Independent volumetric internal fixation reduces posterior column acetabular fracture site motion as compared to plate/screw construct: A biomechanical analysis.

Aims & objectives: To establish whether a suprapectineal pelvic reconstruction plate and posterior column screw (P&S) construct or a single 6.5-mm cannulated posterior column screw (PCS) construct demonstrates greater mechanical stability for fixation of acetabulum fractures involving the posterior column (PC). We hypothesized that the PCS construct would result in less fracture site motion. Materials & methods: Twelve fourth-generation composite hemipelvi were utilized, 6 for each construct. The P&S construct consisted of a suprapectineal pelvic reconstruction plate with two 3.5-mm posterior column screws crossing the fracture site in lag-by-technique fashion and two screws anchoring the plate to the sciatic buttress. The PCS construct consisted of a single 6.5-mm partially threaded cannulated screw placed in an antegrade fashion. Both fixation models were cyclically loaded at 0.5 cycles/second at 400N and 800N, first in a sit-to-stand position that is expected during recovery, and subsequently in a squat-to-stand position to test overload conditions. Results: Under sit-to-stand loading, the PCS construct resulted in less motion at the fracture site than the P&S construct (0.06 ± 0.02 mm vs 0.1 ± 0.02 mm at 400N, p = 0.02; 0.13 ± 0.03 mm vs 0.19 ± 0.04 mm at 800N, p = 0.03). The PCS construct also demonstrated less fracture site motion under squat-to-stand loading (0.22 ± 0.13 mm vs 1.9 ± 0.5 mm at 400N, p = < 0.001; 1.48 ± 0.44 mm vs 4.77 ± 0.3 mm at 800N, p = < 0.001). At 800 N, half of the repairs failed during squat-to-stand loading (2 PCS, 4 P&S). Conclusion: Fixation of the posterior column of the acetabulum with a 6.5-mm cannulated screw demonstrated comparable fracture motion upon loading compared to the plate and screw construct.

Enhanced Fear Extinction Through Infralimbic Perineuronal Net Digestion: The Modulatory Role of Adolescent Alcohol Exposure.

Perineuronal nets (PNNs) are specialized components of the extracellular matrix that play a critical role in learning and memory. In a Pavlovian fear conditioning paradigm, degradation of PNNs affects the formation and storage of fear memories. This study examined the impact of adolescent intermittent ethanol (AIE) exposure by vapor inhalation on the expression of PNNs in the adult rat prelimbic (PrL) and infralimbic (IfL) subregions of the medial prefrontal cortex. Results indicated that following AIE, the total number of PNN positive cells in the PrL cortex increased in layer II/III but did not change in layer V. Conversely, in the IfL cortex, the number of PNN positive cells decreased in layer V, with no change in layer II/III. In addition, the intensity of PNN staining was significantly altered by AIE exposure, which narrowed the distribution of signal intensity, reducing the number of high and low intensity PNNs. Given these changes in PNNs, the next experiment assessed the effects of AIE and PNN digestion on extinction of a conditioned fear memory. In Air control rats, digestion of PNNs by bilateral infusion of Chondroitinase ABC (ChABC) into the IfL cortex enhanced fear extinction and reduced contextual fear renewal. In contrast, both fear extinction learning and contextual fear renewal remained unchanged following PNN digestion in AIE exposed rats. These results highlight the sensitivity of prefrontal PNNs to adolescent alcohol exposure and suggest that ChABC-induced plasticity is reduced in the IfL cortex following AIE exposure.

Clinical profile of patients with acute traumatic brain injury undergoing cranial surgery in the United States: report from the 18-centre TRACK-TBI cohort study.

