bluuebunny/crossref_metadata_2025 huggingface dataset:
Toxin-glycolipid interactions measured by imaging surface plasmon resonance on artificial membranes predicts diffusion behavior and lipid dependence of binding to cells
Authors: Lehnert Sarah , Yildiz Umit Hakan , Haustein Natalie , Li Enlin , Matysik Artur , Oglęcka Kamila , Rashid Rafi , Boschke Elke , Liedberg Bo , Wohland Thorsten , Kraut Rachel
Published: March 2024

Membrane-protein interactions mediate cellular invasion by toxins, and are thought to involve organized plasma membrane lipid domains, often containing glycolipids, other sphingolipids, and/or cholesterol. Here, we characterize an isolated glycolipid-interacting domain of the tetanus toxin heavy chain (Hc) as a fluorescently labelled peptide, TeNT46, and describe its membrane dynamics and binding characteristics on artificial bilayers and cellular membranes. We show that this novel ganglioside-interacting probe TeNT46 retains the glycolipid binding preferences of the parent toxin, using imaging-SPR (iSPR) on a micro-patterned hybrid bilayer surface. On live cell membranes, using fluorescence correlation spectroscopic (FCS) diffusion measurements to compare TeNT46 to the well-studied GM1-binding toxin CTxB, we find that both probes display ordered domain-binding characteristics, but distinct cholesterol and sphingolipid dependencies. Strikingly, the contrasting lipid requirements of TeNT46 from those of CTxB in cells are predicted by their iSPR binding preferences on hybrid synthetic membranes. Based on the combined findings from iSPR and FCS, we propose a model for toxin-membrane interaction whereby a unique lipid constellation determines optimum binding for each probe independently of lateral confinement, which is more generally imposed by cholesterol. Our resulting understanding of the specific lipid requirements of these toxin targets and their dynamics in cell membranes could be important for the future design of preventive membrane-based nano-decoys and cell-delivery tools.
Unusual lineage plasticity revealed by YY1 knockout in pro-B cells
Authors: Banerjee Sarmistha , Sanyal Sulagna , Hodawadekar Suchita , Naiyer Sarah , Bano Nasreen , Banerjee Anupam , Rhoades Joshua , Dong Dawei , Allman David , Atchison Michael L.
Published: March 2024

During B cell development, cells progress through multiple developmental stages with the pro-B cell stage defining commitment to the B cell lineage. YY1 is a ubiquitous transcription factor that is capable of both activation and repression functions. We find here that knockout of YY1 at the pro-B cell stage eliminates B lineage commitment. YY1 knockout pro-B cells can generate T lineage cellsin vitrousing the OP9- DL4 feeder system, as well asin vivoafter injection into sub-lethally irradiated Rag1-/-mice. These T lineage-like cells lose their B lineage transcript profile and gain a T cell lineage profile. Single cell-RNA-seq experiments showed that as YY1 knockout pro-B cells transition into T lineage cells, various cell clusters adopt transcript profiles representing a multiplicity of hematopoietic lineages indicating unusual lineage plasticity. Given the ubiquitous nature of YY1 and its dual activation and repression functions, YY1 likely regulates commitment in multiple cell lineages.
Spectral graph model for fMRI: a biophysical, connectivity-based generative model for the analysis of frequency-resolved resting state fMRI
Authors: Raj Ashish , Sipes Benjamin S , Verma Parul , Mathalon Daniel H , Biswal Bharat B , Nagarajan Srikantan S
Published: March 2024

Resting state functional MRI (rs-fMRI) is a popular and widely used technique to explore the brain's functional organization and to examine if it is altered in neurological or mental disorders. The most common approach for its analysis targets the measurement of the synchronized fluctuations between brain regions, characterized as functional connectivity (FC), typically relying on pairwise correlations in activity across different brain regions. While hugely successful in exploring state- and disease-dependent network alterations, these statistical graph theory tools suffer from two key limitations. First, they discard useful information about the rich frequency content of the fMRI signal. The rich spectral information now achievable from advances in fast multiband acquisitions is consequently being under-utilized. Second, the analyzed FCs are phenomenological without a direct neurobiological underpinning in the underlying structures and processes in the brain. There does not currently exist a complete generative model framework for whole brain resting fMRI that is informed by its underlying biological basis in the structural connectome. Here, we propose that a different approach can solve both challenges at once: the use of an appropriately realistic yet parsimonious biophysical signal generation model followed by graph spectral (i.e. eigen) decomposition. We call this model a Spectral Graph Model (SGM) for fMRI, using which we can not only quantify the structure-function relationship in individual subjects, but also condense the variable and individual-specific repertoire of fMRI signal's spectral and spatial features into a small number of biophysically-interpretable parameters. We expect this model-based inference of rs-fMRI that seamlessly integrates with structure can be used to examine state and trait characteristics of structure-function relations in a variety of brain disorders.
Providing Insights into Health Data Science Education through Artificial Intelligence
Authors: Rohani Narjes , Gal Kobi , Gallagher Michael , Manataki Areti
Published: March 2024

Background

Health Data Science (HDS) is a novel interdisciplinary field that integrates biological, clinical, and computational sciences with the aim of analysing clinical and biological data through the utilisation of computational methods. Training healthcare specialists who are knowledgeable in both health and data sciences is highly required, important, and challenging. Therefore, it is essential to analyse students’ learning experiences through artificial intelligence techniques in order to provide both teachers and learners with insights about effective learning strategies and to improve existing HDS course designs.

