bluuebunny/crossref_metadata_2025 huggingface dataset:
Proximity to Boundaries Reveals Spatial Context Representation in Human Hippocampal CA1
Authors: Geva-Sagiv Maya , Dimsdale-Zucker Halle R. , Williams Ashley B. , Ranganath Charan
Published: April 2023

Recollection of real-world events is often accompanied by a sense of being in the place where the event transpired. Convergent evidence suggests the hippocampus plays a key role in supporting episodic memory by associating information with the time and place it was originally encountered. This representation is reinstated during memory retrieval. However, little is known about the roles of different subfields of the human hippocampus in this process. Research in humans and non-human animal models have suggested that spatial environmental boundaries have a powerful influence on spatial and episodic memory, as well as hippocampal representations of contexts and events. Here, we used high-resolution fMRI to investigate how boundaries influence hippocampal activity patterns during the recollection of objects encountered in different spatial contexts. During the encoding phase, participants viewed objects once in a naturalistic virtual reality task, in which they passively explored two rooms in one of two houses. Following the encoding phase, participants were scanned while they recollected items in the absence of any spatial contextual information. Our behavioral results demonstrated that spatial context memory was enhanced for objects encountered near a boundary. Activity patterns in CA1 carried information about the spatial context associated with each of these boundary items. Exploratory analyses revealed that memory for the room in which each object was studied was correlated with the fidelity of retrieved spatial context representations in anterior parahippocampal cortex and subiculum. Our results highlight the privileged role of boundaries in CA1 and suggest more generally a close relationship between memory for spatial contexts and representations in the hippocampus and parahippocampal region.
Novel protein interaction network of human calcitonin receptor-like receptor revealed by label-free quantitative proteomics
Authors: Manolis Dimitrios , Hasan Shirin , Ettelaie Camille , Maraveyas Anthony , O’Brien Darragh P. , Kessler Benedikt M. , Kramer Holger , Nikitenko Leonid L.
Published: April 2023

Background

G protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) signalling is implicated in skin-related and cardiovascular diseases, migraine and cancer. However, beyond its agonists and receptor activity-modifying proteins (RAMPs), proteins which bind to CLR and define its properties in primary human cells remain insufficiently understood.

Aim

We aimed to profile the CLR interactome in primary human dermal lymphatic endothelial cells (HDLEC), where this GPCR is expressed.

Materials and methods

Immunoprecipitation (IP) of core- and terminally-glycosylated CLR from primaryin vitrocultured HDLEC was conducted using rabbit polyclonal anti-human CLR serum (with pre- immune serum serving as a control) and confirmed by immunoblotting. Total HDLEC and co-immunoprecipitated CLR proteomes were analysed by label-free quantitative nano-liquid chromatography-tandem mass spectrometry (nLC-MS/MS). Quantitativein-situproximity ligation assay (PLA) using ZEISS LSM 710 confocal microscope and ZEN Blue 3.0 and Image J software was performed to confirm nLC-MS/MS findings. All experiments were repeated at least three times (biological replicates). For statistical analysis of PLA data, distribution was analysed using Shapiro-Wilk normality test followed by an unpairedt-test or Mann-Whitney test with ap-value of ≤0.05 interpreted as significant. For MS data of CLR IP samples, statistical analysis was performed usingt-test with a permutation-based false discovery rate (FDR)-adjustedp-value of ≤0.006 interpreted as significant.

Results

A total of 4,902 proteins were identified and quantified by nLC-MS/MS in primary HDLEC and 46 were co-immunoprecipitated with CLR (p<0.006). Direct interaction with the GPCR was confirmed for five of these by PLA (p<0.01).

Conclusions

This is the first study of its kind to identify novel binding partners of CLR expressed in primary human cells. Our integrative quantitative approach, combining immunoprecipitation of core- and terminally-glycosylated CLR, nLC-MS/MS, and PLA, could be applied in a similar fashion to study its interactome in a variety of human cells and tissues, and its contribution to a range of diseases, where the role of this GPCR is implicated.
Continuous Evaluation of Denoising Strategies in Resting-State fMRI Connectivity Using fMRIPrep and Nilearn
Authors: Wang Hao-Ting , Meisler Steven L , Sharmarke Hanad , Clarke Natasha , Gensollen Nicolas , Markiewicz Christopher J , Paugam François , Thirion Bertrand , Bellec Pierre
Published: April 2023

Reducing contributions from non-neuronal sources is a crucial step in functional magnetic resonance imaging (fMRI) connectivity analyses. Many viable strategies for denoising fMRI are used in the literature, and practitioners rely on denoising benchmarks for guidance in the selection of an appropriate choice for their study. However, fMRI denoising software is an ever-evolving field, and the benchmarks can quickly become obsolete as the techniques or implementations change. In this work, we present a denoising benchmark featuring a range of denoising strategies, datasets and evaluation metrics for connectivity analyses, based on the popular fMRIprep software. The benchmark is implemented in a fully reproducible framework, where the provided research objects enable readers to reproduce or modify core computations, as well as the figures of the article using the Jupyter Book project and the Neurolibre reproducible preprint server (https://neurolibre.org/). We demonstrate how such a reproducible benchmark can be used for continuous evaluation of research software, by comparing two versions of the fMRIprep software package. The majority of benchmark results were consistent with prior literature. Scrubbing, a technique which excludes time points with excessive motion, combined with global signal regression, is generally effective at noise removal. Scrubbing however disrupts the continuous sampling of brain images and is incompatible with some statistical analyses, e.g. auto-regressive modeling. In this case, a simple strategy using motion parameters, average activity in select brain compartments, and global signal regression should be preferred. Importantly, we found that certain denoising strategies behave inconsistently across datasets and/or versions of fMRIPrep, or had a different behavior than in previously published benchmarks. This work will hopefully provide useful guidelines for the fMRIprep users community, and highlight the importance of continuous evaluation of research methods. Our reproducible benchmark infrastructure will facilitate such continuous evaluation in the future, and may also be applied broadly to different tools or even research fields.
Kinetic investigation reveals an HIV-1 Nef-dependent increase in AP-2 recruitment and productivity at endocytic sites
Authors: Iwamoto Yuichiro , Ye Anna , Shirazinejad Cyna , Hurley James H. , Drubin David G.
Published: April 2023

