bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure of a dimeric ABC transporter
Authors: Bickers Sarah C. , Benlekbir Samir , Rubinstein John L. , Kanelis Voula 
Published: April 2023

AbstractATP binding cassette (ABC) proteins generally couple ATP hydrolysis to the active transport of solutes across cellular membranes. All ABC proteins contain a core structure of two transmembrane domains (TMD1, TMD2) and two nucleotide binding domains (NBD1, NBD2), and many ABC proteins contain additional domains. Some members of the C subfamily of ABC (ABCC) proteins, such as the multidrug resistant protein 1 (MRP1), contain an N-terminal transmembrane domain (TMD0) and L0 linker that regulate transport activity and cellular trafficking, and mediate interactions with other proteins. Regulation can also be imparted by phosphorylation, proteolytic processing, and/or oligomerization of the proteins. Here we present the structure of yeast cadmium factor 1 (Ycf1p), a homologue of MRP1, in its mature form following cleavage by the yeast protease Pep4p. Remarkably, proteolytically cleaved Ycf1p forms a well-ordered dimer, with some monomeric particles also present in solution. Numerous other ABC proteins have been proposed to form dimers but no high-resolution structures have been reported. The monomeric and dimeric Ycf1p species are differentially phosphorylated at the intrinsically disordered regulatory (R) region, which links NBD1 to TMD2, and possess different ATPase activities indicating that dimerization affects the function of the protein. Protein-protein interactions involving TMD0, the L0 linker, and the R region mediate contacts between Ycf1p protomers in the dimer. In addition, cryo-EM density is observed for lipids at the interface between protomers, which suggests that lipids stabilize the dimer. The Ycf1p dimer structure is consistent with proposed dimerization interfaces of other ABCC dimers, such as MRP1.
Dietary phenolics and their microbial metabolites are poor inhibitors of trimethylamine oxidation to trimethylamine N-oxide by hepatic flavin monooxygenase 3
Authors: Iglesias-Carres Lisard , Chadwick-Corbin Sydney A. , Sweet Michael G. , Neilson Andrew P. 
Published: April 2023

ABSTRACTHigh circulating levels of trimethylamine N-oxide (TMAO) have been associated with cardiovascular disease risk. TMAO is formed through a microbiome-host pathway utilizing primarily dietary choline as a substrate. Specific gut microbiota transform choline into trimethylamine (TMA), and, when absorbed, host hepatic flavin-containing monooxygenase 3 (FMO3) oxidizes TMA into TMAO. Chlorogenic acid and its metabolites reduce microbial TMA productionin vitro. However, little is known regarding the potential for chlorogenic acid and its bioavailable metabolites to inhibit the last step: hepatic conversion of TMA to TMAO. We developed a screening methodology to study FMO3-catalyzed production of TMAO from TMA. HepG2 cells were unable to oxidize TMA into TMAO due to their lack of FMO3 expression. Although Hepa-1 cells did express FMO3 when pre-treated with TMA and NADPH, they lacked enzymatic activity to produce TMAO. Rat hepatic microsomes contained active FMO3. Optimal reaction conditions were: 50 µM TMA, 0.2 mM NADPH and 33 µL microsomes/mL reaction. Methimazole (a known FMO3 competitive substrate) at 200 µM effectively reduced FMO3-catalyzed conversion of TMA to TMAO. However, bioavailable chlorogenic acid metabolites did not generally inhibit FMO3 at physiological (1 µM) nor supra-physiological (50 µM) doses. Thus, the effects of chlorogenic acid in regulating TMAO levelsin vivoare unlikely to occur through direct FMO3 enzyme inhibition. Potential effects on FMO3 expression remain unknown. Intestinal inhibition of TMA production and/or absorption are thus likely their primary mechanisms of action.
Association of inflammation and tissue damage induced biological processes in masseter muscle with the resolution of chronic myalgia
Authors: Lindquist Karen A. , Shein Sergey A. , Hovhannisyan Anahit H. , Mecklenburg Jennifer , Zou Yi , Lai Zhao , Tumanov Alexei V. , Akopian Armen N. 
Published: April 2023

