bluuebunny/crossref_metadata_2025 huggingface dataset:
A Large Language Model Approach to Extracting Causal Evidence across Study Designs for Evidence Triangulation
Authors: Shi Xuanyu , Zhao Wenjing , Chen Ting , Yang Chao , Du Jian
Published: March 2024

Health strategies increasingly emphasize both behavioral and biomedical interventions, yet the complex and often contradictory guidance on diet, behavior, and health outcomes complicates evidence-based decision-making. Evidence triangulation across diverse study designs is essential for establishing causality, but scalable, automated methods for achieving this are lacking. In this study, we assess the performance of large language models (LLMs) in extracting both ontological and methodological information from scientific literature to automate evidence triangulation. A two-step extraction approach—focusing on cause-effect concepts first, followed by relation extraction—outperformed a one-step method, particularly in identifying effect direction and statistical significance. Using salt intake and blood pressure as a case study, we calculated the Convergeny of Evidence (CoE) and Level of Evidence (LoE), finding a trending excitatory effect of salt on hypertension risk, with a moderate LoE. This approach complements traditional meta-analyses by integrating evidence across study designs, thereby facilitating more comprehensive assessments of public health recommendations.
Using machine learning to evaluate the value of genetic liabilities in classification of hypertension within the UK Biobank
Authors: MacCarthy Gideon , Pazoki Raha
Published: March 2024

Background and objective

Hypertension increases the risk of cardiovascular diseases (CVD) such as stroke, heart attack, heart failure, and kidney disease, contributing to global disease burden and premature mortality. Previous studies have utilized statistical and machine learning techniques to develop hypertension prediction models. Only a few have included genetic liabilities and evaluated their predictive values. This study aimed to develop an effective hypertension prediction model and investigate the potential influence of genetic liability for risk factors linked to CVD on hypertension risk using Random Forest (RF) and Neural Network (NN).

Materials and methods

The study included 244,718 participants of European ancestry. Genetic liabilities were constructed using previously identified genetic variants associated with various cardiovascular risk factors through genome-wide association studies (GWAS). The sample was randomly split into training and testing sets at a 70:30 ratio. We used RF and NN techniques to develop prediction models in the training set with or without feature selection. We evaluated the models’ discrimination performance using the area under the curve (AUC), calibration, and net reclassification improvement in the testing set.

Results

The models without genetic liabilities achieved AUCs of 0.70 and 0.72 using RF and NN methods, respectively. Adding genetic liabilities resulted in a modest improvement in the AUC for RF but not for NN. The best prediction model was achieved using RF (AUC =0.71, Spiegelhalter z score= 0.10, P-value= 0.92, calibration slope=0.99) constructed in stage two.

Conclusion

Incorporating genetic factors in the model may provide a modest incremental value for hypertension prediction beyond baseline characteristics. Our study highlighted the importance of genetic liabilities for both total cholesterol and LDL within the same prediction model adds value to the classification of hypertension.
Single Turnover Transient State Kinetics Reveals Processive Protein Unfolding Catalyzed byEscherichia coliClpB
Authors: Banwait Jaskamaljot Kaur , Islam Liana , Lucius Aaron L.
Published: March 2024

E. coliClpB, andS. cerevisiaeHsp104 are AAA+ motor proteins essential for proteome maintenance and thermal tolerance. ClpB and Hsp104 have been proposed to extract a polypeptide from an aggregate and processively translocate the chain through the axial channel of its hexameric ring structure. However, the mechanism of translocation and if this reaction is processive remains disputed. We reported that Hsp104 and ClpB are non-processive on unfolded model substrates. Others have reported that ClpB is able to processively translocate a mechanically unfolded polypeptide chain at rates over 240 amino acids (aa) per second. Here we report the development of a single turnover stopped-flow fluorescence strategy that reports on processive protein unfolding catalyzed by ClpB. We show that when translocation catalyzed by ClpB is challenged by stably folded protein structure, the motor enzymatically unfolds the substrate at a rate of ∼0.9 aa s-1with a step-size of ∼60 amino acids. We reconcile the apparent controversy by defining enzyme catalyzed protein unfolding and translocation as two distinct reactions with different mechanisms of action. We propose a model where slow unfolding followed by fast translocation represents an important mechanistic feature that allows the motor to rapidly translocate up to the next folded region or rapidly dissociate if no additional fold is encountered.
Evaluating a Novel High-Density EEG Sensor Net Structure for Improving Inclusivity in Infants with Curly or Tightly Coiled Hair
Authors: Mlandu Nwabisa , McCormick Sarah A. , Davel Lauren , Zieff Michal R. , Bradford Layla , Herr Donna , Jacobs Chloë A. , Khumalo Anele , Knipe Candice , Madi Zamazimba , Mazubane Thandeka , Methola Bokang , Mhlakwaphalwa Tembeka , Miles Marlie , Goolam Nabi Zayaan , Negota Rabelani , Nkubungu Khanyisa , Pan Tracy , Samuels Reese , Williams Sadeeka , Williams Simone R. , Avery Trey , Foster Gaynor , Donald Kirsten A. , Gabard-Durnam Laurel J.
Published: March 2024