Lentiviruses express non-enzymatic accessory proteins whose function is to subvert cellular machinery in the infected host. The HIV-1 accessory protein Nef hijacks clathrin adaptors to degrade or mislocalize host proteins involved in antiviral defenses. Here, we investigate the interaction between Nef and clathrin-mediated endocytosis (CME), a major pathway for membrane protein internalization in mammalian cells, using quantitative live-cell microscopy in genome-edited Jurkat cells. Nef is recruited to CME sites on the plasma membrane, and this recruitment correlates with an increase in the recruitment and lifetime of CME coat protein AP-2 and late-arriving CME protein dynamin2. Furthermore, we find that CME sites that recruit Nef are more likely to recruit dynamin2, suggesting that Nef recruitment to CME sites promotes CME site maturation to ensure high efficiency in host protein downregulation.
Comparative analysis of twoCaenorhabditis eleganskinesins KLP-6 and UNC-104 reveals a common and distinct activation mechanism in kinesin-3
Authors: Kita Tomoki , Chiba Kyoko , Wang Jiye , Nakagawa Atsushi , Niwa Shinsuke
Published: April 2023

Kinesin-3 is a family of microtubule-dependent motor proteins that transport various cargos within the cell. However, the mechanism underlying kinesin-3 activations remains largely elusive. In this study, we compared the biochemical properties of twoCaenorhabditis eleganskinesin-3 family proteins, KLP-6 and UNC-104. Both KLP-6 and UNC-104 are predominantly monomeric in solution. As previously shown for UNC-104, non-processive KLP-6 monomer is converted to a processive motor when artificially dimerized. We present evidence that releasing the autoinhibition is sufficient to trigger dimerization of monomeric UNC-104 at nanomolar concentrations, which results in processive movement of UNC-104 on microtubules, although it has long been thought that enrichment in the phospholipid microdomain on cargo vesicles is required for the dimerization and processive movement of UNC-104. In contrast, KLP-6 remains to be a non-processive monomer even when its autoinhibition is unlocked, suggesting a requirement of other factors for full activation. By examining the differences between KLP-6 and UNC-104, we identified a coiled-coil domain called CC2 that is required for the efficient dimerization and processive movement of UNC-104. Our results suggest a common activation mechanism for kinesin-3 family members, while also highlighting their diversification.
BrainTACO: An Explorable Multi-Scale Multi-Modal Brain Transcriptomic And Connectivity Data Resource
Authors: Ganglberger Florian , Toepfer Markus , Kargl Dominic , Hernandez-Lallement Julien , Lawless Nathan , Fernandez-Albert Francesc , Haubensak Wulf , Bühler Katja
Published: April 2023

Abstract

Exploring the relationships between genes, brain circuitry, and behaviour is accelerated by the joint analysis of a heterogeneous sets form 3D imaging data, anatomical data, and brain networks at varying scales, res-olutions, and modalities. Hence, generating an integrated view, beyond the individual resources’ original purpose, requires the fusion of these data to a common space, and a visualization that bridges the gap across scales. However, despite ever expanding datasets, few plat-forms for integration and exploration of this heterogeneous data exist. To this end, we present theBrainTACO(Brain Transcriptomic And Connectivity Data) resource, a selection of heterogeneous, and multi-scale neurobiological data spatially mapped onto a common, hierarchical reference space, combined via a holistic data integration scheme. To accessBrainTACO, we extendedBrainTrawler, a web-based visual ana-lytics framework for spatial neurobiological data, with comparative visualizations of multiple resources for gene expression dissection of brain networks with an unprecedented coverage. Using this platform, allows to straightforward explore and extract brain data for identifying potential genetic drivers of connectivity in both mice and humans that may contribute to the discovery of dysconnectivity phenotypes. Hence,BrainTACOreduces the need for time-consuming manual data aggregation often required for computational analyses in script based toolboxes, and supports neuroscientists by focusing on leveraging the data instead of preparing it.
Genomic evidence of genuine wild versus admixed olive populations evolving in the same natural environments in western Mediterranean Basin
Authors: Zunino Lison , Cubry Philippe , Sarah Gautier , Mournet Pierre , Bakkali Ahmed El , Aqbouch Laila , Costes Evelyne , Khadari Bouchaib
Published: April 2023

