bluuebunny/crossref_metadata_2025 huggingface dataset:
AMRomics: a scalable workflow to analyze large microbial genome collection
Authors: Le Duc Quang , Nguyen Tam Thi , Nguyen Canh Hao , Ho Tho Huu , Vo Nam S. , Nguyen Trang , Nguyen Hoang Anh , Cao Minh Duc , Nguyen Son Hoang
Published: April 2024

Whole genome analysis for microbial genomics is critical to studying and monitoring antimicrobial resistance strains. The exponential growth of microbial sequencing data necessitates a fast and scalable computational pipeline to generate the desired outputs in a timely and cost-effective manner. Recent methods have been implemented to integrate individual genomes into large collections of specific bacterial populations and are widely employed for systematic genomic surveillance. However, they do not scale well when the population expands and turnaround time remains the main issue for this type of analysis. Here, we introduce AMRomics, a minimalized microbial genomics pipeline that can work efficiently with big datasets. We use different bacterial data collections to compare AMRomics against competitive tools and show that our pipeline can generate similar results of interest but with better performance. The software is open source and is publicly available athttps://github.com/amromics/amromicsunder an MIT license.
Towards high-resolution modeling of small molecule-ion channel interactions
Authors: Harris Brandon J , Nguyen Phuong T , Zhou Guangfeng , Wulff Heike , DiMaio Frank , Yarov-Yarovoy Vladimir
Published: April 2024

Ion channels are critical drug discovery targets for a wider range of pathologies, such as epilepsy, chronic pain, itch, autoimmunity, and cardiac arrhythmias. To develop effective and safe therapeutics, it is necessary to design small molecules with high potency and selectivity for specific ion channel subtypes. There has been increasing implementation of structure-guided drug design for the development of small molecules targeting ion channels. We evaluated the performance of two Rosetta ligand docking methods, RosettaLigand and GALigandDock, on structures of known ligand-cation channel complexes. Ligands were docked to voltage-gated sodium (NaV), voltage-gated calcium (CaV), and transient receptor potential vanilloid (TRPV) channel families. For each test case, RosettaLigand and GALigandDock methods were able to frequently sample a ligand binding pose within 1-2 Å root mean square deviation (RMSD) relative to the native ligand-channel structure. However, RosettaLigand and GALigandDock scoring functions cannot consistently identify native drug binding poses as top-scoring models. Our study reveals that the proper scoring criteria for RosettaLigand and GALigandDock modeling of ligand-ion channel complexes should be assessed on a case-by-case basis using sufficient ligand and receptor interface sampling, knowledge about state specific interactions of the ion channel and inherent receptor site flexibility that could influence ligand binding.
SARM1 activation induces reversible mitochondrial dysfunction and can be prevented in human neurons by antisense oligonucleotides
Authors: Loreto Andrea , Cramb Kaitlyn M. L. , McDermott Lucy A. , Antoniou Christina , Cirilli Ilenia , Caiazza Maria Claudia , Merlini Elisa , Arthur-Farraj Peter , Mock Elliot D. , Zhao Hien T. , Bennett David L. , Orsomando Giuseppe , Coleman Michael P. , Wade-Martins Richard
Published: April 2024

SARM1 is a key regulator of a conserved program of axon degeneration increasingly linked to human neurodegenerative diseases. Pathological SARM1 activation causes rapid NAD consumption, disrupting cellular homeostasis and leading to axon degeneration. In this study, we develop antisense oligonucleotides targeting human SARM1, demonstrating robust neuroprotection against morphological, metabolic, and mitochondrial impairment in human iPSC-derived dopamine neurons induced by the lethal neurotoxin vacor, a potent SARM1 activator. Furthermore, our findings reveal that axon fragmentation can be prevented, and mitochondrial dysfunction reversed using the NAD precursor nicotinamide, a form of vitamin B3, even after SARM1 activation has occurred, when neurons are already unhealthy. This research identifies ASOs as a promising therapeutic strategy to block SARM1, and provides an extensive characterisation and further mechanistic insights that demonstrate the reversibility of SARM1 toxicity in human neurons. It also identifies the SARM1 activator vacor as a specific and reversible neuroablative agent in human neurons.
A drought stress-responsive metabolite malate modulates stomatal responses through G-protein-dependent pathway in grapevine and Arabidopsis
Authors: Mimata Yoshiharu , Gong Ruhai , Pei Xuanxuan , Qin Guochen , Ye Wenxiu
Published: April 2024

Drought stress is a significant environmental threat to global agricultural production and distribution. Plant adaptation to dehydration stress involves intricate biological processes with substantial changes in metabolite composition. In this study, we investigated the role of tricarboxylic acid (TCA) cycle metabolites in drought tolerance in grapevine and Arabidopsis by metabolome, live cell imaging, electrophysiological and pharmacological approaches. Metabolome analysis revealed that amount of malate, citrate, and isocitrate increased over time in detached grapevine leaves. Ca2+ imaging and ion channel measurements indicated that fumarate, malate, and α-ketoglutarate induced cytosolic free Ca2+ concentration ([Ca2+]cyt) elevation in guard cells and directly activated a guard-cell anion channel SLAC1. However, only malate induced stomatal closure, which required increases in [Ca2+]cyt in guard cells and activation of SLAC1. Through pharmacological experiments and reverse genetics analyses, G-proteins were identified as essential components of malate signaling by regulating second messenger production. These results indicate that TCA cycle metabolites are sensed individually by guard cells and that malate plays a key role in connecting metabolic regulation and drought tolerance through G-protein-dependent signal cascades.
Predicting Functional Conformational Ensembles and Binding Mechanisms of Convergent Evolution for SARS-CoV-2 Spike Omicron Variants Using AlphaFold2 Sequence Scanning Adaptations and Molecular Dynamics Simulations
Authors: Raisinghani Nishank , Alshahrani Mohammed , Gupta Grace , Xiao Sian , Tao Peng , Verkhivker Gennady
Published: April 2024

