bluuebunny/crossref_metadata_2025 huggingface dataset:
A multi-scale clutch model for adhesion complex mechanics
Authors: Venturini C. , Sáez P.
Published: January 2023

Cell-matrix adhesion is a central mechanical function to a large number of phenomena in physiology and disease, including morphogenesis, wound healing and tumor cell invasion. Today, how single cells responds to different extracellular cues has been comprehensibly studied. However, how the mechanical behavior of the main individual molecules that form an adhesion complex cooperatively respond to force within the adhesion complex has not been addressed. This is a key aspect in cell adhesion because how these cell adhesion molecules respond to force determines not only cell-matrix behavior but, ultimately, cell function. To answer this question, we develop a multi-scale computational model for adhesion complexes mechanics. Based on the classical clutch hypothesis, we model individual adhesion chains made of a contractile actin network, a talin rod and an integrin molecule that binds at individual adhesion sites on the extracellular matrix. We explore several scenarios of integrins dynamics and analyze the effects of diverse extracellular matrices on the behavior of the adhesion molecules and on the whole adhesion complex. Our results explains how every single component of the adhesion chain mechanically responds to the contractile actomyosin force and show how they control the tractions forces exerted by the cell on the extracellular space. Importantly, our computational results are in agreement with previous experimental data both at the molecular and cell level. Our multi-scale clutch model presents a step forward not only to further understand adhesion complexes mechanics but also to, e.g., engineer better biomimetic materials, repair biological tissues or arrest invasive tumor migration.

Author summary

Cell-matrix adhesions are directly implicated in key biological processes such as tissue development, regeneration and tumor cell invasion. These cell functions are determined by how adhesion complexes feel and respond to mechanical forces. Still, how forces are transmitted through the individual cell adhesion molecules that integrate the adhesion complex is poorly understood. To address this issue, we develop a multi-scale clutch model for adhesion complexes where individual adhesion chains, made of integrin and talin molecules, are considered within classical clutch models. This approach provides a rich mechanosensivity insight of how the mechanics of cell adhesion works. It allows to integrate accurate biophysical models of individual adhesion molecules into whole adhesion complex models. Our multi-scale clutch approach allows to extend our current knowledge of adhesion complexes for physiology and disease, e.g., the regeneration of biological tissues or arrest invasive tumor migration, and for engineering better biomimetic materials.
Whole genome sequencing of Red Chittagong Cattle (RCC) cattle and insight into genetic variants in candidate genes for disease resistance
Authors: Das Ashutosh , Gupta Mukta Das , Shaha Mishuk , Lima Arjuman , Miazi Omar Faruk , Das Goutam Buddha
Published: January 2023

Detection of genome-wide genetic variation is one of the primary goals in bovine genomics. Genomes of several cattle breeds have been sequenced so far to understand the genetic variation associated with important phenotypes. Red Chittagong Cattle (RCC) is a locally adopted and disease-resistant indicine cattle breed in Bangladesh. In this study, we describe the first genome sequence of the RCC breed and in silico analyses of identified functional variants. Deep sequencing of a RCC bull genome on the NanoBall sequencing platform generated approximately 110 Gb paired-end data, resulting in 31X of genome coverage. Quality filtering retained 360,711,803 paired-end reads. Of the filtered reads, 99.8% were mapped to the bovine reference genome (ARSUCD1.2). A total of 17. 8 million Single nucleotide variants (SNVs) and 2.1 insertions and deletions (INDELs) were identified in the RCC genome. Ts/Tv ratio was computed and found to be 2.21. In total, 332 4621 variants were novel compared with dbSNP data (NCBI dbSNP bovine build 150). Functional annotation identified 54961 SNVs exonic regions, 63.75% of which were synonymous, whereas 30.42% were non-synonymous changes. The percentage of coding INDELs was 0.25% (Frameshift deletion 0.19% and Frameshift insertion 0.06%). We identified 120 variants in 26 candidates for five diseases-foot and mouth disease (FMD), Mastitis, Parasite, para-tuberculosis, and tick. Of the 120 variants, 50 were non-synonymous / frameshift (NS/FS), while 70 were synonymous/non-frameshift (SS/NFS). The identified catalog of genomic variants in RCC may establish a paradigm for cattle research in Bangladesh by filling the void and providing a database for genome-wide variation for future functional studies in RCC.
Humanized CD36 mouse model supports the preclinical evaluation of therapeutic candidates targeting CD36
Authors: Xie Xiulong , Niu Zhenlan , Wang Linlin , Zhou Xiaofei , Yu Xingyan , Jing Hongyan , Yang Yi
Published: January 2023

