bluuebunny/crossref_metadata_2025_split huggingface dataset:
MetaboListem and TABoLiSTM: Two Deep Learning Algorithms for Metabolite Named Entity Recognition
Authors: Yeung Cheng S. , Beck Tim , Posma Joram M. 
Published: February 2022

AbstractReviewing the metabolomics literature is becoming increasingly difficult because of the rapid expansion of relevant journal literature. Text-mining technologies are therefore needed to facilitate more efficient literature review. Here we contribute a standardised corpus of full-text publications from metabolomics studies and describe the development of two new metabolite named entity recognition (NER) methods. We introduce two deep learning methods for metabolite NER based on Bidirectional Long Short-Term Memory (BiLSTM) networks incorporating different transfer learning techniques. Our first model (MetaboListem) follows prior methodology using GloVe word embeddings. Our second model exploits BERT and BioBERT for embedding and is named TABoLiSTM (Transformer-Affixed BiLSTM). The methods are trained on a novel corpus annotated using rule-based methods, and evaluated on manually annotated metabolomics articles. MetaboListem (F1 score 0.890, precision 0.892, recall 0.888) and TABoLiSTM (BioBERT version: F1 score 0.909, precision 0.926, recall 0.893) have achieved state-of-the-art performance on metabolite NER. A corpus with >1,200 full-text Open Access metabolomics publications and >116,000 annotated metabolites was created. This work demonstrates that deep learning algorithms are capable of identifying metabolite names accurately and efficiently in text. The proposed corpus and NER algorithms can be used for metabolomics text-mining tasks such as information retrieval, document classification and literature-based discovery.AvailabilityThe corpus and NER algorithms are freely available with detailed instructions from Github at https://github.com/omicsNLP/MetaboliteNER.
Wide-field Calcium Imaging Reveals Widespread Changes in Cortical Connectivity Following Repetitive, Mild Traumatic Brain Injury in the Mouse
Authors: Cramer Samuel W. , Haley Samuel P. , Popa Laurentiu S. , Carter Russell E. , Scott Earl , Flaherty Evelyn B. , Dominguez Judith , Aronson Justin D. , Sabal Lukas , Surinach Daniel , Chen Clark C. , Kodandaramaiah Suhasa B. , Ebner Timothy J. 
Published: February 2022

AbstractThe physiologic basis underlying the long-term consequences of repetitive, mild traumatic brain injury (mTBI) remains poorly understood. Mild traumatic brain injury often results in brief loss of consciousness, impaired attention and concentration, memory problems, impulsivity, and headache, without objective findings on clinical imaging or examination. The effects of mTBI can persist and become cumulative with repetitive injury, suggesting global alterations in cortical networks. Using transparent polymer skulls, we performed mesoscopic Ca2+ imaging in mice to evaluate how repetitive mTBI alters patterns of neuronal interactions across the dorsal cerebral cortex. Spatial Independent Component Analysis (sICA) and Localized semi-Nonnegative Matrix Factorization (LocaNMF) were used to quantify changes in cerebral functional connectivity (FC). Repetitive, mild, controlled cortical impacts induce temporary neuroinflammatory responses, characterized by increased density of microglia exhibiting de-ramified morphology. These temporary neuro-inflammatory changes were not associated with compromised cognitive performance in the Barnes maze or motor function as assessed by rotarod. However, long-term alterations in functional connectivity were observed. Widespread, bilateral changes in FC occurred immediately following impact and persisted for up to 7 weeks, the duration of the experiment. Network alterations include decreases in global efficiency, clustering coefficient, and nodal strength, thereby disrupting functional interactions and information flow throughout the dorsal cerebral cortex. A subnetwork analysis shows the largest disruptions in FC were concentrated near the impact site. Therefore, repetitive mTBI induces a transient neuroinflammation, without alterations in cognitive or motor behavior, and a reorganized cortical network evidenced by the widespread, chronic alterations in cortical FC.Significance StatementMore than 2.5 million individuals in the United States suffer minor traumatic brain injuries annually. Because these injuries are typically not associated with visible anatomic injuries or objective clinical findings, they were thought benign and fully recoverable. However, there is increasing awareness of the long-term deleterious consequences, particularly in patients who suffer repeated mTBI. Using long-term, mesoscopic neuronal Ca2+ imaging to characterize the dorsal cerebral cortical connectome following repetitive mTBI, we show extensive, persistent changes in functional connectivity, not only at the site of injury but throughout the cortex. These findings provide new insights into the pathophysiology of mTBI.
First passage time analysis of spatial mutation patterns reveals evolutionary dynamics of pre-existing resistance in colorectal cancer
Authors: Haughey Magnus J. , Bassolas Aleix , Sousa Sandro , Baker Ann-Marie , Graham Trevor A. , Nicosia Vincenzo , Huang Weini 
Published: February 2022

