bluuebunny/crossref_metadata_2025_split huggingface dataset:
RNA 5ʹ terminal nucleotide determines the strength of the RIG-I/IFN signaling pathway
Authors: Wolczyk Magdalena , Szymanski Jacek , Trus Ivan , Naz Zara , Bolembach Agnieszka , Choudhury Nila Roy , Tame Tola , Könüç Ceren , Nowak Elżbieta , Spanos Christos , Rappsilber Juri , Michlewski Gracjan 
Published: December 2023

AbstractThe interferon (IFN) response is crucial for antiviral activity, but its overstimulation can lead to a wide range of autoimmune disorders. The cytoplasmic pattern recognition receptor RIG-I detects viral RNAs and endogenous polymerase III transcripts carrying a 5′-triphosphate (5′- ppp) or 5′-diphosphate (5′-pp) moiety, triggering an IFN immune response. While many viral RNAs initiate with 5′-ppp-adenosine (5′-pppA) and most endogenous Pol III transcripts in higher eukaryotes start with 5′-ppp-guanosine (5′-pppG), no apparent reason for this bias has been identified so far. Here we demonstrate that RNAs initiating with 5′-pppA trigger a much stronger RIG-I/IFN response than those starting with 5′-pppG. The structures of the matching RNA pairs have been confirmed to be similar, suggesting that functional differences in RIG-I/IFN pathway stimulation cannot be primarily explained by an altered conformation. We show that several GTP-binding proteins interact with 5′-pppG RNAs creating a steric hindrance and protecting these RNAs from activating RIG-I. Our findings suggest that 5′-pppG RNAs may allow some RNA viruses and Pol III transcripts to evade detection by cellular immune sensors. These results provide a new insight into the mechanism of sequence-dependent RIG-I/IFN pathway activation and have significant implications for understanding the antiviral response to RNA viruses and the contribution of Pol III-derived RNAs to autoimmune disorders.
In silicoandin vitrostudies suggest epigallocatechin gallate (EGCG), a polyphenol in green tea, can bind and modulate the aggregation and cytotoxicity of the full-length TDP-43 protein implicated in TDP-43 proteinopathies
Authors: Meshram Vini D. , Balaji Ramkumar , Saravanan Preethi , Subbamanda Yashashwini , Deeksha Waghela , Bajpai Akarsh , Joshi Himanshu , Bhargava Anamika , Patel Basant K. 
Published: December 2023

ABSTRACTMisfolding and aggregation of TDP-43 protein are implicated in several proteinopathies like ALS and FTLD. Extracellular TDP-43 is also proposed to propagate in a prion-like pathogenic manner to the neighbouring cells. Here, using turbidity and sedimentation assay, we show that a polyphenol in green tea, epigallocatechin gallate (EGCG), can inhibit thein vitroaggregation of the full-length TDP-43 protein. Furthermore, Alexa-Fluor-labelled TDP-43 protein failed to show aggregates in the presence of EGCG in fluorescence microscopy. Also, AFM imaging revealed that EGCG co-incubation with TDP-43 allows formation of only small oligomers in contrast to the larger TDP-43 aggregates formed otherwise. A physical binding of EGCG with TDP-43 was observed using triphenyl tetrazolium chloride (TTC) staining and isothermal titration calorimetry (ITC). ITC also revealed a high-affinity binding site for EGCG on TDP-43 with a Kdvalue of 7.8 µM and a binding free energy of -6.9 kcal/mol. Furthermore,in silicomolecular docking and molecular dynamic simulation (MDS) studies using different available structures of the N-terminal, RRM1-2 and C-terminal domains of TDP-43, predicted a preferable and stable binding of EGCG to the structure of the aggregation prone C-terminal domain (CTD) (PDB ID:7KWZ). Also, EGCG complexed with CTD of TDP-43 yielded a negative ΔG value of -20.29 kcal/mol using MM-PBSA analysis of the MDS data thereby further suggesting a stable complex formation. Also, in MDS, EGCG interacted with the amino acids Phe-313 and Ala-341 of TDP-43, which were previously projected to be important for the recruitment of monomers for the amyloid formation by CTD, thereby suggesting a possible mechanism of EGCG’s inhibition of the TDP-43 aggregation. Notably, while thein vitro-made aggregates of full-length TDP-43 caused mild cytotoxicity to the HEK293 cells, the small oligomers of TDP-43 formed in presence of EGCG did not. In totality, EGCG canin vitrointeract with TDP-43 and inhibit its aggregation, possiblyviainteraction with the amyloidogenic domain, thereby preventing it from assuming cytotoxic conformations. As EGCG is a natural molecule, it could be relevant to the therapeutic quest against the TDP-43 proteinopathies.
Specific inhibition and disinhibition in the higher-order structure of a cortical connectome
Authors: Reimann Michael W. , Santander Daniela Egas , Ecker András , Muller Eilif B. 
Published: December 2023

