bluuebunny/crossref_metadata_2025 huggingface dataset:
Local, calcium- and reward-based synaptic learning rule that enhances dendritic nonlinearities can solve the nonlinear feature binding problem
Authors: Khodadadi Zahra , Trpevski Daniel , Lindroos Robert , Hellgren Kotaleski Jeanette
Published: March 2024

This study investigates the computational potential of single striatal projection neurons (SPN), emphasizing dendritic nonlinearities and their crucial role in solving complex integration problems. Utilizing a biophysically detailed multicompartmental model of an SPN, we introduce a calcium-based, local synaptic learning rule dependent on dendritic plateau potentials. According to what is known about excitatory corticostriatal synapses, the learning rule is governed by local calcium dynamics from NMDA and L-type calcium channels and dopaminergic reward signals. In order to devise a self-adjusting learning rule, which ensures stability for individual synaptic weights, metaplasticity is also used. We demonstrate that this rule allows single neurons to solve the nonlinear feature binding problem, a task traditionally attributed to neuronal networks. We also detail an inhibitory plasticity mechanism that contributes to dendritic compartmentalization, further enhancing computational efficiency in dendrites. Thisin silicostudy highlights the computational potential of single neurons, providing deeper insights into neuronal information processing and the mechanisms by which the brain executes complex computations.
NeuroFold: A Multimodal Approach to Generating Novel Protein Variantsin silico
Authors: Amani Keaun , Fish Michael , Smith Matthew D. , Castroverde Christian Danve M.
Published: March 2024

The generation of high-performance enzyme variants with desired physicochemical and functional properties presents a formidable challenge in the field of protein engineering. Existingin silicodesign methods are limited by inadequate training data, insufficient diversity within datasets, and suboptimal sampling techniques. Here, we introduce a novel approach that addresses these limitations and significantly improves the efficiency of generating functional enzyme variants. Using a multimodal approach, NeuroFold can leverage sequence, structural, and homology data during both sampling and discrimination phases, thereby enabling more diverse and informed sampling of the sequence space. Our model demonstrated a 40-fold increase in Spearman rank correlation as compared to large language models (LLMs) such as ESM-1v and empowers the rapid creation of high-quality enzyme variants, such as the β-lactamase variants generated by NeuroFold in this study, which demonstrated increased thermostability and varying levels of activity. This pipeline represents a promising advancement in the field of enzyme engineering, offering a valuable tool for the development of novel enzymes with enhanced performance and desired chemical properties.
The best of two worlds: using stacked generalization for integrating expert range maps in species distribution models
Authors: Oeser Julian , Zurell Damaris , Mayer Frieder , Çoraman Emrah , Toshkova Nia , Deleva Stanimira , Natradze Ioseb , Benda Petr , Ghazaryan Astghik , Irmak Sercan , Hasanov Nijat Alisafa , Guliyeva Gulnar Gahraman , Gritsina Mariya , Kuemmerle Tobias
Published: March 2024

Species distribution models (SDMs) are powerful tools for assessing suitable habitat across large areas and at fine spatial resolution. Yet, the usefulness of SDMs for mapping species’ realized distributions is often limited, since data biases or missing information on dispersal barriers or biotic interactions hinder them from accurately delineating species’ range limits. One way to overcome this limitation is to integrate SDMs with expert range maps, which provide coarse-scale information on the extent of species’ ranges that is complementary to information offered by SDMs. Here, we propose a new approach for integrating expert range maps in SDMs based on an ensemble method called stacked generalization. Specifically, our approach relies on training a meta-learner regression model using predictions from one or more SDM algorithms alongside the distance of training points to expert-defined ranges as predictor variables. We demonstrate our approach with an occurrence dataset for 49 bat species covering four biodiversity hotspots in the Eastern Mediterranean, Western Asia, and Central Asia. Our approach offers a flexible method to integrate expert range maps with any combination of SDM modeling algorithms, thus facilitating the use of algorithm ensembles. In addition, it provides a novel, data-driven way to account for uncertainty in expert-defined ranges not requiring prior knowledge about their accuracy, which is often lacking. Our approach holds considerable promise for better understanding species distributions, and thus for biogeographical research and conservation planning. In addition, our work highlights the overlooked potential of stacked generalization as an ensemble method in species distribution modeling.
Natural soil suppressiveness against soilborne phytopathogens extends to the control of insect pest
Authors: Harmsen Nadine , Vesga Pilar , Glauser Gaétan , Klötzli Françoise , Heiman Clara M. , Altenried Aline , Vacheron Jordan , Muller Daniel , Moënne-Loccoz Yvan , Steinger Thomas , Keel Christoph , Garrido-Sanz Daniel
Published: March 2024

Since the 1980s, soils in a 22-km2area near Lake Neuchâtel in Switzerland have been recognized for their innate ability to suppress the black root rot plant disease. Their efficacy against insect pests has not been studied. We demonstrate that natural soil suppressiveness also protects plants from the leaf-feeding pest insectOulema melanopus. Plants grown in the most suppressive soil have a reduced stress response toOulemafeeding, reflected by dampened levels of herbivore defense-related phytohormones and benzoxazinoids, and enhanced salicylate levels in plants without the insect indicate defense-priming. The rhizosphere microbiome network of the suppressive soils was highly tolerant to the destabilizing impact of insect exposure. The presence of plant-beneficial bacteria in the suppressive soils along with priming conferred plant resistance to the insect pest, manifesting also in the onset of insect microbiome dysbiosis. This intricate soil-plant-insect feedback extends natural soil suppressiveness from soilborne diseases to insect pests.
ACLASP1variant suggests a phenotypic relation with lissencephaly in humans
Authors: Alsafeh Rawan , AlHashem Amal , Elsayed Aly , Yüksel Zafer , Graies-Tlili Kalthoum , Thabet Farah , Tabarki Brahim
Published: March 2024

