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Briefings in Bioinformatics May 2024This study describes the development of a resource module that is part of a learning platform named "NIGMS Sandbox for Cloud-based Learning"...
This study describes the development of a resource module that is part of a learning platform named "NIGMS Sandbox for Cloud-based Learning" (https://github.com/NIGMS/NIGMS-Sandbox). The overall genesis of the Sandbox is described in the editorial NIGMS Sandbox at the beginning of this Supplement. This module delivers learning materials on de novo transcriptome assembly using Nextflow in an interactive format that uses appropriate cloud resources for data access and analysis. Cloud computing is a powerful new means by which biomedical researchers can access resources and capacity that were previously either unattainable or prohibitively expensive. To take advantage of these resources, however, the biomedical research community needs new skills and knowledge. We present here a cloud-based training module, developed in conjunction with Google Cloud, Deloitte Consulting, and the NIH STRIDES Program, that uses the biological problem of de novo transcriptome assembly to demonstrate and teach the concepts of computational workflows (using Nextflow) and cost- and resource-efficient use of Cloud services (using Google Cloud Platform). Our work highlights the reduced necessity of on-site computing resources and the accessibility of cloud-based infrastructure for bioinformatics applications.
Topics: Cloud Computing; Transcriptome; Computational Biology; Software; Humans; Gene Expression Profiling; Internet
PubMed: 38941113
DOI: 10.1093/bib/bbae313 -
Oncology and Therapy Jun 2024Breast cancer presents diverse molecular subtypes affecting treatment strategies. Human epidermal growth factor receptor 2 (HER2)-low, hormone receptor-positive (HR+)...
BACKGROUND
Breast cancer presents diverse molecular subtypes affecting treatment strategies. Human epidermal growth factor receptor 2 (HER2)-low, hormone receptor-positive (HR+) breast cancer poses a challenge due to limited targeted therapies. Current neoadjuvant treatment primarily utilizes chemotherapy, with conflicting results regarding efficacy in patients with HER2-low breast cancer. Trastuzumab deruxtecan (T-DXd) shows promise in HER2-low metastatic disease, and preliminary evidence suggests synergy with endocrine therapy.
OBJECTIVE
This editorial explores the hypothesis that neoadjuvant T-DXd with or without endocrine therapy offers efficacy in the clinical management of HR+/HER2-low breast cancer.
METHODS
We propose a phase II study with two treatment arms: T-DXd + letrozole and T-DXd alone. The primary endpoint is the radiological complete response rate. Secondary endpoints include pathological complete response rate, safety, event-free survival, and overall survival. Exploratory analyses will compare the arms to identify potential for optimizing treatment efficacy and minimizing side effects.
CONCLUSIONS
This study design allows for initial assessment of T-DXd with or without endocrine therapy in the treatment of HER2-low breast cancer. The findings may pave the way for personalized treatment strategies and inform future research, potentially leading to a chemotherapy-sparing approach.
PubMed: 38941050
DOI: 10.1007/s40487-024-00286-3 -
Membrane protein Bcsdr2 mediates biofilm integrity, hyphal growth and virulence of Botrytis cinerea.Applied Microbiology and Biotechnology Jun 2024Grey mould caused by Botrytis cinerea is a devastating disease responsible for large losses to agricultural production, and B. cinerea is a necrotrophic model fungal...
