bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep Learning disconnectomes to accelerate and improve long-term predictions for post-stroke symptoms
Authors: Matsulevits Anna , Coupe Pierrick , Nguyen Huy-Dung , Talozzi Lia , Foulon Chris , Nachev Parashkev , Corbetta Maurizio , Tourdias Thomas , Thiebaut de Schotten Michel 
Published: September 2023

AbstractDeep learning as a truly transformative force is revolutionizing a wide range of fields, making a significant difference in medical imaging, where recent advancements have yielded some truly remarkable outcomes. In a connected brain, maps of white matter damage — otherwise known as disconnectomes — are essential for capturing the effects of focal lesions. However, the current tools for obtaining such information are prohibitively slow and not admitted for clinical usage. Here, we have explored the potential of deep-learning models to accurately generate disconnectomes in a population of stroke survivors. We trained a 3D U-Net algorithm to producedeep-disconnectomesfrom binary lesion masks. This artificial neural network was able to capture most information obtained in conventional disconnectomes, i.e., statistical maps filtering normative white-matter networks, but output a deep-disconnectome 170 times faster – compared to disconnectome computation with the state-of-the-art BCBToolkit software. Moreover, the deep-disconnectomes were challenged to predict cognitive and behavioral outcomes one-year post-stroke. In an additional cohort of N=139 stroke survivors, N=86 neuropsychological scores were predicted from deep-disconnectomes achieving, on average, 85.2% of accuracy and R2= 0.208. The deep-disconnectomes predictivity power outperformed the conventional disconnectome predictions for clinical scores.In summary, we have achieved a significant milestone for clinical neuroimaging by accelerating and ameliorating the creation of disconnectome maps using deep learning. By integrating deep learning into the management of stroke, one of the most prevailing catalysts for acquired disabilities, we deepen our understanding of its impact on the brain. This novel approach may offer potential avenues for acute intervention, ultimately enhancing patients’ overall quality of life.
mTORC1 Regulates the Metabolic Switch of Postnatal Cardiomyocytes During Regeneration
Authors: Paltzer Wyatt G. , Aballo Timothy J. , Bae Jiyoung , Hubert Katharine A. , Nuttall Dakota J. , Perry Cassidy , Wanless Kayla N. , Nahlawi Raya , Ge Ying , Mahmoud Ahmed I. 
Published: September 2023

ABSTRACTThe metabolic switch from glycolysis to fatty acid oxidation in postnatal cardiomyocytes contributes to the loss of the cardiac regenerative potential of the mammalian heart. However, the mechanisms that regulate this metabolic switch remain unclear. The protein kinase complex mechanistic target of rapamycin complex 1 (mTORC1) is a central signaling hub that regulates cellular metabolism and protein synthesis, yet its role during mammalian heart regeneration and postnatal metabolic maturation is undefined. Here, we use immunoblotting, rapamycin treatment, myocardial infarction, and global proteomics to define the role of mTORC1 in postnatal heart development and regeneration. Our results demonstrate that the activity of mTORC1 is dynamically regulated between the regenerating and the non-regenerating hearts. Acute inhibition of mTORC1 by rapamycin or everolimus reduces cardiomyocyte proliferation and inhibits neonatal heart regeneration following injury. Our quantitative proteomic analysis demonstrates that transient inhibition of mTORC1 during neonatal heart injury did not reduce protein synthesis, but rather shifts the cardiac proteome of the neonatal injured heart from glycolysis towards fatty acid oxidation. This indicates that mTORC1 inhibition following injury accelerates the postnatal metabolic switch, which promotes metabolic maturation and impedes cardiomyocyte proliferation and heart regeneration. Taken together, our results define an important role for mTORC1 in regulating postnatal cardiac metabolism and may represent a novel target to modulate cardiac metabolism and promote heart regeneration.
A Rapid Anterior Auditory Processing Stream Through the Insulo-Parietal Auditory Field in the Rat
Authors: Jankowski Maciej M. , Karayanni Mousa , Harpaz Mor , Polterovich Ana , Nelken Israel 
Published: September 2023