Methods

We applied artificial intelligence methods to uncover learning tactics and strategies employed by students in an HDS massive open online course with over 3,000 students enrolled. We also used statistical tests to explore students’ engagement with different resources (such as reading materials and lecture videos) and their level of engagement with various HDS topics.

Results

We found that students in HDS employed four learning tactics, such as actively connecting new information to their prior knowledge, taking assessments and practising programming to evaluate their understanding, collaborating with their classmates, and repeating information to memorise. Based on the employed tactics, we also found three types of learning strategies, including low engagement (Surface learners), moderate engagement (Strategic learners), and high engagement (Deep learners), which are in line with well-known educational theories. The results indicate that successful students allocate more time to practical topics, such as projects and discussions, make connections among concepts, and employ peer learning.

Conclusions

We applied artificial intelligence techniques to provide new insights into HDS education. Based on the findings, we provide pedagogical suggestions not only for course designers but also for teachers and learners that have the potential to improve the learning experience of HDS students.
Mobile EEG for Neurourbanism Research - What Could Possibly Go Wrong? A Critical Review with Guidelines
Authors: Gramann Klaus
Published: March 2024

Based on increasing incidents of mental ill-health associated with living in dense urban environments, the field of Neurourbanism developed rapidly, aiming at identifying and improving urban factors that impact the health of city dwellers. Neurourbanism and the closely related field of Neuro-Architecture have seen a surge in studies using mobile electroencephalography (EEG) to investigate the impact of the built and natural environment on human brain activity moving from the laboratory into the real world. This trend predominantly arises from the ready availability of affordable and portable consumer hardware, which not only guarantees operational simplicity but also frequently incorporates automated data analysis functions. This significantly streamlines the process of EEG data acquisition, analysis, and interpretation, seemingly challenging the necessity of specialized expertise in the method of EEG or neurosciences in general. As a consequence, numerous studies in the field of Neurourbanism have used such off-the-shelf systems in laboratory and real-world experimental protocols including active movement of participants through the environment. However, the recording and analysis of EEG data entails numerous requisites, the disregard of which may culminate in errors during data acquisition, processing, and subsequent interpretation, potentially compromising the scientific validity of the outcomes. The often relatively low number of electrodes offered by affordable and portable consumer EEG systems further restricts specific analyses approaches to the low-dimensional EEG data. Crucially, a large part of Neurourbanism studies used black-box analyses provided by such consumer systems or incorrectly applied complex data-driven analyses methods that are incompatible with the recorded low-dimensional data. The current manuscript delineates the prerequisites concerning EEG hardware and analytical methodologies applicable to stationary and mobile EEG protocols, whether conducted within a controlled laboratory environment or in real-world settings. It conducts a comprehensive review of EEG studies within the domain of Neurourbanism and Neuro-Architecture, assessing their adherence to these prerequisites. The findings reveal severe deficiencies in the utilization of hardware and data processing methods, thereby rendering these studies unsuitable for scientific scrutiny. Consequently, the present paper provides guidelines for the selection of EEG hardware and analytical strategies for researchers engaged in mobile EEG recordings, be it within a laboratory or real-world context, aimed at steering future investigations in the field of Neurourbanism and Neuro-Architecture.
Overexpression of Sirohydrochlorin Ferrochelatase Boosts Nitrogen Sulfur and Carbon Utilization inArabidopsis thaliana
Authors: Joshi Naveen C. , Tripathy Baishnab C.
Published: March 2024

Nitrogen deficiency in the soil is a significant agronomic problem, and the application of nitrogenous fertilizers to the soil has environmental concerns, such as sodic soil and the emission of greenhouse gases. To increase the nutrient use efficiency, the cDNA ofAtSirBcoding for sirohydrochlorin ferrochelatase, responsible for Fe insertion to the tetrapyrrole moiety of sirohydrochlorin, was overexpressed inArabidopsis thalianaunder the control of 35S promoter for increased synthesis of siroheme. The siroheme is a cofactor for the plastidic enzymes nitrite reductase (NiR) and sulfite reductase (SiR), which reduces nitrite and sulfite to ammonium and sulfide, respectively. A three-step process including methylation, oxidation, and ferro-chelation produces siroheme from uroporphyrinogen III, an intermediate of chlorophyll (Chl) biosynthesis. TheNiRandSiRgene expression and protein abundance increased in the over-expressers due to the increased AtSirB protein level. It resulted in an increase in N and S assimilation and enhanced protein content of over-expressers. Conversely, the total protein content decreased in antisense plants due to reduced NR and NiR activities.AtSirBover-expressers had higher protein and Chl contents and increased photosynthetic rate and biomass. Under N and S limitation, the protein, Chl, and photosynthetic electron transport rates inAtSirBover-expressers were higher than in WT. Results demonstrate that theSirBthat hijacks uroporphyrinogen from the chlorophyll biosynthesis pathway is a crucial player in N and S assimilation. The siroheme is limiting for efficient nitrate and sulfate reduction and utilization. SirB could be genetically manipulated to increase crop productivity for sustainable agriculture.
Evaluation of Treatment of Methicillin-ResistantStaphylococcus aureusBiofilms with Intermittent Electrochemically-Generated H2O2or HOCl
Authors: Anoy Md Monzurul Islam , Kim Won-Jun , Gelston Suzanne , Fleming Derek , Patel Robin , Beyenal Haluk
Published: March 2024