Grey mould caused by Botrytis cinerea is a devastating disease responsible for large losses to agricultural production, and B. cinerea is a necrotrophic model fungal plant pathogen. Membrane proteins are important targets of fungicides and hotspots in the research and development of fungicide products. Wuyiencin affects the permeability and pathogenicity of B. cinerea, parallel reaction monitoring revealed the association of membrane protein Bcsdr2, and the bacteriostatic mechanism of wuyiencin was elucidated. In the present work, we generated and characterised ΔBcsdr2 deletion and complemented mutant B. cinerea strains. The ΔBcsdr2 deletion mutants exhibited biofilm loss and dissolution, and their functional activity was illustrated by reduced necrotic colonisation on strawberry and grape fruits. Targeted deletion of Bcsdr2 also blocked several phenotypic defects in aspects of mycelial growth, conidiation and virulence. All phenotypic defects were restored by targeted gene complementation. The roles of Bcsdr2 in biofilms and pathogenicity were also supported by quantitative real-time RT-PCR results showing that phosphatidylserine decarboxylase synthesis gene Bcpsd and chitin synthase gene BcCHSV II were downregulated in the early stages of infection for the ΔBcsdr2 strain. The results suggest that Bcsdr2 plays important roles in regulating various cellular processes in B. cinerea. KEY POINTS: • The mechanism of wuyiencin inhibits B. cinerea is closely associated with membrane proteins. • Wuyiencin can downregulate the expression of the membrane protein Bcsdr2 in B. cinerea. • Bcsdr2 is involved in regulating B. cinerea virulence, growth and development.
Topics: Botrytis; Biofilms; Virulence; Hyphae; Plant Diseases; Fragaria; Fungal Proteins; Membrane Proteins; Vitis; Spores, Fungal; Gene Deletion
PubMed: 38940906
DOI: 10.1007/s00253-024-13238-8 -
Bioinformatics (Oxford, England) Jun 2024Human epidermal growth factor receptor 2 (HER2) status identification enables physicians to assess the prognosis risk and determine the treatment schedule for patients....
MOTIVATION
Human epidermal growth factor receptor 2 (HER2) status identification enables physicians to assess the prognosis risk and determine the treatment schedule for patients. In clinical practice, pathological slides serve as the gold standard, offering morphological information on cellular structure and tumoral regions. Computational analysis of pathological images has the potential to discover morphological patterns associated with HER2 molecular targets and achieve precise status prediction. However, pathological images are typically equipped with high-resolution attributes, and HER2 expression in breast cancer (BC) images often manifests the intratumoral heterogeneity.
RESULTS
We present a phenotype-informed weakly supervised multiple instance learning architecture (PhiHER2) for the prediction of the HER2 status from pathological images of BC. Specifically, a hierarchical prototype clustering module is designed to identify representative phenotypes across whole slide images. These phenotype embeddings are then integrated into a cross-attention module, enhancing feature interaction and aggregation on instances. This yields a phenotype-based feature space that leverages the intratumoral morphological heterogeneity for HER2 status prediction. Extensive results demonstrate that PhiHER2 captures a better WSI-level representation by the typical phenotype guidance and significantly outperforms existing methods on real-world datasets. Additionally, interpretability analyses of both phenotypes and WSIs provide explicit insights into the heterogeneity of morphological patterns associated with molecular HER2 status.
AVAILABILITY AND IMPLEMENTATION
Our model is available at https://github.com/lyotvincent/PhiHER2.
Topics: Humans; Receptor, ErbB-2; Breast Neoplasms; Phenotype; Female; Supervised Machine Learning; Computational Biology
PubMed: 38940163
DOI: 10.1093/bioinformatics/btae236 -
Bioinformatics (Oxford, England) Jun 2024Identifying cancer genes remains a significant challenge in cancer genomics research. Annotated gene sets encode functional associations among multiple genes, and cancer...
MOTIVATION
Identifying cancer genes remains a significant challenge in cancer genomics research. Annotated gene sets encode functional associations among multiple genes, and cancer genes have been shown to cluster in hallmark signaling pathways and biological processes. The knowledge of annotated gene sets is critical for discovering cancer genes but remains to be fully exploited.
RESULTS
Here, we present the DIsease-Specific Hypergraph neural network (DISHyper), a hypergraph-based computational method that integrates the knowledge from multiple types of annotated gene sets to predict cancer genes. First, our benchmark results demonstrate that DISHyper outperforms the existing state-of-the-art methods and highlight the advantages of employing hypergraphs for representing annotated gene sets. Second, we validate the accuracy of DISHyper-predicted cancer genes using functional validation results and multiple independent functional genomics data. Third, our model predicts 44 novel cancer genes, and subsequent analysis shows their significant associations with multiple types of cancers. Overall, our study provides a new perspective for discovering cancer genes and reveals previously undiscovered cancer genes.
