bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rudhira-mediated microtubule stability controls TGFβ signaling during mouse vascular development
Authors: Joshi Divyesh , Jindal Preeti , Shetty Ronak , Inamdar Maneesha S. 
Published: April 2024

AbstractThe Transforming Growth Factor β (TGFβ) signaling pathway is critical for survival, proliferation, and cell migration, and is tightly regulated during cardiovascular development. Smads, key effectors of TGFβ signaling, are sequestered by microtubules (MTs) and need to be released for pathway function. Independently, TGFβ signaling also stabilizes MTs. Molecular details and thein vivorelevance of this cross-regulation remain unclear, understanding which is important in complex biological processes such as cardiovascular development. Here, we userudhira/Breast Carcinoma Amplified Sequence 3 (BCAS3), a MT-associated, endothelium-restricted and developmentally essential proto-oncogene, as a pivot to decipher cellular mechanisms in bridging TGFβ signaling and MT stability. We show that Rudhira regulates TGFβ signalingin vivo,during mouse cardiovascular development, and in endothelial cells in culture. Rudhira associates with MTs and is essential for the activation and release of Smad2/3 from MTs. Consequently, Rudhira depletion attenuates Smad2/3- dependent TGFβ signaling thereby impairing cell migration. Interestingly, Rudhira is also a transcriptional target of Smad2/3-dependent TGFβ signaling essential for TGFβ-induced MT stability. Our study identifies an immediate early physical role and a slower, transcription-dependent role for Rudhira in cytoskeleton-TGFβ signaling crosstalk. These two phases of control could facilitate temporally-and spatially restricted targeting of the cytoskeleton and/or TGFβ signaling in vascular development and disease.Significance statementThe developmental TGFβ pathway is essential for cell migration, cell-cell communication, adhesion, apoptosis, and matrix remodeling. Dysregulation of TGFβ signaling leads to aberrant vascular patterning and angiogenesis during mouse embryogenesis. Pathway activation involves phosphorylation and nuclear transport of Smads. Microtubules sequester Smads in the cytoplasm, thereby inhibiting TGFβ signaling. Conversely, TGFβ signaling stabilizes microtubules. However, the molecular components involved, and biological relevance of this cross-regulation remain unclear. We show that the oncoprotein Rudhira/BCAS3 facilitates Smad-MT dissociation upon ligand-mediated TGFβ receptor activation. Interestingly, Smad-dependent TGFβ signaling activation enhances rudhira transcription, essential for microtubule stabilization during cardiovascular development. This dual regulation of TGFβ signaling and microtubule stability by Rudhira allows sustained temporal control essential for development, and its dysregulation has pathological outcomes.
Single-nucleus and spatial landscape of the sub-ventricular zone in human glioblastoma
Authors: Licón-Muñoz Y. , Avalos V. , Subramanian S. , Granger B. , Martinez F. , Varela S. , Moore D. , Perkins E. , Kogan M. , Berto S. , Chohan M.O. , Bowers C.A. , Piccirillo S.G.M. 
Published: April 2024

AbstractThe sub-ventricular zone (SVZ) is the most well-characterized neurogenic area in the mammalian brain. We previously showed that in 65% of patients with glioblastoma (GBM), the SVZ is a reservoir of cancer stem-like cells that contribute to treatment resistance and emergence of recurrence. Here, we built a single-nucleus RNA-sequencing-based microenvironment landscape of the tumor mass (T_Mass) and the SVZ (T_SVZ) of 15 GBM patients and 2 histologically normal SVZ (N_SVZ) samples as controls. We identified a mesenchymal signature in the T_SVZ of GBM patients: tumor cells from the T_SVZ relied on theZEB1regulatory network, whereas tumor cells in the T_Mass relied on theTEAD1regulatory network. Moreover, the T_SVZ microenvironment was predominantly characterized by tumor-supportive microglia, which spatially co-exist and establish heterotypic interactions with tumor cells. Lastly, differential gene expression analyses, predictions of ligand-receptor and incoming/outgoing interactions, and functional assays revealed that the IL-1β/IL-1RAcP and Wnt-5a/Frizzled-3 pathways are therapeutic targets in the T_SVZ microenvironment. Our data provide insights into the biology of the SVZ in GBM patients and identify specific targets of this microenvironment.
The transmembrane domain of the desmosomal cadherin desmoglein-1 governs lipid raft association to promote desmosome adhesive strength
Authors: Zimmer Stephanie E. , Giang William , Levental Ilya , Kowalczyk Andrew P. 
Published: April 2024

