bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Use of ctDNA to Identify Muscle-Invasive and Non-Organ Confined Upper Tract Urothelial Carcinoma
Authors: Huelster Heather L , Gould Billie , Schiftan Elizabeth A , Camperlengo Lucia , Davaro Facundo , Rose Kyle M , Soupir Alex C , Jia Shidong , Zheng Tiantian , Sexton Wade J , Pow-Sang Julio , Spiess Philippe E , Grass G. Daniel , Wang Liang , Wang Xuefeng , Vosoughi Aram , Necchi Andrea , Meeks Joshua J , Faltas Bishoy M , Du Pan , Li Roger 
Published: March 2023

ABSTRACTPURPOSEOptimal patient selection for neoadjuvant chemotherapy prior to surgical extirpation is limited by the inaccuracy of contemporary clinical staging methods in high-risk upper tract urothelial carcinoma (UTUC). We investigated whether the detection of plasma circulating tumor DNA (ctDNA) can predict muscle-invasive and non-organ confined (MI/NOC) UTUC.PATIENTS AND METHODSPlasma cell-free DNA was prospectively collected from chemotherapy-naïve, high-risk UTUC patients undergoing surgical extirpation and sequenced using a 152-gene panel and low-pass whole-genome sequencing. To test for concordance, whole exome sequencing was performed on matching tumor samples. The performance of ctDNA for predicting MI/NOC UTUC was summarized using area under a receiver-operating curve and the optimal variant count threshold determined using Younden’s J statistic. Kaplan-Meier methods estimated survival, and Mantel-Cox log-rank testing assessed the association between preoperative ctDNA positivity and clinical outcomes.RESULTSOf 30 patients prospectively enrolled, 14 were found to have MI/NOC UTUC. At least one ctDNA variant was detected from 21/30 (70%) patients with 52% concordance with matching tumor samples. Detection of at least two panel-based molecular alterations provided the optimal sensitivity and specificity to predict MI/NOC UTUC. Imposing this threshold in combination with a plasma copy number burden score >6.5 achieved a sensitivity of 79% and specificity of 94% in predicting MI/NOC UTUC. Furthermore, the presence of ctDNA was strongly prognostic for progression-free survival (1-yr PFS 69% vs. 100%, p<0.01) and overall survival (1-yr OS 56% vs. 100%, p<0.02).CONCLUSIONThe detection of plasma ctDNA prior to extirpative surgery was highly predictive of MI/NOC UTUC and strongly prognostic of PFS and OS. Preoperative ctDNA demonstrates promise as a biomarker for selecting patients to undergo neoadjuvant chemotherapy prior to nephroureterectomy.
Sex-specific difference of long-term mortality after transcatheter edge-to-edge repair for functional mitral regurgitation; Insights from the OCEAN-Mitral Registry
Authors: Hioki Hirofumi , Watanabe Yusuke , Kataoka Akihisa , Kozuma Ken , Shirai Shinichi , Naganuma Toru , Yamawaki Masahiro , Enta Yusuke , Mizuno Shingo , Ueno Hiroshi , Ohno Yohei , Nakajima Yoshifumi , Izumo Masaki , Bouta Hiroki , Kodama Kazuhisa , Yamaguchi Junichi , Kubo Shunsuke , Amaki Makoto , Asami Masahiko , Saji Mike , Mizutani Kazuki , Okazaki Shinya , Hachinohe Daisuke , Otsuka Toshiaki , Adachi Yuya , Yamamoto Masanori , Hayashida Kentaro 
Published: March 2023