Electroencephalography (EEG) is an important tool in the field of developmental cognitive neuroscience for indexing neural activity. However, racial biases persist in EEG research that limit the utility of this tool. One bias comes from the structure of EEG nets/caps that do not facilitate equitable data collection across hair textures and types. Recent efforts have improved EEG net/cap design, but these solutions can be time-intensive, reduce sensor density, and are more difficult to implement in younger populations. The present study focused on testing EEG sensor net designs over infancy. Specifically, we compared EEG data quality and retention between two high-density saline-based EEG sensor net designs from the same company (Magstim EGI, Whitland, UK) within the same infants during a baseline EEG paradigm. We found that within infants, the tall sensor nets resulted in lower impedances during collection, including lower impedances in the key online reference electrode for those with greater hair heights and resulted in a greater number of usable EEG channels and data segments retained during pre-processing. These results suggest that along with other best practices, the modified tall sensor net design is useful for improving data quality and retention in infant participants with curly or tightly-coiled hair.
Tuning non-linear mechanics in collagen hydrogels modulates cellular morphotypes in three dimensions
Authors: Martinez Marco A. Enriquez , Wang Zhao , Ju Robert J. , Turunen Petri , Mata Jitendra , Gilbert Elliot P. , Lauko Jan , Stehbens Samantha J. , Rowan Alan E.
Published: March 2024

Collagen networks contribute to tissue architecture and modulate cellular responses in crowded three-dimensional environments. Therefore, it is the most widely used biological polymer in three-dimensional studies of cellular interactions with the extracellular matrix.In vivo, collagen exists embedded within additional matrix components. Studies have shown that the combination of matrices induces synergistic mechanical interactions, influencing the non-linear mechanical behaviour of collagen networks. However, how cells respond to changes in collagen non-linear elasticity remains largely unknown. By precisely controlling the mechanical behaviour of collagen networks with the biologically inert and semiflexible polymer polyisocyanopeptides, we demonstrate that changes in the non-linear elasticity of collagen induces morphological cell responses that influence how cells migrate, proliferate, and interact with collagen. We found that when collagen rigidifies in the presence of a second component, this induces morphological changes in cell-matrix interactions, resulting in a decrease in migration and the ability of cells to deform collagen matrices. Our results demonstrate that the onset of collagen stiffening is key to inducing intracellular tension which dictates morphological cell responses in three-dimensional collagen networks. We anticipate our findings will prove useful in understanding how cells respond to changes in collagen mechanics when combined in double network systems which better recapitulates tissuesin vivo.
Optogenetic stimulation recruits cortical neurons in a morphology-dependent manner
Authors: Berling David , Baroni Luca , Chaffiol Antoine , Gauvain Gregory , Picaud Serge , Antolík Ján
Published: March 2024

Single-photon optogenetic stimulation is a crucial tool in neuroscience, enabling precise, cell-type-specific modulation of neuronal circuits. Miniaturization of this technique in the form of fully implantable wide-field stimulator arrays enables interrogation of cortical circuits in long-term experiments and promises to enhance Brain-Machine Interfaces for restoring sensory and motor functions. However, for both basic science and clinical applications, it is essential that this technique achieves the precision needed for selective activation of sensory and motor representations at the single-column level. Yet studies report differing and sometimes conflicting neuronal responses within the stimulated cortical areas. While recurrent network mechanisms contribute to complex responses, here we demonstrate that complexity starts already at the level of neuronal morphology. Simulating optogenetic responses in detailed models of layer-2/3 and layer-5 pyramidal neurons, we accounted for realistic physiological dynamics across different stimulation intensities, including threshold, sustained, and depolarization-block responses. Our findings suggest that the spatial distribution of activated neurons from a single stimulator location at the cortical surface can be inhomogeneous and varies with stimulation intensity and neuronal morphology across layers, potentially explaining the observed response heterogeneity in earlier experiments. We found that activation spreads laterally up to several hundred micrometers from the light source due to neuronal morphology. To enhance precision, we explored two strategies: preferentially somatic expression of channelrhodopsin, which was effective only in layer-5 neurons, and narrowing the stimulating light beam, which improved precision in both layers. Our results indicate that, under the right optical setup, single-column precision of stimulation is achievable, and that optical enhancements to the stimulator may offer more significant precision improvements than genetic modifications targeting the soma.
Dysregulated Neurofluid Coupling as a New Noninvasive Biomarker for Primary Progressive Aphasia
Authors: Zeng Xinglin , Zhao Zhiying , Hua Lin , Yuan Zhen
Published: March 2024

Objective

Accumulation of pathological tau is one of the primary causes of Primary Progressive Aphasia (PPA). The glymphatic system is crucial for removing metabolic waste from the brain, whereas the underlying mechanism on the interplay between impairments in glymphatic clearance and PPA is poorly understood. Therefore, the aim of this study is to investigate the role that dysregulated macroscopic cerebrospinal fluid (CSF) movement plays in the pathology of PPA.

Methods

56 PPA patients and 94 healthy controls (HCs) participated this work. The coupling strength between blood-oxygen-level-dependent (BOLD) signals in the gray matter and CSF flow within the subarachnoid space and ventricular system was calculated by using Pearson correlation and made comparison between the two groups. Its associations with clinical characteristics including scores from Clinical Dementia Rating (CDR), Mini-Mental State Exam, Geriatric Depression Scale and with morphological measures in the hippocampus and entorhinal cortex were also quantified.

