Search

Abstract We present a comprehensive and user-friendly framework built upon the pyiron integrated development environment (IDE), enabling researchers to perform the entire Machine Learning Potential (MLP) development cycle consisting of (i) creating systematic DFT databases, (ii) fitting the Density Functional Theory (DFT) data to empirical potentials or MLPs, and (iii) validating the potentials in a largely automatic approach. The power and performance of this framework are demonstrated for three conceptually very different classes of interatomic potentials: an empirical potential (embedded atom method - EAM), neural networks (high-dimensional neural network potentials - HDNNP) and expansions in basis sets (atomic cluster expansion - ACE). As an advanced example for validation and application, we show the computation of a binary composition-temperature phase diagram for Al-Li, a technologically important lightweight alloy system with applications in the aerospace industry.

Abstract Among the numerous driving forces that cause the atherosclerotic cardiovascular disease (ASCVD), pathogenic bacterial extracellular membrane nanovesicles (BEMNs) containing toxins and virulence factors appear to be the key trigger of inflammation and atherogenesis, the major processes involved in the pathogenesis of ASCVD. Since BEMNs are the carriers of nanosized biomolecules to distant sites, they are now being considered as a novel drug delivery system. Nowadays, many therapeutic strategies are used to treat ASCVD. However, the conventional anti-atherosclerotic therapies are not effective enough. This primarily due to the inefficiency of non-targeted drug delivery systems to tissue affected areas, which, in turn, leads to numerous side effects, as well as faulty pharmacokinetics. In this regard, nanomedicine methods using nanoparticles (NPs) as targeted drug delivery vehicles proved to be extremely useful. Bioengineered BEMNs equipped with disease-specific ligand moieties and loaded with corresponding drugs represent a promising tool in nanomedicine, which can be used as a novel drug delivery system for a successful therapy of ASCVD. In this review, we outline the involvement of pathogenic BEMNs in the triggering of ASCVD, the conventional therapeutic strategies for the treatment of ASCVD, and the recent trends in nanomedicine using BEMNs and NPs as a vehicle for targeted drug delivery.

Congregate homeless shelters are disproportionately affected by infectious disease outbreaks. We describe enterovirus epidemiology across 23 adult and family shelters in King County, Washington, USA, during October 2019–May 2021, by using repeated cross-sectional respiratory illness and environmental surveillance and viral genome sequencing. Among 3,281 participants >3 months of age, we identified coxsackievirus A21 (CVA21) in 39 adult residents (3.0% [95% CI 1.9%–4.8%] detection) across 7 shelters during October 2019–February 2020. We identified enterovirus D68 (EV-D68) in 5 adult residents in 2 shelters during October–November 2019. Of 812 environmental samples, 1 was EV-D68–positive and 5 were CVA21–positive. Other enteroviruses detected among residents, but not in environmental samples, included coxsackievirus A6/A4 in 3 children. No enteroviruses were detected during April 2020–May 2021. Phylogenetically clustered CVA21 and EV-D68 cases occurred in some shelters. Some shelters also hosted multiple CVA21 lineages.

Abstract Purpose Loddo et al. (Br J Cancer 100:959–70, 2009) established the prognostic significance of cell cycle markers and "Cell-Cycle Phenotypes" in breast carcinoma. This study aims to 1) identify prognostic cell-cycle markers in sarcoma, and 2) assess the prognostic potential of specific cell-cycle phenotypes in sarcoma. Methods Tissue samples from 128 soft tissue sarcomas were stained for four cell cycle-specific markers: Mcm2, Geminin, Plk1, and H3S10ph. Only primary soft tissue tumors (liposarcoma, leiomyosarcoma, synovial sarcoma, and undifferentiated pleomorphic sarcoma) were included in the analysis. Any tumor coming from a recurrent or metastatic lesion were excluded from the analysis. Three cell-cycle phenotypes (I, II, III) were derived from marker expression patterns. Prognostic significance was evaluated in a subset of primary soft tissue sarcomas using Cox regression for survival analysis. Results Compared to phenotype I, the phenotype III tumors had a decreased 5-year overall survival (HR 6.81 [2.36–19.61]; p =

Abstract Paramyxoviruses including measles, Nipah, and parainfluenza viruses are public health threats with pandemic potential. Human parainfluenza virus type 3 (HPIV3) is a leading cause of illness in pediatric, older, and immunocompromised populations. There are no approved vaccines or therapeutics for HPIV3. Neutralizing monoclonal antibodies (mAbs) that target viral fusion are a potential strategy for mitigating paramyxovirus infection, however their utility may be curtailed by viral evolution that leads to resistance. Paramyxoviruses enter cells by fusing with the cell membrane in a process mediated by a complex consisting of a receptor binding protein (HN) and a fusion protein (F). Existing atomic resolution structures fail to reveal physiologically relevant interactions during viral entry. We present cryo-ET structures of pre-fusion HN-F complexes in situ on surfaces of virions that evolved resistance to an anti-HPIV3 F neutralizing mAb. Single mutations in F abolish mAb binding and neutralization. In these complexes, the HN protein that normally restrains F triggering has shifted to uncap the F apex. These complexes are more readily triggered to fuse. These structures shed light on the adaptability of the pre-fusion HN-F complex and mechanisms of paramyxoviral resistance to mAbs, and help define potential barriers to resistance for the design of mAbs.

Abstract Social connections among individuals are essential components of social‐ecological systems (SESs), enabling people to take actions to more effectively adapt or transform in response to widespread social‐ecological change. Although scholars have associated social connections and cognitions with adaptive capacity, measuring actors' social networks may further clarify pathways for bolstering resilience‐enhancing actions. We asked how social networks and socio‐cognitions, as components of adaptive capacity, and SES regime shift severity affect individual landscape management behaviours using a quantitative analysis of ego network survey data from livestock producers and landcover data on regime shift severity (i.e. juniper encroachment) in the North American Great Plains. Producers who experienced severe regime shifts or perceived high risks from such shifts were not more likely to engage in transformative behaviour like prescribed burning. Instead, we found that social network characteristics explained significant variance in transformative behaviours. Policy implications: Our results indicate that social networks enable behaviours that have the potential to transform SESs, suggesting possible leverage points for enabling capacity and coordination toward sustainability. Particularly where private lands dominate and cultural practices condition regime shifts, clarifying how social connections promote resilience may provide much needed insight to bolster adaptive capacities in the face of global change. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Task functional magnetic resonance imaging research has generally shielded away from studying individuals due to the low reproducibility. Here, we propose that heterogeneous brain activations across individuals localize to a common network. To test this hypothesis, we use working memory (WM) as our example. First, we showed that discrete-brain-based reproducibility of brain activation during WM across individuals was low. Then, we used activation network mapping (ANM) technique to identify each individual’s brain network of WM and found that network-based reproducibility was rather high. Prediction analyses using machine learning algorithms indicated that individual WM networks identified via ANM can predict WM behavioral performance. This predictive ability even outperformed that of brain activations. Our study provides a new explanation on the low reproducibility of brain activations across individuals. The results suggest that ANM can be used to identify individual brain networks of cognitive processes, thus promising broad potential applications.

The publication presents the correspondence of the decadent poet Alexander Tinyakov (1886–1934) with his school teacher and literary mentor, the famous political figure and writer Fyodor Kryukov (1870–1920), who was one of the editors of the magazine “Russkoye Bogatstvo” (“Russian Wealth”) in the 1900s. Most of the letters date back to 1903–1905, when Tinyakov, having left the Oryol gymnasium, took his first steps in the literary world and felt the need to share with his mentor his creative plans (he compiled a handwritten magazine “Luchi zari” (“Rays of Dawn”) and actively sent his texts to the central periodical press), his limited experience of successes and failures. Publishing problems and magazine life in the early 20th century are the main themes of this correspondence. Tinyakov proudly discusses his literary acquaintances with V. Bryusov, L. Andreev, A. Serafimovich, S. Sokolov-Krechetov, et al. The epistolary dialogue between persons from two opposed cultural circles instantly becomes the property of literature: Kryukov uses the personality and messages of his student as a factual substrate for his novels about school life.