AVAILABILITY AND IMPLEMENTATION
DISHyper is freely available for download at https://github.com/genemine/DISHyper.
Topics: Humans; Neoplasms; Neural Networks, Computer; Computational Biology; Genomics; Genes, Neoplasm; Molecular Sequence Annotation; Databases, Genetic
PubMed: 38940121
DOI: 10.1093/bioinformatics/btae257 -
Journal of Integrative Neuroscience Jun 2024root, cataloged as "" in the Korean Pharmacopeia, is rich in various anthraquinones known for their anti-inflammatory and antioxidant properties. Formulations...
BACKGROUND
root, cataloged as "" in the Korean Pharmacopeia, is rich in various anthraquinones known for their anti-inflammatory and antioxidant properties. Formulations containing are traditionally employed for treating neurological conditions. This study aimed to substantiate the antiepileptic and neuroprotective efficacy of root extract (RTE) against trimethyltin (TMT)-induced epileptic seizures and hippocampal neurodegeneration.
METHODS
The constituents of RTE were identified by ultra-performance liquid chromatography (UPLC). Experimental animals were grouped into the following five categories: control, TMT, and three TMT+RTE groups with dosages of 10, 30, and 100 mg/kg. Seizure severity was assessed daily for comparison between the groups. Brain tissue samples were examined to determine the extent of neurodegeneration and neuroinflammation using histological and molecular biology techniques. Network pharmacology analysis involved extracting herbal targets for and disease targets for epilepsy from multiple databases. A protein-protein interaction network was built using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and pivotal targets were determined by topological analysis. Enrichment analysis was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) tool to elucidate the underlying mechanisms.
RESULTS
The RTE formulation was found to contain sennoside A, sennoside B, chrysophanol, emodin, physcion, (+)-catechin, and quercetin-3-O-glucuronoid. RTE effectively inhibited TMT-induced seizures at 10, 30, and 100 mg/kg dosages and attenuated hippocampal neuronal decay and neuroinflammation at 30 and 100 mg/kg dosages. Furthermore, RTE significantly reduced mRNA levels of tumor necrosis factor (), glial fibrillary acidic protein (), and in hippocampal tissues. Network analysis revealed TNF, Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Protein c-fos (FOS), RAC-alpha serine/threonine-protein kinase (AKT1), and Mammalian target of rapamycin (mTOR) as the core targets. Enrichment analysis demonstrated significant involvement of components in neurodegeneration ( = 4.35 × 10-5) and TNF signaling pathway ( = 9.94 × 10-5).
CONCLUSIONS
The and analyses performed in this study suggests that RTE can potentially modulate TMT-induced epileptic seizures and neurodegeneration. Therefore, root is a promising herbal treatment option for antiepileptic and neuroprotective applications.
Topics: Animals; Neuroprotective Agents; Trimethyltin Compounds; Plant Extracts; Rheum; Plant Roots; Male; Anticonvulsants; Epilepsy; Hippocampus; Disease Models, Animal; Neurodegenerative Diseases; Computer Simulation; Network Pharmacology; Protein Interaction Maps; Rats
PubMed: 38940090
DOI: 10.31083/j.jin2306122 -
Journal of Integrative Neuroscience Jun 2024The majority of neuromyelitis optica spectrum disorders (NMOSD) patients are seropositive for aquaporin-4 (AQP4)-specific antibodies [also named neuromyelitis optica...
OBJECTIVES
The majority of neuromyelitis optica spectrum disorders (NMOSD) patients are seropositive for aquaporin-4 (AQP4)-specific antibodies [also named neuromyelitis optica immunoglobulin G antibodies (NMO-IgG)]. Although NMO-IgG can induce pathological changes in the central nervous system (CNS), the immunological changes in the CNS and peripheral tissue remain largely unknown. We investigated whether NMO-IgG binds to tissue expressing AQP4 and induces immunological changes in the peripheral tissue and CNS.