AbstractThe footprint left by early cancer dynamics on the spatial arrangement of tumour cells is poorly understood, and yet could encode information about how therapy resistant sub-clones grew within the expanding tumour. Novel methods of quantifying spatial tumour data at the cellular scale are required to link evolutionary dynamics to the resulting spatial architecture of the tumour. Here, we propose a framework using first passage times of random walks to quantify the complex spatial patterns of tumour cell population mixing. First, using a toy model of cell mixing we demonstrate how first passage time statistics can distinguish between different pattern structures. We then apply our method to simulated patterns of wild-type and mutated tumour cell population mixing, generated using an agent-based model of expanding tumours, to explore how first passage times reflect mutant cell replicative advantage, time of emergence and strength of cell pushing. Finally, we analyse experimentally measured patterns of genetic point mutations in human colorectal cancer, and estimate parameters of early sub-clonal dynamics using our spatial computational model. We uncover a wide range of mutant cell replicative advantages and timings, with the majority of sampled tumours consistent with boundary driven growth or short-range cell pushing. By analysing multiple sub-sampled regions in a small number of samples, we explore how the distribution of inferred dynamics could inform about the initial mutational event. Our results demonstrate the efficacy of first passage time analysis as a new methodology for quantifying cell mixing patterns in vivo, and suggest that patterns of sub-clonal mixing can provide insights into early cancer dynamics.
Recombination smooths the time-signal disrupted by latency in within-host HIV phylogenies
Authors: Castro Lauren A. , Leitner Thomas , Romero-Severson Ethan 
Published: February 2022

AbstractWithin-host HIV evolution involves latency and re-activation of integrated provirus that has the potential to disrupt the temporal signal induced by the evolutionary race between host immune responses and viral evolution. Yet, within-host HIV phylogenies tend to show clear, ladder-like trees structured by the time of sampling. Recombination complicates this dynamic by allowing latent HIV viruses to re-integrate as fragments in the genomes of contemporary virus populations. That is, recombination violates the fundamental assumption made by the phylogenetic methods typically used to study within-host HIV sequence data that evolutionary history can be represented by a single bifurcating tree. In this paper we develop a coalescent-based simulator of within-host HIV evolution that includes, latency, recombination, and population dynamics that allows us to study the relationship between the true, complex genealogy of within-host HIV, encoded as an Ancestral Recombination Graph (ARG), and the observed phylogenetic tree. We show how recombination recovers the disruption of the temporal signal of within-host HIV evolution caused by latency by mixing fragments of ancestral, latent genomes into the contemporary population through recombination. In effect, recombination averages over extant heterogeneity, whether it stems from mixed time-signals or population bottlenecks. Further, we establish that the signals of latency and recombination can be observed in phylogenetic trees despite being an incorrect representation of the true evolutionary history. Using an Approximate Bayesian Computation method, we develop a set of statistical probes to tune our simulation model to nine longitudinally-sampled within-host HIV phylogenies, finding evidence for recombination rates at the lower end of published estimates and relatively small latent pool sizes ranging from about 1000 to 2500 cells.
Myopia alters the structural organization of the retinal astrocyte template, associated vasculature and ganglion layer thickness
Authors: Lin Carol , Toychiev Abduqodir , Slavi Nefeli , Ablordeppey Reynolds , Srinivas Miduturu , Benavente-Perez Alexandra 
Published: February 2022