ABSTRACTNeurons are thought to act as parts of assemblies with strong internal excitatory connectivity. Conversely, inhibition is often reduced to blanket inhibition with no targeting specificity. We analyzed the structure of excitation and inhibition in the MICrONSmm3dataset, an electron microscopic reconstruction of a piece of cortical tissue. We found that excitation was structured around a feed-forward flow in large non-random neuron motifs with a structure of information flow from a small number of sources to a larger number of potential targets. Inhibitory neurons connected with neurons in specific sequential positions of these motifs, implementing targeted and symmetrical competition between them. None of these trends are detectable in only pairwise connectivity, demonstrating that inhibition is structured by these large motifs. While descriptions of inhibition in cortical circuits range from non-specific blanket-inhibition to targeted, our results describe a form of targeting specificity existing in the higher-order structure of the connectome. These findings have important implications for the role of inhibition in learning and synaptic plasticity.
Cyfip2 controls the acoustic startle threshold through FMRP, actin polymerization, and GABABreceptor function
Authors: Deslauriers Jacob C. , Ghotkar Rohit P. , Russ Lindsey A. , Jarman Jordan A. , Martin Rubia M. , Tippett Rachel G. , Sumathipala Sureni H. , Burton Derek F. , Cole D. Chris , Marsden Kurt C. 
Published: December 2023

AbstractAnimals process a constant stream of sensory input, and to survive they must detect and respond to dangerous stimuli while ignoring innocuous or irrelevant ones. Behavioral responses are elicited when certain properties of a stimulus such as its intensity or size reach a critical value, and such behavioral thresholds can be a simple and effective mechanism to filter sensory information. For example, the acoustic startle response is a conserved and stereotyped defensive behavior induced by sudden loud sounds, but dysregulation of the threshold to initiate this behavior can result in startle hypersensitivity that is associated with sensory processing disorders including schizophrenia and autism. Through a previous forward genetic screen for regulators of the startle threshold a nonsense mutation inCytoplasmic Fragile X Messenger Ribonucleoprotein (FMRP)-interacting protein 2(cyfip2) was found that causes startle hypersensitivity in zebrafish larvae, but the molecular mechanisms by which Cyfip2 establishes the acoustic startle threshold are unknown. Here we used conditional transgenic rescue and CRISPR/Cas9 to determine that Cyfip2 acts though both Rac1 and FMRP pathways, but not the closely related FXR1 or FXR2, to establish the acoustic startle threshold during early neurodevelopment. To identify proteins and pathways that may be downstream effectors of Rac1 and FMRP, we performed a candidate-based drug screen that indicated that Cyfip2 can also act acutely to maintain the startle threshold branched actin polymerization and N-methyl D-aspartate receptors (NMDARs). To complement this approach, we used unbiased discovery proteomics to determine that loss of Cyfip2 alters cytoskeletal and extracellular matrix components while also disrupting oxidative phosphorylation and GABA receptor signaling. Finally, we functionally validated our proteomics findings by showing that activating GABABreceptors, which like NMDARs are also FMRP targets, restores normal startle sensitivity incyfip2mutants. Together, these data reveal multiple mechanisms by which Cyfip2 regulates excitatory/inhibitory balance in the startle circuit to control the processing of acoustic information.
Homological landscape of human brain functional sub-circuits
Authors: Duong-Tran Duy , Kaufmann Ralph , Chen Jiong , Wang Xuan , Garai Sumita , Xu Frederick , Bao Jingxuan , Amico Enrico , Kaplan Alan David , Petri Giovanni , Goni Joaquin , Zhao Yize , Shen Li 
Published: December 2023