In this study, we combined AlphaFold-based approaches for atomistic modeling of multiple protein states and microsecond molecular simulations to accurately characterize conformational ensembles and binding mechanisms of convergent evolution for the SARS-CoV-2 Spike Omicron variants BA.1, BA.2, BA.2.75, BA.3, BA.4/BA.5 and BQ.1.1. We employed and validated several different adaptations of the AlphaFold methodology for modeling of conformational ensembles including the introduced randomized full sequence scanning for manipulation of sequence variations to systematically explore conformational dynamics of Omicron Spike protein complexes with the ACE2 receptor. Microsecond atomistic molecular dynamic simulations provide a detailed characterization of the conformational landscapes and thermodynamic stability of the Omicron variant complexes. By integrating the predictions of conformational ensembles from different AlphaFold adaptations and applying statistical confidence metrics we can expand characterization of the conformational ensembles and identify functional protein conformations that determine the equilibrium dynamics for the Omicron Spike complexes with the ACE2. Conformational ensembles of the Omicron RBD-ACE2 complexes obtained using AlphaFold-based approaches for modeling protein states and molecular dynamics simulations are employed for accurate comparative prediction of the binding energetics revealing an excellent agreement with the experimental data. In particular, the results demonstrated that AlphaFold-generated extended conformational ensembles can produce accurate binding energies for the Omicron RBD-ACE2 complexes. The results of this study suggested complementarities and potential synergies between AlphaFold predictions of protein conformational ensembles and molecular dynamics simulations showing that integrating information from both methods can potentially yield a more adequate characterization of the conformational landscapes for the Omicron RBD-ACE2 complexes. This study provides insights in the interplay between conformational dynamics and binding, showing that evolution of Omicron variants through acquisition of convergent mutational sites may leverage conformational adaptability and dynamic couplings between key binding energy hotspots to optimize ACE2 binding affinity and enable immune evasion.
Unveiling the Core Functional Networks of Cognition: An Ontology-Guided Machine Learning Approach
Authors: Wu Guowei , Cui Zaixu , Wang Xiuyi , Du Yi
Published: April 2024

Deciphering the functional architecture that underpins diverse cognitive functions is fundamental quest in neuroscience. In this study, we employed an innovative machine learning framework that integrated cognitive ontology with functional connectivity analysis to identify brain networks essential for cognition. We identified a core assembly of functional connectomes, primarily located within the association cortex, which showed superior predictive performance compared to two conventional methods widely employed in previous research across various cognitive domains. Our approach achieved a mean prediction accuracy of 0.13 across 16 cognitive tasks, including working memory, reading comprehension, and sustained attention, outperforming the traditional methods’ accuracy of 0.08. In contrast, our method showed limited predictive power for sensory, motor, and emotional functions, with a mean prediction accuracy of 0.03 across 9 relevant tasks, slightly lower than the traditional methods’ accuracy of 0.04. These cognitive connectomes were further characterized by distinctive patterns of resting-state functional connectivity, structural connectivity via white matter tracts, and gene expression, highlighting their neurogenetic underpinnings. Our findings reveal a domain-general functional network fingerprint that pivotal to cognition, offering a novel computational approach to explore the neural foundations of cognitive abilities.
The effect of transcutaneous auricular vagus nerve stimulation on cardiovascular function in subarachnoid hemorrhage patients: a safety study
Authors: Tan Gansheng , Huguenard Anna L. , Donovan Kara M. , Demarest Phillip , Liu Xiaoxuan , Li Ziwei , Adamek Markus , Lavine Kory , Vellimana Ananth K. , Kummer Terrance T. , Osbun Joshua W. , Zipfel Gregory J. , Brunner Peter , Leuthardt Eric C.
Published: April 2024

Structured Abstract

Introduction

Subarachnoid hemorrhage (SAH) is characterized by intense central inflammation, leading to substantial post-hemorrhagic complications such as vasospasm and delayed cerebral ischemia. Given the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation (taVNS) and its ability to promote brain plasticity, taVNS has emerged as a promising therapeutic option for SAH patients. However, the effects of taVNS on cardiovascular dynamics in critically ill patients, like those with SAH, have not yet been investigated. Given the association between cardiac complications and elevated risk of poor clinical outcomes after SAH, it is essential to characterize the cardiovascular effects of taVNS to ensure this approach is safe in this fragile population. Therefore, we assessed the impact of both acute taVNS and repetitive taVNS on cardiovascular function in this study.

