Infective Endocarditis in Patients With Bicuspid Aortic Valves: Unique Clinical and Microbiologic Features.

OBJECTIVE: Patients with bicuspid aortic valves (BAV) are at increased risk of infective endocarditis (IE). Information of the clinical presentation and the microbiology of BAV-associated IE, however, is limited. Therefore, our study aimed to characterise the clinical features native valve endocarditis (NVE) in the setting of BAV and compared them to patients with prosthetic valve endocarditis (PVE) following BAV replacement. METHODS: Adult patients with BAV or history of BAV with aortic valve replacement (AVR) and a definite or possible IE diagnosis within the Mayo Clinic Enterprise (USA) from January 2008 to December 2021, were included. BAV was confirmed by trans-oesophageal echocardiography. IE was defined according to the modified Duke criteria and only an initial episode was included. Statistical analyses were performed to compare clinical characteristics, microbiology, and IE complications. RESULTS: Overall, 161 patients with BAV and IE (NVE [n=60], 37.3%) and PVE [n=101, 62.7%) were included. Mean age±SD was 56.5±16.1 years, and 139 (86.3%) patients were males. PVE patients were older (p<0.01) and had a higher rate of hypertension (p<0.01), chronic heart failure (p<0.01), chronic kidney disease (p<0.01), and perivalvular abscess (p<0.01). BAV patients with NVE had a higher prevalence of isolated mitral valve IE (p<0.01), moderate to severe aortic valve regurgitation (p<0.01) and combined aortic with mitral valve IE (p<0.01). Streptococcus mitis was the most common pathogen in NVE (30.0%) while Staphylococcus aureus was the most common in PVE (15.8%). CONCLUSIONS: Patients with BAV are at risk of both NVE and PVE. Each syndrome has unique clinical features, including microbiologic findings, that should be appreciated in IE diagnosis and management.

Hydrodynamic Evaluation of a Filtering Hydrocyclone for Solid Particle/Water Separation.

A conventional hydrocyclones is a versatile equipment with a high processing capacity and low maintenance cost. Currently, several studies aim to alter the typical structure of the conventional hydrocyclone in order to modify its performance and purpose. For this, filtering hydrocyclones have emerged, where a porous membrane replaces the conic or cylindrical wall. During the operation of this equipment, in addition to the traditionally observed streams (feed, underflow, and overflow), there is a liquid stream resulting from the filtration process, commonly referred to as filtrate. This work proposes to numerically investigate the solid particle/liquid water separation process in a filtering hydrocyclone using the commercial software Ansys CFX® 15.0. The proposed mathematical model for the study considers three-dimensional, steady state and turbulent flow, using the Eulerian-Eulerian approach and the Shear Stress Transport (SST) turbulence model. This study presents and analyzes the volume fraction, velocity, and pressure fields, along with flowlines and velocity profiles. The results indicate that the proposed model effectively captures the fluid dynamic behavior within the filtering hydrocyclone, highlighting higher pressures near the porous membrane and a higher concentration of solid particles in the conical region, with water being more concentrated in the cylindrical part of the hydrocyclone. Additionally, the findings show that the volumetric flow rate of the filtrate significantly influences the internal flow dynamics, with conventional hydrocyclones demonstrating higher pressure gradients compared to the proposed filtering hydrocyclone.

Clonal succession after prolonged antiretroviral therapy rejuvenates CD8+ T cell responses against HIV-1.

Human immunodeficiency virus 1 (HIV-1) infection is characterized by a dynamic and persistent state of viral replication that overwhelms the host immune system in the absence of antiretroviral therapy (ART). The impact of prolonged treatment on the antiviral efficacy of HIV-1-specific CD8+ T cells has nonetheless remained unknown. Here, we used single-cell technologies to address this issue in a cohort of aging individuals infected early during the pandemic and subsequently treated with continuous ART. Our data showed that long-term ART was associated with a process of clonal succession, which effectively rejuvenated HIV-1-specific CD8+ T cell populations in the face of immune senescence. Tracking individual transcriptomes further revealed that initially dominant CD8+ T cell clonotypes displayed signatures of exhaustion and terminal differentiation, whereas newly dominant CD8+ T cell clonotypes displayed signatures of early differentiation and stemness associated with natural control of viral replication. These findings reveal a degree of immune resilience that could inform adjunctive treatments for HIV-1.

