bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted NAD+Delivery for Intimal Hyperplasia and Re-endothelialization: A Novel Anti-restenotic Therapy Approach
Authors: Yin Li , Tong Yao , Islam Zain Husain , Zhang Kaijie , Xie Ruosen , Burger Jacobus , Hoyt Nicholas , Kent Eric William , Marcum William Aaron , Johnston Campbell , Kanchetty Rohan , Tetz Zoe , Stanisic Sophia , Huang Yitao , Guo Lian-Wang , Gong Shaoqin , Wang Bowen 
Published: February 2024

AbstractEndovascular interventions often fail due to restenosis, primarily caused by smooth muscle cell (SMC) proliferation, leading to intimal hyperplasia (IH). Current strategies to prevent restenosis are far from perfect and impose significant collateral damage on the fragile endothelial cell (EC), causing profound thrombotic risks. Nicotinamide adenine dinucleotide (NAD+) is a co-enzyme and signaling substrate implicated in redox and metabolic homeostasis, with a pleiotropic role in protecting against cardiovascular diseases. However, a functional link between NAD+repletion and the delicate duo of IH and EC regeneration has yet to be established. NAD+repletion has been historically challenging due to its poor cellular uptake and low bioavailability. We have recently invented the first nanocarrier that enables direct intracellular delivery of NAD+in vivo. Combining the merits of this prototypic NAD+-loaded calcium phosphate (CaP) nanoparticle (NP) and biomimetic surface functionalization, we created a biomimetic P-NAD+-NP with platelet membrane coating, which enabled an injectable modality that targets IH with excellent biocompatibility. Using human cell primary culture, we demonstrated the benefits of NP-assisted NAD+repletion in selectively inhibiting the excessive proliferation of aortic SMC, while differentially protecting aortic EC from apoptosis. Moreover, in a rat balloon angioplasty model, a single-dose treatment with intravenously injected P-NAD+-NP immediately post angioplasty not only mitigated IH, but also accelerated the regeneration of EC (re-endothelialization)in vivoin comparison to control groups (i.e., saline, free NAD+solution, empty CaP-NP). Collectively, our current study provides proof-of-concept evidence supporting the role of targeted NAD+repletion nanotherapy in managing restenosis and improving re-endothelialization.
Contribution of Urea to Nitrite Production in Southern Ocean Waters with Contrasting Nitrifying Communities
Authors: Hollibaugh J T. , Okotie-Oyekan A. , Damashek J. , Ducklow H. , Popp B. N. , Wallsgrove N. , Allen T. 
Published: February 2024

ABSTRACTWe compared the contribution of ammonia and urea to nitrite production in >100 samples of Southern Ocean waters with abundant and diverse ammonia-oxidizing archaeal (AOA) communities. Ammonia (AO) and urea (UO) oxidation rates were distributed uniformly within a water mass across coastal and slope waters west of the Antarctic Peninsula; however, rates and AOA community composition displayed strong vertical gradients. Rates in most samples from Antarctic surface and slope water were at or below the limit of detection. Highest mean rates of both processes were in the Winter Water (WW, epipelagic, 21.2 and 1.6 nmol N L-1d-1), and the Circumpolar Deep Water (CDW, mesopelagic, 7.9 and 2.5 nmol N L-1d-1), for AO and UO, respectively. However, we also found that the response of AO and UO to substrate amendments varied by water mass. AO rates in WW samples increased by ∼200% with 44 vs 6 nM amendments, but decreased (down to 7%) in CDW samples. UO rates responded similarly, but to a lesser degree. This response suggests that even low NH4+amendments may inhibit AO by mesopelagic Thaumarchaeota populations. AO and UO rates were not correlated, nor were they correlated with the abundance or ratios of abundance of marker genes, or with the concentrations of ammonium or urea. Our data suggest that while ammonium is the primary substrate, urea-N is responsible for a significant fraction (∼25% of that from AO alone) of nitrite production in the Southern Ocean, comparable to its contribution at lower latitudes.IMPORTANCESouthern Ocean nitrification fuels denitrification in oxygen depleted zones at higher latitudes, one of the controls of N:P ratios in the global ocean. N2O, a powerful greenhouse gas, is by-product of nitrification. We contrast the contributions of ammonium and urea-N to nitrification in the Southern Ocean. Our work constrains rates and demonstrates that the contribution of urea-N to nitrite production in polar waters is comparable to that in temperate oceans. Correlations between activity and the abundance or ratios of Thaumarchaeota marker genes were weak, questioning their use as indicators of activity. We document differential responses of activity to substrate amendments by water mass: enhanced in epipelagic but inhibited in mesopelagic samples. We interpret this difference in the context of community composition and the production of reactive oxygen species. Our insights into environmental controls of nitrification are relevant to microbial ecologists studying Thaumarchaeota and to modeling the global nitrogen cycle.
The genome of Przewalski’s horse (Equus ferus przewalskii)
Authors: Flack Nicole , Hughes Lauren , Cassens Jacob , Enriquez Maya , Gebeyehu Samrawit , Alshagawi Mohammed , Hatfield Jason , Kauffman Anna , Brown Baylor , Klaeui Caitlin , Mabrouk Islam F. , Walls Carrie , Yeater Taylor , Rivas Anne , Faulk Christopher 
Published: February 2024

