bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analyzing the Mechanism Behind Age-agnostic Prediction of Diastolic Dysfunction Using Echocardiography Variables in Deep Neural Networks
Authors: Jamthikar Ankush D. , Shah Rohan , Tokodi Marton , Sengupta Partho P. , Yanamala Naveena 
Published: September 2023

AbstractObjectiveThis investigation delved into the inner workings of previously published Deep Neural Networks (DNNs) designed to detect changes in diastolic function related to age using echocardiographic parameters. The primary goal was to decipher the predictive mechanism and determine whether biological age and gender played concealed roles within the DNN model.MethodsWe conducted a secondary analysis of a previously published DNN model that was trained using data from 1,009 patients (average age: 62±17 years, 57% females) to forecast risk phenogroups based on nine echocardiographic parameters. This model was assessed on both an internal cohort (n=243, mean age = 62 ± 17 years, ∼57% females) and an external validation cohort (n=5596, mean age = 76 ± 5 years, ∼57% females). To forecast biological age and gender, we developed linear regression and classification models employing hidden layer activations from the DNN. Model performance was assessed using Pearson’s correlation for regression, accuracy, and area under the curve (AUC) metrics for classification.ResultsUpon scrutinizing the hidden layer activations, we observed that the model accurately captured biological age in both younger and older populations, particularly in low-risk phenogroups, with robust correlations for the entire population (0.94, p<0.001), males (0.90, p<0.001), and females (0.94, p<0.001). In high-risk phenogroups, the correlations were lower, standing at 0.31 (p=0.274) for the entire population, 0.76 (p=0.003) for males, and 0.11 (p=0.723) for females. Predicting gender as an underlying factor resulted in an accuracy rate of 58.02% and 52.27%, accompanied by an AUC of 0.65 for both validation cohorts.ConclusionThis study underscores that the latent space within DNNs maintains a link with age in relation to diastolic functional parameters, offering a solution that is independent of age for predicting diastolic dysfunction. The dissection of the network can further enhance our comprehension of the information learned by DNNs, thereby providing novel pathophysiological insights for medical professionals.
Hypoxia-inducible factor-2 (HIF2) regulates alveolar regeneration after repetitive injury
Authors: McCall A. Scott , Tanjore Harikrishna , Burman Ankita , Sherrill Taylor , Chapman Micah , Calvi Carla L. , Camarata Jane , Hunt Raphael P. , Nichols David , Banovich Nicholas E. , Lawson William E. , Gokey Jason J. , Kropski Jonathan A. , Blackwell Timothy S. 
Published: September 2023

AbstractIdiopathic Pulmonary Fibrosis (IPF) is a progressive and often fatal chronic respiratory disease thought to result from repetitive injury and failed repair of the lung alveoli, and recent studies have identified a number of disease-emergent intermediate/transitional cell states in the IPF lung supporting this concept. In this study, we found that persistent activation of hypoxia-inducible factor (HIF)-signaling in airway-derived, repair-associated cell types/states is a hallmark of dysfunctional epithelial repair in the IPF lung epithelium and experimental models of recurrent lung epithelial injury. Disrupting Hif-signaling attenuated experimental lung fibrosis, reduced mucous-secretory cell polarization, and promoted functional alveolar regeneration following repetitive injury. Mouse and human organoid studies demonstrated that small-molecule-based HIF2 inhibition promoted alveolar epithelial cell proliferation and maturation while preventing the emergence of maladaptive intermediate/transitional states analogous to those in IPF. Together, these studies indicate that targeted HIF2-inhibition represents a novel and effective therapeutic strategy to promote functional lung regeneration, and could be readily translated into human studies of IPF and other chronic interstitial lung diseases with disease modifying effect.One sentence summaryInhibiting hypoxia-inducible-factor 2 (HIF2) promotes functional lung alveolar epithelial repair following recurrent injury.
LsTT2encoding R2R3-MYB transcription factor is responsible for a shift from black to white in lettuce seed
Authors: Seki Kousuke , Komatsu Kenji , Yamaguchi Kanami , Murai Yoshinori , Nishida Keiji , Koyama Ryohei , Uno Yuichi 
Published: September 2023

