bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure
Authors: Berthiaume Andrée-Anne , Schmid Franca , Stamenkovic Stefan , Coelho-Santos Vanessa , Nielson Cara D. , Weber Bruno , Majesky Mark W. , Shih Andy Y. 
Published: May 2022

ABSTRACTDeterioration of brain capillary flow and architecture is a hallmark of aging and dementia. It remains unclear how loss of brain pericytes in these conditions contributes to capillary dysfunction. Here, we conduct cause-and-effect studies by optically ablating pericytes in adult and aged mice in vivo. Focal pericyte loss induces capillary dilation without blood-brain barrier disruption. These abnormal dilations are exacerbated in the aged brain, and result in increased flow heterogeneity in capillary networks. A subset of affected capillaries experience reduced perfusion due to flow steal. Some capillaries stall in flow and regress, leading to loss of capillary connectivity. Remodeling of neighboring pericytes restores endothelial coverage and vascular tone within days. Pericyte remodeling is slower in the aged brain, resulting in regions of persistent capillary dilation. These findings link pericyte loss to disruption of capillary flow and structure. They also identify pericyte remodeling as a therapeutic target to preserve capillary flow dynamics.
Focus-ISM for Sharp and Gentle Super-Resolved Microscopy
Authors: Tortarolo Giorgio , Zunino Alessandro , Fersini Francesco , Castello Marco , Piazza Simonluca , Sheppard Colin J.R. , Bianchini Paolo , Diaspro Alberto , Koho Sami , Vicidomini Giuseppe 
Published: May 2022

AbstractSuper-resolution microscopy is routinely used for fixed and thin samples, while its feasibility for imaging live and thick samples is still limited. In the case of stimulated emission depletion (STED) microscopy, the high-intensity illumination required to achieve effective sub-diffraction resolution can introduce photo-damage, thus reducing the compatibility of the technique with live-cell imaging. Moreover, the out-of-focus fluorescence background may overcome the often faint signal stemming from the focal point, thus constraining imaging to thin samples. Here, we combined STED microscopy with image-scanning microscopy (ISM) to mitigate these limitations without any practical disadvantages. We first enhanced a laser scanning microscope (LSM) by introducing a detector array, hence providing access to a set of additional spatial information that is not available with a typical single-element detector. Then, we exploited this extended dataset to implement focus-ISM, a novel method that relaxes the high-intensity requirement of STED microscopy and removes the out-of-focus background. Additionally, we generalized the focus-ISM method to conventional LSM, namely without a STED beam. The proposed approach requires minimal architectural changes compared with conventional STED microscopes but provides substantial advantages for live and thick sample imaging while maintaining all compatibility with all recent advances in STED and confocal microscopy. As such, focus-ISM represents an essential step towards a universal super-resolved LSM technique for subcellular imaging.
PILS proteins provide a homeostatic feedback on auxin signaling output
Authors: Feraru Elena , Feraru Mugurel I. , Moulinier-Anzola Jeanette , Schwihla Maximilian , Ferreira Da Silva Santos Jonathan , Sun Lin , Waidmann Sascha , Korbei Barbara , Kleine-Vehn Jürgen 
Published: May 2022

AbstractAuxin is a crucial regulator of plant growth and development. Multiple internal and external signals converge at the regulation of auxin metabolism, intercellular transport, and signaling (Pernisova and Vernoux, 2021; Anfang and Shani, 2021). Considering this complexity, it remains largely unknown how plant cells monitor and ensure the homeostasis of auxin responses. PIN-LIKES (PILS) intracellular auxin transport facilitators at the endoplasmic reticulum (ER) are suitable candidates to buffer cellular auxin responses, because they limit nuclear abundance and signaling of auxin (Barbez et al., 2012; Beziat et al., 2017; Feraru et al., 2019; Sun et al., 2020). We used forward genetics to identify mechanisms that define the PILS6 protein abundance and thereby auxin signaling outputs. We screened for gloomy and shiny pils (gasp) mutants that define the levels of PILS6-GFP under a constitutive promoter. In this study, we show that GASP1 encodes for an uncharacterized RING/U-box superfamily protein and impacts on auxin signaling output. We conclude that the low auxin signaling in gasp1 mutants correlates with reduced abundance of PILS proteins, such as PILS5 and PILS6, which consequently balances auxin-related phenotypes. In agreement, we show that high and low auxin conditions increase and reduce PILS6 protein levels, respectively. Accordingly, non-optimum auxin concentrations are buffered by alterations in PILS6 abundance, consequently leading to homeostatic auxin output regulation. We envision that this feedback mechanism provides robustness to auxin-dependent plant development.
Genomic analyses identify significant biological processes in DDX21-mediated colorectal cancer cells
Authors: Wang Xueying , Zhang Donghong , Wang Mengshan 
Published: May 2022

