bluuebunny/crossref_metadata_2025_split huggingface dataset:
The ancestry of a genome or The amazing ubiquity of exponential distributions
Authors: Thompson Elizabeth 
Published: September 2024

AbstractMotivated originally by the increasing number of examples where a lone member of a once thriving population or even species now survives, we investigate what genomes of that population the survivor may represent. More generally it is of interest to consider what genomes of our ancestry each of us may represent. We consider only diploid dioecious organisms, and consider primarily the ancestry of a haploid genome, for example the maternal autosomes of the focal individual. Our ancestors are many and, in an unbounded population, increase exponentially in number. Our genetic ancestors are few, bounded by the number of ancestral genome segments which increases linearly over past generations. First we show that the major loss of potential ancestral lineages is at 8-11 generations, and that thereafter the number of genetic ancestors increases approximately linearly, but does not approach the upper bound. Over many generations, there remain tightly linked but not contiguous segments that result from the same ancestral lineage. Second we analyze the process of these ”repeated” ancestral segments that continue to be formed in distant ancestry, even as others are lost by recombination. Thirdly, we consider the effect of a finite population, with one model of a geographically structured population. Ancestors are many, and soon fill the entire species range even with low migration rates. Genetic ancestors are not only few, but remain geographically local.
A scalable approach for genome-wide inference of ancestral recombination graphs
Authors: Gunnarsson Árni Freyr , Zhu Jiazheng , Zhang Brian C. , Tsangalidou Zoi , Allmont Alex , Palamara Pier Francesco 
Published: September 2024

AbstractThe ancestral recombination graph (ARG) is a graph-like structure that encodes a detailed genealogical history of a set of individuals along the genome. ARGs that are accurately reconstructed from genomic data have several downstream applications, but inference from data sets comprising millions of samples and variants remains computationally challenging. We introduce Threads, a threading-based method that significantly reduces the computational costs of ARG inference while retaining high accuracy. We apply Threads to infer the ARG of 487,409 genomes from the UK Biobank using ∼10 million high-quality imputed variants, reconstructing a detailed genealogical history of the samples while compressing the input genotype data. Additionally, we develop ARG-based imputation strategies that increase genotype imputation accuracy for ultra-rare variants (MAC ≤10) from UK Biobank exome sequencing data by 5-10%. We leverage ARGs inferred by Threads to detect associations with 52 quantitative traits in non-European UK Biobank samples, identifying 22.5% more signals than ARG-Needle. These analyses underscore the value of using computationally efficient genealogical modeling to improve and complement genotype imputation in large-scale genomic studies.
Ethanol reduces grapevine water consumption by limiting transpiration
Authors: Kaci Neila Ait , Diot Alice , Quinquiry Beatrice , Yobregat Olivier , Pellegrino Anne , Maury Pierre , Chervin Christian 
Published: September 2024

AbstractStudies suggest that ethanol (EtOH), triggers plant adaptation to various stresses at low concentrations (10 µM to 10 mM). This study investigates whether EtOH induces drought acclimation in grapevine, as demonstrated previously inArabidopsis, rice, and wheat. Preliminary results with bare root Gamay cuttings showed that those pre-treated with 10 µM EtOH aqueous solutions lost fewer leaves when deprived of water compared to controls. Subsequently, we ran a potted-cutting experiment with progressive soil water deficit. Plants pre-treated with 250 mM EtOH solutions exhibited slower depletion of the fraction of transpirable soil water (FTSW), compared to controls. While 250 mM EtOH decreased transpiration in early days, these EtOH pre-treated plants maintained higher leaf transpiration than controls after 10 days of soil water depletion. The transpiration response to FTSW was affected by EtOH application. EtOH pre-treatments limited plant leaf expansion without increasing leaf senescence. Interestingly, plants primed with EtOH followed typical hormesis curves. These results suggest that EtOH improves grapevine acclimation to drought, leading to potential water-savings in wine growing regions prone to high water shortages, linked to climate change. These should encourage further testing under various vineyard conditions.
Anti-Candidaand antibiofilm activity of epinecidin-1 and its variants
Authors: Jeyarajan Sivakumar , Kumarasamy Anbarasu 
Published: September 2024

