graphs. In this paper, we propose to build a domain-specific medicine dictionary (DSMD) based on the principles of knowledge graphs. Our dictionary is composed of structured triples, where each entity is defined as a concept, and these concepts are interconnected through relationships. This comprehensive dictionary boasts more than 348,000 triples, encompassing over 20,000 medicine brands and 1,500 generic medicines. It offers a groundbreaking approach to storing and accessing medical data. Our dictionary facilitates various functionalities, including medicine brand information extraction, brand-specific queries, as well as queries involving two words or question answering. We anticipate that our dictionary will serve a broad spectrum of users, catering to both human users, such as diverse range of healthcare professionals as well as AI applications.

The length of stay (LOS) in the hospital emergency department (ED) is a crucial key performance indicator that is used to track and manage the performance of the ED as a whole. Our study had two objectives. Firstly, we aimed to evaluate the association between LOS and the most common primary ICD-10 diagnoses. To achieve this, we examined LOS in groups with specific (internal, surgical, neurological, and traumatic diseases) and non-specific diagnoses in adult ED visits at a tertiary referral hospital between 2017 and 2019 (134,675 visits in total). Our secondary objective was to measure LOS by age, day of the week, time of day, and season. The mean LOS was 254 minutes and was the shortest in the traumatic group (160 minutes), while in other groups it was significantly longer: neurological by 185 minutes, internal medicine by 158 minutes, surgical by 36 minutes, and non-specific by 24 minutes. In conclusion, non-specific diagnoses accounted for 21% of all ICD-10 primary diagnoses. In this group of patients, the percentage of hospitalizations was the highest. Other significant determinants of LOS were the patients’ age, the day of the week, the time of arrival, and repeated visits.

The COLOSS research association has been assessing honey bee colony losses, associated risk factors and management, focusing on Western countries but with a progressive international expansion. Here, we report the first survey on the loss rates of colonies in 2022/23 in Ethiopia using COLOSS monitoring survey tools. A face-to-face interview questionnaire survey was conducted on 64 beekeepers selected from Oromia and Tigray regions. This covered 1,713 honey bee colonies distributed in 68 apiaries. The percentages of colonies lost were significantly different between Oromia (24.1%) and Tigray (66.4%) regions. Colony losses were attributed as unsolvable queen problems (8% in Oromia; 10% in Tigray), natural disaster (32%; 82%), and empty hives or dead colonies (60%; 8%). The loss rate was significantly affected by queen replacement (p

Dengue virus (DENV) is a member of the Flaviviridae family and is responsible for the most common mosquito-borne human disease. Currently, there are no available antiviral drugs to treat DENV infections. However, certain flavonoids, including baicalein and baicalin, have demon-strated significant anti-DENV effects in vitro. This study aimed to assess the bioavailability of baicalein and its metabolite, baicalin, in the blood serum of Albino Wistar rats using the LC/MS/MS method. The in vitro activity of sera obtained from rats administered baicalein was evaluated for its anti-DENV properties using quantitative RT-PCR and the Foci Forming Reduction Assay (FFRA). The results obtained through LC/MS/MS analysis indicated that the bioavailability of baicalin in rat blood serum reached 44.20 µg/ml one hour after oral administration of baicalein. Furthermore, the sera collected from rats given baicalein exhibited a significant 78.26% inhibition of DENV-2 replication when tested against Dengue-2 using both quantitative RT-PCR and FFRA. These findings suggest that baicalein and baicalin hold promise as potential therapeutic candidates for further investigation in the development of treatments against DENV infections.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and a heterogeneous disease characterized by mature B-cell neoplasms. The standard immunochemotherapy for DLBCL is R-CHOP, which includes rituximab, cyclophosphamide, doxoru-bicin, vincristine, and prednisone. Up to 30-40% of patients with DLBCL either exhibit primary refractory disease to standard treatment or experience relapse after the initial response. A 72-year-old man diagnosed with DLBCL involving chromosomal translocations t(1;22)(q21;q11.2) and t(6;18)(p25;q21) showed primary refractory disease after the fourth cycle of R-CHOP. The patient ultimately experienced cardiac involvement by the lymphoma and received salvage chemotherapy. He passed away about 15 months away after the diagnosis of DLBCL. We conducted fluorescence in situ hybridization (FISH) for further analysis of the chromosomal translocations. The breakpoint of chromosome 1q21 was located at a distance of around 151 Mb from the telomeric end of chromosome 1p. The breakpoint in chromosome 22q11 contains the immunoglobulin lambda locus. Furthermore, the breakpoint of chromosome 6p was in the telomeric region of chromosome 6p21. The breakpoint of chromosome 18q21 contains BCL2. This case report presents the first documented co-occurrence of chromosomal translocations t(1;22)(q21;q11.2) and t(6;18)(p25;q21) in a patient with DLBCL. These chromosomal translocations may indicate a worse clinical outcome.

