J Phys Chem B. 2024 May 23. doi: 10.1021/acs.jpcb.4c01875. Online ahead of print.

ABSTRACT

In modern drug discovery, virtual ligand screening (VLS) is frequently applied to identify possible hits before experimental testing and refinement due to its cost-effective nature for large compound libraries. For decades, efforts have been devoted to developing VLS methods with high accuracy. These include the state-of-the-art FINDSITE suite of approaches FINDSITEcomb2.0, FRAGSITE, and FRAGSITE2 and the meta version FRAGSITEcomb that were developed in our lab. These methods combine ligand homology modeling (LHM), traditional ligand similarity methods, and more recently machine learning approaches to rank ligands and have proven to be superior to most recent deep learning and large language model-based approaches. Here, we describe further improvements to our previous best methods by combining the Morgan fingerprint (MF) with the originally used PubChem fingerprint and FP2 fingerprint. We then benchmarked FINDSITEcomb2.0M, FRAGSITEM, FRAGSITE2M, and the composite meta-approach FRAGSITEcombM. On the 102 target DUD-E set, the 1% enrichment factor (EF1%) and area under the precision-recall curve (AUPR) of FRAGSITEcomb increased from 42.0/0.59 to 47.6/0.72. This 0.72 AUPR is significantly better than that of the state-of-the-art deep learning-based method DenseFS's AUPR of 0.443. An independent test on the 81 targets DEKOIS2.0 set shows that EF1%/AUPR increases from 18.3/0.520 to 23.1/0.683. An ablation investigation shows that the MF contributes to most of the improvement of all four approaches. Thus, the MF is a useful addition to structure-based VLS.

PMID:38783525 | DOI:10.1021/acs.jpcb.4c01875

Nat Biotechnol. 2024 May 23. doi: 10.1038/s41587-024-02235-x. Online ahead of print.

ABSTRACT

Single-nucleotide variants (SNVs) in key T cell genes can drive clinical pathologies and could be repurposed to improve cellular cancer immunotherapies. Here, we perform massively parallel base-editing screens to generate thousands of variants at gene loci annotated with known or potential clinical relevance. We discover a broad landscape of putative gain-of-function (GOF) and loss-of-function (LOF) mutations, including in PIK3CD and the gene encoding its regulatory subunit, PIK3R1, LCK, SOS1, AKT1 and RHOA. Base editing of PIK3CD and PIK3R1 variants in T cells with an engineered T cell receptor specific to a melanoma epitope or in different generations of CD19 chimeric antigen receptor (CAR) T cells demonstrates that discovered GOF variants, but not LOF or silent mutation controls, enhanced signaling, cytokine production and lysis of cognate melanoma and leukemia cell models, respectively. Additionally, we show that generations of CD19 CAR T cells engineered with PIK3CD GOF mutations demonstrate enhanced antigen-specific signaling, cytokine production and leukemia cell killing, including when benchmarked against other recent strategies.

PMID:38783148 | DOI:10.1038/s41587-024-02235-x

Nat Genet. 2024 May 23. doi: 10.1038/s41588-024-01805-8. Online ahead of print.

NO ABSTRACT

PMID:38783122 | DOI:10.1038/s41588-024-01805-8

Nat Genet. 2024 May 23. doi: 10.1038/s41588-024-01760-4. Online ahead of print.

ABSTRACT

Chickpea (Cicer arietinum L.)-an important legume crop cultivated in arid and semiarid regions-has limited genetic diversity. Efforts are being undertaken to broaden its diversity by utilizing its wild relatives, which remain largely unexplored. Here, we present the Cicer super-pangenome based on the de novo genome assemblies of eight annual Cicer wild species. We identified 24,827 gene families, including 14,748 core, 2,958 softcore, 6,212 dispensable and 909 species-specific gene families. The dispensable genome was enriched for genes related to key agronomic traits. Structural variations between cultivated and wild genomes were used to construct a graph-based genome, revealing variations in genes affecting traits such as flowering time, vernalization and disease resistance. These variations will facilitate the transfer of valuable traits from wild Cicer species into elite chickpea varieties through marker-assisted selection or gene-editing. This study offers valuable insights into the genetic diversity and potential avenues for crop improvement in chickpea.

PMID:38783120 | DOI:10.1038/s41588-024-01760-4

Nucleic Acids Res. 2024 May 23:gkae388. doi: 10.1093/nar/gkae388. Online ahead of print.