AbstractTo boost the stability and antimicrobial efficacy of the antimicrobial peptide (AMP) epinecidin-1, we previously engineered two variants — variant-1 and variant-2—by substituting alanine and histidine residues with lysine. This modification led to improved structural integrity and antibacterial function. Our current study builds on this foundation by assessing the anti-Candidacapabilities of epinecidin-1 and its variants against test organismsCandida albicans, Candida tropicalis, andCandida krusei. Both variants exhibited potent anti-Candidaactivity, particularly in disrupting biofilm formation. Minimum Inhibitory Concentrations (MICs) were found to be decreased for both variants compared to the original epinecidin-1 peptide, with variant-2 exhibiting the strongest activity. Electron microscopy confirmed that the mechanism of action involves pore formation and the induction of reactive oxygen species in theCandidacell membrane. Computational analysis showed the peptides have a high tendency to interact with theCandidacell membrane proteins like Exo-B-(1,3)-Glucanase, Secreted aspartic proteinase (Sap) 1, and N-terminal domain adhesin: Als 9-2, to prevent biofilm development.
Vascular network-inspired diffusible scaffolds for engineering functional neural organoids
Authors: Cai Hongwei , Tian Chunhui , Chen Lei , McCracken Kyle , Tchieu Jason , Gu Mingxia , Mackie Ken , Guo Feng 
Published: September 2024

SUMMARYOrganoids, three-dimensional in vitro organ-like tissue cultures derived from stem cells, show promising potential for developmental biology, drug discovery, and regenerative medicine. However, the function and phenotype of current organoids, especially neural organoids, are still limited by insufficient diffusion of oxygen, nutrients, metabolites, signaling molecules, and drugs. Herein, we present Vascular network-Inspired Diffusible (VID) scaffolds to fully recapture the benefits of physiological diffusion physics for generating functional organoids and phenotyping their drug response. In a proof-of-concept application, the VID scaffolds, 3D-printed meshed tubular channel networks, support the successful generation of engineered human midbrain organoids almost without necrosis and hypoxia in commonly used well-plates. Compared to conventional organoids, these engineered organoids develop with more physiologically relevant features and functions including midbrain-specific identity, oxygen metabolism, neuronal maturation, and network activity. Moreover, these engineered organoids also better recapitulate pharmacological responses, such as neural activity changes to fentanyl exposure, compared to conventional organoids with significant diffusion limits. Combining these unique scaffolds and engineered organoids may provide insights for organoid development and therapeutic innovation.
Selective disruption of Traf1/cIAP2 interaction attenuates inflammatory responses and limits sepsis and rheumatoid arthritis
Authors: Tang Yitian , Aleithan Fatemah , Madahar Sahib Singh , Mirzaesmaeili Ali , Saran Sunpreet , Tang Jialing , Zangiabadi Safoura , Inman Robert , Sweeney Gary , Abdul-Sater Ali A. 
Published: September 2024

AbstractTumor necrosis factor receptor-associated factor 1 (TRAF1) is an immune signaling adapter protein linked to increased susceptibility to rheumatoid arthritis (RA). TRAF1 has dual roles in regulating NF-κB and MAPK signaling: it promotes signaling through its association with cellular inhibitor of apoptosis 2 (cIAP2) downstream of certain tumor necrosis factor receptor (TNFR) family members but inhibits Toll-like receptor (TLR) signaling by limiting linear ubiquitination of key signaling proteins. Here, we identify a critical mutation in TRAF1 (V203A in humans, V196A in mice) that disrupts its interaction with cIAP2, leading to a significant reduction in TLR signaling and downstream inflammation in human and murine macrophages. We demonstrate that TRAF1 is recruited to the TLR4 complex and is indispensable for the recruitment of cIAP2, facilitating TAK1 phosphorylation and the activation of NF-κB and MAPK signaling pathways. Remarkably, mice harboring the TRAF1 V196A mutation are protected from LPS-induced septic shock and exhibit markedly reduced joint inflammation and disease severity in a collagen antibody-induced arthritis (CAIA) model of RA. These findings reveal a previously unrecognized and crucial role for the TRAF1/cIAP2 axis in promoting inflammation and offer a promising foundation for the development of novel therapeutic strategies for inflammatory conditions, such as sepsis and RA.
Osteogenic CpG Oligodeoxynucleotide, iSN40, Inhibits Osteo-clastogenesis in a TLR9-Dependent Manner
Authors: Ikeda Rena , Kimura Chihaya , Nihashi Yuma , Umezawa Koji , Shimosato Takeshi , Takaya Tomohide 
Published: September 2024