AbstractHuman whole-brain functional connectivity networks have been shown to exhibit both local/quasilocal (e.g., set of functional sub-circuits induced by node or edge attributes) and non-local (e.g., higher-order functional coordination patterns) properties. Nonetheless, the non-local properties of topological strata induced by local/quasilocal functional sub-circuits have yet to be addressed. To that end, we proposed a homological formalism that enables the quantification of higher-order characteristics of human brain functional sub-circuits. Our results indicated that each homological order uniquely unravels diverse, complementary properties of human brain functional sub-circuits. Noticeably, theH1homological distance between rest and motor task were observed at both whole-brain and sub-circuit consolidated level which suggested the self-similarity property of human brain functional connectivity unraveled by homological kernel. Furthermore, at the whole-brain level, the rest-task differentiation was found to be most prominent between rest and different tasks at different homological orders: i) Emotion task (H0), ii) Motor task (H1), and iii) Working memory task (H2). At the functional sub-circuit level, the rest-task functional dichotomy of default mode network is found to be mostly prominent at the first and second homological scaffolds. Also at such scale, we found that the limbic network plays a significant role in homological reconfiguration across both task- and subject-domain which sheds light to subsequent investigations on the complex neuro-physiological role of such network. From a wider perspective, our formalism can be applied, beyond brain connectomics, to study non-localized coordination patterns of localized structures stretching across complex network fibers.
OmniClustifyXMBD: Uncover putative cell states within multiple single-cell omics datasets
Authors: Yang Fan , Zhou Yitao , Zeng Feng 
Published: December 2023

AbstractClustering plays a pivotal role in characterizing cell states in single-cell omics data. Nonetheless, there is a noticeable gap in clustering algorithms tailored for unveiling putative cell states across datasets containing samples with diverse phenotypes. To bridge this gap, we implement an innovative method termed OmniClustifyXMBD, which integrates adaptive signal isolation with cell clustering. The adaptive signal isolation effectively disentangles gene expression variations linked to distinct factors within individual cells. This separation restores cells to their inherent states, free from external influences. Concurrently, a clustering algorithm built upon a deep variational Gaussian mixture model is devised to identify these putative cell states. Experiments showcase the effectiveness of OmniClustifyXMBDin identifying putative cell states while minimizing the influence of various undesired variations, including batch effects and random inter-sample differences. Moreover, OmniClustifyXMBDdemonstrates robustness in its results across different clustering parameters.
Pervasive selective sweeps across human gut microbiomes
Authors: Wolff Richard , Garud Nandita R. 
Published: December 2023

AbstractThe human gut microbiome is composed of a highly diverse consortia of species which are continually evolving within and across hosts. The ability to identify adaptations common to many human gut microbiomes would not only reveal shared selection pressures across hosts, but also key drivers of functional differentiation of the microbiome that may affect community structure and host traits. However, to date there has not been a systematic scan for adaptations that have spread across human gut microbiomes. Here, we develop a novel selection scan statistic named the integrated Linkage Disequilibrium Score (iLDS) that can detect the spread of adaptive haplotypes across host microbiomes via migration and horizontal gene transfer. Specifically, iLDS leverages signals of hitchhiking of deleterious variants with the beneficial variant. Application of the statistic to∼30 of the most prevalent commensal gut species from 24 populations around the world revealed more than 300 selective sweeps across species. We find an enrichment for selective sweeps at loci involved in carbohydrate metabolism—potentially indicative of adaptation to features of host diet—and we find that the targets of selection significantly differ between Westernized and non-Westernized populations. Underscoring the potential role of diet in driving selection, we find a selective sweep absent from non-Westernized populations but ubiquitous in Westernized populations at a locus known to be involved in the metabolism of maltodextrin, a synthetic starch that has recently become a widespread component of Western diets. In summary, we demonstrate that selective sweeps across host microbiomes are a common feature of the evolution of the human gut microbiome, and that targets of selection may be strongly impacted by host diet.
Short-chain carboxylates facilitate the counting of yeasts in Sub-high temperatureDaqu
Authors: Ren Zhiqiang , Xie Juan , Tang Tuoxian , Huang Zhiguo 
Published: December 2023

