bluuebunny/crossref_metadata_2025_split huggingface dataset:
hopsy - a methods marketplace for convex polytope sampling in Python
Authors: Paul Richard D. , Jadebeck Johann F. , Stratmann Anton , Wiechert Wolfgang , Nöh Katharina 
Published: December 2023

AbstractSummaryEffective collaboration between developers of Bayesian inference methods and users is key to advance our quantitative understanding of biosystems. We here presenthopsy, a versatile open source platform designed to provide convenient access to powerful Markov chain Monte Carlo sampling algorithms tailored to models defined on convex polytopes (CP). Based on the high-performance C++ sampling libraryHOPS,hopsyinherits its strengths and extends its functionalities with the accessibility of the Python programming language. A versatile plugin-mechanism enables seamless integration with domain-specific models, providing method developers with a framework for testing, benchmarking, and distributing CP samplers to approach real-world inference tasks. We showcasehopsyby solving common and newly composed domain-specific sampling problems, highlighting important design choices. By likeninghopsyto a marketplace, we emphasize its role in bringing together users and developers, where users get access to state-of-the-art methods, and developers contribute their own innovative solutions for challenging domain-specific inference problems.Availability and ImplementationSources, documentation and a continuously updated list of sampling algorithms are available athttps://jugit.fz-juelich.de/IBG-1/ModSim/hopsy, with Linux, Windows and MacOS binaries athttps://pypi.org/project/hopsy/.Contactk.noeh@fz-juelich.de
Comprehensive analysis of the functional impact of single nucleotide variants of humanCHEK2
Authors: McCarthy-Leo Claire E. , Brush George S. , Pique-Regi Roger , Luca Francesca , Tainsky Michael A. , Finley Russell L. 
Published: December 2023

AbstractLoss of function mutations in the checkpoint kinase geneCHEK2are associated with increased risk of breast and other cancers. Most of the 3,188 unique amino acid changes that can result from non-synonymous single nucleotide variants (SNVs) ofCHEK2, however, have not been tested for their impact on the function of theCHEK2-enocded protein (CHK2). One successful approach to testing the function of variants has been to test for their ability to complement mutations in the yeast ortholog ofCHEK2,RAD53. This approach has been used to provide functional information on over 100CHEK2SNVs and the results align with functional assays in human cells and known pathogenicity. Here we tested all but two of the 4,887 possible SNVs in theCHEK2open reading frame for their ability to complementRAD53mutants using a novel high throughput technique. Among the non-synonymous changes, 770 were damaging to protein function while 2,417 were tolerated. The results correlate well with previous structure and function data and provide a first or additional functional assay for all the variants of uncertain significance identified in clinical databases. Combined, this approach can be used to help predict the pathogenicity ofCHEK2variants of uncertain significance that are found in patient screening and could be applied to other cancer risk genes.
Harnessing Bilayer Biomaterial Delivery of FTY720 as an Immunotherapy to Accelerate Oral Wound Healing
Authors: Toma Afra I. , Shah Daniel , Roth Daniela , Oliver Piña Jeremie , Hymel Lauren , Turner Thomas , Kamalakar Archana , Liu Ken , Bartsch Perry , Jacobs Leon , D’Souza Rena , Liotta Dennis , Botchwey Edward , Willett Nick J. , Goudy Steven L. 
Published: December 2023