Results

The PPA group exhibited decreased global BOLD and CSF coupling as compared to that of HCs, indicating impaired glymphatic functions of the patients (p= 0.006). More importantly, it was discovered that BOLD-CSF coupling of PPA group rather than that of the HCs demonstrated significant correlations with the CDR scores (p= 0.04), hippocampal volume (p= 0.005), and entorhinal cortex thickness (p= 0.04).

Interpretation

The measured decoupling between global brain activation (hemodynamic response) and CSF flow and its association with symptomology and brain structural changes in PPA revealed the glymphatic dysregulation in PPA. Herein, this evidence supports the potential role of BOLD-CSF coupling as a noninvasive biomarker for the detection and prediction of PPA.
Multi-way modelling of oral microbial dynamics and host-microbiome interactions during induced gingivitis
Authors: van der Ploeg G.R. , Brandt B.W. , Keijser B.J.F. , van der Veen M.H. , Volgenant C.M.C. , Zaura E. , Smilde A.K. , Westerhuis J.A. , Heintz-Buschart A.
Published: March 2024

Gingivitis - the inflammation of the gums - is a reversible stage of periodontal disease. It is caused by dental plaque formation due to poor oral hygiene. However, gingivitis susceptibility involves a complex set of interactions between the oral microbiome, oral metabolome and the host. In this study, we investigated the dynamics of the oral microbiome and its interactions with the salivary metabolome during experimental gingivitis in a cohort of 41 systemically healthy participants. We use Parallel Factor Analysis (PARAFAC), which is a multi-way generalization of Principal Component Analysis (PCA) that can model the variability in the response due to subjects, variables and time. Using the modelled responses, we identified microbial subcommunities with similar dynamics that connect to the magnitude of the gingivitis response. By performing high level integration of the predicted metabolic functions of the microbiome and salivary metabolome, we identified pathways of interest that describe the changing proportions of Gram-positive and Gram-negative microbiota, variation in anaerobic bacteria, biofilm formation and virulence.
Transcriptional Determinism and Stochasticity Contribute to the Complexity of Autism AssociatedSHANKFamily Genes
Authors: Lu Xiaona , Ni Pengyu , Suarez-Meade Paola , Ma Yu , Forrest Emily Niemitz , Wang Guilin , Wang Yi , Quiñones-Hinojosa Alfredo , Gerstein Mark , Jiang Yong-hui
Published: March 2024

Precision of transcription is critical because transcriptional dysregulation is disease causing. Traditional methods of transcriptional profiling are inadequate to elucidate the full spectrum of the transcriptome, particularly for longer and less abundant mRNAs.SHANK3is one of the most common autism causative genes. Twenty-fourShank3mutant animal lines have been developed for autism modeling. However, their preclinical validity has been questioned due to incompleteShank3transcript structure. We applied an integrative approach combining cDNA-capture and long-read sequencing to profile theSHANK3transcriptome in human and mice. We unexpectedly discovered an extremely complexSHANK3transcriptome. SpecificSHANK3transcripts were altered inShank3mutant mice and postmortem brains tissues from individuals with ASD. The enhancedSHANK3transcriptome significantly improved the detection rate for potential deleterious variants from genomics studies of neuropsychiatric disorders. Our findings suggest the stochastic transcription of genome associated withSHANKfamily genes.
Indiscriminate activities of different Henipavirus polymerase complex proteins allow for efficient minigenome replication in hybrid systems
Authors: Li Xiao , Yang Yanling , López Carolina B.
Published: March 2024

The henipaviruses, including Nipah virus (NiV) and Hendra virus (HeV), are biosafety level 4 (BSL-4) zoonotic pathogens that cause severe neurological and respiratory disease in humans. To study the replication machinery of these viruses we developed robust minigenome systems that can be safely used in BSL-2 conditions. The nucleocapsid (N), phosphoprotein (P), and large protein (L) of henipaviruses are critical elements of their replication machinery and thus essential support components of the minigenome systems. Here, we tested the effects of diverse combinations of the replication support proteins on the replication capacity of the NiV and HeV minigenomes by exchanging the helper plasmids coding for these proteins among the two viruses. We demonstrate that all combinations including one or more heterologous proteins were capable of replicating both the NiV and HeV minigenomes. Sequence alignment showed identities of 92% for the N protein, 67% for P, and 87% for L. Notably, variations in amino acid residues were not concentrated in the N-P and P-L interacting regions implying that dissimilarities in amino acid composition among NiV and HeV polymerase complex proteins may not impact their interactions. The observed indiscriminate activity of NiV and HeV polymerase complex proteins is different from related viruses, which can support replication of heterologous genomes only when the whole polymerase complex belongs to the same virus. This newly observed promiscuous property of the henipavirus polymerase complex proteins could potentially be harnessed to develop universal anti-henipavirus antivirals.

