bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel 3D Approach to Model Non-Alcoholic Fatty Liver Disease using human Pluripotent Stem Cells
Authors: Morell Carola Maria , Tilson Samantha Grace , Tomaz Rute Alexandra , Shahsavari Arash , Munteanu Andi , Canu Giovanni , Wesley Brandon Tyler , Perrin Marion , Geti Imbisaat , Mukhopadhyay Subhankar , Mazzacuva Francesca , Gissen Paul , Garcia-Bernardo Jose , Bachman Martin , Rimland Casey Allison , Sampaziotis Fotios , Mohorianu Irina , Vallier Ludovic 
Published: February 2024

ABSTRACTBackground and aimsNon-alcoholic fatty liver disease (NAFLD) is a major health care challenge and new therapies are urgently needed. However, the mechanisms underlying disease remain to be understood. Indeed, studying NAFLD remains challenging due to the lack of model systems recapitulating the different aspects of the human pathology. Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity to address this limitation since they can be differentiated into large quantity of liver cells. Here, we took advantage of hiPSCs to develop a multi-cellular platform mimicking the complex interplays involved in NAFLD progression.MethodshiPSCs-derived hepatocyte like cells (HLCs), cholangiocytes, stellate cells, and macrophages were co-cultured in a collagen-based 3D system to reproduce the liver microenvironment. Fatty acid treatments led to a NAFLD phenotype involving cell-cell interactions which were investigated by transcriptomic and functional analyses.ResultsHepatic cells were grown up to 4weeks in 3D, retaining key functions and markers. Importantly, co-cultured cells spontaneously reorganised into physiologically relevant connections: HLCs arranged around biliary structures, which established contacts with stellate cells, while macrophages organised around HLCs. Fatty acid treatments induced steatosis and lipotoxicity in HLCs. Furthermore, fat-laden HLCs prompted a non-parenchymal cells response altering tissue architecture.ConclusionsOur multicellular platform provides a new approach to model interactions between human hepatic cells during NAFLD progression. Such approach has the potential to investigate the sequential events driving chronic liver diseases, including hepatocellular injury, inflammation and fibrosis. Furthermore, our system provides a unique and urgently needed tool to investigate the molecular mechanisms associated with NAFLD and ultimately to validate new targets for therapeutics development.List of abbreviationsCOs, cholangiocytes organoids; FFA, free fatty acids; hiPSCs, human induced pluripotent stem cells; HLCs, hepatocyte like cells; HSCs, hepatic stellate cells; M0, hiPSCs-derived macrophages; NAFLD, non-alcoholic fatty liver disease; NPCs, non-parenchymal cells; OA, oleic acid; PA, palmitic acid.
Parental effects of pathogenic bacterial infections inDrosophila melanogaster: trans-generational immune priming without apparent costs
Authors: Basu Aabeer Kumar , Prasad Nagaraj Guru 
Published: February 2024

AbstractParental experience with pathogens and parasites can shape offspring susceptibility to infections, a phenomenon commonly referred to as trans-generational immune priming (TgIP) in insects. TgIP can influence the evolution of both host immune traits and pathogen virulence. The host ecology and its environmental pathogen load can in turn shape the evolution of TgIP. Therefore, the functional limits of TgIP and the conditions under which it is observed need to be explored in a variety of species. Majority of empirical studies addressing this phenomenon focus on non-pathogenic infections of parents, implemented via either the use of pathogen substitutes (viz., liposaccharide molecules), or the use of sub-lethal infection doses, by using inactivated pathogens to infect the parents. We tested if exposing parents to pathogenic bacterial infections affects offspring susceptibility to homologous (same pathogen as the one used to infect the parents) and heterologous (different pathogen than the one used to infect the parents) infection challenges inDrosophila melanogaster. We found that parental infection increases offspring survival following a homologous challenge. Similar effects were seen in the case of heterologous challenges too, with the breadth of cross-reactivity being dependent on the pathogen used to infect the parents. Parental infection also improves offspring capacity to restrict systemic pathogen proliferation following a homologous challenge, suggesting increased disease resistance. Parental infection has no effect on offspring reproduction, either in presence or absence of infection, suggesting an absence of associated costs and limited benefit of trans-generational immune priming. Overall, we have demonstrated that parental infection helps offspring better counter infection challenges inD. melanogasterwithout incurring any measurable costs.
The impact of non-neutral synonymous mutations when inferring selection on non-synonymous mutations
Authors: Martinez i Zurita Aina , Kyriazis Christopher C. , Lohmueller Kirk E. 
Published: February 2024

