MaPPeRTrac: A Massively Parallel, Portable, and Reproducible Tractography Pipeline.

Large-scale diffusion MRI tractography remains a significant challenge. Users must orchestrate a complex sequence of instructions that requires many software packages with complex dependencies and high computational costs. We developed MaPPeRTrac, an edge-centric tractography pipeline that simplifies and accelerates this process in a wide range of high-performance computing (HPC) environments. It fully automates either probabilistic or deterministic tractography, starting from a subject's magnetic resonance imaging (MRI) data, including structural and diffusion MRI images, to the edge density image (EDI) of their structural connectomes. Dependencies are containerized with Singularity (now called Apptainer) and decoupled from code to enable rapid prototyping and modification. Data derivatives are organized with the Brain Imaging Data Structure (BIDS) to ensure that they are findable, accessible, interoperable, and reusable following FAIR principles. The pipeline takes full advantage of HPC resources using the Parsl parallel programming framework, resulting in the creation of connectome datasets of unprecedented size. MaPPeRTrac is publicly available and tested on commercial and scientific hardware, so it can accelerate brain connectome research for a broader user community. MaPPeRTrac is available at: https://github.com/LLNL/mappertrac .

Machine Learning-Driven Multiscale Modeling: Bridging the Scales with a Next-Generation Simulation Infrastructure.

Interdependence across time and length scales is common in biology, where atomic interactions can impact larger-scale phenomenon. Such dependence is especially true for a well-known cancer signaling pathway, where the membrane-bound RAS protein binds an effector protein called RAF. To capture the driving forces that bring RAS and RAF (represented as two domains, RBD and CRD) together on the plasma membrane, simulations with the ability to calculate atomic detail while having long time and large length- scales are needed. The Multiscale Machine-Learned Modeling Infrastructure (MuMMI) is able to resolve RAS/RAF protein-membrane interactions that identify specific lipid-protein fingerprints that enhance protein orientations viable for effector binding. MuMMI is a fully automated, ensemble-based multiscale approach connecting three resolution scales: (1) the coarsest scale is a continuum model able to simulate milliseconds of time for a 1 µm2 membrane, (2) the middle scale is a coarse-grained (CG) Martini bead model to explore protein-lipid interactions, and (3) the finest scale is an all-atom (AA) model capturing specific interactions between lipids and proteins. MuMMI dynamically couples adjacent scales in a pairwise manner using machine learning (ML). The dynamic coupling allows for better sampling of the refined scale from the adjacent coarse scale (forward) and on-the-fly feedback to improve the fidelity of the coarser scale from the adjacent refined scale (backward). MuMMI operates efficiently at any scale, from a few compute nodes to the largest supercomputers in the world, and is generalizable to simulate different systems. As computing resources continue to increase and multiscale methods continue to advance, fully automated multiscale simulations (like MuMMI) will be commonly used to address complex science questions.

Multiple Mutations Associated with Emergent Variants Can Be Detected as Low-Frequency Mutations in Early SARS-CoV-2 Pandemic Clinical Samples.

Genetic analysis of intra-host viral populations provides unique insight into pre-emergent mutations that may contribute to the genotype of future variants. Clinical samples positive for SARS-CoV-2 collected in California during the first months of the pandemic were sequenced to define the dynamics of mutation emergence as the virus became established in the state. Deep sequencing of 90 nasopharyngeal samples showed that many mutations associated with the establishment of SARS-CoV-2 globally were present at varying frequencies in a majority of the samples, even those collected as the virus was first detected in the US. A subset of mutations that emerged months later in consensus sequences were detected as subconsensus members of intra-host populations. Spike mutations P681H, H655Y, and V1104L were detected prior to emergence in variant genotypes, mutations were detected at multiple positions within the furin cleavage site, and pre-emergent mutations were identified in the nucleocapsid and the envelope genes. Because many of the samples had a very high depth of coverage, a bioinformatics pipeline, "Mappgene", was established that uses both iVar and LoFreq variant calling to enable identification of very low-frequency variants. This enabled detection of a spike protein deletion present in many samples at low frequency and associated with a variant of concern.