AbstractThe insular cortex is believed to be involved in a wide range of auditory functions in the mammalian brain. We studied the organization and basic response properties of auditory neurons in insular cortex and adjacent areas by recording responses to sound stimuli in anesthetized rats. Auditory neurons were present in an insulo-parietal auditory field that spans the boundary between the posterior insula, particularly in the granular insular cortex and the ventral part of the secondary somatosensory cortex. Neurons in this field had narrow tuning, were preferentially tuned to relatively low frequencies (<16 kHz), and had short response latencies. Intriguingly, some auditory units in this insulo-parietal field displayed shorter onset latencies than the minimal latency in primary auditory cortex. At the same time, these units showed weaker sensitivity to deviance than units in primary auditory cortex. These results establish the existence of a rapid information stream through the insulo-parietal cortex that may parallel the pathway through the primary and anterior auditory fields.
Targeted Transcriptional Activation using a CRISPR-Associated Transposon System
Authors: Elizondo Andrea M. Garza , Chappell James 
Published: September 2023

AbstractSynthetic perturbation of gene expression is central to our ability to reliably uncover genotype-phenotype relationships in microbes. Here, we present a novel gene transcription activation strategy that uses theVibrio choleraeCRISPR-Associated Transposon (CAST) system to selectively insert promoter elements upstream of genes of interest. Through this strategy, we show robust activation of both recombinant and endogenous genes across theE. colichromosome. We then demonstrate precise tuning of expression levels by exchanging the promoter elements being inserted. Finally, we demonstrate that CAST activation can be used to synthetically induce ampicillin-resistant phenotypes inE. coli.
ENHANCED EFFICIENCY OF RNA-GUIDED CAS12a VERSUS CAS9 TRANSGENE KNOCK-IN AND ACTIVITY AT ASCHISTOSOMA MANSONIGENOME SAFE HARBOR
Authors: Moescheid Max F. , Wisitphongpun Prapakorn , Mann Victoria H. , Quack Thomas , Grunau Christoph , Grevelding Christoph G. , Ittiprasert Wannaporn , Brindley Paul J. 
Published: September 2023

ABSTRACTRecently, we reported programmed Cas9 mediated insertion of a reporter gene into a gene safe harbor site, GSH1, ofSchistosoma mansonivia homology-directed repair (HDR) using overlapping guide RNAs. Here, we report efficient and precise CRISPR/Cas12a-mediated homology directed insertion (knockin, KI) of a 5’ C6-PEG10-modified double-stranded transgene bearing microhomology arms, 50 nt in length, at GSH1. At the outset, we undertook bioinformatic and computational analysis following by experimental verification of the regulatory activity of endogenous schistosome ubiquitin (SmUbi) promoter and terminator, to drive strong reporter gene expression. Green fluorescent protein activity driven by SmUbi followed electroporation-mediated transfection of schistosome eggs. HDR induced by RNA-guided CRISPR/Cas12a, which releases overhanging DNA strands of 18-24, delivered more efficient KI than CRISPR/Cas9. In this non-model pathogen, programmed KI facilitated precise chromosomal integration of the reporter-gene with at GSH1. The approach advances schistosome transgenesis field and may also advance functional genomics and transfection methods in related parasitic and non-parasitic helminths, which hitherto lack these tools.Author summaryGenome editing (CRISPR) technology is revolutionizing advances in biology, medicine, and agriculture. Transgenesis approaches are integral in diverse applications including gene therapy, biotherapeutics, deciphering host-pathogen interactions, and enhancements in agricultural production. Parasitic worms that are responsible for infectious diseases including neglected tropical diseases (NTDs), which cause substantial morbidity and mortality. NTDs mainly occur in the Global South, and they are responsible for a disease burden that exceeds that caused by malaria and tuberculosis. Infections with parasitic helminths also are responsible for immense economic burden in the agriculture. Tools for functional genomics in parasitic helminths are limited. Access to CRISPR-based approaches can be expected to hasten development of drug and/or vaccine targets for these diseases. Here, we focused on the helminthSchistosoma mansoni, a water borne parasite of humans, and which is endemic in Africa, and northeastern South America. To advance the state of the art in laboratory techniques currently used to study the biology and pathogenesis of this and related pathogens, we evaluated a spectrum of technological approaches aimed at improved current lab practice in this field. The findings demonstrated that specific technical and chemical modifications, including deploying a DNA cutting enzyme termed Cas12a along with a transgene with chemically modified short flanking sequences (homology arms) provided improved gene editing efficiency for this schistosome.
Manufacturing DNA in E. coli yields higher fidelity DNA thanin vitroenzymatic synthesis
Authors: Hersch Steven J. , Chandrasekaran Siddarth , Lam Jamie , Nafissi Nafiseh , Slavcev Roderick A. 
Published: September 2023