Do risk measure scores and diagnoses predict evaluator opinions in sexually violent predator cases? It depends on the evaluator.

OBJECTIVE: Field research increasingly reveals that forensic evaluators are not interchangeable. Instead, they tend to differ in their patterns of forensic opinions, in ways that likely reflect something about themselves, not just the persons evaluated. This study used data from sexually violent predator (SVP) evaluations to examine whether evaluator differences in making intermediate decisions (e.g., instrument scoring, assigning diagnoses) might explain their different patterns of final opinions. HYPOTHESES: Although this study was generally exploratory and not strongly hypothesis driven, we expected that there might be evidence for a simple form of bias in which some evaluators would be more likely than others to consistently "find" indications of SVP status (i.e., consistently assigning higher risk scores and more SVP-relevant diagnoses) and, therefore, be more likely to find behavioral abnormality, the legal construct qualifying someone for commitment as an SVP. METHOD: The study used data from 745 SVP evaluations conducted by 10 different evaluators who were assigned cases from the same referral stream. Potential evaluator difference variables included behavioral abnormality opinions, paraphilia and antisocial personality disorder diagnoses, and Psychopathy Checklist-Revised and Static-99 scores. RESULTS: Evaluator differences explained a statistically significant (p < .001) amount of variance in behavioral abnormality opinions (17%), paraphilia diagnoses (7%), and Psychopathy Checklist-Revised scores (16%). Contrary to our expectation of a simple tendency for some evaluators to find all indicators of SVP status more often than others, evaluators differed in the ways that underlying diagnoses and scores corresponded with their conclusions. The overall pattern was one in which different evaluators appeared to base their final opinions on different factors. CONCLUSIONS: Findings reveal further evidence of substantial forensic evaluator differences in patterns of assigning instrument scores and reaching forensic conclusions. But these findings are the first to also reveal wide variability in their patterns of reaching forensic conclusions. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Trends in the Completeness and Validity of Sources of Death Data Against the National Death Index From 2010 to 2018.

PURPOSE: We investigated time trends in validation performance characteristics for six sources of death data available within the Healthcare Integrated Research Database (HIRD) over 8 years. METHODS: We conducted a secondary analysis of a cohort of advanced cancer patients with linked National Death Index (NDI) data identified in the HIRD between 2010 and 2018. We calculated sensitivity, specificity, positive predictive value, and negative predictive value for six sources of death status data and an algorithm combining data from available sources using NDI data as the reference standard. Measures were calculated for each year of the study including all members in the cohort for at least 1 day in that year. RESULTS: We identified 27 396 deaths from any source among 40 692 cohort members. Between 2010 and 2018, the sensitivity of the Death Master File (DMF) decreased from 0.77 (95% CI = 0.76, 0.79) to 0.12 (95% CI = 0.11, 0.14). In contrast, the sensitivity of online obituary data increased from 0.43 (95% CI = 0.41, 0.45) in 2012 to 0.71 (95% CI = 0.68, 0.73) in 2018. The sensitivity of the composite algorithm remained above 0.83 throughout the study period. PPV was observed to be high from 2010 to 2016 and decrease thereafter for all sources. Specificity and NPV remained at high levels throughout the study. CONCLUSIONS: We observed that the sensitivity of mortality data sources compared with the NDI could change substantially between 2010 and 2018. Other validation characteristics were less variable. Combining multiple sources of mortality data may be necessary to achieve adequate performance particularly for multiyear studies.

Variable response of eastern filbert blight resistance sources in New Jersey.