AbstractPrickly lettuce (Lactuca serriola), which is considered the wild ancestor of lettuce, has black seeds, whereas the major seed color of domesticated lettuce is black or white. The successfully-selected white seed trait is a key domestication trait for lettuce cultivation and breeding; however, the mechanism underlying the shift from black to white seeds remains to be clarified. We aimed to identify the gene/s responsible for white seed trait in lettuce. Genetic mapping of a candidate gene was performed with double-digest RAD sequencing using an F2population derived from a cross between ‘ShinanoPower’ (white seed) and ‘Escort’ (black seed). The white seed trait was controlled by a single recessive locus (48.055–50.197 Mbp) in linkage group 7. Narrowing down using five PCR-based markers and 84 cultivars, eight candidate genes were mapped in the locus. Only theLG7_v8_49.251Mbp_HinfImarker, which employs a single nucleotide mutation in the stop codon ofLsat_1_v5_gn_7_35020.1was completely linked to the seed color phenotype. In addition, the sequences of the coding region for candidate genes except forLsat_1_v5_gn_7_35020.1were identical in the resequence analysis of ‘ShinanoPower’ (white seed) and ‘Escort’ (black seed). Therefore, we proposedLsat_1_v5_gn_7_35020.1, a gene located in the locus, as the candidate gene and designated it asLsTT2, an ortholog encoding the R2R3 MYB transcription factor inArabidopsis. When we validated the role ofLsTT2in seed color through genome editing,LsTT2knockout mutants harboring an early termination codon showed a change in seed color from black to white. White seeds accumulated less proanthocyanidins than black seeds, which was similar to the phenotype observed inArabidopsis TRANSPARENT TESTA 2(TT2) mutants. Therefore,LsTT2was the allele responsible for the shift in seed color from black to white. The development of a robust marker for marker-assisted selection and identification of the gene responsible for white seeds has implications for future breeding technology and physiological analysis.
A novel MARV glycoprotein-specific antibody with potentials of broad-spectrum neutralization to filovirus
Authors: Zhang Yuting , Zhang Min , Wu Haiyan , Wang Xinwei , Zheng Hang , Feng Junjuan , Wang Jing , Luo Longlong , Xiao He , Qiao Chunxia , Li Xinying , Zheng Yuanqiang , Huang Weijin , Wang Youchun , Wang Yi , Shi Yanchun , Feng Jiannan , Chen Guojiang 
Published: September 2023

AbstractMarburg virus (MARV) is one of the filovirus species that cause deadly hemorrhagic fever in humans, with mortality rates up to 90%. Neutralizing antibodies represent ideal candidates to prevent or treat virus disease. However, no antibody has been approved for MARV treatment to date. In this study, we identified a novel human antibody named AF-03 that targeted MARV glycoprotein (GP). AF-03 possessed a high binding affinity to MARV GP and showed neutralizing and protective activities against the pseudotyped MARV in vitro and in vivo. Epitope identification, including molecular docking and experiment-based analysis of mutated species, revealed that AF-03 recognized the Niemann-Pick C1 (NPC1) binding domain within GP1. Interestingly, we found the neutralizing activity of AF-03 to pseudotyped Ebola viruses (EBOV, SUDV, and BDBV) harboring cleaved GP instead of full-length GP. Furthermore, NPC2-fused AF-03 exhibited neutralizing activity to several filovirus species and EBOV mutants via binding to CI-MPR. In conclusion, this work demonstrates that AF-03 represents a promising therapeutic cargo for filovirus-caused disease.
The diverse evolutionary histories of domesticated metaviral capsid genes in mammals
Authors: Henriques William S. , Young Janet M. , Nemudryi Artem , Nemudraia Anna , Wiedenheft Blake , Malik Harmit S. 
Published: September 2023