AbstractThe Przewalski’s horse (Equus ferus przewalskii) is an endangered equid native to the steppes of central Asia. After becoming extinct in the wild, multiple conservation efforts convened to preserve the species including captive breeding programs, reintroduction and monitoring systems, protected lands, and cloning. Availability of a highly contiguous reference genome is essential to support these continued efforts. We used Oxford Nanopore sequencing to produce a scaffold-level 2.5 Gb nuclear assembly and 16,002 bp mitogenome from a captive Przewalski’s mare. All assembly drafts were generated from 111 Gb of sequence from a single PromethION R10.4.1 flow cell. The mitogenome contained 37 genes in the standard mammalian configuration and was 99.63% identical to the domestic horse (Equus caballus). The nuclear assembly, EquPr2, contained 2,146 scaffolds with an N50 of 85.1 Mb, 43X mean depth, and BUSCO quality score of 98.92%. EquPr2 successfully improves upon the existing Przewalski’s horse reference genome (Burgud), with 25-fold fewer scaffolds, a 166-fold larger N50, and phased pseudohaplotypes. Modified basecalls revealed 79.5% DNA methylation and 2.1% hydroxymethylation globally. Allele-specific methylation analysis between pseudohaplotypes revealed 226 differentially methylated regions (DMRs) in known imprinted genes and loci not previously reported as imprinted. The heterozygosity rate of 0.165% matches previous estimates for the species and compares favorably to other endangered animals. This improved Przewalski’s horse assembly will serve as a valuable resource for conservation efforts and comparative genomics investigations.
Modulation of stress granule dynamics by phosphorylation and ubiquitination in plants
Authors: He Siou-Luan , Wang Xiling , Kim Sungil , Kong Liang , Wang Lei , He Ping , Shan Libo , Wang Ying , Jang Jyan-Chyun 
Published: February 2024

AbstractThe Arabidopsis tandem CCCH zinc finger 1 (TZF1) is an RNA-binding protein that plays a crucial role in plant growth and stress response. TZF1 can localize to ribonucleoprotein (RNP) granules in response to various abiotic stresses. However, very little is known about the composition, function, and assembly mechanism of plant RNP granules. In this report, we show that TZF1 contains two intrinsically disordered regions (IDRs) necessary for its localization to stress granules (SGs), a subclass of RNP granules. TZF1 recruits mitogen-activated protein kinase (MAPK) signaling components and an E3 ubiquitin ligase KEEP-ON-GOING (KEG) to SGs. TZF1 is phosphorylated by MPKs and ubiquitinated by KEG. The phosphorylation sites of TZF1 were mapped by mass spectrometry. Mutant studies revealed that phosphorylation and ubiquitination of specific residues played differential roles in enhancing or reducing TZF1 SG assembly and protein-protein interaction with mitogen-activated kinase kinase 5 (MKK5) in SGs. TZF1 is extremely unstable, and its accumulation can be enhanced by proteosome inhibitor MG132. We showed that TZF1 was ubiquitinated in vivo and in vitro by KEG and TZF1 accumulated at a much lower level in gain-of-function mutantkeg-4, compared to the WT. Ubiquitination appeared to play a positive role in TZF1 SG assembly, because either single or higher order mutations caused reduced number of SGs per cell, while enhanced the coalescence of small SGs into a large nucleus-like SG encompassing the nucleus. Together, our results demonstrate that the assembly of TZF1 SGs is distinctively regulated by ubiquitination and phosphorylation.
Human Alveolar and Monocyte-derived Human Macrophage Responses to Mycobacterium tuberculosis
Authors: Campo Monica , Dill-McFarland Kimberly A. , Peterson Glenna J. , Benson Basilin , Skerrett Shawn J. , Hawn Thomas R. 
Published: February 2024