AbstractBackgroundRecent studies suggested short-term mortality after transcatheter edge-to-edge repair (TEER) was comparable between male and female. However, the sex-specific prognostic difference in long-term follow-up after TEER is still unknown. To evaluate the impact of sex on long-term mortality after TEER for functional mitral regurgitation (FMR) using multicenter registry data.MethodsWe retrospectively analyzed 1220 patients (male 60.3%) who underwent TEER for FMR at 24 centers. Impact of sex on all-cause death and hospitalization for heart failure (HF) after TEER was evaluated using multivariate regression analysis and propensity score (PS) matching methods.ResultsDuring the two-year follow-up, 205 all-cause death and 259 hospitalizations for HF were observed after TEER for FMR. Male had a significantly lower incidence of all-cause death than female (18.7% vs. 14.0%, log-rank p < 0.01). After adjustment by multivariate Cox-regression and PS matching, male was significantly associated with a higher incidence of all-cause mortality after TEER than female (hazard ratio [HR] 2.24, 95% confidence interval [CI] 1.48 to 3.39 in multivariate Cox-regression; HR 2.04, 95% CI 1.17 to 3.57 in PS matching). The sex-specific prognostic difference was even more pronounced after 1-year of TEER. On contrary, there was no sex-related difference in hospitalization for HF after TEER.ConclusionsMale had a higher incidence of two-year all-cause death during after TEER for FMR than female, while this was not observed in hospitalization for HF. This result might indicate that female with FMR is more likely to benefit from TEER for better prognosis.What is known?There were conflicting results in sex-related prognostic difference after TEER for FMR.What the study addsDuring two-year follow-up period, male had higher increased risk of mortality after TEER than female in multivariate regression and propensity score matched analysis, while there was no sex-related difference in hospitalization for HF after TEER. Female with FMR might be likely to derived benefit from TEER concomitant with GDMT as compared to male.
Impact of Transjugular Intracardiac Echocardiography-Guided Self-Expandable Transcatheter Aortic Valve Implantation on Reduction of Conduction Disturbances
Authors: Ishizu Kenichi , Shirai Shinichi , Miyawaki Norihisa , Nakano Kenji , Fukushima Tadatomo , Ko Euihong , Tsuru Yasuo , Tashiro Hiroaki , Tabata Hiroyuki , Nakamura Miho , Morofuji Toru , Morinaga Takashi , Hayashi Masaomi , Isotani Akihiro , Ohno Nobuhisa , Kakumoto Shinichi , Ando Kenji 
Published: March 2023

AbstractBackgroundA high permanent pacemaker implantation (PPI) risk remain a concern of self-expandable transcatheter aortic valve implantation (TAVI), despite continued improvements in implantation methodology. We aimed to assess the impact of real-time direct visualization of the membranous septum using transjugular intracardiac echocardiography (ICE) during TAVI on reducing the rates of conduction disturbances including the need for PPI.MethodsConsecutive patients treated with Evolut R and Evolut PRO/PRO+ from February 2017 to September 2022 were included in this study. We compared outcomes between the conventional implantation method using the 3-cusps view (“3-cusps without ICE” group), the recent method using cusp-overlap view (“cusp-overlap without ICE” group), and our novel method using ICE (“cusp-overlap with ICE” group).ResultsOf the 446 patients eligible for analysis, 211 (47.3%) were categorized as the “3-cusps without ICE” group, 129 (28.9%) were in the “cusp-overlap without ICE” group, and 106 (23.8%) comprised the “cusp-overlap with ICE” group. Compared with the “3-cusps without ICE” group, the “cusp-overlap without ICE” group had a smaller implantation depth (2.2 [IQR 1.0–3.5] mm vs 4.3 [IQR: 3.3–5.4],P<0.001) and lower 30-day PPI rates (7.0% vs 14.2%,P= 0.035). Compared with the “cusp-overlap without ICE” group, the “cusp-overlap with ICE” group had lower 30-day PPI rates (1.0%,P= 0.014), albeit with comparable implantation depths (1.9 [IQR 0.9–2.9] mm,P= 0.150). Multivariable analysis showed that our novel method using ICE with the cusp-overlap view was independently associated with a 30-day PPI rate reduction. There were no group differences in 30-day all-cause mortality (1.4% vs 1.6% vs 0%;P= 0.254).ConclusionsOur novel implantation method using transjugular ICE, which enabled a real-time direct visualization of the membranous septum, achieved a predictably high position of prostheses, resulting in a substantial reduction of conduction disturbances requiring PPI after TAVI.
Biochemical reactions between intra-articular tissues and joint instability in a rat model of osteoarthritis
Authors: Murata Kenji , Kawabata Sora , Kojima Takuma , Oka Yuichiro , Takasu Chiharu , Terada Hidenobu , Kanemura Naohiko 
Published: March 2023

