Clonal relationship, virulence genes, and antimicrobial resistance of Morganella morganii isolated from community-acquired infections and hospitalized patients: a neglected opportunistic pathogen

Morganella morganii is a bacterium belonging to the normal intestinal microbiota and the environment; however, in immunocompromised individuals, this bacterium can become an opportunistic pathogen, causing a series of diseases, both in hospitals and in the community, being urinary tract infections more prevalent. Therefore, the objective of this study was to evaluate the prevalence, virulence profile, and resistance to antimicrobials and the clonal relationship of isolates of urinary tract infections (UTI) caused by M. morganii, both in the hospital environment and in the community of the municipality of Londrina-PR, in southern Brazil, in order to better understand the mechanisms for the establishment of the disease caused by this bacterium. Our study showed that M. morganii presents a variety of virulence factors in the studied isolates. Hospital strains showed a higher prevalence for the virulence genes zapA, iutA, and fimH, while community strains showed a higher prevalence for the ireA and iutA genes. Hospital isolates showed greater resistance compared to community isolates, as well as a higher prevalence of multidrug-resistant (MDR) and extended-spectrum beta lactamase (ESBL)-producing isolates. Several M. morganii isolates from both sources showed high genetic similarity. The most prevalent plasmid incompatibility groups detected were FIB and I1, regardless of the isolation source. Thus, M. morganii isolates can accumulate virulence factors and antimicrobial resistance, making them a neglected opportunistic pathogen. (AU)

Massive RNA sequencing effort proposed.

U.S. plan would harness the "RNome" for medicine and more-but funding is uncertain.

QNetDiff: a quantitative measurement of network rewiring.

Bacteria in the human body, particularly in the large intestine, are known to be associated with various diseases. To identify disease-associated bacteria (markers), a typical method is to statistically compare the relative abundance of bacteria between healthy subjects and diseased patients. However, since bacteria do not necessarily cause diseases in isolation, it is also important to focus on the interactions and relationships among bacteria when examining their association with diseases. In fact, although there are common approaches to represent and analyze bacterial interaction relationships as networks, there are limited methods to find bacteria associated with diseases through network-driven analysis. In this paper, we focus on rewiring of the bacterial network and propose a new method for quantifying the rewiring. We then apply the proposed method to a group of colorectal cancer patients. We show that it can identify and detect bacteria that cannot be detected by conventional methods such as abundance comparison. Furthermore, the proposed method is implemented as a general-purpose tool and made available to the general public.

NIH megastudy analyzes first 250,000 genomes.

All of Us finds new DNA variants and refines genetic risk scores in diverse groups.

Phosphoinositide switches in cell physiology - From molecular mechanisms to disease.

Phosphoinositides are amphipathic lipid molecules derived from phosphatidylinositol that represent low abundance components of biological membranes. Rather than serving as mere structural elements of lipid bilayers, they represent molecular switches for a broad range of biological processes, including cell signaling, membrane dynamics and remodeling, and many other functions. Here, we focus on the molecular mechanisms that turn phosphoinositides into molecular switches and how the dysregulation of these processes can lead to disease.

Reference-Class Problems Are Real: Health-Adjusted Reference Classes and Low Bone Mineral Density.

Elselijn Kingma argues that Christopher Boorse's biostatistical theory (the BST) does not show how the reference classes it uses are objective and naturalistic. Recently, philosophers of medicine have attempted to rebut Kingma's concerns. I argue that these rebuttals are theoretically unconvincing, and that there are clear examples of physicians adjusting their reference classes according to their prior knowledge of health and disease. I focus on the use of age-adjusted reference classes to diagnose low bone mineral density in children. In addition to using the BST's age, sex, and species, physicians also choose to use other factors to define reference classes, such as pubertal status, bone age, body size, and muscle mass. I show that physicians calibrate the reference classes they use according to their prior knowledge of health and disease. Reference classes are also chosen for pragmatic reasons, such as to predict fragility fractures.

Conformational ensembles of the human intrinsically disordered proteome.