ABSTRACT

In recent decades, the development of new drugs has become increasingly expensive and inefficient, and the molecular mechanisms of most pharmaceuticals remain poorly understood. In response, computational systems and network medicine tools have emerged to identify potential drug repurposing candidates. However, these tools often require complex installation and lack intuitive visual network mining capabilities. To tackle these challenges, we introduce Drugst.One, a platform that assists specialized computational medicine tools in becoming user-friendly, web-based utilities for drug repurposing. With just three lines of code, Drugst.One turns any systems biology software into an interactive web tool for modeling and analyzing complex protein-drug-disease networks. Demonstrating its broad adaptability, Drugst.One has been successfully integrated with 21 computational systems medicine tools. Available at https://drugst.one, Drugst.One has significant potential for streamlining the drug discovery process, allowing researchers to focus on essential aspects of pharmaceutical treatment research.

PMID:38783119 | DOI:10.1093/nar/gkae388

NPJ Syst Biol Appl. 2024 May 23;10(1):54. doi: 10.1038/s41540-024-00384-y.

ABSTRACT

Genome-scale metabolic models (GEMs) of microbial communities offer valuable insights into the functional capabilities of their members and facilitate the exploration of microbial interactions. These models are generated using different automated reconstruction tools, each relying on different biochemical databases that may affect the conclusions drawn from the in silico analysis. One way to address this problem is to employ a consensus reconstruction method that combines the outcomes of different reconstruction tools. Here, we conducted a comparative analysis of community models reconstructed from three automated tools, i.e. CarveMe, gapseq, and KBase, alongside a consensus approach, utilizing metagenomics data from two marine bacterial communities. Our analysis revealed that these reconstruction approaches, while based on the same genomes, resulted in GEMs with varying numbers of genes and reactions as well as metabolic functionalities, attributed to the different databases employed. Further, our results indicated that the set of exchanged metabolites was more influenced by the reconstruction approach rather than the specific bacterial community investigated. This observation suggests a potential bias in predicting metabolite interactions using community GEMs. We also showed that consensus models encompassed a larger number of reactions and metabolites while concurrently reducing the presence of dead-end metabolites. Therefore, the usage of consensus models allows making full and unbiased use from aggregating genes from the different reconstructions in assessing the functional potential of microbial communities.

PMID:38783065 | DOI:10.1038/s41540-024-00384-y

Sci Data. 2024 May 23;11(1):530. doi: 10.1038/s41597-024-03343-8.

ABSTRACT

The identification of lead molecules and the exploration of novel pharmacological drug targets are major challenges of medical life sciences today. Genome-wide association studies, multi-omics, and systems pharmacology steadily reveal new protein networks, extending the known and relevant disease-modifying proteome. Unfortunately, the vast majority of the disease-modifying proteome consists of 'orphan targets' of which intrinsic ligands/substrates, (patho)physiological roles, and/or modulators are unknown. Undruggability is a major challenge in drug development today, and medicinal chemistry efforts cannot keep up with hit identification and hit-to-lead optimization studies. New 'thinking-outside-the-box' approaches are necessary to identify structurally novel and functionally distinctive ligands for orphan targets. Here we present a unique dataset that includes critical information on the orphan target ABCA1, from which a novel cheminformatic workflow - computer-aided pattern scoring (C@PS) - for the identification of novel ligands was developed. Providing a hit rate of 95.5% and molecules with high potency and molecular-structural diversity, this dataset represents a suitable template for general deorphanization studies.

PMID:38783061 | DOI:10.1038/s41597-024-03343-8

Commun Biol. 2024 May 23;7(1):625. doi: 10.1038/s42003-024-06318-y.

NO ABSTRACT

PMID:38783006 | DOI:10.1038/s42003-024-06318-y

Bone Res. 2024 May 23;12(1):31. doi: 10.1038/s41413-024-00336-6.

ABSTRACT

Rheumatoid arthritis (RA) is an autoimmune disease. Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility. However, accumulating evidence demonstrates that genetics also shape the gut microbiota. It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis (CIA), while the others are resistant to CIA. Here, we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice. C57BL/6J mice and healthy human individuals have enriched B. fragilis than DBA/1J mice and RA patients. Transplantation of B. fragilis prevents CIA in DBA/1J mice. We identify that B. fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate. Fibroblast-like synoviocytes (FLSs) in RA are activated to undergo tumor-like transformation. Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1, resulting in reduced FOXK1 stability, blocked interferon signaling and deactivation of RA-FLSs. We treat CIA mice with propionate and show that propionate attenuates CIA. Moreover, a combination of propionate with anti-TNF etanercept synergistically relieves CIA. These results suggest that B. fragilis or propionate could be an alternative or complementary approach to the current therapies.

