bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA-dependent RNA polymerases in plants
Authors: Yang Dong-Lei , Huang Kun , Deng Deyin , Zeng Yuan , Wang Zhenxing , Zhang Yu 
Published: July 2023

Abstract
DNA-dependent RNA polymerases (Pols) transfer the genetic information stored in genomic DNA to RNA in all organisms. In eukaryotes, the typical products of nuclear Pol I, Pol II, and Pol III are ribosomal RNAs, mRNAs, and transfer RNAs, respectively. Intriguingly, plants possess two additional Pols, Pol IV and Pol V, which produce small RNAs and long noncoding RNAs, respectively, mainly for silencing transposable elements. The five plant Pols share some subunits, but their distinct functions stem from unique subunits that interact with specific regulatory factors in their transcription cycles. Here, we summarize recent advances in our understanding of plant nucleus-localized Pols, including their evolution, function, structures, and transcription cycles.
PYRIDOX(AM)INE 5′-PHOSPHATE OXIDASE3 ofArabidopsis thalianamaintains carbon/nitrogen balance in distinct environmental conditions
Authors: Steensma Priscille , Eisenhut Marion , Colinas Maite , Rosado-Souza Laise , Fernie Alisdair R , Weber Andreas P M , Fitzpatrick Teresa B 
Published: July 2023

AbstractThe identification of factors that regulate C/N utilization in plants can make a substantial contribution to optimization of plant health. Here, we explored the contribution of pyridox(am)ine 5′-phosphate oxidase3 (PDX3), which regulates vitamin B6 homeostasis, in Arabidopsis (Arabidopsis thaliana). Firstly, N fertilization regimes showed that ammonium application rescues the leaf morphological phenotype of pdx3 mutant lines but masks the metabolite perturbance resulting from impairment in utilizing soil nitrate as a source of N. Without fertilization, pdx3 lines suffered a C/N imbalance and accumulated nitrogenous compounds. Surprisingly, exploration of photorespiration as a source of endogenous N driving this metabolic imbalance, by incubation under high CO2, further exacerbated the pdx3 growth phenotype. Interestingly, the amino acid serine, critical for growth and N management, alleviated the growth phenotype of pdx3 plants under high CO2, likely due to the requirement of pyridoxal 5′-phosphate for the phosphorylated pathway of serine biosynthesis under this condition. Triggering of thermomorphogenesis by growth of plants at 28 °C (instead of 22 °C) did not appear to require PDX3 function, and we observed that the consequent drive toward C metabolism counters the C/N imbalance in pdx3. Further, pdx3 lines suffered a salicylic acid-induced defense response, probing of which unraveled that it is a protective strategy mediated by nonexpressor of pathogenesis related1 (NPR1) and improves fitness. Overall, the study demonstrates the importance of vitamin B6 homeostasis as managed by the salvage pathway enzyme PDX3 to growth in diverse environments with varying nutrient availability and insight into how plants reprogram their metabolism under such conditions.
Standardized 3D-CT lung volumes for patients with acute exacerbation of rheumatoid arthritis-associated interstitial lung disease
Authors: Tanaka Yuko , Suzuki Yuzo , Saku Aiko , Kono Masato , Hashimoto Dai , Hasegawa Hirotsugu , Yokomura Koshi , Inoue Yusuke , Hozumi Hironao , Karayama Masato , Furuhashi Kazuki , Enomoto Noriyuki , Fujisawa Tomoyuki , Inui Naoki , Suda Takafumi 
Published: July 2023

Abstract

Objectives
Fibrotic interstitial lung disease (ILD) is a progressive lung disease characterized by loss of lung volume, resulting in a leading cause of death in patients with RA. Crucially, acute exacerbation (AE) of ILD shows higher morbidity and mortality with rapid deterioration of the lungs. However, a quantitative assessment for physiological changes at AE has yet to be performed. This study hypothesized that quantitative assessments of lung volume (LV) accurately indicate disease severity and mortality risk in patients with AE-RA-ILD.

Methods
This multicentre cohorts study quantitatively assessed physiological changes of RA-ILD at diagnosis (n = 54), at AE (discovery-cohorts; n = 20, and validation-cohort; n = 33), and controls (n = 35) using 3D CT (3D-CT) images. LV was quantitatively measured using 3D-CT and standardized by predicted forced vital capacity.

