bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome dilution by cell growth drives starvation-like proteome remodeling in mammalian and yeast cells
Authors: Lanz Michael C. , Zhang Shuyuan , Swaffer Matthew P. , Ziv Inbal , Götz Luisa Hernández , McCarty Frank , Jarosz Daniel F. , Elias Joshua E. , Skotheim Jan M. 
Published: October 2023

SUMMARYCell size is tightly controlled in healthy tissues and single-celled organisms, but it remains unclear how size influences cell physiology. Increasing cell size was recently shown to remodel the proteomes of cultured human cells, demonstrating that large and small cells of the same type can be biochemically different. Here, we corroborate these results in mouse hepatocytes and extend our analysis using yeast. We find that size-dependent proteome changes are highly conserved and mostly independent of metabolic state. As eukaryotic cells grow larger, the dilution of the genome elicits a starvation-like proteome phenotype, suggesting that growth in large cells is limited by the genome in a manner analogous to a limiting nutrient. We also find that this phenomenon explains many proteomic changes ascribed to yeast aging. Overall, our data suggest that genome concentration is a universal determinant of proteome content in growing cells.
TFEB degradation is regulated by an IKK/β-TrCP2 phosphorylation-ubiquitination cascade
Authors: Xiong Yan , Sharma Jaiprakash , Young Meggie N. , Xiong Wen , Jazayeri Ali , Poncha Karl F. , Ilagan Ma. Xenia G. , Wang Qing , Zheng Hui , Young Nicolas L. , Sardiello Marco 
Published: October 2023

ABSTRACTTranscription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy that plays a key role in the regulation of cellular clearance pathways. TFEB is regulated via a complex array of post-translational modifications (PTMs), but the exact molecular mechanism that regulates TFEB stability has remained elusive. Here, we show that TFEB levels are critically regulated by a defined phosphorylation-ubiquitination cascade. A human kinome screen identifies IKK (inhibitor of κB kinase) as a TFEB modifier, and a combination of phosphorylation assays, mass spectrometry analyses, and site-specific mutagenesis unveils a previously unrecognized TFEB phospho-degron (423SPFPSLS429) as the target of IKK. We show that IKK-mediated phosphorylation of TFEB triggers ubiquitination of adjacent lysine residues (K430 and K431) by the E3 ligase β-TrCP2 (β-Transducin repeat-containing protein 2), thereby tagging TFEB for degradation. Modified TFEB constructs that abolish these PTMs show much increased stability and expression levels but remain equally sensitive to autophagy- or stress- related stimuli while maintaining the capability to promote the expression of TFEB target genes and the clearance of Alzheimer’s associated tau in a cellular model of disease. Our results therefore uncover an IKK/β-TrCP2 phosphorylation-ubiquitination cascade as a major mechanism that governs TFEB stability independently of other TFEB regulators.
Liver regeneration by a population of midzone-located mesenchymal-hepatocyte hybrid cells
Authors: Yu Guo , Zhang Shaoyang , Romo Ana , Biswas Soma , Li Baojie , Li Jing 
Published: October 2023

AbstractRegenerative medicine relies on deep understanding of the mechanisms of organ repair and regeneration. The liver, an organ with critical metabolic functions carried out by hepatocytes located in zones 1-3 of liver lobules, has the capacity to fully regenerate itself, which is mainly attributable to midzone hepatocytes. Yet, how differentiated midzone hepatocytes execute transzone regeneration and quickly recover most of the liver mass remains a myth. Here, we uncover a mesenchymal-hepatocyte population (13.7% of total hepatocytes) that are derived from Twist2-lineage EpCAM+progenitors, midzone-located, highly polyploidy, and equipped with great mitogenic and migratory capabilities to the detriment of metabolism. They regenerate about 50% of new hepatocytes and repopulate zones 1 and 3 in liver regeneration. Mechanistically, expansion of these cells is negatively controlled by Notch1 signaling. This study has thus uncovered a hepatocyte subpopulation with great proliferation potential and important mechanisms of liver regeneration.
A comparison of fMRI presurgical mapping techniques with intraoperative brain mapping-based validation
Authors: Radwan Ahmed M. , Emsell Louise , Vansteelandt Kristof , Cleeren Evy , Peeters Ronald , De Vleeschouwer Steven , Theys Tom , Dupont Patrick , Sunaert Stefan 
Published: October 2023

