bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-Omic Signatures of Sarcoidosis and Progression in Bronchoalveolar Lavage Cells
Authors: Konigsberg Iain R. , Lin Nancy W. , Liao Shu-Yi , Liu Cuining , MacPhail Kristyn , Mroz Margaret M. , Davidson Elizabeth , Restrepo Clara I. , Sharma Sunita , Li Li , Maier Lisa A. , Yang Ivana V. 
Published: January 2023

AbstractIntroductionSarcoidosis is a heterogeneous, granulomatous disease that can prove difficult to diagnose, with no accurate biomarkers of disease progression. Therefore, we profiled and integrated the DNA methylome, mRNAs, and microRNAs to identify molecular changes associated with sarcoidosis and disease progression that might illuminate underlying mechanisms of disease and potential genomic biomarkers.MethodsBronchoalveolar lavage cells from 64 sarcoidosis subjects and 16 healthy controls were used. DNA methylation was profiled on Illumina HumanMethylationEPIC arrays, mRNA by RNA-sequencing, and miRNAs by small RNA-sequencing. Linear models were fit to test for effect of diagnosis and phenotype, adjusting for age, sex, and smoking. We built a supervised multi-omics model using a subset of features from each dataset.ResultsWe identified 46,812 CpGs, 1,842 mRNAs, and 5 miRNAs associated with sarcoidosis versus controls and 1 mRNA,SEPP1- a protein that supplies selenium to cells, associated with disease progression. Our integrated model emphasized the prominence of the PI3K/AKT1 pathway in sarcoidosis, which is important in T cell and mTOR function. Novel immune related genes and miRNAs includingLYST, RGS14, SLFN12L, and hsa-miR-199b-5p, distinguished sarcoidosis from controls. Our integrated model also demonstrated differential expression/methylation ofIL20RB, ABCC11, SFSWAP, AGBL4, miR-146a-3p, and miR-378b between non-progressive and progressive sarcoidosis.ConclusionsLeveraging the DNA methylome, transcriptome, and miRNA-sequencing in sarcoidosis BAL cells, we detected widespread molecular changes associated with disease, many which are involved in immune response. These molecules may serve as diagnostic/prognostic biomarkers and/or drug targets, although future testing will be required for confirmation.
Hyperextended telomeres promote C-circle formation in telomerase positive human cells
Authors: Jones Celina Y. , Williams Christopher L. , Moreno Sara P. , Morris Danna K. , Mondello Chiara , Karlseder Jan , Bertuch Alison A. 
Published: January 2023

ABSTRACTTelomere length maintenance is crucial to cancer cell immortality. Up to 15% of cancers utilize a telomerase-independent, recombination-based mechanism termed alternative lengthening of telomeres (ALT). The primary ALT biomarker is the C-circle, a type of circular DNA with extrachromosomal telomere repeats (cECTRs). How C-circles form is not well characterized. To investigate C-circle formation in telomerase+ cells, we studied the human cen3tel cell line, in which telomeres progressively hyper-elongated postTERT-immortalization. cECTR signal was observed in 2D gels and C-circle assays but not t-circle assays, which also detect cECTRs. Telomerase activity and C-circle signal were not separable in the analysis of clonal populations, consistent with C-circle production occurring within telomerase+ cells. Two other long telomere, telomerase+ (LTT+) cell lines, HeLa1.3 (~23 kb telomeres) and HeLaE1 (~50 kb telomeres), had similar cECTR properties. Telomerase activity did not directly impact C-circle signal in LTT+ cells; instead, C-circle signal correlated with telomere length. LTT+ lines were less sensitive to hydroxyurea than an ALT+ cell line, suggesting that ALT status is a stronger contributor to replication stress levels than telomere length. Additionally, FANCM did not suppress C-circles in LTT+ cells as it does in ALT+ cells. Thus, C-circle formation may be driven by telomere length, independently of telomerase and replication stress, highlighting limitations of C-circles as a stand-alone ALT biomarker.
Drosophila activins adapt gut size to food intake and promote regenerative growth
Authors: Christensen Christian F. , Laurichesse Quentin , Loudhaief Rihab , Colombani Julien , Andersen Ditte S. 
Published: January 2023