Results
Patients with RA-ILD at diagnosis showed decreased LV, predominantly in lower lobes, compared with controls. Further substantial volume loss was found in upper- and lower lobes at AE compared with those at diagnosis. During AE, decreased standardized 3D-CT LV was associated with a worse prognosis in both cohorts. Subsequently, standardized 3D-CT LV was identified as a significant prognostic factor independent of age, sex and the presence of UIP pattern on CT by multivariate analyses. Notably, a composite model of age and standardized 3D-CT LV successfully classified mortality risk in patients with AE-RA-ILD.

Conclusion
Volume loss at AE in patients with RA-ILD was associated with increased mortality. Assessing physiological change using standardized 3D-CT might help evaluate disease severity and mortality risk in patients with AE-RA-ILD.
Unveiling Hidden Connections in Omics DataviapyPARAGON: an Integrative Hybrid Approach for Disease Network Construction
Authors: Arici M. Kaan , Tuncbag Nurcan 
Published: July 2023

AbstractOmics technologies are powerful tools for detecting dysregulated and altered signaling components in various contexts, encompassing disease states, patients, and drug-perturbations. Network inference or reconstruction algorithms play an integral role in the successful analysis and identification of causal relationships between omics hits. However, accurate representation of signaling networks and identification of context-specific interactions within sparse omics datasets in complex interactomes pose significant challenges in integrative approaches. To address these challenges, we present pyPARAGON (PAgeRAnk-flux on Graphlet-guided network for multi-Omic data integratioN), a novel tool that combines network propagation with graphlets. By leveraging network motifs instead of pairwise connections among proteins, pyPARAGON offers improved accuracy and reduces the inclusion of nonspecific interactions in signaling networks. Through comprehensive evaluations on benchmark cancer signaling pathways, we demonstrate that pyPARAGON outperforms state-of-the-art approaches in node propagation and edge inference. Furthermore, pyPARAGON exhibits promising performance in discovering cancer driver networks. Notably, we demonstrate its utility in network-based stratification of patient tumors by integrating phosphoproteomic data from 105 breast cancer tumors with the interactome, leading to the discovery of tumor-specific signaling pathways. Overall, the development and evaluation of pyPARAGON significantly contributes to the field as an effective tool for the analysis and integration of multi-omic data in the context of signaling networks. pyPARAGON is available athttps://github.com/metunetlab/pyPARAGON.
Sustaining wakefulness: Brainstem connectivity in human consciousness
Authors: Edlow Brian L. , Olchanyi Mark , Freeman Holly J. , Li Jian , Maffei Chiara , Snider Samuel B. , Zöllei Lilla , Iglesias J. Eugenio , Augustinack Jean , Bodien Yelena G. , Haynes Robin L. , Greve Douglas N. , Diamond Bram R. , Stevens Allison , Giacino Joseph T. , Destrieux Christophe , van der Kouwe Andre , Brown Emery N. , Folkerth Rebecca D. , Fischl Bruce , Kinney Hannah C. 
Published: July 2023

ABSTRACTConsciousness is comprised of arousal (i.e., wakefulness) and awareness. Substantial progress has been made in mapping the cortical networks that modulate awareness in the human brain, but knowledge about the subcortical networks that sustain arousal is lacking. We integrated data fromex vivodiffusion MRI, immunohistochemistry, andin vivo7 Tesla functional MRI to map the connectivity of a subcortical arousal network that we postulate sustains wakefulness in the resting, conscious human brain, analogous to the cortical default mode network (DMN) that is believed to sustain self-awareness. We identified nodes of the proposed default ascending arousal network (dAAN) in the brainstem, hypothalamus, thalamus, and basal forebrain by correlatingex vivodiffusion MRI with immunohistochemistry in three human brain specimens from neurologically normal individuals scanned at 600-750 µm resolution. We performed deterministic and probabilistic tractography analyses of the diffusion MRI data to map dAAN intra-network connections and dAAN-DMN internetwork connections. Using a newly developed network-based autopsy of the human brain that integratesex vivoMRI and histopathology, we identified projection, association, and commissural pathways linking dAAN nodes with one another and with cortical DMN nodes, providing a structural architecture for the integration of arousal and awareness in human consciousness. We release theex vivodiffusion MRI data, corresponding immunohistochemistry data, network-based autopsy methods, and a new brainstem dAAN atlas to support efforts to map the connectivity of human consciousness.One sentence summaryWe performedex vivodiffusion MRI, immunohistochemistry, andin vivo7 Tesla functional MRI to map brainstem connections that sustain wakefulness in human consciousness.
Theranostic Bottle-Brush Polymers Tailored for Universal Solid-Tumour Targeting
Authors: Zhang Wei , Xu Yanwen , Guo Rongjun , Zhuang Peiling , Hong Huixia , Tan Hui , Wang Mingfeng 
Published: July 2023

