bluuebunny/crossref_metadata_2025_split huggingface dataset:
A general prediction model for substrates of transport proteins
Authors: Kroll Alexander , Niebuhr Nico , Butler Gregory , Lercher Martin J. 
Published: November 2023

ABSTRACTTransport proteins play a crucial role in cellular metabolism and are central to many aspects of molecular biology and medicine. Determining the function of transport proteins experimentally is challenging, as they become unstable when isolated from cell membranes. Machine learning-based predictions could provide an efficient alternative. However, existing methods are limited to predicting a small number of specific substrates or broad transporter classes. These limitations stem partly from using small datasets for model training and a choice of input features that lack sufficient information about the prediction problem. Here, we present SPOT, the first general machine learning model that can successfully predict specific substrates for arbitrary transport proteins, achieving an accuracy above 92% on independent and diverse test data covering widely different transporters and a broad range of metabolites. SPOT uses Transformer Networks to represent transporters and substrates numerically. To overcome the problem of missing negative data for training, it augments a large dataset of known transporter-substrate pairs with carefully sampled random molecules as non-substrates. SPOT not only predicts specific transporter-substrate pairs, but also outperforms previously published models designed to predict broad substrate classes for individual transport proteins. We provide a web server and Python function that allows users to explore the substrate scope of arbitrary transporters.
Substantial urbanization-driven declines of larval and adult moths in a subtropical environment
Authors: Belitz Michael W. , Sawyer Asia , Hendrick Lillian , Kawahara Akito , Guralnick Robert P. 
Published: November 2023

AbstractRecent work has shown the decline of insect abundance, diversity, and biomass, with potential implications for ecosystem services. These declines are especially pronounced in regions with high human activity, and urbanization is emerging as a significant contributing factor. However, the scale of these declines and the traits that determine variation in species-specific responses remain less well understood, especially in subtropical and tropical regions, where insect diversity is high and urban footprints are rapidly expanding. Here, we surveyed moths across an entire year in protected forested sites across an urbanization gradient to test how caterpillar and adult life stages of subtropical moths (Lepidoptera) are impacted by urbanization. Specifically, we assess how urban development affects the total abundance of caterpillars and adult moths, and quantify how richness and phylogenetic diversity of macro-moths are impacted by urban development. Additionally, we determine the effects of urban warming on species-specific adult macro-moth abundance while accounting for urban development and explore how life-history traits condition species’ responses to urban stressors. At the community level, we find that urban development decreases caterpillar biomass and adult moth abundance. We also find sharp declines of adults in response to urban development across the moth phylogeny, leading to a decrease in species richness and phylogenetic diversity in more urban sites. Finally, our study found that smaller macro-moths are less impacted by urban development than larger macro- moths in subtropical environments, perhaps highlighting the tradeoffs of metabolic costs of urban heat island effects favoring smaller moths over the relative benefits of dispersal for larger moths. In summary, our research underscores the far-reaching consequences of urbanization on moths and provides compelling evidence that urban forests alone may not be sufficient to safeguard biodiversity in cities.
Systems profiling reveals recurrently dysregulated cytokine signaling responses in ER+ breast cancer patients’ blood
Authors: Orcutt-Jahns Brian , Lima Junior Joao Rodrigues , Rockne Russell C. , Matache Adina , Branciamore Sergio , Hung Ethan , Rodin Andrei S. , Lee Peter P. , Meyer Aaron S. 
Published: November 2023