AbstractAimsJoint instability is associated with various joint conditions including osteoarthritis (OA) and inflammation, and we have developed model which is determined to role of knee instability. Investigating cartilage maintenance factors such as hyaluronic acid (HA) and glycosaminoglycans (GAGs) can provide insights into the effect of the mechanical stress and the inhibitor used, with the following aims: 1) whether cartilage degeneration is inhibited in the new model, 2) whether combination TGF-β1 inhibition mitigates cartilage degeneration, and to determine the role of TGF-β1 in synovitis using fibroblasts.Main methodsWe used this novel model to investigate inhibition of OA progression with a focus on HA and GAGs, which help maintain the cartilage and synovial membrane. In detail, mechanical tests, X-ray, histological, and protein and mRNA expression analyses were used to determine the role of joint stability using in vivo model or fibroblast from synovial membrane.Key findingsJoint stability mitigated cartilage degeneration loss, decreased osteophytes, increased the expression levels of HA and GAGs in the synovial membrane, and decreased the release of pro-inflammatory factors in rats. Moreover, injection of TGF-β1 inhibitor in an inflammatory synovial membrane promoted HA and GAGs expression. In synovial fibroblast cells, inhibition of TGF-β1 over expression significantly inhibited the downregulation of pro-inflammatory factors and promoted the upregulation of lubrification for cartilage.SignificanceOur results suggest that joint instability is an independent mechanical factor for OA progression. The results provide novel insights into the association between OA and joint instability, which has significant human sciences implications.Research Highlights• Established a new experimental rat model of the different joint instability for elucidate osteoarthritis onset/progression• Using Histological staining to investigated the osteoarthritis including synovitis and osteophytes of the novel model• Using fibroblast from synovial membrane to investigated the fibrosis• Joint instability exacerbates articular cartilage degeneration and decreases HA and GAGs protein expressions in synovial membrane• TGF-β1 inhibitor on early osteoarthritis joints may suppress synovial inflammation
Multiplex, single-cell CRISPRa screening for cell type specific regulatory elements
Authors: Chardon Florence M. , McDiarmid Troy A. , Page Nicholas F. , Daza Riza M. , Martin Beth , Domcke Silvia , Regalado Samuel G. , Lalanne Jean-Benoît , Calderon Diego , Li Xiaoyi , Starita Lea M. , Sanders Stephan J. , Ahituv Nadav , Shendure Jay 
Published: March 2023

AbstractCRISPR-based gene activation (CRISPRa) is a promising therapeutic approach for gene therapy, upregulating gene expression by targeting promoters or enhancers in a tissue/cell-type specific manner. Here, we describe an experimental framework that combines highly multiplexed perturbations with single-cell RNA sequencing (sc-RNA-seq) to identify cell-type-specific, CRISPRa-responsivecis-regulatory elements and the gene(s) they regulate. Random combinations of many gRNAs are introduced to each of many cells, which are then profiled and partitioned into test and control groups to test for effect(s) of CRISPRa perturbations of both enhancers and promoters on the expression of neighboring genes. Applying this method to a library of 493 gRNAs targeting candidatecis-regulatory elements in both K562 cells and iPSC-derived excitatory neurons, we identify gRNAs capable of specifically upregulating intended target genes and no other neighboring genes within 1 Mb, including gRNAs yielding upregulation of six autism spectrum disorder (ASD) and neurodevelopmental disorder (NDD) risk genes in neurons. A consistent pattern is that the responsiveness of individual enhancers to CRISPRa is restricted by cell type, implying a dependency on either chromatin landscape and/or additionaltrans-acting factors for successful gene activation. The approach outlined here may facilitate large-scale screens for gRNAs that activate therapeutically relevant genes in a cell type-specific manner.
Stable mammalian serum albumins designed for bacterial expression
Authors: Khersonsky Olga , Goldsmith Moshe , Zaretsky Irina , Hamer-Rogotner Shelly , Dym Orly , Unger Tamar , Yona Meital , Fridmann-Sirkis Yael , Fleishman Sarel J. 
Published: March 2023