Admixtures between wild animals and plants and their domesticated relatives are widely documented. This can have positive or negative impacts on the evolution of admixed populations in natural environments, yet the phenomenon is still misunderstood in long-lived woody species, contrary to short-lived crops. Wild oliveOlea europaeaL. occurs in the same eco-geographical range as domesticated olive, i.e. the Mediterranean Basin (MB). Moreover, it is an allogamous and anemophilous species whose seeds are disseminated by birds, i.e. factors that drive gene flow between crops and their wild relatives. Here we investigated the genetic structure of western MB wild olive populations in natural environments assuming a homogenous gene pool with limited impact of cultivated alleles, as previously suggested. We used a target sequencing method based on annotated genes from the Farga reference genome to analyze 27 western MB olive tree populations sampled in natural environments in France, Spain and Morocco. We also target sequenced cultivated olive tree accessions from the Worldwide Olive Germplasm Bank of Marrakech and Porquerolles and from an eastern MB wild olive tree population. We combined PCA, sNMF, pairwise Fst and TreeMix and clearly identified genuine wild olive trees throughout their natural distribution range along a north-south gradient including, for the first time, in southern France. However, contrary to our assumption, we highlighted more admixed than genuine wild olive trees. Our results raise questions regarding the admixed population evolution pattern in this environment, which might be facilitated by crop-to-wild gene flow.
YACHT: an ANI-based statistical test to detect microbial presence/absence in a metagenomic sample
Authors: Koslicki David , White Stephen , Ma Chunyu , Novikov Alexei
Published: April 2023

In metagenomics, the study of environmentally associated microbial communities from their sampled DNA, one of the most fundamental computational tasks is that of determining which genomes from a reference database are present or absent in a given sample metagenome. While tools exist to answer this question, all existing approaches to date return point estimates, with no associated confidence or uncertainty associated with it. This has led to practitioners experiencing difficulty when interpreting the results from these tools, particularly for low abundance organisms as these often reside in the “noisy tail” of incorrect predictions. Furthermore, no tools to date account for the fact that reference databases are often incomplete and rarely, if ever, contain exact replicas of genomes present in an environmentally derived metagenome. In this work, we present solutions for these issues by introducing the algorithmYACHT:Yes/NoAnswers toCommunity membership viaHypothesisTesting. This approach introduces a statistical framework that accounts for sequence divergence between the reference and sample genomes, in terms of average nucleotide identity, as well as incomplete sequencing depth, thus providing a hypothesis test for determining the presence or absence of a reference genome in a sample. After introducing our approach, we quantify its statistical power as well as quantify theoretically how this changes with varying parameters. Subsequently, we perform extensive experiments using both simulated and real data to confirm the accuracy and scalability of this approach. Code implementing this approach, as well as all experiments performed, is available athttps://github.com/KoslickiLab/YACHT.
Evolution of ancient satellite DNAs in extant alligators and caimans (Crocodylia, Reptilia)
Authors: Sales-Oliveira Vanessa C. , dos Santos Rodrigo Zeni , Goes Caio Augusto Gomes , Calegari Rodrigo Milan , Garrido-Ramos Manuel A. , Altmanová Marie , Ezaz Tariq , Liehr Thomas , Porto-Foresti Fabio , Utsunomia Ricardo , Cioffi Marcelo de Bello
Published: April 2023

Crocodilians are one of the oldest extant vertebrate lineages, which exhibits a combination of evolutionary success and morphological resilience that have persisted throughout the history of life on Earth. Such an ability to endure over such a long geological time span is of great evolutionary importance. Here, we performed a comprehensive analysis of the satellite DNA diversity of the extant alligators and caimans, making significant progress in our understanding of the evolution of repetitive regions present in ancient genomes. The alligators and caimans displayed a small number of satDNA families (varying between 3 and 13 satDNAs, inA. sinensisandC. latirostris, respectively) as well as little variation both within and between species, highlighting an exceptional long-term conservation of satDNA elements throughout evolution. We also tracked the origin of the ancestral forms of all satDNAs belonging to the common ancestor of Caimaninae and Alligatoridae. Fluorescence in situ experiments showed distinct hybridization patterns for the identical ortholog satDNAs, indicating their inner dynamic evolution. Why, in addition to their previously known low genetic, karyotype, and morphological diversity, have crocodilians altered so little over such a long period of time with such a highly variable genome fraction? We argued that such an “evolutionary package” was likely the outcome of severe demographic declines or founder events and that it represents evolutionary responses to a long-lasting bottleneck history.
Grubraw, a chemogenetic mitochondrial activator, reveals new mechanisms underlying the Warburg effect
Authors: Potekhina Ekaterina S. , Bass Dina Y. , Ivanenko Alexander V. , Moshchenko Alexander A. , Korzhenevskiy Dmitri A. , Shevchenko Evgeniy , Karnaeva Anastasia E. , Zakirova Natalia F. , Ivanov Alexander V. , Shimolina Liubov E. , Shirmanova Marina V. , Lyang Olga V. , Patsap Olga I. , Kudryashova Olga M. , Gazizova Guzel R. , Shagimardanova Elena I. , Gusev Oleg A. , Bogeski Ivan , Nesterenko Alexey M. , Belousov Vsevolod V.
Published: April 2023