AbstractRapidly renewable tissues adapt different strategies to cope with environmental insults. While tissue repair is associated with increased ISC proliferation and accelerated tissue turnover rates, reduced calorie intake triggers a homeostasis-breaking process causing adaptive resizing of the gut. Here we show that activins are key drivers of both adaptive and regenerative growth. Activin-β (Act-β) is produced by progenitor cells in response to intestinal infections and stimulates ISC proliferation and turnover rates to promote tissue repair. Dawdle (Daw), a divergent Drosophila activin, signals through its receptor, BaboC, in progenitor cells to promote their maturation into enterocytes (ECs). Daw is dynamically regulated during starvation-refeeding cycles, where it couples nutrient intake with progenitor maturation and adaptive resizing of the gut. Our results highlight an activin-dependent mechanism coupling nutrient intake with progenitor-to-EC maturation to promote adaptive resizing of the gut and further establish activins as key regulators of adult tissue plasticity.
Activated Oncostatin M signaling drives cancer-associated skeletal muscle wasting
Authors: Domaniku Aylin , Agca Samet , Toledo Batu , Bilgic Sevval Nur , Kashgari Aynur Erkin , Kir Serkan 
Published: January 2023

SummaryProgressive weakness and muscle loss are associated with multiple chronic conditions including muscular dystrophy and cancer. Cancer-associated cachexia, characterized by dramatic weight loss and fatigue, leads to reduced quality of life and poor survival. Inflammatory cytokines have been implicated in muscle atrophy, however, available anti-cytokine therapies failed to prevent muscle wasting in cancer patients. We previously reported that muscle-specific deletion of the Oncostatin M (OSM) receptor (OSMR) preserved muscle mass and function in tumor-bearing mice. Here, we show that OSM is a potent inducer of muscle atrophy. OSM triggers cellular atrophy in primary myotubes utilizing the JAK/STAT3 pathway. Identification of OSM targets by RNA sequencing revealed the induction of various muscle atrophy-related genes, includingAtrogin1. OSM overexpression in mice caused muscle wasting while the neutralization of circulating OSM protected from tumor-driven loss of muscle mass and function. Our results indicate that activated OSM/OSMR signaling drives muscle atrophy, and the therapeutic targeting of this pathway may be useful in preventing muscle wasting.
Sequential restoring O2then unloading CO2is beneficial against reperfusion injury: role of CO2in metabolism
Authors: Liu Nan , Wang Lv , Xing Ying , Wang Chen 
Published: January 2023

AbstractCO2is one of main byproducts during mitochondrial oxidation. Under the acute occlusion of coronary artery situation, the intra-tissue pCO2of heart could be extremely high. This CO2accumulation will be acutely unloaded and discharged by blood reperfusion. However, the effect of this intra-tissue CO2accumulation then unloading process on cardiac ischemic reperfusion injury has not been well investigated yet. In the present study, we show that the perfusion with a high level of pCO2and normal pO2in the initial 30min followed by a 30min normal pCO2and normal pO2is better than the perfusion with 1h normal pCO2and normal pO2simultaneously during the reperfusion after a 45min global ischemia in isolated rat hearts. To observe the effect of high pCO2on cellular metabolism, we exposed C2C12 cells under about 370mmHg pCO2to observe the mitochondrial substrate switch and TCA cycle flux change, by using13C tracers. We show that a short time exposure to the extremely high level of pCO2is not completely destructive for cellular metabolism but has specific effects. The high pCO2inhibits pyruvate transport into mitochondria and the next oxidation, switching to more reliance on fatty acid oxidation and enhancing the glutamine oxidation to maintain the TCA cycle. Intriguingly, the high pCO2significantly activates the reductive carboxylation from glutamine, fixation of mitochondrial excessive CO2. The mechanism under the beneficial effect of the high-then-low CO2sequential reperfusion strategy is discussed further.
Early whole-body mutant huntingtin lowering averts changes in proteins and lipids important for synapse function and white matter maintenance in the LacQ140 mouse model
Authors: Shing Kai , Sapp Ellen , Boudi Adel , Liu Sophia , Seeley Connor , Marchionini Deanna , DiFiglia Marian , Kegel-Gleason Kimberly B. 
Published: January 2023