METHODS
C57BL/6 female mice were assigned into an NMOSD or control group. Pathological and immunological changes in peripheral tissue and CNS were measured by immunostaining and flow cytometry, respectively. Motor impairment was measured by open-field test.
RESULTS
We found that NMO-IgG did bind to astrocyte- and AQP4-expressing peripheral tissue, but induced glial fibrillary acidic protein and AQP4 loss only in the CNS. NMO-IgG induced the activation of microglia and modulated microglia polarization toward the classical (M1) phenotype, but did not affect innate or adaptive immune cells in the peripheral immune system, such as macrophages, neutrophils, Th17/Th1, or IL-10-producing B cells. In addition, NMOSD mice showed significantly less total distance traveled and higher immobility time in the open field.
CONCLUSIONS
We found that injection of human NMO-IgG led to astrocytopathic lesions with microglial activation in the CNS. However, there were no significant pathological or immunological changes in the peripheral tissues.
Topics: Animals; Neuromyelitis Optica; Mice, Inbred C57BL; Immunoglobulin G; Aquaporin 4; Female; Humans; Mice; Disease Models, Animal; Microglia; Autoantibodies; Astrocytes; Glial Fibrillary Acidic Protein; Central Nervous System
PubMed: 38940087
DOI: 10.31083/j.jin2306119 -
Journal of Integrative Neuroscience May 2024The objective of this study is to compare the differences in effective connectivity within the default mode network (DMN) subsystems between patients with Parkinson's...
OBJECTIVE
The objective of this study is to compare the differences in effective connectivity within the default mode network (DMN) subsystems between patients with Parkinson's disease with mild cognitive impairment (PD-MCI) and patients with Parkinson's disease with normal cognition (PD-CN). The mechanisms underlying DMN dysfunction in PD-MCI patients and its association with clinical cognitive function in PD-MCI are aimed to be investigated.
METHODS
The spectral dynamic causal model (spDCM) was employed to analyze the effective connectivity of functional magnetic resonance imaging (fMRI) data in the resting state for the DMN subsystems, which include the medial prefrontal cortex (MPFC), posterior cingulate cortex (PCC), left and right angular gyrus (LAG, RAG) in 23 PD-MCI and 22 PD-CN patients, respectively. The effective connectivity values of DMN subsystems in the two groups were statistically analyzed using a two-sample -test. The Spearman correlation analysis was used to test the correlation between the effective connectivity values of the subsystems with significant differences between the two groups and the clinical cognitive function (as measured by Montreal Cognitive Assessment Scale (MoCA) score).
RESULTS
Statistical analysis revealed significant differences in the effective connections of MPFC-LAG and LAG-PCC between the two patient groups (MPFC-LAG: t = -2.993, < 0.05; LAG-PCC: t = 2.174, < 0.05).
CONCLUSIONS
The study findings suggest that abnormal strength and direction of effective connections between DMN subsystems are found in PD-MCI patients.
Topics: Humans; Parkinson Disease; Cognitive Dysfunction; Male; Female; Default Mode Network; Magnetic Resonance Imaging; Aged; Middle Aged; Prefrontal Cortex; Gyrus Cinguli; Connectome; Nerve Net
PubMed: 38940086
DOI: 10.31083/j.jin2306110 -
Frontiers in Bioscience (Landmark... Jun 2024Although umbilical cord mesenchymal stem cell (UCMSC) infusion has been proposed as a promising strategy for the treatment of acute lung injury (ALI), the parameters of... (Comparative Study)
Comparative Study
BACKGROUND
Although umbilical cord mesenchymal stem cell (UCMSC) infusion has been proposed as a promising strategy for the treatment of acute lung injury (ALI), the parameters of UCMSC transplantation, such as infusion routes and doses, need to be further optimized.
METHODS
In this study, we compared the therapeutic effects of UCMSCs transplanted via intravenous injection and intratracheal instillation on lipopolysaccharide-induced ALI using a rat model. Following transplantation, levels of inflammatory factors in serum; neutrophils, total white blood cells, and lymphocytes in bronchoalveolar lavage fluid (BALF); and lung damage levels were analyzed.