Upregulation of glycolysis and downregulation of mitochondrial oxidative phosphorylation, termed as the Warburg effect, are characteristic of tumor cells1,2. Restriction of pyruvate flux into the mitochondrial matrix is one of the major mechanisms underlying this phenomenon3. Warburg-type metabolism is beneficial for rapidly proliferating cells, however its function remains unclear. Moreover, it is unknown what the metabolic consequences of activation of mitochondrial respiration in Warburg-type cancer cells are. Here we created a chemogenetic instrument, Grubraw, that generates pyruvate directly in the mitochondrial matrix bypassing restricted pyruvate influx. In cancer cells, Grubraw-driven pyruvate synthesis in the matrix increased mitochondrial membrane potential, oxygen consumption rate, and the amounts of TCA cycle intermediates. In a mouse model of human melanoma xenografts, chemogenetic activation of mitochondria caused a decrease in tumor growth rate. Surprisingly, cancer cells actively exported pyruvate generated by Grubraw in the mitochondria into the extracellular medium. In addition, activation of mitochondria induced downregulation of transcription of the genes that drive cell cycle progression, cell proliferation and DNA replication. Our results demonstrate that cells with Warburg-type metabolism use previously unknown mechanisms of carbon flux control to dispose of excessive mitochondrial pyruvate, and activation of mitochondria in these cells downregulates cellular proliferation.
Interpretable deep learning approach for extracting cognitive features from hand-drawn images of intersecting pentagons in older adults
Authors: Tasaki Shinya , Kim Namhee , Truty Tim , Zhang Ada , Buchman Aron S , Lamar Melissa , Bennett David A.
Published: April 2023

Hand drawing involves multiple neural systems for planning and precise control of sequential movements, making it a valuable cognitive test for older adults. However, conventional visual assessment of drawings may not capture intricate nuances that could help track cognitive states. To address this issue, we utilized a deep-learning model, PentaMind, to examine cognition-related features from hand-drawn images of intersecting pentagons. PentaMind, trained on 13,777 images from 3,111 participants in three aging cohorts, explained 23.3% of the variance in global cognitive scores, a comprehensive hour-long cognitive battery. The model’s performance, which was 1.92 times more accurate than conventional visual assessment, significantly improved the detection of cognitive decline. The improvement in accuracy was due to capturing additional drawing features that we found to be associated with motor impairments and cerebrovascular pathologies. By systematically modifying the input images, we discovered several important drawing attributes for cognition, including line waviness. Our results demonstrate that hand-drawn images can provide rich cognitive information, enabling rapid assessment of cognitive decline and suggesting potential clinical implications in dementia.
Gene regulatory network inference with popInfer reveals dynamic regulation of hematopoietic stem cell quiescence upon diet restriction and aging
Authors: Rommelfanger Megan K. , Behrends Marthe , Chen Yulin , Martinez Jonathan , Bens Martin , Xiong Lingyun , Rudolph K. Lenhard , MacLean Adam L.
Published: April 2023

Inference of gene regulatory networks (GRNs) can reveal cell state transitions from single-cell genomics data. However, obstacles to temporal inference from snapshot data are difficult to overcome. Single-nuclei multiomics data offer means to bridge this gap and derive temporal information from snapshot data using joint measurements of gene expression and chromatin accessibility in the same single cells. We developed popInfer to infer networks that characterize lineage-specific dynamic cell state transitions from joint gene expression and chromatin accessibility data. Benchmarking against alternative methods for GRN inference, we showed that popInfer achieves higher accuracy in the GRNs inferred. popInfer was applied to study single-cell multiomics data characterizing hematopoietic stem cells (HSCs) and the transition from HSC to a multipotent progenitor cell state during murine hematopoiesis across age and dietary conditions. From networks predicted by popInfer, we discovered gene interactions controlling entry to/exit from HSC quiescence that are perturbed in response to diet or aging.
Matrisome AnalyzeR: A suite of tools to annotate and quantify ECM molecules in big datasets across organisms
Authors: Petrov Petar B. , Considine James M. , Izzi Valerio , Naba Alexandra
Published: April 2023

The extracellular matrix (ECM) is a complex meshwork of proteins that forms the scaffold of all tissues in multicellular organisms. It plays critical roles in all aspects of life: from orchestrating cell migration during development, to supporting tissue repair. It also plays critical roles in the etiology or progression of diseases. To study this compartment, we defined the compendium of all genes encoding ECM and ECM-associated proteins for multiple organisms. We termed this compendium the “matrisome” and further classified matrisome components into different structural or functional categories. This nomenclature is now largely adopted by the research community to annotate -omics datasets and has contributed to advance both fundamental and translational ECM research. Here, we report the development of Matrisome AnalyzeR, a suite of tools including a web-based application (https://sites.google.com/uic.edu/matrisome/tools/matrisome-analyzer) and an R package (https://github.com/Matrisome/MatrisomeAnalyzeR). The web application can be used by anyone interested in annotating, classifying, and tabulating matrisome molecules in large datasets without requiring programming knowledge. The companion R package is available to more experienced users, interested in processing larger datasets or in additional data visualization options.