AbstractThe distribution of fitness effects (DFE) describes the proportions of new mutations that have different effects on reproductive fitness. Accurate measurements of the DFE are important because the DFE is a fundamental parameter in evolutionary genetics and has implications for our understanding of other phenomena like complex disease or inbreeding depression. Current computational methods to infer the DFE for nonsynonymous mutations from natural variation first estimate demographic parameters from synonymous variants to control for the effects of demography and background selection. Then, conditional on these parameters, the DFE is then inferred for nonsynonymous mutations. This approach relies on the assumption that synonymous variants are neutrally evolving. However, some evidence points toward synonymous mutations having measurable effects on fitness. To test whether selection on synonymous mutations affects inference of the DFE of nonsynonymous mutations, we simulated several possible models of selection on synonymous mutations using SLiM and attempted to recover the DFE of nonsynonymous mutations using Fit∂a∂i, a common method for DFE inference. Our results show that the presence of selection on synonymous variants leads to incorrect inferences of recent population growth. Furthermore, under certain parameter combinations, inferences of the DFE can have an inflated proportion of highly deleterious nonsynonymous mutations. However, this bias can be eliminated if the correct demographic parameters are used for DFE inference instead of the biased ones inferred from synonymous variants. Our work demonstrates how unmodeled selection on synonymous mutations may affect downstream inferences of the DFE.
Tension-induced adhesion mode switching: the interplay between focal adhesions and clathrin-containing adhesion complexes
Authors: Djakbarova Umida , Madraki Yasaman , Chan Emily T. , Wu Tianyao , Atreaga-Muniz Valeria , Akatay A. Ata , Kural Comert 
Published: February 2024

AbstractIntegrin-based adhesion complexes are crucial in various cellular processes, including proliferation, differentiation, and motility. While the dynamics of canonical focal adhesion complexes (FAs) have been extensively studied, the regulation and physiological implications of the recently identified clathrin-containing adhesion complexes (CCACs) are still not well understood. In this study, we investigated the spatiotemporal mechanoregulations of FAs and CCACs in a breast cancer model. Employing single-molecule force spectroscopy coupled with live-cell fluorescence microscopy, we discovered that FAs and CCACs are mutually exclusive and inversely regulated complexes. This regulation is orchestrated through the modulation of plasma membrane tension, in combination with distinct modes of actomyosin contractility that can either synergize with or counteract this modulation. Our findings indicate that increased membrane tension promotes the association of CCACs at integrin αVβ5 adhesion sites, leading to decreased cancer cell proliferation, spreading, and migration. Conversely, lower membrane tension promotes the formation of FAs, which correlates with the softer membranes observed in cancer cells, thus potentially facilitating cancer progression. Our research provides novel insights into the biomechanical regulation of CCACs and FAs, revealing their critical and contrasting roles in modulating cancer cell progression.
Mechanistic models of humoral kinetics following COVID-19 vaccination
Authors: Stocks Daniel , Thomas Amy , Finn Adam , Danon Leon , Brooks-Pollock Ellen 
Published: February 2024