AbstractBiological processes linked to intramuscular inflammation during myogenous temporomandibular disorder (TMDM) are largely unknown. We mimicked this inflammation by intra-masseteric muscle (MM) injections of complete Freund’s adjuvant (CFA) or collagenase type 2 (Col), which emulates tissue damage. CFA triggered mechanical hypersensitivity at 1d post-injection was mainly linked to processes controlling chemotactic activity of monocytes and neutrophils. At 5d post-CFA, when hypersensitivity was resolved, there was minimal inflammation whereas tissue repair processes were pronounced. Low dose Col (0.2U) also produced acute orofacial hypersensitivity that was linked to tissue repair, but not inflammatory processes. High dose Col (10U) triggered prolonged orofacial hypersensitivity with inflammatory processes dominating at 1d post-injection. At pre-resolution time point (6d), tissue repair processes were underway and a significant increase in pro-inflammatory gene expressions compared to 1d post-injection were detected. RNA-seq and flow cytometry showed that immune processes in MM were linked to accumulation of macrophages, natural killer and natural killer T cells, dendritic cells and T-cells. Altogether, CFA and Col treatments induced different immune processes in MM. Importantly, orofacial hypersensitivity resolution was preceded with repairs of muscle cell and extracellular matrix, an elevation in immune system gene expression and accumulation of distinct immune cells in MM.
High prevalence of antibiotic resistance in traditionally fermented foods as a critical risk factor for host gut antibiotic resistome
Authors: Li Yutong , Fu Siying , Klein Matthias S. , Wang Hua 
Published: April 2023

AbstractDisrupted gut microbiota as a critical risk factor for many noncommunicable diseases is largely driven by gut microbiota-impacting drugs, especially orally administrated as well as biliary excreted antibiotics. Fermented food consumption has been encouraged to replenish disrupted gut microbiota, but its overall impact on host gut health remains to be elucidated. This study examined retail traditionally fermented foods and gut microbiota of consumers of fermented foods for antibiotic resistome. Dietary intervention by fermented foods was found leading to a surge of the antibiotic resistome in gut microbiota of most human subjects. Antibiotic resistome was further illustrated in traditionally fermented food samples, and viable antibiotic resistant (AR) bacteria were recovered and highly prevalent in retail kimchi and artisan cheeses assessed in this pilot screening. Identified AR isolates included pathogens of importance in nosocomial infections such asKlebsiella pneumoniae,Enterococcus, etc., as well as commensals and lactic acid bacteria, some exhibited extremely high minimum inhibitory concentration (MIC) against antibiotics of clinical significance. Exposing fermented food microbiota to representative antibiotics further led to a boost of the corresponding antibiotic and multidrug-resistance gene pools and disturbed microbiota. These results revealed an underestimated public health risk associated with fermented foods intervention, particularly to susceptible population with gastrointestinal tract symptoms and compromised immune functions seeking gut microbiota rescue. The findings call for more comprehensive investigation and investment on the benefits and potential safety challenges associated with traditionally fermented foods, productive intervention of foodborne antibiotic resistance, and strategic movements to mitigate unnecessary damages to the host gut microbiota.
AFLOWERING LOCUS Tortholog is associated with photoperiod-insensitive flowering in hemp (Cannabis sativaL.)
Authors: Dowling Caroline A. , Shi Jiaqi , Toth Jacob A. , Quade Michael A. , Smart Lawrence B. , McCabe Paul F. , Melzer Rainer , Schilling Susanne 
Published: April 2023

AbstractHemp (Cannabis sativaL.) is an extraordinarily versatile crop, with applications ranging from medicinal compounds to seed oil and fibre products.Cannabis sativais a short-day plant, and its flowering is tightly controlled by photoperiod. However, substantial genetic variation exists for photoperiod sensitivity inC. sativa,and photoperiod-insensitive (“autoflower”) cultivars are available.Using a bi-parental mapping population and bulked segregant analysis, we identifiedAutoflower2, a 0.5 Mbp locus significantly associated with photoperiod-insensitive flowering in hemp.Autoflower2contains an ortholog of the central flowering time regulatorFLOWERING LOCUS T(FT) fromArabidopsis thalianawhich we termedCsFT1. Extensive sequence divergence between alleles ofCsFT1was identified between photoperiod-sensitive and insensitive cultivars ofC. sativa, including a duplication ofCsFT1and sequence differences especially in introns. Genotyping of several mapping populations and a diversity panel confirmed a strong correlation betweenCsFT1alleles and photoperiod response as well as affirming that at least two independent loci for this agriculturally important trait,Autoflower1andAutoflower2, exist in theC. sativagene pool.This study reveals the multiple independent origins of photoperiod insensitivity inC. sativa,supporting the likelihood of a complex domestication history in this species. By integrating the genetic relaxation of photoperiod sensitivity into novelC. sativacultivars, expansion to higher latitudes will be permitted, thus allowing the full potential of this versatile crop to be reached.
Isoform-specific translational control is evolutionarily conserved in primates
Authors: Draper Jolene , Philipp Julia , Neeb Zach , Thomas Richard , Katzman Solomon , Salama Sofie , Haussler David , Sanford Jeremy R. 
Published: April 2023

