bluuebunny/crossref_metadata_2025_split huggingface dataset:
Smad4 Loss in the Mouse Intestinal Epithelium Alleviates the Pathological Fibrotic Response to Injury in the Colon
Authors: Hashemi Zahra , Hui Thompson , Wu Alex , Matouba Dahlia , Zukowski Steven , Nejati Shima , Lim Crystal , Bruzzese Julianna , Seabold Kyle , Mills Connor , Lin Cindy , Wrath Kylee , Wang Haoyu , Wang Hongjun , Verzi Michael P. , Perekatt Ansu 
Published: March 2024

ABSTRACTMucosal healing is associated with better clinical outcomes in patients with inflammatory bowel diseases (IBDs). Unresolved injury and inflammation, on the other hand, increases pathological fibrosis and the predisposition to cancer. Loss of Smad4, a tumor suppressor, is known to increase colitis-associated cancer in mouse models of chronic IBD. Since common biological processes are involved in both injury repair and tumor growth, we sought to investigate the effect of Smad4 loss on the response to epithelial injury. To this end, Smad4 was knocked out specifically in the intestinal epithelium and transcriptomic and morphological changes compared between wild type mice and Smad4 knock out mice after DSS-induced injury. We find that Smad4 loss alleviates pathological fibrosis and enhances mucosal repair. The transcriptomic changes specific to epithelium indicate molecular changes that affect epithelial extracellular matrix (ECM) and promote enhanced mucosal repair. These findings suggest that the biological processes that promote wound healing alleviate the pathological fibrotic response to DSS. Therefore, these mucosal repair processes could be exploited to develop therapies that promote normal wound healing and prevent fibrosis.NEW AND NOTEWORTHYWe show that transcriptomic changes due to Smad4 loss in the colonic epithelium alleviates the pathological fibrotic response to DSS in an IBD mouse model of acute inflammation. Most notably, we find that collagen deposition in the epithelial ECM, as opposed to that in the lamina propria, correlates with epithelial changes that enhance wound healing. This is the first report on a mouse model providing alleviated fibrotic response in a DSS-IBD mouse modelin vivo.
Natural slab photonic crystals and where to find them among the girdle bands of diatoms
Authors: Ashworth Matt P. , Lam Daryl W. , Lopez-Garcia Martin , Manning Schonna R. , Goessling Johannes W. 
Published: March 2024

AbstractSlab photonic crystals, nanomaterials characterized by periodic pores for manipulating light, have applications in advanced optical technologies. Remarkably, similar materials have been identified in the silica shell of diatoms, in particular the girdle bands. Despite the potential applications and significance for diatom biology, their prevalence remains uncertain due to limited observations across a few species. In this study of 393 SEM girdle band micrographs across major taxonomic groups, we identified slab photonic crystals using Fast Fourier Transform (FFT) analysis. A correlation analysis of these properties on a phylogenetic tree revealed their distribution across the diversity of species and taxonomic groups. Square and hexagonal lattice varieties are prevalent in earlier-diverging groups, and linked to phytoplanktonic lifestyles. More recently-diverged clades lack these structures entirely in their girdle bands. Numerical analysis indicates that square lattice types exhibit anticipated photonic properties (stopbands) in the visible spectrum, while hexagonal lattice types are primarily linked to the near to mid-infrared range. This suggests that girdle band slab photonic crystal morphologies 1) originate from quasi-periodic photonic structures, 2) are primarily found in evolutionarily older clades (Coscinodiscophyceae and Mediophyceae), 3) lost square lattice types through diversification in the Mediophyceae, and 4) are absent in more recent clades (Fragilariophyceae and Bacillariophyceae). The limited inter-species distribution of slab photonic crystals may offer experimental cues to study their biological functionality. While these data suggest that stopband functionalities are a derived frustule trait, the ultimate purpose of slab photonic crystals in nature remains a mystery.
Growing older, growing more diverse: sea turtles and epibiotic cyanobacteria
Authors: Kanjer Lucija , Filek Klara , Mucko Maja , Lupić Mateja Zekan , Frleta-Valić Maša , Gračan Romana , Bosak Sunčica 
Published: March 2024