AbstractRationaleAlveolar macrophages (AMs) and recruited monocyte-derived macrophages (MDMs) mediate early lung immune responses toMycobacterium tuberculosis(Mtb). Differences in the response of these distinct cell types is poorly understood and may provide insight into mechanisms of TB pathogenesis.ObjectivesTo determine whether Mtb induces unique and essential anti-microbial pathways in human AMs compared to MDMs.MethodsUsing paired human AMs and 5-day MCSF-derived MDMs from 6 healthy volunteers, we infected cells with Mtb H37Rv for 6 hours, isolated RNA, and analyzed transcriptomic profiles with RNASeq.Main ResultsWe found 681 genes that were Mtb-dependent in AMs compared to MDMs and 4538 that were Mtb-dependent in MDMs but not AMs (FDR < 0.05). Using hypergeometric enrichment of DEGs in Broad Hallmark gene sets, we found that Type I and II IFN Response were the only gene sets selectively induced in Mtb-infected AM (FDR <0.05). In contrast, MYC targets, unfolded protein response and MTORC1 signaling, were selectively enriched in MDMs (FDR < 0.05). IFNA1, IFNA8, IFNE, and IFNL1 were specifically and highly upregulated in AMs compared to MDMs at baseline and/or after Mtb infection. IFNA8 modulated Mtb-induced pro-inflammatory cytokines and, compared to other interferons, stimulated unique transcriptomes. Several DNA sensors and Interferon Regulatory Factors had higher expression at baseline and/or after Mtb infection in AMs compared to MDMs.ConclusionsThese findings demonstrate that Mtb infection induced unique transcriptional responses in human AMs compared to MDMs, including upregulation of the IFN response pathway and specific DNA sensors.
Adverse structural and mechanical remodelling of main pulmonary artery in experimental pulmonary arterial hypertension is associated with impaired right ventricle-pulmonary artery coupling and function
Authors: Mirani Bahram , Dauz John D. , Yazaki Kana , Latifi Neda , Santerre J Paul , Bendeck Michelle P. , Simmons Craig A. , Friedberg Mark K. 
Published: February 2024

AbstractRationaleCoupling between right ventricular function and the pulmonary vasculature determines outcomes in pulmonary arterial hypertension. The mechanics of the main pulmonary artery is an important but understudied determinant of right ventricular-pulmonary artery coupling.ObjectivesTo investigate the histology and mechanics of the pulmonary artery in relationship to right ventricular remodeling, mechanics, hemodynamics and coupling in experimental pulmonary arterial hypertension.MethodsIn a sugen+hypoxia rat model of pulmonary arterial hypertension, right ventricular hemodynamics were assessed by conductance catheters. Active tension-strain curves were generated using echocardiography. Main pulmonary artery and right ventricle free-wall were harvested to determine their macro- and micro-structure, composition, and mechanical properties. Comprehensive multivariate analyses elucidated relationships between pulmonary artery and right ventricle mechanics, structure and coupling.Measurements and Main ResultsPulmonary hypertensive main pulmonary arteries developed fibrosis relative to healthy controls, as did right ventricles, which also hypertrophied, with re-orientation of muscle fibres toward a tri-layer architecture reminiscent of normal left ventricular architecture. Increased glycosaminoglycan deposition and increased collagen-to-elastin ratio in the pulmonary artery; and increased collagen, as well as hypertrophy and reorganization of myofibers in the right ventricle, led to increased stiffness. This increase in stiffness was more pronounced in the longitudinal direction in the high- and low-strain regime for the pulmonary artery and right ventricle, respectively, causing increased mechanical anisotropy. Main pulmonary artery stiffening correlated significantly with right ventricular tissue mechanical remodelling and reduced systolic performance, cardiac output and right ventricle-pulmonary artery coupling.ConclusionsCompositional, structural, and mechanical changes in the main pulmonary artery correlate with adverse right ventricular remodeling, mechanics, function and coupling in pulmonary arterial hypertension. Therefore, increasing mechanical compliance of the large pulmonary arteries may be an important and novel therapeutic strategy for mitigating right ventricular failure.
Responses of neurons in macaque V4 to object and texture images
Authors: Lieber Justin D. , Oleskiw Timothy D. , Simoncelli Eero P. , Movshon J. Anthony 
Published: February 2024