Lissencephaly is a severe brain developmental disorder; characterized by reduced brain folding due to defective neuronal migration. This study investigates the genetic basis of lissencephaly in a consanguineous family, focusing on theCLASP1gene. Whole-exome sequencing identified a novel homozygous variant (c.4442G>A p.(Arg1481His)) inCLASP1. Clinical evaluation revealed severe developmental delays, microcephaly, seizures, and lissencephaly in the affected siblings. The variant was heterozygous in the healthy parents and a heterozygous carrier in an unaffected sibling. This study underscores the role of CLASP1 in brain development and suggests that the identified variant disrupts CLASP1 interaction with the microtubule cytoskeleton, contributing to lissencephaly pathogenesis.
The β2-adrenergic receptor (ADRB2) entrains circadian gene oscillation and diurnal responses to virus infection in CD8+T cells
Authors: Sharma Drashya , Kohlbach Kira A. , Maples Robert , Farrar J. David
Published: March 2024

Adaptive immune cells are regulated by circadian rhythms (CR) under both steady state conditions and during responses to infection. Cytolytic CD8+T cells display variable responses to infection depending upon the time of day of exposure. However, the neuronal signals that entrain these cyclic behaviors remain unknown. Immune cells express a variety of neurotransmitter receptors including nicotinic, glucocorticoid, and adrenergic receptors. Here, we demonstrate that the β2-adrenergic receptor (ADRB2) regulates the periodic oscillation of select core clock genes, such asPer2andBmal1, and selective loss of theAdrb2gene dramatically perturbs the normal diurnal oscillation of clock gene expression in CD8+T cells. Consequently, their circadian-regulated anti-viral response is dysregulated, and the diurnal development of CD8+T cells into variegated populations of cytolytic T cell (CTL) effectors is dramatically altered in the absence of ADRB2 signaling. Thus, theAdrb2directly entrains core clock gene oscillation and regulates CR-dependent T cell responses to virus infection as a function of time-of-day of pathogen exposure.

One Sentence Summary

The β2-adrenergic receptor regulates circadian gene oscillation and downstream daily timing of cytolytic T cell responses to virus infection.
Emodin: an alveolar macrophage protector in acute pancreatitis induced lung injury
Authors: Chen Zhe , Dong Xuanchi , Song Yongwei , Lan Bowen , Luo Yalan , Wen Haiyun , Li Hailong , Chen Hailong
Published: March 2024

Emodin (EMO), an anthraquinone derivative from roots and leaves of various plants, has been widely used in many inflammatory diseases. Alveolar macrophages (AMs) play a critical role in maintaining alveolar homeostasis in the lung. To investigate the pathophysiological mechanism of AMs in acute pancreatitis-associated lung injury (AP-ALI) and the potential protective therapeutic of EMO for AP-ALI, AMs isolated from AP-ALI mice, murine cell line MH-S and RAW264.7 were pre-treated with EMO to assess its protective roles on regulating inflammation, pyroptosis, and mitophagy of macrophages in AP-ALI. The results showed that 1) in vivo, the relative quantity of AMs was significantly decreased across the time in API-ALI; however, the mitochondria flux presented earlier changes than the resident AMs alteration in our experimental system. EMO pretreatment significantly alleviated the severity of lung injury and improved the damaged alveolar structure, and further reversed the reduction of mitochondria impairment in AMs in mice. 2) In vitro, EMO significantly suppressed LPS/ATP associated NLRP3 inflammasome activation, enhanced mitophagy, and protected mitochondria damage. Furthermore, the data of mitophagy inhibition by 3-MA demonstrated that EMO protective effects were partially via manipulating mitophagy-mitochondria-alveolar macrophage axis. Our data shed light on the comprehensive understanding on EMO therapeutics in AP-ALI.
Hearing loss at 6-monthly assessments from age 12 to 36 months: secondary outcomes from randomised controlled trials of novel pneumococcal conjugate vaccine schedules
Authors: Leach A.J. , Wilson N. , Arrowsmith B. , Beissbarth J. , Mulholland E.K. , Santosham M. , Torzillo P.J. , McIntyre P. , Smith-Vaughan H. , Skull S.A. , Oguoma V.M. , Chatfield M.D. , Lehmann D. , Brennan-Jones C. G. , Binks M. J. , Licciardi P.V. , Andrews R. , Snelling T. , Krause V. , Carapetis J. , Chang A.B. , Morris P.S.
Published: March 2024

Introduction

In remote communities, Australian First Nations children with hearing loss are disproportionately at risk of poor school readiness and performance, compared to those with normal hearing. Our objective was to compare two pneumococcal conjugate vaccine (PCV) formulations and mixed schedules (the PREVIX trials) designed to broaden protection and reduce conductive hearing loss to age 36 months.

Methods

In two sequential parallel, open-label, randomised controlled trials, eligible infants were first allocated 1:1:1 at age 28-38 days to standard or mixed PCV primary schedules, then at age 12 months to a booster dose (1:1) of PCV13 (13-valent pneumococcal conjugate vaccine, +P) or PHiD-CV10 (10-valent pneumococcalHaemophilus influenzaeprotein D conjugate vaccine, +S). Here we report secondary hearing outcomes in the +P and +S groups at 6-monthly scheduled assessments from age 12 to 36 months.