Chronic wound infections can be difficult to treat and may lead to impaired healing and worsened patient outcomes. Novel treatment strategies are needed. This study evaluated effects of intermittently produced H2O2and HOCl, generated via an electrochemical bandage (e-bandage), against methicillin-resistantStaphylococcus aureusbiofilms in an agar membrane biofilm model. By changing the working electrode potential, the e-bandage generated either HOCl (1.5 VAg/AgCl) or H2O2(−0.6 VAg/AgCl). The degree of biocidal activity of intermittent treatment with HOCl and H2O2correlated with HOCl treatment time; HOCl treatment durations of 0, 1.5, 3, 4.5, and 6 hours (with the rest of the 6 hour total treatment time devoted to H2O2generation) resulted in mean biofilm reductions of 1.36±0.2, 2.22±0.16, 3.46±0.38, 4.63±0.74 and 7.66±0.5 log CFU/cm2, respectively vs. non-polarized controls, respectively. However, application of H2O2immediately after HOCl treatment was detrimental to biofilm removal. For example, 3-hours HOCl treatment followed by 3-hours H2O2resulted in a 1.90±0.84 log CFU/cm2lower mean biofilm reduction than 3-hours HOCl treatment followed by 3-hours non-polarization. HOCl generated over 3-hours exhibited biocidal activity for at least 7.5-hours after e-bandage operation ceased; 3-hours of HOCl generation followed by 7.5-hours of non-polarization resulted in a biofilm cell reduction of 7.92±0.12 log CFU/cm2vs. non polarized controls. Finally, intermittent treatment with HOCl (i.e., interspersed with periods of e-bandage non-polarization) for various intervals showed similar effects (approximately 6 log CFU/cm2reduction vs. non-polarized control) to continuous treatment with HOCl for 3-hours, followed by 3-hours of non-polarization. These findings suggest that timing and sequencing of HOCl and H2O2treatments are crucial for maximizing biofilm control.
Modeling responses of macaque and human retinal ganglion cells to natural images using a convolutional neural network
Authors: Gogliettino Alex R. , Cooler Sam , Vilkhu Ramandeep S. , Brackbill Nora J. , Rhoades Colleen , Wu Eric G. , Kling Alexandra , Sher Alexander , Litke Alan M. , Chichilnisky E.J.
Published: March 2024

Linear-nonlinear (LN) cascade models provide a simple way to capture retinal ganglion cell (RGC) responses to artificial stimuli such as white noise, but their ability to model responses to natural images is limited. Recently, convolutional neural network (CNN) models have been shown to produce light response predictions that were substantially more accurate than those of a LN model. However, this modeling approach has not yet been applied to responses of macaque or human RGCs to natural images. Here, we train and test a CNN model on responses to natural images of the four numerically dominant RGC types in the macaque and human retina – ON parasol, OFF parasol, ON midget and OFF midget cells. Compared with the LN model, the CNN model provided substantially more accurate response predictions. Linear reconstructions of the visual stimulus were more accurate for CNN compared to LN model-generated responses, relative to reconstructions obtained from the recorded data. These findings demonstrate the effectiveness of a CNN model in capturing light responses of major RGC types in the macaque and human retinas in natural conditions.
Exploring ligands that target von Willebrand factor selectively under oxidizing conditions through docking and molecular dynamics simulations
Authors: Interlandi Gianluca
Published: March 2024

The blood protein von Willebrand factor (VWF) is a large multimeric protein that, when activated, binds to blood platelets tethering them to the site of vascular injury initiating blood coagulation. This process is critical for the normal haemostatic response, but especially under inflammatory conditions it is thought to be a major player in pathological thrombus formation. For this reason, VWF has been the target for the development of anti-thrombotic therapeutics. However, it is challenging to prevent pathological thrombus formation while still allowing normal physiological blood coagulation as currently available anti-thrombotic therapeutics are known to cause unwanted bleeding in particular intracranial haemorrhage. This work explores the possibility of inhibiting VWF selectively under the inflammatory conditions present during pathological thrombus formation. In particular, the A2 domain of VWF is known to inhibit the neighboring A1 domain from binding to the platelet surface receptor GpIbα and this auto-inhibitory mechanism has been shown to be removed by oxidizing agents released during inflammation. Hence, finding drug molecules that bind at the interface between A1 and A2 only under oxidizing conditions could restore such auto-inhibitory mechanism. Here, by using a combination of computational docking, molecular dynamics simulations and free energy perturbation calculations, a ligand from the ZINC15 database was identified that binds at the A1A2 interface with the interaction being stronger under oxidizing conditions. The results provide a framework for the discovery of drug molecules that bind to a protein selectively in inflammatory conditions.
Dynamic fibrillar assembly of αB-crystallin induced by perturbation of the conserved NT-IXI motif resolved by cryo-EM
Authors: McFarland Russell , Reichow Steve
Published: March 2024