PMID:38782893 | DOI:10.1038/s41413-024-00336-6

Biochim Biophys Acta Mol Basis Dis. 2024 May 21:167260. doi: 10.1016/j.bbadis.2024.167260. Online ahead of print.

ABSTRACT

Lysosomal acid sphingomyelinase (ASM), a critical enzyme in lipid metabolism encoded by the SMPD1 gene, plays a crucial role in sphingomyelin hydrolysis in lysosomes. ASM deficiency leads to acid sphingomyelinase deficiency, a rare genetic disorder with diverse clinical manifestations, and the protein can be found mutated in other diseases. We employed a structure-based framework to comprehensively understand the functional implications of ASM variants, integrating pathogenicity predictions with molecular insights derived from a molecular dynamics simulation in a lysosomal membrane environment. Our analysis, encompassing over 400 variants, establishes a structural atlas of missense variants of lysosomal ASM, associating mechanistic indicators with pathogenic potential. Our study highlights variants that influence structural stability or exert local and long-range effects at functional sites. To validate our predictions, we compared them to available experimental data on residual catalytic activity in 135 ASM variants. Notably, our findings also suggest applications of the resulting data for identifying cases suited for enzyme replacement therapy. This comprehensive approach enhances the understanding of ASM variants and provides valuable insights for potential therapeutic interventions.

PMID:38782304 | DOI:10.1016/j.bbadis.2024.167260

Sci Total Environ. 2024 May 21:173434. doi: 10.1016/j.scitotenv.2024.173434. Online ahead of print.

ABSTRACT

Freshwater ecosystems are highly vulnerable to the impacts of climate change, which affect both diversity and ecosystem functioning. Furthermore, these ecosystems face additional threats from human activities, such as changes in land use, leading to water pollution and habitat degradation. Intermittent streams represent nearly half of all fluvial systems and support a rich diversity adapted to cope with drying. This study examines the impact of drying and different land uses on the taxonomic and functional diversity of aquatic invertebrates in a Mediterranean intermittent stream network. By sampling 16 reaches seasonally, we hypothesised that longer dry-phase duration and agriculture would both reduce α-diversity, with drying dominating impacts on β-diversity over agricultural practices. We anticipated that drying and agriculture would alter species and trait compositions, favouring desiccation-tolerant and generalist taxa. Drying adversely affected the taxonomic and functional α-diversity of aquatic invertebrates, while it positively influenced β-diversity. Land use only affected α-diversity. Specifically, habitat heterogeneity and increased water nutrient levels within the stream network correlated positively with invertebrate diversity. However, the negative effects of drying were less pronounced in upstream forested regions with high habitat heterogeneity compared to downstream areas influenced by agriculture. Our research highlights the importance of preserving natural and forested streams in intermittent networks, particularly in headwater regions, thus facilitating recolonization when flow is restored throughout the stream network.

PMID:38782277 | DOI:10.1016/j.scitotenv.2024.173434

Epidemics. 2024 May 14;47:100773. doi: 10.1016/j.epidem.2024.100773. Online ahead of print.

ABSTRACT

Tracking pathogen transmissibility during infectious disease outbreaks is essential for assessing the effectiveness of public health measures and planning future control strategies. A key measure of transmissibility is the time-dependent reproduction number, which has been estimated in real-time during outbreaks of a range of pathogens from disease incidence time series data. While commonly used approaches for estimating the time-dependent reproduction number can be reliable when disease incidence is recorded frequently, such incidence data are often aggregated temporally (for example, numbers of cases may be reported weekly rather than daily). As we show, commonly used methods for estimating transmissibility can be unreliable when the timescale of transmission is shorter than the timescale of data recording. To address this, here we develop a simulation-based approach involving Approximate Bayesian Computation for estimating the time-dependent reproduction number from temporally aggregated disease incidence time series data. We first use a simulated dataset representative of a situation in which daily disease incidence data are unavailable and only weekly summary values are reported, demonstrating that our method provides accurate estimates of the time-dependent reproduction number under such circumstances. We then apply our method to two outbreak datasets consisting of weekly influenza case numbers in 2019-20 and 2022-23 in Wales (in the United Kingdom). Our simple-to-use approach will allow accurate estimates of time-dependent reproduction numbers to be obtained from temporally aggregated data during future infectious disease outbreaks.

PMID:38781911 | DOI:10.1016/j.epidem.2024.100773

J Comput Biol. 2024 May 23. doi: 10.1089/cmb.2024.0509. Online ahead of print.