Developing recombinant Saccharomyces cerevisiae strains capable of transporting and fermenting cellobiose directly is a promising strategy for second-generation ethanol production from lignocellulosic biomass. In this study we cloned and expressed in the CEN.PK2-1C strain an intracellular βglucosidase (SpBGL7) from Spathaspora passalidarum, and co-expressed the cellobiose transporter SiHXT2.4 from Scheffersomyces illinoinensis, and two putative transporters from Candida tropicalis (CtCBT1) and Meyerozyma guilliermondii (MgCBT2). While all three transporters allowed cell growth on cellobiose, only the MgCBT2 permease allowed cellobiose fermentation, although cellobiose consumption was stuck (incomplete). The analysis of the βglucosidase and transport activities revealed that the cells stopped to consume cellobiose due to a drop in the transport activity. Since ubiquitinylation of lysine residues at the N- or C-terminal domains of the permease are involved in the endocytosis and degradation of sugar transporters, we constructed truncated versions of the permease lacking lysine residues at the C-terminal domain (MgCBT2ΔC), and at both the C- and N-terminal domain (MgCBT2ΔNΔC), and co-expressed these permeases with the SpBGL7 βglucosidase in an industrial strain. While the strain harboring the MgCBT2ΔC transporter continued to produce stuck cellobiose fermentations as the wild-type MgCBT2 permease, the strain with the MgCBT2ΔNΔC permease was able to consume and ferment all the cellobiose present in the medium. Thus, our results highlight the importance of expressing cellobiose transporters lacking lysine at the N- and C-terminal domains for efficient cellobiose fermentation by recombinant S. cerevisiae.

Insect-specific viruses (ISVs) include viruses that are restricted to the infection of mosquitoes and are spread mostly through transovarial transmission. Despite using a distinct mode of transmission, ISVs are often closely related to arthropod-borne viruses (arboviruses) that are responsible for human diseases and able to infect both mosquitoes and vertebrates. ISVs can also induce a phenomenon called “superinfection exclusion”, whereby a primary ISV infection in an insect inhibits subsequent viral infections of the insect. This has sparked interest in the use of ISVs for the control of pathogenic arboviruses transmitted by mosquitoes. In particular, insect-specific flaviviruses (ISF) have been shown to inhibit infection of vertebrate-infecting flaviviruses (VIFs) both in vitro and in vivo. This has shown potential as a new and ecologically friendly biological approach to the control of arboviral disease. For this intervention to have lasting impacts for biological control, it is imperative that ISFs are maintained in mosquito populations with high rates of vertical transmission. Therefore, these strategies will need to optimize vertical transmission of ISFs in order to establish persistently infected mosquito lines for sustainable arbovirus control. This review compares recent observations of vertical transmission of arboviral and insect-specific flaviviruses and potential determinants of transovarial transmission rates to understand how the vertical transmission of ISFs may be optimised for effective arboviral control.

Eotaxin-3 is a key chemokine with a relevant role in eosinophilic esophagitis, a rare chronic immune/antigen-mediated inflammatory disorder. Eotaxin-3 is a potent activator of eosinophil emergence and migration, which may lead to allergic airway inflammation. We investigated by bioinformatics tools the protein structure and the possible effects of the known variations reported in public databases. Following a procedure already established, we created a 3D model of the whole protein and modelled the structure of 105 protein variants due to known point mutations. The effects of the amino acid substitution at the level of impact on protein structure, stability, and possibly function, were detected by the bioinformatics procedure and described in detail. A web application was implemented to browse the results of the analysis and visualize the 3D models, with the opportunity of downloading the models and analyze by the own software. Among 105 amino acid substitutions investigated, the study evidenced in 44 cases at least one change in any of the investigated structural parameters. Other 6 variations are also relevant, although a structural effect is not detected by our analysis, because they substituted amino acids highly conserved, which suggests a possible function role. All these variations should be the object of particular attention, as they may induce loss of functionality in the protein.