AbstractIntroductionFuture COVID-19 vaccine programmes need to take into account the variable responses elicited by different vaccines and their waning protection over time. Existing descriptions of antibody response to COVID-19 vaccination convey limited information about the mechanisms of antibody production and maintenance.MethodsWe describe the antibody dynamics elicited by COVID-19 vaccination with two biologically-motivated mathematical models of antibody production by plasma cells and subsequent decay. We fit the models using Markov Chain Monte Carlo to seroprevalence data from 14,602 uninfected individuals collected via the primary care network in England between May 2020 and September 2022. We ensure our models are structurally and practically identifiable when using antibody data alone. We analyse the effect of age, vaccine type, number of doses, and the interval between doses on antibody production and longevity of response.ResultsWe find evidence that individuals over 35 years of age who received a second dose of ChAdOx1-S generate a persistent antibody response suggestive of long-lived plasma cell induction, while individuals that receive two doses of BNT162b2, or one dose of either vaccine do not. We also find that plasamblast productive capacity, the likely driver of short-term antibody responses, is greater in younger people than older people (≤ 4.5 fold change in point estimates), people vaccinated with two doses than people vaccinated with one dose (≤ 12 fold change), and people vaccinated with BNT162b2 than people vaccinated with ChAdOx1-S (≤ 440 fold change). The effect of age on antibody dynamics is more pronounced in people vaccinated with BNT162b2 than people vaccinated with ChAdOx1-S. We find the half-life of an antibody to be between 23 – 106 days.ConclusionRoutinely-collected seroprevalence data are a valuable source of information for characterising within-host mechanisms of antibody production and persistence. Extended sampling and linking seroprevalence data to outcomes would allow for powerful conclusions about how humoral kinetics protect against disease.
Multimodal Hox5 activity generates motor neuron diversity
Authors: KC Ritesh , López de Boer Raquel , Lin Minshan , Jeannotte Lucie , Philippidou Polyxeni 
Published: February 2024

AbstractMotor neurons (MNs) are the final output of circuits driving fundamental behaviors, such as respiration and locomotion. Hox proteins are essential in generating the MN diversity required for accomplishing these functions, but the transcriptional mechanisms that enable Hox paralogs to assign distinct MN subtype identities despite their promiscuous DNA binding motif are not well understood. Here we show that Hoxa5 controls chromatin accessibility in all mouse spinal cervical MN subtypes and engages TALE co-factors to directly bind and regulate subtype-specific genes. We identify a paralog-specific interaction of Hoxa5 with the phrenic MN-specific transcription factor Scip and show that heterologous expression of Hoxa5 and Scip is sufficient to suppress limb-innervating MN identity. We also demonstrate that phrenic MN identity is stable after Hoxa5 downregulation and identify Klf proteins as potential regulators of phrenic MN maintenance. Our data identify multiple modes of Hoxa5 action that converge to induce and maintain MN identity.
Unveiling the regulatory network controlling natural transformation in lactococci
Authors: Toussaint Frédéric , Henry de Frahan Marie , Poncelet Félix , Ladrière Jean-Marc , Horvath Philippe , Fremaux Christophe , Hols Pascal 
Published: February 2024

SUMMARYLactococcus lactisis a lactic acid bacterium of major importance for food fermentation and biotechnological applications. The ability to manipulate its genome quickly and easily through competence for DNA transformation would accelerate its general use as a platform for a variety of applications. Natural transformation in this species requires the activation of the master regulator ComX. However, the growth conditions that lead to spontaneous transformation, as well as the regulators that control ComX production, are unknown. Here, we identified the carbon source, nitrogen supply, and pH as key factors controlling competence development in this species. Notably, we showed that these conditions are sensed by three global regulators (i.e., CcpA, CodY, and CovR), which represscomXtranscription directly. Furthermore, our systematic inactivation of known signaling systems suggests that classical pheromone-sensing regulators are not involved. Finally, we discovered that the ComX-degrading MecA-ClpCP machinery plays a predominant role based on the identification of a single amino-acid substitution in the adaptor protein MecA of a highly transformable strain. Contrasting with closely-related streptococci, the master competence regulator inL. lactisis regulated both proximally by general sensors and distantly by the Clp degradation machinery. This study not only highlights the diversity of regulatory networks for competence control in Gram-positive bacteria, but it also paves the way for the use of natural transformation as a tool to manipulate this biotechnologically important bacterium.IMPORTANCELactic acid bacteria (LAB) play important roles in our daily lives as members of our microbiota or as starters of dairy products. Understanding the natural horizontal gene transfer mechanisms that shape their genomes will allow us to better control and understand their evolution over time. The DNA transformation machinery is found in all beneficial LAB species. With the exception of streptococci, however, the conditions of its activation remain unknown. In this study, the physiological conditions that activate competence for DNA transformation inLactococcus lactis, the most important lactococcal species, were identified. We also unveiled the guardians of the master competence regulator ComX. In this species, it is directly repressed by global carbon and nitrogen regulators (CcpA and CodY) as well as the general stress system CovRS. Additionally, it was discovered that the Clp machinery degrading ComX plays a dominant role in the strict control of competence activation. In Gram-positive cocci, the hierarchical organization of these regulators for controlling competence development inL. lactisis unprecedented.
Transcription factors across theEscherichia colipangenome: a 3D perspective
Authors: Moreno-Hagelsieb Gabriel 
Published: February 2024