AbstractCytokines mediate cell-to-cell communication across the immune system and therefore are critical to immunosurveillance in cancer and other diseases. Several cytokines show dysregulated abundance or signaling responses in breast cancer, associated with the disease and differences in survival and progression. Cytokines operate in a coordinated manner to affect immune surveillance and regulate one another, necessitating a systems approach for a complete picture of this dysregulation. Here, we profiled cytokine signaling responses of peripheral immune cells from breast cancer patients as compared to healthy controls in a multidimensional manner across ligands, cell populations, and responsive pathways. We find alterations in cytokine responsiveness across pathways and cell types that are best defined by integrated signatures across dimensions. Alterations in the abundance of a cytokine’s cognate receptor do not explain differences in responsiveness. Rather, alterations in baseline signaling and receptor abundance suggesting immune cell reprogramming are associated with altered responses. These integrated features suggest a global reprogramming of immune cell communication in breast cancer.Significance StatementWhile individual cytokine responses have previously been observed to be altered in breast cancer, cytokine signaling responses are tightly interconnected in a way that has not been previously characterized. Here, we profile cytokine signaling responses and find alterations that are shared across both pathways and cell types. The signatures across these measurements better define the alterations and point to a broad immunosuppression response.HighlightsBaseline and post-stimulation cytokine signaling profiles differ between healthy donors and breast cancer patients.Changes in cytokine response are not explained by differences in abundance of the cognate receptorFeatures of signaling response and receptor abundance dysregulation are coordinated across patientsIntegrated patterns of dysregulation in breast cancer patients share features of Th17 like-response as well as regulatory-like B and CD8+T cells
LMO3 is a suppressor of the basal-like/squamous PDAC subtype and reduces disease aggressiveness of pancreatic cancer through glycerol 3-phosphate metabolism
Authors: Ohara Yuuki , Craig Amanda J. , Liu Huaitian , Yang Shouhui , Moreno Paloma , Dorsey Tiffany H. , Cawley Helen , Azizian Azadeh , Gaedcke Jochen , Ghadimi Michael , Hanna Nader , Ambs Stefan , Perwez Hussain S. 
Published: November 2023

AbstractPancreatic ductal adenocarcinoma (PDAC) encompasses diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, each exhibiting distinct characteristics, with the latter known for its aggressiveness. We employed an integrative approach combining transcriptomic and metabolomic analyses to pinpoint potential genes contributing to the basal-like/squamous subtype differentiation. Applying this approach to our NCI-UMD-German and a validation cohort, we identified LIM Domain Only 3 (LMO3), a transcription co-factor, as a candidate suppressor of the basal-like/squamous subtype. Reduced LMO3 expression was significantly associated with higher pathological grade, advanced disease stage, induction of the basal-like/squamous subtype, and decreased survival among PDAC patients.In vitroexperiments demonstrated thatLMO3transgene expression inhibited PDAC cell proliferation and migration/invasion, concurrently downregulating the basal-like/squamous gene signature. Metabolomic analysis of patient tumors and PDAC cells revealed a metabolic program linked to elevated LMO3 expression and the classical/progenitor subtype, characterized by enhanced lipogenesis and suppressed amino acid metabolism. Notably, glycerol 3-phosphate (G3P) levels positively correlated with LMO3 expression and associated with improved patient survival. Furthermore, glycerol-3-phosphate dehydrogenase 1 (GPD1), a crucial enzyme in G3P synthesis, showed upregulation in LMO3-high and classical/progenitor PDAC, suggesting its potential role in mitigating disease aggressiveness. Collectively, our findings suggest that heightened LMO3 expression reduces transcriptomic and metabolomic characteristics indicative of basal-like/squamous tumors with decreased disease aggressiveness in PDAC patients. The observations describe LMO3 as a candidate for diagnostic and therapeutic targeting in PDAC.Graphical abstractHighlightsLMO3 is downregulated in basal-like/squamous PDAC while its expression is maintained in the classical/progenitor PDAC subtypeUpregulated LMO3 expression correlates with improved PDAC survival and reduced proliferation and migration/invasion in PDAC cellsUpregulated LMO3 suppresses basal-like/squamous differentiation and induces a unique metabolic signature characterized by elevated lipogenesis and diminished amino acid metabolism, resembling the classical/progenitor PDAC subtypeEnhanced LMO3 expression associates with elevated glycerol 3-phosphate levels in PDAC, correlating with improved patient survival in PDAC
Chromosome-level genome assemblies of two hemichordates provide new insights into deuterostome origin and chromosome evolution
Authors: Lin Che-Yi , Marlétaz Ferdinand , Pérez-Posada Alberto , Martínez García Pedro Manuel , Schloissnig Siegfried , Peluso Paul , Conception Greg T. , Bump Paul , Chen Yi-Chih , Chou Cindy , Lin Ching-Yi , Fan Tzu-Pei , Tsai Chang-Tai , Gómez Skarmeta José Luis , Tena Juan J. , Lowe Christopher J. , Rank David R. , Rokhsar Daniel S. , Yu Jr-Kai , Su Yi-Hsien 
Published: November 2023