The detection of early biomarkers and molecular mechanisms in Parkinson’s disease (PD) remains a challenge. Recent research has pointed to potential roles for peptidylarginine deiminases (PADs), a family of calcium activated enzymes, and associated post-translational protein citrul-lination/deimination in early stages of the disease, with a focus on hippocampal and cortex re-gions of the brain. Further analysis of brain region specific changes in PAD isozymes and identi-fication of brain-region specific citrullinomes, therefore remain to be studied. This study assessed brain-region specific PAD isozyme expression (PADs 1-4; PAD6) and associated citrullinated protein targets in the 6-hydroxydopamine (6-OHDA) induced rat model of pre-motor PD. Cortex, hippocampus, striatum, midbrain, cerebellum and olfactory bulb were compared between con-trols/shams and the PD model. In cortex, a significant increase of PAD2 and PAD3 was observed in the PD model. In hippocampus, PAD3, PAD4 and PAD6 showed strongest levels, but with no significant changes observed between PD and controls. In striatum, a significant reduction in all PAD isozymes was observed in the PD model. In the olfactory bulb, PAD3 was significantly el-evated in PD. In midbrain, PAD2, PAD4 and PAD6 showed strongest signal but with no signifi-cant changes between PD and controls. In cerebellum, a significant increase was seen in PAD3, PAD4 and PAD6 in the PD model. Citrullinated protein hits were most abundant in cortex and hippocampus, while for the PD model an increase in citrullinated hits was particularly observed in cortex and cerebellum, compared to controls. For all brain regions there was a considerable difference in citrullinated protein IDs between the PD model and the controls. Citrullinome as-sociated KEGG pathways differed in the six brain regions; some were overlapping for controls and PD, some were identified for the PD model only, and some were identified in control brains only. KEGG pathways identified in PD brains onlywere: “Axon guidance”; “Spinocerebellar ataxia”; “Hippo signalling pathway”; “NOD-like receptor signalling pathway”; “Phosphatidyl-inositol signalling system”; “Rap1 signalling pathway”; “Platelet activation”; “Yersinia infection”; “Fc gamma R-mediated phagocytosis”; “Human cytomegalovirus infection”; “Inositol phosphate metabolism”; “Thyroid hormone signalling pathway”; “Progesterone-mediated oocyte matura-tion”; “Oocyte meiosis”; and “Choline metabolism in cancer”. Our findings highlight differences in PAD isozymes, citrullinated proteins and associated KEGG pathways between brain regions, in pre-motor PD.

Until 2021, in the Kyrgyz Republic, tuberculosis(TB) was diagnosed and treated only in the public sector. With funding support of the STOP-TB partnership, the private providers in four regions of the country and Bishkek city were mapped, trained and incentivized to screen for, identify presumptive TB patients, and refer them to the public facilities for diagnosis and treatment. In this study, we describe the cascade of care of such patients. This was a cohort study involving secondary analysis of routine data. Of 79,352 patients screened during February 2021-March 2022, 2,511(3%) had presumptive TB, of whom, 903(36%) were not tested for TB [pre-diagnostic loss-to-follow-up]. A total of 323(13%) patients were diagnosed as TB, of whom, 42(13%) were not started on treatment [pre-treatment loss-to-follow-up]. Among 257 patients eligible for outcome assessment, 197(77%) had treatment success, 29(11%) were lost-to-follow-up, 13(5%) died, 4(2%) had treatment failure and 14(5%) were not evaluated. While this donor-funded, pioneering initiative was successful in engaging the private sector, we recommend the national TB programme to scale-up the initiative nationally with dedicated budgets, activities and plans to monitor the progress. Qualitative research is urgently needed to understand the reasons for the gaps in the care cascade.

The prediction of corticosteroid responses in coronavirus disease 2019 (COVID-19) patients is crucial in clinical practice, and exploring the role of artificial intelligence (AI)-assisted analysis of chest radiographs (CXR) is warranted. This retrospective case-control study involving hospitalized COVID-19 patients treated with corticosteroids was conducted from September 4th, 2021, to August 30th, 2022. The primary endpoint of the study was corticosteroid responsiveness, defined as the advancement of two or more of the eight-categories-ordinal scale. Serial abnormality scores for consolidation and pleural effusion on CXR were obtained using a commercial AI-based software based on days from onset of symptoms. Amongst the 258 participants included in the analysis, 147 (57%) were male. Multivariable logistic regression analysis revealed that high pleural effusion score at 6–9 days from onset of symptoms (adjusted odds ratio of [aOR]: 1.022, 95% confidence interval [CI]: 1.003-1.042, p=0.020) and consolidation scores up to 9 days from onset of symptoms (0-2 days: aOR: 1.025, 95% CI: 1.006-1.045, p=0.010; 3-5 days: aOR: 1.03 95% CI: 1.011-1.051, p=0.002; 6-9 days: aOR; 1.052, 95% CI: 1.015-1.089, p=0.005) were associated with an unfavorable corticosteroid response. AI-generated scores could help intervene in the use of corticosteroids in COVID-19 patients who would not benefit from them

