bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deficiency of neutrophil high-mobility group box-1 in liver transplant recipients exacerbates early allograft injury in mice
Authors: Song Zhuolun , Han Hui , Ge Xiaodong , Das Sukanta , Desert Romain , Athavale Dipti , Chen Wei , Komakula Sai Santosh Babu , Lantvit Daniel , Nieto Natalia 
Published: April 2023

Background and Aims:
Early allograft dysfunction (EAD) is a severe event leading to graft failure after liver transplant (LT). Extracellular high-mobility group box-1 (HMGB1) is a damage-associated molecular pattern that contributes to hepatic ischemia-reperfusion injury (IRI). However, the contribution of intracellular HMGB1 to LT graft injury remains elusive. We hypothesized that intracellular neutrophil-derived HMGB1 from recipients protects from post-LT EAD.

Approach and Results:
We generated mice with conditional ablation or overexpression of Hmgb1 in hepatocytes, myeloid cells, or both. We performed LTs and injected lipopolysaccharide (LPS) to evaluate the effect of intracellular HMGB1 in EAD. Ablation of Hmgb1 in hepatocytes and myeloid cells of donors and recipients exacerbated early allograft injury after LT. Ablation of Hmgb1 from liver grafts did not affect graft injury; however, lack of Hmgb1 from recipient myeloid cells increased reactive oxygen species (ROS) and inflammation in liver grafts and exacerbated injury. Neutrophils lacking HMGB1 were more activated, showed enhanced pro-oxidant and pro-inflammatory signatures, and reduced biosynthesis and metabolism of inositol polyphosphates (InsPs). On LT reperfusion or LPS treatment, there was significant neutrophil mobilization and infiltration into the liver and enhanced production of ROS and pro-inflammatory cytokines when intracellular Hmgb1 was absent. Depletion of neutrophils using anti-Ly6G antibody attenuated graft injury in recipients with myeloid cell Hmgb1 ablation.

Conclusions:
Neutrophil HMGB1 derived from recipients is central to regulate their activation, limits the production of ROS and pro-inflammatory cytokines, and protects from early liver allograft injury.
Kir4.1 deletion prevents salt-sensitive hypertension in early streptozotocin-induced diabetic mice via Na+–Cl− cotransporter in the distal convoluted tubule
Authors: Gao Zhong-Xiuzi , Wei Qi-Chao , Shu Ting-Ting , Li Shu-Ting , Zhou Rui , Li Ming-Yan , Mao Zi-Hui , Liu Dong-Wei , Liu Zhang-Suo , Wu Peng 
Published: April 2023

Objectives:
Functional impairment of renal sodium handling and blood pressure (BP) homeostasis is an early characteristic manifestation of type 1 diabetes. However, the underlying mechanisms remain unclear.

Methods:
Metabolic cages, radio-telemetry, immunoblotting, and electrophysiology were utilized to examine effects of high salt (8% NaCl, HS) intake on Na+/K+ balance, BP, Na+–Cl− cotransporter (NCC) function, and basolateral K+ channel activity in the distal convoluted tubule (DCT) under diabetic conditions.

Results:
Improper Na+ balance, hypernatremia, and a mild but significant increase in BP were found in streptozotocin (STZ)-induced diabetic mice in response to HS intake for 7 days. Compared to the vehicle, STZ mice showed increased Kir4.1 expression and activity in the DCT, a more negative membrane potential, higher NCC abundance, and enhanced hydrochlorothiazide-induced natriuretic effect. However, HS had no significant effect on basolateral Kir4.1 expression/activity and DCT membrane potential, or NCC activity under diabetic conditions, despite a downregulation in phosphorylated NCC abundance. In contrast, HS significantly downregulated the expression of Na+–H+ exchanger 3 (NHE3) and cleaved epithelial sodium channel-γ in STZ mice, despite an increase in NHE3 abundance after STZ treatment. Kir4.1 deletion largely abolished STZ-induced upregulation of NCC expression and prevented BP elevation during HS intake. Interestingly, HS causes severe hypokalemia in STZ-treated kidney-specific Kir4.1 knockout (Ks-Kir4.1 KO) mice and lead to death within a few days, which could be attributed to a higher circulating aldosterone level.