AbstractColorectal cancer is the third most common cancer in the US. There has been an incline in the number of young patients with colorectal cancer due to unclear reasons at this point in time. Currently, DEAD-box RNA helicase protein DDX21 is identified as a prognosis marker for early-stage colorectal cancer. However, the mechanism of DDX21 mediated-colorectal cancer is still unknown. Here, our objective is to determine the key molecules and signaling by analyzing the RNA-seq data. The GSE184726 was created by the Illumina NovaSeq 6000 (Homo sapiens). The KEGG and GO analyses indicated Neuroactive ligand−receptor interaction and Ras signaling pathway were the key signaling pathways during the knockdown of DDX21 in colorectal cancer. Moreover, we identified several interactive genes including PTPRC, FN1, ITGAM, RAD51, TRAF6, CCNB1, FOXP3, CCNA2, HIST2H2AC, and HSPA5. Our study may provide new insights into the treatment of colorectal cancer.
Matrix obstructions cause multiscale disruption in collective epithelial migration by suppressing physical function of leader cells
Authors: Lee Ye Lim , Mathur Jairaj , Walter Christopher , Zmuda Hannah , Pathak Amit 
Published: May 2022

AbstractCellular forces and intercellular cooperation generate collective cell migration. Pathological changes in cell-level genetic and physical properties cause jamming, unjamming, and scattering in epithelial migration. Separately, changes in microenvironment stiffness and confinement can produce varying modes of cell migration. However, it remains unclear whether and how mesoscale disruptions in matrix topology alter collective cell migration. To address this question, we microfabricated matrices with stumps of defined geometry, density, and orientation, which serve as obstructions in the path of collectively migrating healthy mammary epithelial cells. Here, we show that cells lose their speed and directionality when moving through dense obstructions, compared to those sparsely spaced. On flat surfaces, leader cells are significantly stiffer than follower cells, while dense obstructions lead to the overall softening of cells. In moving through dense obstructions, epithelial cells lose the sense of leaders and followers in their physical properties, migration phenotypes, and fluidity. Although Rac inhibition reduces obstruction sensitivity, loss of cell-cell cooperation and induction of leader-like phenotype via α-catenin depletion eliminates the effect of matrix obstructions on epithelial migration. Through a lattice-based model, we identify cellular protrusions, polarity, and leader-follower communication as key mechanisms for obstruction-sensitive collective cell migration. Together, microscale cytoskeletal response, mesoscale softening and disorder, and macroscale multicellular communication enable epithelial cell populations to sense topological obstructions encountered in challenging environments. These results reveal that cohesive, healthy populations are more obstruction sensitive than the dysfunctional, aggressive ones. The ‘obstruction-sensitivity’ could add to the emerging disease ‘mechanotypes’ such as cell stiffness and traction forces.
MCIBox: A Toolkit for Single-molecule Multi-way Chromatin Interaction Visualization and Micro-Domains Identification
Authors: Tian Simon Zhongyuan , Li Guoliang , Ning Duo , Jing Kai , Xu Yewen , Yang Yang , Fullwood Melissa J. , Yin Pengfei , Huang Guangyu , Plewczynski Dariusz , Wang Wenxin , Zhai Jixian , Wang Ziying , Dai Ziwei , Lin Yuxin , Chen Wei , Zheng Meizhen 
Published: May 2022

SUMMARYThe emerging ligation-free three-dimensional (3D) genome mapping technologies can identify multiplex chromatin interactions with single-molecule precision. These technologies offer new insight into high-dimensional chromatin organization and gene regulation, but also introduce new challenges in data visualization and analysis. To overcome these challenges, we developed MCIBox, a toolkit for Multi-way Chromatin Interaction (MCI) analysis, including a visualization tool and a platform for identifying micro-domains with clustered single-molecule chromatin complexes. MCIBox is based on various clustering algorithms integrated with dimensionality reduction methods that can display multiplex chromatin interactions at single-molecule level, allowing users to explore chromatin extrusion patterns and super-enhancers regulation modes in transcription, and to identify single-molecule chromatin complexes that are clustered into micro-domains. Furthermore, MCIBox incorporates a two-dimensional kernel density estimation algorithm to identify micro-domains boundaries automatically. These micro-domains were stratified with distinctive signatures of transcription activity and contained different cell cycle associated genes. MCIBox could potentially distinguish the specificity of single-molecule chromatin interaction patterns in various phases of a cell cycle or cell types.
Adaptation of the eyes of grass puffer (Takifugu niphobles) to the riverine and marine environments
Authors: Osada Misa , Terai Yohey 
Published: May 2022