AbstractA CpG oligodeoxynucleotide (CpG-ODN), iSN40 (5’-GGA ACG ATC CTC AAG CTT-3’), was originally identified to promote osteoblast differentiation independent of Toll-like receptor 9 (TLR9). While CpG-ODNs are generally known to be recognized by TLR9 and inhibit osteoclasto-genesis. This study investigated the anti-osteoclastogenic effect of iSN40. The murine mono-cyte/macrophage cell line RAW264.7 was treated with receptor activator of nuclear factor-κB ligand (RANKL) to induce osteoclast differentiation, and the effects of iSN40 on osteoclast formation were quantified by tartrate-resistant acid phosphatase (TRAP) staining and real-time RT-PCR. iSN40 completely inhibited RANKL-induced differentiation into TRAP+multinucleated osteoclasts by suppressing osteoclastogenic genes (Nfatc1, Ctsk, andDcstamp) and inducing anti-/non-osteoclasto-genic genes (Irf8, Adgre1, andIl1b). Treatment with a TLR9 inhibitor, E6446, or mutation in the CpG motif of iSN40 abolished intracellular uptake and the anti-osteoclastogenic effect of iSN40. These results demonstrate that iSN40 is internalized subcellularly, recognized by TLR9 via its CpG motif, modulates RANKL-dependent osteoclastogenic gene expression, and ultimately inhibits osteoclast formation. Computational simulation of the iSN40 structure also suggested the importance of the superficial CpG motif for iSN40 function. Finally, iSN40 was confirmed to inhibit osteoclastogenesis of RAW264.7 cells cocultured with the murine osteoblast cell line MC3T3-E1, which is a model of bone remodeling. This study demonstrates that iSN40, which exerts both pro-osteogenic and anti-osteoclastogenic effects, may be a promising nucleic acid drug for osteoporosis.
STAMBPL1 activates the GRHL3/HIF1A/VEGFA axis through interaction with FOXO1 to promote angiogenesis in triple-negative breast cancer
Authors: Fang Huan , Liang Huichun , Yang Chuanyu , Jiang Dewei , Luo Qianmei , Cao Wenming , Zhang Huifeng , Chen Ceshi 
Published: September 2024

AbstractIn the clinic, anti-tumor angiogenesis is commonly employed for treating recurrent, metastatic, drug-resistant triple-negative and advanced breast cancer. Our previous research revealed that the deubiquitinase STAMBPL1 enhances the stability of MKP-1, thereby promoting cisplatin resistance in breast cancer. In this study, we discovered that STAMBPL1 could upregulate the expression of the hypoxia-inducible factor HIF1α in breast cancer cells. Therefore, we investigated whether STAMBPL1 promotes tumor angiogenesis. We demonstrated that STAMBPL1 increasedHIF1Atranscription in a non-enzymatic manner, thereby activating the HIF1α/VEGFA signaling pathway to facilitate TNBC angiogenesis. Through RNA-seq analysis, we identified the transcription factor GRHL3 as a downstream target of STAMBPL1 that is responsible for mediatingHIF1Atranscription. Furthermore, we discovered that STAMBPL1 regulatesGRHL3transcription by interacting with the transcription factor FOXO1. These findings shed light on the role and mechanism of STAMBPL1 in the pathogenesis of breast cancer, offering novel targets and avenues for the treatment of triple-negative and advanced breast cancer.
Cluster randomized controlled trial to assess the effectiveness of a package of community-based intervention on continuum of maternal and newborn healthcare in Sidama, Ethiopia:The SiMaNeH trial protocol
Authors: Gebretsadik Achamyelesh , Shiferaw Yemisrach , Gemeda Hirut , Yaya Yaliso 
Published: September 2024