Methods

In this randomized clinical trial, 24 SAH patients were assigned to either a taVNS treatment or a Sham treatment group. During their stay in the intensive care unit, we monitored patient electrocardiogram (ECG) readings and vital signs. We compared long-term changes in heart rate, heart rate variability, QT interval, and blood pressure between the two groups. Additionally, we assessed the effects of acute taVNS by comparing cardiovascular metrics before, during, and after the intervention. We also explored acute cardiovascular biomarkers in patients exhibiting clinical improvement.

Results

We found that repetitive taVNS did not significantly alter heart rate, QT interval, blood pressure, or intracranial pressure. However, taVNS increased overall heart rate variability and parasympathetic activity compared to the sham treatment. The increase in parasympathetic activity was most pronounced from 2–4 days after initial treatment (Cohen’s d = 0.50). Acutely, taVNS increased heart rate, blood pressure, and peripheral perfusion index without affecting the corrected QT interval, intracranial pressure, or heart rate variability. The acute post-treatment elevation in heart rate was more pronounced in patients who experienced a decrease of more than one point in their Modified Rankin Score at the time of discharge.

Conclusions

Our study found that taVNS treatment did not induce adverse cardiovascular effects, such as bradycardia or QT prolongation, supporting its development as a safe immunomodulatory treatment approach for SAH patients. The observed acute increase in heart rate after taVNS treatment may serve as a biomarker for SAH patients who could derive greater benefit from this treatment.

Trial registration

NCT04557618
Microbiome-based biomarkers to guide personalized microbiome-based therapies for Parkinson’s disease
Authors: Payami Haydeh , Sampson Timothy R , Murchison Charles F , Wallen Zachary D
Published: April 2024

We address an unmet challenge in Parkinson’s disease: the lack of biomarkers to identify the right patients for the right therapy, which is a main reason clinical trials for disease modifying treatments have all failed. The gut microbiome is a new target for treatment of Parkinson’s disease, with potential to halt disease progression. Our aim was to develop microbiome-based biomarkers to guide patient selection for microbiome-based clinical trials. We used microbial taxa that have been robustly associated with Parkinson’s disease across studies and at high significance as dysbiotic features of Parkinson’s disease. Using individual-level taxonomic relative abundance data, we classified patients according to their dysbiotic features, effectively defining microbiome-based subtypes of PD. We show that not all persons with Parkinson’s disease have a dysbiotic microbiome, and not all dysbiotic Parkinson’s disease microbiomes have the same features. Grounded in robust and reproducible data from differential abundance studies, we propose an intuitive and easily modifiable method to identify the optimal candidates for microbiome-based clinical trials, and subsequently, for treatments that are personalized for each individual’s dysbiotic features. We demonstrate the method for Parkinson’s disease. The concept, and the method, is generalizable for any disease with a microbiome component.
Multi-ancestry GWAS of diarrhea during acute SARS-CoV2 infection identifies multiple novel loci and contrasting etiological roles of irritable bowel syndrome subtypes
Authors: Chaudhary Ninad S. , Weldon Catherine H. , Nandakumar Priyanka , Shelton Janie F. ,   23andMe Research Team, Holmes Michael V. , Aslibekyan Stella
Published: April 2024

A substantial proportion of acute SARS-CoV2 infection cases exhibit gastrointestinal symptoms, yet the genetic determinants of these extrapulmonary manifestations are poorly understood. Using survey data from 239,866 individuals who tested positively for SARS-CoV2, we conducted a multi-ancestry GWAS of 80,289 cases of diarrhea occurring during acute COVID-19 infection (33.5%). Six loci (CYP7A1, LZFTL1- -CCR9, TEME182, NALCN, LFNG, GCKR) met genome-wide significance in a trans-ancestral analysis. The top significant GWAS hit mapped to theCYP7A1locus, which plays an etiologic role in bile acid metabolism and is in high LD (r2= 0.93) with theSDCBPgene, which was previously implicated in antigen processing and presentation in the COVID-19 context. Another association was observed with variants in theLZTFL1–CCR9region, which is a known locus for COVID-19 susceptibility and severity. PheWAS showed a shared association across three of the six SNPs with irritable bowel syndrome (IBS) and its subtypes. Mendelian randomization showed that genetic liability to IBS-diarrhea increased (OR=1.40,95%,CI[1.33-1.47]), and liability to IBS-constipation decreased (OR=0.86, 95%CI[0.79-0.94]) the relative odds of experiencing COVID-19+ diarrhea. Our genetic findings provide etiological insights into the extrapulmonary manifestations of acute SARS-CoV2 infection.
Identification of moderate effect size genes in autism spectrum disorder through a novel gene pairing approach
Authors: Caballero Madison , Satterstrom F Kyle , Buxbaum Joseph D. , Mahjani Behrang
Published: April 2024

Autism Spectrum Disorder (ASD) arises from complex genetic and environmental factors, with inherited genetic variation playing a substantial role. This study introduces a novel approach to uncover moderate effect size (MES) genes in ASD, which individually do not meet the ASD liability threshold but collectively contribute when paired with specific other MES genes. Analyzing 10,795 families from the SPARK dataset, we identified 97 MES genes forming 50 significant gene pairs, demonstrating a substantial association with ASD when considered in tandem, but not individually. Our method leverages familial inheritance patterns and statistical analyses, refined by comparisons against control cohorts, to elucidate these gene pairs’ contribution to ASD liability. Furthermore, expression profile analyses of these genes in brain tissues underscore their relevance to ASD pathology. This study underscores the complexity of ASD’s genetic landscape, suggesting that gene combinations, beyond high impact single-gene mutations, significantly contribute to the disorder’s etiology and heterogeneity. Our findings pave the way for new avenues in understanding ASD’s genetic underpinnings and developing targeted therapeutic strategies.
Layer-specific input to medial prefrontal cortex is linked to stress susceptibility
Authors: Solakoglu Sabahaddin Taha , Erdener Sefik Evren , Gliko Olga , Can Alp , Sumbul Uygar , Eren-Kocak Emine
Published: April 2024