Background: Contemporary surgical practices for traumatic brain injury (TBI) remain unclear. We describe the clinical profile of an 18-centre US TBI cohort with cranial surgery. Methods: The prospective, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study (2014-2018; ClinicalTrials.gov #NCT02119182) enrolled subjects who presented to trauma centre and received head computed tomography within 24-h (h) post-TBI. We performed a secondary data analysis in subjects aged ≥17-years with hospitalisation. Clinical characteristics, surgery type/timing, hospital and six-month outcomes were reported. Findings: Of 2032 subjects (age: mean = 41.4-years, range = 17-89-years; male = 71% female = 29%), 260 underwent cranial surgery, comprising 65% decompressive craniectomy, 23% craniotomy, 12% other surgery. Subjects with surgery (vs. without surgery) presented with worse neurological injury (median Glasgow Coma Scale = 6 vs. 15; midline shift ≥5 mm: 48% vs. 2%; cisternal effacement: 61% vs. 4%; p < 0.0001). Median time-to-craniectomy/craniotomy was 1.8 h (interquartile range = 1.1-5.0 h), and 67% underwent intracranial pressure monitoring. Seventy-three percent of subjects with decompressive craniectomy and 58% of subjects with craniotomy had ≥3 intracranial lesion types. Decompressive craniectomy (vs. craniotomy) was associated with intracranial injury severity (median Rotterdam Score = 4 vs. 3, p < 0.0001), intensive care length of stay (median = 13 vs. 4-days, p = 0.0002), and six-month unfavourable outcome (62% vs. 30%; p = 0.0001). Earlier time-to-craniectomy was associated with intracranial injury severity. Interpretation: In a large representative cohort of patients hospitalised with TBI, surgical decision-making and time-to-surgery aligned with intracranial injury severity. Multifocal TBIs predominated in patients with cranial surgery. These findings summarise current TBI surgical practice across US trauma centres and provide the foundation for analyses in targeted subpopulations. Funding: National Institute of Neurological Disorders and Stroke; US Department of Defense; Neurosurgery Research and Education Foundation.

ITSxpress version 2: software to rapidly trim internal transcribed spacer sequences with quality scores for amplicon sequencing.

The nuclear ribosomal RNA (rRNA) internal transcribed spacer (ITS) regions are commonly used to identify fungi and other eukaryotic taxa in amplicon sequencing. The highly conserved rRNA regions flanking the ITS are often trimmed before being used for taxonomic assignment. The Python software package ITSxpress rapidly trims single-end or paired-end sequences in FASTQ format for use in amplicon sequence variant clustering methods like DADA2. This new major release of ITSxpress improves the paired-end merging method, simplifies installation of the QIIME 2 ITSxpress plugin, removes major dependencies, adds use cases, and is compatible with newer compression formats. This article discusses the modifications to ITSxpress that improve the output and user experience, leading to a major version increase.IMPORTANCEITSxpress is a sequence trimming method applied to internal transcribed spacer (ITS) amplicon sequences before calling amplicon sequence variants (ASVs). The ITS region is used to understand the composition of eukaryotic microbial communities. ITS sequences provide good taxonomic resolution due to their hypervariability, but are flanked by conserved regions that allow their primers to be more universal. Amplicons generated with such primers contain regions with different evolutionary rates, and trimming these conserved regions results in better taxonomic classification and a more valid set of ASVs. This package can be used for most amplicon sequencing methods including for newer long-read sequencing formats, such as PacBio. ITSxpress can be installed from Bioconda, used as a Docker image, or installed from source code. The package works well with high-performance computing clusters or laptops due to its low-resource requirements.

Lumbar intervertebral disc replacement in Australia: An epidemiological study.

Introduction: Favorable short- and long-term outcomes have been reported for lumbar intervertebral total disc replacement (L-TDR). However, there is little evidence regarding the uptake of L-TDR in practice. The objective of this study was to analyze Australian-based population trends in L-TDR over the past 5 years. Methods: The 5-year incidence of L-TDR from 2019 to 2023 in adult patients was analyzed using the Medicare Benefits Schedule (MBS) database. Data were stratified by sex and year, with an offset term introduced using population data from the Australian Bureau of Statistics to account for population changes over the study period. Results: A total of 1558 L-TDRs were completed in Australia under the MBS in the 5 years of interest. The 5-year annual mean case volume was 311.6 cases per annum. A downtrend and plateau in the rate of L-TDR has been seen from 2021 onward. The distribution of L-TDR across ages showed a significantly higher concentration in the 35-44 and 45-54 age groups (P < 0.05). More operations were performed in males (n = 876, 56.2%) than females (n = 682, 43.8%). Conclusions: The uptake of L-TDR has declined throughout the 5-year study period in Australia. Despite modest use currently, the future of L-TDR will rely on more robust long-term outcome data.