AbstractAlbumin is the most abundant protein in the blood serum of mammals and has essential carrier and physiological roles. Albumins are also used in a wide variety of molecular and cellular experiments and in the cultivated meat industry. Despite their importance, however, albumins are challenging for heterologous expression in microbial hosts, likely due to 17 conserved intramolecular disulfide bonds. Therefore, albumins used in research and biotechnological applications either derive from animal serum, despite severe ethical and reproducibility concerns, or from recombinant expression in yeast or rice. We use the PROSS algorithm to stabilize human and bovine serum albumins, finding that all are highly expressed inE. coli. Design accuracy is verified by crystallographic analysis of a human albumin variant with 16 mutations. This albumin variant exhibits ligand binding properties similar to those of the wild type. Remarkably, a design with 73 mutations relative to human albumin exhibits over 40°C improved stability and is stable beyond the boiling point of water. Our results suggest that proteins with many disulfide bridges have the potential to exhibit extreme stability when subjected to design. The designed albumins may be used to make economical, reproducible, and animal-free reagents for molecular and cell biology. They also open the way to high-throughput screening to study and enhance albumin carrier properties.Graphical abstractHighlights-Computational design stabilized human and bovine serum albumins-Designs express solubly inE. coliand exhibit up to 40 °C increased thermostability-Some designs exhibit identical ligand binding properties-Crystal structure confirms design accuracy-Designs can be used in cell culture andin vitroapplications
Arabidopsis thalianaLSM7 is essential for auxin-mediated regulation ofSAURgenes and thermomorphogenesis
Authors: Nardeli Sarah Muniz , Zacharaki Vasiliki , Rojas-Murcia Nelson , Collani Silvio , Wang Kai , Bayer Martin , Schmid Markus , Goretti Daniela 
Published: March 2023

AbstractTemperature affects plant growth by modulating the expression of genes and subsequent processing of RNAs that govern essential physiological processes. Here, we show thatArabidopsis thalianaSm-like7 (LSM7), a core component of the splicing and decapping machinery, is indispensable for embryogenesis and development. Hypomorphiclsm7-2mutants display severe developmental defects that are exacerbated by high temperatures. Transcriptome analysis verified LSM7’s extensive role in gene regulation. In particular, we found that the key regulator of thermomorphogenesis,PHYTOCHROME INTERACTING FACTOR 4(PIF4), and auxin-related genes, includingSMALL AUXIN UP-REGULATED(SAUR) genes, are misregulated inlsm7-2. Auxin metabolic profiling confirmed that auxin homeostasis was disturbed inlsm7-2. Importantly, overexpression of the auxin-responsiveSAUR19gene partially restored thermomorphogenesis defects inlsm7-2under high ambient temperature. Taken together, our research provides mechanistic insights into the interplay between RNA processing, hormone homeostasis, and the response to temperature regulation in plants and elucidates LSM7’s essential function in plant temperature acclimation and resilience.Significance StatementGiven their sessile nature, plants cannot escape adverse environmental conditions such as cold or heat. Instead, they continuously adjust their gene expression and RNA processing to regulate growth and physiology in response to their surroundings. In this study, we investigated the role of the core RNA processing factor LSM7 in temperature acclimation inArabidopsis thaliana. We found that LSM7 knockdown mutants were impaired in thermomorphogenesis and, as a result, were hypersensitive to elevated temperatures. At the molecular level, we demonstrated that this temperature sensitivity was caused by the misregulation of key regulators of thermomorphogenesis, including PIF4, auxin homeostasis and signaling, and SAUR genes. Our findings provide valuable insights into the role of RNA processing in plant temperature acclimation.
The Road Less Traveled: Uncovering the Convergence Toward Specific Pleiotropic Phenotypes in Aging
Authors: Stoeger Thomas 
Published: March 2023

AbstractAging is a complex process influenced by a wide range of environmental and molecular factors. Despite this complexity, individuals tend to age in highly similar ways, leading to the question of what drives this convergence. Recent research, including my own discoveries, suggests that the length of transcript molecules plays a crucial role in age-dependent changes to the transcriptome. Drawing inspiration from the road trip analogy of cellular transcription, I propose that a non-linear scaling law drives convergence towards specific pleiotropic phenotypes in biological aging. This scaling law is based on the notion that molecular changes observed during aging may reflect unspecific damage to cellular physiology. By validating this hypothesis, I can improve our understanding of biological aging and identify new candidate compounds for anti-aging interventions, as well as re-identify one known intervention. This work has actionable implications for improving human health and extending lifespans.
Myc-regulated miRNAs modulate p53 expression and impact animal survival under nutrient deprivation
Authors: Gervé María P. , Sánchez Juan A. , Ingaramo María C. , Dekanty Andrés 
Published: March 2023