This comprehensive review paper provides a detailed analysis of the extraction methods employed in the dimension stone industry. Natural rock materials used in construction, have been historically extracted using primitive techniques such as thermal shock, hammer and chisel, and plug and feather. However, significant technological advancements have revolutionized the industry, leading to the widespread adoption of mechanized methods. One highly efficient technique is diamond wire cutting, which involves the utilization of diamond-engraved bits affixed to a tensioned steel wire. This method has demonstrated remarkable capabilities in minimizing waste generation and ensuring exceptional machining quality. Nonetheless, challenges such as high operating costs and wire breakage persist and require further investigation. In addition to diamond wire cutting, this review explores the utilization of circular diamond saws and frame sawing as alternative extraction methods. The geotechnical characteristics of the stone play a critical role in the selection of appropriate machinery, and researchers worldwide have conducted numerous studies to investigate the impact of each parameter on the extraction efficiency of these mechanized techniques. Moreover, controlled blasting with explosives emerges as a promising alternative for dimension stone extraction, warranting further exploration and optimization.

The research is devoted to the study of geotectonic and geodynamics of the Shu-Ile belt and petrographic composition and intrusive complexes geochemical features analysis. The Shu-Ile suture is an important geological structure of Kazakhstan. It is characterized by the presence of various intrusive formations and deep faults. The material composition of these intrusions is of interest for understanding the geological and metallogenic processes in this region. The research used modern scientific methods, including petrographic and geochemical studies of various compositions intrusion samples. Based on the results of material composition studies of intrusive complexes, their possible connections with other geological structures of Kazakhstan and the metallogeny of the region have been established. Based on the data obtained, a conclusion was made about the intrusive complexes origin and evolution of the Shu-Ile belt, which may be important for further geological research and forecasting of mineral resources in the region.

This review is focused on synephrine, the principal phytochemical found in bitter orange and other medicinal plants, and widely used as a dietary supplement for weight loss/body fat reduction. We examine different aspects of synephrine biology, delving into its established and potential molecular targets, as well as its mechanisms of action. We present an overview of the origin, chemical composition, receptors, and pharmacological properties of synephrine, including its anti-inflammatory and anti-cancer activity in various in vitro and animal models. Additionally, we conduct a comparative analysis of the molecular targets and effects of synephrine with those of its metabolite, selective glucocorticoid receptor agonist (SEGRA) Compound A (CpdA), which shares a similar chemical structure with synephrine. SEGRA, including CpdA, have been extensively studied as glucocorticoid receptor activators that have a better benefit/risk profile than glucocorticoids due to the reduced adverse effects. We discuss the potential of synephrine usage as a template for the synthesis of new generation of non-steroidal SEGRA. The review also provides insights into the safe pharmacological profile of synephrine.

This paper presents a new methodology that provides the analysis of surface texture changes in areas adjacent to the volcano and its impact product of volcanic activity. To do this, algorithms from digital image processing such as the co-occurrence matrix and the wavelet transform are used. These methods are working on images taken by the Landsat satellite platform sensor 5 TM and Landsat 7 ETM + sensor, and implemented with the purpose of evaluating superficial changes that can warn of surface movements of the volcano. The results were evaluated by similarity metrics for grayscale images, and validated in two different scenarios that have the same type of eruption, but differ, essentially, in climate and vegetation. Finally, the proposed algorithm is presented, setting the parameters and constraints for implementation and use.

The dominant paradigm holds that spontaneous and therapeutically induced anti-tumor responses are mediated mainly by CD8 T cells and directed against tumor-specific antigens (TSAs). The presence of specific TSAs on cancer cells can only be proven by mass spectrometry analyses. Bioinformatic predictions and reverse immunology studies cannot provide this type of conclusive evidence. Most TSAs are coded by unmutated non-canonical transcripts that arise from cancer-specific epigenetic and splicing aberrations. When searching for TSAs, mass spectrometry analyses must therefore interrogate not only the canonical reading frame of annotated exome but all reading frames of the entire translatome. The majority of aberrantly expressed TSAs (aeTSAs) derive from unstable short-lived proteins that are good substrates for direct MHC I presentation but poor substrates for cross-presentation. This is an important caveat because cancer cells are poor antigen-presenting cells and the immune system therefore depends on cross-presentation by dendritic cells (DCs) to detect the presence of TSAs. We therefore postulate that, in the untreated host, most aeTSAs are undetected by the immune system. We present evidence suggesting that vaccines inducing direct aeTSA presentation by DCs represent an attractive strategy for cancer treatment.