AbstractIntroductionResting-state functional MRI (rs-fMRI) could enable preoperative risk assessment and intraoperative guidance for patients who cannot undergo task-based fMRI (tbfMRI). We investigated differences in accuracy between tbfMRI and rsfMRI acquired with single (sTE) at voxel size of 2mm and 3mm, and multi-echo (mTE) scans using intraoperative mapping with direct electrical stimulations (DES) as the ground truth.Material and methodsFunctional sensory-motor mapping results of hands and feet were spatially compared relative to positive (pDES, functional effect) and negative (nDES, no functional effect) coordinates in 16 preoperative patients. General linear model analysis was used for tbfMRI, and seed-based analysis (SBA) for rsfMRI. Minimum Euclidean distances between fMRI and DES were calculated and compared between fMRI methods. Receiver-operating characteristic (ROC) curves were used to compare accuracy and determine distance cutoffs for fMRI agreement with DES, and binary agreement rates were compared at different cutoffs. Two-part mixed-effects linear models were used to compare fMRI methods while accounting for unequal inter-subject DES repetition.ResultsOnly minor differences were found between fMRI methods in unthresholded distances (mean differences ∼ 2 mm). ROCs and binary agreement measures showed comparable accuracy for tbfMRI and sTE-rsfMRI 2mm, but mildly worse for sTE-rsfMRI 3mm and mTE-rsfMRI. However, differences in relative accuracy between sTE- and mTE-rsfMRI were minor when the same distance cutoff was applied to all methods. This was also reflected on comparing rates of binary agreement and confirmed by the two-part linear models, which showed no significant differences between fMRI methods and a significant effect of DES response.ConclusionThe similar accuracy for SBA rsfMRI functional sensory-motor mapping compared to tbfMRI for the hands and feet, indicate that rsfMRI may be suitable for presurgical mapping. The differences in relative accuracy between sTE- and mTE rsfMRI warrant further investigation in a larger sample.
Separating representational and noise components of speech prosody perception after stroke
Authors: Zarrabi Aynaz Adl , Jeulin Mélissa , Bardet Pauline , Commère Pauline , Naccache Lionel , Aucouturier JJ , Ponsot Emmanuel , Villain Marie 
Published: October 2023

AbstractAfter a right hemisphere stroke, more than half of the patients are impaired in their capacity to produce or comprehend speech prosody. Yet, and despite its social-cognitive consequences for patients, aprosodia following stroke has received scant attention. In this report, we introduce a novel, simple psychophysical procedure which, by combining systematic digital manipulations of speech stimuli and reverse-correlation analysis, allows estimating the internal sensory representations that subtend how individual patients perceive speech prosody, and the level of internal noise that govern behavioral variability in how patients apply these representations. Tested on a sample of N=22 right-hemisphere stroke survivors and N=12 healthy controls, the representation+noise model provides a promising alternative to the clinical gold standard for evaluating aprosodia (MEC): both parameters strongly associate with receptive, and not expressive, aprosodia measured by MEC within the patient group; they have better sensitivity than MEC for separating high-functioning patients from controls; and have good specificity with respect to non-prosody-related impairments of auditory attention and processing. Taken together, individual differences in either internal representation, internal noise, or both, paint a potent portrait of the variety of sensory/cognitive mechanisms that can explain impairments of prosody processing after stroke.
Mechanism and cellular function of direct membrane binding by the ESCRT and ERES-associated Ca2+-sensor ALG-2
Authors: Shukla Sankalp , Chen Wei , Rao Shanlin , Yang Serim , Ou Chenxi , Larsen Kevin P. , Hummer Gerhard , Hanson Phyllis I. , Hurley James H. 
Published: October 2023