αB-crystallin is an archetypical member of the small heat-shock proteins (sHSPs) vital for cellular proteostasis and mitigating protein misfolding diseases. Gaining insights into the principles defining their molecular organization and chaperone function have been hindered by intrinsic dynamic properties and limited high-resolution structural analysis. To disentangle the mechanistic underpinnings of these dynamical properties, we mutated a conserved IXI-motif located within the N-terminal (NT) domain of human αB-crystallin. This resulted in a profound structural transformation, from highly polydispersed caged-like native assemblies into a comparatively well-ordered helical fibril state amenable to high-resolution cryo-EM analysis. The reversible nature of the induced fibrils facilitated interrogation of functional effects due to perturbation of the NT-IXI motif in both the native-like oligomer and fibril states. Together, our investigations unveiled several features thought to be key mechanistic attributes to sHSPs and point to a critical significance of the NT-IXI motif in αB-crystallin assembly, dynamics and chaperone activity.
Switching between newly learned motor skills
Authors: Kita Kahori , Du Yue , Haith Adrian M.
Published: March 2024

Studies of cognitive flexibility suggest that switching between different tasks can entail a transient switch cost. Here, we asked whether analogous switch costs exist in the context of switching between different motor skills. We tested whether participants could switch between a newly learned skill associated with a novel visuomotor mapping, and an existing skill associated with an intuitive mapping. Participants showed increased errors in trials immediately following a switch between mappings. These errors were attributable to persisting with the pre-switch policy, rather than imperfect implementation or retrieval of the post-switch policy. A subset of our participants further learned a second new skill. Switching between these two novel skills was initially very challenging, but improved with further training. Our findings suggest that switching between newly learned motor skills can be challenging, and that errors in the context of switching between skills are primarily attributable to perseveration with the wrong control policy.
ELO-6 expression predicts longevity in isogenic populations ofCaenorhabditis elegans
Authors: Kong Weilin , Gu Guoli , Dai Tong , Chen Beibei , Pu Mintie
Published: March 2024

Variations of individual lifespans within genetically identical populations in homogenous environments are remarkable, with the cause largely unknown. Gene expression changes with age, and the transcriptome changes correlate with chronological aging. Here, we show that inCaenorhabditis elegans, the expression dynamic of the fatty acid elongase ELO-6 during aging predicts individual longevity in isogenic populations. The expression ofelo-6is reduced with age. From adult day 5, ELO-6 expression level exhibits variation between individuals, and the expression level is positively correlated with adult lifespan and health span. Interventions that prolong longevity enhance the expression stability of ELO-6 during aging from adult day 4 to adult day 8, indicating ELO-6 is also a populational lifespan predictor. We performed transcriptome analysis in short-lived and long-lived isogenic worms and identified differentially expressed genes, which are enriched for PQM-1 binding sites. Decreasingpqm-1expression in young adults improved the homogeneity of ELO-6 levels between individuals and enhanced health span. Furthermore, we found reducing the expression of genes that are highly expressed in short-lived individuals, including PQM-1 target genes, enhanced ELO-6 expression stability with age and extended lifespan. Thus, our study identified ELO-6 as a predictor of individual and populational lifespan and revealed the role ofpqm-1in restricting health span and possibly causing individual lifespan variation.
Molecular Dynamics Study of α-Synuclein Domain Deletion Mutant Monomers
Authors: Onishi Noriyo , Mazzaferro Nicodemo , Kunstelj Špela , Alvarado Daisy A. , Muller Anna M. , Vázquez Frank X.
Published: March 2024

Aggregates of misfolded α-synuclein proteins (asyn) are key markers of Parkinson’s disease. Asyn proteins have three domains: an N-terminal domain, a hydrophobic NAC core implicated in aggregation, and a proline-rich C-terminal domain. Proteins with truncated C-terminal domains are known to be prone to aggregation and suggest that understanding domain-domain interactions in asyn monomers could help elucidate the role of the flanking domains in modulating protein structure. To this end, we used Gaussian accelerated molecular dynamics (GAMD) to simulate wild-type (WT), N-terminal truncated (ΔN), C-terminal truncated (ΔC), and isolated NAC domain asyn protein variants (isoNAC). Using clustering and contact analysis, we found that removal of the N-terminal domain led to increased contacts between NAC and C-terminal domains and the formation of interdomain Δ-sheets. Removal of either flanking domain also resulted in increased compactness of every domain. We also found that the contacts between flanking domains in the WT protein result in an electrostatic potential (ESP) that may lead to favorable interactions with anionic lipid membranes. Removal of the C-terminal domain disrupts the ESP in a way that could result in over-stabilized protein-membrane interactions. These results suggests that cooperation between the flanking domains may modulate the protein’s structure in a way that helps maintain elongation and creates an ESP that may aid favorable interactions with the membrane.
Analysis of Protein Cysteine Acylation Using a Modified Suspension Trap (Acyl-Trap)
Authors: Forrester Michael T , Egol Jacob R , Tata Aleksandra , Tata Purushothama Rao , Foster Matthew W
Published: March 2024