ABSTRACTSelfish genetic elements and their remnants comprise at least half of the human genome. Active transposons duplicate by inserting copies at new sites in a host genome. Following insertion, transposons can acquire mutations that render them inactive; the accrual of additional mutations can render them unrecognizable over time. However, in rare instances, segments of transposons become useful for the host, in a process called gene domestication. Using the first complete human genome assembly and 25 additional vertebrate genomes, we analyzed the evolutionary trajectories and functional potential of genes domesticated from the capsid genes ofMetaviridae, a retroviral-like retrotransposon family. Our analysis reveals four families of domesticated capsid genes in placental mammals with varied evolutionary outcomes, ranging from universal retention to lineage-specific duplications or losses and from purifying selection to lineage-specific rapid evolution. The four families of domesticated capsid genes have divergent amino-terminal domains, inherited from four distinct ancestral metaviruses. Structural predictions reveal that many domesticated genes encode a previously unrecognized RNA-binding domain retained in multiple paralogs in mammalian genomes both adjacent to and independent from the capsid domain. Collectively, our study reveals diverse outcomes of domestication of diverse metaviruses, which led to structurally and evolutionarily diverse genes that encode important, but still largely-unknown functions in placental mammals.
Human adolescent brain similarity development is different for paralimbic versus neocortical zones
Authors: Dorfschmidt Lena , Váša František , White Simon R. , Romero-García Rafael , Kitzbichler Manfred G. , Alexander-Bloch Aaron , Cieslak Matthew , Mehta Kahini , Satterthwaite Theodore D. ,   the NSPN consortium, Bethlehem Richard A.I. , Seidlitz Jakob , Vértes Petra E. , Bullmore Edward T. 
Published: September 2023

AbstractAdolescent development of human brain structural and functional networks is increasingly recognised as fundamental to emergence of typical and atypical adult cognitive and emotional processes. We analysed multimodal magnetic resonance imaging (MRI) data collected from N ∼ 300 healthy adolescents (51%; female; 14-26 years) each scanned repeatedly in an accelerated longitudinal design, to provide an analyzable dataset of 469 structural scans and 448 functional MRI scans. We estimated the morphometric similarity between each possible pair of 358 cortical areas on a feature vector comprising six macro- and micro-structural MRI metrics, resulting in a morphometric similarity network (MSN) for each scan. Over the course of adolescence, we found that morphometric similarity increased in paralimbic cortical areas, e.g., insula and cingulate cortex, but generally decreased in neocortical areas; and these results were replicated in an independent developmental MRI cohort (N ∼ 304). Increasing hubness of paralimbic nodes in MSNs was associated with increased strength of coupling between their morphometric similarity and functional connectivity. Decreasing hubness of neocortical nodes in MSNs was associated with reduced strength of structure-function coupling and increasingly diverse functional connections in the corresponding fMRI networks. Neocortical areas became more structurally differentiated and more functionally integrative in a metabolically expensive process linked to cortical thinning and myelination; whereas paralimbic areas specialised for affective and interoceptive functions became less differentiated, as hypothetically predicted by a developmental transition from peri-allocortical to pro-isocortical organization of cortex. Cytoarchitectonically distinct zones of human cortex undergo distinct neurodevelopmental programmes during typical adolescence.
Elevated temperature fatally disrupts nuclear divisions in the earlyDrosophilaembryo
Authors: Kale Girish , Agarwal Pratika , Diaz-Larrosa J Jaime , Lemke Steffen 
Published: September 2023

AbstractTemperature variations can challenge animal survival, with different life cycle stages presenting distinct vulnerabilities to elevated temperature. Here, embryonic development is known to be especially vulnerable to elevated temperature, though the molecular mechanism remain unclear. In this context, we investigate how elevated temperature affects embryogenesis inDrosophila melanogaster, utilizing it as a model with a well-characterized genetic makeup and developmental processes.InDrosophilaembryos, we identified the first three hours as a critical, temperature-sensitive time window. This period includes the formation of a syncytial blastoderm, which involves 4 rounds of meta-synchronous nuclear divisions at the embryo cortex, and cellularization that leads to formation of the cellular blastoderm. Embryos exposed to elevated temperature during this period showed increased lethality due to subsequent developmental defects during the gastrulation stage. We observed an increase in mitotic failures causing a loss of cortical nuclei, both, during syncytial blastoderm and cellularization stages in embryos developing at elevated temperature. Additionally, these embryos show a local crowding of nuclei and an increase in asynchrony between the nuclear cycles in the center vs. the poles. Interestingly, nuclear crowding and nuclear cycle asynchrony cooperatively amplify the frequency of mitotic failures, leading to holes in the blastoderm epithelium. We functionally tested known regulators of mitosis, to rescue these developmental defects and improve embryo survival, and asked whether existing wild populations carry signatures of adaptation in these regulators of mitosis.Our genetic rescue experiments expose a vulnerability at elevated temperatures in the interaction between cortical F-actin and microtubules, leading to mitotic failures, which can be potentially rescued by modulating the expression of just a few factors. We propose that the expression levels of the corresponding genes could be used as indicators to predict fitness effects on insect populations that are exposed to increasing temperature variations.
A proposed function for the red body ofNannochloropsisin the formation of the recalcitrant cell wall polymer, algaenan
Authors: Gee Christopher W. , Andersen-Ranberg Johan , Rosen Rachel Z. , Jorgens Danielle , Grob Patricia , Holman Hoi-Ying N. , Niyogi Krishna K. 
Published: September 2023