AbstractAlternative splicing (AS) alters messenger RNA (mRNA) coding capacity, localization, stability, and translation. Here we use comparative transcriptomics to identify cis-acting elements coupling AS to translational control (AS-TC). We sequenced total cytosolic and polyribosome-associated mRNA from human, chimpanzee, and orangutan induced pluripotent stem cells (iPSCs), revealing thousands of transcripts with splicing differences between subcellular fractions. We found both conserved and species-specific polyribosome association patterns for orthologous splicing events. Intriguingly, alternative exons with similar polyribosome profiles between species have stronger sequence conservation than exons with lineage-specific ribosome association. These data suggest that sequence variation underlies differences in the polyribosome association. Accordingly, single nucleotide substitutions in luciferase reporters designed to model exons with divergent polyribosome profiles are sufficient to regulate translational efficiency. We used position specific weight matrixes to interpret exons with species-specific polyribosome association profiles, finding that polymorphic sites frequently alter recognition motifs for trans-acting RNA binding proteins. Together, our results show that AS can regulate translation by remodeling the cis-regulatory landscape of mRNA isoforms.
Sensory Eye Dominance Plasticity in the Human Adult Visual Cortex
Authors: Kam Ka Yee , Chang Dorita H. F. 
Published: April 2023

AbstractSensory eye dominance occurs when the visual cortex weighs one eye’s data more heavily than those of the other. Encouragingly, mechanisms underlying sensory eye dominance in human adults retain a certain degree of plasticity. Notably, perceptual training using dichoptically presented motion signal-noise stimuli has been shown to elicit changes in sensory eye dominance both in visually impaired and normal observers. However, the neural mechanisms underlying these learning-driven improvements are not well understood. Here, we measured changes in fMRI responses before and after a five-day visual training protocol to determine the neuroplastic changes along the visual cascade. Fifty visually normal observers received training on a dichoptic or binocular variant of a signal-in-noise (left-right) motion discrimination task over five consecutive days. We show significant shifts in sensory eye dominance following training, but only for those who received dichoptic training. Pattern analysis of fMRI responses revealed that responses of V1 and hMT+ predicted sensory eye dominance for both groups, but only before training. After dichoptic (but not binocular) visual training, responses of V1 and hMT+ could no longer predict sensory eye dominance. Our data suggest that perceptual training-driven changes in eye dominance are driven by a reweighting of the two eyes’ data in both primary and task-related extrastriate visual areas. These findings may provide insight into developing region-targeted rehabilitative paradigms for the visually impaired, particularly those with severe binocular imbalance.
Uniform cerebral organoid culture on a pillar plate by simple and reproducible spheroid transfer from an ultralow attachment well plate
Authors: Acharya Prabha , Joshi Pranav , Shrestha Sunil , Choi Na Young , Jeong Sehoon , Lee Moo-Yeal 
Published: April 2023