The article reviews the monograph by Kapitalina Antonovna Koksheneva, DSc in Philology, dedicated to the cultural and philosophical aspects of N. N. Strakhov’s legacy. The book under review is an innovative study that links the problems of nihilism and devaluing of the idea of personality, and the crisis of rationality in the European philosophical culture of the last third of the 19th century. The monograph examines the legacy of K. S. Stanislavsky in the context of the theory of “organic art.” The study is characterized by both new approaches and interdisciplinary thoroughness. Based on the concepts of understanding man and the national nature of the soul, created by Russian philosophers of the second half of the 19th century, the author defines the range of national ideals that N. N. Strakhov developed in “The Struggle with the West in Our Literature,” and which is fundamental, eternally relevant for Russian culture. The research of K. A. Koksheneva convincingly proves that only the metaphysical method allows us to understand the cultural studies of N. N. Strakhov and the circle of artists-creators and thinkers-creators close to him.

The Internet has become the primary vehicle for doing almost everything online, and smartphones are needed for almost everyone to live their daily lives. As a result, cybersecurity is a top priority in today’s world. As Internet usage has grown exponentially with billions of users and the proliferation of Internet of Things (IoT) devices, cybersecurity has become a cat-and-mouse game between attackers and defenders. Cyberattacks on systems are commonplace, and defense mechanisms are continually updated to prevent them. Based on a literature review of cybersecurity vulnerabilities, attacks, and preventive measures, we find that cybersecurity problems are rooted in computer system architectures, operating systems, network protocols, design options, heterogeneity, complexity, evolution, open systems, open-source software vulnerabilities, user convenience, ease of Internet access, global users, advertisements, business needs, and the global market. We investigate common cybersecurity vulnerabilities and find that the bare machine computing (BMC) paradigm is a possible solution to address and eliminate their root causes at many levels. We study 22 common cyberattacks, identify their root causes, and investigate preventive mechanisms currently used to address them. We compare conventional and bare machine characteristics and evaluate the BMC paradigm and its applications with respect to these attacks. Our study finds that BMC applications are resilient to most cyberattacks, except for a few physical attacks. We also find that BMC applications have inherent security at all computer and information system levels. Further research is needed to validate the security strengths of BMC systems and applications.

Abstract Semiconductor nanoplatelets are atomically flat nanocrystals which emit light with high spectral purity at wavelengths controlled by their thickness. Despite their technological potential, efforts to further sharpen the emission lines of nanoplatelets have generally failed for unknown reasons. Here, we demonstrate theoretically that the linewidth is controlled by surface chemistry—specifically, inhomogeneities in the ligand layer on the nanoplatelet surface lead to a spatially fluctuating potential that localizes excitons. This localization leads to increased scattering and optical broadening. Importantly, localization also reduces the rate of radiative emission. Our model explains the observed linewidth and predicts that a more uniform ligand layer will sharpen the lines and increase the emission rates. These findings demonstrate that light emission from nanoplatelets can be controlled by optimizing their surface chemistry, an important advantage for their eventual use in optical technologies.

Background: Chronic pruritus (CP) is a poorly characterized condition associated with intense pruritus without a primary skin eruption. This condition tends to emerge more commonly in older adults, and there is limited research on triggering factors. Objective: To explore the clinical characteristics and pathophysiology of CP following exposure to an immune stimulus. Methods: Clinical characteristics and plasma samples were collected from 15 patients who developed CP following an immune stimulus such as checkpoint inhibitors or vaccination. A multiplex panel was used to analyze plasma cytokine concentrations within these patients. Results: Most immunotherapy-treated patients experienced CP during treatment or after 21 to 60 days of receiving treatment, while vaccine-stimulated patients developed pruritus within a week of vaccination. Plasma cytokine analysis revealed elevated levels of 12 cytokines in patients with immune-stimulated CP compared to healthy controls. Notably, T helper 2 (Th2) related cytokines interleukin (IL)-5 (fold change 2.65; q

Coronary-pulmonary artery fistulas (CPAFs) are rare entities that can cause significant left-to-right shunting and complicate routine coronary artery bypass grafting. There are no best practice guidelines and a scarcity of reports regarding concomitant treatment of CPAF with coronary artery disease. We present a case of bilateral CPAFs in a 60-year-old man with symptomatic coronary artery disease treated successfully with coronary artery bypass, epicardial ligation, and transpulmonary closure of CPAF with patch reconstruction. This case highlights the importance of optimal myocardial protection and complete closure of the fistula to prevent risk of coronary steal.

Keratins 6, 16, and 17 occupy unique positions within the keratin family. These proteins are not commonly found in the healthy, intact epidermis, but their expression increases in response to damage, inflammation, and hereditary skin conditions, as well as cancerous cell transformations and tumor growth. As a result, there is an active investigation into the potential use of these proteins as biomarkers for different pathologies. Recent studies have revealed the role of these keratins in regulating keratinocyte migration, proliferation, and growth, and more recently, their nuclear functions, including their role in maintaining nuclear structure and responding to DNA damage, have also been identified. This review aims to summarize the latest research on keratins 6, 16, and 17, their regulation in the epidermis, and their potential use as biomarkers in various skin conditions.

Abstract Background The Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD (DPYD*2A/rs3918290, c.1236G > A/rs75017182, c.2846A > T/rs67376798 and c.1679 T > G/rs56038477) can mitigate the risk of severe fluoropyrimidine toxicity. However, this could not prevent all toxicities. The goal of this study was to identify additional genetic variants, both inside and outside DPYD, that may contribute to fluoropyrimidine toxicity. Methods Biospecimens and data from the Alpe-DPD study were used. Exon sequencing was performed to identify risk variants inside DPYD. In silico and in vitro analyses were used to classify DPYD variants. A genome-wide association study (GWAS) with severe fluoropyrimidine-related toxicity was performed to identify variants outside DPYD. Association with severe toxicity was assessed using matched-pair analyses for the exon sequencing and logistic, Cox, and ordinal regression analyses for GWAS. Results Twenty-four non-synonymous, frameshift, and splice site DPYD variants were detected in ten of 986 patients. Seven of these variants (c.1670C > T, c.1913 T > C, c.1925 T > C, c.506delC, c.731A > C, c.1740 + 1G > T, c.763 − 2A > G) were predicted to be deleterious. The carriers of either of these variants showed a trend towards a 2.14-fold (95% CI, 0.41–11.3, P = 0.388) increased risk of severe toxicity compared to matched controls (N = 30). After GWAS of 942 patients, no individual single nucleotide polymorphisms achieved genome-wide significance (P ≤ 5 × 10−8), however, five variants were suggestive of association (P

Abstract Background One major goal of total knee arthroplasty (TKA) is to achieve balanced medial and lateral gaps in flexion and extension. While bone resections are planned by the surgeon, soft tissue laxity is largely intrinsic and patient-specific in the absence of additional soft tissue releases. We sought to determine the variability in soft tissue laxity in patients undergoing TKA. Methods We retrospectively reviewed 113 patients undergoing TKA. Data on preoperative knee deformity were collected. Data from a dynamic intraoperative stress examination were collected by a robotic tracking system to quantify maximal medial and lateral opening in flexion (85–95 degrees) and extension (-5–20 degrees). T-tests were used to assess the differences between continuous variables. Results A valgus stress opened the medial compartment a mean of 4.3 ± 2.3 mm (0.0–12.4 mm) in extension and 4.6 ± 2.3 mm (0.0–12.9 mm) in flexion. A varus stress opened the lateral compartment a mean of 5.4 ± 2.4 mm (0.3–12.6 mm) in extension and 6.2 ± 2.5 mm (0.0–13.4 mm) in flexion. The medial compartment of varus knees opened significantly more in response to valgus stress than valgus knees in both extension (5.2 mm vs. 2.6 mm; P