AbstractStramenopile algae contribute significantly to global primary productivity, and one class, Eustigmatophyceae, is increasingly studied for applications in high-value lipid production. Yet much about their basic biology remains unknown, including the nature of an enigmatic, pigmented globule found in vegetative cells. Here, we present an in-depth examination of this “red body”, focusing onNannochloropsis oceanica. During the cell cycle, the red body formed adjacent to the plastid, but unexpectedly it was secreted and released with the autosporangial wall following cell division. Shed red bodies contained antioxidant ketocarotenoids, and overexpression of a beta-carotene ketolase resulted in enlarged red bodies. Infrared spectroscopy indicated long-chain, aliphatic lipids in shed red bodies and cell walls, and LC-HRMS detected a C32 alkyl diol, a potential precursor of algaenan, a recalcitrant cell wall polymer. We propose that the red body transports algaenan precursors from plastid to apoplast to be incorporated into daughter cell walls.
p53 dosage impedes KrasG12D- and KrasQ61R-mediated tumorigenesis
Authors: Le Roux Özgün , Everitt Jeffery I. , Counter Christopher M. 
Published: September 2023

AbstractMice engineered with G12D versus Q61R mutant of Kras exhibit differences in the number and grade of tumors. Namely, the incidence or grade of oral or forestomach squamous epithelial lesions was more prevalent in the KrasG12Dbackground while hematolymphopoietic disease was more prevalent in the KrasQ61Rbackground. Loss of theTrp53gene encoding p53 enhances the ability of oncogenic Kras to initiate tumorigenesis in carcinogen and genetic models of lung cancer, while an extra copy ofTrp53(Super p53) was recently shown to suppress Kras-induced tumorigenesis in a genetic model of this disease. Given this, we evaluated whether such an extra copy ofTrp53would alter tumorigenesis upon global activation of a modifiedKrasallele engineered with either a G12D or Q61R mutation. We report that an increase in p53 dosage generally reduced tumor number or grade across a number of organs in a manner largely independent of the type of Kras mutation, which was sufficient to extend lifespan in the less aggressive background of aKrasG12Dinitiating mutation.
Basal spot junctions of epithelial tissues respond to morphogenetic forces and regulate Hippo signaling
Authors: Kroeger Benjamin , Manning Samuel A. , Fonseka Yoshana , Oorschot Viola , Crawford Simon A. , Ramm Georg , Harvey Kieran F. 
Published: September 2023

SUMMARYOrgan size is controlled by numerous factors including mechanical forces, which are mediated in part by the Hippo pathway. In growingDrosophila melanogasterepithelial tissues, cytoskeletal tension influences Hippo signalling by modulating the subcellular localisation of key pathway proteins in different apical domains, namely adherens junctions, the sub-apical region and the medial apical cortex. Here, using both electron and light microscopy, we have discovered the existence of basal spot junctions inD. melanogasterepithelial tissues, and that they respond to morphogenetic forces and also influence Hippo signalling. Like adherens junctions, the Warts kinase is recruited to basal spot junctions via Ajuba and E-cadherin, which prevent Warts activation by segregating it from upstream Hippo pathway proteins. Basal spot junctions are prominent when tissues undergo morphogenesis and are highly sensitive to fluctuations in cytoskeletal tension. Basal spot junctions are distinct from focal adhesions, but the latter profoundly influences the abundance of spot junctions by modulating the basal-medial actomyosin network and tension experienced by spot junctions. Thus, basal spot junctions potentially couple morphogenetic forces to Hippo pathway activity and organ growth.
Revisiting the potency of Tbx2 expression in transforming outer hair cells into inner hair cells at multiple agesin vivo
Authors: Bi Zhenghong , Ren Minhui , Zhang Yu , He Shunji , Song Lei , Li Xiang , Liu Zhiyong 
Published: September 2023