The allosteric SERCA (Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase) activator CDN1163 has been recently added to the group of pharmacological tools for probing SERCA function. We chose to investigate the effects of the compound on T lymphocyte Ca2+ stores, using the well-described Jurkat T lymphocyte as a reliable cell system for Ca2+ signaling pathways. Our study identified the lowest concentrations of the SERCA inhibitors thapsigargin (TG) and 2,5-di-(tert butyl)-1,4-benzohydroquinone (tBHQ) capable of releasing Ca2+, permitting the differentiation of the TG-sensitive SERCA 2b Ca2+ store from the tBHQ-sensitive SERCA 3 Ca2+ store. We proceeded to test the effects of CDN1163 on Ca2+ stores, examining specific actions on the SERCA 2b and SERCA 3 Ca2+ pools using our low dose SERCA blocker regimen. In contrast to previous work, we find CDN1163 exerts complex time-sensitive and SERCA isoform-specific actions on Ca2+ stores. Surprisingly, short-term exposure (0-30 minutes) to CDN1163 perturbs T cell Ca2+ stores by suppressing Ca2+ uptake with diminished Ca2+ release from the SERCA 2b-controlled store. Concomitantly, we find evidence for a SERCA-activating effect of CDN1163 on the SERCA 3 regulated store, given the observation of increased Ca2+ release inducible by low dose tBHQ. Intriguingly, longer-term (&gt;12 hours) CDN1163 exposure reversed this pattern, with increased Ca2+ release from SERCA 2b-regulated pools, yet decreased Ca2+ release responses from tBHQ-sensitive SERCA 3 pool. Our results reveal differential effects of CDN1163 on Ca2+ stores regulated by distinct SERCA isoforms, prompting the need for careful interpretation of the compound’s effects, particularly in cells expressing multiple SERCA isoforms.

Dispersion of antibiotic in livestock farming represents a health concern worldwide, contributing to the spread of antimicrobial resistant bacteria through animals, the environment, and humans. Phenolic compounds could be alternatives to antibiotics, once drawbacks such as low water solubility, bioavailability, and reduced stability are overcome. Although nano- or microsized formulations could respond to these shortcomings they do not represent cost-effective options. Here, three phenolic compounds, obtained from wood processing manufacturers, were characterized, revealing suitable features such as antioxidant activity, size, and chemical and colloidal stability for in-field applications. The Minimum Inhibitory Concentration (MIC) of these colloidal suspensions was measured against six bacterial strains isolated from livestock. These particles showed different inhibition behaviors: Colloidal chestnut was effective against one of the most threatening antibiotic resistant pathogens such as S. aureus but was ineffective toward E. coli. On the other hand, colloidal pine showed a weak effect on S. aureus but specificity toward E. coli. The present proof-of-concept points at colloidal polyphenols as valuable alternatives for antimicrobial substitutes in the livestock context.

The Fusarium fujikuroi species complex (FFSC) includes socioeconomically important pathogens that cause disease and/or mycotoxin contamination on numerous crops. Here, we used comparative genomics to elucidate processes underlying the ability of pine-associated and grass-associated FFSC species to colonize tissues of their respective plant hosts. We characterized the identity, possible functions, evolutionary origins, and chromosomal positions of the host-range-associated genes encoded by the two groups of fungi. The 72 and 47 genes identified as unique to the respective genome groups were potentially involved in diverse processes, ranging from transcription, regulation, and substrate transport, through to virulence/pathogenicity. Most emerged early during the evolution of Fusarium/FFSC and were subsequently retained only in some lineages, while some had origins outside Fusarium. Although differences in the densities of these genes were especially noticeable on the conditionally dispensable chromosome of F. temperatum (representing the grass-associates) and F. circinatum (representing the pine-associates), the host-range-associated genes tended to be located towards the subtelomeric regions of chromosomes. Taken together, these results demonstrate that multiple mechanisms drive the emergence of genes in grass- and pine-associated FFSC taxa examined and highlighted the diversity of molecular processes potentially underlying niche-specificity in these and other Fusarium species.