Intrinsically disordered proteins and regions (collectively, IDRs) are pervasive across proteomes in all kingdoms of life, help to shape biological functions and are involved in numerous diseases. IDRs populate a diverse set of transiently formed structures and defy conventional sequence-structure-function relationships1. Developments in protein science have made it possible to predict the three-dimensional structures of folded proteins at the proteome scale2. By contrast, there is a lack of knowledge about the conformational properties of IDRs, partly because the sequences of disordered proteins are poorly conserved and also because only a few of these proteins have been characterized experimentally. The inability to predict structural properties of IDRs across the proteome has limited our understanding of the functional roles of IDRs and how evolution shapes them. As a supplement to previous structural studies of individual IDRs3, we developed an efficient molecular model to generate conformational ensembles of IDRs and thereby to predict their conformational properties from sequences4,5. Here we use this model to simulate nearly all of the IDRs in the human proteome. Examining conformational ensembles of 28,058 IDRs, we show how chain compaction is correlated with cellular function and localization. We provide insights into how sequence features relate to chain compaction and, using a machine-learning model trained on our simulation data, show the conservation of conformational properties across orthologues. Our results recapitulate observations from previous studies of individual protein systems and exemplify how to link-at the proteome scale-conformational ensembles with cellular function and localization, amino acid sequence, evolutionary conservation and disease variants. Our freely available database of conformational properties will encourage further experimental investigation and enable the generation of hypotheses about the biological roles and evolution of IDRs.

MACC: a visual interactive knowledgebase of metabolite-associated cell communications.

Metabolite-associated cell communications play critical roles in maintaining the normal biological function of human through coordinating cells, organs and physiological systems. Though substantial information of MACCs has been continuously reported, no relevant database has become available so far. To address this gap, we here developed the first knowledgebase (MACC), to comprehensively describe human metabolite-associated cell communications through curation of experimental literatures. MACC currently contains: (a) 4206 carefully curated metabolite-associated cell communications pairs involving 244 human endogenous metabolites and reported biological effects in vivo and in vitro; (b) 226 comprehensive cell subtypes and 296 disease states, such as cancers, autoimmune diseases, and pathogenic infections; (c) 4508 metabolite-related enzymes and transporters, involving 542 pathways; (d) an interactive tool with user-friendly interface to visualize networks of multiple metabolite-cell interactions. (e) overall expression landscape of metabolite-associated gene sets derived from over 1500 single-cell expression profiles to infer metabolites variations across different cells in the sample. Also, MACC enables cross-links to well-known databases, such as HMDB, DrugBank, TTD and PubMed etc. In complement to ligand-receptor databases, MACC may give new perspectives of alternative communication between cells via metabolite secretion and adsorption, together with the resulting biological functions. MACC is publicly accessible at: http://macc.badd-cao.net/.

The Monarch Initiative in 2024: an analytic platform integrating phenotypes, genes and diseases across species.

Bridging the gap between genetic variations, environmental determinants, and phenotypic outcomes is critical for supporting clinical diagnosis and understanding mechanisms of diseases. It requires integrating open data at a global scale. The Monarch Initiative advances these goals by developing open ontologies, semantic data models, and knowledge graphs for translational research. The Monarch App is an integrated platform combining data about genes, phenotypes, and diseases across species. Monarch's APIs enable access to carefully curated datasets and advanced analysis tools that support the understanding and diagnosis of disease for diverse applications such as variant prioritization, deep phenotyping, and patient profile-matching. We have migrated our system into a scalable, cloud-based infrastructure; simplified Monarch's data ingestion and knowledge graph integration systems; enhanced data mapping and integration standards; and developed a new user interface with novel search and graph navigation features. Furthermore, we advanced Monarch's analytic tools by developing a customized plugin for OpenAI's ChatGPT to increase the reliability of its responses about phenotypic data, allowing us to interrogate the knowledge in the Monarch graph using state-of-the-art Large Language Models. The resources of the Monarch Initiative can be found at monarchinitiative.org and its corresponding code repository at github.com/monarch-initiative/monarch-app.

TheMarker: a comprehensive database of therapeutic biomarkers.

Distinct from the traditional diagnostic/prognostic biomarker (adopted as the indicator of disease state/process), the therapeutic biomarker (ThMAR) has emerged to be very crucial in the clinical development and clinical practice of all therapies. There are five types of ThMAR that have been found to play indispensable roles in various stages of drug discovery, such as: Pharmacodynamic Biomarker essential for guaranteeing the pharmacological effects of a therapy, Safety Biomarker critical for assessing the extent or likelihood of therapy-induced toxicity, Monitoring Biomarker indispensable for guiding clinical management by serially measuring patients' status, Predictive Biomarker crucial for maximizing the clinical outcome of a therapy for specific individuals, and Surrogate Endpoint fundamental for accelerating the approval of a therapy. However, these data of ThMARs has not been comprehensively described by any of the existing databases. Herein, a database, named 'TheMarker', was therefore constructed to (a) systematically offer all five types of ThMAR used at different stages of drug development, (b) comprehensively describe ThMAR information for the largest number of drugs among available databases, (c) extensively cover the widest disease classes by not just focusing on anticancer therapies. These data in TheMarker are expected to have great implication and significant impact on drug discovery and clinical practice, and it is freely accessible without any login requirement at: https://idrblab.org/themarker.