SUMMARY STATEMENT

Matrisome AnalyzeR is a suite of tools, including a web-based app and an R package, designed to facilitate the annotation and quantification of extracellular matrix components in big datasets.
Partitioning to ordered membrane domains regulates the kinetics of secretory traffic
Authors: Castello-Serrano Ivan , Heberle Fred A. , Diaz-Rohrer Barbara , Ippolito Rossana , Shurer Carolyn R. , Lujan Pablo , Campelo Felix , Levental Kandice R. , Levental Ilya
Published: April 2023

The organelles of eukaryotic cells maintain distinct protein and lipid compositions required for their specific functions. The mechanisms by which many of these components are sorted to their specific locations remain unknown. While some motifs mediating subcellular protein localization have been identified, many membrane proteins and most membrane lipids lack known sorting determinants. A putative mechanism for sorting of membrane components is based on membrane domains known as lipid rafts, which are laterally segregated nanoscopic assemblies of specific lipids and proteins. To assess the role of such domains in the secretory pathway, we applied a robust tool for synchronized secretory protein traffic (RUSH,RetentionUsingSelectiveHooks) to protein constructs with defined affinity for raft phases. These constructs consist solely of single-pass transmembrane domains (TMDs) and, lacking other sorting determinants, constitute probes for membrane domain-mediated trafficking. We find that while raft affinity can be sufficient for steady-state PM localization, it is not sufficient for rapid exit from the endoplasmic reticulum (ER), which is instead mediated by a short cytosolic peptide motif. In contrast, we find that Golgi exit kinetics are highly dependent on raft affinity, with raft preferring probes exiting Golgi ∼2.5-fold faster than probes with minimal raft affinity. We rationalize these observations with a kinetic model of secretory trafficking, wherein Golgi export can be facilitated by protein association with raft domains. These observations support a role for raft-like membrane domains in the secretory pathway and establish an experimental paradigm for dissecting its underlying machinery.
Single-cell analysis reveals distinct fibroblast plasticity during tenocyte regeneration in zebrafish
Authors: Rajan Arsheen M. , Rosin Nicole L. , Labit Elodie , Biernaskie Jeff , Liao Shan , Huang Peng
Published: April 2023

Despite their importance in tissue maintenance and repair, fibroblast diversity and plasticity remain poorly understood. Using single-cell RNA sequencing, we uncover distinct sclerotome-derived fibroblast populations in zebrafish, including progenitor-like perivascular/interstitial fibroblasts, and specialized fibroblasts such as tenocytes. To determine fibroblast plasticityin vivo, we develop a laser-induced tendon ablation and regeneration model. Lineage tracing reveals that laser-ablated tenocytes are quickly regenerated by preexisting fibroblasts. By combining single-cell clonal analysis and live imaging, we demonstrate that perivascular/interstitial fibroblasts actively migrate to the injury site, where they proliferate and give rise to new tenocytes. By contrast, perivascular fibroblast-derived pericytes or specialized fibroblasts, including tenocytes, exhibit no regenerative plasticity. Interestingly, active Hedgehog (Hh) signaling is required for the proliferation of activated fibroblasts to ensure efficient tenocyte regeneration. Together, our work highlights the functional diversity of fibroblasts and establishes perivascular/interstitial fibroblasts as tenocyte progenitors that promote tendon regeneration in a Hh signaling-dependent manner.

TEASER

Perivascular/interstitial fibroblasts function as plastic progenitors during tenocyte regeneration.
The condition for dynamic stability in humans walking with feedback control
Authors: Reimann Hendrik , Bruijn Sjoerd M.
Published: April 2023

The walking human body is mechanically unstable. Loss of stability and falling is more likely in certain groups of people, such as older adults or people with neuromotor impairments, as well as in certain situations, such as when experiencing conflicting or distracting sensory inputs. Stability during walking is often characterized biomechanically, by measures based on body dynamics and the base of support.

Neural control of upright stability, on the other hand, does not factor into commonly used stability measures. Here we analyze stability of human walking accounting for both biomechanics and neural control, using a modeling approach. We define a walking system as a combination of biomechanics, using the well known inverted pendulum model, and neural control, using a proportional-derivative controller for foot placement based on the state of the center of mass at midstance. We analyze this system formally and show that for any choice of system parameters there is always one periodic orbit. We then determine when this periodic orbit is stable, i.e. how the neural control gain values have to be chosen for stable walking. Following the formal analysis, we use this model to make predictions about neural control gains and compare these predictions with the literature and existing experimental data. The model predicts that control gains should increase with decreasing cadence. This finding appears in agreement with literature showing stronger effects of visual or vestibular manipulations at different walking speeds.

Author summary

The walking human body is mechanically unstable and humans frequently lose upright stability and fall while walking. Stability of human walking is usually analyzed from a biomechanical perspective. We argue that sensorimotor control is an essential aspect of walking stability. We model a walking system as a combination of inverted pendulum biomechanics and a neural feedback controller for foot placement and analyze the properties of this hybrid dynamical system. We find that there is always exactly one periodic orbit and derive a criterion for the asymptotic stability of this periodic orbit. This analytic criterion allows us to characterize the region in the parameter space where the walking system is stable. We use these theoretical results to analyze stability of human walking depending on different sensorimotor control gains. The model predicts that control gains should be larger for slower-paced walking, which is partially consistent with the available experimental data.
Intermediate antiparallel beta structure in amyloid plaques revealed by infrared spectroscopic imaging
Authors: Holcombe Brooke , Foes Abigail , Banerjee Siddhartha , Yeh Kevin , Wang Shih-Hsiu J. , Bhargava Rohit , Ghosh Ayanjeet
Published: April 2023