Stress response is essential for adapting to an ever-changing environment. However, the mechanisms that render some individuals susceptible to stress are poorly understood. While chronic stress is known to induce dendritic atrophy and spine loss in medial prefrontal cortex (mPFC), its impact on synapses made by long-range projections terminating on the mPFC remains unknown. Here, we labeled synapses on male mouse mPFC dendrites formed by ventral hippocampus (VH), basolateral amygdala (BLA) and ventral tegmental area (VTA) long-range afferents using different-colored eGRASP constructs. We obtained multispectral 3D-images of the mPFC covering all cortical laminae, and automatically segmented the dendrites and synapses. In layer II/III, the relative abundances and spatial organizations of VH-mPFC and BLA-mPFC synapses changed similarly in stress resilient (SR) and stress susceptible (SS) mice when compared to stress naive (SN) mice. In layers Vb and VI, on the other hand, the percentage of BLA-mPFC increased and that of VH-mPFC decreased only in SS mice. Moreover, the distances of VH synapses to their corresponding closest BLA synapses decreased and the distances of BLA synapses to their corresponding closest VH synapses increased in the SS group. Consistently, the percentage of single dendritic segments receiving input from multiple brain regions increased in the SS group, suggesting that long-range synaptic inputs to deep layers of mPFC were disorganized in SS mice. Our findings demonstrate afferent- and lamina-specific differential reorganization of synapses between different stress phenotypes, suggesting specific roles for different long-range projections in mediating the stress response.
ROS Mediated the Photodynamic Antibacterial ofVibrio vulnificusby a DNA-Targeted Molecular Rotor Probe
Authors: Yue Haiyun , Bian Qing , Li Xintong , Yu Chao , Chen Chao , Wang Kangnan , Cao Yuan
Published: April 2024

Vibrio vulnificus, a highly pathogenic Gram-negative bacterium, is capable of inducing sepsis, necrotizing fasciitis, and skin and soft tissue infections through contact with wounds. Currently, the majority ofV. vulnificusstrains have developed resistance to multiple drugs, highlighting the critical necessity for the development of novel therapeutics capable of effectively targeting and eradicating this bacterium. In recent years, material molecules have emerged as promising antimicrobial agents. This study introduces a novel molecular fluorescent probe, BDTP, which demonstrates a wide-ranging antimicrobial effect against both Gram-negative and Gram-positive bacteria while exhibiting minimal toxicity to normal mammalian cells. Of particular significance is BDTP’s ability to rapidly detect V. vulnificus, bind to bacterial DNA, and exhibit fluorescence monitoring behavior. Furthermore, BDTP displays enhanced photodynamic antibacterial activity when exposed to white light irradiation. Under a low dose of white light (15mW cm-2), the killing efficiency ofV. vulnificusirradiated with 4uM for 10 minutes was more than 99.8%. Moreover, it could significantly inhibit and eliminate the biofilm formed byV. vulnificus. It can induce the production of reactive oxygen species (ROS) inV. vulnificuscells, leading to bacterial cell damage. More importantly, BDTP significantly promoted the healing of infected wounds in an animal model ofV. vulnificusinfection. Therefore, BDTP shows great promise as a potent antibacterial agent againstV. vulnificusinfection.
Morphological, pathological and phylogenetic analyses identify a diverse group ofColletotrichumspp. causing leaf, pod, and flower diseases on the orphan legume African yam bean
Authors: Ogunsanya Olaide Mary , Adebisi Moruf Ayodele , Popoola Akinola Rasheed , Afolabi Clement Gboyega , Oyatomi Olaniyi , Colgan Richard , Armitage Andrew , Thompson Elinor , Abberton Michael , Ortega-Beltran Alejandro
Published: April 2024

African yam bean (AYB;Sphenostylis stenocarpaHochst. Ex A. Rich.) is an underutilized legume indigenous to Africa. The crop has great potential as it can enhance food security and its chemical composition offers nutritional and medicinal opportunities. However, the low grain yield caused by fungal diseases, including pod blight and leaf tip dieback, deters farmers from large-scale cultivation. The causal agents of pod and leaf tip dieback on AYB are largely uncharacterized. To determine the prevalence of fungal diseases affecting leaves, pods, and flowers of AYB, a survey was conducted in 2018 and 2019 in major AYB-growing areas in Nigeria. Leaf tip dieback, flower bud rot, and pod blight were the most common symptoms. Morphological and molecular assays were conducted to identify the causal agents of the observed diseases. In all the samples examined, fungi from eight genera were isolated from leaves and pods showing disease symptoms. However, Koch’s postulates were fulfilled only for fungi belonging to theColletotrichumgenus. Fungi from the other seven genera did not produce disease symptoms in healthy AYB tissues. SeveralColletotrichumisolates were characterized by sequencing the ITS, glyceraldehyde-3-phosphate dehydrogenase, calmodulin, and ApMAT loci. A combined phylogenetic analysis revealed fourColletotrichumspecies:C. siamense,C. theobromicola,andC. fructicola, which were recovered from the diseased leaves, andC. truncatum, which was recovered from diseased pods and buds. Our results are useful to gear efforts to develop integrated management strategies to control diseases affecting AYB in Nigeria and other parts of Africa. The availability of such strategies may stimulate greater cultivation of AYB to contribute to diet diversification, which has been repeatedly advocated by a range of stakeholders to increase food security and the prosperity of smallholder farmers.
Machine learning recognises senescence in glioblastoma and discovers senescence-inducing compounds
Authors: Martin Lucy , Irving Anna , Suwanlikit Yossawat , Morrison Gillian , Elliott Richard J.R. , Carragher Neil , Pollard Steven , Chandra Tamir
Published: April 2024