Proteins undergo reversibleS-acylation via a thioester linkage in vivo.S-palmitoylation, modification by C16:0 fatty acid, is a commonS-acylation that mediates critical protein-membrane and protein-protein interactions. The most widely usedS-acylation assays, including acyl-biotin exchange and acyl resin-assisted capture, utilize blocking of free Cys thiols, hydroxylamine-dependent cleavage of the thioester and subsequent labeling of nascent thiol. These assays generally require >500 micrograms of protein input material per sample and numerous reagent removal and washing steps, making them laborious and ill-suited for high throughput and low input applications. To overcome these limitations, we devised Acyl-Trap, a suspension trap-based assay that utilizes a thiol-reactive quartz to enable buffer exchange and hydroxylamine-mediatedS-acyl enrichment. We show that the method is compatible with protein-level detection ofS-acylated proteins (e.g. H-Ras) as well asS-acyl site identification and quantification using on-trap isobaric labeling and LC-MS/MS from as little as 20 micrograms of protein input. In mouse brain, Acyl-Trap identified 279 reported sites ofS-acylation and 1298 previously unreported putative sites. Also described are conditions for long-term hydroxylamine storage, which streamlines the assay. More generally, Acyl-Trap serves as a proof-of-concept for PTM-tailored suspension traps suitable for both traditional protein detection and chemoproteomic workflows.
[mixglm]: A tool for modelling ecosystem resilience
Authors: Klimeš Adam , Chipperfield Joseph Daniel , Töpper Joachim Paul , Macias-Fauria Marc , Spiegel Marcus , Vandvik Vigdis , Velle Liv Guri , Robin Seddon Alistair William
Published: March 2024

Aims

A number of modelling frameworks exist to aid in the identification and exploration of stable states and the assessment of resilience from ecological datasets. However, because such models are complex to implement there is a substantial barrier for the application in ecological research. Here we develop a flexible model of ecological resilience based on Bayesian approximation of the “stability landscape”. We illustrate its usage on a tropical area where variation in tree cover has been previously interpreted as alternative stable states.

Methods

The stability landscape, from which stable states and resilience parameters are computed, is modelled using a mixture of multiple distributions, each representing a regression between the system state variable and the environmental covariates. Our “mixglm” model allows the mean, precision, and probability parameters of these distributions in the landscape to be dependent on multiple external covariates. “Mixglm” is implemented as a function in R package with the same name, internally using Bayesian inference via NIMBLE. We also conducted a power analysis to provide guidance regarding required sample size.

Results

We illustrate the use of the “mixglm” on a published case of tree cover in South America which reports a stability landscape with three distinct stable states. Using “mixglm”, we were able to replicate the identification of these states. Moreover, we quantified uncertainty of our estimates, and computed resilience of South America’s forests.

Conclusions

“Mixglm” can be readily used for description of stability landscapes and identification of stable states in most spatial datasets of system state variables, and it is accompanied by tools for calculation of resilience metrics. It can also be further expanded using regression framework to account for more complex data structures such as spatio-temporal data.
Multi-trait genome-wide analysis identified novel risk loci and candidate drugs for heart failure
Authors: Yu Zhengyang , Lin Maohuan , Liang Zhanyu , Ren Bozhen , Yang Ying , Chen Wen , Wang Yonghua , Lin Xiaoling , Chen Yangxin , Ning Kaida , Xia Li C.
Published: March 2024

Heart failure (HF) is a common cardiovascular syndrome that poses significant morbidity and mortality risks. While genome-wide association studies reporting on HF abound, its genetic etiology remains poorly elucidated, primarily due to its inherent polygenic nature. Furthermore, these genetic insights have not been fully leveraged for the development of effective primary treatment strategies for HF. In this study, we conducted a large-scale integrated multi-trait analysis using European-ancestry GWAS summary statistics of coronary artery disease and HF, involving near 2 million samples to identify novel risk loci associated with HF. 72 loci were newly identified with HF, of which 44 were validated in the replication phase. Transcriptome association analysis revealed 215 HF risk genes, includingEDNRAandFURIN. Pathway enrichment analysis of risk genes revealed their enrichment in pathways closely related to HF, such as response to endogenous stimulus (adjusted P = 8.83×10-3), phosphate-containing compound metabolic process (adjusted P = 1.91×10-2). Single-cell analysis indicated significant enrichments of these genes in smooth muscle cells, fibroblast of cardiac tissue, and cardiac endothelial cells. Additionally, our analysis of HF risk genes identified 74 potential drugs for further pharmacological evaluation. These findings provide novel insights into the genetic determinants of HF, highlighting new genetic loci as potential interventional targets to HF treatment, with significant implications for public health and clinical practice.
Five millennia of mitochondrial introgression in Atlantic bluefin tuna identified using ancient DNA
Authors: Eriksen Emma Falkeid , Andrews Adam Jon , Nielsen Svein Vatsvåg , Persson Per , Malca Estrella , Onar Vedat , Aniceti Veronica , Piquès Gäel , Piattoni Federica , Fontani Francesco , Wiech Martin , Ferter Keno , Kersten Oliver , Ferrari Giada , Cariani Alessia , Tinti Fausto , Cilli Elisabetta , Atmore Lane M. , Star Bastiaan
Published: March 2024