Aggregation of amyloid beta (Aβ) peptides into extracellular plaques is a hallmark of the molecular pathology of Alzheimer’s disease (AD). Amyloid aggregates have been extensively studied in-vitro, and it is well known that mature amyloid fibrils contain an ordered parallel β structure. The structural evolution from unaggregated peptide to fibrils can be mediated through intermediate structures that deviate significantly from mature fibrils, such as antiparallel β-sheets. However, it is currently unknown if these intermediate structures exist in plaques, which limits the translation of findings from in-vitro structural characterizations of amyloid aggregates to AD. This arises from the inability to extend common structural biology techniques to ex-vivo tissue measurements. Here we report the use of infrared (IR) imaging, wherein we can spatially localize plaques and probe their protein structural distributions with the molecular sensitivity of IR spectroscopy. Analyzing individual plaques in AD tissues, we demonstrate that fibrillar amyloid plaques exhibit antiparallel β-sheet signatures, thus providing a direct connection between in-vitro structures and amyloid aggregates in AD brain. We further validate results with IR imaging of in-vitro aggregates and show that antiparallel β-sheet structure is a distinct structural facet of amyloid fibrils.
Complete Genome Sequences and Characteristics of Seven Novel Mycobacteriophages
Authors: Weiss Skylar M , Happy Kezia K , Baliraine Faith W , Beach Abigail K , Brobston Sean M , Martinez Claire P , Menard Kaitlyn J , Orton Savannah M , Salazar Angela L , Frederick Gregory D , Baliraine Frederick N
Published: April 2023

Full genome sequences of seven mycobacteriophages isolated from environmental soil samples are presented. These bacteriophages, with their respective cluster or subclusters, are Duplo (A2), Dynamo (P1), Gilberta (A11), MaCh (A11), Nikao (K1), Phloss (N), and Skinny (M1). All were temperate Siphoviridae, with genome sizes ranging from 43,107–82,071 bp.
MACI: A machine learning-based approach to identify drug classes of antibiotic resistance genes from metagenomic data
Authors: Chowdhury Rohit Roy , Dhar Jesmita , Robinson Stephy Mol , Lahiri Abhishake , Paul Sandip , Basak Kausik , Banerjee Rachana
Published: April 2023

Novel methodologies are now essential for identification of antibiotic resistant pathogens in order to resist them. Here, we are presenting a model, MACI (Machine learning-based Antibiotic resistance gene-specific drug Class Identification) that can take metagenomic fragments as input and predict the drug class of antibiotic resistant genes. We trained the model to learn underlying patterns of genes using the Comprehensive Antibiotic Resistance Database. It comprises of 116 drug classes with a total of 2960 representative sequences. Among these 116 drug classes, we found 22 categories (contributing approximately 85% of the overall sequence-data) surpassed other 94 drug classes based on the number of fragments. The model showed an average precision of 0.83 and a recall of 0.81 for these 22 drug classes. Moreover, the model predicted multidrug resistant classes with higher performance score (precision and recall: 0.9 and 0.88 respectively) compared to single drug resistant categories (0.77 and 0.75). Post to this, we analysed these 22 drug classes to find out class-specific overlapping patterns of nucleotides that led to accurate classification. This way, we found five drug classes viz. “carbapenem;cephalosporin;penam”, “cephalosporin”, “cephamycin”, “cephalosporin;monobactam;penam;penem”, and “fluoroquinolone”. Additionally, the positions of these significant patterns corroborated with the functional domains of majority of antibiotic resistance genes in that drug class, indicating their biological importance. These class-specific patterns play a pivotal role in rapid identification of some drug classes comprising antibiotic resistance genes. Further analysis showed that bacterial species, containing these five-drug classes, were found to have well-known multidrug resistance property.
Exhaustive benchmarking ofde novoassembly methods for eukaryotic genomes
Authors: Southwood Dean , Rane Rahul V , Lee Siu Fai , Oakeshott John G , Ranganathan Shoba
Published: April 2023

The assembly of reference-quality, chromosome-resolution genomes for both model and novel eukaryotic organisms is an increasingly achievable task for single research teams. However, the overwhelming abundance of sequencing technologies, assembly algorithms, and post-assembly processing tools currently available means that there is no clear consensus on a best-practice computational protocol for eukaryoticde novogenome assembly. Here, we provide a comprehensive benchmark of 28 state-of-the-art assembly and polishing packages, in various combinations, when assembling two eukaryotic genomes using both next-generation (Illumina HiSeq) and third-generation (Oxford Nanopore and PacBio CLR) sequencing data, at both controlled and open levels of sequencing coverage. Recommendations are made for the most effective tools for each sequencing technology and the best performing combinations of methods, evaluated against common assessment metrics such as contiguity, computational performance, gene completeness, and reference reconstruction, across both organisms and across sequencing coverage depth.
Cardiac age prediction using graph neural networks
Authors: Inácio Marco H. de A. , Shah Mit , Jafari Mina , Shehata Nairouz , Meng Qingjie , Bai Wenjia , Gandy Axel , Glocker Ben , O’Regan Declan P.
Published: April 2023