Abstract Background Among the non-traditional antibacterial agents in development, only a few targets critical Gram-negative bacteria such as carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter baumannii or cephalosporin-resistant Enterobacteriaceae. Endolysins and their genetically modified versions meet the World Health Organization criteria for innovation, have a novel mode of antibacterial action, no known bacterial cross-resistance, and are being intensively studied for application against Gram-negative pathogens. Methods The study presents a multidisciplinary approach, including genetic engineering of LysECD7-SMAP and production of recombinant endolysin, its analysis by crystal structure solution following molecular dynamics simulations and evaluation of antibacterial properties. Two types of antimicrobial dosage forms were formulated, resulting in lyophilized powder for injection and hydroxyethylcellulose gel for topical administration. Their efficacy was estimated in the treatment of sepsis, and pneumonia models in BALB/c mice, diabetes-associated wound infection in the leptin receptor-deficient db/db mice and infected burn wounds in rats. Results In this work, we investigate the application strategies of the engineered endolysin LysECD7-SMAP and its dosage forms evaluated in preclinical studies. The catalytic domain of the enzyme shares the conserved structure of endopeptidases containing a putative antimicrobial peptide at the C-terminus of polypeptide chain. The activity of endolysins has been demonstrated against a range of pathogens, such as Klebsiella pneumoniae, A. baumannii, P. aeruginosa, Staphylococcus haemolyticus, Achromobacter spp, Burkholderia cepacia complex and Haemophylus influenzae, including those with multidrug resistance. The efficacy of candidate dosage forms has been confirmed in in vivo studies. Some aspects of the interaction of LysECD7-SMAP with cell wall molecular targets are also discussed. Conclusions Our studies demonstrate the potential of LysECD7-SMAP therapeutics for the systemic or topical treatment of infectious diseases caused by susceptible Gram-negative bacterial species and are critical to proceed LysECD7-SMAP-based antimicrobials trials to advanced stages.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in more than 692 million cases worldwide and nearly 7 million deaths (August 2023). Severe COVID-19 is characterised in part by vascular thrombosis and a cytokine storm due to increased plasma concentrations of pro-thrombotic proteins such as von Willebrand factor and cytokines secreted from endothelial and T-cells. EFCAB4B is a gene that encodes for two proteins (CRACR2A and Rab46) that play important roles in endothelial and T-cell secretion. In this study, using patient data recorded in the UK Biobank, we demonstrate the importance of variants in the EFCAB4B genetic sequence with COVID-19 fatality. Using logistic regression analysis, we determined that three single-nucleotide polymorphisms (SNPs) in the gene cause missense variations in CRACR2A and Rab46, which are associated with COVID-19 fatality (rs9788233: p = 0.004, odds ratio = 1.511; rs17836273: p = 0.012, odds ratio = 1.433; rs36030417: p = 0.013, odds ratio = 1.393). All three SNPs cause changes in amino acid residues that are highly conserved across species, indicating their importance in protein structure and function. Two SNPs, rs17836273 (A98T) and rs36030417 (H212Q), cause amino acid substitutions in important functional domains: the EF-hand and coiled-coil domain, respectively. Molecular modelling shows minimal impact by the substitution of threonine at position 98 on the structure of the EF-hand. Since Rab46 is a GTPase that regulates both endothelial cell secretion and T-cell signalling, these missense variants may play a role in the molecular mechanisms underlying the thrombotic and inflammatory characteristics observed in patients with severe COVID-19 outcomes.

Background: Proximal humerus fractures are a common injury, predominantly affecting older adults. This study aimed to develop risk-prediction models for prolonged length of hospital stay (LOS), serious adverse complications, and readmission within 30 days of surgically treated proximal humerus fractures using machine learning (ML) techniques. Methods: Adult patients (age >18) who underwent open reduction internal fixation (ORIF), hemiarthroplasty, or total shoulder arthroplasty for proximal humerus fracture between 2016 and 2021 were included. Preoperative demographic and clinical variables were collected for all patients and used to establish ML-based algorithms. The model with optimal performance was selected according to area under the curve (AUC) on the receiver operating curve (ROC) curve and overall accuracy, and the specific predictive features most important to model derivation were identified. Results: A total of 7473 patients were included (72.1% male, mean age 66.2 ± 13.7 years). Models produced via gradient boosting performed best for predicting prolonged LOS and complications. The model predicting prolonged LOS demonstrated good discrimination and performance, as indicated by (Mean: 0.700, SE: 0.017), recall (Mean: 0.551, SE: 0.017), accuracy (Mean: 0.717, SE: 0.010), F1-score (Mean: 0.616, SE: 0.014), AUC (Mean: 0.779, SE: 0.010), and Brier score (Mean: 0.283, SE: 0.010) Preoperative hematocrit, preoperative platelet count, and patient age were considered the strongest predictive features. The model predicting serious adverse complications exhibited comparable discrimination [precision (Mean: 0.226, SE: 0.024), recall (Mean: 0.697, SE: 0.048), accuracy (Mean: 0.811, SE: 0.010), F1-score (Mean: 0.341, SE: 0.031)] and superior performance relative to the LOS model [AUC (Mean: 0.806, SE: 0.024), Brier score (Mean: 0.189, SE: 0.010), noting preoperative hematocrit, operative time, and patient age to be most influential. However, the 30-day readmission model achieved the weakest relative performance, displaying low measures of precision (Mean: 0.070, SE: 0.012) and recall (Mean: 0.389, SE: 0.053), despite good accuracy (Mean: 0.791, SE: 0.009). Conclusion: Predictive models constructed using ML techniques demonstrated favorable discrimination and satisfactory-to-excellent performance in forecasting prolonged LOS and serious adverse complications occurring within 30 days of surgical intervention for proximal humerus fracture. Modifiable preoperative factors such as hematocrit and platelet count were identified as significant predictive features, suggesting that clinicians could address these factors during preoperative patient optimization to enhance outcomes. Overall, these findings highlight the potential for ML techniques to enhance preoperative management, facilitate shared decision-making, and enable more effective and personalized orthopedic care by exploring alternative approaches to risk stratification.

Introduction: 3-(2-butyl-5-chloro-1H-imidazole-4-yl)-N-[4-methoxy-3-(trifluoromethyl)phenyl]-4,5-dihydro-1,2-oxazole-5-carboxamide is new antirheumatic drug. It is necessary to identify and synthesize the biotransformation products for its complete pharmacokinetic study. Materials and Methods: A biotransformation study was carried out by intraperitoneal administration of the drug to Wistar rats and Soviet Chinchilla breed rabbits. Animal blood sampling was performed before the injection and 0.5 h, 1 h, 2 h, 4 h, 24 h after the injection of the investigated compound. The samples were immediately centrifuged for plasma separation. Urine was simultaneously collected from rats before the administration and at intervals of 0-2 h, 2-4 h, 4-6 h, 6-24 h after administration, faeces – before administration and at intervals of 0-12 h and 12-24 h after administration. The samples were analyzed by HPLC-MS/MS after immediate preparation by adding acetonitrile. Results and Discussion: 3-(2-butyl-5-chloro-1H-imidazole-4-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid and 4-methoxy-3-(trifluoromethyl)aniline – hydrolysis products of the active substance were found during the analysis of plasma, urine and fecal samples. The 4,5-dihydro-1,2-oxazole-5-carboxylic acid derivative has been synthesized. The second metabolite is a raw material for production of active pharmaceutical substance. During comparative tests, no significant difference between the retention times, ratio areas of chromatographic peaks at the main MRM-transitions and mass spectra of these metabolites on chromatograms of standard and animal samples was found, which indicates the correct identification of biotransformation products. Conclusion: The studied drug undergoes biotransformation by hydrolysis to form two main metabolites: 3-(2-butyl-5-chloro-1H-imidazole-4-yl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid and 4-methoxy-3-(trifluoromethyl)aniline. The structure of the metabolites was confirmed by comparison with the synthesized standard samples using HPLC-MS/MS.

The subject of this article is the study of the detention of prisoners of war of the German army and its allies in the Cherepovets NKVD–MVD Camp тo. 158. The specific feature of this camp was that it operated from 1942 to 1948, i.e. from the initial period of the Great Patriotic War until the completion of the repatriation of the majority of prisoners of war. That is why, the application of historical genetic and historical systemic methods, it is possible to consider the evolution of the policy of the Soviet state in relation to the enemy soldiers who found themselves at its mercy and to identify the mechanisms of its implementation in a single detention facility. Based on the analysis of a wide range of sources, the author considers the principles of the internal structure of the camp and the characteristics of the material and living situation of the prisoners of war detained there and the features of medical care for prisoners of war; the connection between the provision of prisoners of war with food, medical care, and clothing, on the one hand, and their physical condition, morbidity and mortality rates are determined; the content and dynamics of political propaganda among prisoners of war are revealed; the features of the repatriation process are shown.