AbstractOrofacial clefts are the most common craniofacial congenital anomaly. Following cleft palate repair, up to 60% of surgeries have wound healing complications leading to oronasal fistula (ONF), a persistent connection between the roof of the mouth and the nasal cavity. The current gold standard methods for ONF repair use human allograft tissues; however, these procedures have risks of graft infection and/or rejection, requiring surgical revisions. Immunoregenerative therapies present a novel alternative approach to harness the body’s immune response and enhance the wound healing environment. We utilized a repurposed FDA-approved immunomodulatory drug, FTY720, to reduce the egress of lymphocytes and induce immune cell fate switching toward pro-regenerative phenotypes. Here, we engineered a bilayer biomaterial system using Tegaderm™, a liquid-impermeable wound dressing, to secure and control the delivery of FTY720- nanofiber scaffolds (FTY720-NF). We optimized release kinetics of the bilayer FTY720-NF to sustain drug release for up to 7d with safe, efficacious transdermal absorption and tissue biodistribution. Through comprehensive immunophenotyping, our results illustrate a pseudotime pro-regenerative state transition in recruited hybrid immune cells to the wound site. Additional histological assessments established a significant difference in full thickness ONF closure in mice on Day 7 following treatment with bilayer FTY720-NF, compared to controls. These findings demonstrate the utility of immunomodulatory strategies for oral wound healing, better positing the field to develop more efficacious treatment options for pediatric patients.One Sentence SummaryLocal delivery of bilayer FTY720-nanofiber scaffolds in an ONF mouse model promotes complete wound closure through modulation of pro-regenerative immune and stromal cells.
Atomic context-conditioned protein sequence design using LigandMPNN
Authors: Dauparas Justas , Lee Gyu Rie , Pecoraro Robert , An Linna , Anishchenko Ivan , Glasscock Cameron , Baker D. 
Published: December 2023

AbstractProtein sequence design in the context of small molecules, nucleotides, and metals is critical to enzyme and small molecule binder and sensor design, but current state-of-the-art deep learning-based sequence design methods are unable to model non-protein atoms and molecules. Here, we describe a deep learning-based protein sequence design method called LigandMPNN that explicitly models all non-protein components of biomolecular systems. LigandMPNN significantly outperforms Rosetta and ProteinMPNN on native backbone sequence recovery for residues interacting with small molecules (63.3% vs. 50.4% & 50.5%), nucleotides (50.5% vs. 35.2% & 34.0%), and metals (77.5% vs. 36.0% & 40.6%). LigandMPNN generates not only sequences but also sidechain conformations to allow detailed evaluation of binding interactions. Experimental characterization demonstrates that LigandMPNN can generate small molecule and DNA-binding proteins with high affinity and specificity.One-sentence summaryWe present a deep learning-based protein sequence design method that allows explicit modeling of small molecule, nucleotide, metal, and other atomic contexts.
Machine learning reveals the diversity of human 3D chromatin contact patterns
Authors: Gilbertson Erin N. , Brand Colin M. , McArthur Evonne , Rinker David C. , Kuang Shuzhen , Pollard Katherine S. , Capra John A. 
Published: December 2023

AbstractUnderstanding variation in chromatin contact patterns across human populations is critical for interpreting non-coding variants and their ultimate effects on gene expression and phenotypes. However, experimental determination of chromatin contacts at a population-scale is prohibitively expensive. To overcome this challenge, we develop and validate a machine learning method to quantify the diversity 3D chromatin contacts at 2 kilobase resolution from genome sequence alone. We then apply this approach to thousands of diverse modern humans and the inferred human-archaic hominin ancestral genome. While patterns of 3D contact divergence genome-wide are qualitatively similar to patterns of sequence divergence, we find that 3D divergence in local 1-megabase genomic windows does not follow sequence divergence. In particular, we identify 392 windows with significantly greater 3D divergence than expected from sequence. Moreover, 26% of genomic windows have rare 3D contact variation observed in a small number of individuals. Usingin silicomutagenesis we find that most sequence changes to do not result in changes to 3D chromatin contacts. However in windows with substantial 3D divergence, just one or a few variants can lead to divergent 3D chromatin contacts without the individuals carrying those variants having high sequence divergence. In summary, inferring 3D chromatin contact maps across human populations reveals diverse contact patterns. We anticipate that these genetically diverse maps of 3D chromatin contact will provide a reference for future work on the function and evolution of 3D chromatin contact variation across human populations.
Unsupervised mapping of causal relations between brain and behavior
Authors: Wahle Iman A. , Adolphs Ralph , Tranel Daniel , Boes Aaron , Eberhardt Frederick 
Published: December 2023