Findings

From March 2013 to September 2018, 461 hearing assessments were performed. Prevalence of mild-moderate hearing loss declined in both groups from ∼75% at age 12 months to ∼53% at 36 months. At primary endpoint age 18 months, prevalence of moderate (disabling) hearing loss was 21% and 41% in the +P and +S groups, respectively (difference −19% [95% confidence interval −38, −1], p=0.07) and prevalence of normal hearing was 36% and 16%, respectively (difference 19% [95%CI 2, 37], p=0.05). At subsequent timepoints prevalence of moderate hearing loss remained lower in the +P group at −3% [95% CI −23, 18] at age 24 months, −12% [95%CI −30, 6] at 30 months, and −9% [95%CI −23, 5] at 36 months.

Interpretation

This study provides first evidence of the high prevalence and persistence of mild and moderate hearing loss throughout early childhood. A lower prevalence of moderate (disabling) hearing loss in the +P group may have substantial benefits for high-risk children and warrants further investigation.

Trial registration

ClinicalTrials.govNCT01735084andNCT01174849https://clinicaltrials.gov/study/NCT01735084https://clinicaltrials.gov/study/NCT01174849

Funding

National Health and Medical Research Council of Australia (GNT605810, GNT1046999, GNT1120353)
Sparse haplotype-based fine-scale local ancestry inference at scale reveals recent selection on immune responses
Authors: Yang Yaoling , Durbin Richard , Iversen Astrid K. N. , Lawson Daniel J.
Published: March 2024

Increasingly efficient methods for inferring the ancestral origin of genome regions are needed to gain new insights into genetic function and history as biobanks grow in scale. Here we describe two near-linear time algorithms to learn ancestry harnessing the strengths of a Positional Burrows-Wheeler Transform (PBWT). SparsePainter is a faster, sparse replacement of previous model-based ‘chromosome painting’ algorithms to identify recently shared haplotypes, whilst PBWTpaint uses further approximations to obtain lightning-fast estimation optimized for genome-wide relatedness estimation. The computational efficiency gains of these tools for fine-scale local ancestry inference offer the possibility to analyse large-scale genomic datasets in completely novel ways. Application to the UK Biobank shows that haplotypes better represent ancestries than principal components, whilst linkage-disequilibrium of ancestry identifies signals of recent changes to population-specific selection for many genomic regions associated with immune responses, suggesting new avenues for understanding the pathogen-immune system interplay on a historical timescale.
Bioluminescence Imaging of Potassium Ion Using a Sensory Luciferin and an Engineered Luciferase
Authors: Zhao Shengyu , Xiong Ying , Sunnapu Ranganayakulu , Zhang Yiyu , Tian Xiaodong , Ai Hui-wang
Published: March 2024

Bioluminescent indicators are power tools for studying dynamic biological processes. In this study, we present the generation of novel bioluminescent indicators by modifying the luciferin molecule with an analyte-binding moiety. Specifically, we have successfully developed the first bioluminescent indicator for potassium ions (K+), which are critical electrolytes in biological systems. Our approach involved the design and synthesis of a K+-binding luciferin named potassiorin. Additionally, we engineered a luciferase enzyme called BRIPO (bioluminescent red indicator for potassium) to work synergistically with potassiorin, resulting in optimized K+-dependent bioluminescence responses. Through extensive validation in cell lines, primary neurons, and live mice, we demonstrated the efficacy of this new tool for detecting K+. Our research demonstrates an innovative concept of incorporating sensory moieties into luciferins to modulate luciferase activity. This approach has great potential for developing a wide range of bioluminescent indicators, advancing bioluminescence imaging (BLI), and enabling the study of various analytes in biological systems.

Abstract Figure
Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product
Authors: Mishra Avanish , Huang Shih-Bo , Dubash Taronish , Burr Risa , Edd Jon F. , Wittner Ben S. , Cunneely Quinn E. , Putaturo Victor R. , Deshpande Akansha , Antmen Ezgi , Gopinathan Kaustav A. , Otani Keisuke , Miyazawa Yoshiyuki , Kwak Ji Eun , Guay Sara Y. , Kelly Justin , Walsh John , Nieman Linda , Galler Isabella , Chan PuiYee , Lawrence Michael S. , Sullivan Ryan J. , Bardia Aditya , Micalizzi Douglas S. , Sequist Lecia V. , Lee Richard J. , Franses Joseph W. , Ting David T. , Brunker Patricia A. R. , Maheswaran Shyamala , Miyamoto David T. , Haber Daniel A. , Toner Mehmet
Published: March 2024

Circulating Tumor Cells (CTCs), interrogated by sampling blood from patients with cancer, contain multiple analytes, including intact RNA, high molecular weight DNA, proteins, and metabolic markers. However, the clinical utility of tumor cell-based liquid biopsy has been limited since CTCs are very rare, and current technologies cannot process the blood volumes required to isolate a sufficient number of tumor cells for in-depth assays. We previously described a high-throughput microfluidic prototype utilizing high-flow channels and amplification of cell sorting forces through magnetic lenses. Here, we apply this technology to analyze patient-derived leukapheresis products, interrogating a mean blood volume of 5.83 liters from patients with metastatic cancer, with a median of 2,799 CTCs purified per patient. Isolation of many CTCs from individual patients enables characterization of their morphological and molecular heterogeneity, including cell and nuclear size and RNA expression. It also allows robust detection of gene copy number variation, a definitive cancer marker with potential diagnostic applications. High-volume microfluidic enrichment of CTCs constitutes a new dimension in liquid biopsies.
Towards an Eye-Brain-Computer Interface: Combining Gaze with the Stimulus-Preceding Negativity for Target Selections in XR
Authors: Reddy G. S. Rajshekar , Proulx Michael J. , Hirshfield Leanne , Ries Anthony J.
Published: March 2024