AbstractThe rise of biotechnologies such as gene therapy have brought DNA vectors to the forefront of pharmaceutical development. The quality of the genetic starting material plays a pivotal role in determining the quality of the final product. In this study we examined the fidelity of DNA replication using enzymatic methods (in vitro) compared to plasmid DNA producedin vivoinE. coli. Next-generation sequencing approaches predominantly rely onin vitropolymerases, which have inherent limitations in sensitivity. To address this challenge, we introduce a novel assay based on loss-of-function (LOF) mutations in the conditionally toxicsacBgene. Our findings show that DNA production inE. coliresults in significantly fewer LOF mutations (approximately 80-to 3000-fold less) compared to various enzymatic DNA synthesis methods. This includes the most accurate PCR polymerase (Q5) and a commonly employed rolling circle amplification (RCA) DNA polymerase (Phi29). These results suggest that using low-fidelity starting material DNA synthesizedin vitroby PCR or RCA may introduce a substantial number of impurities, potentially affecting the quality and yield of final pharmaceutical products. In summary, our study underscores that DNA synthesizedin vitrohas a significantly higher mutation rate than DNA produced traditionally inE. coli. Therefore, utilizingin vitroenzymatically-produced DNA in biotechnology and biomanufacturing may entail considerable fidelity-related risks, while DNA starting material derived fromE. colisubstantially mitigates this risk, enhancing overall quality in the production processes.
Analysis of 26S Proteasome Activity Across Arabidopsis Tissues
Authors: Ganapathy Jagadeesan , Hand Katherine A. , Shabek Nitzan 
Published: September 2023

AbstractPlants utilize the ubiquitin proteasome system (UPS) to orchestrate numerous essential cellular processes, including the rapid responses required to cope with abiotic and biotic stresses. The 26S proteasome serves as the central catalytic component of the UPS that allows for proteolytic degradation of ubiquitin-conjugated proteins in a highly specific manner. Despite the increasing number of studies employing cell-free degradation assays to dissect the pathways and target substrates of the UPS, the precise extraction methods of highly potent tissues remain unexplored. Here, we utilize a fluorogenic reporting assay using two extraction methods to survey proteasomal activity in differentArabidopsis thalianatissues. This study provides new insights into the enrichment of activity and varied presence of proteasomes in specific plant tissues.
BrainLM: A foundation model for brain activity recordings
Authors: Caro Josue Ortega , Fonseca Antonio H. de O. , Averill Christopher , Rizvi Syed A. , Rosati Matteo , Cross James L. , Mittal Prateek , Zappala Emanuele , Levine Daniel , Dhodapkar Rahul M. , Han Insu , Karbasi Amin , Abdallah Chadi G. , van Dijk David 
Published: September 2023

AbstractWe introduce the Brain Language Model (BrainLM), a foundation model for brain activity dynamics trained on 6,700 hours of fMRI recordings. Utilizing self-supervised masked-prediction training, BrainLM demonstrates proficiency in both fine-tuning and zero-shot inference tasks. Fine-tuning allows for the accurate prediction of clinical variables like age, anxiety, and PTSD as well as forecasting of future brain states. Critically, the model generalizes well to entirely new external cohorts not seen during training. In zero-shot inference mode, BrainLM can identify intrinsic functional networks directly from raw fMRI data without any network-based supervision during training. The model also generates interpretable latent representations that reveal relationships between brain activity patterns and cognitive states. Overall, BrainLM offers a versatile and interpretable framework for elucidating the complex spatiotemporal dynamics of human brain activity. It serves as a powerful “lens” through which massive repositories of fMRI data can be analyzed in new ways, enabling more effective interpretation and utilization at scale. The work demonstrates the potential of foundation models to advance computational neuroscience research.
Predicting fungal secondary metabolite activity from biosynthetic gene cluster data using machine learning
Authors: Riedling Olivia , Walker Allison S. , Rokas Antonis 
Published: September 2023