AbstractCyanobacteria are known for forming associations with various animals, including sea turtles, yet our understanding of sea turtles associated cyanobacteria remains limited. This study aims to address this knowledge gap by investigating the diversity of cyanobacteria in biofilm samples from loggerhead sea turtle carapaces, utilizing a 16S rDNA amplicon sequencing approach. The predominant cyanobacterial order identified wasNodosilineales, with the genusRhodoplocahaving highest relative abundance. Our results suggest that cyanobacterial communities became more diverse as sea turtles age as we had found a positive correlation between community diversity and the length of a sea turtle’s carapace. Since larger and older turtles predominantly utilize neritic habitats, the shift to more diverse cyanobacterial community aligned with a shift in loggerheads habitat. Our research provided detailed insights into the cyanobacterial communities associated with loggerhead sea turtles, establishing a foundation for future studies delving into this fascinating ecological relationship and its potential implications for sea turtle conservation.
3DCellComposer - A Versatile Pipeline Utilizing 2D Cell Segmentation Methods for 3D Cell Segmentation
Authors: Chen Haoran , Murphy Robert F. 
Published: March 2024

AbstractBackgroundCell segmentation is crucial in bioimage informatics, as its accuracy directly impacts conclusions drawn from cellular analyses. While many approaches to 2D cell segmentation have been described, 3D cell segmentation has received much less attention. 3D segmentation faces significant challenges, including limited training data availability due to the difficulty of the task for human annotators, and inherent three-dimensional complexity. As a result, existing 3D cell segmentation methods often lack broad applicability across different imaging modalities.ResultsTo address this, we developed a generalizable approach for using 2D cell segmentation methods to produce accurate 3D cell segmentations. We implemented this approach in 3DCellComposer, a versatile, open-source package that allows users to choose any existing 2D segmentation model appropriate for their tissue or cell type(s) without requiring any additional training. Importantly, we have enhanced our open source CellSegmentationEvaluator quality evaluation tool to support 3D images. It provides metrics that allow selection of the best approach for a given imaging source and modality, without the need for human annotations to assess performance. Using these metrics, we demonstrated that our approach produced high-quality 3D segmentations of tissue images, and that it could outperform an existing 3D segmentation method on the cell culture images with which it was trained.Conclusions3DCellComposer, when paired with well-trained 2D segmentation models, provides an important alternative to acquiring human-annotated 3D images for new sample types or imaging modalities and then training 3D segmentation models using them. It is expected to be of significant value for large scale projects such as the Human BioMolecular Atlas Program.
The carrier proteome limit should be reassessed for each mass analyzer architecture
Authors: Orsburn Benjamin C. 
Published: March 2024

AbstractA clever utilization of classic proteomics reagents now allows the effective amplification of peptide sequencing potential in shotgun proteomics. The application of this method has helped usher in the exciting new field of single cell proteomics. While it was easy to first think that the discovery of Budnik et al., was finally the answer for protein PCR, limitations were carefully described by the authors and others. A study by Cheung et al., systematically identified the consequences of higher concentration carrier proteomes and defined the “carrier proteome limit”. While this work has been replicated by others, every analysis published to date has used a variation of the same mass analyzer. When the same analysis is performed on alternative instruments, these limits appear to be very different and attributable to defined characteristics of each mass analyzer. Specifically, in mass analyzers with higher relative intrascan linear dynamic range, increased carrier channels appear far less detrimental to quantitative accuracy. As such, we may be limiting the power of isobaric peptide signal “amplification” by restricting ourselves to traditional mass analyzer options.
Aberrant lipid accumulation and retinal pigmental epithelium dysfunction in PRCD-deficient mice
Authors: Motipally Sree I. , Kolson Douglas R. , Guan Tongju , Kolandaivelu Saravanan 
Published: March 2024