The function of the human heart is characterised by complex patterns of motion that change throughout our lifespan due to accumulated damage across biological scales. Understanding the drivers of cardiac ageing is key to developing strategies for attenuating age-related processes. The motion of the surface of the heart can be conceived as a graph of connected points in space moving through time. Here we develop a generalisable framework for modelling three-dimensional motion as a graph and apply it to a task of predicting biological age. Using sequences of segmented cardiac imaging from 5064 participants in UK Biobank we train a graph neural network (GNN) to learn motion traits that predict healthy ageing. The GNN outperformed (mean absolute error, MAE = 4.74 years) a comparator dense neural network and boosting methods (MAE = 4.90 years and 5.08 years, respectively). We produce human-intelligible explanations of the predictions and using the trained model we also assess the effect of hypertension on biological age. This work shows how graph representations of complex motion can efficiently predict biologically meaningful outcomes.
Diagnosing diastolic dysfunction using explainable advanced electrocardiography
Authors: McColl Hayden , Chowdhury Sabbab , Schlegel Todd T , Maanja Maren , Yang Kevin , Lindow Thomas , Price Michelle , Fulthorp Elias , Lal Sean , McGrady Michele , Kozor Rebecca , Ugander Martin
Published: April 2023

BACKGROUND AND AIMS

Diastolic dysfunction of the left ventricle is a precursor to heart failure with preserved ejection fraction (HFpEF). Detection by electrocardiography (ECG) when asymptomatic (stage B heart failure) would be valuable. We hypothesised that an explainable advanced ECG (A-ECG) score derived from standard 12-lead ECG could accurately diagnose diastolic dysfunction.

METHODS

Included patients had undergone resting 12-lead ECG and echocardiography demonstrating normal systolic function, with at most mild valve disease, and either the presence (n=150) or absence (n=264) of grade II or III diastolic dysfunction. Stepwise multivariable logistic regression was used to generate an A-ECG score that was crossvalidated using bootstrapping.

RESULTS

A 6-measure A-ECG score was able to identify diastolic dysfunction with an area under the receiver operating characteristics curve [95% confidence interval] of 0.91 [0.88-0.94], sensitivity 83 [76-91]%, specificity 87 [77-92]%, positive predictive value 78 [69-85]%, negative predictive value 90 [86-94]%, positive likelihood ratio 6.38 [3.30-11.38] and inverse negative likelihood ratio 5.12 [3.21-10.22].

CONCLUSIONS

Standard 12-lead ECG can be used to accurately identify diastolic dysfunction by echocardiography via A-ECG. This may have clinical utility for early identification of patients who may benefit from further cardiac assessment and risk factor management to prevent progression to symptomatic heart failure.
Repeatability and agreement of central corneal thickness measurements with a new handheld non-contact pachymeter
Authors: Lawrenson John G , Gill Simranjit , Masuid Isra , Rashid Fardip
Published: April 2023

Purpose

To compare the repeatability of central corneal thickness (CCT) measurements taken with a new hand-held pachymeter (Occuity PM1 Pachymeter) and to assess its agreement with ultrasound biometry and two commercially available optical biometers in participants with normal eyes.

Methods

Three consecutive CCT measurements of the right eye of 105 participants with normal corneas were acquired by the PM1 pachymeter, Lenstar LS900 and Oculus Pentacam HR in a random order. This was followed by three measurements with a hand-held ultrasound pachymeter (UP) (Pachmate-2). Repeatability and the repeatability limit were calculated with each device and Bland-Altman limits of agreement (LoA) were determined for the PM1 pachymeter compared to the other devices.

Results

The mean CCT (±SD) was 551.04±33.43 μm, 558.62±31.46 μm, 549.41±31.00 μm, and 539.73±29.50 μm for the PM1 pachymeter, UP, Lenstar and Pentacam, respectively. The repeatability limits (expressed as the within subject SD for repeat measurements) were 14.02, 13.68, 4.99 and 9.90 μm respectively. The closest agreement was between the PM1 and Lenstar (mean difference = 1.63 μm with LoA 10.72 μm below and 13.97 μm above the readings obtained with the Lenstar. The PM1 underestimated CCT compared to UP (mean difference = 7.58 μm, LoA 24.63 μm below and 9.47 μm above UP. The agreement was lowest between the PM1 and Pentacam (mean difference= -11.30 μm, LoA between 4.29 μm and 26.89 μm).

Conclusions

The PM1 pachymeter shows excellent precision for CCT measurements across a range of corneal thicknesses in normal eyes and provides a safe and easy to use alternative to ultrasound pachymetry.

Key points

Measurement of central corneal thickness (CCT) is an important clinical measurement in the diagnosis and management of glaucoma and certain corneal dystrophies, it also provides useful information prior to refractive surgery

The Occuity PM1 pachymeter is a new hand-held non-contact perimeter that uses confocal technology to measure CCT. The device showed excellent precision for CCT measurements across a range of corneal thicknesses in normal eyes

The PM1 pachymeter provides a safe and easy to use alternative to ultrasound pachymetry that could facilitate an increased uptake of pachymetry in routine optometric practice
Outcomes of non-hospitalized isolation service during COVID-19 pandemic
Authors: Tansawet Amarit , Atiksawedparit Pongsakorn , Piebpien Pongsathorn , Kunakorntham Patratorn , Suthutvoravut Unyaporn , Arnuntasupakul Vanlapa , Numthavaj Pawin , Ingsathit Atiporn , Pattanaprateep Oraluck , Thakkinstian Ammarin
Published: April 2023

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or COVID-19 affected more than 500 million patients worldwide and overwhelmed hospital resources. Rapid increase of new cases forced patient isolation to be conduct outside the hospital where many strategies have been implemented. This study aimed to compare outcomes among non-hospitalized isolation service.