CD36 (also known as scavenger receptor B2) is a multifunctional receptor that mediates lipid uptake, advanced oxidation protein products, and immunological recognition, and has roles in lipid accumulation, apoptosis, as well as in metastatic colonization in cancer. CD36 is involved in tumor immunity, metastatic invasion, and therapy resistance through various molecular mechanisms. Targeting CD36 has emerged as an effective strategy for tumor immunotherapy. In this study, we have successfully generated a novel CD36 humanized mouse strain where the sequences encoding the extracellular domains of the mouseCd36gene were replaced with the corresponding human sequences. The results showed that CD36 humanized mice expressed only human CD36, and the proportion of each lymphocyte was not significantly changed compared with wild-type mice. Furthermore, CD36 monoclonal antibody could significantly inhibit tumor growth after treatment. Therefore, the CD36 humanized mice provided a validated preclinical mouse model for the evaluation of tumor immunotherapy targeting CD36.
Direct visualization of emergent metastatic features within anex vivomodel of the tumor microenvironment
Authors: Anandi Libi , Garcia Jeremy , Ros Manon , Janská Libuše , Liu Josephine , Carmona-Fontaine Carlos
Published: January 2023

Metabolic conditions such as hypoxia, nutrient starvation, and media acidification, together with interactions with stromal cells are critical drivers of metastasis. Since these conditions arise deep within tumor tissues with poor access to the bloodstream, the observation of nascent metastasesin vivois exceedingly challenging. On the other hand, conventional cell culture studies cannot capture the complex nature of metastatic processes. We thus designed and implemented anex vivomodel of the tumor microenvironment to study the emergence of metastatic features in tumor cells in their native 3-dimensional (3D) context. In this system, named 3MIC, tumor cells spontaneously create ischemic-like conditions, and it allows the direct visualization of tumor-stroma interactions with high spatial and temporal resolution. We studied how 3D tumor spheroids evolve in the 3MIC when cultured under different metabolic environments and in the presence or absence of stromal cells. Consistent with previous experimental and clinical data, we show that ischemic environments increase cell migration and invasion. Importantly, the 3MIC allowed us to directly observe the emergence of these pro-metastatic features with single-cell resolution allowing us to track how changes in tumor motility were modulated by macrophages and endothelial cells. With these tools, we determined that the acidification of the extracellular media was more important than hypoxia in the induction of pro-metastatic tumor features. We also illustrate how the 3MIC can be used to test the effects of anti-metastatic drugs on cells experiencing different metabolic conditions. Overall, the 3MIC allows us to directly observe the emergence of metastatic tumor features in a physiologically relevant model of the tumor microenvironment. This simple and cost-effective system can dissect the complexity of the tumor microenvironment to test perturbations that may prevent tumors from becoming metastatic.
FastRecomb: Fast inference of genetic recombination rates in biobank scale data
Authors: Naseri Ardalan , Yue William , Zhang Shaojie , Zhi Degui
Published: January 2023

While rates of recombination events across the genome (genetic maps) are fundamental to genetic research, the majority of current studies only use one standard map. There is evidence suggesting population differences in genetic maps, and thus estimating population-specific maps are of interest. While the recent availability of biobank-scale data offers such opportunities, current methods are not efficient at leveraging very large sample sizes. The most accurate methods are still linkage-disequilibrium (LD)-based methods that are only tractable for a few hundred samples. In this work, we propose a fast and memory-efficient method for estimating genetic maps from population genotyping data. Our method, FastRecomb, leverages the efficient positional Burrows-Wheeler transform (PBWT) data structure for counting IBD segment boundaries as potential recombination events. We used PBWT blocks to avoid redundant counting of pairwise matches. Moreover, we used a panel smoothing technique to reduce the noise from errors and recent mutations. Using simulation, we found that FastRecomb achieves state-of-the-art performance at 10k resolution, in terms of correlation coefficients between the estimated map and the ground truth. This is mainly due to the fact that FastRecomb can effectively take advantage of large panels comprising more than hundreds of thousands of haplotypes. At the same time, other methods lack the efficiency to handle such data. We believe further refinement of FastRecomb would deliver more accurate genetic maps for the genetics community.
DNA-origami line-actants control domain organisation and fission in synthetic membranes
Authors: Rubio-Sánchez Roger , Mognetti Bortolo Matteo , Cicuta Pietro , Di Michele Lorenzo
Published: January 2023

Cells can precisely program the shape and lateral organisation of their membranes using protein machinery. Aiming to replicate a comparable degree of control, here we introduce DNA-Origami Line-Actants (DOLAs) as synthetic analogues of membrane-sculpting proteins. DOLAs are designed to selectively accumulate at the line-interface between co-existing domains in phase-separated lipid membranes, modulating the tendency of the domains to coalesce. With experiments and coarse-grained simulations, we demonstrate that DOLAs can reversibly stabilise two-dimensional analogues of Pickering emulsions on synthetic giant liposomes, enabling dynamic programming of membrane lateral organisation. The control afforded over membrane structure by DOLAs extends to three-dimensional morphology, as exemplified by a proof-of-concept synthetic pathway leading to vesicle fission. With DOLAs we lay the foundations for mimicking, in synthetic systems, some of the critical membrane-hosted functionalities of biological cells, including signalling, trafficking, sensing, and division.
Multifaceted roles of a light-responsive factor LhWRKY44 in promoting anthocyanin accumulation in Asiatic hybrid lilies (Liliumspp.)
Authors: Bi Mengmeng , Liang Rui , Qu Yuxiao , Wang Jiawen , Cao Yuwei , Liu Xin , He Guoren , Zhang Wenliang , Yang Yue , Tang Yuchao , Yang Panpan , Xu Leifeng , Ming Jun
Published: January 2023