AbstractApoptosis Linked Gene-2 (ALG-2) is a multifunctional intracellular Ca2+sensor and the archetypal member of the penta-EF hand protein family. ALG-2 functions in the repair of damage to both the plasma and lysosome membranes and in COPII-dependent budding atendoplasmicreticulumexitsites (ERES). In the presence of Ca2+, ALG-2 binds to ESCRT-I and ALIX in membrane repair and to SEC31A at ERES. ALG-2 also binds directly to acidic membranes in the presence of Ca2+by a combination of electrostatic and hydrophobic interactions. By combining GUV-based experiments and molecular dynamics simulations, we show that charge-reversed mutants of ALG-2 at these locations disrupt membrane recruitment. ALG-2 membrane binding mutants have reduced or abrogated ERES localization in response to Thapsigargin-induced Ca2+release but still localize to lysosomes following lysosomal Ca2+release.In vitroreconstitution shows that the ALG-2 membrane-binding defect can be rescued by binding to ESCRT-I. These data thus reveal the nature of direct Ca2+-dependent membrane binding and its interplay with Ca2+-dependent protein binding in the cellular functions of ALG-2.
Dicer deficiency in microglia leads to accelerated demyelination and failed remyelination
Authors: Tripathi Ajai , Rai Nagendra , Perles Aaron , Jones Claire , Dutta Ranjan 
Published: October 2023

SummaryMicroglia are the resident immune cells of the central nervous system (CNS) and are important regulators of normal brain functions. In CNS demyelinating diseases like multiple sclerosis (MS), the functions of these cells are of particular interest. Here we probed the impact of microRNA (miRNA)-mediated post-transcriptional gene regulation using a mouse model lacking microglia/macrophage-specificDicerexpression during demyelination and remyelination. ConditionalDicerablation and loss of miRNAs in adult microglia led to extensive demyelination and impaired myelin processing. Interestingly, demyelination was accompanied by increased apoptosis of mature oligodendrocytes (OLs) and arresting OL progenitor cells (OPCs) in the precursor stage. At the transcriptional level,Dicer-deficient microglia led to downregulation of microglial homeostatic genes, increased cell proliferation, and a shift towards a disease-associated phenotype. Loss of remyelination efficiency in these mice was accompanied by stalling of OPCs in the precursor stage. Collectively, these results highlight a new role of microglial miRNAs in promoting a pro-regenerative phenotype in addition to promoting OPC maturation and differentiation during demyelination and remyelination.Graphical Abstract
Guanine quadruplexes mediate mitochondrial RNA polymerase pausing
Authors: Snyder Ryan , Delker Don , Burdick Joshua T , Cheung Vivian G. , Watts Jason A. 
Published: October 2023

AbstractThe information content within nucleic acids extends beyond the primary sequence to include secondary structures with functional roles in cells. Guanine-rich sequences form structures called guanine quadruplexes (G4) that result from non-canonical base pairing between guanine residues. These stable structures are enriched in gene promoters and have been correlated with the locations of RNA polymerase II pausing (Pol II). While promoter-proximal RNA polymerase pausing regulates gene expression, the effects of guanine quadruplexes on gene transcription have been less clear. We determined the pattern of mitochondrial RNA polymerase (mtRNAP) pausing in human fibroblasts and found that it pauses over 400 times on the mitochondrial genome. We identified quadruplexes as a mediator of mtRNAP pausing and show that stabilization of quadruplexes impeded transcription by mtRNAP. Gene products encoded by the mitochondrial genome are required for oxidative phosphorylation and the decreased transcription by mtRNAP resulted in lower expression of mitochondrial genes and significantly reduced ATP generation. Energy from mitochondria is essential for transport function in renal epithelia, and impeded mitochondrial transcription inhibits transport function in renal proximal tubule cells. These results link formation of guanine quadruplex structures to regulation of mtRNAP elongation and mitochondrial function.
De novogeneration of antibody CDRH3 with a pre-trained generative large language model
Authors: He Haohuai , He Bing , Guan Lei , Zhao Yu , Chen Guanxing , Zhu Qingge , Chen Calvin Yu-Chian , Li Ting , Yao Jianhua 
Published: October 2023

AbstractArtificial Intelligence (AI) techniques have made great advances in assisting antibody design. However, antibody design still heavily relies on isolating antigen-specific antibodies from serum, which is a resource-intensive and time-consuming process. To address this issue, we propose a Pre-trained Antibody generative large Language Model (PALM) for the de novo generation of artificial antibodies heavy chain complementarity-determining region 3 (CDRH3) with desired antigen-binding specificity, reducing the reliance on natural antibodies. We also build a high-precision model antigen-antibody binder (A2binder) that pairs antigen epitope sequences with antibody sequences to predict binding specificity and affinity. PALM-generated antibodies exhibit binding ability to SARS-CoV-2 antigens, including the emerging XBB variant, as confirmed throughin-silicoanalysis andin-vitroassays. Thein-vitroassays validated that PALM-generated antibodies achieve high binding affinity and potent neutralization capability against both wild-type and XBB spike proteins of SARS-CoV-2. Meanwhile, A2binder demonstrated exceptional predictive performance on binding specificity for various epitopes and variants. Furthermore, by incorporating the attention mechanism into the PALM model, we have improved its interpretability, providing crucial insights into the fundamental principles of antibody design.
N-acetyl Cysteine attenuates intrinsic functional connectivity, but not neural alcohol cue reactivity, in treatment-seeking individuals with alcohol use disorder
Authors: Logge Warren B , Haber Paul S , Hurzeler Tristan P , Towers Ellen E , Morley Kirsten C 
Published: October 2023