AbstractNanomedicines involving nanotechnologies and engineering of nanomaterials for medicines have shown great promise in diagnosis and treatment of diseases including cancers. A major hurdle that limits the successful clinical translation of nanomedicines, however, is how to overcome the cascaded biological barriers and improve the delivery efficacy towards the disease sites and minimize the toxicity against healthy tissues and cells. Here, we report a type of bottle-brush-like polymers systematically optimized in their chemical structures, sizes, and surface charges that lead to their outstanding pharmacokinetics and tumour-targeting performances in a variety of both subcutaneous and orthotopic tumour models. The potential mechanism has been studied by revealing the structure-activity relationship of these polymers in overcoming the biological barriers, including their avoidance by the immune system and deep tumour infiltration. Our study may offer insight for a rational design of highly efficient delivery platform of polymeric nanomedicines that could effectively overcome the cascaded biological barriers and thus lead to high tumour-targeting efficacy and low toxicity.
Beam search decoder for enhancing sequence decoding speed in single-molecule peptide sequencing data
Authors: Kipen Javier , Jaldén Joakim 
Published: July 2023

AbstractNext-generation single-molecule protein sequencing technologies have the potential to accelerate biomedical research significantly. These technologies offer sensitivity and scalability for proteomic analysis. One auspicious method is fluorosequencing, which involves: cutting naturalized proteins into peptides, attaching fluorophores to specific amino acids, and observing variations in light intensity as one amino acid is removed at a time. The original peptide is classified from the sequence of light-intensity reads, and proteins can subsequently be recognized with this information. The amino acid step removal is achieved by attaching the peptides to a wall on the C-terminal and using a process called Edman Degradation to remove an amino acid from the N-Terminal. Even though a framework (Whatprot) has been proposed for the peptide classification task, processing times remain restrictive due to the massively parallel data acquisicion system. In this paper, we propose a new beam search decoder with a novel state formulation that obtains much lower processing times with slightly higher accuracies than Whatprot. Furthermore, we explore how our novel state formulation may lead to even faster decoders in the future.Author summaryProteomic analyses are often carried on with mass spectrometry, but this method cannot identify low-abundance proteins. Single-molecule protein sequencing methods can overcome this issue, and fluorosequencing is one of these technologies. Fluorosequencing has attracted interest from investors, as evidenced by the recent funding of Erisyon, a company developing this technology. This technique contains a challenging classification task: determining the original peptide sequence from light-intensity observations obtained after several Edman cycles. A classifier based on a combination ofkNearest Neighbors (kNN) with Hidden Markov Models (HMM) had been shown to have close-to-optimal accuracy with tractable complexity. We propose in this paper a new algorithm that not only improves accuracy compared to state-of-the-art methods but also reduces computation time.
Applying Hierarchical Generalized Additive Models to Non-Compartmental Analysis of Pharmacokinetic Data
Authors: Woodward Andrew P. 
Published: July 2023

AbstractNon-compartmental analysis (NCA) is a popular strategy for obtaining estimates of pharmacokinetic parameters, while requiring both minimal structural assumptions, and limited input by the analyst. As typically applied, its scope and depth are constrained by its statistical simplicity. Embedding the NCA within a hierarchical generalized additive model (HGAM) may facilitate the simultaneous analysis of data from multiple subjects, estimation of covariate effects in one stage, and implementation of censored responses, similarly to the capabilities of nonlinear multilevel models as widely applied in pharmacometrics. HGAM is an interesting extension to multilevel linear models that allows the effects of predictors to be implemented as smooth functions, which has been widely implemented in various disciplines to nonlinear trends, including for longitudinal data.This approach extends the capability of previous implementations of spline-based methods applied to NCA, within an accessible workflow in open software. Application of HGAM to two example datasets, one describing oral drug administration, and one describing IV and oral drug administration with categorical covariates and censoring, illustrates the overall approach, including parameter estimation, visualization and model checking, and uncertainty quantification. A Bayesian approach to estimation facilitates interpretable expressions of the uncertainty in individual parameters, population parameters, and functions of parameters such as contrasts.
Impact of angiotensin-receptor blockers on intrarenal renin-angiotensin system activity in hypertension: A PK/PD modelling study
Authors: Smith Delaney , Layton Anita 
Published: July 2023