The coloration of Asiatic hybrid lily results mostly from anthocyanin accumulation in flowers. Although anthocyanin accumulation-related genes and MBW complexes are well studied, the transcriptional regulation of WRKY transcription factors involved in anthocyanin accumulation remains poorly understood.Here, we identified a lily WRKY protein, LhWRKY44, whose expression is highly expressed downstream of LhHY5 by light and positively correlated with anthocyanin accumulation.LhWRKY44overexpression enhanced anthocyanin accumulation and silencing decreased anthocyanin accumulation in flowers. As a trans-acting regulator, LhWRKY44 activited the anthocyanin biosynthesis pathway-related genesPALandF3Hby binding to the their promoters. And the encoded TF also participates in anthocyanin transport and targets the intracellular anthocyanin transport proteinGSTpromoters. Additionally, a novel dual activity of LhWRKY44 and LhMYBSPLATTER regulatory module, with LhWRKY44 binds to the promoter ofLhMYBSPLATTERand interacts with LhMYBSPLATTER, strongly enhanced the interaction of LhMYBSPLATTER and LhbHLH2, indirectly enhancingDFR, UFGTandGSTexpression targeted by LhMYBSPLATTER. These results show a regulatory mode for light-induced anthocyanin accumulation enhancement by LhWRKY44 in lily, expanding our understanding of the complex transcriptional regulatory hierarchy modulating anthocyanin accumulation.
MESH-FREE HIGH-RESOLUTION SIMULATION OF CEREBROCORTICAL OXYGEN SUPPLY WITH FAST FOURIER PRECONDITIONING
Authors: Ventimiglia Thomas , Linninger Andreas A
Published: January 2023

Oxygen transfer from blood vessels to cortical brain tissue is representative of a class of problems with mixed-domain character. Large-scale efficient computation of tissue oxygen concentration is dependent on the manner in which the tubular network of blood vessels is coupled to the tissue mesh. Models which explicitly resolve the interface between the tissue and vasculature with a contiguous mesh are prohibitively expensive for very dense cerebral microvasculature. We propose amixed-domain mesh-freetechnique whereby a vascular anatomical network (VAN) represented as a thin directed graph serves for convection of blood oxygen, and the surrounding extravascular tissue is represented as a Cartesian grid of 3D voxels throughout which oxygen is transported by diffusion. We split the network and tissue meshes by the Schur complement method of domain decomposition to obtain a reduced set of system equations for the tissue oxygen concentration. The use of a Cartesian grid allows the corresponding matrix equation to be solved approximately with a fast Fourier transform based Poisson solver, which serves as an effective preconditioner for Krylov subspace iteration. The performance of this method enables the steady state simulation of cortical oxygen perfusion for anatomically accurate vascular networks down to single micron resolution without the need for supercomputers.

Practitioner Points

We present a novel mixed-domain framework for efficiently modeling O2extraction kinetics in the brain.

Model equations are generated by graph-theoretic methods for mixed domains.

Dual mesh domain decomposition with FFT preconditioning yields very fast simulation times for extremely high spatial resolution.
Dopamine and norepinephrine differentially mediate the exploration-exploitation tradeoff
Authors: Chen Cathy S. , Mueller Dana , Knep Evan , Ebitz R. Becket , Grissom Nicola M.
Published: January 2023

The catecholamines dopamine (DA) and norepinephrine (NE) have been implicated in neuropsychiatric vulnerability, in part via their roles in mediating the decision making processes. Although the two neuromodulators share a synthesis pathway and are co-activated, they engage in distinct circuits and roles in modulating neural activity across the brain. However, in the computational neuroscience literature, they have been assigned similar roles in modulating the exploration-exploitation tradeoff. Revealing how each neuromodulator contributes to this explore-exploit process is important in guiding mechanistic hypotheses emerging from computational psychiatric approaches. To understand the differences and overlaps of the roles of dopamine and norepinephrine in mediating exploration, a direct comparison using the same dynamic decision making task is needed. Here, we ran mice in a restless bandit task, which encourages both exploration and exploitation. We systemically administered a nonselective DA antagonist (flupenthixol), a nonselective DA agonist (apomorphine), a NE beta-receptor antagonist (propranolol), and a NE beta-receptor agonist (isoproterenol), and examined changes in exploration within subjects across sessions. We found a bidirectional modulatory effect of dopamine receptor activity on exploration - increasing dopamine activity decreased exploration and decreasing dopamine activity increased exploration. The modulation of exploration via beta-noradrenergic activity was mediated by sex. Computational model parameters revealed that dopamine modulation affected exploration via decision noise and norepinephrine modulation via outcome sensitivity. Together, these findings suggested that the mechanisms that govern the transition between exploration and exploitation are sensitive to changes in both catecholamine functions and revealed differential roles for NE and DA in mediating exploration.