Conclusions:
We concluded that Kir4.1 is required for upregulating NCC activity and may be essential for developing salt-sensitive hypertension in early STZ-induced diabetes.
Beyond Scenarios - Optimization of breeding program design (MoBPSopti)
Authors: Hassanpour Azadeh , Geibel Johannes , Simianer Henner , Pook Torsten 
Published: April 2023

AbstractIn recent years, breeding programs have become increasingly larger and more structurally complex, with various highly interdependent parameters and contrasting breeding goals. Therefore, resource allocation in a breeding program has become more complex, and the derivation of an optimal breeding strategy has become more and more challenging. As a result, it is a common practice to reduce the optimization problem to a set of scenarios that are only changed in a few parameters and, in turn, can be deeply analyzed in detail. This paper aims to provide a framework for the numerical optimization of breeding programs beyond just comparing scenarios. For this, we first determine the space of potential breeding programs that is only limited by basic constraints like the budget and housing capacities. Subsequently, the goal is to identify the optimal breeding program by finding the parametrization that maximizes the target function, as a combination of the different breeding goals. To assess the value of the target function for a parametrization, we propose the use of stochastic simulations and the subsequent use of a kernel regression method to cope with the stochasticity of simulation outcomes. This procedure is performed iteratively to narrow down the most promising areas of the search space and perform more and more simulations in these areas of interest. The developed concept was applied to a dairy cattle program with a target function aiming at genetic gain and genetic diversity conservation limited by budget constraints.
Structure and Interactions of the Endogenous Human Commander Complex
Authors: Laulumaa Saara , Kumpula Esa-Pekka , Huiskonen Juha T , Varjosalo Markku 
Published: April 2023

SummaryThe Commander complex, a 16-protein subunit assembly, plays multiple roles in various intracellular events, including regulation of cell homeostasis, cell cycle, and immune response. The complex is composed of COMMD1-10, CCDC22, CCDC93, DENND10, VPS26C, VPS29, and VPS35L. These proteins are expressed ubiquitously in the human body and have been linked to diseases including Wilson’s disease, atherosclerosis, and several cancers. Despite its importance, the structure and molecular functions of the Commander complex are poorly understood. Here, we report the structure and key interactions of the endogenous human Commander complex by cryogenic electron microscopy (cryo-EM) and mass spectrometry-based proteomics. Our results show that the complex is asymmetric, consisting of a stable core of a pseudo-symmetric ring of COMMD proteins 1–10 and a mobile effector consisting of DENND10 and the Retriever sub-complex, constituted by VPS35L, VPS29 and VPS26C. The two halves are scaffolded together by CCDC22 and CCDC93. This study directly confirms the cellular composition of Commander and identifies major interaction interfaces, defining the structure and interaction landscape of the complex. These findings offer new insights into its known roles in endosomal processes and intracellular transport, and uncovers a strong association with cilium assembly, and centrosome and centriole functions.HighlightsHigh-resolution structure of the Commander complex determined by cryo-EM shows a rigid COMMD1–10 core decorated by mobile effectors DENND10 and the Retriever sub-complex.Comprehensive interactome analysis uncovers a plethora of novel interactions, implicating the Commander complex in previously unidentified processes, such as cilium assembly, cell cycle, and organelle biogenesis.Structural organization and identified interaction partners of the Commander complex provide a basis for further research into its molecular functions, related diseases, and potential therapeutic targets.eTOC blurbWe provide a comprehensive structural analysis of the endogenous human Commander complex, revealing its functional organization and novel interactions involved in diverse cellular processes. These findings uncover new interaction surfaces and pave the way for further research into the molecular mechanisms of the Commander complex.
Robust analysis of allele-specific copy number alterations from scRNA-seq data with XClone
Authors: Huang Rongting , Huang Xianjie , Tong Yin , Yan Helen Y.N. , Leung Suet Yi , Stegle Oliver , Huang Yuanhua 
Published: April 2023