Abstract On 13 April 2023, Cyclone Ilsa crossed Bedout Island in the Timor Sea off Western Australia’s remote north coast. Extensive damage was done to the entire island, with all coastal vegetation stripped clear from the island’s surface. Here we use repeated aerial and ground-based transect surveys of Bedout’s important seabird populations during 17 April – 21 July 2023 and Monte Carlo modelling to estimate total mortality for three species. We estimate that 80–90% of the populations of three seabird species (Masked Booby Sula dactylatra bedouti, Brown Booby S. leucogaster, and Lesser Frigatebird Fregata ariel) were killed in the storm, with only 40 breeding Masked Booby (a putative endemic subspecies) recorded on the island 15 weeks later. The frequency and intensity of such storms is likely approaching a threshold beyond which Bedout’s seabirds cannot readily recover, with cyclones hitting the island, on average, every seven years in recent decades. We discuss the implications for Bedout Island, and for wildlife conservation more broadly in the face of increasing, climate-driven storms and impacts documented worldwide.

ABSTRACT Human parainfluenza virus 3 (HPIV3) infection is driven by the coordinated action of viral surface glycoproteins hemagglutinin-neuraminidase (HN) and fusion protein (F). Receptor-engaged HN activates F to insert into the target cell membrane and drive virion-cell membrane fusion. For F to mediate entry, its precursor (F0) must first be cleaved by host proteases. F0 cleavage has been thought to be executed during viral glycoprotein transit through the trans-Golgi network by the ubiquitously expressed furin because F0 proteins of laboratory-adapted viruses contain a furin recognition dibasic cleavage motif RXKR around residue 108. Here, we show that the F proteins of field strains have a different cleavage motif from laboratory-adapted strains and are cleaved by unidentified proteases expressed in only a narrow subset of cell types. We demonstrate that extracellular serine protease inhibitors block HPIV3 F0 cleavage for field strains, suggesting F0 cleavage occurs at the cell surface facilitated by transmembrane proteases. Candidate proteases that may process HPIV3 F in vivo were identified by a genome-wide CRISPRa screen in HEK293/dCas9-VP64 + MPH cells. The lung-expressed extracellular serine proteases TMPRSS2 and TMPRSS13 are both sufficient to cleave HPIV3 F and enable infectious virus release by otherwise non-permissive cells. Our findings support an alternative mechanism of F activation in vivo, reliant on extracellular membrane-bound serine proteases expressed in a narrow subset of cells. The proportion of HPIV3 F proteins cleaved and infectious virus release is determined by host cell expression of requisite proteases, allowing just-in-time activation of F and positioning F cleavage as another key regulator of HPIV3 spread.IMPORTANCEEnveloped viruses cause a wide range of diseases in humans. At the first step of infection, these viruses must fuse their envelope with a cell membrane to initiate infection. This fusion is mediated by viral proteins that require a critical activating cleavage event. It was previously thought that for parainfluenza virus 3, an important cause of respiratory disease and a representative of a group of important pathogens, this cleavage event was mediated by furin in the cell secretory pathways prior to formation of the virions. We show that this is only true for laboratory strain viruses, and that clinical viruses that infect humans utilize extracellular proteases that are only made by a small subset of cells. These results highlight the importance of studying authentic clinical viruses that infect human tissues for understanding natural infection.

Ocean observing systems in coastal, shelf and marginal seas collect diverse oceanographic information supporting a wide range of socioeconomic needs, but observations are necessarily sparse in space and/or time due to practical limitations. Ocean analysis and forecast systems capitalize on such observations, producing data-constrained, four-dimensional oceanographic fields. Here we review efforts to quantify the impact of ocean observations, observing platforms, and networks of platforms on model products of the physical ocean state in coastal regions. Quantitative assessment must consider a variety of issues including observation operators that sample models, error of representativeness, and correlated uncertainty in observations. Observing System Experiments, Observing System Simulation Experiments, representer functions and array modes, observation impacts, and algorithms based on artificial intelligence all offer methods to evaluate data-based model performance improvements according to metrics that characterize oceanographic features of local interest. Applications from globally distributed coastal ocean modeling systems document broad adoption of quantitative methods, generally meaningful reductions in model-data discrepancies from observation assimilation, and support for assimilation of complementary data sets, including subsurface in situ observation platforms, across diverse coastal environments.

IntroductionThe mechanisms of the SARS-CoV-2-triggered complex alterations in immune cell activation and production of cytokines in lung tissue remain poorly understood, in part because of the limited use of adequate tissue models that simulate the structure and cell composition of the lung in vivo. We developed a novel ex vivo model of SARS-CoV-2 infection of lung explants, that maintains the intact tissue composition and the viral load for up to 7–10 days. Using this model, we studied cytokine production during SARS-CoV-2 infection.Materials and methodsLung tissue was monitored for viability and cell composition using flow cytometry and histological analysis. SARS-CoV-2 infection was verified immunohistochemically, viral loads in tissue and culture medium were monitored by qPCR. A panel of 41 cytokines was measured in culture medium using xMAP technology.ResultsThe explant lung tissue was viable and maintained viral infection that influenced the cytokine production. Elevated concentrations of G-CSF, GM-CSF, GRO-a, IFN-g, IL-6, IL-8, IP-10, MCP-3, MIP-1a, PDGF-AA, and VEGF, and decreased IL-1RA concentration were observed in infected tissue compared to non-infected tissue.DiscussionOur results generally reflect the data obtained in COVID-19 patients. GRO-a, IFN-g, IL-6, IL-8, MCP-1, MCP-3, and RANTES correlated with the viral load, forming a distinct pro-inflammatory cluster. Thus, our lung ex vivo model faithfully reproduces some aspects of cytokine alterations in COVID-19 patients at an early disease stage, making the investigation of SARS-CoV-2 infection mechanisms more accessible and providing a potential platform for antiviral drug testing.

Abstract This work investigates the application of poly(3,4‐ethylenedioxythiophene) polystyrenesulfonate (PEDOT:PSS) with polyethylene oxide (PEO) in lithium batteries (LIBs). This composite film comprising PEDOT:PSS and PEO was 3D printed onto a carbon nanofiber (CNF) substrate to serve as a layer between the polypropylene (PP) separator and the lithium anode in LIBs. The resulting CNF‐PEDOT:PSS‐PEO film exhibited superior mechanical and thermal properties compared to conventional PP separators. Mechanical tests revealed a high Young's modulus and puncture strength for the composite film. Thermal stability tests indicated that the CNF‐PEDOT:PSS‐PEO film remained stable at higher temperatures compared to the commercial PP separator, and combustion tests confirmed its superior fire‐resistance properties. In terms of conductivity, the composite film maintained comparable ionic conductivity to the commercial PP separator. Electrochemical tests demonstrated that LIBs incorporating the CNF‐PEDOT:PSS‐PEO film exhibited slight improvement in cycling performance, with a 7.9 % increase in long‐term cycling capacity compared to LIBs using only the commercial PP separator. These findings indicate that the developed CNF‐PEDOT:PSS‐PEO composite film holds promise to improve safety, while maintaining the electrochemical performance of LIBs by reducing dendrite formation and enhancing thermal stability.