ABSTRACTThe conserved transcription factor Myc regulates cell growth, proliferation and apoptosis, and its deregulation has been associated with human pathologies. Although specific miRNAs have been identified as fundamental components of the Myc tumorigenic program, how Myc regulates miRNA biogenesis remains controversial. Here we showed that Myc functions as an important regulator of miRNA biogenesis inDrosophilaby influencing both miRNA gene expression and processing. Through the analysis of ChIP-Seq datasets, we discovered that nearly 56% ofDrosophilamiRNA genes show dMyc binding, exhibiting either the canonical or non-canonical E-box sequences within the peak region. Consistently, reduction of dMyc levels resulted in widespread downregulation of miRNAs gene expression. dMyc also modulates miRNA processing and activity by controlling Drosha and AGO1 levels through direct transcriptional regulation. By usingin vivomiRNA activity sensors we demonstrated that dMyc promotes miRNA-mediated silencing in different tissues, including the wing primordium and the fat body. We also showed that dMyc-dependent expression of miR-305 in the fat body modulates Dmp53 levels depending on nutrient availability, having a profound impact on the ability of the organism to respond to nutrient stress. Indeed, dMyc depletion in the fat body resulted in extended survival to nutrient deprivation which was reverted by expression of either miR-305 or a dominant negative version of Dmp53. Our study reveals a previously unrecognized function of dMyc as an important regulator of miRNA biogenesis and suggests that Myc-dependent expression of specific miRNAs may have important tissue-specific functions.
TET2lesions enhance the aggressiveness ofCEBPA-mutant AML by rebalancingGATA2expression
Authors: Heyes Elizabeth , Wilhelmson Anna S. , Wenzel Anne , Manhart Gabriele , Eder Thomas , Schuster Mikkel B. , Rzepa Edwin , Pundhir Sachin , D’Altri Teresa , Gentil Coline , Meggendorfer Manja , Schwaller Jürg , Haferlach Torsten , Grebien Florian , Porse Bo T. 
Published: March 2023

ABSTRACTThe myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated;CEBPADM) in acute myeloid leukemia (AML) with a combination of hypermorphic N-terminal mutations (CEBPANT), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. The most frequently co-mutated genes inCEBPADMAML areGATA2andTET2, however the molecular mechanisms underlying this co-mutational spectrum are incomplete.By combining transcriptomic and epigenomic analyses ofCEBPA-TET2co-mutated patients with models thereof, we identifyGATA2as a conserved target of theCEBPA-TET2mutational axis, providing a rationale for the mutational spectra inCEBPADMAML. Elevated CEBPA levels, driven byCEBPANT, mediate recruitment of TET2 to theGata2distal hematopoietic enhancer thereby increasingGata2expression. Concurrent loss of TET2 inCEBPADMAML induces a competitive advantage by increasingGata2promoter methylation, thereby rebalancing GATA2 levels. Of clinical relevance, demethylating treatment ofCebpa-Tet2co-mutated AML restoresGata2levels and prolongs disease latency.
aPEAR:an R package for autonomous visualisation of pathway enrichment networks
Authors: Kerseviciute Ieva , Gordevicius Juozas 
Published: March 2023

AbstractSummaryThe interpretation of pathway enrichment analysis (PEA) results is frequently complicated by an overwhelming and redundant list of significantly affected pathways. Here, we present an R packageaPEAR(Advanced Pathway Enrichment Analysis Representation) which leverages similarities between the pathway gene sets and represents them as a network of interconnected clusters. Each cluster is assigned a meaningful name which highlights the main biological themes in the experiment. Our approach enables automated and objective overview of the data without manual and time-consuming parameter tweaking.Availability and implementationThe packageaPEARis implemented in R, published under the MIT open source licence. The source code, documentation, and usage instructions are available onhttps://gitlab.com/vugene/aPEARas well as on CRAN (https://CRAN.R-project.org/package=aPEAR).Contactkerseviciute.ieva@gmail.comorjuozas@vugene.com.Supplementary informationThe complete analysis used to evaluate the package can be found athttps://github.com/ievaKer/aPEAR-publication.