AbstractThe renin-angiotensin system (RAS) is a primary regulator of volume homeostasis and blood pressure, whose over-activation is commonly associated with hypertension. Indeed, medications that target the RAS are generally effective in reducing blood pressure. However, more can be learned about how these medications influence the intrarenal RAS. Angiotensin-receptor blockers (ARBs) in particular have been shown to exert different effects on the intrarenal and systemic RASs in various experimental models of hypertension. In rats chronically infused with angiotensin II (Ang II), ARBs consistently prevent intrarenal, but not systemic Ang II levels from rising. The former effect is sufficient in preventing the development of hypertension. The regulation of intrarenal RAS, independently of the systemic RAS, by ARBs has been hypothesized to be mediated by the inhibition of all positive feedback loops inherent to the intrarenal RAS, also known as the “key point breakdown effect.” To investigate the validity of this hypothesis, we developed a PK/PD model of the ARB Losartan that considers the kidney, and applied the model to study how this class of medication influences intrarenal RAS activity and consequently blood pressure regulation in male rats. Simulations indicate that ARBs more effectively inhibit the activation of the intrarenal RAS because, unlike in the plasma, this process relies on the accumulation of cell-associated Ang II. We hypothesize that it is by blocking this intracellular uptake pathway, and restricting Ang II to extracellular regions of the kidney where the peptide cannot initiate downstream signalling, that Losartan normalizes blood pressure. While the key point break down effect assists in this response, it alone is not sufficient. Our results highlight the intrarenal RAS as the key pharmacological target of ARB treatment and emphasize the importance of this local tissue RAS in the development of hypertension.
Multidrug Efflux in Gram-Negative Bacteria: Rationally Modifying Compounds to Avoid Efflux Pumps
Authors: Gurvic Dominik , Zachariae Ulrich 
Published: July 2023

AbstractGram-negative bacteria cause the majority of critically drug-resistant infections, necessitating the rapid development of new drugs with Gram-negative activity. However, drug design is hampered by the low permeability of the Gram-negative cell envelope and the function of drug efflux pumps, which extrude foreign molecules from the cell. A better understanding of the molecular determinants of compound recognition by efflux pumps is, therefore, essential. Here, we quantitatively analyse the activity of over 73,000 compounds across three strains ofE. coli– the wild-type, an efflux-deficient variant, and a hyper-permeable variant – to elucidate the molecular principles of evading efflux pumps. Our results show that, alongside a range of physicochemical features, the presence or absence of specific chemical groups in the compounds substantially increases the probability of avoiding efflux. Furthermore, comparison of our findings with inward permeability data highlights the primary role of efflux in determining drug bioactivity in Gram-negative bacteria.
HATCHet2: clone- and haplotype-specific copy number inference from bulk tumor sequencing data
Authors: Myers Matthew A. , Arnold Brian J. , Bansal Vineet , Mullen Katelyn M. , Zaccaria Simone , Raphael Benjamin J. 
Published: July 2023

AbstractMulti-region DNA sequencing of primary tumors and metastases from individual patients helps identify somatic aberrations driving cancer development. However, most methods to infer copy-number aberrations (CNAs) analyze individual samples. We introduce HATCHet2 to identify haplotype- and clone-specific CNAs simultaneously from multiple bulk samples. HATCHet2 introduces a novel statistic, the mirrored haplotype B-allele frequency (mhBAF), to identify mirrored-subclonal CNAs having different numbers of copies of parental haplotypes in different tumor clones. HATCHet2 also has high accuracy in identifying focal CNAs and extends the earlier HATCHet method in several directions. We demonstrate HATCHet2’s improved accuracy using simulations and a single-cell sequencing dataset. HATCHet2 analysis of 50 prostate cancer samples from 10 patients reveals previously-unreported mirrored-subclonal CNAs affecting cancer genes.
Enigmas no longer: using Ultraconserved Elements to place several unusual hawk taxa and address the non-monophyly of the genusAccipiter(Accipitriformes: Accipitridae)
Authors: Catanach Therese A. , Halley Matthew R. , Pirro Stacy 
Published: July 2023