Abstract A rapidly growing population across mountain regions is pressuring expansion onto steeper slopes, leading to increased exposure of people and their assets to slow‐moving landslides. These moving hillslopes can inflict damage to buildings and infrastructure, accelerate with urban alterations, and catastrophically fail with climatic and weather extremes. Yet, systematic estimates of slow‐moving landslide exposure and their drivers have been elusive. Here, we present a new global database of 7,764 large (A ≥ 0.1 km2) slow‐moving landslides across nine IPCC regions. Using high‐resolution human settlement footprint data, we identify 563 inhabited landslides. We estimate that 9% of reported slow‐moving landslides are inhabited, in a given basin, and have 12% of their areas occupied by human settlements, on average. We find the density of settlements on unstable slopes decreases in basins more affected by slow‐moving landslides, but varies across regions with greater flood exposure. Across most regions, urbanization can be a relevant driver of slow‐moving landslide exposure, while steepness and flood exposure have regionally varying influences. In East Asia, slow‐moving landslide exposure increases with urbanization, gentler slopes, and less flood exposure. Our findings quantify how disparate knowledge creates uncertainty that undermines an assessment of the drivers of slow‐moving landslide exposure in mountain regions, facing a future of rising risk, such as Central Asia, Northeast Africa, and the Tibetan Plateau.

The advancement of experimental methods has provided new information about the structure and structural fluctuations of water. Despite the appearance of numerous models, which aim to describe a wide range of thermodynamic and electrical characteristics of water, there is a deficit in systemic understanding of structuring in aqueous solutions. A particular challenge is the fact that even pure water is a heterogeneous, multicomponent system composed of molecular and supramolecular structures. The possibility of the existence of such structures and their nature are of fundamental importance for various fields of science. However, great difficulties arise in modeling relatively large supramolecular structures (e.g. extended hydration shells), where the bonds between molecules are characterized by low energy. Generally, such structures may be non-equilibrium but relatively long-lived. Evidently, the short times of water microstructure exchanges do not mean short lifetimes of macrostructures, just as the instability of individual parts does not mean the instability of the entire structure. To explain this paradox, we review the data from experimental and theoretical research. Today, only some of the experimental results on the lifetime of water structures have been confirmed by modeling, so there is not a complete theoretical picture of the structure of water yet. We propose a new hierarchical water macrostructure model to resolve the issue of the stability of water structures. In this model, the structure of water is presented as consisting of many hierarchically related levels (the stratification model). The stratification mechanism is associated with symmetry breaking at the formation of the next level, even with minimal changes in the properties of the previous level. Such a hierarchical relationship can determine the unique physico-chemical properties of water systems and, in the future, provide a complete description of them.

ABSTRACT Filoviruses are some of the most lethal viruses in the modern world, and increasing numbers of filovirus species and genera have been discovered in recent years. Despite the potential severity of filovirus outbreaks in the human population, comparably few sensitive pan-filovirus RT-PCR assays have been described that might facilitate early detection and prevention. Here, we present a new pan-filovirus RT-PCR assay targeting the L polymerase gene for detection of all known mammalian filoviruses. We demonstrate the detection of 10 synthetic filovirus RNA templates with analytical sensitivity ranging from 178 to 3,354 copies/mL, without cross-reactivity on 10 non-filoviral human viral species. We verified assay performance on 10 inactivated filovirus isolates, yielding initial sensitivities of 0.012–44.17 TCID50/mL. We coupled this broadly reactive RT-PCR with a deep sequencing workflow that is amenable to high-throughput pooling to maximize detection and discovery potential. In summary, this pan-filovirus RT-PCR assay targets the most conserved filovirus gene, offers the widest breadth of coverage to date, and may help in the detection and discovery of novel filoviruses.IMPORTANCEFiloviruses remain some of the most mysterious viruses known to the world, with extremely high lethality rates and significant pandemic potential. Yet comparably few filovirus species and genera have been discovered to date and questions surround the definitive host species for zoonotic infections. Here, we describe a novel broadly reactive RT-PCR assay targeting the conserved L polymerase gene for high-throughput screening for filoviruses in a variety of clinical and environmental specimens. We demonstrate the assay can detect all known mammalian filoviruses and determine the sensitivity and specificity of the assay on synthetic RNA sequences, inactivated filovirus isolates, and non-filoviral species.

Robust methods are needed for preclinical evaluation of novel Alzheimer Disease (AD) therapies to accelerate drug discovery. Quantitative Gradient Recalled Echo (qGRE) MRI has shown promise to provide insight into neurodegeneration in AD prior to atrophy development in humans, highlighting areas of low neuronal density. In this study a novel qGRE method (20 echoes, TE=2-40ms) is shown to non-invasively measure the longitudinal neuronal loss in the hippocampus of a mouse model of AD tauopathy Tg4510.Tg4510 (n=10) and wild type (WT, n=6) mice underwent MRI (7T field strength) at 3-7 months old. 3D qGRE approach was used to generate brain-specific R2* maps free of magnetic field inhomogeneity artifacts. Light-sheet microscopy of the brains stained with NeuN and MBP served to visualize neuronal nuclei and myelin content respectively.Significant decrease in NeuN staining between 3mo and 5mo was observed in the hippocampus of Tg4510, validating the mouse AD model.Longitudinal analysis showed clear decreases in R2* metric of qGRE signal in the Tg4510 mice hippocampus undergoing neurodegeneration between 3 and 5 months old. Histogram analysis revealed an upward trend in patterns of low R2* value (Dark Matter, DM), and broadening of R2* distribution. These were quantified as significant increase in both DM Volume Fraction (DMVF) and R2* Standard Deviation (SD) in Tg4510 mice (p=0.004/p=0.016 DMVF/SD) but not in WT controls (p>0.25). Further monotonical increase was also observed in both metrics in time. A significant negative correlation was observed between the DMVF and myelin content (p=0.01, r=-0.76), suggesting sensitivity of the technique to the loss of myelinated axons.The presented qGRE technique, validated by histological measurements, can be readily applied as in vivo tool in preclinical models of neurodegeneration for pharmacodynamics and mechanism of action assessment.

Summary: Background: Gut L-type enteroendocrine cells (EECs) are intestinal chemosensory cells that secrete satiety hormones GLP-1 and PYY in response to activation of G-protein coupled receptors (GPCRs) by luminal components of nutrient digestion and microbial fermentation. Regulator of G-protein Signaling (RGS) proteins are negative regulators of GPCR signaling. The expression profile of RGS in EECs, and their potential role in satiety hormone secretion and obesity is unknown. Methods: Transcriptomic profiling of RGS was completed in native colonic EECs was completed using single-cell RNA sequencing (scRNA-Seq) in lean and obesity, and human jejunal EECs with data obtained from a publicly available RNAseq dataset (GSE114853). RGS validation studies were completed using whole mucosal intestinal tissue obtained during endoscopy in 61 patients (n = 42 OB, n = 19 Lean); a subset of patients’ postprandial plasma was assayed for GLP-1 and PYY. Ex vivo human intestinal cultures and in vitro NCI–H716 cells overexpressing RGS9 were exposed to GLP-1 secretagogues in conjunction with a nonselective RGS-inhibitor and assayed for GLP-1 secretion. Findings: Transcriptomic profiling of colonic and jejunal enteroendocrine cells revealed a unique RGS expression profile in EECs, and further within GLP-1+ L-type EECs. In obesity the RGS expression profile was altered in colonic EECs. Human gut RGS9 expression correlated positively with BMI and negatively with postprandial GLP-1 and PYY. RGS inhibition in human intestinal cultures increased GLP-1 release from EECs ex vivo. NCI–H716 cells overexpressing RGS9 displayed defective nutrient-stimulated GLP-1 secretion. Interpretation: This study introduces the expression profile of RGS in human EECs, alterations in obesity, and suggests a role for RGS proteins as modulators of GLP-1 and PYY secretion from intestinal EECs. Funding: AA is supported by the NIH(C-Sig P30DK84567, K23 DK114460), a Pilot Award from the Mayo Clinic Center for Biomedical Discovery, and a Translational Product Development Fund from The Mayo Clinic Center for Clinical and Translational Science Office of Translational Practice in partnership with the University of Minnesota Clinical and Translational Science Institute.