AbstractDeuterostomes are an animal superphylum that includes Hemichordata and Echinodermata (together Ambulacraria) and Chordata. The diversity of deuterostome body plans has made it challenging to reconstruct their ancestral condition and to decipher the genetic changes that drove the diversification of deuterostome lineages. Here, we generate chromosome-level genome assemblies of two hemichordate species,Ptychodera flavaandSchizocardium californicum, and use comparative genomic approaches to infer the chromosomal architecture of the deuterostome common ancestor and delineate lineage-specific chromosomal modifications. We show that hemichordate chromosomes (1N=23) exhibit remarkable chromosome-scale macrosynteny when compared to other deuterostomes, and can be derived from 24 deuterostome ancestral linkage groups (ALGs). These deuterostome ALGs in turn match previously inferred bilaterian ALGs, consistent with a relatively short transition from the last common bilaterian ancestor to the origin of deuterostomes. Based on this deuterostome ALG complement, we deduced chromosomal rearrangement events that occurred in different lineages. For example, a fusion-with-mixing event produced an Ambulacraria-specific ALG that subsequently split into two chromosomes in extant hemichordates, while this homologous ALG further fused with another chromosome in sea urchins. Orthologous genes distributed in these rearranged chromosomes are enriched for functions in various developmental processes. We found that the deeply conserved Hox clusters are located in highly rearranged chromosomes but have lower densities of transposable elements within the clusters. We also provide evidence that the deuterostome-specific pharyngeal gene cluster was established via the combination of three pre-assembled microsyntenic blocks. We suggest that since chromosomal rearrangement events and formation of new gene clusters may change the regulatory controls of developmental genes, these events may have contributed to the evolution of diverse body plans among deuterostomes.
Recruitment of FBXO22 for Targeted Degradation of NSD2
Authors: Nie David Y. , Tabor John R. , Li Jianping , Kutera Maria , St-Germain Jonathan , Hanley Ronan P. , Wolf Esther , Paulakonis Ethan , Kenney Tristan M.G. , Duan Shili , Shrestha Suman , Owens Dominic D.G. , Pon Ailing , Szewczyk Magdalena , Lamberto Anthony Joseph , Menes Michael , Li Fengling , Barsyte-Lovejoy Dalia , Brown Nicholas G. , Barsotti Anthony M. , Stamford Andrew W. , Collins Jon L. , Wilson Derek J. , Raught Brian , Licht Jonathan D. , James Lindsey I. , Arrowsmith Cheryl H. 
Published: November 2023

AbstractTargeted protein degradation (TPD) is an emerging therapeutic strategy that would benefit from new chemical entities with which to recruit a wider variety of ubiquitin E3 ligases to target proteins for proteasomal degradation. Here, we describe a TPD strategy involving the recruitment of FBXO22 to induce degradation of the histone methyltransferase and oncogene NSD2. UNC8732 facilitates FBXO22-mediated degradation of NSD2 in acute lymphoblastic leukemia cells harboring the NSD2 gain of function mutation p.E1099K, resulting in growth suppression, apoptosis, and reversal of drug resistance. The primary amine of UNC8732 is metabolized to an aldehyde species, which engages C326 of FBXO22 in a covalent and reversible manner to recruit the SCFFBXO22Cullin complex. We further demonstrate that a previously reported alkyl amine-containing degrader targeting XIAP is similarly dependent on SCFFBXO22. Overall, we present a highly potent NSD2 degrader for the exploration of NSD2 disease phenotypes and a novel FBXO22-dependent TPD strategy.
Mediterranean Diet Protects Against a Neuroinflammatory Cortical Transcriptome: Associations with Brain Volumetrics, Peripheral Inflammation, Social Isolation and Anxiety
Authors: Negrey Jacob D. , Frye Brett M. , Johnson Corbin S.C. , Kim Jeongchul , Barcus Richard A. , Lockhart Samuel N. , Whitlow Christopher T. , Sutphen Courtney , Chiou Kenneth L. , Snyder-Mackler Noah , Montine Thomas J. , Craft Suzanne , Shively Carol A. , Register Thomas C. 
Published: November 2023

