bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of Noisy Labels as Weak Learners to Identify Incompletely Ascertainable Outcomes: A Feasibility Study with Opioid-Induced Respiratory Depression
Authors: Jeffery Alvin D. , Fabbri Daniel , Reeves Ruth M. , Matheny Michael E. 
Published: January 2024

AbstractObjectiveAssigning outcome labels to large observational data sets in a timely and accurate manner, particularly when outcomes are rare or not directly ascertainable, remains a significant challenge within biomedical informatics. We examined whether noisy labels generated from subject matter experts’ heuristics using heterogenous data types within a data programming paradigm could provide outcomes labels to a large, observational data set. We chose the clinical condition of opioid-induced respiratory depression for our use case because it is rare, has no administrative codes to easily identify the condition, and typically requires at least some unstructured text to ascertain its presence.Materials and MethodsUsing de-identified electronic health records of 52,861 post-operative encounters, we applied a data programming paradigm (implemented in the Snorkel software) for the development of a machine learning classifier for opioid-induced respiratory depression. Our approach included subject matter experts creating 14 labeling functions that served as noisy labels for developing a probabilistic Generative model. We used probabilistic labels from the Generative model as outcome labels for training a Discriminative model on the source data. We evaluated performance of the Discriminative model with a hold-out test set of 599 independently-reviewed patient records.ResultsThe final Discriminative classification model achieved an accuracy of 0.977, an F1 score of 0.417, a sensitivity of 1.0, and an AUC of 0.988 in the hold-out test set with a prevalence of 0.83% (5/599).DiscussionAll of the confirmed Cases were identified by the classifier. For rare outcomes, this finding is encouraging because it reduces the number of manual reviews needed by excluding visits/patients with low probabilities.ConclusionApplication of a data programming paradigm with expert-informed labeling functions might have utility for phenotyping clinical phenomena that are not easily ascertainable from highly-structured data.
Histone variant H2BE enhances chromatin accessibility in neurons to promote synaptic gene expression and long-term memory
Authors: Feierman Emily R. , Louzon Sean , Prescott Nicholas A. , Biaco Tracy , Gao Qingzeng , Qiu Qi , Choi Kyuhyun , Palozola Katherine C. , Voss Anna J. , Mehta Shreya D. , Quaye Camille N. , Lynch Katherine T. , Fuccillo Marc V. , Wu Hao , David Yael , Korb Erica 
Published: January 2024

SUMMARYRegulation of histone proteins affects gene expression through multiple mechanisms including exchange with histone variants. However, widely expressed variants of H2B remain elusive. Recent findings link histone variants to neurological disorders, yet few are well studied in the brain. We applied new tools including novel antibodies, biochemical assays, and sequencing approaches to reveal broad expression of the H2B variant H2BE, and defined its role in regulating chromatin structure, neuronal transcription, and mouse behavior. We find that H2BE is enriched at promoters and a single unique amino acid allows it to dramatically enhance chromatin accessibility. Lastly, we show that H2BE is critical for synaptic gene expression and long-term memory. Together, these data reveal a novel mechanism linking histone variants to chromatin regulation, neuronal function, and memory. This work further identifies the first widely expressed H2B variant and uncovers a single histone amino acid with profound effects on genomic structure.
ListPred: A predictive ML tool for virulence potential and disinfectant tolerance inListeria monocytogenes
Authors: Gmeiner Alexander , Ivanova Mirena , Kaas Rolf Sommer , Xiao Yinghua , Otani Saria , Leekitcharoenphon Pimlapas 
Published: January 2024