Gaze-assisted interaction techniques enable intuitive selections without requiring manual pointing but can result in unintended selections, known as Midas touch. A confirmation trigger eliminates this issue but requires additional physical and conscious user effort. Brain-computer interfaces (BCIs), particularly passive BCIs harnessing anticipatory potentials such as the Stimulus-Preceding Negativity (SPN) - evoked when users anticipate a forthcoming stimulus - present an effortless implicit solution for selection confirmation. Within a VR context, our research uniquely demonstrates that SPN has the potential to decode intent towards the visually focused target. We reinforce the scientific understanding of its mechanism by addressing a confounding factor - we demonstrate that the SPN is driven by the user’s intent to select the target, not by the stimulus feedback itself. Furthermore, we examine the effect of familiarly placed targets, finding that SPN may be evoked quicker as users acclimatize to target locations; a key insight for everyday BCIs.

CCS CONCEPTS

Human-centered computing→Virtual reality;Mixed / augmented reality;Accessibility technologies;Interaction techniques.

ACM Reference Format

G. S. Rajshekar Reddy, Michael J. Proulx, Leanne Hirshfield, and Anthony J. Ries. 2024. Towards an Eye-Brain-Computer Interface: Combining Gaze with the Stimulus-Preceding Negativity for Target Selections in XR. InProceedings of the CHI Conference on Human Factors in Computing Systems (CHI ‘24), May 11–16, 2024, Honolulu, HI, USA. ACM, New York, NY, USA, 17 pages.https://doi.org/10.1145/3613904.3641925
A possible path to persistent re-entry waves at the outlet of the left pulmonary vein
Authors: Jæger Karoline Horgmo , Tveito Aslak
Published: March 2024

Atrial fibrillation (AF) is the most common form of cardiac arrhythmia, often evolving from paroxysmal episodes to persistent stages over an extended timeframe. While various factors contribute to this progression, the precise biophysical mechanisms driving it remain unclear. Here we explore how rapid firing of cardiomyocytes at the outlet of the pulmonary vein of the left atria can create a substrate for a persistent re-entry wave. This is grounded in a recently formulated mathematical model of the regulation of calcium ion channel density by intracellular calcium concentrations. According to the model, the density of membrane proteins carrying calcium ions is controlled by the intracellular calcium concentrations. In particular, if the concentration increases above a certain target level, the calcium current is weakened in order to restore the target level of calcium. During rapid pacing, the intracellular calcium concentration of the cardiomyocytes increases leading to a substantial reduction of the calcium current across the membrane of the myocytes, which again reduces the action potential duration. In a spatially resolved cell-based model of the outlet of the pulmonary vein of the left atria, we show that the reduced action potential duration can lead to re-entry.

Initiated by rapid pacing, often stemming from paroxysmal AF episodes lasting several days, the reduction in calcium current is a critical factor. Our findings illustrate how such episodes can foster a conducive environment for persistent AF through electrical remodeling, characterized by diminished calcium currents. This underscores the importance of promptly addressing early AF episodes to prevent their progression to chronic stages.
AQP1 Differentially Orchestrates Endothelial Cell Senescence
Authors: Shabanian Khatereh , Shabanian Taraneh , Karsai Gergely , Lettlova Sandra , Pontiggia Luca , Ruschitzka Frank , Beer Jürg H. , Saravi Seyed Soheil Saeedi
Published: March 2024

Accumulation of senescent endothelial cells (ECs) with age is a pivotal driver of cardiovascular diseases in aging. However, little is known about the mechanisms and signaling pathways that regulate EC senescence. In this report, we delineate a previously unrecognized role of aquaporin 1 (AQP1) in orchestrating extracellular hydrogen peroxide (H2O2)-induced cellular senescence in aortic ECs. Our findings underscore AQP1’s differential impact on senescence hallmarks, including cell-cycle arrest, senescence-associated secretory phenotype (SASP), and DNA damage responses, intricately regulating angiogenesis. In proliferating ECs, AQP1 is crucial for maintaining angiogenic capacity, whereas disruption of AQP1 induces morphological and mitochondrial alterations, culminating in senescence and impaired angiogenesis. Conversely,Aqp1knockdown or selective blockade of AQP1 in senescent ECs rescues the excess H2O2-induced cellular senescence phenotype and metabolic dysfunction, thereby ameliorating intrinsic angiogenic incompetence. Mechanistically, AQP1 facilitates H2O2transmembrane transport, exacerbating oxidant-sensitive kinases CaMKII-AMPK. This process suppresses HDAC4 translocation, consequently de-repressing Mef2A-eNOS signaling in proliferating ECs. However, in senescent ECs, AQP1 overexpression is linked to preserved HDAC4-Mef2A complex and downregulation of eNOS signaling. Together, our studies identify AQP1 as a novel epigenetic regulator of HDAC4-Mef2A-dependent EC senescence and angiogenic potential, highlighting its potential as a therapeutic target for antagonizing age-related cardiovascular diseases.