AbstractMotivationIdentification of complete sets of transcription factors (TFs) is a foundational step in the inference of genetic regulatory networks. With the availability of high-quality predictions of protein three-dimensional structures (3D), it has become possible to use structural comparisons for the inference of homology beyond what is possible from sequence analyses alone. This work explores the potential to use predicted 3D structures for the identification of TFs in theEscherichia colipangenome.ResultsComparisons between predicted structures and their experimentally confirmed counterparts confirmed the high-quality of predicted structures, with most 3D structural alignments showing TM-scores well above established structural similarity thresholds, though the quality seemed slightly lower for TFs than for other proteins. As expected, structural similarity decreased with sequence similarity, though most TM-scores still remained above the structural similarity threshold. This was true regardless of the aligned structures being experimental or predicted. Results at the lowest sequence identity levels revealed potential for 3D structural comparisons to extend homology inferences below the “twilight zone” of sequence-based methods. The body of predicted 3D structures covered 99.7% of available proteins from theE. colipangenome, missing only two of those matching TF domain sequence profiles. Structural analyses increased the inferred TFs in theE. colipangenome by 18% above the amount obtained with sequence profiles alone.
Experience and behavior modulate piriform cortex odor representation in freely moving mice
Authors: Chapman Ian F. , Raymond Martin A. , Fletcher Max L. 
Published: February 2024

AbstractIn rodents, activity in the piriform cortex (PC) has been shown to reliably encode the identity of olfactory information within single sessions of odor delivery. However, recent evidence from chronic PC recordings found significant unreliability in this ensemble code over longer periods. The causes of this phenomenon, termed representational drift, are still being investigated across multiple sensory systems, but prior work has suggested a role for animal behavior in this observed unreliability of coding. To explore this possibility in PC, we recorded from the same populations of neurons in freely-moving, awake mice using micro-endoscopic calcium imaging as they gained passive experience with a panel of odorants over 5 consecutive days. As in prior studies, PC odor responses within a single session could be used to accurately decode odor identity. However, responses became less consistent across days of experience as odor-evoked response properties of the neurons shifted with experience. During these recordings, within and across sessions, decreases in olfactory investigative behavior correlated with decreased odor-evoked response from PC neurons. Similarly, decreases in odor investigation correlated with a decrease in representational consistency, and trials with greater odor investigation could be used to decode odor identity from PC neurons more accurately over time. Overall, this data supports recent evidence of long-term shifts in the ensembles of PC neurons encoding odor-identity (drift) but supports a role for behavioral modulation of overall PC activity and ensemble response consistency.
Learning within a sensory-motor circuit links action to expected outcome
Authors: Zhou WenXi , Schneider David M. 
Published: February 2024