Eastern filbert blight (EFB), caused by Anisogramma anomala, is the primary limiting factor for hazelnut (Corylus sp.) production in the United States. In this study, 82 cultivars and selections shown to be resistant or tolerant to EFB in Oregon were field planted in New Jersey in 2017 and 2019 and evaluated for their EFB response under high disease pressure. The trees carry known single resistance (R) genes with most mapped to their respective linkage groups (LG), including LG2, LG6, and LG7, or they express quantitative resistance (QR, horizontal resistance). Disease incidence and severity was documented, stem cankers counted and measured, and the proportion of diseased wood calculated. The EFB disease response of some cultivars/selections varied considerably between New Jersey and Oregon while others were consistent. Trends were observed in relation to resistance source origin and LGs, which provide insight into durability and usefulness of resistance. In striking contrast to Oregon, nearly all selections with R-genes mapped to LG6, including those carrying the 'Gasaway' resistance allele, exhibited severe EFB infections (232 of 266 [87%]). This finding is of consequence since the U.S. hazelnut industry currently relies solely on LG6 resistance for EFB resistance. Further, for the first time, EFB was observed on several selections carrying LG7 resistance, specifically offspring of 'Ratoli' from Spain. Interestingly, selections carrying LG7 resistance from origins other than 'Ratoli' remained free of EFB, with one exception, all selections carrying LG2 (n=9) resistance also remained free from EFB. Interestingly, the EFB responses of selections expressing QR (n=26) more closely resembled the disease phenotypes they exhibited in Oregon. Overall, the divergence in EFB response between Oregon and New Jersey, where pathogen populations differ, supports the presence of pathogenic variation in A. anomala and highlights potential limitations of using single R-genes to manage the disease. Results also suggest trees expressing QR may be more stable across pathogenic populations.

Trends in Drug Overdose Deaths by Intent and Drug Categories, United States, 1999‒2022.

Objectives. To examine trends in overdose deaths by intent and drug category to better understand the recent decrease in overdose suicides amid the overdose epidemic. Methods. We examined trends in rates of overdose deaths by intent (unintentional, suicide, or undetermined) across 9 drug categories from 1999 to 2022 using US National Vital Statistics System mortality data. Results. Unintentional overdoses involving synthetic opioids, polydrug toxicity involving synthetic opioids, psychostimulants, and cocaine increased exponentially with annual percentage changes ranging from 15.0% to 104.9% during 2010 to 2022. The death rates also increased for suicides involving these drugs, especially for psychostimulants (annual percentage change = 12.9% for 2010-2022; P < .001). However, these drugs accounted for relatively small percentages of overdose suicides. The leading drug categories among suicides were antidepressants, prescription opioids, and benzodiazepines, though these deaths have decreased or leveled off in recent years. Conclusions. Different drugs commonly involved in suicides and unintentional overdoses may contribute to their divergent trends. Public Health Implications. Amid the overdose epidemic, safe storage of medications remains a crucial strategy to prevent overdose suicides. The large increases in suicides involving psychostimulants warrant monitoring. (Am J Public Health. Published online ahead of print August 8, 2024:e1-e5. https://doi.org/10.2105/AJPH.2024.307745).

Passive infusion of an S2-Stem broadly neutralizing antibody protects against SARS-CoV-2 infection and lower airway inflammation in rhesus macaques.