AbstractFungal secondary metabolites (SMs) play a significant role in the diversity of ecological communities, niches, and lifestyles in the fungal kingdom. Many fungal SMs have medically and industrially important properties including antifungal, antibacterial, and antitumor activity, and a single metabolite can display multiple types of bioactivities. The genes necessary for fungal SM biosynthesis are typically found in a single genomic region forming biosynthetic gene clusters (BGCs). However, whether fungal SM bioactivity can be predicted from specific attributes of genes in BGCs remains an open question. We adapted previously used machine learning models for predicting SM bioactivity from bacterial BGC data to fungal BGC data. We trained our models to predict antibacterial, antifungal, and cytotoxic/antitumor bioactivity on two datasets: 1) fungal BGCs (dataset comprised of 314 BGCs), and 2) fungal (314 BGCs) and bacterial BGCs (1,003 BGCs); the second dataset was our control since a previous study using just the bacterial BGC data yielded prediction accuracies as high as 80%. We found that the models trained only on fungal BGCs had balanced accuracies between 51-68%, whereas training on bacterial and fungal BGCs yielded balanced accuracies between 61-74%. The lower accuracy of the predictions from fungal data likely stems from the small number of BGCs and SMs with known bioactivity; this lack of data currently limits the application of machine learning approaches in studying fungal secondary metabolism. However, our data also suggest that machine learning approaches trained on bacterial and fungal data can predict SM bioactivity with good accuracy. With more than 15,000 characterized fungal SMs, millions of putative BGCs present in fungal genomes, and increased demand for novel drugs, efforts that systematically link fungal SM bioactivity to BGCs are urgently needed.
Discovery of specific activity of 2-HPA acting on the membrane progestin receptor α (paqr7) by purification of natural products from the marine algaePadina
Authors: Amin Mohammad Tohidul , Acharjee Mrityunjoy , Sarwar Jyoti Md. Maisum , Rezanujjaman Md. , Hassan Md. Maksudul , Hossain Md. Forhad , Ahamed Saokat , Kodani Shinya , Tokumoto Toshinobu 
Published: September 2023

ABSTRACTMembrane progestin receptors (mPRs) are members of the progestin and adipoQ (PAQR) receptor family that are stimulated by endogenous steroids to initiate rapid intracellular signalling through a nongenomic pathway. Previously, water-soluble compounds with mPRα-binding activity from the marine algaePadina arborescenswere fractionated by HPLC steps. In this study, the structure of one of the major compounds in the fraction was identified as 2-hydroxypentanoic acid (2-HPA) using Nuclear Magnetic Resonance spectroscopy. 2-HPA showed a substantial competitive binding affinity for hmPRα in the GQD-hmPRα binding assay. In contrast, synthetic structural analogues of 2-HPA showed no competitive binding activity. The physiological activity of 2-HPA and its analogues was then investigated usingin vitrogoldfish andin vivozebrafish oocyte maturation and ovulation assays. As with the hmPRα binding assay, only 2-HPA showed inhibitory activity on oocyte maturation and ovulation of fish oocytes. Furthermore, the inhibitory activity of 2-HPA was compared between S- and R-type 2-HPA. The results showed that both types had the same level of activity. These results indicate that 2-HPA, found as a secreted compound fromPadina arborescens, is a novel mPRα antagonist and its chemical structure is highly restricted to show its activity.
Alström Syndrome protein Alms1 is required for maintaining meiotic centriole engagement in spermatocytes ofDrosophila
Authors: Hou Yanan , Wu Zhimao , Wei Qing 
Published: September 2023