A Scoping Review of Implementation Science Studies in the Field of Traumatic Brain Injury: State of the Science and Future Directions.

OBJECTIVE: Implementation research is essential to accelerating the public health benefits of innovations in health settings. However, the US National Academies of Sciences, Engineering, and Medicine 2022 report identified a lag in published implementation research applied to traumatic brain injury (TBI). Our objectives were to characterize implementation science studies published to date in TBI clinical care and rehabilitation and provide recommendations for future directions. METHODS: A scoping review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. Articles published between 2011 and 2023 were identified (MEDLINE, PubMed, PsychInfo, and Web of Science), and included if the study focused on the TBI population, measured at least one Proctor (2011) implementation outcome and aligned with implementation research designs. Data were charted using an extraction template. RESULTS: Of the 38 articles, 76% were published between 2018 and 2023. About 37% of articles were in the pre-implementation phase, and 57.9% were in the implementation phase. Over half of articles used a theory, model, or framework to guide the research. Fifteen studies were descriptive, 10 were qualitative, 7 were mixed methods, and 4 were randomized controlled trials. Most studies investigated implementation outcomes regarding national guidelines following TBI or TBI symptom management. Adoption (42.1%) and fidelity (42.1%) were the most commonly studied implementation outcomes, followed by feasibility (18.4%), acceptability (13.2%), and penetration (10.5%). Only 55% of studies used or tested the effectiveness of one or more implementation strategies, with training and education used most commonly, followed by data warehousing techniques. CONCLUSIONS: Future research should prioritize the selection and investigation of implementation strategy effectiveness and mechanisms across contexts of care and use implementation research reporting standards to improve study rigor. Additionally, collaborative efforts between researchers, community partners, individuals with TBI, and their care partners could improve the equitable translation of innovations across service contexts.

Predicting the Presence of Pain in Youth Baseball Pitchers Using the Concept of Biomechanical Efficiency.

Background: Increases in peak shoulder distraction force and peak elbow valgus torque may influence throwing-arm pain and injury risk in youth pitchers. Purpose/Hypothesis: The purpose of this study was to determine whether shoulder distraction force and elbow valgus torque while accounting for anthropometrics and pitch velocity can predict the presence of pain in youth baseball pitchers. It was hypothesized that throwing-arm pain could be predicted using the concept of biomechanical efficiency, where a pitcher who is less efficient (having higher force or torque with the same pitch velocity) is more likely to experience pain. Study Design: Descriptive laboratory study. Methods: A total of 38 youth baseball pitchers (mean age, 13.3 ± 1.7 years) were divided into a pain group and pain-free group based on presence of throwing-arm pain as reported on a health history questionnaire. Each pitcher threw 3 maximal-effort fastballs to a catcher at regulation distance, and kinematics were measured using an electromagnetic motion-capture system (minimum 100 Hz). Height and weight as well as mean peak shoulder distraction force, peak elbow valgus torque, and pitch velocity across the 3 trials were evaluated. Logistic regression analyses determined whether shoulder distraction force or elbow valgus torque could predict the presence of throwing-arm pain when holding anthropometrics (body weight for shoulder distraction force; body weight and height for elbow valgus torque) and pitch velocity constant. Results: Shoulder distraction force significantly predicted the presence of throwing-arm pain after accounting for body weight and pitch velocity (χ2 = 9.49; P = .023). Specifically, for every 1-N increase in peak shoulder distraction force while holding body weight and pitch velocity constant, there was a 0.6% increased likelihood of experiencing throwing-arm pain. Elbow valgus torque could not predict the presence of pain when holding body weight, height, and pitch velocity constant. Conclusion: The models demonstrated that increases in peak shoulder distraction forces when holding pitch velocity and body weight constant increased a youth baseball pitcher's likelihood of experiencing throwing-arm pain. The study results support the concept of the biomechanical efficiency framework by offering evidence that maintaining pitch velocity with a lower joint load led to a lower likelihood of pain. Clinical Relevance: Results suggest that practicing efficient movement strategies can decrease the likelihood of experiencing throwing-arm pain while maintaining performance.