ABSTRACT

The thresholding problem is studied in the context of graph theoretical analysis of gene co-expression data. A number of thresholding methodologies are described, implemented, and tested over a large collection of graphs derived from real high-throughput biological data. Comparative results are presented and discussed.

PMID:38781420 | DOI:10.1089/cmb.2024.0509

Compend Contin Educ Dent. 2024 Mar;45(Suppl 1):18-19.

ABSTRACT

The Philips® Sonicare® Power Flosser (PSPF) is highly effective in reducing gum disease. Next to effective supragingival cleaning, this may be partially driven by subgingival cleaning. This in vitro study aimed to assess the effectiveness of the PSPF in removing biofilm from a model periodontal pocket up to 6 mm deep and to investigate the taxonomic composition of biofilm regrown after use of the PSPF.

PMID:38781413

Science. 2024 May 24;384(6698):eadh3707. doi: 10.1126/science.adh3707. Epub 2024 May 24.

ABSTRACT

The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) included the central nucleus of the amygdala, hippocampal dentate gyrus, and medial prefrontal cortex (mPFC). Genes and exons within the mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal and synaptic regulation, and stress hormones. Multiomic factor and gene network analyses provided the underlying genomic structure. Single nucleus RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) signals in neuronal and non-neuronal cell types. Analyses of brain-blood intersections in >50,000 UK Biobank participants were conducted along with fine-mapping of the results of PTSD and MDD genome-wide association studies to distinguish risk from disease processes. Our data suggest shared and distinct molecular pathology in both disorders and propose potential therapeutic targets and biomarkers.

PMID:38781393 | DOI:10.1126/science.adh3707

Science. 2024 May 24;384(6698):eadi5199. doi: 10.1126/science.adi5199. Epub 2024 May 24.

ABSTRACT

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.

PMID:38781369 | DOI:10.1126/science.adi5199

Proc Natl Acad Sci U S A. 2024 May 28;121(22):e2405123121. doi: 10.1073/pnas.2405123121. Epub 2024 May 23.

ABSTRACT

Mitochondria play a central role in muscle metabolism and function. A unique family of iron-sulfur proteins, termed CDGSH Iron Sulfur Domain-containing (CISD/NEET) proteins, support mitochondrial function in skeletal muscles. The abundance of these proteins declines during aging leading to muscle degeneration. Although the function of the outer mitochondrial CISD/NEET proteins, CISD1/mitoNEET and CISD2/NAF-1, has been defined in skeletal muscle cells, the role of the inner mitochondrial CISD protein, CISD3/MiNT, is currently unknown. Here, we show that CISD3 deficiency in mice results in muscle atrophy that shares proteomic features with Duchenne muscular dystrophy. We further reveal that CISD3 deficiency impairs the function and structure of skeletal muscles, as well as their mitochondria, and that CISD3 interacts with, and donates its [2Fe-2S] clusters to, complex I respiratory chain subunit NADH Ubiquinone Oxidoreductase Core Subunit V2 (NDUFV2). Using coevolutionary and structural computational tools, we model a CISD3-NDUFV2 complex with proximal coevolving residue interactions conducive of [2Fe-2S] cluster transfer reactions, placing the clusters of the two proteins 10 to 16 Å apart. Taken together, our findings reveal that CISD3/MiNT is important for supporting the biogenesis and function of complex I, essential for muscle maintenance and function. Interventions that target CISD3 could therefore impact different muscle degeneration syndromes, aging, and related conditions.

PMID:38781208 | DOI:10.1073/pnas.2405123121

Angiogenesis. 2024 May 23. doi: 10.1007/s10456-024-09921-z. Online ahead of print.