AbstractBackgroundMaternal and newborn mortality and morbidity remain high in low-and middle-income countries such as Ethiopia. Limited access and dropouts from essential continuum of care interventions are critical factors. In Ethiopia about one in five complete the continuum of essential care through pregnancy, childbirth, and postnatal period Ethiopia. Evidence is limited on whether a package of interventions involving key community health actors increase the proportion completing essential maternal and newborn healthcare continuum in rural Sidama regional state, Ethiopia.ObjectiveThis study aims to implement and evaluate the effectiveness of community-based interventions designed to enhance involvement of key community health actors to improve completion rate of continuum of maternal care and utilization of newborn care.MethodsTwenty rural kebeles (clusters) in Sidama Regional State, Ethiopia, are randomly allocated to intervention and control arms. A total of 2000 pregnant women, 1000 per arm, will be recruited between 20thand 26thweek of gestation after intervention. Then they will be followed until six weeks postpartum between June 2024 and February 2025. In the intervention arm, mothers and newborns will receive targeted interventions at home and in their community through a package of interventions designed to improve completion rate of recommended maternal and newborn care. Control clusters will receive normal care from the state public health system. Primary outcomes will be the difference in the completion of continuum of maternal care and essential and emergency newborn care between intervention and control clusters measured by composite indicator constructed from variables. Secondary outcomes include rates of antenatal care completion, facility deliveries with skilled care, completion of at least four postnatal care, essential newborn care, and emergency identification and referrals, mortality measures.ConclusionThis trial will implement and evaluate community-based intervention package within existing community healthcare infrastructure to produce evidence for informed policy and practice to achieve improved community-based healthcare.
Identification of multimodal mental health signatures in the young population using deep phenotyping
Authors: Mørch Niels , Calderón Andrés B. , Kvamme Timo L. , Donskov Julie G. , Zana Blanka , Durand Simon , Bjekic Jovana , Machizawa Maro G. , Yamada Makiko , Ottosson Filip A. , Bybjerg-Grauholm Jonas , Ernst Madeleine , Børglum Anders D. , Sandberg Kristian , Qvist Per 
Published: September 2024

AbstractBackgroundMental health encompasses emotional, psychological, and social dimensions, extending beyond the mere absence of illness. Shaped by a complex interplay of hereditary factors and life experiences, mental health can deteriorate into clinical conditions necessitating intervention. However, the ambiguity between pathological and non-pathological states, along with overlapping clinical profiles, challenges traditional diagnostic procedures, highlighting the need for a dimensional approach in stratified psychiatry.MethodsWe analyzed comprehensive phenotypic data from ∼300 young Danish participants, including psychometric assessments, brain imaging, genetics, and circulatory OMICs markers. Using a novel psychometry-based archetyping approach, we employed soft-clustering analyses to stratify participants based on distinct cognitive, emotional, and behavioral patterns, while exploring their genetic and neurobiological underpinnings.ResultsFive psychometric archetypes were identified, representing a continuum of mental health traits. One archetype, characterized by high neuroticism, emotional dysregulation, and elevated stress and depression scores, was firmly associated with self-reported mental health diagnoses, psychiatric comorbidities, and family history of mental illness. Genetic predisposition to mental health conditions, reflected in polygenic scores (PGSs), accounted for up to 9% of the variance in archetypes, with significant contributions from neuroimaging-related PGSs. The overlaps between broader genetic profiles and archetypes further confirmed their biological foundations. Neuroimaging data linked the risk-associated archetype to both regional and global brain volumetric changes, while metabolomic analysis identified differentiating metabolites related to mood regulation and neuroinflammation.ConclusionsThis study demonstrates the feasibility of data-driven stratification of the general population into distinct risk groups defined by multimodal mental health signatures. This stratification offers a robust framework for understanding mental health variation and holds significant potential for advancing early screening and targeted intervention strategies in the young population.
Negative feedback of cyclic di-GMP levels optimizes switching between sessile and motile lifestyles inVibrio cholerae
Authors: Rangarajan Aathmaja Anandhi , Schroeder Jeremy W. , Hurto Rebecca L. , Severin Geoffrey B. , Pell Macy E. , Hsieh Meng-Lun , Waters Christopher M. , Freddolino Lydia 
Published: September 2024