AbstractMany marine fish species migrate to rivers, but little is known about whether these species switch their vision when inhabiting rivers or adapt their vision to the environment of both rivers and the sea. Grass puffer (Takifugu niphobles) is a marine fish species frequently migrating to rivers. In this study, we investigated grass puffers from riverine and marine populations and analyzed the gene expression in their eyes. The phylogeny and population genetics of riverine and marine grass puffers indicated that riverine and marine grass puffers are from the same population. Gene expression levels by high-throughput RNA sequencing indicated no differences in the expression patterns of vision-related genes in marine and riverine grass puffers. This result indicates that the adaption of their visual system to both marine and riverine environments rather than switching the expression of vision-related genes. Additionally, riverine grass puffers increase the expression levels of heat shock proteins and related genes. These genes showed higher expression in riverine grass puffer than in other marine and river pufferfish species, suggesting that the grass puffer individuals adapt to the environmental difference when they migrate to the river by increasing the expression levels of heat shock protein and related genes.
Experimental Guidance for Discovering Genetic Networks through Iterative Hypothesis Reduction on Time Series
Authors: Cummins Breschine , Motta Francis C. , Moseley Robert C. , Deckard Anastasia , Campione Sophia , Gedeon Tomáš , Mischaikow Konstantin , Haase Steven B. 
Published: May 2022

AbstractLarge programs of dynamic gene expression, like cell cyles and circadian rhythms, are controlled by a relatively small “core” network of transcription factors and post-translational modifiers, working in concerted mutual regulation. Recent work suggests that system-independent, quantitative features of the dynamics of gene expression can be used to identify core regulators. We introduce an approach of iterative network hypothesis reduction from time-series data in which increasingly complex features of the dynamic expression of individual, pairs, and entire collections of genes are used to infer functional network models that can produce the observed transcriptional program. The culmination of our work is a computational pipeline, Iterative Network Hypothesis Reduction from Temporal Dynamics (Inherent Dynamics Pipeline), that provides a priority listing of targets for genetic perturbation to experimentally infer network structure. We demonstrate the capability of this integrated computational pipeline on synthetic and yeast cell-cycle data.Author SummaryIn this work we discuss a method for identifying promising experimental targets for genetic network inference by leveraging different features of time series gene expression data along a chained set of previously published software tools. We aim to locate small networks that control oscillations in the genome-wide expression profile in biological functions such as the circadian rhythm and the cell cycle. We infer the most promising targets for further experimentation, emphasizing that modeling and experimentation are an∗Corresponding author: breschine.cummins@montana.edu essential feedback loop for confident predictions of core network structure. Our major offering is the reduction of experimental time and expense by providing targeted guidance from computational methods for the inference of oscillating core networks, particularly in novel organisms.
Independent Replication and Drug-specificity of an Antidepressant Response Polygenic Risk Score
Authors: Lin Bochao , Arns Martijn , Rutten Bart , Gordon Evian , Luykx Jurjen J. 
Published: May 2022

AbstractWe here examine associations of a recently published polygenic risk score of antidepressant response (PRS-AR) with antidepressant treatment outcomes (remission and depression score change) in an independent clinical trial. We not only replicate the PRS-AR for escitalopram, but also find antidepressant interaction effects, suggesting drug-specificity of PRS-AR. We therefore also tested the utility of this PRS-AR to stratify between antidepressants and demonstrate a 14% increase in remission rate (from 43.6% to 49.7%), relative to the randomized remission rate.
Genetically determining individualized clinical reference ranges for the biomarker tryptase can limit unnecessary procedures and unmask myeloid neoplasms
Authors: Chovanec Jack , Tunc Ilker , Hughes Jason , Halstead Joseph , Mateja Allyson , Liu Yihui , O’Connell Michael P. , Kim Jiwon , Park Young Hwan , Wang Qinlu , Le Quang , Pirooznia Mehdi , Trivedi Neil N. , Bai Yun , Yin Yuzhi , Hsu Amy P. , McElwee Josh , Lassiter Sheryce , Nelson Celeste , Bandoh Judy , DiMaggio Thomas , Šelb Julij , Rijavec Matija , Carter Melody C. , Komarow Hirsh D. , Sabato Vito , Steinberg Joshua , Hafer Kurt M. , Feuille Elizabeth , Hourigan Christopher S. , Lack Justin , Khoury Paneez , Maric Irina , Zanotti Roberta , Bonadonna Patrizia , Schwartz Lawrence B. , Milner Joshua D. , Glover Sarah C. , Ebo Didier G. , Korošec Peter , Caughey George H. , Brittain. Erica H. , Busby Ben , Metcalfe Dean D. , Lyons Jonathan J. 
Published: May 2022