ABSTRACTCholesterol- and sphingolipid-enriched domains called lipid rafts are hypothesized to selectively coordinate protein complex assembly within the plasma membrane to regulate cellular functions. Desmosomes are mechanically resilient adhesive junctions that associate with lipid raft membrane domains, yet the mechanisms directing raft association of the desmosomal proteins, particularly the transmembrane desmosomal cadherins, are poorly understood. We identified the desmoglein-1 (DSG1) transmembrane domain (TMD) as a key determinant of desmoglein lipid raft association and designed a panel of DSG1TMDvariants to assess the contribution of TMD physicochemical properties (length, bulkiness, and palmitoylation) to DSG1 lipid raft association. Sucrose gradient fractionations revealed that TMD length and bulkiness, but not palmitoylation, govern DSG1 lipid raft association. Further, DSG1 raft association determines plakoglobin recruitment to raft domains. Super-resolution imaging and functional assays uncovered a strong relationship between the efficiency of DSG1TMDlipid raft association and the formation of morphologically and functionally robust desmosomes. Lipid raft association regulated both desmosome assembly dynamics and DSG1 cell surface stability, indicating that DSG1 lipid raft association is required for both desmosome formation and maintenance. These studies identify the biophysical properties of desmoglein transmembrane domains as key determinants of lipid raft association and desmosome adhesive function.
Increased host diversity limits bacterial generalism but may promote microbe-microbe interactions
Authors: Holmes Iris A , Martínez-Fonseca José G , von May Rudolf , Sealey Briana A , Cerda Peter A , Grundler Maggie R , Westeen Erin P , Nondorf Daniel , Larson Joanna G , Myers Christopher R , Hendry Tory A 
Published: April 2024

AbstractHost-associated bacteria vary in their host breadth, which can impact ecological interactions. By colonizing diverse hosts, host generalists can have disproportionate ecological impacts. For bacteria, host generalism may advantageous, particularly when the availability of specific hosts is variable. It is unclear how much the ability to evolve generalism, by inhabiting diverse hosts, is constrained in host-associated bacteria. We hypothesized that constraints on bacterial generalism will differ depending on the availability of specific host species. To test this, we assessed patterns of diversity and specialization in the cloacal microbiomes of reptile communities from the temperate zone to the tropics, where the diversity and abundance of host species varies substantially. Within these communities, generalist taxa tended to be Proteobacteria, whereas specialists tended to be Firmicutes. We found that bacterial generalists were less prevalent in the highest diversity host communities, and in keeping with this, Proteobacteria were less diverse in these communities. Generalist taxa became relatively less widespread across host species only in the two most diverse host communities. We therefore conclude that the constraint on generalism is not driven by absolute incompatibility with some host species, but rather from competition with host adapted specialist lineages. In the high-diversity communities, we found that the successful generalists, typically Proteobacteria, were disproportionately likely to co-occur with one another across evolutionarily disparate hosts within the community. Our data indicate that bacterial lineages can adapt to the evolutionary pressures of high diversity host communities either by specializing on hosts or by forming cohorts of co-occurring bacterial lineages.
CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer
Authors: Zhong Chunge , Jiang Wen-Jie , Yao Yingjia , Li Zexu , Li You , Wang Shengnan , Wang Xiaofeng , Zhu Wenjuan , Wu Siqi , Wang Jing , Fan Shuangshuang , Ma Shixin , Liu Yeshu , Zhang Han , Zhao Wenchang , Zhao Lu , Feng Yi , Li Zihan , Guo Ruifang , Yu Li , Pei Fengyun , Hu Jun , Feng Xingzhi , Yang Zihuan , Yang Zhengjia , Yang Xueying , Hou Yue , Zhang Danni , Xu Dake , Sheng Ren , Li Yihao , Liu Lijun , Wu Hua-Jun , Huang Jun , Fei Teng 
Published: April 2024

AbstractResistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.
Sex Differences in Pulmonary Hypertension and Associated Right Ventricular Dysfunction
Authors: Ma Janet I. , Owunna Ndidi , Jiang Nona M. , Huo Xiaodan , Zern Emily , McNeill Jenna N. , Lau Emily S. , Pomerantsev Eugene , Picard Michael H. , Wang Dongyu , Ho Jennifer E. 
Published: April 2024

ABSTRACTBackgroundPrior studies have established the impact of sex differences on pulmonary arterial hypertension (PAH). However, it remains unclear whether these sex differences extend to other hemodynamic subtypes of pulmonary hypertension (PH).MethodsWe examined sex differences in PH and hemodynamic PH subtypes in a hospital-based cohort of individuals who underwent right heart catheterization between 2005-2016. We utilized multivariable linear regression to assess the association of sex with hemodynamic indices of RV function [PA pulsatility index (PAPi), RV stroke work index (RVSWI), and right atrial: pulmonary capillary wedge pressure ratio (RA:PCWP)]. We then used Cox regression models to examine the association between sex and clinical outcomes among those with PH.ResultsAmong 5208 individuals with PH (mean age 64 years, 39% women), there was no significant sex difference in prevalence of PH overall. However, when stratified by PH subtype, 31% of women vs 22% of men had pre-capillary (P<0.001), 39% vs 51% had post-capillary (P=0.03), and 30% vs 27% had mixed PH (P=0.08). Female sex was associated with better RV function by hemodynamic indices, including higher PAPi and RVSWI, and lower RA:PCWP ratio (P<0.001 for all). Over 7.3 years of follow-up, female sex was associated with a lower risk of heart failure hospitalization (HR 0.83, CI 95% CI 0.74– 0.91, p value <0.001).ConclusionsAcross a broad hospital-based sample, more women had pre-capillary and more men had post-capillary PH. Compared with men, women with PH had better hemodynamic indices of RV function and a lower risk of HF hospitalization.CLINICAL PERSPECTIVEWhat Is New?Although sex differences have been explored in pulmonary arterial hypertension, sex differences across pulmonary hypertension (PH) in broader samples inclusive of all hemodynamic subtypes remain less well definedWe delineate sex differences in hemodynamic subtypes of PH and associated right ventricular function in a large, heterogenous, hospital-based sample of individuals who underwent right heart catheterizationSex has a significant impact on prevalence of PH across hemodynamic subtypes as well as associated RV functionWhat Are the Clinical Implications?Understanding sex differences across different PH hemodynamic subtypes is paramount to refining risk stratification between men and womenFurther elucidating sex differences in associated RV function and clinical outcomes may aid in developing sex-specific therapies or management strategies to improve clinical outcomes
Personalizing supportive healthcare for patients with immunological disorders
Authors: Folkertsma Tessa S. , Bos Reinhard , Vodegel Robert M. , Bloem Sjaak , Liefveld Aad R. , Tack Greetje J. 
Published: April 2024