SARS-CoV-2 Monitoring in Wastewater Reveals Novel Variants and Biomarkers of Infection.

Wastewater-based epidemiology (WBE) is a popular tool for the early indication of community spread of infectious diseases. WBE emerged as an effective tool during the COVID-19 pandemic and has provided meaningful information to minimize the spread of infection. Here, we present a combination of analyses using the correlation of viral gene copies with clinical cases, sequencing of wastewater-derived RNA for the viral mutants, and correlative analyses of the viral gene copies with the bacterial biomarkers. Our study provides a unique platform for potentially using the WBE-derived results to predict the spread of COVID-19 and the emergence of new variants of concern. Further, we observed a strong correlation between the presence of SARS-CoV-2 and changes in the microbial community of wastewater, particularly the significant changes in bacterial genera belonging to the families of Lachnospiraceae and Actinomycetaceae. Our study shows that microbial biomarkers could be utilized as prediction tools for future infectious disease surveillance and outbreak responses. Overall, our comprehensive analyses of viral spread, variants, and novel bacterial biomarkers will add significantly to the growing body of literature on WBE and COVID-19.

Antipsychotic factors related to time to competency for forensic inpatients in a state psychiatric facility.

Introduction: A defendant who is deemed incompetent to stand trial may go through competency restoration consisting of mental health treatment and legal education. Antipsychotics are often used in treatment; however, there is little data examining their role. Methods: This retrospective study included subjects opined competent to stand trial from July 2016 to February 2020 and prescribed an antipsychotic. The primary outcome was difference in time to competency between antipsychotics. Secondary outcomes included difference in time to competency between groups of antipsychotics, difference in length of stay after opined competent based on medication availability in jail, individual antipsychotics, and formulations. Results: There were 117 subjects included for analysis. There were no differences in time to competency between individual antipsychotics, first- and second-generation antipsychotics, or formulations. Length of stay after opined competent was significantly longer for subjects who were prescribed a long-acting injectable antipsychotic (103 days vs 56 days), who were not able to receive their antipsychotic in jail (104 days vs 54 days), or who were prescribed any formulation of paliperidone compared with olanzapine (88 days vs 35 days). Discussion: Since there were no differences in time to competency, patient-specific factors should be used to choose an agent for competency restoration. Length of stay differences are likely related to the antipsychotic access differences between jails and state psychiatric facilities. Therefore, policies related to antipsychotic access should better align between state psychiatric facilities and jails to improve the capacity of the system and provide better care.

The Case for Optimized Edge-Centric Tractography at Scale.

The anatomic validity of structural connectomes remains a significant uncertainty in neuroimaging. Edge-centric tractography reconstructs streamlines in bundles between each pair of cortical or subcortical regions. Although edge bundles provides a stronger anatomic embedding than traditional connectomes, calculating them for each region-pair requires exponentially greater computation. We observe that major speedup can be achieved by reducing the number of streamlines used by probabilistic tractography algorithms. To ensure this does not degrade connectome quality, we calculate the identifiability of edge-centric connectomes between test and re-test sessions as a proxy for information content. We find that running PROBTRACKX2 with as few as 1 streamline per voxel per region-pair has no significant impact on identifiability. Variation in identifiability caused by streamline count is overshadowed by variation due to subject demographics. This finding even holds true in an entirely different tractography algorithm using MRTrix. Incidentally, we observe that Jaccard similarity is more effective than Pearson correlation in calculating identifiability for our subject population.

Energetics of Swimming With Hand Paddles of Different Surface Areas.