Familiarity preferences in zebrafish (Danio rerio) depend on shoal proximity.

Individuals of many species prefer to associate with familiar conspecifics from their established social group over unfamiliar conspecifics. Such familiarity preferences are thought to be adaptive and have been documented widely in many social fishes. Zebrafish (Danio rerio) are extensively studied, highly social fish that form stable shoals in the wild, however there is only mixed evidence for familiarity preferences in this species. Here, we test how a small variation in experimental design can influence preferences for familiar conspecifics in D. rerio by varying the distance between two stimulus shoals of fish in a shoaling choice paradigm. Individual subjects tested for their preference to shoal with familiar or unfamiliar groups of conspecifics showed a preference for familiar fish when the two shoals were 30 cm apart, but not when they were 45 or 60 cm apart. Thus, choice tests can be used to detect familiarity preferences in D. rerio, but only when alternate shoals are close together, as increased intershoal distances seemingly prevent subjects from displaying their preference. Longer distances may inhibit preference behavior due to the higher risk of crossing between shoals, alternatively subjects may be unable to reliably discern distinguishing cues of familiarity when the shoals are further apart. Our results demonstrate that while familiarity preferences exist in D. rerio, experimental test design is critical for detecting and measuring these successfully.

Ketamine use in a large global sample: Characteristics, patterns of use and emergency medical treatment.

BACKGROUND: Ketamine's popularity has surged globally in the past decade, especially among young men. Emergency department visits due to its toxicity remain relatively rare, often linked to co-occurring use of other substances. AIMS: Using data from the Global Drug Survey (GDS) 2018, this study explored the correlates associated with lifetime and past-year ketamine use, and estimated the socio-demographic characteristics, usage patterns and experiences of respondents seeking emergency medical treatment (EMT) after ketamine use. METHODS: Secondary analysis of GDS 2018, an online cross-sectional survey on drug use patterns conducted between November 2017 and January 2018. RESULTS: The survey received 130,761 valid responses, with 5.93% reporting lifetime ketamine use, of which 57.70% used ketamine within the past year. Predominantly, respondents were from Germany, England and Denmark. Within the past year, 8.55% met the criteria for ketamine dependence. Respondents who used ketamine in their lifetime tended to be young (mean (x̄) = 27.37 years), men, heterosexual and of white ethnicity. Younger age (x̄ = 24.84 years), gay sexual orientation, student status, past-year use of other drugs and no lifetime mental health diagnosis were associated with past-year ketamine use. Among 4477 respondents reporting past-year ketamine use, 120 adverse events were reported, with less than 0.10% prompting EMT seeking. CONCLUSION: The study reveals frequent ketamine use but low harm occurrence, underscoring the complex interplay between ketamine use, substance use and dependence, and related factors. This underscores the need to reassess EMT priorities, implement tailored harm reduction strategies and incorporate comprehensive screening for addressing ketamine and substance dependence challenges.

Analyzing the Social Vulnerability Index With Metabolic Surgery.

INTRODUCTION: The social vulnerability index (SVI) is a census tract-level population-based measure generated from 16 socioeconomic and demographic variables on a scale from 1 (least) to 100 (most) vulnerable. This study has three objectives as follows: 1) to analyze multiple ways of utilizing SVI, 2) compare SVI as a group measure of marginalization to individual markers, and 3) to understand how SVI is associated with choice of surgery in metabolic surgery. METHODS: We retrospectively identified adults undergoing Roux-en-Y gastric bypass and gastric sleeve in 2013-2018 National Surgical Quality Improvement Program data from a single academic center. High SVI was defined as >75th percentile. Low SVI was coded as <75th percentile in measure 1 and < 25th percentile in measure 2. Chi-square and Mann-Whitney U tests were utilized for categorical and continuous variables, respectively. Multivariable regression models were performed comparing SVI to marginalized status as a predictor for type of metabolic surgery. RESULTS: We identified 436 patients undergoing metabolic surgery, with a low overall morbidity (6.1%). Complication and readmission rates were similar across comparator groups. The logistic regression models had similar area under the curve, supporting SVI as a proxy for individual measures of marginalization. CONCLUSIONS: SVI performed as well as marginalized status in predicting preoperative risk. This suggests the validity of using SVI to identify high risk patients. By providing a single, quantitative score encompassing many social determinants of health, SVI is a useful tool in identifying patients facing the greatest health disparities.