AbstractSomatic copy number alterations (CNAs) are major mutations that contribute to the development and progression of various cancers. Despite a few computational methods proposed to detect CNAs from single-cell transcriptomic data, the technical sparsity of such data makes it challenging to identify allele-specific CNAs, particularly in complex clonal structures. In this study, we present a statistical method, XClone, that strengthens the signals of read depth and allelic imbalance by effective smoothing on cell neighborhood and gene coordinate graphs to detect haplotype-aware CNAs from scRNA-seq data. By applying XClone to multiple datasets with challenging compositions, we demonstrated its ability to robustly detect different types of allele-specific CNAs and potentially indicate whole genome duplication, therefore enabling the discovery of corresponding subclones and the dissection of their phenotypic impacts.
The role of microglial LRRK2 in manganese-induced inflammatory neurotoxicity via NLRP3 inflammasome and RAB10-mediated autophagy dysfunction
Authors: Pajarillo Edward , Kim Sang Hoon , Digman Alexis , Dutton Matthew , Son Deok-Soo , Aschner Michael , Lee Eunsook 
Published: April 2023

AbstractChronic exposure to manganese (Mn) can lead to manganism, a neurological disorder sharing common symptoms with Parkinson’s disease (PD). Studies have shown that Mn can increase the expression and activity of leucine-rich repeat kinase 2 (LRRK2), leading to inflammation and toxicity in microglia. LRRK2 G2019S mutation also elevates LRRK2 kinase activity. Thus, we tested if Mn-increased microglial LRRK2 kinase is responsible for Mn-induced toxicity, and exacerbated by G2019S mutation, using WT and LRRK2 G2019S knock-in mice, and BV2 microglia. Mn (30 mg/kg, nostril instillation, daily for 3 weeks) caused motor deficits, cognitive impairments, and dopaminergic dysfunction in WT mice, which were exacerbated in G2019S mice. Mn induced proapoptotic Bax, NLRP3 inflammasome, IL-1β and TNF-α in the striatum and midbrain of WT mice, and these effects were exacerbated in G2019S mice. BV2 microglia were transfected with human LRRK2 WT or G2019S, followed by Mn (250 μM) exposure to better characterize its mechanistic action. Mn increased TNF-α, IL-1β, and NLRP3 inflammasome activation in BV2 cells expressing WT LRRK2, which was exacerbated in G2019S-expressing cells, while pharmacological inhibition of LRRK2 mitigated these effects in both genotypes. Moreover, the media from Mn-treated BV2 microglia expressing G2019S caused greater toxicity to cath.a-differentiated (CAD) neuronal cells compared to media from microglia expressing WT. Mn-LRRK2 activated RAB10, which was exacerbated in G2019S. RAB10 played a critical role in LRRK2-mediated Mn toxicity by dysregulating the autophagy-lysosome pathway, and NLRP3 inflammasome in microglia. Our novel findings suggest that microglial LRRK2 via RAB10 plays a critical role in Mn-induced neuroinflammation.
The Functional RNA Identification (FRID) Pipeline: Identification of Potential Pseudoknot-Containing RNA Elements as Therapeutic Targets for SARS-CoV-2
Authors: Forstmeier Peter C. , Meyer McCauley O. , Bevilacqua Philip C. 
Published: April 2023

AbstractThe COVID-19 pandemic persists despite the development of effective vaccines. As such, it remains crucial to identify new targets for antiviral therapies. The causative virus of COVID-19, SARS-CoV-2, is a positive-sense RNA virus with RNA structures that could serve as therapeutic targets. One such RNA with established function is the frameshift stimulatory element (FSE), which promotes programmed ribosomal frameshifting. To accelerate identification of additional functional RNA elements, we introduce a novel computational approach termed the Functional RNA Identification (FRID) pipeline. The guiding principle of our pipeline, which uses established component programs as well as customized component programs, is that functional RNA elements have conserved secondary and pseudoknot structures that facilitate function. To assess the presence and conservation of putative functional RNA elements in SARS-CoV-2, we compared over 6,000 SARS-CoV-2 genomic isolates. We identified 22 functional RNA elements from the SARS-CoV-2 genome, 14 of which have conserved pseudoknots and serve as potential targets for small molecule or antisense oligonucleotide therapeutics. The FRID pipeline is general and can be applied to identify pseudoknotted RNAs for targeted therapeutics in genomes or transcriptomes from any virus or organism.
Coronary Artery Disease Risk GenePRDM16is Preferentially Expressed in Vascular Smooth Muscle Cells and a Potential Novel Regulator of Smooth Muscle Homeostasis
Authors: Dong Kunzhe , He Xiangqin , Hu Guoqing , Yao Yali , Zhou Jiliang 
Published: April 2023