Significance Statement

Both dopamine (DA) and norepinephrine (NE) has been implicated in the decision making process. Although these two catecholamines have shared aspects of their biosynthetic pathways and projection targets, they are thought to exert many core functions via distinct neural targets and receptor subtypes. However, the computational neuroscience literature often ascribes similar roles to these catecholamines, despite the above evidence. Resolving this discrepancy is important in guiding mechanistic hypotheses emerging from computational psychiatric approaches. This study examines the role of dopamine and norepinephrine on the explore-exploit tradeoff. By testing mice, we were able to compare multiple pharmacological agents within subjects, and examine source of individual differences, allowing direct comparison between the effects of these two catecholamines in modulating decision making.
Aclarubicin stimulates RNA polymerase II elongation at closely spaced divergent promoters
Authors: Wooten Matthew , Takushi Brittany , Ahmad Kami , Henikoff Steven
Published: January 2023

Anthracyclines are a class of widely prescribed anti-cancer drugs that disrupt chromatin by intercalating into DNA and enhancing nucleosome turnover. To understand the molecular consequences of anthracycline-mediated chromatin disruption, we utilized CUT&Tag to profile RNA polymerase II during anthracycline treatment inDrosophilacells. We observed that treatment with the anthracycline aclarubicin leads to elevated levels of elongating RNA polymerase II and changes in chromatin accessibility. We found that promoter proximity and orientation impacts chromatin changes during aclarubicin treatment, as closely spaced divergent promoter pairs show greater chromatin changes when compared to codirectionally-oriented tandem promoters. We also found that aclarubicin treatment changes the distribution of non-canonical DNA G-quadruplex structures both at promoters and at G-rich pericentromeric repeats. Our work suggests that the anti-cancer activity of aclarubicin is driven by the effects of nucleosome disruption on RNA polymerase II, chromatin accessibility and DNA structures.
Sirtuin 2 inhibition modulates chromatin landscapes genome-wide to induce senescence in ATRX-deficient malignant glioma
Authors: Malgulwar Prit Benny , Danussi Carla , Dharmaiah Sharvari , Johnson William E. , Rao Arvind , Huse Jason T.
Published: January 2023

Inactivating mutations inATRXcharacterize large subgroups of malignant gliomas in adults and children. ATRX deficiency in glioma induces widespread chromatin remodeling, driving transcriptional shifts and oncogenic phenotypes. Effective strategies to therapeutically target these broad epigenomic sequelae remain undeveloped. We utilized integrated mulit-omics and the Broad Institute Connectivity Map (CMAP) to identify drug candidates that could potentially revert ATRX-deficient transcriptional changes. We then employed disease-relevant experimental models to evaluate functional phenotypes, coupling these studies with epigenomic profiling to elucidate molecular mechanim(s). CMAP analysis and transcriptional/epigenomic profiling implicated the Class III HDAC Sirtuin2 (Sirt2) as a central mediator of ATRX-deficient cellular phenotypes and a driver of unfavorable prognosis in ATRX-deficient glioma. Sirt2 inhibitors reverted Atrx-deficient transcriptional signatures in murine neuroprogenitor cells (mNPCs) and impaired cell migration in Atrx/ATRX-deficient mNPCs and human glioma stem cells (GSCs). While effects on cellular proliferation in these contexts were more modest, markers of senescence significantly increased, suggesting that Sirt2 inhibition promotes terminal differentiation in ATRX-deficient glioma. These phenotypic effects were accompanied by genome-wide shifts in enhancer-associated H3K27ac and H4K16ac marks, with the latter in particular demonstrating compelling transcriptional links to Sirt2-dependent phenotypic reversals. Motif analysis of these data identified the transcription factor KLF16 as a mediator of phenotype reversal in Atrx-deficient cells upon Sirt2 inhibition. Finally, Sirt2 inhibition impaired growth and increased senescence in ATRX-deficient GSCsin vivo. Our findings indicate that Sirt2 inhibition selectively targets ATRX-deficient gliomas through global chromatin remodeling, while demonstrating more broadly a viable approach to combat complex epigenetic rewiring in cancer.

Graphical Abstract

One Sentence Summary

Our study demonstrates that SIRT2 inhibition promotes senescence in ATRX-deficient glioma model systems through global epigenomic remodeling, impacting key downstream transcriptional profiles.
Genome-wide analysis of anterior-posterior mRNA regionalization inStentor coeruleusreveals a role for the microtubule cytoskeleton
Authors: Albright Ashley R. , Yan Connie , Angeles-Albores David , Makushok Tatyana , Allen-Henderson Jamarc , Marshall Wallace F.
Published: January 2023