Association between postoperative complications and hospital length of stay: a large-scale observational study of 4,495,582 patients in the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) registry.

BACKGROUND: Precise estimates of risk-adjusted increases in postoperative length of stay (LOS) associated with postoperative complications across a range of complications and operations are not available in the existing literature. METHODS: Associations between preoperative characteristics, postoperative complications and postoperative LOS were tested using medians, interquartile ranges, and nonparametric rank sum tests in a retrospective cohort study using the 2005-2018 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) dataset. A negative binomial model was used with postoperative LOS as the dependent variable and preoperative characteristics and postoperative complications as independent variables. The model was applied to estimate each patient's postoperative LOS with and without each postoperative complication to measure the association between each complication and risk-adjusted change in postoperative LOS. RESULTS: A total of 4,495,582 patients were included. After risk-adjustment, occurrence of each postoperative complication was associated with significantly increased postoperative LOS (between + 3.9 and + 20.1 days, p < 0.0001). The longest risk-adjusted postoperative LOS increases were associated with prolonged ventilator use (+ 20.1 days), wound disruption (+ 19.4 days), and acute renal failure (+ 17.1 days). CONCLUSION: Occurrence of any postoperative complication was associated with increased risk-adjusted postoperative LOS. Degree of increase varied by complication. These data could be useful for patient counseling, allocation of resources, discharge planning, and quality improvement efforts.

The correlation of neurosurgery motor examinations with ISNCSCI motor examinations in patients with spinal cord injury: a multicenter TRACK-SCI study.

OBJECTIVE: The International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) assessment is the gold standard for evaluation of neurological function after spinal cord injury (SCI). Although it is an invaluable tool for diagnostic and research purposes, it is time consuming and can be impractical in acute injury settings. Clinical neurosurgery motor examinations (NMEs) could serve as an expeditious surrogate for SCI research when ISNCSCI motor examinations are not feasible. The aim of this study was to evaluate the agreement between motor examinations performed by the neurosurgery clinical team and ISNCSCI examiners. METHODS: The multicenter prospective Transforming Research and Clinical Knowledge in Spinal Cord Injury (TRACK-SCI) registry was queried to identify patients with recorded neurosurgery and research motor examinations within 24 hours of each other. Pearson correlations and modified Bland-Altman analyses were performed using data from matching upper-extremity, lower-extremity, and combined examinations. Kappa analysis was used to test interrater reliability with respect to determination of American Spinal Injury Association Impairment Scale (AIS) grade. RESULTS: There were 72 pairs of matching clinical and research examinations in 63 patients. NME scores were strongly correlated with ISNCSCI motor scores (R = 0.962, p < 0.001). Both upper- and lower-extremity NME scores were strongly correlated with upper- and lower-extremity ISNCSCI motor scores, respectively (R = 0.939, p < 0.001; and R = 0.959, p < 0.001, respectively). In modified Bland-Altman analyses, total, upper-extremity, and lower-extremity NME scores and ISNCSCI motor scores showed low systematic bias and high agreeability (total: bias = 0.3, limit of agreement [LoA] = 36.6; upper extremity: bias = -0.5, LoA = 17.6; lower extremity: bias = 0.8, LoA = 24.0). There were 66 pairs of examinations that had thorough sensory and rectal examinations for AIS grade calculation. Using kappa analysis to test the interrater reliability of AIS grade calculation using NME versus ISNCSCI motor scores, the authors found a weighted kappa of 0.883 (SE 0.061, 95% CI 0.736-0.976), indicating strong agreement. CONCLUSIONS: Overall, this study suggests that ISNCSCI motor scores and NME scores are strongly correlated and highly agreeable. When conducting SCI research, a thorough clinical motor examination may be a useful surrogate when ISNCSCI examinations are missing.