ABSTRACTDespite current surveillance and sanitation strategies, foodborne pathogens continue to threaten the food industry and public health. Whole genome sequencing (WGS) has reached an unprecedented resolution to analyse and compare pathogenic bacterial isolates. The increased resolution significantly enhances the possibility of tracing transmission routes and contamination sources of foodborne pathogens. In addition, machine learning (ML) on WGS data has shown promising applications for predicting important microbial traits such as virulence, growth potential, and resistance to antimicrobials. Many regulatory agencies have already adapted WGS and ML methods. However, the food industry hasn’t followed a similarly enthusiastic implementation. Some possible reasons for this might be the lack of computational resources and limited expertise to analyse WGS and ML data and interpret the results. Here, we present ListPred, a ML tool to analyse WGS data ofListeria monocytogenes, a very concerning foodborne pathogen. ListPred is able to predict two important bacterial traits, namely virulence potential and disinfectant tolerance, and only requires limited computational resources and practically no bioinformatic expertise, which is essential for a broad application in the food industry.AUTHOR SUMMARYThe contamination of food products with microbes such as pathogenic bacteria is a big concern for the food industry. The rapid detection, characterisation and eradication of microbial contaminants are of utmost importance to ensure safe food products. Fortunately, strict food safety regulations and stringent cleaning protocols prevent the transmission of harmful bacteria to humans. Individual bacteria of the same species can have varying abilities to resist cleaning agents or infect a host, meaning that some pathogen isolates might be more dangerous than others. Novel techniques such as genome sequencing and machine learning can help to determine such differences in individual bacteria. Unfortunately, these techniques require a lot of computational power and expertise that is limited in the food industry. This is why we developed an easy-to-use software tool called ListPred that can be used with few computational requirements and little expertise. ListPred helps food companies to answer two essential questions: how dangerous areListeria monocytogenespathogens, and how to get rid of them most efficiently?
Wild Patagonian yeast improve the evolutionary potential of novel interspecific hybrid strains for Lager brewing
Authors: Molinet Jennifer , Navarrete Juan P. , Villarroel Carlos A. , Villarreal Pablo , Sandoval Felipe I. , Nespolo Roberto F. , Stelkens Rike , Cubillos Francisco A. 
Published: January 2024

ABSTRACTLager yeasts are limited to a few strains worldwide, imposing restrictions on flavour and aroma diversity and hindering our understanding of the complex evolutionary mechanisms during yeast domestication. The recent finding of diverseS. eubayanuslineages from Patagonia offers potential for generating new Lager yeasts and obtaining insights into the domestication process. Here, we leverage the natural genetic diversity ofS. eubayanusand expand the Lager yeast repertoire by including three distinct PatagonianS. eubayanuslineages. We used experimental evolution and selection on desirable traits to enhance the fermentation profiles of novelS. cerevisiaexS. eubayanushybrids. Our analyses reveal an intricate interplay of pre-existing diversity, selection on species-specific mitochondria,de-novomutations, and gene copy variations in sugar metabolism genes, resulting in high ethanol production and unique aroma profiles. Hybrids withS. eubayanusmitochondria exhibited greater evolutionary potential and superior fitness post-evolution, analogous to commercial Lager hybrids. Using genome-wide screens of the parental subgenomes, we identified genetic changes inIRA2,SNF3,IMA1andMALXgenes that influence maltose metabolism, and increase glycolytic flux and sugar consumption in the evolved hybrids. Functional validation and transcriptome analyses confirmed increased maltose-related gene expression, influencing grater maltotriose consumption in evolved hybrids. This study demonstrates the potential for generating industrially viable Lager yeast hybrids from wild Patagonian strains. Our hybridization, evolution, and mitochondrial selection approach produced hybrids with high fermentation capacity, expands Lager beer brewing options, and deepens our knowledge of Lager yeast domestication.
graded-CRISPRi, a novel tool for tuning the strengths of CRISPRi-mediated knockdowns inVibrio natriegensusing gRNA libraries
Authors: Stukenberg Daniel , Faber Anna , Becker Anke 
Published: January 2024

AbstractIn recent years, the fast-growing bacteriumVibrio natriegenshas gained increasing attention as it has the potential to become a next-generation chassis for Synthetic Biology. A wide range of genetic parts and genome engineering methods have already been developed. However, there is still a need for a well-characterized tool to effectively and gradually reduce the expression level of native genes. To bridge this gap, we created graded-CRISPRi, a system utilizing gRNA variants that lead to varying levels of repression strength. By incorporating multiple gRNA sequences into our design, we successfully extended this concept to simultaneously repress four distinct reporter genes. Furthermore, we demonstrated the capability of using graded-CRISPRi to target native genes, thereby examining the effect of various knockdown levels on growth.
Mathematical model of replication-mutation dynamics in coronaviruses
Authors: Blyuss K.B. , Kyrychko Y.N. 
Published: January 2024