AbstractINTRODUCTIONMediterranean diets may be neuroprotective and prevent cognitive decline relative to Western diets, however the underlying biology is poorly understood.METHODSWe assessed the effects of Western vs. Mediterranean-like diets on RNAseq generated transcriptional profiles in temporal cortex and their relationships with changes in MRI neuroimaging phenotypes, circulating monocyte gene expression, and observations of social isolation and anxiety in 38 socially-housed, middle-aged female cynomolgus macaques.RESULTSDiet resulted in differential expression of seven transcripts (FDR<0.05). Cyclin dependent kinase 14 (CDK14), a proinflammatory regulator, was lower in the Mediterranean group. The remaining six transcripts [i.e., “lunatic fringe” (LFNG), mannose receptor C type 2 (MRC2), solute carrier family 3 member 2 (SLCA32), butyrophilin subfamily 2 member A1 (BTN2A1), katanin regulatory subunit B1 (KATNB1), and transmembrane protein 268 (TMEM268)] were higher in cortex of the Mediterranean group and generally associated with anti-inflammatory/neuroprotective pathways.KATNB1encodes a subcomponent of katanin, important in maintaining microtubule homeostasis.BTN2A1is involved in immunomodulation of γδ T-cells which have anti-neuroinflammatory and neuroprotective effects.CDK14,LFNG,MRC2,andSLCA32are associated with inflammatory pathways. The latter four differentially expressed cortex transcripts were associated with monocyte transcript levels, changes in AD-relevant brain volumes determined by MRI over the course of the study, and social isolation and anxiety.CDK14was positively correlated with monocyte inflammatory transcripts, changes in total brain, gray matter, cortical gray matter volumes, and time alone and anxious behavior, and negatively correlated with changes in total white matter and cerebrospinal fluid (CSF) volumes. In contrast,LFNG,MRC2, andSLCA32were negatively correlated with monocyte inflammatory transcripts and changes in total gray matter volume, and positively correlated with CSF volume changes, and SLCA32 was negatively correlated with time alone.DISCUSSIONCollectively, our results suggest that relative to Western diets, Mediterranean diets confer protection against peripheral and central inflammation which is reflected in preserved brain structure and behavior.
Neuropeptide Signaling is Required to Implement a Line Attractor Encoding a Persistent Internal Behavioral State
Authors: Mountoufaris George , Nair Aditya , Yang Bin , Kim Dong-Wook , Anderson David J. 
Published: November 2023

ABSTRACTInternal states drive survival behaviors, but their neural implementation is not well understood. Recently we identified a line attractor in the ventromedial hypothalamus (VMH) that represents an internal state of aggressiveness. Line attractors can be implemented by recurrent connectivity and/or neuromodulatory signaling, but evidence for the latter is scant. Here we show that neuropeptidergic signaling is necessary for line attractor dynamics in this system, using a novel approach that integrates cell type-specific, anatomically restricted CRISPR/Cas9-based gene editing with microendoscopic calcium imaging. Co-disruption of receptors for oxytocin and vasopressin in adult VMH Esr1+neurons that control aggression suppressed attack, reduced persistent neural activity and eliminated line attractor dynamics, while only modestly impacting neural activity and sex- or behavior-tuning. These data identify a requisite role for neuropeptidergic signaling in implementing a behaviorally relevant line attractor. Our approach should facilitate mechanistic studies in neuroscience that bridge different levels of biological function and abstraction.
Sequential Modelling for Medical Image Segmentation
Authors: How Chun Hung , Rajapakse Jagath C. 
Published: November 2023