Cells have complex and beautiful structures that are important for their function. However, understanding the molecular mechanisms that produce these structures is a challenging problem due to the gap in size scales between molecular interactions and cellular structures. The giant ciliateStentor coeruleusis a unicellular model organism whose large size, reproducible structure, and ability to heal wounds and regenerate have historically allowed the formation of structure in a single cell to be addressed using methods of experimental embryology. Such studies have shown that specific cellular structures, such as the membranellar band, always form in particular regions of the cell, which raises the question: what is the source of positional information within this organism? By analogy with embryonic development, in which regionalized mRNA is often used to mark position, we asked whether specific regionalized mRNAs might mark position along the anterior-posterior axis ofStentor. By physically bisecting cells and conducting bulk RNA sequencing, we were able to identify sets of messages enriched in either the anterior or posterior half. We then conducted half-cell RNA-sequencing in paired anteriors and posteriors of cells in which the microtubule cytoskeleton was disrupted by RNAi of β-tubulin or dynein intermediate chains. We found that many messages either lost their regionalized distribution or switched to an opposite distribution, such that anterior-enriched messages in control became posterior-enriched in the RNAi cells, or vice versa. This study indicates that mRNA can be regionalized within a single giant cell and that microtubules may play a role, possibly by serving as tracks for the movement of the messages.
Metagenomic Data Reveal Type I Polyketide Synthase Distributions Across Biomes
Authors: Singh Hans W. , Creamer Kaitlin E. , Chase Alexander B. , Klau Leesa J. , Podell Sheila , Jensen Paul R.
Published: January 2023

Microbial polyketide synthase (PKS) genes encode the biosynthesis of many biomedically important natural products, yet only a small fraction of nature’s polyketide biosynthetic potential has been realized. Much of this potential originates from type I PKSs (T1PKSs), which can be delineated into different classes and subclasses based on domain organization and structural features of the compounds encoded. Notably, phylogenetic relationships among PKS ketosynthase (KS) domains provide a method to classify the larger and more complex genes in which they occur. Increased access to large metagenomic datasets from diverse habitats provides opportunities to assess T1PKS biosynthetic diversity and distributions through the analysis of KS domain sequences. Here, we used the webtool NaPDoS2 to detect and classify over 35,000 type I KS domains from 137 metagenomic data sets reported from eight diverse biomes. We found biome-specific separation with soils enriched in modularcis-AT and hybridcis-AT KSs relative to other biomes and marine sediments enriched in KSs associated with PUFA and enediyne biosynthesis. By extracting full-length KS domains, we linked the phylum Actinobacteria to soil-specific enediyne andcis-AT clades and identified enediyne and monomodular KSs in phyla from which the associated compound classes have not been reported. These sequences were phylogenetically distinct from those associated with experimentally characterized PKSs suggesting novel structures or enzyme functions remain to be discovered. Lastly, we employed our metagenome-extracted KS domains to evaluate commonly used type I KS PCR primers and identified modifications that could increase the KS sequence diversity recovered from amplicon libraries.

Importance

Polyketides are a crucial source of medicines, agrichemicals, and other commercial products. Advances in our understanding of polyketide biosynthesis coupled with the accumulation of metagenomic sequence data provide new opportunities to assess polyketide biosynthetic potential across biomes. Here, we used the webtool NaPDoS2 to assess type I PKS diversity and distributions by detecting and classifying KS domains across 137 metagenomes. We show that biomes are differentially enriched in KS domain classes, providing a roadmap for future biodiscovery strategies. Further, KS phylogenies reveal both biome-specific clades that do not include biochemically characterized PKSs, highlighting the biosynthetic potential of poorly explored environments. The large metagenome-derived KS dataset allowed us to identify regions of commonly used type I KS PCR primers that could be modified to capture a larger extent of KS diversity. These results facilitate both the search for novel polyketides and our understanding of the biogeographical distribution of PKSs across earth’s major biomes.
Tomato brown rugose fruit virus Mo gene is a novel microbial source tracking marker
Authors: Natarajan Aravind , Fremin Brayon J. , Schmidtke Danica T. , Wolfe Marlene K. , Zlitni Soumaya , Graham Katherine E. , Brooks Erin F. , Severyn Christopher J. , Sakamoto Kathleen M. , Lacayo Norman J. , Kuersten Scott , Koble Jeff , Caves Glorianna , Kaplan Inna , Singh Upinder , Jagannathan Prasanna , Rezvani Andrew R. , Bhatt Ami S. , Boehm Alexandria B.
Published: January 2023

Microbial source tracking (MST) identifies sources of fecal contamination in the environment using fecal host-associated markers. While there are numerous bacterial MST markers, there are few viral markers. Here we design and test novel viral MST markers based on tomato brown rugose fruit virus (ToBRFV) genomes. We assembled eight nearly complete genomes of ToBRFV from wastewater and stool samples from the San Francisco Bay Area in the United States of America. Next, we developed two novel probe-based RT-PCR assays based on conserved regions of the ToBRFV genome, and tested the markers’ sensitivities and specificities using human and non-human animal stool as well as wastewater. TheToBRFV markers are sensitive and specific; in human stool and wastewater, they are more prevalent and abundant than a currently used marker, the pepper mild mottle virus (PMMoV) coat protein (CP) gene. We applied the assays to detect fecal contamination in urban stormwater samples and found that the ToBRFV markers matched cross-assembly phage (crAssphage), an established viral MST marker, in prevalence across samples. Taken together, ToBRFV is a promising viral human-associated MST marker.