Highlights

• AQP1 is upregulated in aortic endothelial cells with aging

• AQP1 differentially orchestrates H2O2-mediated EC senescence

• AQP1 plays a dual role in regulating angiogenesis in proliferating and senescent ECs

• AQP1 controls EC function by differentially modulating HDAC4-Mef2A pathway

• AQP1 deficiency restores angiogenic capacity in senescent ECs
Fast and accurate imputation of genotypes from noisy low-coverage sequencing data in bi-parental populations
Authors: Cécile Triay , Boizet Alice , Fragoso Christopher , Gkanogiannis Anestis , Rami Jean-Francois , Lorieux Mathias
Published: March 2024

Motivation

Genotyping of bi-parental populations can be performed with low-coverage next-generation sequencing (LC-NGS). This allows the creation of highly saturated genetic maps at reasonable cost, precisely localized recombination breakpoints (i.e., the crossovers), and minimized mapping intervals for quantitative-trait locus analysis. The main issues with these low-coverage genotyping methods are (1) poor performance at heterozygous loci, (2) high percentage of missing data, (3) local errors due to erroneous mapping of sequencing reads and reference genome mistakes, and (4) global, technical errors inherent to NGS itself. Recent methods like Tassel-FSFHap or LB-Impute are excellent at addressing issues 1 and 2, but nonetheless perform poorly when issues 3 and 4 are persistent in a dataset (i.e., “noisy” data). Here, we present a new algorithm for imputation of LC-NGS data that eliminates the need of complex pre-filtering of noisy data, accurately types heterozygous chromosomal regions, precisely estimates crossover positions, corrects erroneous data, and imputes missing data. The imputation of genotypes and recombination breakpoints is based on maximum-likelihood estimation. We compare its performance with Tassel-FSFHap and LB-Impute using simulated data and two real datasets. NOISYmputer is consistently more efficient than the two other software tested and reaches average breakpoint precision of 99.9% and average recall of 99.6% on illumina simulated dataset.

NOISYmputer consistently provides precise map size estimations when applied to real datasets while alternative tools may exhibit errors ranging from 3 to 1845 times the real size of the chromosomes in centimorgans. Furthermore, the algorithm is not only highly effective in terms of precision and recall but is also particularly economical in its use of RAM and computation time, being much faster than Hidden Markov Model methods.

Availability

NOISYmputer and its source code are available as a multiplatform (Linux, macOS, Windows) Java executable at the URLhttps://gitlab.cirad.fr/noisymputer/noisymputerstandalone/-/tree/1.0.0-RELEASE?reftype=tags.
Allometric multi-scaling of weight-for-height relation in children and adolescents: Revisiting the theoretical basis of body mass index of thinness and obesity assessment
Authors: Ogata Hitomi , Nose-Ogura Sayaka , Nagai Narumi , Kayaba Momoko , Isoyama Yosuke , Kruse João , Seleznov van , Kaneko Miki , Shigematsu Taiki , Kiyono Ken
Published: March 2024

The body mass index (BMI), defined as weight in kilograms divided by height in meters squared, has been widely used to assess thinness and obesity in all age groups, including children and adolescents. However, the validity and utility of BMI as a reliable measure of nutritional health have been questioned. This study discusses the mathematical conditions that support the validity of BMI based on population statistics. Here, we propose a condition defined as allometric uni-scaling to ensure the validity of BMI as an objective height-adjusted measure. Any given centile curve, including the median curve, in a weight-for-height distribution should be approximated using power-law functions with the same scaling exponent. In contrast, when the scaling exponent varies depending on the position of the centile curve, it is called allometric multi-scaling. By introducing a method for testing these scaling properties using quantile regression, we analyzed a large-scale Japanese database that included 7,863,520 children aged 5-17 years. We demonstrated the remarkable multi-scaling properties at ages 5-13 years for males and 5-11 years for females, and the convergence to uni-scaling with a scaling exponent close to 2 as they approached 17 years of age for both sexes. We confirmed that conventional BMI is appropriate as an objective height-adjusted mass measure at least 17 years of age, close to adulthood, for both males and females. However, the validity of BMI could not be confirmed in younger age groups. Our findings indicate that the growth of children’s weight-for-height relation is much more complex than previously assumed. Therefore, a single BMI-type formula cannot be used to assess thinness and obesity in children and adolescents.
The extracellular heparan sulfatase SULF2 limits myeloid IFNβ signaling and Th17 responses in inflammatory arthritis
Authors: Swart Maarten , Redpath Andia , Ogbechi Joy , Cardenas Ryan , Topping Louise , Compeer Ewoud B. , Goddard Michael , Chanalaris Anastasios , Williams Richard , Brewer Daniel S. , Smart Nicola , Monaco Claudia , Troeberg Linda
Published: March 2024

Heparan sulfate (HS) proteoglycans are important regulators of cellular responses to soluble mediators such as chemokines, cytokines and growth factors. We profiled changes in expression of genes encoding HS core proteins, biosynthesis enzymes and modifiers during macrophage polarisation, and found that the most highly regulated gene wasSulf2, an extracellular HS 6-O-sulfatase that was markedly downregulated in response to pro-inflammatory stimuli. We then generatedSulf2+/-bone marrow chimeric mice and examined inflammatory responses in antigen-induced arthritis, as a model of rheumatoid arthritis. Resolution of inflammation was impaired in myeloidSulf2+/-chimeras, with elevated joint swelling and increased abundance of pro-arthritic Th17 cells in synovial tissue. Transcriptomic andin vitroanalyses indicated thatSulf2deficiency increased type I interferon signaling in bone marrow-derived macrophages, leading to elevated expression of the Th17-inducing cytokine IL-6. This establishes that dynamic remodeling of HS bySulf2limits type I interferon signaling in macrophages, and so protects against Th17-driven pathology.
Defects in exosome biogenesis are associated with sensorimotor defects in zebrafishvps4amutants
Authors: Shipman Anna , Gao Yan , Liu Desheng , Sun Shan , Zang Jingjing , Sun Peng , Syed Zoha , Bhagavathi Amol , Smith Eliot , Erickson Timothy , Hill Matthew , Neuhauss Stephan CF , Sui Sen-Fang , Nicolson Teresa
Published: March 2024