ABSTRACTObjectiveVascular smooth muscle cells (VSMCs) are the primary contractile component of blood vessels and can undergo phenotypic switching from a contractile to a synthetic phenotype in vascular diseases such as coronary artery disease (CAD). This process leads to decreased expression of SMC lineage genes and increased proliferative, migratory and secretory abilities that drive disease progression. Super-enhancers (SE) and occupied transcription factors are believed to drive expression of genes that maintain cell identify and homeostasis. The goal of this study is to identify novel regulator of VSMC homeostasis by screening for SE-regulated transcription factors in arterial tissues.Approach and ResultsWe characterized human artery SEs by analyzing the enhancer histone mark H3K27ac ChIP-seq data of multiple arterial tissues. We unexpectedly discovered the transcription factor PRDM16, a GWAS identified CAD risk gene with previously well-documented roles in brown adipocytes but with an unknown function in vascular disease progression, is enriched with artery-specific SEs. Further analysis of public bulk RNA-seq and scRNA-seq datasets, as well as qRT-PCR and Western blotting analysis, demonstrated that PRDM16 is preferentially expressed in arterial tissues and in contractile VSMCs but not in visceral SMCs, and down-regulated in phenotypically modulated VSMCs. To explore the function ofPrdm16in vivo, we generatedPrdm16SMC-specific knockout mice and performed histological and bulk RNA-Seq analysis of aortic tissues. SMC-deficiency ofPrdm16does not affect the aortic morphology but significantly alters expression of many CAD risk genes and genes involved in VSMC phenotypic modulation. Specifically,Prdm16negatively regulates the expression ofTgfb2that encodes for an upstream ligand of TGF-β signaling pathway, potentially through binding to the promoter region ofTgfb2. These transcriptomic changes likely disrupt VSMC homeostasis and predispose VSMCs to a disease state.ConclusionsOur results suggest that the CAD risk genePRDM16is preferentially expressed in VSMCs and is a novel regulator of VSMC homeostasis. Future studies are warranted to investigate its role in VSMCs under pathological conditions such as atherosclerosis.
Objective assessment of visual attention in toddlerhood
Authors: Braithwaite E. , Kyriakopoulou V. , Mason L. , Davidson A. , Tusor N. , Harper N. , Earl M. , Datoo-Partridge S. , Young A. , Chew A. , Falconer S. , Hajnal Joseph V , Johnson M.H. , Nosarti C. , Edwards A.D. , Jones E.J.H. 
Published: April 2023

AbstractVisual attention is an important mechanism through which children learn about their environment, and individual differences could substantially shape later development. Eyetracking provides a sensitive and scalable tool for assessing visual attention that has potential for objective assessment of child development, but to date the majority of studies are small and replication attempts are rare. This study investigates the feasibility of a comprehensive eye-tracking assessment of visual attention and introduces a shared data resource for the scientific community. Data from eight eyetracking tasks were collected from 350 term-born (166 females) 18-month-olds recruited as neonateshttp://www.developingconnectome.org/). Analyses showed expected condition effects for seven of eight tasks (p-values from <.001 to .04), an important indication of replicability. Consistent with some theoretical models of visual attention, structural equation modelling indicated participants’ performance could be explained by two factors representing social and non-social attention. Comprehensive eye-tracking batteries can objectively measure individual differences in core components of visual attention in large-scale toddlerhood studies. This is the first large-scale comprehensive study to present high-quality normative eye-tracking data from a large task battery in toddlers and make them freely available to the scientific community.
Interplay between Nrf2 and αB-crystallin in the lens and heart of zebrafish under proteostatic stress
Authors: Park Jinhee , MacGavin Samantha , Niederbrach Laurie , Mchaourab Hassane S. 
Published: April 2023