AbstractThe cochlea, the auditory organ, contains two types of sound receptors: inner hair cells (IHCs) and outer hair cells (OHCs). Tbx2 is expressed in IHCs but repressed in OHCs. The neonatal OHCs with Tbx2 misexpression transdifferentiate into IHC-like cells. However, the extent of the switch from OHCs to IHC-like cells and the underlying molecular mechanism remain poorly understood. Furthermore, it is unknown whether Tbx2 can transform fully mature adult OHCs into IHC-like cells. In this study, we employ single-cell transcriptomic analysis, revealing that 85.6% of IHC genes, includingSlc17a8, are upregulated, whereas only 38.6% of OHC genes, includingIkzf2andSlc26a5, are downregulated in neonatal OHCs with Tbx2 misexpression. Thus, our findings suggest that Tbx2 cannot fully reprogram neonatal OHCs into IHCs, contrary to previous assumptions. Consistently, Tbx2 also fails to fully reprogram cochlear progenitors into IHCs. Finally, Ikzf2 restoration alleviates the abnormalities present in the Tbx2+ OHCs, supporting the notion that Ikzf2 repression by Tbx2 contributes to the transdifferentiation of OHCs into IHC-like cells. Overall, our study reevaluates the effects of ectopic Tbx2 expression on OHC lineage development at different stages and provides molecular insights into how Tbx2 disrupts the gene expression profiles of OHCs. This research also lays the groundwork for future studies on OHC regeneration.Significance StatementUnderstanding the molecular and genetic mechanisms that govern the determination and stability of cochlear inner hair cells (IHCs) and outer hair cells (OHCs) would provide valuable insights into regenerating damaged IHCs and OHCs. In this manuscript, we conductin vivoconditional overexpression of Tbx2 in cochlear sensory progenitors, neonatal OHCs and adult OHCs, respectively. Our findings challenge previous assumptions by revealing that Tbx2 expression alone can partially destabilize OHC fates but cannot fully convert OHCs into IHCs. Specifically, we demonstrate that the repression of Ikzf2 expression due to Tbx2 overexpression is one of the key pathways disrupting OHC fate.
Dopamine encoding of novelty facilitates efficient uncertainty-driven exploration
Authors: Wang Yuhao , Lak Armin , Manohar Sanjay G. , Bogacz Rafal 
Published: September 2023

AbstractWhen facing an unfamiliar environment, animals need to explore to gain new knowledge about which actions provide reward, but also put the newly acquired knowledge to use as quickly as possible. Optimal reinforcement learning strategies should therefore assess the uncertainties of these action– reward associations and utilise them to inform decision making. We propose a novel model whereby direct and indirect striatal pathways act together to estimate both the mean and variance of reward distributions, and mesolimbic dopaminergic neurons provide transient novelty signals, facilitating effective uncertainty-driven exploration. We utilised electrophysiological recording data to verify our model of the basal ganglia, and we fitted exploration strategies derived from the model to data from behavioural experiments. We also compared the performance of directed exploration strategies inspired by our basal ganglia model with classic variants of upper confidence bound (UCB) strategy in simulation. The exploration strategies inspired by the basal ganglia model performed better than the classic algorithms in simulation in some cases, and we found qualitatively similar results in fitting model to behavioural data compared with the fitting of more idealised normative models with less implementation level detail. Overall, our results suggest that transient dopamine levels in the basal ganglia that encode novelty could contribute to an uncertainty representation which efficiently drives exploration in reinforcement learning.Author summaryHumans and other animals learn from rewards and losses resulting from their actions to maximise their chances of survival. In many cases, a trial-and-error process is necessary to determine the most rewarding action in a certain context. During this process, determining how much resource should be allocated to acquiring information (“exploration”) and how much should be allocated to utilising the existing information to maximise reward (“exploitation”) is key to the overall effectiveness, i.e., the maximisation of total reward obtained with a certain amount of effort. We propose a theory whereby an area within the mammalian brain called the basal ganglia integrates current knowledge about the mean reward, reward uncertainty and novelty of an action in order to implement an algorithm which optimally allocates resources between exploration and exploitation. We verify our theory using behavioural experiments and electrophysiological recording, and show in simulations that the model also achieves good performance in comparison with established benchmark algorithms.