AbstractStudies of patients with focal brain lesions provided the historical foundation for cognitive neuroscience, but how to identify a precise mapping between specific brain regions and the cognitive variables affected remains unclear. The challenge lies both in identifying anatomical regions wherein lesions have a shared causal effect, as well as in the precise delineation of the behavioral outcome. Currently, either the relevant brain region or the dimensionality of the behavior being mapped are pre-specified by the investigators rather than both being informed by optimal brain-behavior relationships. Here we apply a novel data-driven causal aggregation algorithm, Causal Feature Learning (CFL) to tackle this challenge in 520 individuals with focal brain lesions. CFL simultaneously constructs macro-level summaries of the spatial distribution of brain lesions and the itemized responses on psychometric tests to optimally characterize the causal brain-behavior relationships. Focusing on the domains of language, visuospatial ability, and depression, we recapitulate established findings, provide new and more precise anatomical results, and present an aggregation of item-wise data that provides an empirical test of extant behavioral scores and can be used to identify novel, psychologically meaningful factors. Future work could use our approach to construct entirely new psychometric variables that might cut across established categories.
Assessing Protein Surface-Based Scoring for Interpreting Genomic Variants
Authors: Dsouza Nikita R. , Haque Neshatul , Tripathi Swarnendu , Zimmermann Michael T. 
Published: December 2023

AbstractClinical genomics sequencing is rapidly expanding the number of variants that need to be functionally elucidated. Interpreting genetic variants (i.e., mutations) usually begins by identifying how they affect protein-coding sequences. Still, the 3D protein molecule is rarely considered for large-scale variant analysis, nor for their effects on how proteins interact with each other and their environment. We propose a standardized approach to scoring protein surface property changes as a new dimension for functionally and mechanistically interpreting genomic variants. Further, it directs hypothesis generation for functional genomics research to learn more about the encoded protein’s function. We developed a novel method leveraging 3D structures and time-dependent simulations to score and statistically evaluate protein surface property changes. We evaluated positive controls composed of 8 thermophilic versus mesophilic orthologs and variants that experimentally change protein solubility, which all showed large and statistically significant differences in charge distribution (p<0.01). We scored static 3D structures and dynamic ensembles for 43 independent variants (23 pathogenic and 20 uninterpreted) across four proteins. Focusing on the potassium ion channel, KCNK9, average local surface potential shifts were 0.41 kBT/ec with an average p-value of 1×10−2. In contrast, dynamic ensemble shifts averaged 1.15 kBT/ec and an average p-value of 1×10−5, enabling the identification of changes far from mutated sites. This study demonstrates that an objective assessment of how mutations affect electrostatic distributions of protein surfaces can aid in interpreting genomic variants discovered through clinical genomics sequencing.
A computational procedure for predicting excipient effects on protein-protein affinities
Authors: Dignon Gregory L. , Dill Ken A. 
Published: December 2023

AbstractProtein-protein interactions lie at the center of much biology and are a challenge in formulating biological drugs such as antibodies. A key to mitigating protein association is to use small molecule additives, i.e. excipients that can weaken protein-protein interactions. Here, we develop a computationally efficient model for predicting the viscosity-reducing effect of different excipient molecules by combining atomic-resolution MD simulations, binding polynomials and a thermodynamic perturbation theory. In a proof of principle, this method successfully rank orders four types of excipients known to reduce the viscosity of solutions of a particular monoclonal antibody. This approach appears useful for predicting effects of excipients on protein association and phase separation, as well as the effects of buffers on protein solutions.TOC Graphic
Brood care in shell-dwelling cichlids is timed by independent maternal and larval clocks
Authors: Parker Ash V , Stemmer Manuel , Grätsch Swantje , Dorigo Alessandro , Ramirez Oriolson Rodriguez , Adel Abdelrahman , Jordan Alex , Baier Herwig 
Published: December 2023