AbstractHumans and monkeys can effortlessly recognize objects in everyday scenes. This ability relies on neural computations in the ventral stream of visual cortex. The intermediate computations that lead to object selectivity are not well understood, but previous studies implicate V4 as an early site of selectivity for object shape. To explore the mechanisms of this selectivity, we generated a continuum of images between “scrambled” textures and photographic images of both natural and manmade environments, using techniques that preserve the local statistics of the original image while discarding information about scene and shape. We measured the responses of single units in awake macaque V4 to these images. On average, V4 neurons were slightly more active in response to photographic images than to their scrambled counterparts. However, responses in V4 varied widely both across different cells and different sets of images. An important determinant of this variation was the effectiveness of image families at driving strong neural responses. Across the full V4 population, a cell’s average evoked firing rate for a family reliably predicted that family’s preference for photographic over scrambled images. Accordingly, the cells that respond most strongly to each image family showed a much stronger difference between photographic and scrambled images and a graded level of modulation for images scrambled at intermediate levels. This preference for photographic images was not evident until ∼50 ms after the onset of neuronal activity and did not peak in strength until 140 ms after activity onset. Finally, V4 neural responses seemed to categorically separate photographic images from all of their scrambled counterparts, despite the fact that the least scrambled images in our set appear similar to the originals. When these same images were analyzed with DISTS (Deep Image Structure and Texture Similarity), an image-computable similarity metric that predicts human judgements of image degradation, this same pattern emerged. This suggests that V4 responses are highly sensitive to small deviations from photographic image structure.
Transcriptional perturbation of LINE-1 elements reveals theircis-regulatory potential
Authors: Pérez-Rico Yuvia A , Bousard Aurélie , Misikova Lenka Henao , Mulugeta Eskeatnaf , de Almeida Sérgio F , Muotri Alysson R , Heard Edith , Gendrel Anne-Valerie 
Published: February 2024

AbstractLong interspersed element-1 (LINE-1 or L1) retrotransposons constitute the largest transposable element (TE) family in mammalian genomes and contribute prominently to inter- and intra-individual genetic variation. Although most L1 elements are inactive, some evolutionary younger elements remain intact and genetically competent for transcription and occasionally retrotransposition. Despite being generally more abundant in gene-poor regions, intact or full-length L1s (FL-L1) are also enriched around specific classes of genes and on the eutherian X chromosome. How proximal FL-L1 may affect nearby gene expression remains unclear. In this study, we aim to examine this in a systematic manner using engineered mouse embryonic stem cells (ESCs) where the expression of one representative active L1 subfamily is specifically perturbed. We found that ∼1,024 genes are misregulated following FL-L1 activation and to a lesser extent (∼81 genes), following their repression. In most cases (68%), misexpressed genes contain an intronic FL-L1 or lie near a FL-L1 (<260 kb). Gene ontology analysis shows that upon L1 activation, up-regulated genes are enriched for neuronal function-related terms, suggesting that some L1 elements may have evolved to control neuronal gene networks. These results illustrate thecis-regulatory impact of FL-L1 elements and suggest a broader role for L1s than originally anticipated.
Long read subcellular fractionation and sequencing reveals the translational fate of full length mRNA isoforms during neuronal differentiation
Authors: Ritter Alexander J , Draper Jolene M , Vollmers Chris , Sanford Jeremy R 
Published: February 2024