Mutations in humanVPS4Aare associated with neurodevelopmental defects, including motor delays and defective muscle tone.VPS4Aencodes a AAA-ATPase that is required for membrane scission, but how mutations inVPS4Alead to impaired control of motor function is not known. Here we identified a mutation in zebrafishvps4a, T248I, that affects sensorimotor transformation. In biochemical experiments we show that the T248I mutation reduces the ATPase activity of Vps4a and disassembly of its substrate, ESCRT filaments, which mediate membrane scission. Consistent with the established role for Vps4a in the endocytic pathway and exosome biogenesis,vps4aT248Imutants have enlarged endosomal compartments in the CNS and decreased numbers of circulating exosomes. Resembling the central form of hypotonia in humanVPS4Apatients, motor neurons and muscle cells are unaffected in mutant zebrafish as touch sensitivity in intact. Unlike somatosensory function, optomotor responses, vestibulospinal (VS), and acoustic startle reflexes are severely impaired invps4aT248Imutants, indicating a greater sensitivity of these circuits to the T248I mutation. ERG recordings indicate that visual ability is largely reduced in the mutants, however,in vivoimaging of tone-evoked responses in the inner ear and ascending auditory pathway show comparable activity. Further investigation of central pathways invps4aT248Imutants revealed that sensory cues failed to fully activate neurons in the VS and medial longitudinal fasciculus (MLF) nuclei that directly innervate motor neurons. Our results suggest that a defect in sensorimotor transformation underlies the profound yet selective effects on motor reflexes resulting from the loss of membrane scission mediated by Vps4a.
Hi-C profiling in tissues reveals 3D chromatin-regulated breast tumor heterogeneity and tumor-specific looping-mediated biological pathways
Authors: Choppavarapu Lavanya , Fang Kun , Liu Tianxiang , Jin Victor X.
Published: March 2024

Current knowledge in three-dimensional (3D) chromatin regulation in normal and disease states was mostly accumulated through Hi-C profiling inin vitrocell culture system. The limitations include failing to recapitulate disease-specific physiological properties and often lacking clinically relevant disease microenvironment. In this study, we conduct tissue-specific Hi-C profiling in a pilot cohort of 12 breast tissues comprising of two normal tissues (NTs) and ten ER+ breast tumor tissues (TTs) including five primary tumors (PTs), and five tamoxifen-treated recurrent tumors (RTs). We find largely preserved compartments, highly heterogeneous topological associated domains (TADs) and intensively variable chromatin loops among breast tumors, demonstrating 3D chromatin-regulated breast tumor heterogeneity. Further cross-examination identifies RT-specific looping-mediated biological pathways and suggests CA2, an enhancer-promoter looping (EPL)-mediated target gene within the bicarbonate transport metabolism pathway, might play a role in driving the tamoxifen resistance. Remarkably, the inhibition of CA2 not only impedes tumor growth bothin vitroandin vivo, but also reverses chromatin looping. Our study thus yields significant mechanistic insights into the role and clinical relevance of 3D chromatin architecture in breast cancer endocrine resistance.
Evaluating machine learning algorithms to predict lameness in dairy cattle
Authors: Neupane Rajesh , Aryal Ashrant , Haeussermann Angelika , Hartung Eberhard , Pinedo Pablo , Paudyal Sushil
Published: March 2024

Dairy cattle lameness represents one of the common concerns in intensive and commercial dairy farms. Lameness is characterized by gait-related behavioral changes in cows and multiple approaches are being utilized to associate these changes with lameness conditions including data from accelerometers, and other precision technologies. The objective was to evaluate the use of machine learning algorithms for the identification of lameness conditions in dairy cattle. In this study, 310 multiparous Holstein dairy cows from a herd in Northern Colorado were affixed with a leg-based accelerometer (Icerobotics® Inc, Edinburg, Scotland) to obtain the lying time (min/d), daily steps count (n/d), and daily change (n/d). Subsequently, study cows were monitored for 4 months and cows submitted for claw trimming (CT) were differentiated as receiving corrective claw trimming (CCT) or as being diagnosed with a lameness disorder and consequent therapeutic claw trimming (TCT) by a certified hoof trimmer. Cows not submitted to CT were considered healthy controls. A median filter was applied to smoothen the data by reducing inherent variability. Three different machine learning (ML) models were defined to fit each algorithm which included the conventional features (containing daily lying, daily steps, and daily change derived from the accelerometer), slope features (containing features extracted from each variable in Conventional feature), or all features (3 simple features and 3 slope features). Random forest (RF), Naive Bayes (NB), Logistic Regression (LR), and Time series (ROCKET) were used as ML predictive approaches. For the classification of cows requiring CCT and TCT, ROCKET classifier performed better with accuracy (> 90%), ROC-AUC (> 74%), and F1 score (> 0.61) as compared to other algorithms. Slope features derived in this study increased the efficiency of algorithms as the better-performing models included All features explored. However, further classification of diseases into infectious and non-infectious events was not effective because none of the algorithms presented satisfactory model accuracy parameters. For the classification of observed cow locomotion scores into severely lame and moderately lame conditions, the ROCKET classifier demonstrated satisfactory accuracy (> 0.85), ROC-AUC (> 0.68), and F1 scores (> 0.44). We conclude that ML models using accelerometer data are helpful in the identification of lameness in cows but need further research to increase the granularity and accuracy of classification.
Enhancer-targeted CRISPR-Activation Rescues Haploinsufficient Autism Susceptibility Genes
Authors: Chen George T. , Nair Gayatri , Osorio Aubrey J. , Holley Sandra M. , Ghassemzadeh Kimiya , Gonzalez Jose , Lu Congyi , Sanjana Neville E. , Cepeda Carlos , Geschwind Daniel H
Published: March 2024