ABSTRACTBackgroundExpansion of a triplet repeat tract in exon1 of the HTT gene causes Huntington’s disease (HD). The mutant HTT protein (mHTT) has numerous aberrant interactions with diverse, pleiomorphic effects. No disease modifying treatments exist but lowering mutant huntingtin (mHTT) by gene therapy is a promising approach to treat Huntington’s disease (HD). It is not clear when lowering should be initiated, how much lowering is necessary and for what duration lowering should occur to achieve benefits. Furthermore, the effects of mHTT lowering on brain lipids have not been assessed.MethodsUsing a mHtt-inducible mouse model we analyzed whole body mHtt lowering initiated at different ages and sustained for different time-periods. Subcellular fractionation (density gradient ultracentrifugation), protein chemistry (gel filtration, western blot, and capillary electrophoresis immunoassay), liquid chromatography and mass spectrometry of lipids, and bioinformatic approaches were used to test effects of mHTT transcriptional lowering.ResultsmHTT protein in cytoplasmic and synaptic compartments of the caudate putamen, which is most affected in HD, was reduced 38-52%. Little or no lowering of mHTT occurred in nuclear and perinuclear regions where aggregates formed at 12 months of age. mHtt transcript repression partially or fully preserved select striatal proteins (SCN4B, PDE10A). Total lipids in striatum were reduced in LacQ140 mice at 9 months and preserved by early partial mHtt lowering. The reduction in total lipids was due in part to reductions in subclasses of ceramide (Cer), sphingomyelin (SM), and monogalactosyldiacylglycerol (MGDG), which are known to be important for white matter structure and function. Lipid subclasses phosphatidylinositol (PI), phosphatidylserine (PS), and bismethyl phosphatidic acid (BisMePA) were also changed in LacQ140 mice. Levels of all subclasses other than ceramide were preserved by early mHtt lowering. Pathway enrichment analysis of RNAseq data imply a transcriptional mechanism is responsible in part for changes in myelin lipids, and some but not all changes can be rescued by mHTT lowering.ConclusionsOur findings suggest that early and sustained reduction in mHtt can prevent changes in levels of select striatal proteins and most lipids but a misfolded, degradation-resistant form of mHTT hampers some benefits in the long term.
PortPred: exploiting deep learning embeddings of amino acid sequences for the identification of transporter proteins and their substrates
Authors: Anteghini Marco , dos Santos Vitor AP Martins , Saccenti Edoardo 
Published: January 2023

AbstractThe physiology of every living cell is regulated at some level by transporter proteins which constitute a relevant portion of membrane-bound proteins and are involved in the movement of ions, small and macromolecules across bio-membranes. The importance of transporter proteins is unquestionable. The prediction and study of previously unknown transporters can lead to the discovery of new biological pathways, drugs and treatments. Here we present PortPred, a tool to accurately identify transporter proteins and their substrate starting from the protein amino acid sequence. PortPred successfully combines pre-trained deep learning-based protein embeddings and machine learning classification approaches and outperforms other state-of-the-art methods. In addition, we present a comparison of the most promising protein sequence embeddings (Unirep, SeqVec, ProteinBERT, ESM-1b) and their performances for this specific task.
Building a Pangenome Alignment Index via Recursive Prefix-Free Parsing
Authors: Oliva Marco , Gagie Travis , Boucher Christina 
Published: January 2023

AbstractMotivationPangenomics alignment has emerged as an opportunity to reduce bias in biomedical research. Traditionally, short read aligners—such as Bowtie and BWA—were used to index a single reference genome, which was then used to find approximate alignments of reads to that genome. Unfortunately, these methods can only index a small number of genomes due to the linear-memory requirement of the algorithms used to construct the index. Although there are a couple of emerging pangenome aligners that can index a larger number of genomes more algorithmic progress is needed to build an index for all available data.ResultsEmerging pangenomic methods include VG, Giraffe, and Moni, where the first two methods build an index a variation graph from the multiple alignment of the sequences, and Moni simply indexes all the sequences in a manner that takes the repetition of the sequences into account. Moni uses a preprocessing technique calledprefix-free parsingto build a dictionary and parse from the input—these, in turn, are used to build the main run-length encoded BWT, and suffix array of the input. This is accomplished in linear space in the size of the dictionary and parse. Therein lies the open problem that we tackle in this paper. Although the dictionary scales nicely (sub-linear) with the size of the input, the parse becomes orders of magnitude larger than the dictionary. To scale the construction of Moni, we need to remove the parse from the construction of the RLBWT and suffix array. We accomplish this, in this paper by applying prefix-free parsing recursively on the parse. Although conceptually simple, this leads to an algorithmic challenge of constructing the RLBWT and suffix array without access to the parse. We solve this problem, implement it, and demonstrate that this improves the construction time by a factor of 8.9 the running time and by a factor of 2.7 the memory required.AvailabilityOur implementation is open source and available athttps://github.com/marco-oliva/r-pfbwt.ContactMarco Oliva atmarco.oliva@ufl.edu
Electrophysiological signatures of veridical head direction in humans
Authors: Griffiths Benjamin J. , Schreiner Thomas , Schaefer Julia K. , Vollmar Christian , Kaufmann Elisabeth , Quach Stefanie , Remi Jan , Noachtar Soheyl , Staudigl Tobias 
Published: January 2023