AbstractMaintaining proper mother-daughter centriole engagement is crucial for controlling centrosome numbers and ensuring accurate cell division in both mitosis and meiosis. However, the mechanism responsible for this maintenance remains unclear. Here, we report that theDrosophilahomolog of human ciliopathy gene Alström Syndrome 1 (Alms1) is required for maintaining centriole engagement during spermatocyte meiosis. We demonstrated that deletion of Alms1 results in premature centriole disengagement in prophase of meiosis I, leading to the formation of multipolar spindles and abnormal cell division inDrosophilaspermatocytes. Further studies reveal that Alms1 localizes to the proximal centrioles, and functions downstream of cartwheel protein Sas-6 to regulate centriole engagement, and its highly conserved ALMS motif is required for Alms1’s function in centriole engagement. Moreover, we show that the centriole size and pericentriolar materials (PCM) have antagonistic roles on maintaining centriole engagement inalms1mutant flies. Our findings highlight the critical role of Alms1 as a “glue protein” in maintaining mother-daughter centriole pair cohesion, potentially advancing our comprehension of the pathogenesis of Alström Syndrome.Significance statementAlström syndrome (AS) is a human ciliopathy that results from mutations in the ALMS1 gene inherited in an autosomal recessive manner. Elucidating the roles of ALMS1 and the underlying molecular mechanisms of AS is of paramount importance. In this study, usingDrosophilamodel, we discovered that ALMS1 is localized at the proximal centrioles, and is crucial for the proper centriole engagement, spindle polarity, cell division in spermatocytes. Our findings reveal the new role of ALSM1 in maintaining centriole engagement, and suggest that non-ciliary function of ALMS1 may contribute to the pathogenesis of Alström Syndrome, warranting further investigation.
NOC1 is a Direct MYC Target, and Its Protein Interactome Dissects Its Activity in Controlling Nucleolar Function
Authors: Manara Valeria , Radoani Marco , Belli Romina , Peroni Daniele , Destefanis Francesca , Angheben Luca , Tome Gabriele , Tebaldi Toma , Bellosta Paola 
Published: September 2023

AbstractThe nucleolus is a subnuclear compartment critical in ribosome biogenesis and cellular stress responses. These mechanisms are governed by a complex interplay of proteins, including NOC1, a member of the NOC family of nucleolar proteins responsible for controlling rRNA processing and ribosomal maturation. This study reveals a novel relationship between NOC1 and MYC transcription factor, known for its crucial role in controlling ribosomal biogenesis, cell growth, and proliferation. Here, we demonstrate that NOC1 functions as a direct target of MYC, as it is transcriptionally induced through a functional MYC-binding E-box sequence in the NOC1 promoter region. Furthermore, protein interactome analysis reveals that NOC1-complex includes the nucleolar proteins NOC2 and NOC3 and other nucleolar components such as Nucleostemin1 Ns1 transporters of ribosomal subunits and components involved in rRNA processing and maturation. In response to MYC, NOC1 expression and localization within the nucleolus significantly increase, suggesting a direct functional link between MYC activity and NOC1 function. Notably, NOC1 over-expression leads to the formation of large nuclear granules and enlarged nucleoli, which co-localize with nucleolar fibrillarin and Ns1. Additionally, we demonstrate that NOC1 expression is necessary for Ns1 nucleolar localization, suggesting a role for NOC1 in maintaining nucleolar structure. Finally, the co-expression of NOC1 and MYC enhances the formation of abnormal structures formed by NOC1 within the nucleolus, outlining another aspect of NOC1 and MYC cooperation in nucleolar dynamics.This study also reveals an enrichment with NOC1 with few proteins involved in RNA processing, modification, and splicing. Moreover, proteins such as Ythdc1, Flacc, and splenito are known to mediate N6-methyladenosine (m6A) methylation of mRNAs in nuclear export, revealing NOC1’s potential involvement in coordinating RNA splicing and nuclear mRNA export.In summary, we uncovered novel roles for NOC1 in nucleolar homeostasis and established its direct connection with MYC in the network governing nucleolar structure and function. These findings also highlight NOC1’s interaction with proteins relevant to specific RNA functions, suggesting a broader role in addition to its control of nucleolar homeostasis and providing new insight that can be further investigated.