Senescence is a cell-intrinsic tumour suppressive response. A one-two-punch cancer treatment strategy aims to induce senescence in cancerous cells before removing them with a senolytic. It is important to accurately recognise senescent cells to investigate the feasibility of such a treatment strategy and identify compounds that induce senescence in cancer. We focus specifically on the terminal brain cancer glioblastoma, firstly identifying senescent glioblastoma cells with conventional stains, before training a machine learning model to distinguish senescent cells using only a DAPI nuclear stain. To demonstrate how our method can aid drug discovery, we apply our pipeline to existing glioblastoma high-throughput phenotypic drug screening imaging data to identify compounds that induce senescence in glioblastoma and verify these predictions experimentally.

Author Summary

Damaged cells can enter a senescent cell state, in which they do not divide, but continue to interact with the environment around them. A novel potential cancer treatment strategy is to make tumor cells senescent, before removing senescent cancer cells with a targeted drug. To investigate this treatment strategy in the brain cancer glioblastoma, it is important to be able to accurately recognise senescent glioblastoma cells. As identifying senescent cells is challenging, we create a machine learning pipeline which can detect senescent glioblastoma cells in imaging data. We show that by applying our method to existing data we can discover compounds that induce senescence in glioblastoma. We verify our predictions by testing the compounds experimentally.
Seeding competent TDP-43 persists in human patient and mouse muscle
Authors: Lynch Eileen M. , Pittman Sara , Daw Jil , Ikenaga Chiseko , Chen Sheng , Dhavale Dhruva D. , Jackrel Meredith E. , Ayala Yuna M. , Kotzbauer Paul , Ly Cindy V. , Pestronk Alan , Lloyd Thomas E. , Weihl Conrad C.
Published: April 2024

TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous system of some neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy (IBM). TDP-43 aggregates from ALS and FTD brain lysates may serve as self-templating aggregate seedsin vitroandin vivo,supporting a prion-like spread from cell to cell. Whether a similar process occurs in IBM patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis and changes in TDP-43-related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with IBM, IMNM and ALS we found that TDP-43 seeding capacity was specific to IBM. Surprisingly, TDP-43 seeding capacity anti-correlated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease.

TDP-43 aggregate seeds persist in mouse and human skeletal muscle independent of large TDP-43 inclusions.
Molecular characterization of Rft1, an ER membrane protein associated with congenital disorder of glycosylation RFT1-CDG
Authors: Hirata Eri , Sakata Ken-taro , Dearden Grace I. , Noor Faria , Menon Indu , Chiduza George N. , Menon Anant K.
Published: April 2024

The oligosaccharide needed for proteinN-glycosylation is assembled on a lipid carrier via a multi-step pathway. Synthesis is initiated on the cytoplasmic face of the endoplasmic reticulum (ER) and completed on the luminal side after transbilayer translocation of a heptasaccharide lipid intermediate. More than 30 Congenital Disorders of Glycosylation (CDGs) are associated with this pathway, including RFT1-CDG which results from defects in the membrane protein Rft1. Rft1 is essential for the viability of yeast and mammalian cells and was proposed as the transporter needed to flip the heptasaccharide lipid intermediate across the ER membrane. However, other studies indicated that Rft1 is not required for heptasaccharide lipid flipping in microsomes or unilamellar vesicles reconstituted with ER membrane proteins, nor is it required for the viability of at least one eukaryote. It is therefore not known what essential role Rft1 plays inN-glycosylation. Here, we present a molecular characterization of human Rft1, using yeast cells as a reporter system. We show that it is a multi-spanning membrane protein located in the ER, with its N and C-termini facing the cytoplasm. It is notN-glycosylated. The majority of RFT1-CDG mutations map to highly conserved regions of the protein. We identify key residues that are important for Rft1’s ability to supportN-glycosylation and cell viability. Our results provide a necessary platform for future work on this enigmatic protein.
Sexually dimorphic control of aggression by androgen signaling in a cichlid
Authors: Jackson Lillian R. , Alward Beau
Published: April 2024