ABSTRACT

The presence of atherosclerotic plaque vessels is a critical factor in plaque destabilization. This may be attributable to the leaky phenotype of these microvessels, although direct proof for this notion is lacking. In this study, we investigated molecular and cellular patterns of stable and hemorrhaged human plaque to identify novel drivers of intraplaque vessel dysfunction. From transcriptome data of a human atherosclerotic lesion cohort, we reconstructed a co-expression network, identifying a gene module strongly and selectively correlated with both plaque microvascular density and inflammation. Spectrin Beta Non-Erythrocytic 1 (sptbn1) was identified as one of the central hubs of this module (along with zeb1 and dock1) and was selected for further study based on its predominant endothelial expression. Silencing of sptbn1 enhanced leukocyte transmigration and vascular permeability in vitro, characterized by an increased number of focal adhesions and reduced junctional VE-cadherin. In vivo, sptbn1 knockdown in zebrafish impaired the development of the caudal vein plexus. Mechanistically, increased substrate stiffness was associated with sptbn1 downregulation in endothelial cells in vitro and in human vessels. Plaque SPTBN1 mRNA and protein expression were found to correlate with an enhanced presence of intraplaque hemorrhage and future cardiovascular disease (CVD) events during follow-up. In conclusion, we identify SPTBN1 as a central hub gene in a gene program correlating with plaque vascularisation. SPTBN1 was regulated by substrate stiffness in vitro while silencing blocked vascular development in vivo, and compromised barrier function in vitro. Together, SPTBN1 is identified as a new potential regulator of the leaky phenotype of atherosclerotic plaque microvessels.

PMID:38780883 | DOI:10.1007/s10456-024-09921-z

Cell Mol Life Sci. 2024 May 23;81(1):231. doi: 10.1007/s00018-024-05268-2.

ABSTRACT

CD200 is an anti-inflammatory protein that facilitates signal transduction through its receptor, CD200R, in cells, resulting in immune response suppression. This includes reducing M1-like macrophages, enhancing M2-like macrophages, inhibiting NK cell cytotoxicity, and downregulating CTL responses. Activation of CD200R has been found to modulate dendritic cells, leading to the induction or enhancement of Treg cells expressing Foxp3. However, the precise mechanisms behind this process are still unclear. Our previous study demonstrated that B cells in Peyer's patches can induce Treg cells, so-called Treg-of-B (P) cells, through STAT6 phosphorylation. This study aimed to investigate the role of CD200 in Treg-of-B (P) cell generation. To clarify the mechanisms, we used wild-type, STAT6 deficient, and IL-24 deficient T cells to generate Treg-of-B (P) cells, and antagonist antibodies (anti-CD200 and anti-IL-20RB), an agonist anti-CD200R antibody, CD39 inhibitors (ARL67156 and POM-1), a STAT6 inhibitor (AS1517499), and soluble IL-20RB were also applied. Our findings revealed that Peyer's patch B cells expressed CD200 to activate the CD200R on T cells and initiate the process of Treg-of-B (P) cells generation. CD200 and CD200R interaction triggers the phosphorylation of STAT6, which regulated the expression of CD200R, CD39, and IL-24 in T cells. CD39 regulated the expression of IL-24, which sustained the expression of CD223 and IL-10 and maintained the cell viability. In summary, the generation of Treg-of-B (P) cells by Peyer's patch B cells was through the CD200R-STAT6-CD39-IL-24 axis pathway.

PMID:38780647 | DOI:10.1007/s00018-024-05268-2

Biomacromolecules. 2024 May 23. doi: 10.1021/acs.biomac.4c00187. Online ahead of print.

ABSTRACT

Lignocellulosic biomass is a highly sustainable and largely carbon dioxide neutral feedstock for the production of biofuels and advanced biomaterials. Although thermochemical pretreatment is typically used to increase the efficiency of cell wall deconstruction, genetic engineering of the major plant cell wall polymers, especially lignin, has shown promise as an alternative approach to reduce biomass recalcitrance. Poplar trees with reduced lignin content and altered composition were previously developed by overexpressing bacterial 3-dehydroshikimate dehydratase (QsuB) enzyme to divert carbon flux from the shikimate pathway. In this work, three transgenic poplar lines with increasing QsuB expression levels and different lignin contents were studied using small-angle neutron scattering (SANS) and wide-angle X-ray scattering (WAXS). SANS showed that although the cellulose microfibril cross-sectional dimension remained unchanged, the ordered organization of the microfibrils progressively decreased with increased QsuB expression. This was correlated with decreasing total lignin content in the QsuB lines. WAXS showed that the crystallite dimensions of cellulose microfibrils transverse to the growth direction were not affected by the QsuB expression, but the crystallite dimensions parallel to the growth direction were decreased by ∼20%. Cellulose crystallinity was also decreased with increased QsuB expression, which could be related to high levels of 3,4-dihydroxybenzoate, the product of QsuB expression, disrupting microfibril crystallization. In addition, the cellulose microfibril orientation angle showed a bimodal distribution at higher QsuB expression levels. Overall, this study provides new structural insights into the impact of ectopic synthesis of small-molecule metabolites on cellulose organization and structure that can be used for future efforts aimed at reducing biomass recalcitrance.

PMID:38780531 | DOI:10.1021/acs.biomac.4c00187