AbstractSuccessful brood care requires a finely tuned interplay between caregiving parent and offspring. Cichlids are a diverse group of teleost fish known for their extensive parental care of altricial young. FemaleLamprologus ocellatuslay their eggs in the protective confines of an abandoned snail shell, where they raise them to free-swimming larvae. Here we investigated whether the transition to larval independence is driven by the behavior of the mother, the offspring, or an interaction between the two. Using 3D printed shells with a window, we were able to observe the behavior of both mother and offspring inside the nest using automated object detection and tracking. We found that, once hatched, the larvae remain in the deep chambers of the shell, and at 9 dpf, actively emerge from the shell during the day. An inversion of larval phototactic behavior from dark- to light-seeking leads up to this emergence. Removal of the mother causes premature emergence of the larvae by a few days. The natural schedule (emergence at 9 dpf) is restored if the larvae are supplied with fresh water in the mother’s absence. In cross-fostering experiments, we found that swapping out the mother’s own clutch for older larvae forces a delay in emergence, as the foster mother prevents the larvae from leaving at 9 dpf. We conclude that larval and maternal behavior are each controlled by independent internal clocks, which, although normally synchronized, can be experimentally manipulated and brought into conflict. This study has thus revealed an innate sequence of behavioral adaptations that orchestrate brood care in shell-dwelling cichlids.
Visualizing PIEZO1 Localization and Activity in hiPSC-Derived Single Cells and Organoids with HaloTag Technology
Authors: Bertaccini Gabriella A. , Casanellas Ignasi , Evans Elizabeth L. , Nourse Jamison L. , Dickinson George D. , Liu Gaoxiang , Seal Sayan , Ly Alan T. , Holt Jesse R. , Wijerathne Tharaka D. , Yan Shijun , Hui Elliot E. , Lacroix Jerome J. , Panicker Mitradas M. , Upadhyayula Srigokul , Parker Ian , Pathak Medha M. 
Published: December 2023

AbstractPIEZO1 is critical to numerous physiological processes, transducing diverse mechanical stimuli into electrical and chemical signals. Recent studies underscore the importance of visualizing endogenous PIEZO1 activity and localization to understand its functional roles. To enable physiologically and clinically relevant studies on human PIEZO1, we genetically engineered human induced pluripotent stem cells (hiPSCs) to express a HaloTag fused to endogenous PIEZO1. Combined with advanced imaging, our chemogenetic platform allows precise visualization of PIEZO1 localization dynamics in various cell types. Furthermore, the PIEZO1-HaloTag hiPSC technology facilitates the non-invasive monitoring of channel activity across diverse cell types using Ca2+-sensitive HaloTag ligands, achieving temporal resolution approaching that of patch clamp electrophysiology. Finally, we used lightsheet imaging of hiPSC-derived neural organoids to achieve molecular scale imaging of PIEZO1 in three-dimensional tissue organoids. Our advances offer a novel platform for studying PIEZO1 mechanotransduction in human cells and tissues, with potential for elucidating disease mechanisms and targeted therapeutic development.
Combining transcutaneous spinal stimulation and functional electrical stimulation increases force generated by lower limbs: When more is more
Authors: Steele Alexander G. , Vette Albert H. , Martin Catherine , Masani Kei , Sayenko Dimitry G. 
Published: December 2023

AbstractBackgroundTranscutaneous Spinal Stimulation (TSS) has been shown to promote activation of the lower limb and trunk muscles and is being actively explored for improving the motor outcomes of people with neurological conditions. However, individual responses to TSS vary, and often the muscle responses are insufficient to produce enough force for self-supported standing. Functional electrical stimulation (FES) can activate individual muscles and assist in closing this functional gap, but it introduces questions regarding timing between modalities.MethodsTo assess the effects of TSS and FES on force generation, ten neurologically intact participants underwent (1) TSS only, (2) FES only, and (3) TSS + FES. TSS was delivered using four electrodes placed at T10–T11 through the L1–L2 intervertebral spaces simultaneously, while FES was delivered to the skin over the right knee extensors and plantarflexors. For all conditions, TSS and FES were delivered using three 0.5 ms biphasic square-wave pulses at 15 Hz. During the TSS + FES condition, timing between the two modalities was adjusted in increments of ¼ time between pulses (16.5 ms).ResultsWhen TSS preceded FES, a larger force production was observed. We also determined several changes in muscle activation amplitude at different relative stimulus intervals, which help characterize our finding and indicate the facilitating and inhibitory effects of the modalities.ConclusionsUtilizing a delay ranging from 15 to 30 ms between stimuli resulted in higher mean force generation in both the knee and ankle joints, regardless of the selected FES location (Average; knee: 112.0%, ankle: 103.1%).
LinkedOXTRVariants Are Associated with Social Behavior Differences in Bonobos (Pan paniscus)
Authors: Skiba Sara A. , Hansen Alek , McCall Ryan , Byers Azeeza , Waldron Sarah , Epping Amanda J. , Taglialatela Jared P. , Hudson Martin L. 
Published: December 2023