AbstractCurrent insights to personalize supportive care for patients with immunological disorders, especially in the context of medical treatments, remain inadequate. Delivering and guiding supportive care unquestionably contributes to a higher quality of life and better overall healthcare. The ‘Subjective Health Experience (SHE) Model’ provides a general framework, comprising four segments, to differentiate supportive healthcare in a quick and practical approach. In this report both health care workers and patients tailored the unique needs of patients with immunological disorders to improve their supportive care.Employing qualitative methods, group discussions and individual interviews were conducted with 19 healthcare professionals and 18 patients suffering from Rheumatoid Arthritis/Spondylarthritis, Inflammatory Bowel Disease (Crohn’s disease and Ulcerative colitis), and Psoriasis/Hidradenitis Suppurativa. The aim was to ascertain nuanced insights into the behaviour, questions, and needs of patients with six common immunological conditions guided by the SHE-model, thereby refining the personalized supportive care framework.A detailed description was made for patients with immunological disorders per SHE-model segment. Based on these insights, it was determined for each segment‘WHAT’kind of supportive care is needed and‘HOW’it should be offered. Notably, patients emphasized the qualitative aspects of their interactions with healthcare professionals (attention, acknowledgment, and empathetic communication), contrasting with professionals’ focus on the treatment plan. This led to a strategic allocation of supportive care interventions across patient segments.This study has significantly advanced our understanding of appropriate supportive healthcare for patients with immunological disorders from the perspective of the SHE-model. These findings not only enrich the existing literature but also equip healthcare professionals with a concrete guide for enhancement of supportive care, as the SHE-model is easy to perform in daily clinical care. Attention, acknowledgment, and listening comprise the foundational elements for offering and guiding supportive care.
Combining transformer and 3DCNN models to achieve co-design of structures and sequences of antibodies in a diffusional manner
Authors: Hu Yue , Tao Feng , Lan WenJun , Zhang Jing 
Published: April 2024

AbstractAntibody drugs are among the fastest growing therapeutic modalities in modern drug research and development. Due to the huge search space of antibody sequences, the traditional experimental screening method cannot fully meet the needs of antibody discover. More and more rational design methods have been proposed to improve the success rate of antibody drugs. In recent years, artificial intelligence methods have increasingly become an important means of rational design. We have proposed an algorithm for antibody design, called AlphaPanda (AlphaFold2 inspired Protein-specific antibody design in a diffusional manner). The algorithm mainly combines the transformer model, the 3DCNN model and the diffusion generative model, use the transformer model to capture the global information and uses the 3DCNN model to capture the local structural characteristics of the antibody-antigen complexes, and then uses the diffusion model to generate sequences and structures of antibodies. The 3DCNN model can capture pairwise interactions in antibody-antigen complex, as well as non-pairwise interactions in antibody-antigen complex, and it requires less training sample data, while avoiding the defects of the generation progress by the autoregressive model and by the self-consistent iterative model. Diffusion generative model can generate sequence and structure effectively and with high quality. By combining 3DCNN method and diffusion model method, we have achieved the integration of 3DCNN model to the protein design with flexible main chains. By utilizing the advantages of these aspects, a good performance has been achieved by the AlphaPanda algorithm. The algorithm we propose can not only be applied to antibody design, but also be more widely applied to various fields of other protein design. The source code can be get from github (https://github.com/YueHuLab/AlphaPanda).
SAMP: Identifying Antimicrobial Peptides by an Ensemble Learning Model Based on Proportionalized Split Amino Acid Composition
Authors: Feng Junxi , Sun Mengtao , Liu Cong , Zhang Weiwei , Xu Changmou , Wang Jieqiong , Wang Guangshun , Wan Shibiao 
Published: April 2024

AbstractIt is projected that 10 million deaths could be attributed to drug-resistant bacteria infections in 2050. To address this concern, identifying new-generation antibiotics is an effective way. Antimicrobial peptides (AMPs), a class of innate immune effectors, have received significant attention for their capacity to eliminate drug-resistant pathogens, including viruses, bacteria, and fungi. Recent years have witnessed widespread applications of computational methods especially machine learning (ML) and deep learning (DL) for discovering AMPs. However, existing methods only use features including compositional, physiochemical, and structural properties of peptides, which cannot fully capture sequence information from AMPs. Here, we present SAMP, an ensemble random projection (RP) based computational model that leverages a new type of features called Proportionalized Split Amino Acid Composition (PSAAC) in addition to conventional sequence-based features for AMP prediction. With this new feature set, SAMP captures the residue patterns like sorting signals at around both the N-terminus and the C-terminus, while also retaining the sequence order information from the middle peptide fragments. Benchmarking tests on different balanced and imbalanced datasets demonstrate that SAMP consistently outperforms existing state-of-the-art methods, such as iAMPpred and AMPScanner V2, in terms of accuracy, MCC, G-measure and F1-score. In addition, by leveraging an ensemble RP architecture, SAMP is scalable to processing large-scale AMP identification with further performance improvement, compared to those models without RP. To facilitate the use of SAMP, we have developed a Python package freely available athttps://github.com/wan-mlab/SAMP.
An amyloidogenic fragment of the SARS CoV-2 envelope protein promotes serum amyloid A misfolding and fibrillization
Authors: Nady Asal , Reichheld Sean E. , Sharpe Simon 
Published: April 2024