AbstractRNA viruses are known for their fascinating evolutionary dynamics, characterised by high mutation rates, fast replication, and ability to form quasispecies - clouds of genetically related mutants. Fast replication in RNA viruses is achieved by a very fast but error-prone RNA-dependent RNA polymerase (RdRP). High mutation rates are a double-edged sword: they provide RNA viruses with a mechanism of fast adaptation to a changing environment or host immune system, but at the same time they pose risk to virus survivability in terms of virus mutating beyond its error threshold. Coronaviruses, being a subset of RNA viruses, are unique in having a special enzyme, exoribonuclease (ExoN), responsible for proofreading and correcting errors induced by the RdRP. In this paper we consider replication dynamics of coronaviruses with account for mutations that can be neutral, deleterious or lethal, as well as ExoN. Special attention is paid to different virus replication modes that are known to be crucial for controlling the dynamics of virus populations. We analyse extinction, mutant-only and quasispecies steady states, and study their stability in terms of different parameters, identifying regimes of error catastrophe and lethal mutagenesis. With coronaviruses being responsible for some of the largest pandemics in the last twenty years, we also model the effects of antiviral treatment with various replication inhibitors and mutagenic drugs.
The EGF/EGFR-YAP1/TEAD2 axis-mediated BRAF inhibitor vemurafenib resistance upregulates STIM1 in melanoma
Authors: Bai Weiyu , Yan Chenghao , Yang Yichen , Sang Lei , Hao Qinggang , Yao Xinyi , Yu Jia , Wang Yifan , Li Xiaowen , Meng Mingyao , Yang Jilong , Shen Junling , Sun Yan , Sun Jianwei 
Published: January 2024

AbstractSTIM1 is the endoplasmic reticulum (ER) Ca2+sensor for store-operated entry (SOCE) and closely correlated to carcinogenesis and tumor progression. Previously we found that STIM1 is upregulated in melanoma cells resistant to the BRAF inhibitor vemurafenib, but the regulation mechanism is unknown. Here, we show that vemurafenib resistance upregulates STIM1 through an EGF/EGFR-YAP1/TEAD2 axis. Vemurafenib resistance can lead to the increase of EGF and EGFR levels to activate the EGFR signaling pathway. Reactivated EGFR signal promotes YAP1 nuclear localization to increase the expression of STIM1. Our finding not only demonstrates the mechanism by which vemurafenib resistance promotes STIM1 expression, but also provides combined targeting EGF/EGFR-YAP1/TEAD2-STIM1 to improve the therapeutic efficiency of BRAF inhibitor in melanoma patients.
Understanding species-specific and conserved RNA-protein interactionsin vivoandin vitro
Authors: Harris Sarah E. , Alexis Maria S. , Giri Gilbert , Cavazos Francisco F. , Murn Jernej , Aleman Maria M. , Burge Christopher B. , Dominguez Daniel 
Published: January 2024

ABSTRACTWhile evolution is often considered from a DNA- and protein-centric view, RNA-based regulation can also impact gene expression and protein sequences. Here we examined interspecies differences in RNA-protein interactions using the conserved neuronal RNA binding protein, Unkempt (UNK) as model. We find that roughly half of mRNAs bound in human are also bound in mouse. Unexpectedly, even when transcript-level binding was conserved across species differential motif usage was prevalent. To understand the biochemical basis of UNK-RNA interactions, we reconstituted the human and mouse UNK-RNA interactomes using a high-throughput biochemical assay. We uncover detailed features driving binding, show thatin vivopatterns are capturedin vitro, find that highly conserved sites are the strongest bound, and associate binding strength with downstream regulation. Furthermore, subtle sequence differences surrounding motifs are key determinants of species-specific binding. We highlight the complex features driving protein-RNA interactions and how these evolve to confer species-specific regulation.
Dysregulated acetylcholine-mediated dopamine neurotransmission in the eIF4E Tg mouse model of autism spectrum disorders
Authors: Carbonell-Roig Josep , Aaltonen Alina , Cartocci Veronica , McGuirt Avery , Mosharov Eugene , Kehr Jan , Lieberman Ori J. , Sulzer David , Borgkvist Anders , Santini Emanuela 
Published: January 2024