Innate social behaviors like aggression are modulated by sex steroid hormones such as androgens and estrogens. However, we know little about how the same hormone regulates similar behaviors in both sexes. We investigated the role of androgenic signaling in the regulation of aggression inAstatotilapia burtoni, a social fish in which males and females perform similar aggressive behaviors. We used ARα knockout (KO) animals for this study, which was recently shown to be required for male-typical aggression and mating. Surprisingly, ARα KO females did not show deficits in aggression. We also determined that females lacking the other AR, ARβ showed normal levels of aggression. Blocking both ARs pharmacologically confirmed that neither AR is necessary for aggression in females. However, ARα KO males showed clear deficits in attacks. Thus, inA. burtonithere appears to be a sexual dimorphism in the role of ARα in the control of aggression.
Quinoline-based compounds can inhibit diverse enzymes that act on DNA
Authors: Zhou Jujun , Chen Qin , Ren Ren , Yang Jie , Liu Bigang , Horton John R. , Chang Caleb , Li Chuxuan , Maksoud Leora , Yang Yifei , Rotili Dante , Zhang Xing , Blumenthal Robert M. , Chen Taiping , Gao Yang , Valente Sergio , Mai Antonello , Cheng Xiaodong
Published: April 2024

DNA methylation, as exemplified by cytosine-C5 methylation in mammals and adenine-N6 methylation in bacteria, is a crucial epigenetic mechanism driving numerous vital biological processes. Developing non-nucleoside inhibitors to cause DNA hypomethylation is a high priority, in order to treat a variety of significant medical conditions without the toxicities associated with existing cytidine-based hypomethylating agents. In this study, we have characterized fifteen quinoline-based analogs. Notably, compounds with additions like a methylamine (9) or methylpiperazine (11) demonstrate similar low micromolar inhibitory potency against both human DNMT1 (which generates C5-methylcytosine) andClostridioides difficileCamA (which generates N6-methyladenine). Structurally, compounds9and11specifically intercalate into CamA-bound DNA via the minor groove, adjacent to the target adenine, leading to a substantial conformational shift that moves the catalytic domain away from the DNA. This study adds to the limited examples of DNA methyltransferases being inhibited by non-nucleotide compounds through DNA intercalation, following the discovery of dicyanopyridine-based inhibitors for DNMT1. Furthermore, our study shows that some of these quinoline-based analogs inhibit other enzymes that act on DNA, such as polymerases and base excision repair glycosylases. Finally, in cancer cells compound11elicits DNA damage response via p53 activation.

Abstract Figure

Highlights

Six of fifteen quinoline-based derivatives demonstrated comparable low micromolar inhibitory effects on human cytosine methyltransferase DNMT1, and the bacterial adenine methyltransferasesClostridioides difficileCamA andCaulobacter crescentusCcrM.

Compounds9and11were found to intercalate into a DNA substrate bound by CamA.

These quinoline-based derivatives also showed inhibitory activity against various base excision repair DNA glycosylases, and DNA and RNA polymerases.

Compound11provokes DNA damage response via p53 activation in cancer cells.
Functional redundancy and formin-independent localization of tropomyosin isoforms in Saccharomyces cerevisiae
Authors: Dhar Anubhav , Bagyashree VT , Biswas Sudipta , Kumari Jayanti , Sridhara Amruta , Jeevan Subodh B , Shekhar Shashank , Palani Saravanan
Published: April 2024

Tropomyosin is an actin binding protein which protects actin filaments from cofilin-mediated disassembly. Distinct tropomyosin isoforms have long been hypothesized to differentially sort to subcellular actin networks and impart distinct functionalities. Nevertheless, a mechanistic understanding of the interplay between Tpm isoforms and their functional contributions to actin dynamics has been lacking. In this study, we present and charcaterize mNeonGreen-Tpm fusion proteins that exhibit good functionality in cells as a sole copy, surpassing limitations of existing probes and enabling real-time dynamic tracking of Tpm-actin filamentsin vivo. Using these functional Tpm fusion proteins, we find thatS. cerevisiaeTpm isoforms, Tpm1 and Tpm2, colocalize on actin cables and indiscriminately bind to actin filaments nucleated by either formin isoform-Bnr1 and Bni1in vivo, in contrast to the long-held paradigm of Tpm-formin pairing. We show that cellular Tpm levels regulate endocytosis by affecting balance between linear and branched actin networks in yeast cells. Finally, we discover that Tpm2 can protect and organize functional actin cables in absence of Tpm1. Overall, our work supports a concentration-dependent and formin isoform independent model of Tpm isoform binding to F-actin and demonstrates for the first time, the functional redundancy of the paralog Tpm2 in actin cable maintenance inS. cerevisiae.
Caspase cleavage of Influenza A virus M2 disrupts M2-LC3 interaction and regulates virion production
Authors: Figueras-Novoa Carmen , Akutsu Masato , Murata Daichi , Jiang Ming , Montaner Beatriz , Dubois Christelle , Shenoy Avinash , Beale Rupert
Published: April 2024

Influenza A virus (IAV) Matrix 2 (M2) protein is an ion channel, required for efficient viral entry and egress. M2 interacts with the small ubiquitin-like LC3 protein through a cytoplasmic C-terminal LC3 interacting region (LIR). Here, we report that M2 is cleaved by caspases, abolishing the M2-LC3 interaction. A crystal structure of the M2 LIR in complex with LC3 indicates the caspase cleavage tetrapeptide motif (82SAVD85) is an unstructured linear motif that does not overlap with the LIR. Furthermore, an IAV mutant expressing a permanently truncated M2, mimicking caspase cleavage, is impaired in M2 plasma membrane transport and produces a significantly attenuated virus. Our results reveal a dynamic regulation of the M2-LC3 interaction by caspases. This highlights the role of host proteases in regulating IAV exit, relating virion production with host cell state.
Nuclear deformability facilitates apical nuclear migration in the developing zebrafish retina
Authors: Maia-Gil Mariana , Gorjão Maria , Belousov Roman , Espina Jaime A. , Coelho João , Ramos Ana P. , Barriga Elias H. , Erzberger Anna , Norden Caren
Published: April 2024