AbstractInformation about heading direction is critical for navigation as it provides the means to orient ourselves in space. However, given that veridical head direction signals require physical rotation of the head and most human neuroimaging experiments depend upon fixing the head in position, little is known about how the human brain is tuned to such heading signals. To address this, we asked fifty-two healthy participants undergoing simultaneous EEG and motion tracking recordings (split into two experiments) and ten patients undergoing simultaneous intracranial EEG and motion tracking recordings to complete a series of orientation tasks in which they made physical head rotations to target positions. We then used a series of forward encoding models and linear mixed-effects models to isolate electrophysiological activity that was specifically tuned to heading direction. We identified a robust posterior central signature that predicts changes in veridical head orientation after regressing out confounds including sensory input and muscular activity. Both source localisation and intracranial analysis implicated the medial temporal lobe as the origin of this effect. Subsequent analyses disentangled head direction signatures from signals relating to head rotation and those reflecting location-specific effects. Lastly, when directly comparing head direction and eye gaze-related tuning, we found that the brain maintains both codes while actively navigating, with stronger tuning to head direction in the medial temporal lobe. Together, these results reveal a taxonomy of population-level head direction signals within the human brain that is reminiscent of those reported in the single units of rodents.
Costimulatory domains direct distinct fates of CAR-driven T cell dysfunction
Authors: Selli Mehmet Emrah , Landmann Jack H. , Terekhova Marina , Lattin John , Heard Amanda , Hsu Yu-Sung , Chang Tien-Ching , Chang Jufang , Warrington John , Ha Helen , Kingston Natalie , Hogg Graham , Slade Michael , Berrien-Elliot Melissa M. , Foster Mark , Kersting-Schadek Samantha , Gruszczynska Agata , DeNardo David , Fehniger Todd A. , Artyomov Maxim , Singh Nathan 
Published: January 2023

AbstractChimeric antigen receptor (CAR) engineered T cells often fail to enact effector functions after infusion into patients. Understanding the biological pathways that lead CAR T cells to failure is of critical importance in the design of more effective therapies. We developed and validated anin vitromodel that drives T cell dysfunction through chronic CAR activation and interrogated how CAR costimulatory domains contribute to T cell failure. We found that dysfunctional CD28-based CARs targeting CD19 bear hallmarks of classical T cell exhaustion while dysfunctional 41BB-based CARs are phenotypically, transcriptionally and epigenetically distinct. We confirmed activation of this unique transcriptional program in CAR T cells that failed to control clinical disease. Further, we demonstrate that 41BB-dependent activation of the transcription factor FOXO3 is a significant contributor to this dysfunction and disruption ofFOXO3improves CAR T cell function. These findings identify that chronic activation of 41BB leads to novel state of T cell dysfunction that can be alleviated by genetic modification of FOXO3.SummaryChronic stimulation of CARs containing the 41BB costimulatory domain leads to a novel state of T cell dysfunction that is distinct from T cell exhaustion.
Cytokines reprogram airway sensory neurons in asthma
Authors: Crosson Théo , Bhat Shreyas , Wang Jo-Chiao , Salaun Clara , Fontaine Eleanne , Roversi Katiane , Herzog Herbert , Rafei Moutih , Blunck Rikard , Talbot Sebastien 
Published: January 2023