AbstractSub-high temperature Daqu is a traditional solid fermenting agent that produces Chinese strong-aroma Baijiu. It is abundant in various microorganisms, including bacteria, yeasts, molds, and actinomycetes, of which yeasts play a crucial role in ethanol production and flavor formation. Counting yeasts in Daqu is difficult due to the interference of molds and bacteria. Antibiotics are employed to inhibit bacterial growth, but there is no effective way to suppress molds without affecting the growth of yeasts. In this study, short-chain carboxylates (C1-C6) were added to the culture medium at various pH conditions to investigate their effects on the growth of molds and yeasts. Results showed that they have distinct inhibitory effects in a pH-and concentration-dependent manner. A few of these tested short-chain carboxylates effectively suppress mold growth in agar plates without affecting yeast growth. Herein, a simple and feasible method for improving the efficiency of yeast isolation and counting in Daqu has been proposed, which may be useful for studying yeasts from complex habitats.
Evolution of Multicellularity Genes in the Lead Up to the Great Oxidation Event
Authors: Boden Joanne S. , Nieves-Morión Mercedes , Nürnberg Dennis J. , Arévalo Sergio , Flores Enrique , Sánchez-Baracaldo Patricia 
Published: December 2023

AbstractCyanobacteria are among the most morphologically diverse prokaryotic phyla on Earth. Their morphotypes range from unicellular to multicellular filaments, yet mechanisms underlying the evolution of filamentous morphologies remain unknown. Here, we implement phylogenomic, Bayesian molecular clock and gene-tree-species-tree reconciliation analyses to estimate when genes encoding cell-cell joining structures first evolved. We also characterise septal structures and measure intercellular communication rates in non-model and early-branching filamentous strains. Our results suggest that genes encoding septal proteins (namelysepJ, sepI,andfraE) and potentially pattern formation (hetR) evolved in the Neoarchaean ∼2.6-2.7 billion years (Ga) ago. Later, at the start of the Great Oxygenation Event ∼2.5 Ga, genes involved in cellular differentiation (namelyhetZ, patU3andhglK) appeared. Our results predict that early-branching lineages likePseudanabaenawere capable of intercellular communication, but further innovations in cellular differentiation were needed to drive ecological expansion on a scale large enough to permanently oxygenate Earth’s atmosphere.
Mechanism of human PINK1 activation at the TOM complex in a reconstituted system
Authors: Raimi Olawale G. , Ojha Hina , Ehses Kenneth , Dederer Verena , Lange Sven M , Rivera Cristian Polo , Deegan Tom D. , Chen Yinchen , Wightman Melanie , Toth Rachel , Labib Karim P. M. , Mathea Sebastian , Ranson Neil , Fernández-Busnadiego Rubén , Muqit Miratul M. K. 
Published: December 2023

AbstractLoss of function mutations in PTEN-induced kinase 1 (PINK1) are a frequent cause of early-onset Parkinson’s disease (PD). Stabilisation of PINK1 at the Translocase of Outer Membrane (TOM) complex of damaged mitochondria is a critical step for its activation. To date the mechanism of how PINK1 is activated in the TOM complex is unclear. Herein we report co-expression of human PINK1 and all seven TOM subunits inSaccharomyces cerevisiaeis sufficient for PINK1 activation. We use this reconstitution system to systematically assess the role of each TOM subunit towards PINK1 activation. We unambiguously demonstrate that the TOM20 and TOM70 receptor subunits are required for optimal PINK1 activation and map their sites of interaction with PINK1 using AlphaFold structural modelling and mutagenesis. We also demonstrate an essential role of the pore-containing subunit TOM40 and its structurally associated subunits TOM7 and TOM22 for PINK1 activation. These molecular findings will aid in the development of small molecule activators of PINK1 as a therapeutic strategy for PD.
Change in US farm sector's financial position and performance in 2020 compared to pre-pandemic expectations: An analysis using financial ratios
Authors: Giri Anil K. , Litkowski Carrie , Subedi Dipak , McDonald Tia M. 
Published: December 2023