The continued evolution of SARS-CoV-2 variants capable of subverting vaccine and infection-induced immunity suggests the advantage of a broadly protective vaccine against betacoronaviruses (ß-CoVs). Recent studies have isolated monoclonal antibodies (mAbs) from SARS-CoV-2 recovered-vaccinated donors capable of neutralizing many variants of SARS-CoV-2 and other ß-CoVs. Many of these mAbs target the conserved S2 stem region of the SARS-CoV-2 spike protein, rather the receptor binding domain contained within S1 primarily targeted by current SARS-CoV-2 vaccines. One of these S2-directed mAbs, CC40.8, has demonstrated protective efficacy in small animal models against SARS-CoV-2 challenge. As the next step in the pre-clinical testing of S2-directed antibodies as a strategy to protect from SARS-CoV-2 infection, we evaluated the in vivo efficacy of CC40.8 in a clinically relevant non-human primate model by conducting passive antibody transfer to rhesus macaques (RM) followed by SARS-CoV-2 challenge. CC40.8 mAb was intravenously infused at 10mg/kg, 1mg/kg, or 0.1 mg/kg into groups (n=6) of RM, alongside one group that received a control antibody (PGT121). Viral loads in the lower airway were significantly reduced in animals receiving higher doses of CC40.8. We observed a significant reduction in inflammatory cytokines and macrophages within the lower airway of animals infused with 10mg/kg and 1mg/kg doses of CC40.8. Viral genome sequencing demonstrated a lack of escape mutations in the CC40.8 epitope. Collectively, these data demonstrate the protective efficiency of broadly neutralizing S2-targeting antibodies against SARS-CoV-2 infection within the lower airway while providing critical preclinical work necessary for the development of pan-ß-CoV vaccines.

The Impact of Double Pelvic Osteotomy on Dorsolateral Subluxation in 24 Dogs.

OBJECTIVE: The aim of this study was to determine the effect of double pelvic osteotomy (DPO) on dorsolateral subluxation (DLS) of the femoral head in a weight-bearing position. STUDY DESIGN: Retrospective observational study with treatment effect analysis. Twenty-four client-owned dogs that underwent DPO due to hip dysplasia. METHODS: Computed tomography (CT) studies were performed on 24 dogs that underwent a DPO between 2015 and 2021. The patients were positioned with the femora in a weight-bearing position. The DLS score was measured pre-DPO, immediately post-DPO, and at follow-up to determine if DPO resulted in an increase in the DLS score. RESULTS: A total of 21 dogs underwent single-stage bilateral DPO and 3 dogs underwent unilateral DPO resulting in 45 hip joints available for analysis. Follow-up CT was available for 29 of these at a median of 51 days (range: 35-482 days). The mean DLS score was 36.1% ± 14.6 preoperatively, 71.4% ± 12.5 post-DPO, and 70.0% ± 15.3 at follow-up. The increase between the pre- and postoperative measurement was significant (p < 0.001). CONCLUSION: DPO results in reduced subluxation of the femoral head in a weight-bearing position. CLINICAL SIGNIFICANCE: The in vivo results suggest that DPO will result in reduced femoral subluxation during weight-bearing.

Neural evidence of core foundations and conceptual change in preschool numeracy.

Symbolic numeracy first emerges as children learn the meanings of number words and how to use them to precisely count sets of objects. This development starts before children enter school and forms a foundation for lifelong mathematics achievement. Despite its importance, exactly how children acquire this basic knowledge is unclear. Here we test competing theories of early number learning by measuring event-related brain potentials during a novel number word-quantity comparison task in 3-4-year-old preschool children (N = 128). We find several qualitative differences in neural processing of number by conceptual stage of development. Specifically, we find differences in early attention-related parietal electrophysiology (N1), suggesting that less conceptually advanced children process arrays as individual objects and more advanced children distribute attention over the entire set. Subsequently, we find that only more conceptually advanced children show later-going frontal (N2) sensitivity to the numerical-distance relationship between the number word and visual quantity. The nature of this response suggested that exact rather than approximate numerical meanings were being associated with number words over frontal sites. No evidence of numerical distance effects was observed over posterior scalp sites. Together these results suggest that children may engage parallel individuation of objects to learn the meanings of the first few number words, but, ultimately, create new exact cardinal value representations for number words that cannot be defined in terms of core, nonverbal number systems. More broadly, these results document an interaction between attentional and general cognitive mechanisms in cognitive development. RESEARCH HIGHLIGHTS: Conceptual development in numeracy is associated with a shift in attention from objects to sets. Children acquire meanings of the first few number words through associations with parallel attentional individuation of objects. Understanding of cardinality is associated with attentional processing of sets rather than individuals. Brain signatures suggest children attribute exact rather than approximate numerical meanings to the first few number words. Number-quantity relationship processing for the first few number words is evident in frontal but not parietal scalp electrophysiology of young children.