Mitogenomic (MT) introgression between species is readily documented in marine fishes. Such introgression events may either be long-term natural phenomena or the result of human-driven shifts in spatial distributions of previously separated species. Determining the drivers behind MT introgression is stymied by the difficulty of directly observing patterns of interbreeding over long timescales. Using ancient DNA spanning five millennia, we here investigate the long-term presence of MT introgression from Pacific bluefin tuna (Thunnus orientalis) and albacore (Thunnus alalunga) into Atlantic bluefin tuna (Thunnus thynnus), a species with extensive exploitation history and observed shifts in abundance, and demographic distribution. Comparing ancient (n=130) and modern (n=78) mitogenomes of specimens covering most of the range of Atlantic bluefin tuna we detect no significant spatial or temporal population structure. This lack of spatiotemporal genomic differentiation is indicative of ongoing gene flow between populations and large effective population sizes over millennia. Moreover, we identify introgressed MT genomes in ancient specimens up to 5000 years old and find that this rate of introgression has remained similar through time. We therefore conclude that MT introgression in the Atlantic bluefin tuna is to date unaffected by anthropogenic impacts. By providing the oldest example of directly observed MT introgression in the marine environment, our results highlight the utility of ancient DNA to obtain temporal insights in the long-term persistence of such phenomena.
Does Vibrotactile Stimulation of the Auricular Vagus Nerve Enhance Working Memory? A Behavioral and Physiological Investigation
Authors: Tan Gansheng , Adams Josh , Donovan Kara , Demarest Phillip , Willie Jon T. , Brunner Peter , Gorlewicz Jenna L. , Leuthardt Eric C.
Published: March 2024

Background

Working memory is essential to a wide range of cognitive functions and activities. Transcutaneous auricular VNS (taVNS) is a promising method to improve working memory performance. However, the feasibility and scalability of electrical stimulation are constrained by several limitations, such as auricular discomfort and inconsistent electrical contact.

Objective

We aimed to develop a novel and practical method, vibrotactile taVNS, to improve working memory. Further, we investigated its effects on arousal, measured by skin conductance and pupil diameter.

Method

This study included 20 healthy participants. Behavioral response, skin conductance, and eye tracking data were concurrently recorded while the participants performed N-back tasks under three conditions: vibrotactile taVNS delivered to the cymba concha, earlobe (sham control), and no stimulation (baseline control).

Results

In 4-back tasks, which demand maximal working memory capacity, active vibrotactile taVNS significantly improved the performance metricd’ compared to the baseline but not to the sham. Moreover, we found that the reduction rate ofd’ with increasing task difficulty was significantly smaller during vibrotactile taVNS sessions than in both baseline and sham conditions. Arousal, measured as skin conductance and pupil diameter, declined over the course of the tasks. Vibrotactile taVNS rescued this arousal decline, leading to arousal levels corresponding to optimal working memory levels. Moreover, pupil diameter and skin conductance level were higher during high-cognitive-load tasks when vibrotactile taVNS was delivered to the concha compared to baseline and sham.

Conclusion

Our findings suggest that vibrotactile taVNS modulates the arousal pathway and could be a potential intervention for enhancing working memory.

Highlights

Vibrotactile stimulation of the auricular vagus nerve increases general arousal.

Vibrotactile stimulation of the auricular vagus nerve mitigates arousal decreases as subjects continuously perform working memory tasks.

6 Hz Vibrotactile auricular vagus nerve stimulation is a potential intervention for enhancing working memory performance.
Mutation bias alters the distribution of fitness effects of mutations
Authors: Sane Mrudula , Parveen Shazia , Agashe Deepa
Published: March 2024

Mutation bias is an important factor determining the diversity of genetic variants available for selection, and can therefore constrain the genetic paths to adaptation. An additional constraint emerges over the course of evolution. As adaptation proceeds and some beneficial mutations are fixed, new beneficial mutations become rare, limiting further adaptation. Recent theoretical work predicts that these constraints may be alleviated by a change in the direction of mutation bias (i.e., a bias reversal). As populations sample previously underexplored types of mutations, the distribution of fitness effects (DFE) of mutations should shift towards more beneficial mutations. Here, we test this prediction usingEscherichia coli, which has a transition mutation bias, with ∼55% of single-nucleotide mutations being transitions compared to the unbiased expectation of ∼33% transitions. We generated mutant strains with a wide range of mutation biases from 96% transitions to 98% transversions, either reinforcing or reversing the wild type transition bias. Quantifying DFEs of hundreds of single mutations obtained from mutation accumulation experiments for each strain, we find strong support for the theoretical prediction. Strains that oppose the ancestral bias (i.e., with a strong transversion bias) have DFEs with the highest proportion of beneficial mutations, whereas strains that exacerbate the ancestral transition bias have up to 10-fold fewer beneficial mutations. Such dramatic differences in the DFE should drive large variation in the rate and outcome of adaptation. Our results thus strongly suggest an important and generalized evolutionary role for mutation bias shifts.
Complete telomere-to-telomere assemblies of two sorghum genomes to guide biological discovery
Authors: Wei Chuanzheng , Gao Lei , Xiao Ruixue , Wang Yanbo , Chen Bingru , Zou Wenhui , Li Jihong , Mace Emma , Jordan David , Tao Yongfu
Published: March 2024