ABSTRACTSARS CoV-2 infection can affect a surprising number of organs in the body and cause symptoms such as abnormal blood coagulation, fibrinolytic disturbances, and neurodegeneration. Our study delves into the intricate pathogenic potential of a SARS-CoV-2 envelope protein peptide, shedding light on its implications for multi-organ effects and amyloid formation. Specifically, we focus on the peptide SK9 or54SFYVYSRVK62derived from the C-terminus of human SARS coronavirus 2 envelope protein. We demonstrate that SK9 containing peptides readily form classic amyloid structures consistent with predictions of amyloid aggregation algorithms.In vivo, overexpression of proteases such as neutrophil elastase during inflammation can potentially lead to C-terminal peptides containing SK9. We also demonstrate that SK9 can promote the fibrillization of SAA, a protein marker of acute inflammation. Our investigations reveal that the aromatic residues Phe2 and Tyr3 of SK9 play a pivotal role in its amyloidogenic function. We show that the primary sites of SK9-SAA binding lie in the amyloidogenic hotspots of SAA itself. Our results highlight two possible complications of SARS CoV-2 infection in individuals with hyper-inflammation either due to amyloids arising from SK9 containing peptides or SK9-induced AA amyloidosis.
The T3SS structural and effector genes ofChlamydia trachomatisare expressed in distinct phenotypic cell forms
Authors: Grieshaber Nicole A. , Appa Cody , Ward Megan , Grossman Alorah , McCormik Sean , Grieshaber Brendan S. , Chiarelli Travis , Yang Hong , Omsland Anders , Grieshaber Scott S. 
Published: April 2024

AbstractBacteria in the chlamydiales order are obligate intracellular parasites of eukaryotic cells. Within this order, the genusChlamydiacontains the causative agents of a number of clinically important infections of humans. Biovars ofC. trachomatisare the causative agents of trachoma, the leading cause of preventable blindness worldwide, as well as sexually transmitted infections with the potential to cause pelvic inflammatory disease and infertility. Irrespective of the resulting disease, all chlamydial species share the same obligate intracellular life cycle and developmental cell forms. They are reliant on an infectious cycle consisting of at least three phenotypically distinct cell forms termed the reticulate body (RB), the intermediate body (IB) and the elementary body (EB). The EB is infectious but does not replicate. The RB replicates in the host cell but is non-infectious, while the IB is an intermediate form that transitions to the EB form. In this study, we ectopically expressed the transcriptional repressor Euo, the two nucleoid-associated proteins HctA and HctB, and the two component sensor kinase CtcB in the RB. Transcriptional analysis using RNA-seq, differential expression clustering and fluorescencein situhybridization analysis show that the chlamydial developmental cycle is driven by three distinct regulons corresponding to the RB, IB or EB cell forms. Moreover, we show that the genes for the T3SS were cell type restricted, suggesting defined functional roles for the T3SS in specific cell forms.ImportanceChlamydia trachomatis, a sexually transmitted bacterial infection, poses a significant global health threat, causing over 100 million infections annually and leading to complications like ectopic pregnancy and infertility. This study investigates the gene expression patterns ofChlamydia trachomatisduring its unique life cycle within human cells. As an obligate intracellular parasite,C. trachomatistransitions through distinct developmental stages - one for infection and dissemination, another for replication, and a third for transitioning back to the infectious form. By analyzing gene expression profiles at each stage, we identified key genes involved in these processes. Interestingly, our research also reveals the presence of two separate T3SS (Type III Secretion System) translocons expressed in distinct stages, suggesting their crucial roles in specific functions during the infection cycle.