Acute neuromuscular and perceptual responses to blood flow restriction exercise in adults with severe haemophilia: A pilot study.

INTRODUCTION: No previous studies have implemented a standard blood flow restriction (BFR) training session in people with severe haemophilia (PwH), where this type of training has been contraindicated. AIMS: The purpose of this study was to evaluate the tolerability, adverse events, and neuromuscular and perceptual responses to an acute session of low load (LL) knee extensions with BFR in PwH under prophylaxis. METHODS: Eight PwH performed one LL-BFR session with 40% arterial occlusion pressure (AOP). Perceptual responses and adverse effects were assessed, together with high-density surface electromyography of vastus medialis (VM) and lateralis (VL). RESULTS: Significant normalized root mean square differences were found within each set, but not between sets. Spatial distribution (centroid displacement (p > .05), modified entropy (VM, set two, cycles three and five, p = .032) and coefficient of variation (VM, set two, cycles four and five lower than cycle three (p = .049; p = .036)) showed changes within each set. Median frequency showed a slight increase during cycle four of set four (p = .030). Rate of perceived exertion slightly increased with each set while tolerability slightly decreased in the last set and fear of training with BFR generally decreased after the session. CONCLUSIONS: In PwH, a LL-BFR session at 40% AOP is safe and feasible. Our results suggest that potential muscle impairments may blunt neuromuscular adaptations induced by BFR.

Differences in reasons for secure and unsecure firearm storage: Results from a representative cross-sectional study of nine states.

Objectives: To examine factors that differentiate firearm owners who endorse specific reasons for secure and unsecure firearm storage. Methods: A subsample of firearm-owning adults (n = 3,119) drawn from a representative sample of adults (n = 7,785) residing in nine US states participated in an online survey. Results: The most common reason for not always using a gun safe was concerns that they render firearms too slow to access during an emergency (60.2%). The most common reasons for current firearm storage were ensuring ready access in case of emergency (59.7%) and preventing access by children and adolescents (44.6%). Firearm owners varied on their reasons based upon current storage habits, reasons for ownership, and the presence of firearms in the home. Conclusions: Firearm owners with children in the home are more likely to select storage methods they feel will prevent access by vulnerable individuals, whereas those who own for defensive purposes and those who store firearms loaded and unlocked are more likely to endorse storing their firearms for quick home defense and convenience and to see gun safes as unnecessary obstacles.

Cloaking antibodies are prevalent in Burkholderia cepacia complex infection and their removal restores serum killing.

Introduction: The Burkholderia cepacia complex encompasses a group of gram-negative opportunistic pathogens that cause chronic lung infections in people with cystic fibrosis. Distinct from other respiratory pathogens, Burkholderia causes a unique clinical disease in a subset of patients known as 'cepacia syndrome', fulminant pneumonia accompanied by bacteraemia and sepsis with a mortality rate of up to 75%. Due to the bacteraemia associated with this disease, the mechanisms that allow Burkholderia to resist the bactericidal effects of serum complement-depending killing are vital. Antibodies usually promote serum killing; however, we have described 'cloaking antibodies', specific for lipopolysaccharides that paradoxically protect serum-sensitive bacteria from complement-mediated lysis. Cloaking antibodies that protect Pseudomonas aeruginosa have been found in 24%-41% of patients with chronic lung diseases. The presence of these antibodies is also associated with worse clinical outcomes. Here, we sought to determine the relevance of cloaking antibodies in patients with Burkholderia infection. Methods: Twelve Burkholderia spp. were isolated from nine pwCF and characterised for susceptibility to healthy control serum. Patient serum was analysed for the titre of the cloaking antibody. The ability of the patient serum to prevent healthy control serum (HCS) killing of its cognate isolates was determined. Results: We found that several of the Burkholderia strains were shared between patients. Ten of the 12 isolates were highly susceptible to HCS killing. Four of nine (44%) patients had cloaking antibodies that protected their cognate strain from serum killing. Depleting cloaking antibodies from patient serum restored HCS killing of Burkholderia isolates. Discussion: Cloaking antibodies are prevalent in patients with Burkholderia pulmonary infection and protect these strains from serum killing. Removal of cloaking antibodies via plasmapheresis, as previously described for individuals with life-threatening Pseudomonas infection, may be a useful new strategy for those with serious and life-threatening Burkholderia infection.