IMPORTANCE

Given the severity of disease induced by Hendra and Nipah viruses in humans and the continuous emergence of new henipaviruses as well as henipa-like viruses, it is necessary to conduct more comprehensive investigation of the biology of henipaviruses and their interaction with the host. The replication of henipaviruses and the development of antiviral agents can be studied in systems that allow experiments to be performed under biosafety level 2 conditions. Here, we developed two robust minigenome systems for Nipah virus (NiV) and Hendra virus (HeV) that provide a convenient alternative system for studying NiV and HeV replication. Using these systems, we demonstrate that any combinations of the three polymerase complex proteins of NiV and HeV could effectively initiate the replication of both viral minigenomes, which suggest that the interaction regions of the polymerase complex proteins could be effective targets for universal and effective anti-henipavirus interventions.
The 3’-untranslated regions of yeast ribosomal protein mRNAs determine paralog incorporation into ribosomes and recruit factors necessary for specialized functions
Authors: Singh Raman K. , Crawford Robert A. , Mall Dheerendra P. , Pavitt Graham D. , Gerst Jeffrey E.
Published: March 2024

Ribosome heterogeneity arises via the differential incorporation of ribosomal protein (RP) paralogs, post-transcriptionally modified rRNA, post-translationally modified RPs, and ribosome-associated proteins (RAPs) into ribosomes. This has led to the hypothesis that heterogeneous or “specialized” ribosomes, which translate specific mRNA subsets, confer key roles in cell growth and development. While proven examples of functional ribosome heterogeneity in eukaryotes exist, there is no comprehensive analysis of specialized ribosome formation. We employed yeast RP paralog deletion libraries and high-throughput screening to investigate the functional specificity and redundancy between paralogs under various growth conditions. Composition and translatome analyses verified paralog specificity in the assembly and function of ribosomes specialized for growth on different carbon sources, and identified a novel RAP required for the efficient translation of peroxisomal proteins. Importantly, we also show that the mechanism by which specific RP paralogs incorporate into ribosomes requires their unique 3’-untranslated regions to yield ribosomes that differ in composition and function.

Graphical Abstract
Dysfunctional β-cell longevity in diabetes relies on energy conservation and positive epistasis
Authors: Raval Kavit , Jamshidi Neema , Seyran Berfin , Salwinski Lukasz , Pillai Raju , Yang Lixin , Ma Feiyang , Pellegrini Matteo , Shin Juliana , Yang Xia , Tudzarova Slavica
Published: March 2024

Long-lived PFKFB3 expressing β-cells are dysfunctional cells because of prevailing glycolysis that compromises metabolic coupling of insulin secretion. Their accumulation in type-2 diabetes (T2D) appears to be related to the loss of apoptotic competency of cell fitness competition (CFC) that maintains tissue function by favoring constant selection of healthy “winner” cells. To investigate how PFKFB3 can disguise the competitive traits of dysfunctional “loser” β-cells, we analyzed the overlap between human β-cells with bona-fide “loser signature” across diabetes pathologies utilizing the HPAP scRNA-seq and spatial transcriptomics of PFKFB3 positive β-cells from nPOD T2D pancreata. The overlapping transcriptional profile of “loser” β-cells was represented by downregulated ribosomal biogenesis- and genes encoding for mitochondrial respiration. PFKFB3 positive “loser” β-cells had reduced expression of HLA Class I and II genes. Gene-gene interaction analysis revealed that PFKFB3rs1983890can interact with anti-apoptotic geneMAIP1implicating positive epistasis as a mechanism for prolonged survival of “loser” β-cells in T2D. Inhibition of PFKFB3 resulted in the clearance of dysfunctional “loser” β-cells leading to restored glucose tolerance in mouse model of T2D.
A novel nabelschnur protein regulates segregation of the kinetoplast DNA inTrypanosoma brucei
Authors: Cadena Lawrence Rudy , Hammond Michael , Tesařová Martina , Chmelová Ľubomíra , Svobodová Michaela , Durante Ignacio M. , Yurchenko Vyacheslav , Lukeš Julius
Published: March 2024

The kinetoplast DNA (kDNA), a distinctive arrangement of mitochondrial DNA found in trypanosomatid protists, comprises a concatenated network of minicircles and maxicircles that undergo division and segregation once during each cell cycle. Despite the identification and characterization of numerous proteins involved in kDNA maintenance and replication, its segregation and the formation of the nabelschnur remain poorly understood on a molecular level. This enigmatic filamentous structure, transiently appearing inTrypanosoma brucei,connects the daughter kDNA networks prior to their complete segregation. Here, we characterize TbNAB70, a high mobility group box-like protein localized exclusively to the nabelschnur and the kDNA disc. Our findings demonstrate that TbNAB70 is critical for the segregation, but not replication, of kDNA, a so far unprecedented phenotype. Furthermore, structural predictions suggest that this protein holds the capacity to bind to kDNA illuminating the exact molecular mechanisms of segregation involved. Thus, we propose that TbNAB70 plays a pivotal role in the faithful and efficient segregation of the daughter kDNA networks.
A salmon fish model reveals genetic signals in brain associated with early maturation
Authors: Pashay Ahi Ehsan , Verta Jukka-Pekka , Kurko Johanna , Ruokolainen Annukka , Singh Pooja , Debes Paul Vincent , Erkinaro Jaakko , Primmer Craig R.
Published: March 2024