AbstractPurposeTo describe the effect of myopic eye growth on the structure and distribution of astrocytes, vasculature and ganglion cell thickness, critical for inner retinal tissue homeostasis and survival.MethodsAstrocyte and capillary distribution, retinal nerve fiber (RNFL) and ganglion cell layer (GCL) thicknesses were assessed using immunochemistry and spectral domain optical coherence tomography on eleven retinas of juvenile common marmosets (Callithrix Jacchus), six of which were induced with lens-induced myopia (refraction, Rx: −7.01±1.8D). Five untreated age-matched juvenile marmoset retinas were used as controls (Rx: −0.74±0.4D).ResultsAs control marmoset eyes grew normally, there was an age-related increase in astrocyte numbers associated with RNFL thickening. Marmosets with induced myopia did not show this trend and, on the contrary, had reduced astrocyte numbers, increased positive GFAP immunopositive staining, thinner RNFL, lower peripheral capillary branching, and increased numbers of string vessels.ConclusionThe myopic changes in retinal astrocytes, vasculature, and ganglion cell layer thickness suggest a reorganization of the astrocyte and vascular templates during myopia development and progression. Whether these adaptations are beneficial or harmful to the retina remains to be investigated.Summary StatementThis article provides new information on how progressive myopia affects key elements of the retinal neurovascular unit.
PKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression
Authors: Lakhia Ronak , Ramalingam Harini , Chang Chun-Mien , Cobo-Stark Patricia , Biggers Laurence , Flaten Andrea , Alvarez Jesus , Valencia Tania , Wallace Darren P. , Lee Edmund , Patel Vishal 
Published: February 2022

ABSTRACTAutosomal dominant polycystic kidney disease (ADPKD), among the most common human genetic conditions and a frequent etiology of kidney failure, is primarily caused by heterozygous PKD1 mutations. Kidney cyst formation ensues when the PKD1 dosage falls below a critical threshold. However, no framework exists to harness the remaining allele or reverse PKD1 decline. Here, we show that mRNAs produced by the noninactivated PKD1 allele are cis-repressed via their 3’-UTR miR-17 binding element. Eliminating this motif (Pkd1Δ17) improves mRNA stability, raises Polycystin-1 levels, and alleviates cyst growth in cellular, ex vivo, and mouse PKD models. Remarkably, Pkd2 is also autoinhibited via its 3’-UTR miR-17 motif, and Pkd2Δ17-induced Polycystin-2 derepression partly compensates and retards cyst growth in Pkd1-mutant models. Moreover, acutely blocking Pkd1/2 cis-inhibition, including after cyst onset, attenuates murine PKD. Finally, PKD1Δ17 or PKD2Δ17 alleles revert cyst-pathogenic sequala in patient-derived primary ADPKD cultures. Thus, evading 3’-UTR cis-interference and enhancing PKD1/2 mRNA translation is a potentially mutation-agnostic ADPKD-arresting approach.
Long read mitochondrial genome sequencing using Cas9-guided adaptor ligation
Authors: Vandiver Amy R. , Pielstick Brittany , Gilpatrick Timothy , Hoang Austin N. , Vernon Hillary J. , Wanagat Jonathan , Timp Winston 
Published: February 2022

ABSTRACTThe mitochondrial genome (mtDNA) is an important source of disease-causing genetic variability, but existing sequencing methods limit understanding, precluding phased measurement of mutations and clear detection of large sporadic deletions. We adapted a method for amplification-free sequence enrichment using Cas9 cleavage to obtain full length nanopore reads of mtDNA. We then utilized the long reads to phase mutations in a patient with an mtDNA-linked syndrome and demonstrated that this method can map age-induced mtDNA deletions. We believe this method will offer deeper insight into our understanding of mtDNA variation.
Convergence of monosynaptic inputs from neurons in the brainstem and forebrain on parabrachial neurons that project to the paraventricular nucleus of the thalamus
Authors: Kirouac Gilbert J. , Li Sa , Li Shuanghong 
Published: February 2022