AbstractThe cortex integrates sound- and movement-related signals to predict the acoustic consequences of behavior and detect violations from expectations. Although expectation- and prediction-related activity has been observed in the auditory cortex of humans, monkeys, and mice during vocal and non-vocal acoustic behaviors, the specific cortical circuitry required for forming memories, recalling expectations, and making predictions remains unknown. By combining closed-loop behavior, electrophysiological recordings, longitudinal pharmacology, and targeted optogenetic circuit activation, we identify a cortical locus for the emergence of expectation and error signals. Movement-related expectation signals and sound-related error signals emerge in parallel in the auditory cortex and are concentrated in largely distinct neurons, consistent with a compartmentalization of different prediction-related computations. On a trial-by-trial basis, expectation and error signals are correlated in auditory cortex, consistent with a local circuit implementation of an internal model. Silencing the auditory cortex during motor-sensory learning prevents the emergence of expectation signals and error signals, revealing the auditory cortex as a necessary node for learning to make predictions. Prediction-like signals can be experimentally induced in the auditory cortex, even in the absence of behavioral experience, by pairing optogenetic motor cortical activation with sound playback, indicating that cortical circuits are sufficient for movement-like predictive processing. Finally, motor-sensory experience realigns the manifold dimensions in which auditory cortical populations encode movement and sound, consistent with predictive processing. These findings show that prediction-related signals reshape auditory cortex dynamics during behavior and reveal a cortical locus for the emergence of expectation and error.
Repetition in Social Contact Interactions: Implications in Modelling the Transmission of Respiratory Infectious Diseases in Pre-pandemic & Pandemic Settings
Authors: Loedy Neilshan , Wallinga Jacco , Hens Niel , Torneri Andrea 
Published: February 2024

AbstractThe spread of viral respiratory infections is intricately linked to human interactions, and this relationship can be characterised and modelled using social contact data. However, many analyses tend to overlook the recurrent nature of these contacts. To bridge this gap, we undertake the task of describing individuals’ contact patterns over time, by characterising the interactions made with distinct individuals during a week. Moreover, we gauge the implications of this temporal reconstruction on disease transmission by juxtaposing it with the assumption of random mixing over time. This involves the development of an age-structured individual-based model, utilising social contact data from a pre-pandemic scenario (the POLYMOD study) and a pandemic setting (the Belgian CoMix study), respectively. We found that accounting for the frequency of contacts impacts the number of new, distinct, contacts, revealing a lower total count than a naive approach, where contact repetition is neglected. As a consequence, failing to account for the repetition of contacts can result in an underestimation of the transmission probability given a contact, potentially leading to inaccurate conclusions when using mathematical models for disease control. We therefore underscore the necessity of acknowledging the longitudinal nature of contacts when formulating effective public health strategies.
Staff responses to management control systems changes in an Australian university
Authors: Billah Mamun , Ahmed Zahir Uddin , Ali Mohobbot 
Published: February 2024

Purpose
This study aims to examine staff responses to management control systems (MCS) changes in an Australian university. Through the analysis of the category of staff responses, it aims to understand the perception gaps among the staff at different levels of the university.

Design/methodology/approach
Using a case study approach on an Australian university, data was collected from interviews with staff across three hierarchical levels to explore their behavioural responses.

Findings
This study finds that staff at all levels largely complied with MCS changes due to institutional enforcement. Top management emphasised aligning with government policies and funding, often using manipulation and compartmentalisation tactics in implementing the new MCS. Mid-level managers generally favour research strategies but feel excluded from decision-making and have limited influence over funding. They adopted a balancing tactic within a compromise strategy. Meanwhile, operating-level academics had mixed experiences, feeling largely powerless in influencing MCS while also showing instances of self-motivated compliance. Overall, the study reveals varying responses across different hierarchical levels, highlighting the complexities of MCS changes in staff behaviour and attitudes.

Research limitations/implications
The insights from this study can guide university administrators and policymakers in understanding the intricate variations in staff reactions to institutional changes. By recognising the factors that drive compliance and defiance, institutions can better navigate and implement changes in MCS.

Originality/value
This research offers a unique perspective on the behavioural side of MCS changes in higher education. By focusing on varied hierarchical levels within a university, the study provides a granular understanding of individual responses, enriching the existing literature on MCS transitions in academia.