Cxcr4 regulates a pool of adipocyte progenitors and contributes to adiposity in a sex-dependent manner.

Sex steroids modulate the distribution of mammalian white adipose tissues. Moreover, WAT remodeling requires adipocyte progenitor cells. Nevertheless, the sex-dependent mechanisms regulating adipocyte progenitors remain undetermined. Here, we uncover Cxcr4 acting in a sexually dimorphic manner to affect a pool of proliferating cells leading to restriction of female fat mass. We find that deletion of Cxcr4 in Pparγ-expressing cells results in female, not male, lipodystrophy, which cannot be restored by high-fat diet consumption. Additionally, Cxcr4 deletion is associated with a loss of a pool of proliferating adipocyte progenitors. Cxcr4 loss is accompanied by the upregulation of estrogen receptor alpha in adipose-derived PPARγ-labelled cells related to estradiol hypersensitivity and stalled adipogenesis. Estrogen removal or administration of antiestrogens restores WAT accumulation and dynamics of adipose-derived cells in Cxcr4-deficient mice. These findings implicate Cxcr4 as a female adipogenic rheostat, which may inform strategies to target female adiposity.

DNA methylation and gene expression as determinants of genome-wide cell-free DNA fragmentation.

Circulating cell-free DNA (cfDNA) is emerging as an avenue for cancer detection, but the characteristics of cfDNA fragmentation in the blood are poorly understood. We evaluate the effect of DNA methylation and gene expression on genome-wide cfDNA fragmentation through analysis of 969 individuals. cfDNA fragment ends more frequently contained CCs or CGs, and fragments ending with CGs or CCGs are enriched or depleted, respectively, at methylated CpG positions. Higher levels and larger sizes of cfDNA fragments are associated with CpG methylation and reduced gene expression. These effects are validated in mice with isogenic tumors with or without the mutant IDH1, and are associated with genome-wide changes in cfDNA fragmentation in patients with cancer. Tumor-related hypomethylation and increased gene expression are associated with decrease in cfDNA fragment size that may explain smaller cfDNA fragments in human cancers. These results provide a connection between epigenetic changes and cfDNA fragmentation with implications for disease detection.

Chloroformate-mediated ring cleavage of indole alkaloids leads to re-engineered antiplasmodial agents.

Natural product ring distortion strategies have enabled rapid access to unique libraries of stereochemically complex compounds to explore new chemical space and increase our understanding of biological processes related to human disease. Herein is described the development of a ring-cleavage strategy using the indole alkaloids yohimbine, apovincamine, vinburnine, and reserpine that were reacted with a diversity of chloroformates paired with various alcohol/thiol nucleophiles to enable the rapid synthesis of 47 novel small molecules. Ring cleavage reactions of yohimbine and reserpine produced two diastereomeric products in moderate to excellent yields, whereas apovincamine and vinburnine produced a single diastereomeric product in significantly lower yields. Free energy calculations indicated that diastereoselectivity regarding select ring cleavage reactions from yohimbine and apovincamine is dictated by the geometry and three-dimensional structure of reactive cationic intermediates. These compounds were screened for antiplasmodial activity due to the need for novel antimalarial agents. Reserpine derivative 41 was found to exhibit interesting antiplasmodial activities against Plasmodium falciparum parasites (EC50 = 0.50 µM against Dd2 cultures), while its diastereomer 40 was found to be three-fold less active (EC50 = 1.78 µM). Overall, these studies demonstrate that the ring distortion of available indole alkaloids can lead to unique compound collections with re-engineered biological activities for exploring and potentially treating human disease.