RESULTS
The results indicated that UCMSCs administered via both intravenous and intratracheal routes were effective in alleviating ALI, as determined by analyses of arterial blood gas, lung histopathology, BALF contents, and levels of inflammatory factors. Comparatively, the intratracheal instillation of UCMSCs was found to result in lower levels of lymphocytes and total proteins in BALF, whereas greater reductions in the serum levels of tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) were detected in rats receiving intravenously injected stem cells.
CONCLUSIONS
Our findings in this study provide convincing evidence to indicate the efficacy of UCMSC therapy in the treatment of ALI mediated via different delivery routes, thereby providing a reliable theoretical basis for further clinical studies. Moreover, these findings imply that the effects obtained using the two assessed delivery routes for UCMSC transplantation are mediated via different mechanisms, which could be attributable to different cellular or molecular targets.
Topics: Animals; Acute Lung Injury; Lipopolysaccharides; Mesenchymal Stem Cell Transplantation; Umbilical Cord; Rats, Sprague-Dawley; Rats; Male; Bronchoalveolar Lavage Fluid; Mesenchymal Stem Cells; Tumor Necrosis Factor-alpha; Injections, Intravenous
PubMed: 38940047
DOI: 10.31083/j.fbl2906217 -
Frontiers in Bioscience (Landmark... May 2024Polycystic ovary syndrome (PCOS) is a prevalent reproductive, endocrine, and metabolic disease that affects 5-18% of women worldwide, with a rising incidence.... (Review)
Review
Polycystic ovary syndrome (PCOS) is a prevalent reproductive, endocrine, and metabolic disease that affects 5-18% of women worldwide, with a rising incidence. Hyperandrogenemia and insulin resistance are two key pathophysiological factors that contribute to PCOS, both of which contribute to a variety of health issues such as menstrual irregularities, obesity, dysfunctional glucose and lipid homeostasis, infertility, mental disorders, and cardiovascular and cerebrovascular diseases. Despite ongoing studies, the origin and pathogenesis of PCOS remain elusive; there is also a clinical need for simpler, more effective, longer lasting, and more comprehensive treatments for women with PCOS. The gut-fat axis, a critical regulatory route for metabolism, endocrine function, and immune response, has received considerable interest in recent years in the research of the etiology and treatment of metabolic illnesses such as type 2 diabetes mellitus and non-alcoholic fatty liver disease. The latest research in PCOS has revealed significant alterations in the homogeneity and phylogenetic diversity of the gut microbiota. Animal research using fecal microbiota transplantation has confirmed the importance of gut microbiota in regulating insulin sensitivity and sex hormone balance in PCOS. Furthermore, studies have shown a decrease in the volume and/or activity of brown adipose tissue (BAT) in PCOS patients, a change that alters adipokine release, leading to insulin resistance and hyperandrogenemia, aggravating PCOS progression. Given the function of BAT in increasing energy expenditure and alleviating metabolic parameters, efforts to activate BAT or induce browning of white adipose tissue have emerged as possible treatments for PCOS. Recent research has suggested that the gut microbiota can influence BAT creation and activity via metabolites such as short-chain fatty acids and bile acids, as well as the gut-brain axis. Cold exposure, healthy dieting, metformin, bariatric surgery, glucagon-like peptide 1 receptor agonists and melatonin have all been shown in basic and clinical studies to modulate BAT activity by influencing the gut microbiota, demonstrating significant clinical potential. However, more studies into the regulation mechanisms of the gut-BAT axis are required to produce more effective, comfortable, and safe tailored therapeutics for PCOS.
Topics: Polycystic Ovary Syndrome; Humans; Female; Gastrointestinal Microbiome; Adipose Tissue, Brown; Animals; Insulin Resistance; Fecal Microbiota Transplantation; Obesity
PubMed: 38940030
DOI: 10.31083/j.fbl2906208