ABSTRACTA coordinated oxidative stress response, partly triggered by the transcription factor Nrf2, protects cells from the continual production of reactive oxygen species. Left unbuffered, reactive oxygen species can lead to protein aggregation which has been implicated in a spectrum of diseases including cataract of the ocular lens and myopathy of the heart. While proteostasis is maintained by diverse families of heat shock proteins, the interplay between the oxidative and proteostatic stress responses in the lens and the heart have not been investigated. Capitalizing on multiple zebrafish lines that have compromised function of Nrf2 and/or the two zebrafish small heat-shock proteins αBa- and αBb-crystallin, we uncovered a transcriptional relationship that leads to a substantial increase in αBb-crystallin transcripts in the heart in response to compromised function of Nrf2. In the lens, the concomitant loss of function of Nrf2 and αBa-crystallin leads to upregulation of the cholesterol biosynthesis pathway thus mitigating the phenotypic consequences of the αBa-crystallin knockout. In contrast, abrogation of Nrf2 function accentuates the penetrance of a heart edema phenotype characteristic of embryos of αB-crystallin knockout lines. Multiple molecular pathways, such as genes involved in extracellular interactions and implicated in cardiomyopathy, are revealed from transcriptome profiling thus identifying novel targets for further investigation. Together our transcriptome/phenotypic analysis establishes an intersection between the oxidative stress and chaperone responses in the lens and the heart.
Comparing chromatin contact maps at scale: methods and insights
Authors: Gunsalus Laura M. , McArthur Evonne , Gjoni Ketrin , Kuang Shuzhen , Pittman Maureen , Capra John A. , Pollard Katherine S. 
Published: April 2023

AbstractComparing chromatin contact maps is an essential step in quantifying how three-dimensional (3D) genome organization shapes development, evolution, and disease. However, no gold standard exists for comparing contact maps, and even simple methods often disagree. In this study, we propose novel comparison methods and evaluate them alongside existing approaches using genome-wide Hi-C data and 22,500in silicopredicted contact maps. We also quantify the robustness of methods to common sources of biological and technical variation, such as boundary size and noise. We find that simple difference-based methods such as mean squared error are suitable for initial screening, but biologically informed methods are necessary to identify why maps diverge and propose specific functional hypotheses. We provide a reference guide, codebase, and benchmark for rapidly comparing chromatin contact maps at scale to enable biological insights into the 3D organization of the genome.
Using macromolecular electron densities to improve the enrichment of active compounds in virtual screening
Authors: Ma Wenzhi , Zhang Wei , Le Yuan , Shi Xiaoxuan , Xu Qingbo , Xiao Yang , Dou Yueying , Wang Xiaoman , Zhou Wenbiao , Peng Wei , Zhang Hongbo , Huang Bo 
Published: April 2023

ABSTRACTThe quest for more effective virtual screening algorithms is hindered by the scarcity of training data, calling for innovative approaches. This study presents the first use of experimental electron density (ED) data for improving active compound enrichment in virtual screening, supported by ED’s ability to reflect the time-averaged behavior of ligands and solvents in the binding pocket. Experimental ED-based grid matching score (ExptGMS) was developed to score compounds by measuring the degree of matching between their binding conformations and a series of multi-resolution experimental ED grids. The efficiency of ExptGMS was validated using bothin-silicotests with the Directory of Useful Decoys–Enhanced dataset and wet-lab tests on Covid-19 3CLpro-inhibitors. ExptGMS improved the active compound enrichment in top-ranked molecules by approximately 20%. Furthermore, ExptGMS helped identify four new and active inhibitors of 3CLpro, with the top showing an IC50 value of 1.9 µM. To facilitate the use of ExptGMS, we developed an online database containing experimental ED grids for over 17,000 proteins.
Sequential effect and temporal orienting in pre-stimulus oculomotor inhibition
Authors: Tal-Perry Noam , Yuval-Greenberg Shlomit 
Published: April 2023

AbstractWhen faced with unfamiliar circumstances, we often turn to our past experiences with similar situations to shape our expectations. This results in the well-established sequential effect, in which previous trials influence the expectations of the current trial. Studies have revealed that, in addition to the classical behavioral metrics, the inhibition of eye movement could be used as a biomarker to study temporal expectations. This pre-stimulus oculomotor inhibition is found a few hundred milliseconds prior to predictable events, with a stronger inhibition for predictable than unpredictable events. The phenomenon has been found to occur in various temporal structures, such as rhythms, cue-association and conditional probability, yet it is still unknown whether it reflects local sequential information of the previous trial. To explore this, we examined the relationship between the sequential effect and the pre-stimulus oculomotor inhibition. Our results (N=40) revealed that inhibition was weaker when the previous trial was longer than the current trial, in line with findings of behavioral metrics. These findings indicate that the pre-stimulus oculomotor inhibition covaries with expectation based on local sequential information, demonstrating the tight connection between this phenomenon and expectation and providing a novel measurement for studying sequential effects in temporal expectation.