AbstractHuman induced pluripotent stem cell (iPSCs)-derived brain organoids have potential to recapitulate the earliest stages of brain development, serving as an effectivein vitromodel for studying both normal brain development and disorders. However, current brain organoid culture methods face several challenges, including low throughput, high variability in organoid generation, and time-consuming, multiple transfer and encapsulation of cells in hydrogels throughout the culture. These limitations hinder the widespread application of brain organoids including high-throughput assessment of compounds in clinical and industrial lab settings. In this study, we demonstrate a straightforward approach of generating multiple cerebral organoids from iPSCs on a pillar plate platform, eliminating the need for labor-intensive, multiple transfer and encapsulation steps to ensure the reproducible generation of cerebral organoids. We formed embryoid bodies (EBs) in an ultra-low attachment (ULA) 384-well plate and subsequently transferred them to the pillar plate containing Matrigel, using a straightforward sandwiching and inverting method. Each pillar on the pillar plate contains a single spheroid, and the success rate of spheroid transfer was in a range of 95 - 100%. By differentiating the EBs on the pillar plate, we achieved robust generation of cerebral organoids with a coefficient of variation (CV) below 19%. Notably, our spheroid transfer method in combination with the pillar plate allows miniaturized culture of cerebral organoids, alleviates the issue of organoid variability, and has potential to significantly enhance assay throughput by allowingin situorganoid assessment as compared to conventional organoid culture in 6-/24-well plates, petri dishes, and spinner flasks.
Progesterone is an Inducement of Heritable Pulmonary Arterial Hypertension with BMPR2 Mutation
Authors: Hu Wei-Ping , Zhang Si-Jin , Ding Yong-Jie , Fang Jie , Zhou Ling , Xie Si-Min , Ge Xiao , Fu Li-Jun , Li Qing-Yun , Qu Jie-Ming , Li Shan-Qun , Liu Dong 
Published: April 2023

AbstractBackgroundBone morphogenetic protein type II receptor (BMPR2) gene mutation accounts for 80% of patients with heritable pulmonary artery hypertension (HPAH), and female mutation carriers have significantly higher penetrance rate than males. The inducement of HPAH penetrance and the mechanism of sex differential penetrance are still elusive.MethodsWe infected or transfected pulmonary artery smooth muscle cells (PASMCs) with shBMPR2 lentivirus or siBMPR2 to simulate the pathologic condition of BMPR2 heterozygous mutation and treated them with progesterone. The HPAH patient-derived induced pluripotent stem cells (iPSCs) were induced into vascular smooth muscle cells (VSMCs) to further verify the cellular phenotype. Wild-type flox+/-female mice and SM22-cre BMPR2 flox+/-female mice (CKO mice) were administered with 1-month progesterone, and their phenotype of PAH was evaluated by right heart catheterization and histopathological examination.ResultsProgesterone promoted the proliferation of PASMCs with BMPR2-knockdownby activating ERK pathway via progesterone receptor (PGR). Activated ERK not only upregulated the phosphorylation and elevation of cMYC, but also induced the transcription of endothelin (EDN1) by promoting the nuclear entry of c-JUN and combination on the its promoter region. Similar results were confirmed by iPSCs-VSMCs experiment. CKO mice developed PAH spontaneously and had increased expression of EDN1, which was further aggravated by exogenous progesterone.ConclusionsProgesterone might be an inducement of HPAH penetrance caused by BMPR2 mutation, accounting for sex differential penetrance.
Spatiotemporal transcriptome atlas of human embryos after gastrulation
Authors: Pan Jiexue , Li Yuejiao , Lin Zhongliang , Lan Qing , Chen Huixi , Zhai Man , Sui Shengwei , Zhang Gaochen , Cheng Yi , Tang Yunhui , Wang Qingchen , Zhang Ying , Ma Fuhe , Xu Yue , Mao Yiting , Chen Qinfang , Guan Yichun , Meng Nan , Lu Haiqian , Li Xiangjuan , Zheng Tingting , Yao Xiaoying , Qin Qiuyu , Jiang Bin , Ren Yuxing , Luo Meiqi , Nancuo Ji , Jin Xin , Sheng Jianzhong , Xu Congjian , Liu Xinmei , Wu Yanting , Xu Chenming , Zhao Lijian , Yang Hongbo , Gao Ya , Ding Guolian , Xu Xun , Huang Hefeng 
Published: April 2023

AbstractThe spatial and temporal atlas of gene expression in the human embryo at early gestation is critical in understanding embryo development, organogenesis, and disease origins. We obtained the spatiotemporal transcriptome from 90 sagittal sections of 16 whole human embryos from 3 to 8 post-conception weeks by Stereo-seq with high resolution and ultra-large field, establishing the development trajectory/regulatory profiling of 49 organs. We uncovered the organ-specific regulons as potential lineage-determining factors and identified the new regulatory networks during heart and brain development. The atlas refines the key organs/cell types vulnerable to virus infection and genetic disorders, and, reveals the dynamics of allelic gene expression in specific organs at different stages. These results present the first comprehensive delineation of the spatiotemporal transcriptomic dynamics of human organogenesis.One Sentence SummaryThe spatiotemporal transcriptome atlas presents a comprehensive delineation of human embryogenesis after gastrulation.
Factorized visual representations in the primate visual system and deep neural networks
Authors: Lindsey Jack W. , Issa Elias B. 
Published: April 2023