Emerging evidence suggests a link between adiposity and early maturation, potentially impacting hormonal signaling pathways governing puberty timing. Fish models have proven invaluable in studying these processes, given their genetic and physiological similarities to humans. In Atlantic salmon, in addition to being linked with environmental shifts and lipid reserves, the timing of sexual maturation also has a strong genetic basis. A gene encoding a co-factor of Hippo pathway,vgll3, is a major determinant of maturation timing in salmon, and the same gene was found to be associated with maturation timing in humans. Intriguingly,vgll3also inhibits adipogenesis in mice. Recent studies in salmon revealed correlations betweenvgll3genotypes and reproductive axis gene expression, possibly modulated through the Hippo signaling pathway. The Hippo pathway is known for its role in sexual maturation and adipogenesis and responds to environmental cues such as dietary fat and temperature. In this study, we employed a custom gene expression panel in male Atlantic salmon with differentvgll3 early(E) andlate(L) maturation genotypes testing components of this pathway in brain at immature and mature stages. We found increased brain expression of a major Hippo pathway kinase (lats1b) and melanocortin receptor encoding genes (mc4raandmc4rc) in individuals withearly(E) maturation genotypes ofvgll3before maturation development of testes. Moreover, we found components and interacting partners of Hippo pathway showing differential expression in brain of individuals withearly(E) andlate(L)vgll3genotypes prior to maturation. This could indicate extensive and complex roles of Hippo pathway in brain processes required for preparing for [the onset of] maturation at upstream of reproductive axis. This study elucidates molecular mechanisms underpinning early maturation, and for the first time in fish, offering insights into detecting it at molecular level in brain before visible gonadal changes occur.
Genome-Wide Transcription Response ofStaphylococcus epidermidisto Heat Shock and Medically Relevant Glucose Levels
Authors: Benjamin Kaisha N , Goyal Aditi , Nair Ramesh , Endy Drew
Published: March 2024

Skin serves as both barrier and interface between body and environment. Skin microbes are intermediaries evolved to respond, transduce, or act in response to changing environmental or physiological conditions. Here, we quantify genome-wide changes in gene expression levels for one abundant skin commensal,Staphylococcus epidermidis, in response to an internal physiological signal, glucose levels, and an external environmental signal, temperature. We find 85 of 2354 genes change up to∼34-fold in response to medically relevant changes in glucose concentration (0 mM to 17 mM; adjPvalue ≤ 0.05). We observed carbon catabolite repression in response to a range of glucose spikes, as well as upregulation of genes involved in glucose utilization in response to persistent glucose. We observed 366 differentially expressed genes in response to a physiologically relevant change in temperature (37°C to 45°C; adjPvalue ≤ 0.05) and anS. epidermidisheat-shock response that mostly resembles the heat-shock response of related staphylococcal species. DNA motif analysis also revealed CtsR and CIRCE operator sequences arranged in tandem upstream ofdnaKandgroESLoperons. We further identified 38 glucose-responsive genes as candidate ON or OFF switches for use in controlling synthetic genetic systems. Such systems might be used to instrument the in-situ skin microbiome or help control microbes bioengineered to serve as embedded diagnostics, monitoring, or treatment platforms.
Natural variation in neuraminidase activity influences the evolutionary potential of the seasonal H1N1 lineage hemagglutinin
Authors: Liu Tongyu , Reiser William K. , Tan Timothy J C , Lv Huibin , Rivera-Cardona Joel , Heimburger Kyle , Wu Nicholas C , Brooke Christopher B.
Published: March 2024

The antigenic evolution of the influenza A virus hemagglutinin (HA) gene poses a major challenge for the development of vaccines capable of eliciting long-term protection. Prior efforts to understand the mechanisms that govern viral antigenic evolution mainly focus on HA in isolation, ignoring the fact that HA must act in concert with the viral neuraminidase (NA) during replication and spread. Numerous studies have demonstrated that the degree to which the receptor binding avidity of HA and receptor cleaving activity of NA are balanced with each other influences overall viral fitness. We recently showed that changes in NA activity can significantly alter the mutational fitness landscape of HA in the context of a lab-adapted virus strain. Here, we test whether natural variation in relative NA activity can influence the evolutionary potential of HA in the context of the seasonal H1N1 lineage (pdmH1N1) that has circulated in humans since the 2009 pandemic. We observed substantial variation in the relative activities of NA proteins encoded by a panel of H1N1 vaccine strains isolated between 2009 and 2019. We comprehensively assessed the effect of NA background on the HA mutational fitness landscape in the circulating pdmH1N1 lineage using deep mutational scanning and observed pronounced epistasis between NA and residues in or near the receptor binding site of HA. To determine whether NA variation could influence the antigenic evolution of HA, we performed neutralizing antibody selection experiments using a panel of monoclonal antibodies targeting different HA epitopes. We found that the specific antibody escape profiles of HA were highly contingent upon NA background. Overall, our results indicate that natural variation in NA activity plays a significant role in governing the evolutionary potential of HA in the currently circulating pdmH1N1 lineage.
Single-cell sequencing of rodent ventral pallidum reveals diverse neuronal subtypes with non-canonical interregional continuity
Authors: Ottenheimer David J. , Simon Rhiana C. , Burke Cassidy T. , Bowen Anna J. , Ferguson Susan M. , Stuber Garret D.
Published: March 2024