ABSTRACTSerum tryptase is a biomarker used to aid in the identification of certain myeloid neoplasms, most notably systemic mastocytosis, where baseline (BST) levels >20 ng/mL are a minor criterion for diagnosis. Whereas clonal myeloid neoplasms are rare, the common cause for elevated BST is the genetic trait hereditary alpha-tryptasemia (HαT) caused by increased germline TPSAB1 copy number. To date, the precise structural variation and mechanism(s) underlying elevated BST in HαT and the general clinical utility of tryptase genotyping, remain undefined. Through cloning, long-read sequencing, and assembling of the human tryptase locus from an individual with HαT, and validating our findings in vitro and in silico, we demonstrate that BST elevations arise from over-expression of replicated TPSAB1 loci encoding wild-type α-tryptase due to co-inheritance of a linked over-active promoter element. Modeling BST levels based upon TPSAB1 replication number we generate new individualized clinical reference values for the upper limit of ‘normal’. Using this personalized laboratory medicine approach, we demonstrate the clinical utility of tryptase genotyping, finding that in the absence of HαT, BST levels >11.4 ng/mL frequently identify indolent clonal mast cell disease. Moreover, substantial BST elevations (e.g., >100 ng/mL) which would ordinarily prompt bone marrow biopsy, can result from TPSAB1 replications alone and thus be within ‘normal’ limits for certain individuals with HαT.
Therapeutic effects of PTCD and ERCP in patients with obstructive severe acute biliary pancreatitis
Authors: Zhang Xue Ling , Sun Jia Huan , Wu Yue , Xie Min , Li Cong Cong , Lv Dong , Yu Wei , Cui Pei Lin 
Published: May 2022

AbstractObjectiveWe evaluated the therapeutic effects of PTCD and ERCP in patients with obstructive severe acute biliary pancreatitis (SABP).MethodsA total of 62 patients with obstructive SABP were enrolled in this study from July 2013 to July 2019 and divided into three groups: PTCD group (n=22), ERCP group (n=24) and conservative group (n=16). Based on treatment time, PTCD and ERCP groups were further separated into early (⩽ 72 h) and delayed (>72 h) groups. Laboratory indices, hospitalization days, recovery of liver functions and remission of abdominal pain as well as complications were evaluated to establish the efficacy and suitable time.ResultsThe average hospitalization days, time for abdominal pain relief and laboratory indices (leukocyte, blood amylase, ALT and TBiL) recovery were shorter (p<0.05) in PTCD and ERCP groups. The average hospitalization days for the ERCP group (16.71±3.99) were shorter, compared to the PTCD group (19.64±4.27) (p<0.05). Complications were few in ERCP (33.33%) and PTCD (27.27%) groups. The average length of stay (13.88±3.27), recovery time of leukocyte (6.31±0.92) and TBiL (9.13±1.98) in the early ERCP group were shorter than in both delayed ERCP and early PTCD groups (p<0.05). The average length of stay (18.63±4.06) and ALT recovery time (12.25±2.59) in delayed ERCP group were shorter than in delayed PTCD group (p<0.05).ConclusionsBoth ERCP and PTCD are effective for relieving biliary obstruction during SABP, and early ERCP or PTCD within 72 h for obstructive SABP are more beneficial.
H4K16ac activates the transcription of transposable elements and contributes to their cis-regulatory function
Authors: Pal Debosree , Patel Manthan , Boulet Fanny , Sundarraj Jayakumar , Grant Olivia A , Branco Miguel R. , Basu Srinjan , Santos Silvia , Zabet Nicolae Radu , Scaffidi Paola , Pradeepa Madapura M 
Published: May 2022