ABSTRACTObject classification has been proposed as a principal objective of the primate ventral visual stream and has been used as an optimization target for deep neural network models (DNNs) of the visual system. However, visual brain areas represent many different types of information, and optimizing for classification of object identity alone does not constrain how other information may be encoded in visual representations. Information about different scene parameters may be discarded altogether (“invariance”), represented in non-interfering subspaces of population activity (“factorization”) or encoded in an entangled fashion. In this work, we provide evidence that factorization is a normative principle of biological visual representations. In the monkey ventral visual hierarchy, we found that factorization of object pose and background information from object identity increased in higher-level regions and strongly contributed to improving object identity decoding performance. We then conducted a large-scale analysis of factorization of individual scene parameters – lighting, background, camera viewpoint, and object pose – in a diverse library of DNN models of the visual system. Models which best matched neural, fMRI and behavioral data from both monkeys and humans across 12 datasets tended to be those which factorized scene parameters most strongly. Notably, invariance to these parameters was not as consistently associated with matches to neural and behavioral data, suggesting that maintaining non-class information in factorized activity subspaces is often preferred to dropping it altogether. Thus, we propose that factorization of visual scene information is a widely used strategy in brains and DNN models thereof.
Interactions between fitness components across the life cycle constrain competitor coexistence
Authors: Gómez‐Llano Miguel , Boys Wade A. , Ping Taylor , Tye Simon P. , Siepielski Adam M. 
Published: April 2023

Abstract

Numerous mechanisms can promote competitor coexistence. Yet, these mechanisms are often considered in isolation from one another. Consequently, whether multiple mechanisms shaping coexistence combine to promote or constrain species coexistence remains an open question.

Here, we aim to understand how multiple mechanisms interact within and between life stages to determine frequency‐dependent population growth, which has a key role stabilizing local competitor coexistence.

We conducted field experiments in three lakes manipulating relative frequencies of two Enallagma damselfly species to evaluate demographic contributions of three mechanisms affecting different fitness components across the life cycle: the effect of resource competition on individual growth rate, predation shaping mortality rates, and mating harassment determining fecundity. We then used a demographic model that incorporates carry‐over effects between life stages to decompose the relative effect of each fitness component generating frequency‐dependent population growth.

This decomposition showed that fitness components combined to increase population growth rates for one species when rare, but they combined to decrease population growth rates for the other species when rare, leading to predicted exclusion in most lakes.

Because interactions between fitness components within and between life stages vary among populations, these results show that local coexistence is population specific. Moreover, we show that multiple mechanisms do not necessarily increase competitor coexistence, as they can also combine to yield exclusion. Identifying coexistence mechanisms in other systems will require greater focus on determining contributions of different fitness components across the life cycle shaping competitor coexistence in a way that captures the potential for population‐level variation.
Manhood, Military Forts and Ethnological Thought: John Gregory Bourke and the Rise of Border Ethnology, 1870s–90s
Authors: Hernández Kris Klein 
Published: April 2023

AbstractThis article explores how some army forts in 1870s, 1880s and 1890s Texas, New Mexico and Arizona emerged as sites for the production of ethnological knowledge about Mexican and native (Apache, Zuni) peoples. It focuses primarily on US Army Captain John Gregory Bourke's diary entries and publications about his time in Texas, New Mexico and Arizona military garrisons from the late 1860s to the 1890s. Expanding upon cultural studies scholar José Limón's discussions of Bourke's ambivalent relationship to the subjects of his ethnographic study, this article investigates how Bourke's excursions into the built‐environment in and beyond border military forts shaped his understanding of the logics of empire and how his writing, in turn, influenced popular conceptions of the borderlands. Turning to historian Gail Bederman's exploration of turn‐of‐the‐century conceptions of manhood, this article examines how Bourke's ethnographic forays from the homosocial and white‐dominated enclosure of the military fort into the multi‐racial and gendered borderlands defined and challenged ideas about manhood and masculinity on the ‘frontier’. This article proposes that the study of army fort personnel helps tease out how militarised individuals made sense of the built‐environment through their racial and gendered observations of border populations.