AbstractAn image can be seen as a long sequence of tokens with spatial structure hence an image segmentation task can be treated as a sequence-to-sequence task. Existing attention-based segmentation models have incorporated an up-sampling module at the pixel decoder, such design assumed the backbone to have multiple feature scales. Furthermore, the existing models did not emphasize the ability of sequential modelling for multi-tasking. In this paper, we propose to model image segmentation task as a long sequence prediction task with an improvisation on MegaByte. As MegaByte efficiently reduced the self-attention cost using multi-scale structure known as global and local models, we train two MegaByte models as an encoder and decoder for multi-tasking. Our multi-task model allows different segmentation tasks to be trained simultaneously and inferenced with a task prompt. The encoder takes in the image sequence to encode them as a key while the decoder takes in the conditional input as a query. As decoder conditional input is usually sparser than the image, we use a relatively shallow decoder. We demonstrate our method on segmentation of intracranial haemorrhages from computed tomography (CT) head scans and show comparable performance to existing models. On a brain tissue segmentation task on CT images, our method outperformed the existing methods especially on tiny structure.Clinical relevanceCT images are the first line of head scans when stroke or haemorrhage is suspected. Segmentation of intracranial haemorrhages (ICH) can provide clinicians with important measures of brain lesions to decide on treatment procedure or surgical decision. Brain and tissue volumes are indicative of neurodegenerative diseases. The proposed techniques can be used to segment ICH and brain tissues from CT head scans.
Sida cordifolia, a medicinal plant, is efficacious in models of Huntington’s disease by reducing ER stress
Authors: Simha Prasanna K , Mukherjee Chandramouli , Bhatia Karishma , Gupta Vikas Kumar , Sapariya Neerav M , Nagar Padmanabhi , Azim Nazeer ZA , Godbole Ashwini , Sahu Bhavani Shankar , Upadhyay Sanjeev K 
Published: November 2023

ABSTRACTBackground and aimHuntington’s Disease is a severe neurodegenerative disorder caused by misfolded mutant huntingtin proteins with expanded stretches of polyglutamines aggregating and destroying cells in the nervous system.Sida cordifoliaandAcorus calamusare medicinal plants used in traditional Ayurvedic medicine to treat neurological disorders. Here, we tested the effectiveness of extracts of both medicinal plants in decreasing aggregation of mutant huntingtin protein in models of Huntington’s Disease and explored the mode of action.Experimental procedureWe used two models, the nematodeCaenorhabditis elegansand a transgenic mouse neuroblastoma cell line, both expressing mutant huntingtin proteins with elongated polyglutamines. We assessed the effect ofSida cordifoliaandAcorus calamuson mutant huntingtin protein aggregation in both models, and additionally used the cell line for mechanistic studies to identify cellular pathways underlying the effects of treatment.Results and conclusionHere, we show that an extract ofSida cordifoliainhibits aggregation of mutant huntingtin proteins. In theC. elegansmodel, the extract prolonged life span and improved motility of the nematode by reducing aggregation of the mutant huntingtin protein.Acorus calamusdid not exhibit these effects. In the transgenic mouse neuroblastoma cell line, the extract decreased aggregation of the mutant huntingtin protein by suppressing key pathways in the ER stress response caused by the mutant protein. Our results highlight the potential therapeutic value ofSida cordifoliaand its promise as a source for novel medications.HighlightsSida cordifoliaextract reduces aggregates in HD model of transgenic wormsReduction in aggregates leads to improved motility and longevitySida cordifoliaextract reduces ER stress in cells expressing mHTT proteinFirst report on the pharmacology ofSida cordifoliain neurodegeneration
Generating, modeling, and evaluating a large-scale set of CRISPR/Cas9 off-target sites with bulges
Authors: Yaish Ofir , Orenstein Yaron 
Published: November 2023

The CRISPR/Cas9 system is a highly accurate geneediting technique, but it can also lead to unintended off-target sites (OTS). Consequently, many high-throughput assays have been developed to measure OTS in a genome-wide manner, and their data was used to train machine-learning models to predict OTS. However, these models are inaccurate when considering OTS with bulges due to limited data compared to OTS without bulges. Recently, CHANGE-seq, a newin vitrotechnique to detect OTS, was used to produce a dataset of unprecedented scale and quality. In addition, the same study producedin cellulaGUIDE-seq experiments, but none of these experiments included bulges. Here, we generated the most comprehensive GUIDE-seq dataset with bulges, and trained and evaluated state-of-the-art machine-learning models that consider OTS with bulges. We first reprocessed the publicly available experimental raw data of the CHANGE-seq study to gener-ate 20 new GUIDE-seq experiments, and hundreds of OTS with bulges among the original and new GUIDE-seq experiments. We then trained multiple machine-learning models, and demonstrated their state-of-the-art performance bothin vitroandin cellulaoverall and when focusing on OTS with bulges. Last, we visualized the key features learned by our models on OTS with bulges in a unique representation.Graphical abstract