AbstractAutism Spectrum Disorders (ASD) consist of diverse neurodevelopmental conditions where core behavioral symptoms are critical for diagnosis. Altered dopamine neurotransmission in the striatum has been suggested to contribute to the behavioral features of ASD. Here, we examine dopamine neurotransmission in a mouse model of ASD characterized by elevated expression of the eukaryotic initiation factor 4E (eIF4E), a key regulator of cap-dependent translation, using a comprehensive approach that encompasses genetics, behavior, synaptic physiology, and imaging. The results indicate that increased eIF4E expression leads to behavioral inflexibility and impaired striatal dopamine release. The loss of normal dopamine neurotransmission is due to a defective nicotinic receptor signaling that regulates calcium dynamics in dopaminergic axons. These findings reveal an intricate interplay between eIF4E, DA neurotransmission, and behavioral flexibility, provide a mechanistic understanding of ASD symptoms and offer a foundation for targeted therapeutic interventions.
Cisplatin drives mitochondrial dysregulation in sensory hair cells
Authors: Lee David S. , Schrader Angela , Zou Jiaoxia , Ang Wee Han , Warchol Mark , Sheets Lavinia 
Published: January 2024

SummaryCisplatin is a chemotherapy drug that causes permanent hearing loss by injuring cochlear hair cells. The mechanisms that initiate injury are not fully understood, but mitochondria have emerged as potential mediators of hair cell cytotoxicity. Usingin vivolive imaging of hair cells in the zebrafish lateral-line organ expressing a genetically encoded indicator of cumulative mitochondrial activity, we first demonstrate that greater redox history increases susceptibility to cisplatin. Next, we conducted time-lapse imaging to understand dynamic changes in mitochondrial homeostasis and observe elevated mitochondrial and cytosolic calcium that surge prior to hair cell death. Furthermore, using a localized probe that fluoresces in the presence of cisplatin, we show that cisplatin directly accumulates in hair cell mitochondria, and this accumulation occurs before mitochondrial dysregulation and apoptosis. Our findings provide evidence that cisplatin directly targets hair cell mitochondria and support that the mitochondria are integral to cisplatin cytotoxicity in hair cells.
Multiplexed Short-wave Infrared Imaging Highlights Anatomical Structures in Mice
Authors: Zhong Xingjian , Patel Amish , Sun Yidan , Saeboe Alexander M. , Dennis Allison M. 
Published: January 2024

AbstractWhile multiplexed fluorescence imaging is frequently used forin vitromicroscopy, extending the technique to whole animal imagingin vivohas remained challenging due to the attenuation and scattering of visible and traditional near infrared (NIR-I) wavelengths. Fluorescence imaging using short-wave infrared (SWIR, 1000 – 1700 nm, a.k.a. NIR-II) light enables deeper tissue penetration for preclinical imaging compared to previous methods due to reduced tissue scattering and minimal background autofluorescence in this optical window. Combining NIR-I excitation wavelengths with multiple distinct SWIR emission peaks presents a tremendous opportunity to distinguish multiple fluorophores with high precision for non-invasive, multiplexed anatomical imaging in small animal models. SWIR-emitting semiconductor quantum dots (QDs) with tunable emission peaks and optical stability have emerged as powerful contrast agents, but SWIR imaging demonstrations have yet to move beyond two-color imaging schemes. In this study, we engineered a set of three high quantum yield lead sulfide/cadmium sulfide (PbS/CdS) core/shell QDs with distinct SWIR emissions ranging from 1100 – 1550 nm and utilize these for simultaneous three-color imaging in mice. We first use QDs to non-invasively track lymphatic drainage, highlighting the detailed network of lymphatic vessels with high-resolution with a widefield imaging over a 2 hr period. We then perform multiplexed imaging with all three QDs to distinctly visualize the lymphatic system and spatially overlapping vasculature network. This work establishes optimized SWIR QDs for next-generation multiplexed preclinical imaging, moving beyond the capability of previous dual-labeling techniques. The capacity to discriminate several fluorescent labels through non-invasive NIR-I excitation and SWIR detection unlocks numerous opportunities for studies of disease progression, drug biodistribution, and cell trafficking dynamics in living organisms.
Cellular Modeling of CLN6 with IPSC-derived Neurons and Glia
Authors: Otero Maria Gabriela , Kim Jaemin , Kushwaha Yogesh Kumar , Rajewski Alex , Nonis Fabian David , Santiskulvong Chintda , Bannykh Serguei I. , Oza Hiral , Farooqi Hafiz Muhammad Umer , Babros Madeline , Freeman Christina , Dupuis Lucie , Mercimek-Andrews Saadat , Mendoza-Londono Roberto , Bresee Catherine , Adams David R. , Tifft Cynthia J. , Toro Camilo , Khanlou Negar , Gahl William A. , Salamon Noriko , Pierson Tyler Mark 
Published: January 2024