AbstractSingle-nucleotide polymorphisms (SNPs) in forkhead box protein P2 (FOXP2) and oxytocin receptor (OXTR) genes have been associated with linguistic and social development in humans, as well as to symptom severity in autism spectrum disorder (ASD). Studying biobehavioral mechanisms in the species most closely related to humans can provide insights into the origins of human communication, and the impact of genetic variation on complex behavioral phenotypes. Here, we aimed to determine if bonobos (Pan paniscus) exhibit individual variation inFOXP2andOXTRloci that have been associated with human social development and behavior. Although the ASD-related variants were reported in 13-41% of the human population, we did not find variation at these loci in our sample of 13 bonobos. However, we did identify a novel variant in bonoboFOXP2, as well as four novel variants in bonoboOXTRthat were 17-184 base pairs from the human ASD variants. We also found the same linked, homozygous allelic combination across the 4 novelOXTRSNPs (homozygous TGTC) in 6 of the 13 bonobos, indicating that this combination may be under positive selection. When comparing the combinedOXTRgenotypes, we found significant group differences in social behavior; bonobos with zero copies of the TGTC combination were less social than bonobos with one copy of the TGTC combination. Taken together, our findings suggest that theseOXTRvariants may influence individual-level social behavior in bonobos and support the notion that linked genetic variants are promising risk factors for social communication deficits in humans.
Human cerebrospinal fluid single exosomes in Parkinson’s and Alzheimer’s diseases
Authors: Yakabi Koya , Berson Eloise , Montine Kathleen S. , Bendall Sean C. , MacCoss Michael J. , Poston Kathleen L. , Montine Thomas J. 
Published: December 2023

ABSTRACTExosomes are proposed to be important in the pathogenesis of prevalent neurodegenerative diseases. We report the first application of solid-state technology to perform multiplex analysis of single exosomes in human cerebrospinal fluid (CSF) obtained from the lumbar sac of people diagnosed with Alzheimer’s disease dementia (ADD, n=30) or Parkinson’s disease dementia (PDD, n=30), as well as age-matched health controls (HCN, n=30). Single events were captured with mouse monoclonal antibodies to one of three different tetraspanins (CD9, CD63, or CD81) or with mouse (M) IgG control, and then probed with fluorescently labeled antibodies to prion protein (PrP) or CD47 to mark neuronal or presynaptic origin, as well as ADD- and PDD-related proteins: amyloid beta (Aβ), tau, α-synuclein, and Apolipoprotein (Apo) E. Data were collected only from captured events that were within the size range of 50 to 200 nm. Exosomes were present at approximately 100 billion per mL human CSF and were similarly abundant for CD9+ and CD81+ events, but CD63+ were only 22% to 25% of CD9+ (P<0.0001) or CD81+ (P<0.0001) events. Approximately 24% of CSF exosomes were PrP+, while only 2% were CD47+. The vast majority of exosomes were surface ApoE+, and the number of PrP-ApoE+ (P<0.001) and PrP+ApoE+ (P<0.01) exosomes were significantly reduced in ADD vs. HCN for CD9+ events only. Aβ, tau, and α-synuclein were not detected on the exosome surface or in permeabilized cargo. These data provide new insights into single exosome molecular features and highlight reduction in the CSF concentration of ApoE+ exosomes in patients with ADD.