AbstractMammalian genomes harbour a large number of transposable elements (TEs) and their remnants. Many epigenetic repression mechanisms are known to silence TE transcription. However, TEs are upregulated during early development, neuronal lineage, and cancers, although the epigenetic factors contributing to the transcription of TEs have yet to be fully elucidated. Here we demonstrated that the male-specific lethal (MSL) complex mediated acetylation of histone H4 lysine 16 (H4K16ac) activates transcription of long interspersed nuclear elements (LINE1, L1) and long terminal repeats (LTRs). Furthermore, we show that the H4K16ac marked L1 and LTR subfamilies function as enhancers and are enriched with chromatin features associated with active enhancers and looping factors. L1 and LTRs enriched with histone acetylations are bound by chromatin looping factors and these regions loop with genes. CRISPR-based epigenetic perturbation and genetic deletion of L1s reveal that H4K16ac marked L1s and LTRs regulate the expression of genes in cis. Overall, TEs enriched with H4K16ac contribute to the cis-regulatory landscape of a significant portion of the mammalian genome by maintaining an active chromatin landscape at TEs.One Sentence SummaryH4K16ac activates LINE1 and ERV/LTR transcription and rewires the cis-regulatory landscape of a significant portion of the mammalian genome by increasing the transcriptional activity at TEs.
Robustness of the autophagy pathway to somatic copy number losses
Authors: Polo Pierfrancesco , Gremke Niklas , Stiewe Thorsten , Wanzel Michael 
Published: May 2022

AbstractAutophagy allows cells to temporarily tolerate energy stress by replenishing critical metabolites through self-digestion, thereby attenuating the cytotoxic effects of anticancer drugs that target tumor metabolism. Autophagy defects could therefore mark a metabolically vulnerable cancer state and open a therapeutic window. While mutations of autophagy genes (ATGs) are notably rare in cancer, haploinsufficiency network analyses across many cancers have shown that the autophagy pathway is frequently hit by somatic copy number losses of ATGs likeMAP1LC3B/ATG8F(LC3),BECN1/ATG6(Beclin-1), andATG10. Here, we used CRISPR/Cas9 technology to delete increasing numbers of copies of one or more of these ATGs in non-small cell lung cancer cells and examined the effects on sensitivity to compounds targeting aerobic glycolysis, a hallmark of cancer metabolism. Whereas complete knock-out of one ATG blocked autophagy and led to profound metabolic vulnerability, this was not the case for combinations of different non-homozygous deletions. In cancer patients, the effect of ATG copy number loss was blunted at the protein level and did not lead to accumulation of p62 as a sign of reduced autophagic flux. Thus, the autophagy pathway is shown to be markedly robust and resilient, even with concomitant copy number loss of key autophagy genes.
Ablation of palladin in adult heart causes dilated cardiomyopathy associated with intercalated disc abnormalities
Authors: Mastrototaro Giuseppina , Carullo Pierluigi , Zhang Jianlin , Scellini Beatrice , Piroddi Nicoletta , Nemska Simona , Filomena Maria Carmela , Serio Simone , Otey Carol A , Tesi Chiara , Emrich Fabian , Linke Wolfgang A. , Poggesi Corrado , Boncompagni Simona , Bang Marie-Louise 
Published: May 2022

AbstractPalladin (PALLD) belongs to the PALLD/myopalladin (MYPN)/myotilin family of actin-associated immunoglobulin-containing proteins in the sarcomeric Z-line. PALLD is ubiquitously expressed in several isoforms and its longest 200 kDa isoform, predominantly expressed in striated muscle, shows high structural homology to MYPN. MYPN gene mutations are associated with human cardiomyopathies, whereas the role of PALLD in the heart has remained unknown, partly due to embryonic lethality of PALLD knockout mice. In a yeast two-hybrid screening, CARP/Ankrd1 and FHOD1 were identified as novel interaction partners of PALLD’s N-terminal region. To study the role of PALLD in the heart, we generated conditional (cPKO) and inducible (cPKOi) cardiomyocyte-specific PALLD knockout mice. While cPKO mice exhibited no pathological phenotype, ablation of PALLD in adult cPKOi mice caused progressive cardiac dilation and systolic dysfunction, associated with reduced cardiomyocyte contractility, intercalated disc abnormalities, and fibrosis, demonstrating that PALLD is essential for normal cardiac function. Double cPKO and MYPN knockout mice exhibited a similar phenotype as MKO mice, suggesting that MYPN does not compensate for the loss of PALLD in cPKO mice. Transcript levels of MYPN and the PALLD long isoform were significantly increased in myocardial tissue from human dilated cardiomyopathy patients, suggesting a role of PALLD in cardiac disease.