AbstractThe paraventricular nucleus of the thalamus (PVT) projects to areas of the forebrain involved in behavior. Homeostatic challenges and salient cues activate the PVT and evidence shows that the PVT regulates appetitive and aversive responses. The brainstem is a source of afferents to the PVT and the present study was done to determine if the lateral parabrachial nucleus (LPB) is a relay for inputs to the PVT. Retrograde tracing experiments with cholera toxin B (CTB) demonstrate that the LPB contains more PVT projecting neurons than other regions of the brainstem including the catecholamine cell groups. The hypothesis that the LPB is a relay for brainstem signals to the PVT was assessed using an intersectional monosynaptic rabies tracing approach. Sources of inputs included the reticular formation, periaqueductal gray (PAG), nucleus cuneiformis, superior and inferior colliculi, and the LPB. Distinctive clusters of input cells to LPB-PVT projecting neurons were also found in the dorsolateral bed nucleus of the stria terminalis (BSTDL) and the lateral central nucleus of the amygdala (CeL). Anterograde viral tracing demonstrates that LPB-PVT neurons densely innervate all of the PVT in addition to providing collateral innervation to the preoptic area, lateral hypothalamus, zona incerta and PAG but not the BSTDL and CeL. The paper discusses the anatomical evidence that suggests that the PVT is part of a network of interconnected neurons involved in arousal, homeostasis, and the regulation of behavioral states with forebrain regions potentially providing descending modulation or gating of signals relayed from the LPB to the PVT.
Vitronectin mediates survival of human WJ-MSCs under inflammatory temperature stress via cell cycle arrest
Authors: Goyal Umesh , Khader C Ashiq , Ta Malancha 
Published: February 2022

AbstractDue to their anti-inflammatory and immunomodulatory capabilities, mesenchymal stem cells (MSCs) are being widely used in cell-based therapies for the treatment of a wide spectrum of inflammatory disorders. Despite their promises, substantial cell loss post transplantation leads to compromised therapeutic benefits in clinical trials, which remains a challenge to overcome. Inflammatory microenvironment comprises the presence of pro-inflammatory cytokines, elevated temperature, etc., which could hamper MSC viability following transplantation. Thus, identifying the underlying molecular factors controlling survival mechanism under such stress conditions, thereby, improving MSC survival becomes important for optimising MSC-based therapy. Also, since MSCs from different origins have significantly varied biology, choosing the appropriate MSC source could be crucial in determining the fate of transplanted MSCs in stressful milieu.As extracellular matrix (ECM) components can mediate cell survival signals, in the present study, we have evaluated the role of ECM matricellular protein, vitronectin (VTN), in the survival of human umbilical cord-derived Wharton’s Jelly MSCs (WJ-MSCs) under the condition of inflammatory temperature stress. On exposure to 40°C, WJ-MSCs underwent cell cycle arrest with no significant change in viability status, along with an induction in VTN expression both at mRNA and protein levels. Interestingly, inhibition of pro-survival signalling pathways, ERK or PI3K, at 40°C led to further upregulation in VTN expression without any significant impact on viability or cell cycle arrest status. However, on knocking down VTN in WJ-MSCs at 40°C, decrease in viable population along with reversal of cell cycle arrest were noted. Moreover, inhibition of pro-survival pathways ERK or PI3K, in VTN knocked down WJ-MSCs at 40°C, led to a dramatic reduction in the viable population accompanied with reversal in cell cycle arrest.Altogether, our findings highlighted the protective role of VTN in mediating survival of WJ-MSCs under inflammatory temperature stress condition, by possibly involving autophagy as an underlying mechanism.
Regional and cell type-specific afferent and efferent projections of the mouse claustrum
Authors: Wang Quanxin , Wang Yun , Xie Peng , Kuo Hsien-Chi , Hirokawa Karla E , Naeemi Maitham , Yao Shenqin , Ouellette Ben , Mallory Matt , Lesnar Phil , Kuang Xiuli , Li Yaoyao , Ye Min , Chen Chao , Xiong Wei , Ahmadinia Leila , El-Hifnawi Laila , Cetin Ali , Harris Julie A , Zeng Hongkui , Koch Christof 
Published: February 2022

SummaryThe claustrum (CLA) is a conspicuous subcortical structure interconnected with cortical and subcortical regions. However, its regional anatomy and cell-type-specific connections in the mouse remain largely undetermined. Here, we accurately delineated the boundary of the mouse CLA and quantitatively investigated its inputs and outputs brain-wide using anterograde and retrograde viral tracing and fully reconstructed single claustral principal neurons. At a population level, the CLA reciprocally connects with all isocortical modules. It also receives inputs from at least 35 subcortical structures but sends projections back to only a few of them. We found that cell types projecting to the CLA are differentiated by cortical areas and layers. We classified single CLA principal neurons into at least 9 cell types that innervate the diverse sets of functionally linked cortical targets. Axons of interneurons within the CLA arborize along almost its entire anteroposterior extent. Together, this detailed wiring diagram of the cell-type-specific connections of the mouse CLA lays a foundation for studying its functions.
Functional definition of thyroid hormone response elements based on a synthetic STARR-seq screen
Authors: Flamant Frédéric , Guyot Romain 
Published: February 2022