AbstractProgressive Rod-Cone Degeneration (PRCD) is an integral membrane protein found in photoreceptor outer segment (OS) disc membranes and its function remains unknown. Mutations inPrcdare implicated inRetinitis pigmentosa(RP) in humans and multiple dog breeds. PRCD-deficient models exhibit decreased levels of cholesterol in the plasma. However, potential changes in the retinal cholesterol remain unexplored. In addition, impaired phagocytosis observed in these animal models points to potential deficits in the retinal pigment epithelium (RPE). Here, using aPrcd-/-murine model we investigated the alterations in the retinal cholesterol levels and impairments in the structural and functional integrity of the RPE. Lipidomic and immunohistochemical analyses show a 5-fold increase in the levels of cholesteryl esters (C.Es) and accumulation of neutral lipids in the PRCD-deficient retina, respectively, indicating alterations in total retinal cholesterol. Longitudinal fundus and spectral domain optical coherence tomography (SD-OCT) examinations showed focal lesions and RPE hyperreflectivity. Strikingly, the RPE ofPrcd-/-mice exhibited age-related pathological features such as neutral lipid deposits, lipofuscin accumulation, Bruch’s membrane (BrM) thickening and drusenoid focal deposits, mirroring an Age-related Macular Degeneration (AMD)-like phenotype. We propose that the extensive lipofuscin accumulation likely impairs lysosomal function, leading to the defective phagocytosis observed inPrcd-/-mice. Our findings support the dysregulation of retinal cholesterol homeostasis in the absence of PRCD. Further, we demonstrate that progressive photoreceptor degeneration inPrcd-/-mice is accompanied by progressive structural and functional deficits in the RPE, which likely exacerbates vision loss over time.
Effect of prior tuberculosis on cardiovascular status in perinatally HIV-1-infected adolescents
Authors: Magodoro Itai M , Guerrero-Chalela Carlos E , Myer Landon , Jao Jennifer , Ntsekhe Mpiko , Wilkinson Katalin A , Wilkinson Robert J , Zar Heather , Ntusi Ntobeko AB 
Published: March 2024

SummaryWhether, and how, co-occurring HIV-1 infection (HIV) and tuberculosis (TB) impact cardiovascular status, especially in adolescents with perinatally acquired HIV (APHIV), have not been examined. We hypothesized that APHIV with previous active TB have worse cardiac efficiency than APHIV without TB, which is mediated by increased inflammation. Arterial elastance (Ea) and ventricular end-systolic elastance (Ees) were assessed by cardiovascular magnetic resonance, and ventriculoarterial coupling (VAC) estimated as Ea/Ees ratio. Inflammation was measured by high sensitivity C-reactive protein (hsCRP). Previous TB in APHIV was associated with reduced cardiac efficiency, related to an altered ventriculoarterial coupling. However, we did not find evidence of hsCRP mediated effects in the association between prior TB and cardiac efficiency. The clinical significance of these findings requires further study, including a wider range of biomarkers of specific immune pathways.
A mechanistic modeling approach to assessing the sensitivity of outcomes of water, sanitation, and hygiene interventions to local contexts and intervention factors
Authors: Brouwer Andrew F. , Kraay Alicia N.M. , Zahid Mondal H. , Eisenberg Marisa C. , Freeman Matthew C. , Eisenberg Joseph N.S. 
Published: March 2024

AbstractBackgroundDiarrheal disease is a leading cause of morbidity and mortality in young children. Water, sanitation, and hygiene (WASH) improvements have historically been responsible for major public health gains by reducing exposure to enteropathogens, but many individual interventions have failed to consistently reduce diarrheal disease burden. Analytical tools that can estimate the potential impacts of individual WASH improvements in specific contexts would support program managers and policymakers to set targets that would yield health gains.MethodsTo understand the impact of WASH improvements on diarrhea, we developed a disease transmission model to simulate an intervention trial with a single intervention. We accounted for contextual factors, including preexisting WASH conditions and baseline disease prevalence, as well as intervention WASH factors, including community coverage, compliance, efficacy, and the intervenable fraction of transmission. We illustrated the sensitivity of intervention effectiveness to the contextual and intervention factors in each of two scenarios in which a 50% reduction in disease was achieved through a different combination of factors (higher preexisting WASH conditions, compliance, and intervenable fraction vs higher intervention efficacy and community coverage).ResultsAchieving disease elimination depended on more than one factor, and factors that could be used to achieve disease elimination in one scenario could be ineffective in the other scenario. Community coverage interacted strongly with both the contextual and intervention factors. For example, the positive impact of increasing intervention community coverage increased non-linearly with increasing intervention compliance. Additionally, counterfactually improving the contextual preexisting WASH conditions could have a positive or negative effect on the intervention effectiveness, depending on the values of other factors.ConclusionsWhen developing interventions, it is important to account for both contextual conditions and the intervention parameters. Our mechanistic modeling approach can provide guidance for developing locally specific policy recommendations.
Dilated cardiomyopathy-associated skeletal muscle actin (ACTA1) mutation R256H disrupts actin structure and function and causes cardiomyocyte hypocontractility
Authors: Garg Ankit , Jansen Silvia , Zhang Rui , Lavine Kory J. , Greenberg Michael J. 
Published: March 2024