The ventral pallidum (VP) was defined as a basal ganglia nucleus with dense input from ventral striatum. To further investigate a VP regional identity, we conducted a cross-species transcriptional characterization of VP cell types. We performed single nucleus RNA-sequencing of VP tissue from mice and rats and identified 16 VP neuronal subclasses with striking cross-species conservation. VP GABAergic neurons were surprisingly heterogeneous, consisting of 14 sub-classes from 3 developmental classes. Combining our sequencing data with a spatial atlas revealed that all VP subclasses extended beyond the traditional borders of VP. Integrating our VP data with prior sequencing data from striatal, hypothalamic, and extended amygdalar tissue confirmed that cell types are shared among these regions. Due to the role of VP in feeding behavior, we also assessed the transcriptional impact of high-fat diet consumption, which induced altered expression of genes involved in oxidative phosphorylation and inhibitory signaling. Overall, our results demonstrate that VP is not a transcriptionally discrete nucleus; rather, VP contains cell types with diverse expression patterns that overlap with regions beyond the basal ganglia.
Metric Ion Classification (MIC): A deep learning tool for assigning ions and waters in cryo-EM and x-ray crystallography structures
Authors: Shub Laura , Liu Wenjin , Skiniotis Georgios , Keiser Michael J. , Robertson Michael J.
Published: March 2024

At sufficiently high resolution, x-ray crystallography and cryogenic electron microscopy are capable of resolving small spherical map features corresponding to either water or ions. Correct classification of these sites provides crucial insight for understanding structure and function as well as guiding downstream design tasks, including structure-based drug discovery and de novo biomolecule design. However, direct identification of these sites from experimental data can prove extremely challenging, and existing empirical approaches leveraging the local environment can only characterize limited ion types. We present a novel representation of chemical environments using interaction fingerprints and develop a machine-learning model to predict the identity of input water and ion sites. We validate the method, named Metric Ion Classification (MIC), on a wide variety of biomolecular examples to demonstrate its utility, identifying many probable mismodeled ions deposited in the PDB. Finally, we collect all steps of this approach into an easy-to-use open-source package that can integrate with existing structure determination pipelines.
Characterizing the temporal dynamics and maturation of brain activity during sleep: an EEG microstate study in preterm and full-term infants
Authors: Adibpour Parvaneh , Nasser Hala , Pedoux Amandine , Devisscher Laurie , Elbaz Nicolas , Ghozland Chloé , Hinnekens Elodie , Neumane Sara , Kabdebon Claire , Lefebvre Aline , Kaminska Anna , Hertz-Pannier Lucie , Heneau Alice , Sibony Olivier , Alison Marianne , Delanoë Catherine , Delorme Richard , Barbu-Roth Marianne , Biran Valérie , Dubois Jessica
Published: March 2024

By interfering with the normal sequence of mechanisms serving the brain maturation, premature birth and related stress can alter perinatal experiences, with potential long-term consequences on a child’s neurodevelopment. The early characterization of brain functioning and maturational changes is thus of critical interest in premature infants who are at high risk of atypical outcomes and could benefit from early diagnosis and dedicated interventions. Using high-density electroencephalography (HD-EEG), we recorded brain activity in extreme and very preterm infants at the equivalent age of pregnancy term (n=43), and longitudinally 2-months later (n=33), compared with full-term born infants (n=14). We characterized the maturation of brain activity by using a dedicated microstate analysis to quantify the spatio-temporal dynamics of the spontaneous transient network activity while controlling for vigilance states. The comparison of premature and full-term infants first showed slower dynamics as well as altered spatio-temporal properties of brain activity in preterm infants. Maturation of functional networks between term-equivalent age and 2 months later in preterms was linked to the emergence of faster dynamics, manifested in part by shorter duration of microstates, as well as an evolution in the spatial organization of the dominant microstates. The inter-individual differences in the temporal dynamics of brain activity at term-equivalent age were further impacted by sex (with slower microstate dynamics in boys) and by gestational age at birth for some microstate dynamics but not by other considered risk factors. This study highlights the potential of the microstate approach to reveal maturational properties of the emerging brain network activity in premature infants.
Efficient test for deviation from Hardy Weinberg Equilibrium with known or ambiguous typing in highly polymorphic loci
Authors: Shkuri Or , Israeli Sapir , Tshuva Yuli , Maiers Martin , Louzoun Yoram
Published: March 2024

The Hardy-Weinberg Equilibrium (HWE) assumption is essential to many population genetics models. Multiple tests were developed to test its applicability in observed genotypes. Current methods are divided into exact tests applicable to small populations and a small number of alleles, and approximate goodness of fit tests. Existing tests cannot handle ambiguous typing in multi-allelic loci. We here present a novel exact test (UMAT - Unambiguous Multi Allelic Test) practically not limited in the number of alleles and population size, based on a perturbative approach around the current observations. We show its accuracy in the detection of deviation from HWE. We then propose an additional model to handle ambiguous typing using either sampling into UMAT or a goodness of fit test with a variance estimate taking ambiguity into account, named ASTA (Asymptotic Statistical Test with Ambiguity). We show the accuracy of ASTA and the possibility to detect of the source of deviation from HWE. We apply these tests to the HLA loci to recover multiple previously reported deviations from HWE, and a large number of new ones.
Expression dynamics of long non-coding RNAs during imaginal disc development and regeneration inDrosophila
Authors: Camilleri-Robles Carlos , Amador Raziel , Tiebe Marcel , Teleman Aurelio A , Serras Florenci , Guigó Roderic , Corominas Montserrat
Published: March 2024