AbstractWhen bound to thyroid hormone, the nuclear receptor TRα1 activates the transcription of a number of genes in many cell types. It mainly acts by binding DNA as an heterodimer with RXRs at specific response elements related to the DR4 consensus sequence. However, the number of DR4-like elements in the genome exceed by far the number of occupied sites, indicating that minor variations in nucleotides composition deeply influence the DNA-binding capacity and transactivation activity of TRα1. An improved protocol of synthetic STARR-seq was used to quantitatively assess the transcriptional activity of thousands of synthetic sites in parallel. This functional screen highlights a strong correlation between the affinity of the heterodimers for DNA and their capacity to mediate the thyroid hormone response.
Single-cell analysis of skeletal muscle macrophages reveals age-associated functional subpopulations
Authors: Krasniewski Linda K. , Chakraborty Papiya , Cui Chang-Yi , Mazan-Mamczarz Krystyna , Dunn Christopher , Piao Yulan , Fan Jinshui , Shi Changyou , Wallace Tonya , Nguyen Cuong , Rathbun Isabelle A. , Munk Rachel , Tsitsipatis Dimitrios , De Supriyo , Sen Payel , Ferrucci Luigi , Gorospe Myriam 
Published: February 2022

AbstractTissue-resident macrophages represent a group of highly responsive innate immune cells that acquire diverse functions by polarizing towards distinct subgroups. The subgroups of macrophages that reside in skeletal muscle (SKM) and their changes during aging are poorly characterized. By single-cell transcriptomic analysis, we found that mouse SKM macrophages primarily comprise two large populations, “healing” LYVE1+ and “proinflammatory” LYVE1-macrophages. SKM macrophages were further classified into four functional subgroups based on the expression levels of another cell-surface marker, MHCII: LYVE1+/MHCII-lo (similar to alternatively activated M2), LYVE1-/MHCII-hi (similar to classically activated M1), and two new subgroups, LYVE1+/MHCII-hi and LYVE1-/MHCII-lo. Notably, the new subgroup LYVE1+/MHCII-hi had traits of both M2 and M1 macrophages, while the other new subgroup, LYVE1-/MHCII-lo, expressed high levels of mRNAs encoding cytotoxicity proteins. Flow cytometric analysis validated the presence of the four macrophage subgroups in SKM. In old SKM, LYVE1-macrophages were more abundant than LYVE1+ macrophages. Furthermore, complementary unsupervised classification revealed the emergence of specific macrophage subclusters expressing abundant proinflammatory markers, including S100a8 and S100a9 in aged SKM. In sum, our study has identified dynamically polarized mouse SKM macrophages and further uncovered the contribution of specific macrophage subpopulations to the proinflammatory status in old SKM.
Neutral sphingomyelinase 1 regulates cellular fitness at the level of ER stress and cell cycle
Authors: Choezom Dolma , Gross Julia Christina 
Published: February 2022

AbstractNeutral sphingomyelinase 1 (nSMase1) belongs to the sphingomyelinase enzyme family that hydrolyzes sphingomyelin to produce signaling active lipid ceramide and phosphorylcholine. The molecular characterization and biological function of nSMase1 remain poorly studied. Here, we report that nSMase1 (gene name: SMPD2) knockdown reduces LAMP1 at the mRNA levels and is required for initiating a full-potential unfolded protein response under ER stress. Additionally, SMPD2 KD dramatically reduces the global protein translation rate. We further show that SMPD2 KD cells are arrested in the G1 phase of the cell cycle and that two important cell cycle regulating processes - PI3K/Akt pathway and Wnt signaling pathway are altered. Taken together, we propose a role for nSMase1 in buffering ER stress and modulating cellular fitness via cell cycle regulation.