Purpose: Palliative radiotherapy (RT) plays a crucial role in alleviating symptoms associated with metastatic sarcoma. However, there is a lack of consensus on the optimal palliative radiation dose and fractionation for metastatic sarcomas. We analyzed the association between biologically effective radiation dose and symptom response for patients who underwent palliative RT for metastatic sarcomas Methods and materials: We retrospectively identified patients with metastatic sarcoma treated with palliative RT between 1999 and 2021 at our institution. We assessed the association between equivalent dose in 2 Gy fractions (EQD2) with an α/β of three and symptom relief or overall survival (OS) using univariable and multivariable analyses. Results: Of the 198 metastatic sites treated, the most common indications for palliative radiation were pain (n = 181, 91 %) and compression of adjacent structures (n = 16, 8 %). In our analysis, an EQD2 of > 20 Gy was associated with greater rates of short-term symptom relief (n = 143, 85 %) at the RT site compared to an EQD2 of ≤ 20 Gy (n = 14, 54 %, P = 0.001) with no reports of grade 3 or higher toxicity. However, there was no significant improvement in short-term symptom relief for higher radiation doses. Patients treated with an EQD2 of ≤ 20 Gy had a significantly worse performance status, but there was no significant difference in overall survival based on EQD2 on multivariable analysis. Conclusions: An EQD2 ≤ 20 Gy (e.g., 8 Gy in 1 fraction) provided inadequate palliative benefit in this series. An EQD2 > 20 Gy resulted in greater rates of symptom palliation in metastatic sarcomas, but further dose escalation did not improve symptom response or durability. These findings suggest standard palliative regimens such as 20 Gy in 5 fractions (EQD2 of 28 Gy) are effective for patients with metastatic sarcomas.

Abstract Sensorimotor control of complex, dynamic systems such as humanoids or quadrupedal robots is notoriously difficult. While artificial systems traditionally employ hierarchical optimisation approaches or black-box policies, recent results in systems neuroscience suggest that complex behaviours such as locomotion and reaching are correlated with limit cycles in the primate motor cortex. A recent result suggests that, when applied to a learned latent space, oscillating patterns of activation can be used to control locomotion in a physical robot. While reminiscent of limit cycles observed in primate motor cortex, these dynamics are unsurprising given the cyclic nature of the robot’s behaviour (walking). In this preliminary investigation, we consider how a similar approach extends to a less obviously cyclic behaviour (reaching). This has been explored in prior work using computational simulations. But simulations necessarily make simplifying assumptions that do not necessarily correspond to reality, so do not trivially transfer to real robot platforms. Our primary contribution is to demonstrate that we can infer and control real robot states in a learnt representation using oscillatory dynamics during reaching tasks. We further show that the learned latent representation encodes interpretable movements in the robot’s workspace. Compared to robot locomotion, the dynamics that we observe for reaching are not fully cyclic, as they do not begin and end at the same position of latent space. However, they do begin to trace out the shape of a cycle, and, by construction, they are driven by the same underlying oscillatory mechanics.

Abstract Hypercholesterolemia (HC) induces, propagates and exacerbates cardiovascular diseases via various mechanisms that are yet not properly understood. Extracellular vesicles (EVs) are involved in the pathomechanism of these diseases. To understand how circulating or cardiac-derived EVs could affect myocardial functions, we analyzed the metabolomic profile of circulating EVs, and we performed an in-depth analysis of cardiomyocyte (CM)-derived EVs in HC. Circulating EVs were isolated with Vezics technology from male Wistar rats fed with high-cholesterol or control chow. AC16 human CMs were treated with Remembrane HC supplement and EVs were isolated from cell culture supernatant. The biophysical properties and the protein composition of CM EVs were analyzed. THP1-ASC-GFP cells were treated with CM EVs, and monocyte activation was measured. HC diet reduced the amount of certain phosphatidylcholines in circulating EVs, independently of their plasma level. HC treatment significantly increased EV secretion of CMs and greatly modified CM EV proteome, enriching several proteins involved in tissue remodeling. Regardless of the treatment, CM EVs did not induce the activation of THP1 monocytes. In conclusion, HC strongly affects the metabolome of circulating EVs and dysregulates CM EVs, which might contribute to HC-induced cardiac derangements.

Abstract Background Total knee arthroplasty (TKA) is a successful treatment for end-stage osteoarthritis, yet some patients still experience postoperative pain. Genicular nerve radiofrequency ablation (GNRFA) has become a potential modality to address pain in TKA. This systematic review aims to critically analyze the applicability of GNRFA in perioperative pain control prior to TKA, as well as a treatment modality for chronic painful well-appearing TKA. Methods PubMed, Medline, EMBASE, Google Scholar, Scopus, and COCHRANE databases, as well as the ClinicalTrials.gov register, were reviewed. The search included randomized controlled trials and cohort studies. The sample population focused on two cohorts; those who underwent TKA and utilized intentional GNRFA as a perioperative pain control modality, and those utilizing the treatment modality for chronic pain in well-appearing TKA. GNRFA was the intervention studied, and postoperative outcomes were compared with the control group, which consisted of those not receiving GNRFA. Result Eight total publications were identified as relevant to this search. Among the pre-TKA studies, there was variability in results; these inconsistencies were attributed to a lack of standardization, especially with regard to type, timing, and targeted nerves with ablation. Likewise, while the results were improved among the population with chronic painful TKA receiving GNRFA, these inconsistencies still existed. Conclusions Current evidence suggests GNRFA as a possible pre-TKA intervention to potentially minimize opioid consumption, patient-reported pain, length of stay, and increased range of motion and activity. However, the short-lived duration in the setting of chronically painful well-appearing TKA represents a major barrier that warrants further investigation. Limitations include small sample size, heterogeneity, lack of standardization of techniques among studies, and lack of direct comparison and meta-analysis. Further research should focus on the standardization of technique as well as analyzing various patient and health-system-related factors that correlate with sustained positive outcomes.

Abstract Beef production systems are at the center of ongoing discussion and debate on food systems sustainability. There is a growing interest among beef producers, consumers, and other beef supply chain stakeholders in achieving greater sustainability within the industry, but the relationship of this interest to general sustainability issues such as climate change, biodiversity loss, food security, livelihood risks, and animal welfare concerns is unclear. Specifically, there is very little research documenting how beef producers define and view the concept of sustainability and how to achieve it. Producer perspectives are critical to identifying constraints to sustainability transitions or to help build agreement with other producers about the shared values such transitions may support. Through a secondary analysis of survey data of U.S. beef producers (n = 911) conducted in 2021 by the Trust in Food division of Farm Journal, a corporation that provides content, data, and business insights to the agricultural community (e.g., producers, processors/distributors, and retailers), we investigated what “sustainable beef” means to U.S. beef producers, highlighting the key components and constraints they perceive to achieving desirable sustainability outcomes. Leveraging the three-pillar model of sustainability as a framework for analysis, we identified key themes producers use to define “sustainable beef.” We found that producers collectively viewed sustainability as: (1) multidimensional and interconnected; (2) semi-closed and regenerative; (3) long-lasting; and (4) producer-centered, although an integrated perspective uniting these aspects was rare. We discuss how these perspectives may be the basis for sustainability efforts supported by producers and raise future research considerations toward a shared understanding of what sustainability is and what is needed for enduring sustainability solutions in the U.S. beef industry.

Background: Gait impairment has a major impact on quality of life in patients with Parkinson's disease (PD). It is believed that basal ganglia oscillatory activity at β frequencies (15–30 Hz) may contribute to gait impairment, but the precise dynamics of this oscillatory activity during gait remain unclear. Additionally, auditory cues are known to lead to improvements in gait kinematics in PD. If the neurophysiological mechanisms of this cueing effect were better understood they could be leveraged to treat gait impairments using adaptive Deep Brain Stimulation (aDBS) technologies. Objective: We aimed to characterize the dynamics of subthalamic nucleus (STN) oscillatory activity during stepping movements in PD and to establish the neurophysiological mechanisms by which auditory cues modulate gait. Methods: We studied STN local field potentials (LFPs) in eight PD patients while they performed stepping movements. Hidden Markov Models (HMMs) were used to discover transient states of spectral activity that occurred during stepping with and without auditory cues. Results: The occurrence of low and high β bursts was suppressed during and after auditory cues. This manifested as a decrease in their fractional occupancy and state lifetimes. Interestingly, α transients showed the opposite effect, with fractional occupancy and state lifetimes increasing during and after auditory cues. Conclusions: We show that STN oscillatory activity in the α and β frequency bands are differentially modulated by gait-promoting oscillatory cues. These findings suggest that the enhancement of α rhythms may be an approach for ameliorating gait impairments in PD.