ABSTRACTHawks, eagles, and their relatives (Accipitriformes: Accipitridae) are a diverse and charismatic clade of modern birds, with many members that are instantly recognized by the general public. However, surprisingly little is known about the relationships among genera within Accipitridae, and several studies have suggested that some genera (in particular, the megadiverse genusAccipiter) are not monophyletic. Here, we combine a new large dataset obtained from Ultraconserved Elements (UCEs), generated from whole genome sequencing (WGS) of 120 species, with publicly available legacy markers (i.e., a suite of commonly sequenced mitochondrial and nuclear genes) to infer a well-supported, time-calibrated phylogeny of 236 extant or recently extinct species. Our densely-sampled phylogeny, which includes 90% of recognized species, confirms the non-monophyly ofAccipiterand provides a sufficient basis to revise the genus-level taxonomy, such that all genera in Accipitridae represent monophyletic groups.
Bimodal distribution ofCandida albicansin children with Autism linked with ASD symptoms
Authors: Nirmalkar Khemlal , Patel Jigar , Kang Dae-Wook , Bellinghiere Andrew , Bowes Devin A. , Adams James B. , Krajmalnik-Brown Rosa 
Published: July 2023

ABSTRACTThe gastrointestinal (GI) tract harbors an intricate and remarkably diverse microbial ecosystem that profoundly impacts various aspects of health and pathophysiology. While bacteria overwhelmingly represent most of the GI microbiota, it is imperative to consider the presence and function of fungal constituents (i.e., mycobiota) within the GI ecosystem. The substantial incidence of GI disorders and associated manifestations in children diagnosed with autism spectrum disorder (ASD) suggests a plausible contributory role of the gut mycobiota. Our investigation aimed to elucidate the gut mycobiota in a cohort comprising 38 typically developing children (TD) and 40 children with ASD. Fecal samples were collected from all participants and autism severity and GI symptoms were assessed to unravel the potential implications of mycobiota alterations in the gut. We employed fungal internal transcribed spacer (ITS) gene amplicon sequencing to analyze the fungal composition and investigate their relationship with GI and autism symptoms. Among gut mycobiota,Saccharomyces cerevisiaewas significantly lower (relative abundance) in ASD compared to TD children. TotalCandidaandC. albicansdemonstrated a bimodal distribution among children with ASD. Children with ASD with elevated Autism Treatment Evaluation Checklist (ATEC) scores (a more severe diagnosis) displayed an increased abundance ofC. albicansand a decreased abundance ofS. cerevisiae. A significant positive correlation was observed between ATEC scores and GI symptoms and between ATEC scores andC. albicans. Our findings propose that a deficit of beneficial fungi, specificallyS. cerevisiae,and an overgrowth ofC. albicansmay worsen autism severity in children with ASD. Future work employing more advanced techniques (i.e., shotgun metagenomics) is encouraged to advance understanding of the functional role of fungi/yeast, and their interplay between GI symptoms and autism severity in children with ASD.
Nanoscale clustering by O-antigen-Secretory Immunoglobulin-A binding limits outer membrane diffusion by encaging individualSalmonellacells
Authors: Hockenberry Alyson , Radiom Milad , Arnoldini Markus , Turgay Yagmur , Dunne Matthew , Adamcik Jozef , Stadtmueller Beth , Mezzenga Raffaele , Ackermann Martin , Slack Emma 
Published: July 2023

AbstractSecreted immunoglobulins, predominantly SIgA, influence the colonization and pathogenicity of mucosal bacteria. While part of this effect can be explained by SIgA-mediated bacterial aggregation, we have an incomplete picture of how SIgA binding influences cells independently of aggregation. Here we show that akin to microscale crosslinking of cells, SIgA targeting theSalmonellaTyphimurium O-antigen extensively crosslinks the O-antigens on the surface of individual bacterial cells at the nanoscale. This crosslinking results in an essentially immobilized bacterial outer membrane. Membrane immobilization, combined with Bam-complex mediated outer membrane protein insertion results in biased inheritance of IgA-bound O-antigen, concentrating SIgA-bound O-antigen at the oldest poles during cell growth. By combining empirical measurements and simulations, we show that this SIgA-driven biased inheritance increases the rate at which phase-varied daughter cells become IgA-free: a process that can accelerate IgA escape via phase-variation of O-antigen structure. Our results show that O-antigen-crosslinking by SIgA impacts workings of the bacterial outer membrane, helping to mechanistically explain how SIgA may exert aggregation-independent effects on individual microbes colonizing the mucosae.