More Efficient Smaller Multi-Cancer Screening Trials.

BACKGROUND: The NHS-Galleri trial has demonstrated feasibility for multi-cancer screening trial design where all participants provide a 'sample' for screening, but only samples from the intervention arm are tested and acted upon during the trial. We assess efficiency of analysis methods when the control arm may be retrospectively tested at time of analysis. METHODS: Analyses considered are: (1, traditional) by randomised allocation with all events included; (2, 'intended-effect') nested in those who tested positive in both arms and all events therein; and (3, targeted) by randomised allocation but with endpoint 'test-positive event'. They are compared using approximate statistical methods and scenario analysis. RESULTS: Provided the number who die from cancer after a test-positive sample is a small fraction of the total number who die from cancer, intended-effect and targeted analyses require a much smaller sample size to evaluate cancer-specific mortality than the traditional approach. Intended-effect analysis has a smaller sample size requirement than targeted analysis. This gain is only substantial when the risk of cancer death in test positives is high. CONCLUSION: Intended-effect or targeted analysis will substantially reduce the sample size needed to evaluate cancer-specific mortality in blood-based screening trials. Targeted analysis requires many fewer retrospective tests and avoids potential effects of needing to inform those whose stored samples test positive. Trialists should consider the trade-off of costs between sample size and retrospective testing requirements when choosing the analysis.

Cellular signaling pathways in the nervous system activated by various mechanical and electromagnetic stimuli.

Mechanical stimuli, such as stretch, shear stress, or compression, activate a range of biomolecular responses through cellular mechanotransduction. In the nervous system, studies on mechanical stress have highlighted key pathophysiological mechanisms underlying traumatic injury and neurodegenerative diseases. However, the biomolecular pathways triggered by mechanical stimuli in the nervous system has not been fully explored, especially compared to other body systems. This gap in knowledge may be due to the wide variety of methods and definitions used in research. Additionally, as mechanical stimulation techniques such as ultrasound and electromagnetic stimulation are increasingly utilized in psychological and neurorehabilitation treatments, it is vital to understand the underlying biological mechanisms in order to develop accurate pathophysiological models and enhance therapeutic interventions. This review aims to summarize the cellular signaling pathways activated by various mechanical and electromagnetic stimuli with a particular focus on the mammalian nervous system. Furthermore, we briefly discuss potential cellular mechanosensors involved in these processes.

Molecular recognition of peptides and proteins by cucurbit[n]urils: systems and applications.

The development of methodology for attaching ligand binding sites to proteins of interest has accelerated biomedical science. Such protein tags have widespread applications as well as properties that significantly limit their utility. This review describes the mechanisms and applications of supramolecular systems comprising the synthetic receptors cucurbit[7]uril (Q7) or cucurbit[8]uril (Q8) and their polypeptide ligands. Molecular recognition of peptides and proteins occurs at sites of 1-3 amino acids with high selectivity and affinity via several distinct mechanisms, which are supported by extensive thermodynamic and structural studies in aqueous media. The commercial availability, low cost, high stability, and biocompatibility of these synthetic receptors has led to the development of myriad applications. This comprehensive review compiles the molecular recognition studies and the resulting applications with the goals of providing a valuable resource to the community and inspiring the next generation of innovation.

HIV testing services and HIV self-testing programming within emergency care in Kenya: a qualitative study of healthcare personnel to inform enhanced service delivery approaches.