ABSTRACT: Crocker, GH, Moon, JF, Nessler, JA, and Newcomer, SC. Energetics of swimming with hand paddles of different surface areas. J Strength Cond Res 35(1): 205-211, 2021-Hand paddles are one of the most common training aids used by the competitive swimmer, yet little is known regarding how hand paddle surface area affects the metabolic cost of transport (COT) while swimming. The purpose of this study was to determine how altering hand paddle size affects energy use during submaximal, front-crawl (i.e., freestyle) swimming. Twenty-six proficient, adult swimmers (13 men and 13 women) completed six 3-minute trials in a flume at a constant pace (102 cm·s-1; 1:38 per 100 m). Trials were performed in random order, using 1 of 5 pairs of hand paddles of different sizes or no paddles at all. Paddle surface areas were 201, 256, 310, 358, and 391 cm2 per hand. Without paddles, COT, arm cadence, and distance per stroke were 7.87 ± 1.32 J·kg-1·m-1, 29.4 ± 4.9 min-1, and 2.13 ± 0.34 m, which corresponded to a rate of oxygen consumption (V̇o2) of 23.3 ± 3.7 ml·kg-1·min-1 and a heart rate (HR) of 118 ± 17 b·min-1. The use of larger hand paddles decreased COT, cadence, V̇o2, and HR and increased distance traveled per stroke (all p < 0.001). However, the magnitude of the change of COT decreased as paddle size increased, indicating diminishing marginal return with increasing paddle surface area. The largest sized paddles increased COT per stroke compared with swimming without paddles (p = 0.001). Therefore, results from this study suggest that an optimal hand paddle size exists (210-358 cm2) for proficient, adult swimmers, which reduces COT without increasing COT per stroke.

Characterization of Activity and Cardiovascular Responses During Surfing in Recreational Male Surfers Between the Ages of 18 and 75 Years Old.

Participation in surfing has evolved to include all age groups. Therefore, the purpose of this study was to determine whether activity levels and cardiovascular responses to surfing change with age. Surfing time and heart rate (HR) were measured for the total surfing session and within each activity of surfing (paddling, sitting, wave riding, and miscellaneous). Peak oxygen consumption (VO2peak) was also measured during laboratory-based simulated surfboard paddling on a modified swim bench ergometer. VO2peak decreased with age during simulated paddling (r = -.455, p < .001, n = 68). Total time surfing (p = .837) and time spent within each activity of surfing did not differ with age (n = 160). Mean HR during surfing significantly decreased with age (r = -.231, p = .004). However, surfing HR expressed as a percent of age-predicted maximum increased significantly with age. Therefore, recreational surfers across the age spectrum are achieving intensities and durations that are consistent with guidelines for cardiovascular health.

Vitamin D status of psychiatric inpatients at a community teaching hospital in the Midwest.

BACKGROUND: Vitamin D deficiency is a re-emerging epidemic in North America. It is increasingly linked to the pathology of cognition and mental illness and is also common in psychiatric patients. AIMS: This study was designed to determine the prevalence of vitamin D deficiency among psychiatric inpatients in Kansas City, to explore the association between vitamin D status and clinical characteristics, and to identify the association of medical problems related to vitamin D deficiency in mental illness. METHODS: In this descriptive study we recruited 52 psychiatric inpatients at a community teaching hospital in Kansas City between August and November 2013. A vitamin D-deficient state was defined as serum 25-hydroxyvitamin D (25-(OH) D) level ≤ 20 ng/mL. In addition to descriptive statistics, the Student t-test and Pearson test were used in the study. RESULTS: A total of 15 patients (28.8%) were classified as deficient, 20 patients (38.5%) had an insufficiency, 17 patients (32.7%) were categorized as sufficient. Interestingly, there was a statistically significant difference in 25-(OH) D levels between African Americans and Caucasians (t = -2.216, p = 0.03) but no significant relationship between 25-(OH) D level and gender, major psychiatric diagnoses, type 2 diabetes mellitus or obesity. There was also no correlation between 25-(OH) D level and age, body mass index or haemoglobin A1C. CONCLUSIONS: Low 25-(OH) D level was found in a high percentage of psychiatric inpatients in Kansas City. Screening for vitamin D deficiency could be a routine work-up for psychiatric inpatients. Vitamin D supplement for African American inpatients with low vitamin D levels could be considered.

Investigation of the binding pocket of human hematopoietic prostaglandin (PG) D2 synthase (hH-PGDS): a tale of two waters.