Sorghum is a C4 crop well-known for its high efficiency of biomass accumulation and adaptation to drought and hot environments. This study reports the assembly of complete genome sequence of two sorghum genomes using a combination of ultra-long reads from Oxford Nanopore Technology, high-fidelity long reads from Pacbio and Hi-C reads. The accuracy and completeness of the T2T assemblies were comprehensively validated using a range of parameters, including coverage depth assessment, BUSCO, LTR assembly index, ect. Our T2T assembly of BTx623 identified 36.25 Mb of new sequence, in addition to dozens of misoritation and mispositioning of large DNA segments in the BTx623-v3. Correcting these assembly errors in the reference genome is critical for exploiting genetic information in these complex regions in sorghum. Comparison of the two T2T genomes shed new insights on variation of centromeres in sorghum. The two high-quality T2T genomes represent an important resource for sorghum improvement and gene discovery. They would serve as the new reference genomes to unlock the full potential of global sequence variation of this valuable crop.
BetaAlign: a deep learning approach for multiple sequence alignment
Authors: Dotan Edo , Wygoda Elya , Ecker Noa , Alburquerque Michael , Avram Oren , Belinkov Yonatan , Pupko Tal
Published: March 2024

The multiple sequence alignment (MSA) problem is a fundamental pillar in bioinformatics, comparative genomics, and phylogenetics. Here we characterize and improve BetaAlign, the first deep learning aligner, which substantially deviates from conventional algorithms of alignment computation. BetaAlign draws on natural language processing (NLP) techniques and trains transformers to map a set of unaligned biological sequences to an MSA. We show that our approach is highly accurate, comparable and sometimes better than state-of-the-art alignment tools. We characterize the performance of BetaAlign and the effect of various aspects on accuracy; for example, the size of the training data, the effect of different transformer architectures, and the effect of learning on a subspace of indel-model parameters (subspace learning). We also introduce a new technique that leads to improved performance compared to our previous approach. Our findings further uncover the potential of NLP-based approaches for sequence alignment, highlighting that AI-based methodologies can substantially challenge classic tasks in phylogenomics and bioinformatics.
Fat body lipogenic capacity in honey bee workers is affected by age, social role, and dietary protein
Authors: Scofield Sebastian , Amdam Gro. V.
Published: March 2024

All organisms need to balance processes that consume energy against those that produce energy. With an increase in biological complexity over evolutionary time, regulation of this balance has become much more complex, resulting in specialization of metabolic tasks between organelles, cells, organs, and in the case of eusocial organisms, between the individuals who comprise the ‘superorganism.’ Exemplifying this, nurse honey bees maintain high abdominal lipids, while foragers have very low lipid stores, likely contributing to efficient performance of their social role, and thus to colony fitness. The proximate mechanisms responsible for these metabolic differences remain poorly understood. Here, we investigated the effects of age, age class, and dietary macronutrients on the abdominal activity of fatty acid synthase (FAS), the enzyme responsible forde novosynthesis of fatty acids. We found that FAS activity declines as bees age past peak nursing age. Feeding both nurses and foragers carbohydrates increased FAS activity compared with starved bee, but, whether fed or starved, nurses had much higher FAS activity than similarly treated foragers, implicating reduced lipid synthesis as one component of foragers’ low lipid stores. Finally, we used artificial diets with different amounts of protein and fat to precociously induce low, forager-like FAS activity levels in nurse-age bees deprived of protein. We speculate that reduced protein appetite and consumption during the nurse-forager transition is responsible for suppressed lipid synthesis in foragers.

Summary statement

Honey bee workers show reduced fat synthesis capacity as they age and leave the nest to forage. Young bees deprived of protein have low, forager-like fat synthesis capacity.
A domain-swapped CaMKII conformation facilitates linker-mediated allosteric regulation
Authors: Nguyen Bao V. , Özden Can , Dong Kairong , Torres-Ocampo Ana P. , Dziedzic Noelle , Flaherty Daniel , Huang Jian , Sankura Saketh , Abromson Nikki Lyn , Tomchick Diana R. , Chen Jianhan , Garman Scott C , Stratton Margaret M
Published: March 2024