ABSTRACTAlternative splicing (AS) alters the cis-regulatory landscape of mRNA isoforms leading to transcripts with distinct localization, stability and translational efficiency. To rigorously investigate mRNA isoform-specific ribosome association, we generated subcellular fractionation and sequencing (Frac-seq) libraries using both conventional short reads and long reads from human embryonic stem cells (ESC) and neural progenitor cells (NPC) derived from the same ESC. We performedde novotranscriptome assembly from high-confidence long reads from cytosolic, monosomal, light and heavy polyribosomal fractions and quantified their abundance using short reads from their respective subcellular fractions. Almost half of all transcripts exhibited association with particular subcellular fractions relative to the cytosol. Of the multi-isoform genes, 27% and 18% exhibited significant differential isoform sedimentation in ESC and NPC, respectively. Alternative promoter usage and internal exon skipping accounted for the majority of differences between isoforms from the same gene. Random forest classifiers implicated 3’ and 5’ untranslated region (UTR) GC-content and coding sequence (CDS) and UTR lengths as important determinants of isoform-specific sedimentation profiles. Taken together our data demonstrate that alternative mRNA processing within the CDS and UTRs impacts the translational control of mRNA isoforms during stem cell differentiation, and highlights the utility of using a novel long read sequencing-based method to study translational control.
Gene expression differences associated with intrinsic hindfoot muscle loss in the jerboa,Jaculus jaculus
Authors: Tran Mai P. , Ochoa Reyes Daniel , Weitzel Alexander J. , Saxena Aditya , Hiller Michael , Cooper Kimberly L. 
Published: February 2024

AbstractVertebrate animals that run or jump across sparsely vegetated habitats, such as horses and jerboas, have reduced the number of distal limb bones, and many have lost most or all distal limb muscle. We previously showed that nascent muscles are present in the jerboa hindfoot at birth and that these myofibers are rapidly and completely lost soon after by a process that shares features with pathological skeletal muscle atrophy. Here, we apply an intra- and inter-species approach, comparing jerboa and mouse muscles, to identify gene expression differences associated with the initiation and progression of jerboa hindfoot muscle loss. We show evidence for reduced Hepatocyte Growth Factor (HGF) and Fibroblast Growth Factor (FGF) signaling and an imbalance in nitric oxide signaling; all are pathways that are necessary for skeletal muscle development and regeneration. We also find evidence for phagosome formation, which hints at how myofibers may be removed by autophagy or by non-professional phagocytes without evidence for cell death or immune cell activation. Last, we show significant overlap between genes associated with jerboa hindfoot muscle loss and genes that are differentially expressed in a variety of human muscle pathologies and rodent models of muscle loss disorders. All together, these data provide molecular insight into the mechanism of evolutionary and developmental muscle loss in jerboa hindfeet.
Large-pore connexin hemichannels function as molecule transporters independently of ion conduction
Authors: Gaete Pablo S. , Kumar Deepak , Fernandez Cynthia I. , Valdez-Capuccino Juan Manuel , Bhatt Aashish , Jiang Wenjuan , Lin Yi-Chun , Liu Yu , Harris Andrew L. , Luo Yun L. , Contreras Jorge E. 
Published: February 2024

ABSTRACTConnexin hemichannels were identified as the first members of the eukaryotic large-pore channel family that mediate permeation of both atomic ions and small molecules between the intracellular and extracellular environments. The conventional view is that their pore is a large passive conduit through which both ions and molecules diffuse in a similar manner. In stark contrast to this notion, we demonstrate that the permeation of ions and of molecules in connexin hemichannels can be uncoupled and differentially regulated. We find that human connexin mutations that produce pathologies and were previously thought to be loss-of-function mutations due to the lack of ionic currents are still capable of mediating the passive transport of molecules with kinetics close to those of wild-type channels. This molecular transport displays saturability in the micromolar range, selectivity, and competitive inhibition, properties that are tuned by specific interactions between the permeating molecules and the N-terminal domain that lies within the pore — a general feature of large-pore channels. We propose that connexin hemichannels and, likely, other large-pore channels, are hybrid channel/transporter-like proteins that might switch between these two modes to promote selective ion conduction or autocrine/paracrine molecular signaling in health and disease processes.