ABSTRACTNeuronal ceroid lipofuscinosis (NCL), type 6 (CLN6) is a neurodegenerative disorder associated with progressive neurodegeneration leading to dementia, seizures, and retinopathy.CLN6encodes a resident-ER protein involved in trafficking lysosomal proteins to the Golgi. CLN6p deficiency results in lysosomal dysfunction and deposition of storage material comprised of Nile Red+lipids/proteolipids that include subunit C of the mitochondrial ATP synthase (SUBC). White matter involvement has been recently noted in several CLN6 animal models and several CLN6 subjects had neuroimaging was consistent with leukodystrophy. CLN6 patient-derived induced pluripotent stem cells (IPSCs) were generated from several of these subjects. IPSCs were differentiated into oligodendroglia or neurons using well-established small-molecule protocols. A doxycycline-inducible transgenic system expressing neurogenin-2 (the I3N-system) was also used to generate clonal IPSC-lines (I3N-IPSCs) that could be rapidly differentiated into neurons (I3N-neurons). All CLN6 IPSC-derived neural cell lines developed significant storage material, CLN6-I3N-neuron lines revealed significant Nile Red+and SUBC+storage within three and seven days of neuronal induction, respectively. CLN6-I3N-neurons had decreased tripeptidyl peptidase-1 activity, increased Golgi area, along with increased LAMP1+in cell bodies and neurites. SUBC+signal co-localized with LAMP1+signal. Bulk-transcriptomic evaluation of control- and CLN6-I3N-neurons identified >1300 differentially-expressed genes (DEGs) with Gene Ontogeny (GO) Enrichment and Canonical Pathway Analyses having significant changes in lysosomal, axonal, synaptic, and neuronal-apoptotic gene pathways. These findings indicate that CLN6-IPSCs and CLN6-I3N-IPSCs are appropriate cellular models for this disorder. These I3N-neuron models may be particularly valuable for developing therapeutic interventions with high-throughput drug screening assays and/or gene therapy.
Non-CG DNA methylation and MeCP2 stabilize repeated tuning of long genes that distinguish closely related neuron types
Authors: Moore J. Russell , Nemera Mati T. , D’Souza Rinaldo D. , Hamagami Nicole , Clemens Adam W. , Beard Diana C. , Urman Alaina , Mendoza Victoria Rodriguez , Gabel Harrison W. 
Published: January 2024

AbstractThe extraordinary diversity of neuron types in the mammalian brain is delineated at the highest resolution by subtle gene expression differences that may require specialized molecular mechanisms to be maintained. Neurons uniquely express the longest genes in the genome and utilize neuron-enriched non-CG DNA methylation (mCA) together with the Rett syndrome protein, MeCP2, to control gene expression, but the function of these unique gene structures and machinery in regulating finely resolved neuron type-specific gene programs has not been explored. Here, we employ epigenomic and spatial transcriptomic analyses to discover a major role for mCA and MeCP2 in maintaining neuron type-specific gene programs at the finest scale of cellular resolution. We uncover differential susceptibility to MeCP2 loss in neuronal populations depending on global mCA levels and dissect methylation patterns and intragenic enhancer repression that drive overlapping and distinct gene regulation between neuron types. Strikingly, we show that mCA and MeCP2 regulate genes that are repeatedly tuned to differentiate neuron types at the highest cellular resolution, including spatially resolved, vision-dependent gene programs in the visual cortex. These repeatedly tuned genes display genomic characteristics, including long length, numerous intragenic enhancers, and enrichment for mCA, that predispose them to regulation by MeCP2. Thus, long gene regulation by the MeCP2 pathway maintains differential gene expression between closely-related neurons to facilitate the exceptional cellular diversity in the complex mammalian brain.