Nuclear positioning is an important aspect of cell and developmental biology. One example is the apical positioning of nuclei in retinal and other neuroepithelia. Here, apical nuclear migration is crucial for correct tissue formation. Cytoskeletal mechanisms that drive nuclei to the apical side have been explored. Yet, whether also nuclear properties influence apical nuclear migration remained comparatively less understood. Lamin A/C expression levels have been shown to be directly related to nuclear deformability. Further, it was shown that many nuclei in early development, including neuroepithelial nuclei, express only low levels of Lamin A/C.

Thus, we asked whether increased expression of Lamin A in the densely packed zebrafish retinal neuroepithelium affects nuclear migration phenomena. We find that overexpressing Lamin A in retinal nuclei of single cells or in the whole tissue increased nuclear stiffness and consequently impaired apical positioning. Interestingly, also nuclei of control cells embedded in a Lamin A overexpressing environment displayed impaired apical nuclear migration. When Lamin A is overexpressed at the tissue level this further leads to a delay in mitotic entry. Thus, nuclear material properties, within cells but also in the surrounding environment, can influence nuclear and cell behavior in densely packed neuroepithelia.

Overall, this work quantitatively shows a relevance of low Lamin A/C levels in early neuroepithelial development. These findings are most likely also applicable for other developing tissues which feature nuclear and cell motion through crowded environments.
Dynamic solar Primakoff process
Authors: Liang Zheng-Liang , Zhang Lin
Published: April 2024

The Primakoff mechanism is one of the primary channels for the production of solar axions. In canonical estimations of the Primakoff photon-axion conversion rate, the recoil effect is neglected and a static structure factor in adopted. By use of linear response theory, we provide a dynamic description of the solar Primakoff process. It is found that the collective electrons overtake ions as the dominant factor, in contrast to the static screening picture, where ions contribute more to the photon-axion conversion. Nonetheless, the resulting axion flux is only 1% to 2% lower than the standard estimate based on the static structure factor.

Published by the American Physical Society
2024
More on closed string effective actions at order
α′2
Authors: Gholian Hadi , Garousi Mohammad R.
Published: April 2024

Recent progress in string theory has unveiled the discovery of Neveu Schwarz-Neveu Schwarz couplings in bosonic and heterotic effective actions at order α′2, which were achieved by imposing O(1,1) symmetry on the circle reduction of classical effective actions. While the bosonic theory features 25 couplings, the heterotic theory encompasses 24 parity-even and 3 parity-odd couplings, excluding the pure gravity couplings. In this study, we redefine the even-parity couplings in the bosonic and heterotic theories through the application of appropriate field redefinitions, resulting in 10 and 8 couplings, respectively. To establish the validity of these couplings, a cosmological reduction is conducted, demonstrating that the cosmological couplings in the heterotic theory vanish, subject to one-dimensional field redefinitions that include the lapse function and total derivative terms. Additionally, it is observed that the cosmological couplings in the bosonic theory can be expressed as tr(S˙6). These results are consistent with existing literature, where such behavior is attributed to the pure gravity component of the couplings. Furthermore, the consistency of the obtained couplings with 4-point string theory S-matrix elements is confirmed.

Published by the American Physical Society
2024
Crystal structure and Hirshfeld surface analysis of dimethyl 4′-bromo-3-oxo-5-(thiophen-2-yl)-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2,4-dicarboxylate
Authors: Naghiyev Farid N. , Khrustalev Victor N. , Akkurt Mehmet , Asadov Khammed A. , Bhattarai Ajaya , Khalilov Ali N. , Mamedov İbrahim G.
Published: April 2024

In the title compound, C20H17BrO5S, molecules are connected by intermolecular C—H...S hydrogen bonds with R
2
2(10) ring motifs, forming ribbons along the b-axis direction. C—H...π interactions consolidate the ribbon structure while van der Waals forces between the ribbons ensure the cohesion of the crystal structure. According to a Hirshfeld surface analysis, H...H (40.5%), O...H/H...O (27.0%), C...H/H...C (13.9%) and Br...H/H...Br (11.7%) interactions are the most significant contributors to the crystal packing. The thiophene ring and its adjacent dicarboxylate group and the three adjacent carbon atoms of the central hexene ring to which they are attached were refined as disordered over two sets of sites having occupancies of 0.8378 (15) and 0.1622 (15). The thiophene group is disordered by a rotation of 180° around one bond.
The impact of live background visual complexity on consumer purchase intention: an eye-tracking study
Authors: Tang Xiaoli , Li Xiaolin , Hao Zefeng
Published: April 2024

Purpose

Based on sensory marketing theory and cognitive appraisal theory, this study investigates whether and how the background visual complexity of live-streaming affects consumers' purchase intention and reveals the underlying mechanisms through which background visual complexity influences consumers' purchase decisions.