ABSTRACTNociceptor neurons play a crucial role in maintaining the body’s homeostasis by detecting and responding to potential dangers in the environment. However, this function can be detrimental during allergic reactions, since vagal nociceptors can contribute to immune cell infiltration, bronchial hypersensitivity, and mucus imbalance, in addition to causing pain and coughing. Despite this, the specific mechanisms by which nociceptors acquire pro-inflammatory characteristics during allergic reactions are not yet fully understood. In this study, we aimed to investigate the molecular profile of airway nociceptor neurons during allergic airway inflammation and identify the signals driving such reprogramming. Using retrograde tracing and lineage reporting, we identified a unique class of inflammatory vagal nociceptor neurons that exclusively innervate the airways. In the ovalbumin mouse model of airway inflammation, these neurons undergo significant reprogramming characterized by the upregulation of the NPY receptorNpy1r. A screening of cytokines and neurotrophins revealed that IL-1β, IL-13 and BDNF drive part of this reprogramming. IL-13 triggeredNpy1roverexpression in nociceptors via the JAK/STAT6 pathway. In parallel, sympathetic neurons and macrophages release NPY in the bronchoalveolar fluid of asthmatic mice, which limits the excitability of nociceptor neurons. Single-cell RNA sequencing of lung immune cells has revealed that a cell-specific knockout of Npy1r in nociceptor neurons in asthmatic mice leads to an increase in airway inflammation mediated by T cells. Opposite findings were observed in asthmatic mice in which nociceptor neurons were chemically ablated. In summary, allergic airway inflammation reprograms airway nociceptor neurons to acquire a pro-inflammatory phenotype, while a compensatory mechanism involving NPY1R limits nociceptor neurons’ activity.
PP1β opposes classic PP1 function, inhibiting spine maturation and promoting LTP
Authors: Foley Karl , McKee Cody , Mayer Abigail , Ganguly Archan , Barnett Daniel , Ward Nancy , Zhang Yu , Nairn Angus C. , Xia Houhui 
Published: January 2023

SummaryProtein phosphatase 1 (PP1) regulates synaptic plasticity and has been described as a molecular constraint on learning and memory. There are three neuronal isoforms, PP1α, PP1β, and PP1γ, but little is known about their individual functions. PP1α and PP1γ are assumed to mediate the effects of PP1 on learning and memory based on their enrichment at dendritic spines and their preferential binding to neurabin and spinophilin, major PP1 synaptic scaffolding proteins. However, it was recently discovered that human de novo PP1β mutations cause intellectual disability, suggesting an important but ill-defined role for PP1β. In this study, we investigated the functions of each PP1 isoform in hippocampal synaptic physiology using conditional CA1-specific knockout mice. In stark contrast to classic PP1 function, we found that PP1β promotes synaptic plasticity as well as spatial memory. These changes in synaptic plasticity and memory are accompanied by changes in GluA1 phosphorylation, GluN2A levels, and dendritic spine density and morphology, including silent synapse number. These functions of PP1β reveal a previously unidentified signaling pathway regulating spine maturation and plasticity, broadening our understanding of the complex role of PP1 in synaptic physiology.
Senescence of cortical neurons following persistent DNA double-strand breaks induces cerebrovascular lesions
Authors: Kopsidas Caroline A. , Lowe Clara C. , Zhang Jun , Kang Wenjun , Zhou Xiaoming , Feng Yuanyi 
Published: January 2023

AbstractDNA double strand breaks (DSBs), neuroinflammation, and vascular alterations in the brain are all associated with neurodegenerative disorders. However, the interconnections between these neuropathological changes and how they act synergistically to promote irreversible neurodegeneration remain unclear. Here we show that abrogating the BRCA1-associated protein Brap in cerebral cortical neurons, as opposed to vascular endothelium cells, causes cerebrovascular defects. This non-cell autonomous effect is mediated by cellular senescence resulting from persistent neuronal DSBs. We show that in the state of senescence, there is a massive upregulation of genes involved in cell secretion, inflammatory responses, and vascular changes, which coincides with cerebral microclots and microbleeds. The vascular lesions intertwine with neuroinflammation and exacerbate neuronal DSBs, culminating in oxidative stress, metabolic alteration, and downregulation of genes essential for neuronal function. By demonstrating the cerebrovascular impact of cortical neuronal DSBs, our data suggest that senescence-associated secretory phenotype can initiate brain-wide neurodegeneration.