In Kenya, persons insufficiently engaged in HIV Testing Services (HTS) are often treated in emergency departments (ED). There are limited data from healthcare workers on ED-HTS. A qualitative study was completed to understand challenges and facilitators for ED-HTS and HIV self-testing (HIVST). Data were collected via six focus groups of healthcare workers. Data were inductively analyzed and mapped to the Capability-Opportunity-Motivation Behavioral Model. Focus groups were completed with 49 healthcare workers: 18 nurses, 15 HIV counselors, 10 physicians and 6 administrators. HTS challenges included staff burdens, resources access, deficiencies in systems integration and illness severity. HTS facilitators included education of healthcare workers and patients, services coordination, and specific follow-up processes. HIVST challenges included accuracy concerns, follow-up barriers and psychosocial risks. HIVST facilitators were patient autonomy and confidentiality, resource utilization and ability to reach higher-risk persons. Mapping to the Capability-Opportunity-Motivation Behavioral Model interventions within the domains of knowledge, decision processes, environmental aspects, social influences and professional identities could support enhanced ED-HTS with integrated HIVST delivery. This study provided insights into challenges and facilitators on ED-HTS and identifies pragmatic approaches to improve healthcare workers' behaviors and abilities to provide services to persons already in contact with healthcare.

Expanding Automated Multiconformer Ligand Modeling to Macrocycles and Fragments.

Small molecule ligands exhibit a diverse range of conformations in solution. Upon binding to a target protein, this conformational diversity is generally reduced. However, ligands can retain some degree of conformational flexibility even when bound to a receptor. In the Protein Data Bank (PDB), a small number of ligands have been modeled with distinct alternative conformations that are supported by X-ray crystallography density maps. However, the vast majority of structural models are fit to a single ligand conformation, potentially ignoring the underlying conformational heterogeneity present in the sample. We previously developed qFit-ligand to sample diverse ligand conformations and to select a parsimonious ensemble consistent with the density. While this approach indicated that many ligands populate alternative conformations, limitations in our sampling procedures often resulted in non-physical conformations and could not model complex ligands like macrocycles. Here, we introduce several improvements to qFit-ligand, including the use of routines within RDKit for stochastic conformational sampling. This new sampling method greatly enriches low energy conformations of small molecules and macrocycles. We further extended qFit-ligand to identify alternative conformations in PanDDA-modified density maps from high throughput X-ray fragment screening experiments. The new version of qFit-ligand improves fit to electron density and reduces torsional strain relative to deposited single conformer models and our previous version of qFit-ligand. These advances enhance the analysis of residual conformational heterogeneity present in ligand-bound structures, which can provide important insights for the rational design of therapeutic agents.

An infrastructure for qualified data sharing and team science in late-stage translational spinal cord injury research.

The complex and heterogeneous nature of spinal cord injury has limited translational bench-to-bedside results. The wide variety of data, including injury parameters, biochemical, histological, and behavioral outcome measures represent a 'big data' problem, calling for modern data science solutions. There are some instances in which SCI researchers collect sensitive data that needs to remain private, such as datasets designed to meet regulatory approval, sensitive intellectual property, and non-human primate studies. For these types of data, we have developed a Private Data Commons for SCI (PDC-SCI). Our objective is to give an overview of this novel data commons, describing how this type of commons works, how it can benefit the research community, and the cases in which it would be most useful. This private infrastructure is ideal for multi-lab transdisciplinary studies that require a well-organized, scalable data commons for rapid data sharing within a closed, distributed team. As a use-case for the PDC-SCI, we demonstrate the VA Gordon Mansfield SCI Consortium, in which multimodal data from behavior, biomechanics of injury, hospital records, imaging, and histology are integrated, shared, and analyzed to facilitate insights and knowledge discovery.

DNA Methylation in Alzheimer's Disease.

To date, DNA methylation is the best characterized epigenetic modification in Alzheimer's disease. Involving the addition of a methyl group to the fifth carbon of the cytosine pyrimidine base, DNA methylation is generally thought to be associated with the silencing of gene expression. It has been hypothesized that epigenetics may mediate the interaction between genes and the environment in the manifestation of Alzheimer's disease, and therefore studies investigating DNA methylation could elucidate novel disease mechanisms. This chapter comprehensively reviews epigenomic studies, undertaken in human brain tissue and purified brain cell types, focusing on global methylation levels, candidate genes, epigenome wide approaches, and recent meta-analyses. We discuss key differentially methylated genes and pathways that have been highlighted to date, with a discussion on how new technologies and the integration of multiomic data may further advance the field.