Design/methodology/approach

The experiment was conducted with 180 college students, using eye-tracking technology to explore the impact mechanism of live background visual complexity on consumers' purchase intention, considering three types of background visual complexity (high vs medium vs low) and two levels of need for cognitive closure (high vs low).

Findings

Firstly, the background visual complexity of live-streaming positively influences consumers' purchase intention by eliciting positive emotions (pleasure and arousal), and the relationship between consumer emotions and purchase intention is nonlinear. Secondly, need for cognitive closure to significantly moderate the influence of background visual complexity on purchase intention.

Research limitations/implications

The limited sample size makes it difficult to generalize to other consumer groups. Also, the study only focuses on one visual factor, lacking comprehensive analysis from multiple perspectives.

Practical implications

It is recommended that live e-commerce companies optimize the visual design of live-streaming backgrounds and identify consumer traits to match the visual complexity with consumers' level of need for cognitive closure, thereby stimulating positive emotions and facilitating more satisfactory shopping decisions.

Originality/value

This paper addresses an interesting and practical issue related to the effects of live background visual complexity on consumers' purchase intention.
How social values gained from sharing travel experiences influence tourists’ satisfaction: moderated mediation effect of onsite mobile sharing behaviour
Authors: Wong Jose Weng Chou , Lai Ivan Ka Wai , Wang Shan
Published: April 2024

Purpose

While travelling, tourists like to use mobile technology to share their travel experiences. This study aims to understand how the social value gained by tourists from sharing a travel experience with mobile technology affects their satisfaction with the travel experience through onsite mobile sharing behaviour.

Design/methodology/approach

A second-order hierarchical model is constructed to examine the moderated mediating role of onsite mobile sharing behaviour in improving tourists’ travel satisfaction. Through systematic sampling, 304 responses were collected at ten attraction points in Guangzhou and Shenzhen, China.

Findings

The results show that, compared with self-centred values (self-presentation and self-identification), other-centred values (building social connection and reciprocity) contribute more to forming social values of sharing. In addition, onsite mobile sharing behaviour partially mediates and moderates the effect of social values on travel satisfaction.

Originality/value

This study applies the social capital theory to identify the value gained by sharing travel experiences and empirically evaluates the impact of these values on the overall value of sharing travel experiences. This study also contributes to tourism research by examining the moderated mediating role of onsite mobile sharing behaviour in improving travel satisfaction. This study helps destination marketing to make strategies to motivate tourists to use mobile technology to share their travel experiences while travelling.
Organizational culture, knowledge sharing and organizational performance: a multi-country study
Authors: Raziq Muhammad Mustafa , Jabeen Qudsia , Saleem Sharjeel , Shamout Mohamed Dawood , Bashir Samad
Published: April 2024

Purpose

Drawing on the competing values framework, we look at the relationship of different organizational cultures (clan, hierarchy, adhocracy and market) with organizational performance. Furthermore, we examine the mediating role of knowledge sharing (attitude and behavior) in the organizational culture and organizational performance relationship.

Design/methodology/approach

We draw on survey data from 241 respondents working in the aerospace and aviation manufacturing and services firms in Pakistan (85), Turkey (65) and the United Arab Emirates (91). We employ structural equation modeling for data analysis.

Findings

Results suggest that knowledge sharing partially mediates the relationship between clan culture and organizational performance, and fully mediates the market culture and organizational performance relationship. Hierarchy culture is only positively related to organizational performance, while adhocracy culture shows no relationship with knowledge sharing, let alone organizational performance.

Originality/value

While knowledge sharing enhances organizational performance, there is limited knowledge with regard to the specific organizational culture(s) conducive to knowledge sharing and organizational performance. The study extends existing research on the topic and contributes by showing which cultures are more conducive to knowledge sharing and organizational performance and which are less.
How green finance boosts carbon efficiency in agriculture: a quasi-experiment from China
Authors: Ren Yayun , Ding Zhongmin , Liu Junxia
Published: April 2024

Purpose

The research objective of this paper is to investigate the direct and indirect impacts of green finance on agricultural carbon total factor productivity (ACTFP) within the framework of the carbon peaking and carbon neutrality (dual carbon) goals, while also identifying the driving factors through an exponential decomposition of ACTFP, aiming to provide policy recommendations to enhance financial support for low-carbon agricultural development.

Design/methodology/approach

In this paper, the Global Malmquist Luenberger (GML) Index method was employed to analyze and decompose the ACTFP, while the direct and spillover effects of China’s green finance pilot policy (GFPP) on ACTFP were assessed using the difference-in-differences (DID) method and the spatial differences-in-differences (SDID) method, respectively.

Findings

After the implementation of the GFPP, the ACTFP in the pilot area has experienced significant improvement, with the enhancement of technical efficiency serving as the main driving force. In addition, the GFPP exhibits a positive low-carbon spatial spillover effect, indicating it benefits ACTFP in both the pilot and adjacent areas.

Originality/value

Within the framework of the dual carbon goals, the paper highlights agriculture as a significant carbon emitter. ACTFP is assessed by considering the agricultural carbon emission factor as the sole non-desired output, and the impact of the GFPP on ACTFP is investigated through the DID method, thereby providing substantial validation of the hypotheses inferred from the mathematical model. Subsequently, the spillover effects of GFPP on ACTFP are analyzed in conjunction with the spatial econometric model.