Autism Spectrum Disorder (ASD) is a highly heritable condition with diverse clinical presentations. Approximately 20% of ASD’s genetic susceptibility is imparted byde novomutations of major effect, most of which cause haploinsufficiency. We mapped enhancers of two high confidence autism genes –CHD8andSCN2Aand used CRISPR-based gene activation (CRISPR-A) in hPSC-derived excitatory neurons and cerebral forebrain organoids to correct the effects of haploinsufficiency, taking advantage of the presence of a wildtype allele of each gene and endogenous gene regulation. We found that CRISPR-A induced a sustained increase inCHD8andSCN2Aexpression in treated neurons and organoids, with rescue of gene expression levels and mutation-associated phenotypes, including gene expression and physiology. These data support gene activation via targeting enhancers of haploinsufficient genes, as a therapeutic intervention in ASD and other neurodevelopmental disorders.
Soil viruses reduce greenhouse gas emissions and promote microbial necromass accrual
Authors: Liang Xiaolong , Sun Shiyu , Zhong Yujun , Zhang Ying , Wang Shuo , Wang Yongfeng , Xie Ninghui , Yang Lu , Radosevich Mark
Published: March 2024

Viral-induced microbial mortality has been proposed as a major contributor in shaping microbial community structure and function, soil carbon (C) accrual and mobilization of plant available nutrients. Yet, how soil viruses influence soil organic C (SOC) turnover and sequestration remains unknown. Here, we performed microcosm experiments with two distinct soils from grassland (GL) and agricultural (AG) sites and interrogated the roles of soil viruses in driving microbial community succession, SOC transformation and sequestration. The results show that soil viruses affected microbial C use efficiency and reduced respiration in microbial communities obtained from both GL and AG soils. Soil viruses affected microbial successional trajectories (via predation of dominant populations) and functional gene profiles triggering a significant decrease in CO2and N2O emissions. The impact of soil viruses on microbial community composition in GL microcosms was much less pronounced compared with that in AG microcosms, suggesting contrasting virus-host interaction patterns under different environmental settings. Viral infection significantly enhanced microbial necromass accumulation thereby increasing SOC and total nitrogen (TN) content. The results implicate viral-mediated microbial mortality as a key factor influencing the distribution of C between mineralization and soil C storage pathways. We proposed“viral loop”to explain the crucial function of soil viruses in SOC turnover and sequestration.
Circulating SFRP5 levels are elevated in colorectal cancer and correlate with overall survival in stage II-III disease
Authors: Li Runhao , Liu Saifei , Yeo Kenny , Edwards Suzanne , Li Man Ying , Santos Ryan , Kianpour Rad Sima , Wu Fangmeinuo , Maddern Guy , Young Joanne , Tomita Yoko , Townsend Amanda , Fenix Kevin , Hauben Ehud , Price Timothy , Smith Eric
Published: March 2024

Secreted Frizzled-Related Protein 5 (SFRP5) modulates Wnt signalling pathways, affecting diverse biological processes. We assessed the diagnostic and prognostic value of circulating SFRP5 (cSFRP5) in colorectal cancer (CRC). Plasma cSFRP5 concentrations were measured using ELISA in healthy donors (n=133), individuals diagnosed with CRC (n=449), colorectal polyps (n=85), and medical conditions in other organs including cancer, inflammation, and benign states (n=64). Patients with CRC, polyps, and other conditions showed higher cSFRP5 levels than healthy individuals (p<0.0001). Receiver operating characteristic curves comparing healthy donors with medical conditions, polyps, and CRC were 0.814 (p<0.0001), 0.763 (p<0.0001), and 0.762 (p<0.0001), respectively. In CRC, cSFRP5 correlated with patient age (p<0.0001), tumour stage (p<0.0001), and histological differentiation (p=0.0273). Levels peaked in stage II versus I (p<0.0001), III (p=0.0007), or IV (p<0.0001), and were higher in stage III versus I (p=0.0007) and IV (p=0.0054), with no difference between I and IV. Elevated cSFRP5 levels predicted longer overall survival in stage II-III CRC (univariate: HR 1.82, 95% CI 1.02-3.26, p=0.024; multivariable: HR 2.34, 95% CI 1.12-4.88, p=0.015). This study confirms elevated cSFRP5 levels in CRC and reveals a correlation between elevated cSFRP5 and overall survival in stage II-III disease.