Importance

Human exposure to fecal contamination in the environment can cause transmission of infectious diseases. Microbial source tracking (MST) can identify sources of fecal contamination so that contamination can be remediated and human exposures can be reduced. MST requires the use of fecal host-associated MST markers. Here we design and test novel MST markers from genomes of tomato brown rugose fruit virus (ToBRFV). The markers are sensitive and specific to human stool, and highly abundant in human stool and wastewater samples.
Neural phoneme discrimination in variable speech in newborns – associations with dyslexia risk and later language skills
Authors: Virtala P. , Kujala T. , Partanen E. , Hämäläinen J. A. , Winkler I.
Published: January 2023

A crucial skill in infant language acquisition is learning of the native language phonemes. This requires the ability to group complex sounds into distinct auditory categories based on their shared features. Problems in phonetic learning have been suggested to underlie language learning difficulties in dyslexia, a developmental reading-skill deficit. We investigated auditory abilities important for language acquisition in newborns with or without a familial risk for dyslexia with electrophysiological mismatch responses (MMRs). We presented vowel changes in a sequence of acoustically varying vowels, requiring grouping of the stimuli to two phoneme categories. The vowel changes elicited an MMR which was significantly diminished in infants whose parents had the most severe dyslexia in our sample. Phoneme-MMR amplitude and its hemispheric lateralization were associated with language test outcomes assessed at 28 months, an age at which it becomes possible to behaviourally test children and several standardized tests are available. In addition, statistically significant MMRs to violations of a complex sound-order rule were only found in infants without dyslexia risk, but these results are very preliminary due to small sample size. The results demonstrate the relevance of the newborn infants’ readiness for phonetic learning for their emerging language skills. Phoneme extraction difficulties in infants at familial risk may contribute to the phonological deficits observed in dyslexia.

Research highlights

We recorded mismatch responses (MMRs) to vowel changes in a variable speech stream

Newborns extracted relevant phonetic information from the stream, evidenced by MMRs

High dyslexia risk infants had diminished MMRs to vowel changes

MMR amplitudes and hemispheric lateralization correlated with later language skills

Poor phoneme extraction may compromise phonological and language development
To be or not to be an anti-CRISPR: AcrIII-1 and the importance of working with native biological systems
Authors: Martínez-Alvarez Laura , Stickel Dominic , Salegi-Díez Andrea , Bhoobalan-Chitty Yuvaraj , Peng Xu
Published: January 2023

Viral members of the protein family DUF1874 have been reported to act as anti-CRISPR (acr) proteins that degrade cyclic tetra-adenylate (cA4), a nucleotide second messenger produced after the activation of several type III CRISPR-Cas systems in bacteria and archaea. Specifically, protein SIRV1 gp29 inhibits type III-A and type III-B CRISPR systems in plasmid-born assays in heterologous systems. In this work, we investigate the function of SIRV1 gp29 and its close homolog SIRV2 gp37 in a native biological context, i.e. in cultures infected by SIRV2. SIRV2 was selected instead of SIRV1 because the latter is not available any more from any laboratories. We demonstrate that gp37 has no anti-CRISPR activity during infection ofSaccharolobus islandicusLAL14/1 with SIRV2, although it is able to protect SIRV2 from type III targeting when expressed from a plasmid. The inability of gp37 to act as an acr in the native, biological system is due to the protein expression timing: gp37 is a middle/late gene, thus unable to inhibit CRISPR-Cas targeting at the onset of infection. On the other hand, we find that while gp37 is a non-essential gene, it confers a mild replicative advantage to the virus. This advantage is mediated, in hosts with active CRISPR-Cas targeting, by the interaction between gp37 and host protein SiL_1451, which results in the inhibition of the lysine methyltransferase activity of SiL_1451, responsible for extensive methylation of surface lysines of two-thirds of the cellular proteins. Heterologous gene expression from a plasmid-borne non-native promoter has allowed the discovery and characterization of dozens of prokaryotic defense systems in recent years. Although this experimental strategy has several advantages, our study highlights the importance of validating relevant results under native conditions, and the limitations of extrapolating results obtained using heterologous systems.
A class-specific effect of dysmyelination on the excitability of hippocampal interneurons
Authors: Pinatel Delphine , Pearlstein Edouard , Bonetto Giulia , Goutebroze Laurence , Karagogeos Domna , Crépel Valérie , Faivre-Sarrailh Catherine
Published: January 2023

The role of myelination for axonal conduction is well-established in projection neurons but little is known about its significance in GABAergic interneurons. Myelination is discontinuous along interneuron axons and the mechanisms controlling myelin patterning and segregation of ion channels at the nodes of Ranvier have not been elucidated. Protein 4.1B is implicated in the organization of the nodes of Ranvier as a linker between paranodal and juxtaparanodal membrane proteins to the spectrin cytoskeleton. In the present study, 4.1B KO mice are used as a genetic model to analyze the functional role of myelin in Lhx6-positive parvalbumin and somatostatin neurons, two major classes of GABAergic neurons in the hippocampus. We show that deletion of 4.1B induces disruption of juxtaparanodal K+channel clustering and mislocalization of nodal or heminodal Na+channels. Strikingly, 4.1B-deficiency causes loss of myelin in GABAergic axons in the hippocampus. In particular, stratum oriens O-LM cells display severe axonal dysmyelination and a reduced excitability. This reduced excitability is associated with a decrease in occurrence probability of small amplitude synaptic inhibitory events on pyramidal cells. In contrast, stratum pyramidale fast-spiking basket cells do not appear affected. The aberrant myelination of hippocampal interneurons is also correlated with impairment of spatial memory in 4.1B KO mice. In conclusion, our results indicate a class-specific effect of dysmyelination on the excitability of hippocampal interneurons associated with a functional alteration of inhibitory drive and impairment of spatial memory.
Human iPS cell-derived sensory neurons can be infected by SARS-CoV-2 strain WA1/2020 as well as variants delta and omicron
Authors: Flamier Anthony , Bisht Punam , Richards Alexsia , Tomasello Danielle , Jaenisch Rudolf
Published: January 2023