The inhibition of hH-PGDS has been proposed as a potential target for the development of anti-allergic and anti-inflammatory drugs. Herein we describe our investigation of the binding pocket of this important enzyme and our observation that two water molecules bind to our inhibitors and the enzyme. A series of compounds were prepared to the probe the importance of the water molecules in determining the binding affinity of the inhibitors to the enzyme. The study provides insight into the binding requirements for the design of potent hH-PGDS inhibitors.

Design, synthesis, and biological evaluation of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent, orally active, brain penetrant inhibitor of phosphodiesterase 5 (PDE5).

We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials.

Discovery of an Oral Potent Selective Inhibitor of Hematopoietic Prostaglandin D Synthase (HPGDS).

Hematopoietic prostaglandin D synthase (HPGDS) is primarly expressed in mast cells, antigen-presenting cells, and Th-2 cells. HPGDS converts PGH2 into PGD2, a mediator thought to play a pivotal role in airway allergy and inflammatory processes. In this letter, we report the discovery of an orally potent and selective inhibitor of HPGDS that reduces the antigen-induced response in allergic sheep.

Optimization of the aminopyridopyrazinones class of PDE5 inhibitors: discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one.

We describe efforts to improve the pharmacokinetic profile of the aminopyridopyrazinone class of PDE5 inhibitors. These efforts led to the discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent and selective inhibitor of PDE5 with an excellent PK profile.

Investigation of aminopyridiopyrazinones as PDE5 inhibitors: Evaluation of modifications to the central ring system.

Efforts to improve the potency and physical properties of the aminopyridiopyrazinone class of PDE5 inhibitors through modification of the core ring system are described. Five new ring systems are evaluated and features that impart improved potency and improved solubility are delineated.

Identification, synthesis and SAR of amino substituted pyrido[3,2b]pyrazinones as potent and selective PDE5 inhibitors.

A new class of potent and selective PDE5 inhibitors is disclosed. Guided by X-ray crystallographic data, optimization of an HTS lead led to the discovery of a series of 2-aryl, (N8)-alkyl substituted-6-aminosubstituted pyrido[3,2b]pyrazinones which show potent inhibition of the PDE5 enzyme. Synthetic details and some structure-activity relationships are also presented.

Potent and selective isophthalamide S2 hydroxyethylamine inhibitors of BACE1.

The design and synthesis of a novel series of potent BACE1 hydroxyethylamine inhibitors. These inhibitors feature hydrogen bonding substituents at the C-5 position of the isophthalamide ring with improved selectivity over cathepsin D.

Design, synthesis, and crystal structure of hydroxyethyl secondary amine-based peptidomimetic inhibitors of human beta-secretase.

The design and synthesis of a novel series of potent and cell permeable peptidomimetic inhibitors of the human beta-secretase (BACE) are described. These inhibitors feature a hydroxyethyl secondary amine isostere and a novel aromatic ring replacement for the C-terminus. The crystal structure of BACE in complex with this hydroxyethyl secondary amine isostere inhibitor is also presented.

Design of potent inhibitors of human beta-secretase. Part 2.

We describe an optimized series of acyclic hydroxyethylamine transition state isosteres of beta-secretase that incorporates a variety of P(2) side chains that yield potent inhibitors with excellent cellular activity. A 2.2A crystal structure of compound 13 is shown.

Design of potent inhibitors of human beta-secretase. Part 1.

We describe a novel series of potent inhibitors of human beta-secretase. These compounds possess the hydroxyethyl amine transition state isostere. A 2.5A crystal structure of inhibitor 32 bound to BACE is provided.

Design and synthesis of hydroxyethylene-based peptidomimetic inhibitors of human beta-secretase.

The hydroxyethylene (HE) transition state isostere was developed as a scaffold to provide potent, small molecule inhibitors of human beta-secretase (BACE). The previous work on the statine series proved critical to the discovery of HE structure-activity relationships. Compound 20 with the N-terminal isophthalamide proved to be the most potent HE inhibitor (IC(50) = 30 nM) toward BACE. Unlike the statine series, we identified HE inhibitors without carboxylic acids on the C terminus, leading to enhanced cell penetration and making them attractive candidates for further drug development in Alzheimer's disease.