AbstractN-acetyl cysteine (NAC) is a potential pharmacotherapy for alcohol use disorder (AUD), but it is not known whether it modulates neural activation to alcohol cues or intrinsic functional connectivity. We investigated whether NAC attenuates i) alcohol cue-elicited activation, and ii) intrinsic functional connectivity compared to placebo in patients with AUD. Twenty-three individuals (7 females) with moderate-severe AUD received daily NAC (2400 mg/day,n= 9), or a placebo (n= 14) for at least 2 weeks. Participants completed a pre-treatment functional magnetic resonance imaging session (T0) and a post-treatment session (T1) comprising a resting-state and visual alcohol cue reactivity task acquisitions. Activation differences between sessions, treatment, and session-by-treatment interaction were assessed. Resting-state functional connectivity examined using 376 node ROI-to-ROIs evaluated whether NAC reduced intrinsic functional connectivity after treatment. There were no differences in alcohol cue reactivity for brain activation or subjective craving between NAC and placebo during treatment or across sessions, or significant interaction. A significant treatment-by- time interaction, with reduced intrinsic connectivity was observed after treatment (T1) for NAC- treated compared to placebo-treated patients in the posterior cingulate node (9, left hemisphere) of the dorsal attentional network and connections to salience, ventral-attentional, somatosensory, and visual-peripheral networks implicated in AUD. NAC reduced intrinsic functional connectivity in patients with moderate-severe AUD after treatment compared to placebo, but did not attenuate alcohol cue-elicited activation. The reduced intrinsic functional connectivity pattern seen may signify reduced external processing of environmental alcohol cues, though no reduced visual cue reactivity associations were evidenced.
Deciphering the Effect of High-Density Lipoprotein Cholesterol on Renal Function: a Mendelian Randomization Study
Authors: Le Nhu Ngoc , Tran Tran Quoc Bao , Gill Dipender , Padmanabhan Sandosh 
Published: October 2023

AbstractBackgroundThe causal relationship between high-density lipoprotein cholesterol (HDL) and cardiovascular protection remains unresolved. Mounting evidence now points towards a link between lipid levels, including HDL, and renal function. However, previous epidemiological and animal studies provide a mixed picture. This study investigates the causal interplay between HDL and renal function by leveraging the specific and substantial increase in HDL achieved with cholesteryl ester transfer protein (CETP) inhibition.Method and ResultsTwo-sample and multivariable Mendelian randomization (MR) methods were used to explore the causal impact of HDL through genetically-proxied CETP inhibition on serum cystatin C-estimated glomerular filtration rate (eGFRcys). Secondary analyses delved into other renal markers and systolic blood pressure (SBP). Summary-based Mendelian Randomization (SMR) and genetic colocalisation analyses were used to evaluate the probability of shared causal variants within a 100Kb window of the gene.Genetically-proxied CETP inhibition, using HDL level as a biomarker, was linked to lower eGFRcys (effect size per 1 SD increase in HDL, −0.008, 95% CI −0.011 to - 0.005; p = 1.38 × 10−06) and reduced chronic kidney disease (CKD) risk (OR 0.895 [0.838, 0.956]; p = 0.001). The HDL-eGFRcys relationship persisted after adjusting for low-density lipoprotein cholesterol (LDL) and SBP in multivariable MR, but the association with CKD risk attenuated. Decreased CETP expression in blood was associated with lower eGFRcys (effect size per 1-SD, −0.008 [−0.016, −0.001]; pSMR= 0.029), a reduced CKD risk (OR, 0.85 [0.74, 0.98]; pSMR= 0.03), and lower SBP (−0.71 [−1.177, −0.244]; pSMR= 0.003). Colocalisation results indicated low posterior probabilities for both shared and distinct causal variants between CETP gene expression and eGFRcys.ConclusionMR analyses support a causal inverse relationship between HDL and eGFRcys that is independent of SBP. The results warrant further studies to validate the nuanced roles of HDL and LDL on renal function.
DNAm scores for serum GDF15 and NT-proBNP levels associate with a range of traits affecting the body and brain
Authors: Gadd Danni A. , Smith Hannah M. , Mullin Donncha , Chybowska Ola , Hillary Robert F. , Kimenai Dorien M , Bernabeu Elena , Cheng Yipeng , Fawns-Ritchie Chloe , Campbell Archie , Page Danielle , Taylor Adele , Corley Janie , Valdés-Hernández Maria Del C. , Maniega Susana Muñoz , Bastin Mark E. , Wardlaw Joanna M. , Walker Rosie M. , Evans Kathryn L. , McIntosh Andrew M. , Hayward Caroline , Russ Tom , Harris Sarah E. , Welsh Paul , Sattar Naveed , Cox Simon R. , McCartney Daniel L. , Marioni Riccardo E. 
Published: October 2023