The charge properties and regularities of mutual influence of the electro-physical parameters in a metal (M)/insulator (I)/two-dimensional crystal heterostructure were studied. In one case, the transition metal dichalcogenide (TMD) MoS2 was considered as a two-dimensional crystal, and in another the Weyl semi-metal (WSM) ZrTe5, representative of a quasi-two-dimensional crystal was chosen for this purpose. By self-consistently solving the electrostatic equations of the heterostructures under consideration and the Fermi–Dirac distribution, the relationship between such parameters as the concentration of charge carriers, chemical potential, and quantum capacitance of the TMD (WSM), as well as the capacitance of the I layer and the interface capacitance I–TMD (WSM), and their dependence on the field electrode potential, have been derived. The conditions for the emergence of charge instability and the critical phenomena caused by it are also determined.

Purpose. Recognition of deer individuals by their graphic images based on convolutional neural network models. Research methods and materials. The material for the research was marked images of deer in different habitats, published in the public domain. Research methods: theory of design and development of artificial intelligence systems; image augmentation for computer vision tasks; hyperparameter tuning algorithms for training neural network models. Results. Conservation of the deer population is one of the important goals in ecology and agriculture. The control of the number of individuals affects the conservation of rare species of deer, and supports the production volumes on farms. For example, such a control method may be the detection of deer individuals in photographs. To accurately determine and count the number of deer, you can use a tool such as a neural network. We used deep learning methods for convolutional neural networks, as well as the concept of “transfer learning”. On the basis of the Faster R-CNN Resnet50 network, a neural network was trained, which allows, with an accuracy of 0.91, to determine individual individuals in the images using the F1-score metric with a threshold value of 0.6 (coincidence of the area of the predicted markup and the actual one) with an accuracy of 0.91. Conclusion. To solve the problem of deer detection, a data set has been prepared, including more than 30 thousand images, with markings of individual individuals. The marking of each individual included the coordinates of the bounding rectangle in the image. Based on this information, a neural network model was developed and trained using software tools to solve the problem of detecting deer objects in images. The experiments carried out showed that the accuracy of detection with augmentation in accordance with the F1-score indicator with a threshold value of 0.6 on the training sample was 0.96, and on the test sample was 0.91.

Abstract Background Young adults have historically high levels of cannabis use at a time which coincides with emotional and cognitive development. Age of regular onset of cannabis use and sex at birth are hypothesized to influence the relationship between cannabis use and cognition. Here we investigated past 6-month cannabis use in relation to emotional and executive functioning. We further considered age of onset and sex in subgroup analyses. Method Young adults (N = 225; ages 16–22) completed a substance use interview and cognitive battery, including the Emotional Word-Emotional Face Stroop and NIH toolbox executive functioning tasks. Linear regressions examined relationships between past 6-month cannabis use episodes and performance. Subgroup analyses investigated whether age of onset or sex impacted relationships. Results After correcting for multiple comparisons, greater past 6-month cannabis use episodes were related to poorer Emotional Stroop Congruent Accuracy (p = .0004, FDR-p = .002) and List Sorting Working Memory (p = .02, FDR-p = .10) performance. Younger age of regular use onset marginally related to lower Emotional Stroop Congruent Accuracy performance (p = .03, FDR-p = .13). There were no cannabis use by sex interactions on cognition. Conclusions Consistent with prior findings, results suggest small reductions in cannabis-related performance in processing speed during emotional Stroop and working memory tasks. Age of onset was modestly related to Stroop performance, but not sex. Longitudinal studies which detail patterns of cannabis and other substance use are needed to better assess brain-behavior relationships and other factors (e.g., age of onset of regular use, sex) which could influence cannabis-related impairments in cognitive functioning.

Abstract Knockout of the ORF8 protein has repeatedly spread through the global viral population during SARS-CoV-2 evolution. Here we use both regional and global pathogen sequencing to explore the selection pressures underlying its loss. In Washington State, we identified transmission clusters with ORF8 knockout throughout SARS-CoV-2 evolution, not just on novel, high fitness viral backbones. Indeed, ORF8 is truncated more frequently and knockouts circulate for longer than for any other gene. Using a global phylogeny, we find evidence of positive selection to explain this phenomenon: nonsense mutations resulting in shortened protein products occur more frequently and are associated with faster clade growth rates than synonymous mutations in ORF8. Loss of ORF8 is also associated with reduced clinical severity, highlighting the diverse clinical impacts of SARS-CoV-2 evolution.

Abstract Prurigo nodularis (PN) is a chronic inflammatory skin disease that is associated with variability in peripheral blood eosinophil levels and response to T-helper 2 targeted therapies (Th2). Our objective was to determine whether circulating immune profiles with respect to type 2 inflammation differ by race and peripheral blood eosinophil count. Plasma from 56 PN patients and 13 matched healthy controls was assayed for 54 inflammatory biomarkers. We compared biomarker levels between PN and HCs, among PN patients based on absolute eosinophil count, and across racial groups in PN. Eleven biomarkers were elevated in PN versus HCs including interleukin (IL)-12/IL-23p40, tumor necrosis factor-alpha (TNF-α), Thymic stromal lymphopoietin (TSLP), and macrophage-derived chemokine (MDC/CCL22). Additionally, PN patients with AEC > 0.3 K cells/μL had higher Th2 markers (eotaxin, eotaxin-3, TSLP, MCP-4/CCL13), and African American PN patients had lower eosinophils, eotaxin, and eotaxin-3 versus Caucasian and Asian PN patients (p 0.3 K and Asian and Caucasian races are associated with Th2 skewed circulating immune profiles and response to Th2 targeted therapies.

The article is aimed at research of the current state of legal linguistics as a branch of linguistics in the Republic of Belarus, which is characterized by polyparadigmality and the formation of its own methodological system. The purpose of the scientific work is to determine the specifics of legal linguistics in Belarus and outline a range of promising areas that require fundamental development. The material for the study was the scientific works of Western and Russian scientists who had the greatest influence on the formation of the subject area of legal linguistics. The methodology of the research included general scientific methods of generalization and systematization, as well as descriptive, analytical and comparative methods.The specifics of the subject area of scientific research is manifested in all spheres of legal linguistics developing in Belarus. For example, within the framework of linguistic controlling, the text of a legal act is evaluated for compliance with the norms of both Russian and Belarusian literary languages. Judicial rhetoric defines the requirements for the range of subjects of public speeches in accordance with the procedural legislation. In line with legal terminology, the unique units of the terminological system of Belarusian law are studied. Within the framework of linguistic expertise, tools are being developed that allow for the proper correlation of signs of speech offense, the composition of which is reflected in the Belarusian legislation, with appropriate linguistic markers.The conducted research shows that the development of Western and Russian scientists had a significant impact on the formation of the subject area of domestic legal linguistics, however, some areas of the integrative industry still have not found proper development. Promising areas for the development of legal linguistics in Belarus are the establishment of the authorship of the text, the fight against plagiarism, the study of trademarks (service marks) and advertising slogans for the coincidence of designations.

Introduction: The determination of biotransformation products is an essential part of the preclinical trial of original medicines. These studies have not been conducted before for the new drug 5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide. Identification and synthesis of metabolite substances are necessary for subsequent tests of bioavailability, linearity of pharmacokinetics, accumulation, distribution and excretion. Materials and methods: The study was carried out on Wistar rats and rabbits of the Soviet Chinchilla breed. The substance of the drug was administered to animals intraperitoneally. The collection of animal blood samples was performed before administration and 1 h, 2 h, 4 h, 24 h after administration into K3EDTA-tubes. A part of each sample was centrifuged to separate the plasma. Rat urine samples were taken before administration and at intervals of 0-2 h, 2-4 h, 4-6 h, 6-24 h after administration of the drug. The HPLC-MS/MS method was used to identify metabolites in biological fluids. The assumed biotransformation products were synthesized after preliminary analysis. The structure of the obtained substances was confirmed by NMR spectroscopy and high-resolution mass spectrometry. Then, a comparison was carried out with the compounds identified in biological fluids by retention time, ratios of chromatographic peak areas at the main MRM-transitions using HPLC-MS/MS. Results and discussion: A metabolite formed by addition an oxygen atom to a drug molecule, as well as an acylated metabolite were detected during the analysis of plasma and blood samples. A compound with an increased molecular weight of 1 dalton compared to the drug substance was also present in a rat urine. N-hydroxy-5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide, 5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonic acid, which could potentially be obtained during biotransformation, as well as N-acetyl-5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide were synthesized. Repeated HPLC-MS/MS tests confirmed the correctness of the initial hypothesis. It was found that a sulfonic acid derivative is formed in urine as a result of decomposition of N-hydroxymetabolite during sample collection. Conclusion: The studied drug is metabolized by formation of two metabolites: N-hydroxy-5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide and N-acetyl-5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonamide. N-hydroxymetabolite is able to decompose in biological fluids samples with formation of 5-[5-(trifluoromethyl)-1,2-oxazole-3-yl]-furan-2-sulfonic acid.