A new era of synthetic biology-microbial community design.

Synthetic biology conceptualizes biological complexity as a network of biological parts, devices, and systems with predetermined functionalities and has had a revolutionary impact on fundamental and applied research. With the unprecedented ability to synthesize and transfer any DNA and RNA across organisms, the scope of synthetic biology is expanding and being recreated in previously unimaginable ways. The field has matured to a level where highly complex networks, such as artificial communities of synthetic organisms, can be constructed. In parallel, computational biology became an integral part of biological studies, with computational models aiding the unravelling of the escalating complexity and emerging properties of biological phenomena. However, there is still a vast untapped potential for the complete integration of modelling into the synthetic design process, presenting exciting opportunities for scientific advancements. Here, we first highlight the most recent advances in computer-aided design of microbial communities. Next, we propose that such a design can benefit from an organism-free modular modelling approach that places its emphasis on modules of organismal function towards the design of multispecies communities. We argue for a shift in perspective from single organism-centred approaches to emphasizing the functional contributions of organisms within the community. By assembling synthetic biological systems using modular computational models with mathematical descriptions of parts and circuits, we can tailor organisms to fulfil specific functional roles within the community. This approach aligns with synthetic biology strategies and presents exciting possibilities for the design of artificial communities. Graphical Abstract.

In silico approaches to study the human asparagine synthetase: An insight of the interaction between the enzyme active sites and its substrates.

Cancer is a leading concern and important cause of death worldwide. Cancer is a non-communicable illness defined as uncontrolled division of cells. It can develop into metastatic cancer when tumor cells migrate to other organs. In recent years evidence has emerged that the bioavailability of Asn play a crucial role in cancer metastasis. Asn is a non-essential amino acid formed from an ATP dependent catalyzed reaction by the enzyme asparagine synthetase (ASNS), where Asp and Gln are converted to Asn and Glu, respectively. The human ASNS enzyme consist of 561 amino acids, with a molecular weight of 64 KDa. ASNS governs the activation of transcriptional factors that regulate the process of metastasis. In this work the 3D model of ASNS in E. coli (AS-B) and the human ASNS docked with its different ligands have been used to study the 3D mechanism of the conversion of Asp and Gln to Asn and Glu, in human ASNS. The stability evaluation of the docked complexes was checked by molecular dynamic simulation through the bioinformatic tool Desmond. The binding residues and their interactions can be exploited for the development of inhibitors, as well as for finding new drug molecules against ASNS and prevention of metastatic cancer.

Deep learning segmentation of mandible with lower dentition from cone beam CT.

OBJECTIVES: This study aimed to train a 3D U-Net convolutional neural network (CNN) for mandible and lower dentition segmentation from cone-beam computed tomography (CBCT) scans. METHODS: In an ambispective cross-sectional design, CBCT scans from two hospitals (2009-2019 and 2021-2022) constituted an internal dataset and external validation set, respectively. Manual segmentation informed CNN training, and evaluations employed Dice similarity coefficient (DSC) for volumetric accuracy. A blinded oral maxillofacial surgeon performed qualitative grading of CBCT scans and object meshes. Statistical analyses included independent t-tests and ANOVA tests to compare DSC across patient subgroups of gender, race, body mass index (BMI), test dataset used, age, and degree of metal artifact. Tests were powered for a minimum detectable difference in DSC of 0.025, with alpha of 0.05 and power level of 0.8. RESULTS: 648 CBCT scans from 490 patients were included in the study. The CNN achieved high accuracy (average DSC: 0.945 internal, 0.940 external). No DSC differences were observed between test set used, gender, BMI, and race. Significant differences in DSC were identified based on age group and the degree of metal artifact. The majority (80%) of object meshes produced by both manual and automatic segmentation were rated as acceptable or higher quality. CONCLUSION: We developed a model for automatic mandible and lower dentition segmentation from CBCT scans in a demographically diverse cohort including a high degree of metal artifacts. The model demonstrated good accuracy on internal and external test sets, with majority acceptable quality from a clinical grader.