The discovery of functional long non-coding RNAs (lncRNAs) changed their initial concept as transcriptional noise. LncRNAs have been found to participate in the regulation of multiple biological processes, including chromatin structure, gene expression, splicing, and mRNA degradation and translation. However, functional studies of lncRNAs are hindered by the usual lack of phenotypes upon deletion or inhibition. Here, we usedDrosophilaimaginal discs as a model system to identify lncRNAs involved in development and regeneration. We examined a subset of lncRNAs expressed in the wing, leg, and eye disc development. Additionally, we analyzed transcriptomic data from regenerating wing discs to profile the expression pattern of lncRNAs during tissue repair. We focused on the lncRNACR40469, which is upregulated during regeneration. We generatedCR40469mutant flies that developed normally but showed impaired wing regeneration upon the induction of cell death. The ability of these mutants to regenerate was restored by the ectopic expression ofCR40469. Furthermore, we found that the lncRNACR34335has a high degree of sequence similarity withCR40469and can partially compensate for its function during regeneration in the absence ofCR40469. Our findings point to a potential role of the lncRNACR40469intransduring the response to damage in the wing imaginal disc.
Loss of intermicrovillar adhesion impairs basolateral junctional complexes in transporting epithelia
Authors: Cencer Caroline S. , Robinson Kianna L. , Tyska Matthew J.
Published: March 2024

Transporting epithelial cells in the gut and kidney rely on protocadherin-based apical adhesion complexes to organize microvilli that extend into the luminal space. In these systems, CDHR2 and CDHR5 localize to the distal ends of microvilli, where they form an intermicrovillar adhesion complex (IMAC) that links the tips of these structures, promotes the formation of a well-ordered array of protrusions, and in turn maximizes apical membrane surface area. Recently, we discovered that IMACs can also form between microvilli that extend from neighboring cells, across cell-cell junctions. As an additional point of physical contact between cells, transjunctional IMACs are well positioned to impact the integrity of canonical tight and adherens junctions that form more basolaterally. Here, we sought to test this idea using cell culture and mouse models that lacked CDHR2 expression and were unable to form IMACs. CDHR2 knockout perturbed cell and junction morphology, led to loss of key components from tight and adherens junctions, and impaired barrier function and wound healing. These results indicate that, in addition to organizing apical microvilli, IMACs provide a layer of cell-cell contact that functions in parallel with canonical tight and adherens junctions to support the physiological functions of transporting epithelia.
Intestinal tuft cells assemble a cytoskeletal superstructure composed of co-aligned actin bundles and microtubules
Authors: Silverman Jennifer B. , Krystofiak Evan E. , Caplan Leah R. , Lau Ken S. , Tyska Matthew J.
Published: March 2024

Background & Aims

All tissues consist of a distinct set of cell types, which collectively support organ function and homeostasis. Tuft cells are a rare epithelial cell type found in diverse epithelia, where they play important roles in sensing antigens and stimulating downstream immune responses. Exhibiting a unique polarized morphology, tuft cells are defined by an array of giant actin filament bundles that support ∼2 μm of apical membrane protrusion and extend over 7 μm towards the cell’s perinuclear region. Despite their established roles in maintaining intestinal epithelial homeostasis, tuft cells remain understudied due to their rarity (e.g. ∼ 1% in the small intestinal epithelium). Details regarding the ultrastructural organization of the tuft cell cytoskeleton, the molecular components involved in building the array of giant actin bundles, and how these cytoskeletal structures support tuft cell biology remain unclear.

Methods

To begin to answer these questions, we used advanced light and electron microscopy to perform quantitative morphometry of the small intestinal tuft cell cytoskeleton.

Results

We found that tuft cell core bundles consist of actin filaments that are crosslinked in a parallel “barbed-end out” configuration. These polarized structures are also supported by a unique group of tuft cell enriched actin-binding proteins that are differentially localized along the giant core bundles. Furthermore, we found that tuft cell actin bundles are co-aligned with a highly ordered network of microtubules.

Conclusions

Tuft cells assemble a cytoskeletal superstructure that is well positioned to serve as a track for subcellular transport along the apical-basolateral axis and in turn, support the dynamic sensing functions that are critical for intestinal epithelial homeostasis.