Ca2+signaling plays a key role in physiological processes such as memory formation and cardiac function. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is the primary kinase that responds to Ca2+inputs in these cells. There are four CaMKII paralogs in mammals which are alternatively spliced in the variable linker region to create upwards of 70 different variants. In this study, we systematically studied different linker regions and determined that the position of charged residues within the linker region modulates the Ca2+/CaM sensitivity of the holoenzyme. We present an X-ray crystal structure of full-length CaMKIIδ that shows a domain-swapped conformation of the subunits within the dodecameric holoenzyme. In this structure, the kinase domain of one subunit is docked onto the hub domain of a different subunit, providing an additional interface within the holoenzyme. Mutations at the equatorial and lateral interfaces revealed that the kinase-hub interaction dissociates as the hub-hub interfaces are disturbed, which led alterations in the stoichiometry of CaMKII holoenzyme and Ca2+/CaM sensitivity. Molecular dynamics simulations of linker-containing domain-swapped and non-domain-swapped CaMKIIs reveal that the domain-swapped configuration facilitates an interaction between the calmodulin binding domain and the variable linker region, such that dynamic electrostatic forces between charges on these segments can modulate the equilibrium between the compact and extended conformational states of the holoenzyme. Small angle X-ray scattering data confirms that a negatively charged linker CaMKII holoenzyme adopts a more compact conformation compared to a positively charged linker. These data support a model where patches of charged linker residues interact with the calmodulin binding domain to allosterically regulate sensitivity to Ca2+/CaM. Our findings provide a new framework for understanding CaMKII structure and allosteric regulation by the variable linker region in Ca2+-sensitive cells.
Muscle-resident mesenchymal progenitors sense and repair peripheral nerve injury via the GDNF-BDNF axis
Authors: Yoo Kyusang , Jo Young-Woo , Yoo Takwon , Hann Sang-Hyeon , Park Inkuk , Kim Yea-Eun , Kim Ye Lynne , Rhee Joonwoo , Song In-Wook , Kim Ji-Hoon , Baek Daehyun , Kong Young-Yun
Published: March 2024

Fibro-adipogenic progenitors (FAPs) are muscle-resident mesenchymal progenitors that can contribute to muscle tissue homeostasis and regeneration, as well as postnatal maturation and lifelong maintenance of the neuromuscular system. Recently, traumatic injury to the peripheral nerve was shown to activate FAPs, suggesting that FAPs can respond to nerve injury. However, questions of how FAPs can sense the anatomically distant peripheral nerve injury and whether FAPs can directly contribute to nerve regeneration remained unanswered. Here, utilizing single-cell transcriptomics and mouse models, we discovered that a subset of FAPs expressing GDNF receptorsRetandGfra1can respond to peripheral nerve injury by sensing GDNF secreted by Schwann cells. Upon GDNF sensing, this subset becomes activated and expressesBdnf. FAP-specific inactivation ofBdnf(Prrx1Cre;Bdnffl/fl) resulted in delayed nerve regeneration owing to defective remyelination, indicating that GDNF-sensing FAPs play an important role in the remyelination process during peripheral nerve regeneration. In aged mice, significantly reducedBdnfexpression in FAPs was observed upon nerve injury, suggesting the clinical relevance of FAP-derived BDNF in the age-related delays in nerve regeneration. Collectively, our study revealed the previously unidentified role of FAPs in peripheral nerve regeneration, and the molecular mechanism behind FAPs’ response to peripheral nerve injury.
The regulatory architecture of the primed pluripotent cell state
Authors: Li Bo I. , Alvarez Mariano J. , Zhao Hui , Chirathivat Napon , Califano Andrea , Shen Michael M.
Published: March 2024

Although numerous studies have focused on defining transcriptional cell states in normal and disease contexts, the gene regulatory architecture that governs and defines specific mammalian cell states remains poorly understood. Here we present an integrative computational and experimental systems biology approach to elucidate the regulatory architecture of a conserved cell state of critical importance in development and stem cell biology, namely primed state pluripotency. We have used an unbiased approach to analyze protein activity profiles from mouse epiblast stem cells (EpiSCs), leading to identification and experimental confirmation of 132 transcription factors that are master regulators (MRs) of primed state pluripotency. These MRs include known as well as novel factors, many of which were further validated for their role in lineage-specific differentiation using CRISPR-mediated functional assays. To assemble a comprehensive regulatory network, we silenced each of the 132 MRs to assess their effects on the other MRs and their transcriptional targets, yielding a network of 1,273 MR→MR interactions. Network architecture analyses revealed four functionally distinct MR modules (communities), largely independent of lineage-specific differentiation, and identified key Speaker and Mediator MRs based on their hierarchical rank and centrality in mediating information flow in the pluripotent cell. Taken together, our findings elucidate the de-centralized logic of a “communal interaction” model in which the balanced activities of four MR communities maintain pluripotency, and define the primed pluripotent cell state in terms of its transcriptional regulatory network.
Longitudinal analysis of Flower-dependent cell competition fitness markers inDrosophila melanogaster
Authors: Marques-Reis Mariana , Hauert Barbara , Moreno Eduardo
Published: March 2024

Cell competition is a conserved phenomenon spanning from arthropods to humans. It involves the elimination of viable yet suboptimal “loser” cells when juxtaposed with their fitter “winner” counterparts. This process has received increased attention for its implications in cancer initiation and progression, neurodegeneration, and ageing.

This study investigates the presence of the loser fitness fingerprint Flower LoseB (Fwe LB) and the fitness checkpoint Azot in the optic lobes over a period of 28 days. Notably, the absence of Azot is conventionally linked to the accumulation of loser cells over time. However, our investigation reveals that this accumulation is not perpetual and, intriguingly, Azot is not required for loser cell elimination in this context. Furthermore, we estimate that fewer than 50% of Fwe LB-expressing cells also express Azot and undergo apoptosis. Remarkably, our calculations also demonstrate that over 50% of cells undergoing apoptosis at any given time point are positive for the loser markers Fwe LB and Azot.

This comprehensive analysis of fitness marker dynamics over a 28-day timeframe sheds new light on the intricate mechanisms governing Flower-dependent cell competition.