AbstractBackgroundPlasma growth differentiation factor 15 (GDF15) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are cardiovascular biomarkers that associate with a range of diseases. Epigenetic scores (EpiScores) for GDF15 and NT-proBNP may provide new routes for risk stratification.ResultsIn the Generation Scotland cohort (N ≥ 16,963), GDF15 levels were associated with incident dementia, ischaemic stroke and type 2 diabetes, whereas NT-proBNP levels were associated with incident ischaemic heart disease, ischaemic stroke and type 2 diabetes (all PFDR< 0.05). Bayesian Epigenome-wide association studies (EWAS) identified 12 and 4 DNA methylation (DNAm) CpG sites associated (Posterior Inclusion Probability [PIP] > 95%) with levels of GDF15 and NT-proBNP, respectively. EpiScores for GDF15 and NT-proBNP that were trained in a subset of the population. The GDF15 EpiScore replicated protein associations with incident dementia, type 2 diabetes and ischaemic stroke in the Generation Scotland test set (Hazard Ratios (HR) range 1.36 – 1.41, PFDR<0.03). The EpiScore for NT-proBNP replicated the protein association with type 2 diabetes, but failed to replicate an association with ischaemic stroke. EpiScores explained comparable variance in protein levels across both the Generation Scotland test set and the external LBC1936 test cohort (R2range of 5.7-12.2%). In LBC1936, both EpiScores were associated with indicators of poorer brain health. Neither EpiScore was associated with incident dementia in the LBC1936 population.ConclusionsEpiScores for serum levels of GDF15 and Nt-proBNP associate with body and brain health traits. These EpiScores are provided as potential tools for disease risk stratification.
Approach in Inputs & Outputs Selection of Data Envelopment Analysis (DEA) Efficiency Measurement in Hospital: A Systematic Review
Authors: Zubir M Zulfakhar , Noor A Azimatun , Rizal AM Mohd , Harith A Aziz , Abas M Ihsannuddin , Zakaria Zuriyati , A.Bakar Anwar Fazal 
Published: October 2023

AbstractData Envelopment Analysis (DEA) has been employed as a performance evaluation tool in the evaluation of efficiency and productivity in numerous fields. This includes hospitals in particular as well as the broad healthcare industry. This review examines 89 papers that discuss the use of DEA in hospitals, paying particular attention to approaches for choosing inputs and outputs as well as the most recent developments in DEA studies. English articles with empirical data from year 2014-2022 (Web of Science, Scopus, PubMed, ScienceDirect, Springer Link, and Google Scholar) were extracted based on PRISMA methodology. DEA Model parameters were specified based on previous studies and approaches were identified narratively. The approaches can be grouped into four: (1) Literature review, (2) Data availability, (3) Systematic method and (4) Expert judgement. The approaches were applied as one strategy either by itself or in combination with others. This review’s emphasis on approaches used in hospital may constrain its conclusions. There might be another strategy or method used to select the input and output for a DEA study in a different area or strategies based on different viewpoints. The trend for DEA application were quite similar to previous studies. There is no evidence that one model fits all DEA model parameters better than another. Based on the reviewed literature, we offer some recommendations and methodological principles for DEA studies.