PurposeThe purpose of this study is to examine how US farm sector performed in 2020, the first year of the pandemic. There were significant supply and demand shocks due to the pandemic. Furthermore, there was significant fluctuation in commodity prices and record high government payments in 2020. This study aims to examine the performance and position of US farm sector (financially) to system (and global economy) wide shocks.Design/methodology/approachThe authors examine 2020 values for farm sector financial ratios before and after the onset of the Coronavirus (COVID-19) pandemic using the data from the United States Department of Agriculture to understand the financial position and performance of the US farm sector.FindingsThe authors find solvency ratios (which are indicators of the sector's ability to repay financial liabilities via the sale of assets) worsened in 2020 relative to pre-pandemic expectations. Efficiency ratios (which evaluate the conversion of assets into production and revenue) and liquidity ratios (which are indicators of the availability of cash to cover debt payments) showed mixed outcomes for the realized results in 2020 relative to the pre-pandemic forecasts. Four profitability ratios were stronger in 2020 relative to pre-pandemic expectations. All solvency, liquidity and profitability ratios plus 2 out of 5 efficiency ratios for 2020 were weaker than their respective average ratios obtained from 2000 to 2019 data.Originality/valueThis research is one of the first papers to use financial ratios to examine how the US farm sector performed in 2020 compared to expectations prior to the pandemic.
Subjective preferences, liquidity constraints and price risk management under large-scale farm management
Authors: Peng Peng , Xu Zhigang 
Published: December 2023

PurposeLarge-scale farm management in China has developed rapidly in recent years. Large-scale farmers face substantial operating risks, requiring extensive price risk management. However, the agricultural insurance and futures markets in China are incomplete. This study aims to analyze the price-risk-management behaviors of large-scale farmers under incomplete market conditions, with a focus on the interconnections between large scale farmers' subjective preferences (risk preferences, time preferences), liquidity constraints and their price risk management.Design/methodology/approachThe authors construct an analysis framework to reveal the impact of large-scale farmers' risk preferences, time preferences and liquidity conditions on their price-risk-management behaviors under incomplete market conditions. Using data from field surveys and subjective preference experiments involving 409 large-scale grain farmers in China, an empirical analysis was conducted using the bivariate probit model.FindingsThe results show that risk-averse farmers will use risk transfer (such as contract farming) and risk diversification (such as multi-period sales) to avoid price risk. However, farmers subject to liquidity constraints and strong time preferences will not choose risk diversification, and the interaction between time preferences and liquidity constraints will strengthen this decision. The larger the farm-management scale, the greater the impact.Originality/valueThe authors focus on rapidly developed large-scale farm management in China. Appropriate price risk management is required by large-scale farmers due to their substantial operating risks. Considering the incomplete conditions of agricultural insurance and futures markets, the results of this study will help identify behavioral characteristics of large-scale farmers and optimize their price-risk-management strategies, further stabilizing large-scale farm management.
Beyond the boss: how distributed leadership elevates team effectiveness in startup organizations? – a multi-level analysis
Authors: Shagirbasha Shameem , Madhan Kumar , Iqbal Juman 
Published: December 2023

PurposeThough there is an increasing corpus of work on contemporary styles of leadership, studies on distributed leadership (DL) are still in the nascent stage. Therefore, the purpose of this paper is to investigate how DL affects team effectiveness from the neglected perspectives of team cognition, team motivation and team coordination in startup companies using multi-level analysis.Design/methodology/approachThe authors investigated the study variables through the lens of 42 teams in 18 startup organizations operating in India, representing an equitable distribution of the manufacturing and service sectors. M-plus was used to do statistical analysis on the multi-level model.FindingsDrawing upon social exchange theory (SET), results indicated that DL had a favorable impact on team effectiveness and team cognitive processes, team motivation and team coordination mediates the association between DL and individual perceptions of team effectiveness.Originality/valueVarious studies have been carried out relating to leadership and how it impacts effectiveness. However, as far as the authors know, previous studies have failed to empirically address how DL drives team effectiveness by uncovering the mediating impact of team cognitive processes, team motivation and team coordination in the Indian startup context.