AbstractSkeletal muscle actin (ACTA1) mutations are a prevalent cause of skeletal myopathies consistent with ACTA1’s high expression in skeletal muscle. Rarede novomutations in ACTA1 associated with combined cardiac and skeletal myopathies have been reported, but ACTA1 represents only ∼20% of the total actin pool in cardiomyocytes, making its role in cardiomyopathy controversial. Here we demonstrate how a mutation in an actin isoform expressed at low levels in cardiomyocytes can cause cardiomyopathy by focusing on a unique ACTA1 mutation, R256H. We previously identified this mutation in multiple family members with dilated cardiomyopathy (DCM), who had reduced systolic function without clinical skeletal myopathy. Using a battery of multiscale biophysical tools, we show that R256H has potent functional effects on ACTA1 function at the molecular scale and in human cardiomyocytes. Importantly, we demonstrate that R256H acts in a dominant manner, where the incorporation of small amounts of mutant protein into thin filaments is sufficient to disrupt molecular contractility, and that this effect is dependent on thepresenceof troponin and tropomyosin. To understand the structural basis of this change in regulation, we resolved a structure of R256H filaments using Cryo-EM, and we see alterations in actin’s structure that have the potential to disrupt interactions with tropomyosin. Finally, we show thatACTA1R256H/+human induced pluripotent stem cell cardiomyocytes demonstrate reduced contractility and sarcomeric disorganization. Taken together, we demonstrate that R256H has multiple effects on ACTA1 function that are sufficient to cause reduced contractility and establish a likely causative relationship between ACTA1 R256H and clinical cardiomyopathy.Significance StatementSkeletal muscle actin mutations are well-known to cause skeletal myopathies, but their role in cardiomyopathies have been controversial as skeletal muscle actin is only expressed at modest levels in the heart. Here, we demonstrate that a skeletal muscle actin mutation potently causes multiple defects in actin function at the atomic and molecular scales, and it functions in a dominant fashion, leading to cardiomyocyte contractile defects. Our results establish how skeletal muscle actin mutations may cause cardiomyocyte dysfunction and lay the foundation for future studies of the role of skeletal muscle actin in cardiomyopathy.
Increased layer 5 Martinotti cell excitation reduces pyramidal cell population plasticity and improves motor execution
Authors: Malfatti Thawann , Velica Anna , Winne Jéssica , Ciralli Barbara , Henriksson Katharina , Nascimento George , Leao Richardson , Kullander Klas 
Published: March 2024

AbstractDuring motor activity and motor learning, pyramidal cells in the motor cortex receive inputs from local interneurons as well as deeper structures. Layer 5 pyramidal cells in the primary motor cortex then feed commands to spinal circuits for motor execution. The genetic ablation of layer 5 Chrna2 Martinotti cells, which selectively target pyramidal tract pyramidal cells, results in disturbed fine motor functions. Using calcium imaging combined with chemogenetics, we show that activation of layer 5 Chrna2 Martinotti cells during training increases pyramidal cell tuning, temporal patterning and assembly reconfiguration while not affecting motor learning success rates. However, in mice that had already learned a reach-and-grasp (prehension) task, Chrna2 Martinotti cell activation resulted in improved prehension and increased power in low theta and high gamma bands of local field potentials in the motor cortex. This work indicates that activation of Chrna2 Martinotti cells reduces pyramidal cell assembly plasticity during learning, facilitating preservation of already acquired motor skills.
Competitive assembly resolves the stoichiometry of essential proteins in infectious HIV-1 virions
Authors: Durden Haley , Preece Benjamin , Gallegos Rodrigo , Saha Ipsita , MacArthur Brian , Petersen Abby , Peppel Wiley , Saffarian Saveez 
Published: March 2024