COVID-19 has impacted billions of people in the world since 2019 and unfolded a major healthcare crisis. With an increasing number of deaths and the emergence of more transmissible variants, it is crucial to better understand the biology of the disease-causing virus, the SARS-CoV-2. Peripheral neuropathies appeared as a specific COVID-19 symptom occurring at later stages of the disease. In order to understand the impact of SARS-CoV-2 on the peripheral nervous system, we generated human sensory neurons from induced pluripotent stem cells that we infected with the SARS-CoV-2 strain WA1/2020 and the variants delta and omicron. Using single cell RNA sequencing, we found that human sensory neurons can be infected by SARS-CoV-2 but are unable to produce new viruses. Our data suggests that sensory neurons can be infected by the original WA1/2020 strain of SARS-CoV-2 as well as the delta and omicron variants.
Syntheses and crystal structure of 4-[(pyridin-3-yl)diazenyl]morpholine and 1-[(pyridin-3-yl)diazenyl]-1,2,3,4-tetrahydroquinoline
Authors: Sokhna Seynabou , Seck Insa , Thiam Ibrahima El Hadj , Presset Marc , Ndoye Samba Fama , Ba Lalla Aïcha , Samb Issa , Coles Simon , Orton James , Seck Matar , Le Gall Erwan , Gaye Mohamed
Published: January 2023

Two new heterocyclic 1,2,3-triazenes were synthesized by diazotation of 3-aminopyridine following respectively by coupling with morpholine or 1,2,3,4-tetrahydroquinoline. 4-[(Pyridin-3-yl)diazenyl]morpholine (I), C9H12N4O, has monoclinic P21/c symmetry at 100 K, while 1-[(pyridin-3-yl)diazenyl]-1,2,3,4-tetrahydroquinoline (II), C14H14N4, has monoclinic P21/n symmetry at 100 K. These 1,2,3-triazene derivatives were synthesized by the organic medium method by coupling reactions of 3-aminopyridine with morpholine and 1,2,3,4-tetrahydroquinoline, respectively, and characterized by 1H NMR, 13C NMR, IR, mass spectrometry, and single-crystal X-ray diffraction. The molecule of compound I consists of pyridine and morpholine rings connected by an azo moiety (–N=N–). In the molecule of II, the pyridine ring and the 1,2,3,4-tetrahydroquinoline unit are also connected by an azo moiety. The double- and single-bond distances in the triazene chain are comparable for the two compounds. In both crystal structures, the molecules are connected by C—H...N interactions, forming infinite chains for I and layers parallel to the bc plane for II.
In situ ligand restraints from quantum-mechanical methods
Authors: Liebschner Dorothee , Moriarty Nigel W. , Poon Billy K. , Adams Paul D.
Published: January 2023

In macromolecular crystallographic structure refinement, ligands present challenges for the generation of geometric restraints due to their large chemical variability, their possible novel nature and their specific interaction with the binding pocket of the protein. Quantum-mechanical approaches are useful for providing accurate ligand geometries, but can be plagued by the number of minima in flexible molecules. In an effort to avoid these issues, the Quantum Mechanical Restraints (QMR) procedure optimizes the ligand geometry in situ, thus accounting for the influence of the macromolecule on the local energy minima of the ligand. The optimized ligand geometry is used to generate target values for geometric restraints during the crystallographic refinement. As demonstrated using a sample of >2330 ligand instances in >1700 protein–ligand models, QMR restraints generally result in lower deviations from the target stereochemistry compared with conventionally generated restraints. In particular, the QMR approach provides accurate torsion restraints for ligands and other entities.
3-Chloro-N,N-dimethylpropan-1-aminium chloride
Authors: Bond Marcus R. , Silwal Sajan
Published: January 2023

The organic cation in the title molecular salt, C5H13NCl+·Cl−, exhibits the gauche effect with a C—H bond of the C atom β to the chloro group donating electrons to the antibonding orbital of the C—Cl bond to stabilize the gauche conformation [Cl—C—C—C = −68.6 (6)°], as confirmed by DFT geometry optimizations that show a lengthening of the C—Cl bond relative to that of the anti conformation. Of further interest is the higher point group symmetry of the crystal (\overline{4}), compared that of the that of the molecular cation, which arises from a supramolecular head-to-tail square arrangement of four molecular cations that circulate in a counterclockwise direction when viewed down the tetragonal c axis.
The working relationship between internal and external auditors and the moral courage of internal auditors: Tunisian evidence
Authors: Khelil Imen
Published: January 2023

Purpose

This paper aims to examine the association between the working relationship between internal and external auditors and the moral courage of internal auditors to report management fraud in the Tunisian setting.