AbstractThe signaling molecule cyclic di-GMP (cdG) controls the switch between bacterial motility and biofilm production, and fluctuations in cellular levels of cdG have been implicated inVibrio choleraepathogenesis. Intracellular concentrations of cdG are controlled by the interplay of diguanylate cyclase (DGC) enzymes, which synthesize cdG to promote biofilms, and phosphodiesterase (PDE) enzymes, which hydrolyse cdG to drive motility. To track the complete regulatory logic of howV. choleraeresponds to changing cdG levels, we followed a timecourse of overexpression of either theV. harveyidiguanylate cyclase QrgB or a variant of QrgB lacking catalytic activity (QrgB*). We find that QrgB increases cdG levels relative to QrgB* for 30 minutes after overexpression, but the effect of QrgB on cdG levels plateaus at 30 minutes, indicating tight adaptive control of cdG levels. In contrast, loss of VpsR, a master regulator activating biofilm formation upon binding to cdG, leads to higher baseline levels of cdG and continuously increasing cdG through 60 minutes after QrgB induction, revealing the existence of a negative feedback loop on cdG levels operating through VpsR. Through a combination of RNA polymerase ChIP-seq, RNA-seq, and genetic approaches, we show that transcription of a gene encoding a PDE,cdgC, is activated by VpsR at high cdG concentrations, mediating this negative feedback on cdG levels. We further identify a transcript encoded within, and antisense to, thecdgCopen reading frame which we namesRNAnegativeregulator ofCdgC (SnrC). RNA polymerase ChIP-seq and RNA-seq demonstrate SnrC to be expressed specifically under conditions of high cdG in the absence of VpsR. Ectopic SnrC expression increases cdG levels in a manner dependent on CdgC, demonstrating that its effect on cdG levels is likely through interference with CdgC production. Further, although cells lackingcdgCexhibit enhanced biofilm formation, these mutants are outcompeted by wild typeV. choleraein colonization assays that reward a combination of attachment, dispersal, and motility behaviors. These results underscore the importance of negative feedback regulation of cdG to maintain appropriate homeostatic levels for efficient transitioning between biofilm formation and motility, both of which are necessary over the course of theV. choleraeinfection cycle.
Sense codon-misassociated eRF1 elicits widespread ribosome stalling and induction of quality control
Authors: Han Peixun , Mito Mari , Ito Takuhiro , Iwasaki Shintaro 
Published: September 2024

AbstractRibosome-associated quality control (RQC) is a surveillance system for aberrant translation that senses ribosome collisions. Although the molecular mechanism has been extensively studied, the endogenous targets of RQC in human cells are poorly understood. Here, beginning with a study of the codon specificity of the eukaryotic translation termination factor eRF1, we show that transient binding of eRF1 to the UUA sense codon leads to ribosome collision and provides a source of RQC substrates in humans. eRF1-selective Monosome-Seq and Disome-Seq revealed that eRF1 was recruited not only to stop codons but also to subcognate sense codons, including the UUA codon. The eRF1 on UUA codons delays translation elongation but does not trigger the termination reaction. Remarkably, Disome-Seq with the depletion of ASCC3 and 4EHP, key factors in RQC, showed that ribosomes stalled at UUA codons constitute a predominant subpopulation rescued by RQC. Failure to resolve ribosome collisions by RQC triggers p38 phosphorylation and expression of the stress-induced transcription factor ATF3. This study highlights the impact of sense codon misrecognition by the termination factor on translation homeostasis in human cells.
Enzyme activation by urea reveals the interplay between conformational dynamics and substrate binding: a single-molecule FRET study
Authors: Scheerer David , Levy Dorit , Casier Remi , Riven Inbal , Mazal Hisham , Haran Gilad 
Published: September 2024

AbstractProteins often harness extensive motions of domains and subunits to promote their function. Deciphering how these movements impact activity is key for understanding life’s molecular machinery. The enzyme adenylate kinase is an intriguing example for this relationship; it ensures efficient catalysis by large- scale domain motions that lead to the enclosure of the bound substrates ATP and AMP. At high concentrations, AMP also operates as an allosteric inhibitor of the protein. Surprisingly, the enzyme is activated by urea, a compound commonly acting as a denaturant. Combining single-molecule FRET spectroscopy and enzymatic activity studies, we find that urea interferes with two key mechanisms that contribute to enzyme efficacy. First, urea promotes the open conformation of the enzyme, aiding the proper positioning of the substrates. Second, urea decreases AMP affinity, paradoxically facilitating a more efficient progression towards the catalytically active complex. These results signify the important interplay between conformational dynamics and chemical steps, including binding, in the activity of enzymes. State-of-the-art tools, such as single-molecule fluorescence spectroscopy, offer new insights into how enzymes balance different conformations to regulate activity.