AbstractDuring assembly on the plasma membrane, HIV-1 virions incorporate Gag-Pol as well as gp120/gp41 trimers. The Pol region consists of protease, reverse transcriptase and integrase precursors which are essential enzymes required for maturation, reverse transcription, and integration of the viral genome in the next host. gp120/gp41 trimers catalyze the fusion of the virion with its next host. Only a fraction of released virions are infectious. The stoichiometry of gp120/gp41 and Gag-Pol proteins in HIV virions was previously measured using cryotomography and ratiometric protein analysis, but what is the stoichiometry of these proteins in infectious virions remained to be determined. Here we developed a method based on competition between infectious HIV backbones with noninfectious mutants and measured 100 ± 10 Gag-Pol and 15 ± 3 gp120/gp41 proteins incorporated in infectious virions assembled in HEK293 cells from NL4.3 HIV-1 backbone. Our measurements are in broad agreement with cryotomography and ratiometric protein analysis and therefore stoichiometry of gp120/gp41 and Gag-Pol in infectious virions is the same as all released virions. With the development of appropriate mutants and infectivity assays, our method is applicable to other infectious viruses.Statement of significanceThere are 30 million people who have succumbed to the AIDS pandemic with 600,000 additional deaths per year. HIV has an accelerated rate of mutational accumulation with the virus mutating out of neutralizing antibodies within the same patient making development of vaccines challenging. Like most enveloped viruses, only a fraction of released virions are infectious and the question of what selects these virions has remained a mystery. The method developed in this article will allow stoichiometric measurements on infectious virions and therefore allows further studies of causes of infectivity.
Detection of Chikungunya virus in The Gambia through a newly implemented sentinel surveillance program
Authors: Jallow Amadou Woury , Dieng Idrissa , Sanneh Bakary , Barry Mamadou Aliou , Talla Cheikh , Sanneh Modou Lamin , Sagne Samba Niang , Cisse Mamadou , Mendy Alphonse , Kijera Muhammed , York Karamo , Faal Alieu , Sey Alhagie Papa , Jallow Ebrima K. , Manneh Lamin , Darboe Sheriffo M.K. , Jatta Balla , Kalisa Momodou , Sanneh Adama M.B. , Njie Modou , Nyassi Momodou T. , Bittaye Mustapha , Dia Ndongo , Sall Amadou Alpha , Faye Ousmane , Diagne Moussa Moise , Faye Oumar , Diallo Boubacar , Jagne Sheriffo , Sow Abdourahmane 
Published: March 2024

AbstractWe characterized 01 autochthonous chikungunya virus (CHIKV) case from (The Gambia) through a newly implemented local arboviruses surveillance program in the, highlighting the first notification of the virus in the Country. Identified virus is closely related to CHIKV West African genotype detected in Kédougou (Senegal) in 2023 and responsible of a large outbreak with up to 300 confirmed cases. This work describes the first genomic proof subregional spread of CHIKV West African genotype in West Africa.
Discovering CRISPR-Cas system with self-processing pre-crRNA capability by foundation models
Authors: Li Wenhui , Jiang Xianyue , Wang Wuke , Hou Liya , Cai Runze , Li Yongqian , Gu Qiuxi , Chuai Guohui , Chen Qinchang , Ma Peixiang , Tang Jin , Guo Menghao , Huang Xingxu , Zhang Jun , Liu Qi 
Published: March 2024

AbstractThe discovery and functional annotation of CRISPR-Cas systems laid the groundwork for the development of novel CRISPR-based gene editing tools. Traditional similarity- search-based Cas discovery strategies, which rely heavily on local sequence alignment and reference Cas homologs, may overlook a significant number of remote homologs with limited sequence similarity; and it can not be applied directly for functional recognition. With the rapid development of protein large language models (LLMs), protein foundation models are expected to help model Cas systems with limited Cas homologs without extensive task-specific training data; however, the full potential of these models for Cas discovery and functional annotation has yet to be determined. To this end, we present a novel, effective and unified AI framework, CHOOSER (CasHOmlogObserving andSElf-processing scReening), for alignment-free discovery of novel CRISPR-Cas systems with self-processing precursor CRISPR RNA (pre-crRNA) capability utilizing protein foundation models. CHOOSER successfully retrieved 11 novel homologs of Casλ, the majority of which are predicted to be able to self-process pre-crRNA, nearly doubling the current catalog. One of the candidates, EphcCasλ, was subsequently experimentally validated for its ability to self-process pre-crRNA, target DNA cleavage, and trans-cleavage and was shown to be a promising candidate for use as a CRISPR-Cas-based pathogen detection system. Overall, our study provides an unprecedented perspective and methodology for discovering novel CRISPR-Cas systems with specific functions using foundation models, underscoring the potential for transforming newly identified Cas homologs into genetic editing tools.