Novelty and Impact

Our study unveils the clinical significance of circulating Secreted Frizzled-Related Protein 5 (cSFRP5) as a potential diagnostic and prognostic marker in colorectal cancer (CRC). Analysing plasma from 731 participants, we provide novel insights into cSFRP5, observing elevated levels in CRC compared to healthy controls, with the highest concentrations in stage II. Importantly, elevated cSFRP5 levels correlate with prolonged survival in stage II-III patients, suggesting a promising avenue for improving outcomes and reducing recurrence.
Pure-tone audiometry and dichotic listening in primary progressive aphasia and Alzheimer’s disease
Authors: Jiang Jessica , Johnson Jeremy , Levett Benjamin A , Core Lucy B , Volkmer Anna , Koohi Nehzat , Bamiou Doris-Eva , Marshall Charles R , Warren Jason D , Hardy Chris JD
Published: March 2024

Hearing is multifaceted and the relative contributions of peripheral and central hearing loss are rarely considered together in the context of dementia. Here, we assessed peripheral (as measured with pure-tone audiometry) and central (as measured with dichotic listening) hearing in 19 patients with typical amnestic Alzheimer’s disease (tAD), 10 patients with logopenic variant primary progressive aphasia (lvPPA), 11 patients with nonfluent/agrammatic variant PPA (nfvPPA), 15 patients with semantic variant PPA (svPPA), and 28 healthy age-matched individuals. Participants also underwent neuropsychological assessment and magnetic resonance image scanning, allowing us to use voxel-based morphometry to assess associations between hearing scores and grey matter volume. Dichotic listening was impaired in all patient groups relative to healthy controls. In the combined patient (but not healthy control) cohort, dichotic listening scores were significantly correlated with measures of global cognitive functioning and speech-based neuropsychological tasks. Pure-tone audiometry scores were not significantly elevated in any patient group relative to the healthy control group, and no significant correlations were observed between peripheral hearing and neuropsychological task performance in either the combined patient or healthy control cohorts. Neuroanatomically, dichotic listening performance was associated with grey matter volume in a bilateral fronto-temporo-parietal network over the combined patient cohort, but no correlates were identified for pure-tone audiometry. Our findings highlight the importance of speech parsing mechanisms beyond elementary sound detection in driving cognitive test performance, underline the importance of assessing central hearing alongside peripheral hearing in people with dementia, and further delineate the complex auditory profiles of neurodegenerative dementias.
Predictive Modeling for Diabetes Using GraphLIME
Authors: Costi Flavia , Onchis Darian , Hogea Eduard , Istin Codruta
Published: March 2024

The purpose of this paper is to present a detailed investigation of the advantages of employing GraphLIME (Local Interpretable Model Explanations for Graph Neural Networks) for the trustworthy prediction of diabetes mellitus. Our pursuit involves identifying the strengths of GraphLIME combined with the attention-mechanism over the standard coupling of deep learning neural networks with the original LIME method. The system build this way, provided us a proficient method for extracting the most relevant features and applying the attention mechanism exclusively to those features. We have closely monitored the performance metrics of the two approaches and conducted a comparative analysis. Leveraging attention mechanisms, we have achieved an accuracy of 92.6% for the addressed problem. The model’s performance is meticulously demonstrated throughout the study, and the results are furthermore evaluated using the Receiver Operating Characteristic (ROC) curve. By implementing this technique on a dataset of 768 patients diagnosed with or without diabetes mellitus, we have successfully boosted the model’s performance by over 18%.
Comparative cardiovascular safety of romosozumab versus bisphosphonates in Japanese patients with osteoporosis A new-user, active comparator design with instrumental variable analyses
Authors: Tominaga Ryoji , Ikenoue Tatsuyoshi , Ishii Ryosuke , Niihata Kakuya , Aita Tetsuro , Okuda Tadahisa , Shimizu Sayaka , Taguri Masataka , Kurita Noriaki
Published: March 2024

Importance

Romosozumab, a novel anti-osteoporotic agent, confers marked improvement in bone mineral density; however, its cardiovascular safety remains a concern.

Objective

To compare the cardiovascular safety of romosozumab to bisphosphonates in patients with osteoporosis.

Design

A cohort study using a new-user, active comparator design.

Setting

Medical facilities, including clinics and hospitals, visited by a wide range of populations in Japan that are covered by a commercial administrative claims database, collected from March 4, 2019 to August 31, 2021.

Participants

Japanese adults aged ≥40 years who were diagnosed with osteoporosis or experienced a fragility fracture. Those who received romosozumab or bisphosphonates after the commercialization of romosozumab started in Japan (March 4, 2019) were included.

Exposure

A new prescription of romosozumab or bisphosphonate (based on verification of a 180-day washout period).

Main Outcomes and Measures

The primary outcome was the incidence rate of cardiovascular disease (consisting of myocardial infarction and stroke) within one year of prescription. Cardiovascular disease was identified by algorithms with a combination of diagnosis, medical procedure, and drug codes. Facility-level prescription preference for romosozumab was used as an instrumental variable, defined as the proportion of romosozumab prescribed at the patient’s facility within 90 days prior to the index date.

Results

Of the 61,558 included prescriptions, 8,806 were for romosozumab and 52,752 were for bisphosphonates. The mean age of the romosozumab group was higher than that of the bisphosphonates group (80.5 vs. 78.3 years, respectively). The majority of patients were female (80.2 vs. 85.3%, respectively). The incidence of cardiovascular disease was 7.98 per 100 person-years for romosozumab versus 7.15 for bisphosphonates (unadjusted incidence rate ratio: 1.12 (95% confidence interval: 1.03-1.21)). An instrumental variable analysis using the two-stage residual inclusion method yielded a hazard ratio of 1.09 (95% confidence interval: 0.79-1.76) for romosozumab compared to bisphosphonates over one year.

Conclusions and Relevance

In this large observational study, there was no definitive evidence of increased risk of cardiovascular disease associated with romosozumab use compared with bisphosphonates in patients with osteoporosis. These findings alleviate clinicians’ excessive concerns about the potential cardiovascular safety of romosozumab in treatment decision-making for osteoporosis.