In the conditions of globalization and development of information technologies, the competition of enterprises on national and international scales is significantly aggravated, which determines the importance of ensuring competitive advantages for any enterprise through innovation. In modern conditions, the effectiveness of innovation activity of the enterprise and, accordingly, its competitiveness depends primarily on the completeness and reliability of business information about the activities of counterparties and the conditions of the external environment. The value of informing about possible changes in the business environment has a manifestation through the prevention of tactical and strategic errors of enterprise management. Innovative development is the basis of competitiveness of modern economies, which provides the possibility of accelerated growth at macro- and micro-levels on the basis of creation and strengthening of intellectual potential in the global business environment. Despite the presence of significant conditions for qualitative changes on an innovative basis, the Russian Federation continues to be in a complex highly turbulent period of unstable growth. Therefore, the task of domestic economic science is to find mechanisms for the implementation of modern management of innovative development in the practice of enterprises in the Russian Federation, systematizing and developing its methodology. This requires an in-depth scientific study in the direction of searching for conceptual foundations for the activation of innovative development of enterprises to make a technological leap in the Russian Federation, in particular, on the basis of attracting breakthrough innovations, modern concepts of knowledge management, formation of relevant business models, management of high added value processes and the use of information and communication technologies in the digital space.

Regional trade agreements (RTAs) are important instruments of the world trade system, which have been increasingly developed in recent decades, since they complement the existing World Trade Organization (WTO) and WTO+ agreements and allow taking into account the specificities of regions. The principle of ensuring non-discriminatory trade is the main principle of multilateral trade of the WTO, or in other words, observes the rule of not favoring one trading partner over another. RTAs are, in fact, an exception to this approach, as it is the signatories that enjoy more favorable market access conditions. At the same time, the WTO recognizes the legitimate role of RTAs in facilitating trade between their parties, but requires that they not create barriers to trade with third parties. RTAs cover more than half of world trade, and new transcontinental agreements have been concluded in recent years: the Comprehensive and Progressive Agreement for Trans-Pacific Partnership, the Comprehensive Regional Economic Partnership, and the African Continental Free Trade Area. There are different types of RTAs in international cooperation, ranging from free trade agreements to common markets, including between countries of a territorially contiguous or transcontinental nature, based on WTO and WTO+ agreements or protectionist in nature. The article reflects the consequences for the national economies of developing countries, it is revealed that the European Union in the RTAs is actively promoting its values as the absolute truth for all peoples and nations, and their non-acceptance is considered as a factor causing possible restrictions. Other developed economies have also imposed obligations on signatories in terms of ensuring the transformation of the national economies of developing countries, but in recent years this trend has weakened somewhat. China, initiating the RTA, pursues the realization of its national interests, without imposing any political, mental or social aspects, and at the same time is ready to develop mutually acceptable compromises. The transformation of RTАs in modern conditions is carried out in three basic directions: preference for the preservation of full sovereignty by the signatory countries; the inclusion of articles that condition the promotion of sustainable development; control and monitoring to ensure compliance with labor safety regulations, non-damage to the ecological environment, as well as the use of tools of responsible corporate business conduct.

Abstract In the ENSEMBLE randomized, placebo-controlled phase 3 trial (NCT04505722), estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe–critical COVID-19. SARS-CoV-2 Spike sequences were determined from 484 vaccine and 1,067 placebo recipients who acquired COVID-19. In this set of prespecified analyses, we show that in Latin America, VE was significantly lower against Lambda vs. Reference and against Lambda vs. non-Lambda [family-wise error rate (FWER) p

Proenkephalin (PENK) is a novel biomarker of kidney function associated with cardiovascular risk in patients with cardiovascular disease. Its association with cardiovascular outcomes in ambulatory individuals is less described. In an observational study of 199 ambulatory Veterans enrolled from April to September 2010, we assessed PENK’s association with major adverse cardiac events (MACE − cardiovascular death, heart failure [HF] hospitalization, myocardial infarction [MI], or stroke) and individual outcomes of all-cause mortality, incident HF, and cardiovascular death using Cox regression. We also assessed the association of PENK with left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDd), and left ventricular mass index (LVMi) with linear regression. The mean age was 66 ± 12 years, 99 % were men, and 76 % were White, with median follow-up of 12.7 years. Each two-fold higher PENK was associated with a 73 % higher risk of MACE in unadjusted analysis (HR 1.73; 95 % CI 1.00, 2.99; p = 0.043), though this association lost significance after adjusting for confounders (HR 1.69; 95 % CI 0.90–3.15; p = 0.098). PENK was not associated with all-cause mortality, incident HF or cardiovascular death, although risk estimates were elevated with wide confidence intervals for incident HF and cardiovascular death. PENK was not associated with LVMi or LVEDd but had a non-linear relationship with LVEF with low and high PENK associated with lower LVEF. In conclusion, PENK may be associated with a higher risk of MACE in ambulatory Veterans with diverse health statuses; however, further studies are needed.Abbreviations: PENK: Proenkephalin A; MACE: Major Adverse Cardiac Events.

Background: The purpose of this study is to compare 30-day perioperative outcomes following treatment of intertrochanteric (IT) fractures with intramedullary nail (IMN), total hip arthroplasty (THA), or hemiarthroplasty (HA). Methods: Using the National Surgical Quality Improvement Program database, we conducted a retrospective cohort study of patients who had sustained an IT fracture treated with primary IMN, THA, or HA between 2017 and 2020. International Classification of Diseases, 10th Revision codes S72.141-S72.146, subtypes A through C, were used to identify eligible patients and were cross-referenced to primary Current Procedural Terminology codes, used to identify the following procedure types: 27245: IMN; 27130: THA; and 27236: HA. Revision cases and patients who underwent arthroplasty for osteoarthritis were excluded. Outcomes of interest included reoperation, readmission, operative time, length of stay, and major and minor complications. Multivariate regression was used to evaluate differences in postoperative outcomes between groups. Results: There were 29,809 IT fractures treated with IMN (94.6%), 1493 treated with HA (4.7%), and 217 treated with THA (0.70%). There was a statistically significant increase in 30-day reoperation rates (adjusted odds ratio [aOR] = 1.99 [95% confidence interval = 1.51, 2.63], P < .001) when combining all arthroplasty patients compared to IMN. There was no statistically significant difference in the overall complication rate between IMN (13.58%) and HA (14.60%, aOR = 1.09, P = .315) or THA (11.98%, aOR = 1.00, P = .998). When compared to IMN (0.12%), there was a statistically significantly decreased need for transfusion in the HA group (aOR = 0.71 [95% confidence interval = 0.61, 0.80], P < .001). Conclusions: Primary HA is associated with an increased 30-day reoperation rate and decreased need for blood transfusion, but there were no other significant differences in postoperative morbidity identified among IMN, THA, and HA in the treatment of IT fractures. Given the challenges and inferior outcomes associated with conversion arthroplasty, the lack of significant difference in morbidity between the 3 groups suggests that primary arthroplasty may be a safe and viable treatment option in selected patients with IT fractures. Comparative studies with longer clinical follow-up will be necessary to establish the appropriate indications and further evaluate the clinical outcomes of primary arthroplasty in the treatment of IT fractures.