Methods

A retrospective cohort study was conducted in asymptomatic and mildly symptomatic adult patients who were allocated to home isolation, community isolation, and hospitel (i.e., hotel isolation) under service of Ramathibodi Hospital and Chakri Naruebodindra Medical Institute. Variables including patients’ characteristics, comorbidities, symptoms, and medication were retrieved for use in inverse-probability-weighted regression adjustment model. Risks and risk differences (RDs) of death, oxygen requirement, and hospitalization were estimated from the model afterward.

Results

A total of 3869 patients were included in the analysis. Mean age was 41.8 ± 16.5 years. Cough was presented in 62.2% of patients, followed by hyposmia (43.7%), runny nose (43.5%), sore throat (42.2%), and fever (38.6%). Among the isolation strategies, hospitel yielded the lowest risks of death (0.3%), oxygen requirement (4.5%), and hospitalization (3.3%). Hospitel had significantly lower oxygen requirements and hospitalization rates compared with home isolation with the RDs (95% CI) of -0.016 (−0.029, -0.002) and -0.025 (−0.038, -0.012), respectively. Death rates did not differ among isolation strategies.

Conclusion

Non-hospitalized isolation is feasible and could ameliorate hospital demands. Given the lowest risks of death, hospitalization, and oxygen requirement, hospitel might be the best isolation strategy.
SMOOTH protocol: A pilot randomised prospective intra-patient single-blinded observational study for examining the mechanistic basis of ablative fractional carbon dioxide laser therapy in treating hypertrophic scarring
Authors: Chen Yung-Yi , Patel Krupali M. , Imran Rizwana , Hassouna Tarek , Amirize Ezekwe , Abdulsalam Abdulrazak , Bishop Jonathan , Slade Anita , Ventura Maximina , Yarrow Jeremy , Lord Janet M. , Wilson Yvonne , Moiemen Naiem S.
Published: April 2023

Background

Burn injuries are the fourth most common type of trauma and are associated with substantial morbidity and mortality. The impact of burn injury is clinically significant as burn injuries often give rise to exuberant scarring. Hypertrophic scarring (HTS) is a particular concern as up to 70% of burns patients develop HTS. Laser therapy is used for treating HTS and has shown positive clinical outcomes, although the mechanisms remain unclear limiting approaches to improve its effectiveness. Emerging evidence has shown that fibroblasts and senescent cells are important modifiers of scarring. This study aims to investigate the cellular kinetics in HTS after laser therapy, with a focus on the association of scar reduction with the presence of senescent cells.

Methods

We will conduct a multicentre, intra-patient, single-blinded, randomised controlled longitudinal pilot study with parallel assignments to achieve this objective. 60 participants will be recruited to receive 3 interventional ablative fractional CO2laser treatments over a 12-month period. Each participant will have two scars randomly allocated to receive either laser treatment or standard care. Biopsies will be obtained from laser-treated, scarred- no treatment and non-scarred tissues for immune-histological staining to investigate the longitudinal kinetics of p16INK4A+-senescent cells and fibroblast subpopulations (CD90+/Thy1+and αSMA+). Combined subjective scar assessments including Modified Vancouver Scar Scale, Patient and Observer Scar Assessment Scale and Brisbane Burn Scar Impact Profile; and objective assessment tools including 3D-Vectra-H1 photography, DermaScan®Cortex, Cutometer®and ColoriMeter®DSMIII will be used to evaluate clinical outcomes. These will then be used to investigate the association between senescent cells and scar reduction after laser therapy. This study will also collect blood samples to explore the systemic biomarkers associated with the response to laser therapy.

Discussion

This study will provide an improved understanding of mechanisms potentially mediating scar reduction with laser treatment, which will enable better designs of laser treatment regimens for those living with HTS.

Trial registration

ClinicalTrials.gov:NCT04736251.
Hybridization and its impact on the ontogenetic allometry of skulls in macaques
Authors: Ito Tsuyoshi , Kimura Ryosuke , Wakamori Hikaru , Tanaka Mikiko , Tezuka Ayumi , Nagano Atsushi J. , Hamada Yuzuru , Kawamoto Yoshi
Published: April 2023

The role of hybridization in morphological diversification is a fundamental topic in evolutionary biology. However, despite the accumulated knowledge on adult hybrid variation, how hybridization affects ontogenetic allometry is less well understood. Here, we investigated the effects of hybridization on postnatal ontogenetic allometry in the skulls of a putative hybrid population of introduced Taiwanese macaques (Macaca cyclopis) and native Japanese macaques (M. fuscata). Genomic analyses indicated that the population consisted of individuals with varying degrees of admixture, formed by male migration from Japanese to Taiwanese macaques. For overall skull shape, ontogenetic trajectories were shifted by hybridization in a nearly additive manner, with moderate transgressive variation observed throughout development. In contrast, for the maxillary sinus (hollow space in the face), hybrids grew as fast as Taiwanese macaques, diverging from Japanese macaques, which showed slow growth. Consequently, adult hybrids showed a mosaic pattern, i.e., the maxillary sinus is as large as that of Taiwanese macaques, while the overall skull shape is intermediate. Our findings suggest that the transgressive variation can be caused by prenatal shape modification and non-additive inheritance on regional growth rates, highlighting the complex genetic and ontogenetic bases underlying hybridization-induced morphological diversification.