bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

ABSTRACTBioluminescent 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

AbstractCirculating 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

ABSTRACTGaze-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 CONCEPTSHuman-centered computing→Virtual reality;Mixed / augmented reality;Accessibility technologies;Interaction techniques.ACM Reference FormatG. 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

AbstractAtrial 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

AbstractAccumulation 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

AbstractMotivationGenotyping 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.AvailabilityNOISYmputer 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

AbstractThe 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

AbstractHeparan 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.
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

SUMMARYCurrent 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.
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

AbstractAutism 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

AbstractViral-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

ABSTRACTSecreted 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 ImpactOur 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.