Design/methodology/approach

Data are gathered from 163 internal auditors working in Tunisian companies and a partial least squares–structural equation model (PLS-SEM) is used to test the hypothesis regarding the effect of the cooperation between internal and external auditors on internal auditors’ moral courage.

Findings

The results of this study provide strong empirical support for the positive impact of the working relationship between internal and external auditors on internal auditors’ moral courage to report management fraud and unethical behaviors.

Practical implications

The reported results increase the awareness of Tunisian regulators to enact regulations that strengthen the collaboration between internal and external auditors to promote internal auditors’ moral courage and then limit fraud and improve organizational performance in the Tunisian setting.

Originality/value

This paper fills one of the major research gaps in internal audit and moral courage research streams by revealing that the courageous behavior of internal auditors can be fostered by specific means efficacy such as the working relationship between internal and external auditors.
Transformational leadership and supply chain innovativeness: mediating role of knowledge sharing climate and moderating role of supply base rationalization
Authors: Zhang Cailin , Li Suicheng , Liu Xinmeng , Wang Xiang
Published: January 2023

Purpose

The purpose of this paper is to explore whether and how transformational leadership affects innovativeness in the supply chain context by addressing the following research questions: (1) Whether transformational leadership might help foster conditions for knowledge sharing and lead to supply chain innovativeness (SCI) in China firms? (2) Does supply base rationalization play a moderating role in the above relationship?

Design/methodology/approach

Survey data consisting of 144 valid responses were collected from supply chain innovation and application pilot projects in 55 cities of China. Confirmatory factor analysis (CFA) confirmed the reliability and validity of measures, and hierarchical linear regression and bootstrapping were used to test all hypotheses.

Findings

The results obtained reveal that supply chain knowledge sharing partially mediate the relationship between transformational leadership and SCI. Also, supply base rationalization positively moderates the mediated relationship between transformational leadership and SCI.

Practical implications

Managers and decision-makers of supply chain leader firms who want to enhance their entire SCI to deal with unexpected supply chain disruptions are highly recommended to adopt transformational behavior across the supply chain, as well as to develop the knowledge sharing culture, resulting from transformational leadership. In addition, leading firms should be dedicated to structuring their supply base, keeping it at the right size and complexity.

Originality/value

The present study emphasizes previous results and provides additional evidence that supply chain leaders’ adoption of transformational behavior can reinforce entire SCI through knowledge sharing in light of the disruptions facing supply chains in developing countries.
Exploring team collective voice: the case of software development teams in Vietnam
Authors: Hoang An L. , Phan Anh T.T. , Dong Dam X. , Tran Trang T.H. , Nguyen Chinh T.
Published: January 2023

Purpose

The team voice (TV) concept has been largely understudied, with different definitions and understandings among prior research creating confusion for readers and future researchers. This study proposes a unified definition and connotation of TV that captures TV's collective meaning and highlights TV's vital role in Eastern contexts.

Design/methodology/approach

This study applied the constructivist grounded theory (CGT) methodology to collect and analyze qualitative data from Vietnam software companies. A total of 32 software development managers and employees were interviewed regarding TV behavior of the managers and employees.

Findings

The findings emphasize that TV should not be understood as team members' average or aggregate voice. Rather, TV should be understood as the shared voice of team members toward higher management, other teams or individuals in the organization in an attempt to challenge/change the status quo [team collective voice (TCV)]. The findings also reveal the characteristics of TCV (purpose, voicing and consensus mechanisms), TCV's different types and important roles in the context of an Eastern country operating under weak institutions.

Originality/value

This exploratory study was able to clarify different connotations of employee voice at the team level, which helps raise awareness among scholars on the collective nature of TV and guides successive researchers away from inconsistent understandings of the term. The study also reveals certain institutional conditions that foster this type of voice and suggests the employee voice concept should not be examined independently from the concept's institutional context. The proposed typology contributes comprehensively to this conceptual work of TCV as the topology reveals the concept's multidimensionality and aids future research on measurement construction.
Experimental investigation on structural response of multi-story buildings subjected to differential settlement of its foundations
Authors: Chen Wenxue , Hanna Adel
Published: January 2023

Purpose

This article aims to address an outstanding problem dealing with the structure of multi-story buildings subjected to differential settlement of the building's foundation.

Design/methodology/approach

Differential settlement between foundation units of multi-story structures has been responsible for causing damage to buildings and often catastrophic failure and loss of life. The dynamic changes in the loading conditions of the structure and the changes in the underlying ground due to environmental changes are causing this undesirable differential settlement, which is manifested in the form of additional stresses in beams, columns and distortion of the structure elements. This study presents the results of an experimental investigation on a prototype model of a multi-story building subjected to differential settlement of the building's foundation. The model is a four-floor aluminum structure, instrumented to measure the stresses induced in the structure elements due to the settlement of a center, edge and corner column, respectively, which represent the critical conditions of the structure.

Findings

The experimental results of this study can be used as a guideline for the design of structures.

Originality/value

The current study is the original research developed by the authors.