SYNOPSIS

This research leveraged advanced light and electron microscopy to perform quantitative morphometry of the intestinal tuft cell cytoskeleton. Three-dimensional reconstructions of segmented image data revealed a co-aligned actin-microtubule superstructure that may play a fundamental role in tuft cell function.
Vison crystal in quantum spin ice on the breathing pyrochlore lattice
Authors: Sanders Alaric , Castelnovo Claudio
Published: March 2024

Recent excitement in the quantum spin ice (QSI) community has come from the experimental discovery of pseudospin-12 breathing pyrochlores, including Ba3Yb2Zn5O11, in which inversion symmetry is broken by the “up” and “down” tetrahedra taking different physical sizes. We show here that the often-neglected Jz± coupling between Kramers ions, in combination with the breathing nature of the lattice, can produce an imaginary ring flip term. This can lead to an unconventional “U(1)π/2 phase”, corresponding to a maximally dense packing of visons on the lattice. The coherent, emergent QED dynamics of conventional QSI persist in this phase, in a manner reminiscent of fragmentation in spinon crystals. We characterize the excitations of the system within the enlarged QSI phase diagram, showing that the imaginary ring flip acts both as a chemical potential for visons and as an effective three-photon vertex akin to strong light-matter coupling. The coupling causes a structured high-energy continuum to emerge above the photon dispersion, which is naturally interpreted as three photon up-conversion in a nonlinear optical crystal.

Published by the American Physical Society
2024
Contributions of the subprocess
K0*(1430)→Kη′
in the charmless three-body
B
meson decays
Authors: Ma Ai-Jun , Wang Wen-Fei
Published: March 2024

We study the contributions for Kη′ pair originating from the scalar intermediate state K0*(1430) in the three-body decays B→Kη′h (h=π, K) within the perturbative QCD approach. The contribution of K0*(1430)→Kη′ is described by the Flatté formula with coupled channels Kπ, Kη, and Kη′. The strong coupling constants gK0*Kη(′) are extracted from gK0*Kπ within flavor SU(3) symmetry. In spite of the strong depression by phase space near the threshold of Kη′, the CP averaged branching fractions for the B→K0*(1430)h→Kη′h decays are predicted to be on the order of 10−8 to 10−5, which are non-negligible for the corresponding three-body B decays. Since the Kη system is almost decoupled from the even-spin strange mesons under flavor SU(3) symmetry, those quasi-two-body B decays with subprocess K0*(1430)→Kη shall have quite small branching ratios and are not taken into account in this work. We also estimate that the branching fraction for K0*(1430)→Kη′ is about one fifth of that for K0*(1430)→Kπ. The predictions for the relevant decays are expected to be tested by the LHCb and Belle-II experiments in the future.

Published by the American Physical Society
2024
Heat flow from a measurement apparatus monitoring a dissipative qubit
Authors: Yamamoto Tsuyoshi , Tokura Yasuhiro
Published: March 2024

We investigate the heat flow of a qubit coupled to heat baths under continuous quantum measurement. In the steady-state limit, we show that heat always flows from the measurement apparatus into the qubit regardless of the measured qubit state and derive lower and upper bounds for the heat current between the qubit and the measurement apparatus. Furthermore, we study the transient dynamics of the heat current and the excess heat during the transient regime.

Published by the American Physical Society
2024
Problems and promises of postmodernism in (re)liberating disaster studies
Authors: Cadag Jake Rom
Published: March 2024

Purpose

This paper is a critique of Western modernity and the problems and promises of postmodernism in (re)liberating disaster studies. It criticizes metanarratives and grand theories of Western discourses to advance postmodern discourses in disaster studies.

Design/methodology/approach

This paper outlines a conceptual domain through which approaches of postmodernism can be employed to (re)liberate disaster studies.

Findings

Metanarratives and grand theories frame the scope and focus of disaster studies. But the increasing number and the aggravated impacts of disasters and environmental challenges in the late 20th and early 21st centuries are proofs that our current “frames” do not capture the complexities of disasters. Postmodernism, in its diversity and various meanings, offers critical and complementary perspectives and approaches to capture the previously neglected dimensions of disasters.

Research limitations/implications

Postmodernism offers ways forward to (re)liberate disaster studies through ontological pluralism, epistemological diversity and hybridity of knowledge.

Originality/value

The agenda of postmodernism in disaster studies is proposed in terms of the focus of inquiry, ontological and epistemological positionalities, research paradigm, methodologies and societal goals.
Legitimacy of community-based social enterprises (CBSE) in service provision in rural areas
Authors: Rinne-Koski Katja , Lähdesmäki Merja
Published: March 2024

Purpose

Municipalities seek new opportunities for co-producing services in rural areas. One potential partner is community-based social enterprises (CBSEs). However, whilst service co-production through CBSEs obscures the traditional roles of actors, it may lead to a legitimation crisis in local service provision. In this paper, the ways CBSEs are legitimised as service providers in rural areas are addressed from the CBSE and municipality perspectives.

Design/methodology/approach

Empirical data combine interviews with CBSE representatives and open-ended national survey responses from municipality decision-makers. The data analysis is based on a qualitative content analysis to examine legitimation arguments.

Findings

Results show that unestablished legitimacy and un-institutionalised support structures for co-production models build mistrust between CBSEs and municipalities, which prevents the parties from seeing the benefits of cooperation in service production.

Research limitations/implications

The research focusses on the legitimation of CBSEs in service co-production in rural areas. As legitimation seems to be a context-specific process, future research is needed regarding other contexts.

Practical implications

Municipalities interested in the co-production of services might benefit from establishing a collaborative and responsive (rural) service policy forum that would institutionalise new models of co-production and enable better design and governance of service provision.

Originality/value

Results will give new theoretical and practical insights into the importance of legitimacy in the development of service co-production relationships.