J Invest Dermatol. 2023 Jun 15:S0022-202X(23)01962-0. doi: 10.1016/j.jid.2023.01.042. Online ahead of print.

ABSTRACT

Neurofibromatosis 1 (NF1) is caused by a nonfunctional copy of the NF1 tumor suppressor gene that predisposes patients to the development of cutaneous neurofibromas (cNFs), the skin tumor that is the hallmark of this condition. Innumerable benign cNFs, each appearing by an independent somatic inactivation of the remaining functional NF1 allele, form in nearly all patients with NF1. One of the limitations in developing a treatment for cNFs is an incomplete understanding of the underlying pathophysiology and limitations in experimental modeling. Recent advances in preclinical in vitro and in vivo modeling have substantially enhanced our understanding of cNF biology and created unprecedented opportunities for therapeutic discovery. We discuss the current state of cNF preclinical in vitro and in vivo model systems, including two- and three-dimensional cell cultures, organoids, genetically engineered mice, patient-derived xenografts, and porcine models. We highlight the models' relationship to human cNFs and how they can be used to gain insight into cNF development and therapeutic discovery.

PMID:37330719 | DOI:10.1016/j.jid.2023.01.042

Int Immunol. 2023 Jun 18:dxad021. doi: 10.1093/intimm/dxad021. Online ahead of print.

ABSTRACT

Vaccination stands as the cornerstone in the battle against infectious diseases, and its efficacy hinges upon multifaceted host-related factors encompassing genetics, age, and metabolic status. Remarkably, suboptimal immune responses triggered by metabolic dysregulation is frequently observed in susceptible populations - ranging from malnourished individuals to the obese and elderly - pose a formidable threat to vaccine efficacy. The emerging field of immunometabolism aims to unravel the intricate interplay between immune regulation and metabolic pathways, and recent research has revealed diverse metabolic signatures linked to various vaccine responses and outcomes. In this review, we summarise the major metabolic pathways utilised by B and T cells during vaccine responses, their complex and varied metabolic requirements, and the impact of micronutrients and metabolic hormones on vaccine outcomes. Furthermore, we examine how systemic metabolism influences vaccine responses and the evidence suggesting that metabolic dysregulation in vulnerable populations can lead to impaired vaccine responses. Lastly, we reflect on the challenge of proving causality with respect to the contribution of metabolic dysregulation to poor vaccine outcomes, and highlight the need for a systems biology approach that combines multimodal profiling and mathematical modelling to reveal the underlying mechanisms of such complex interactions.

PMID:37330692 | DOI:10.1093/intimm/dxad021

Microbiome. 2023 Jun 17;11(1):136. doi: 10.1186/s40168-023-01568-0.

ABSTRACT

BACKGROUND: Disruption of the microbial community in the respiratory tract due to infections, like influenza, could impact transmission of bacterial pathogens. Using samples from a household study, we determined whether metagenomic-type analyses of the microbiome provide the resolution necessary to track transmission of airway bacteria. Microbiome studies have shown that the microbial community across various body sites tends to be more similar between individuals who cohabit in the same household than between individuals from different households. We tested whether there was increased sharing of bacteria from the airways within households with influenza infections as compared to control households with no influenza.

RESULTS: We obtained 221 respiratory samples that were collected from 54 individuals at 4 to 5 time points across 10 households, with and without influenza infection, in Managua, Nicaragua. From these samples, we generated metagenomic (whole genome shotgun sequencing) datasets to profile microbial taxonomy. Overall, specific bacteria and phages were differentially abundant between influenza positive households and control (no influenza infection) households, with bacteria like Rothia, and phages like Staphylococcus P68virus that were significantly enriched in the influenza-positive households. We identified CRISPR spacers detected in the metagenomic sequence reads and used these to track bacteria transmission within and across households. We observed a clear sharing of bacterial commensals and pathobionts, such as Rothia, Neisseria, and Prevotella, within and between households. However, due to the relatively small number of households in our study, we could not determine if there was a correlation between increased bacterial transmission and influenza infection.

CONCLUSION: We observed that airway microbial composition differences across households were associated with what appeared to be different susceptibility to influenza infection. We also demonstrate that CRISPR spacers from the whole microbial community can be used as markers to study bacterial transmission between individuals. Although additional evidence is needed to study transmission of specific bacterial strains, we observed sharing of respiratory commensals and pathobionts within and across households. Video Abstract.

PMID:37330554 | DOI:10.1186/s40168-023-01568-0

Parasit Vectors. 2023 Jun 17;16(1):204. doi: 10.1186/s13071-023-05800-6.

ABSTRACT

BACKGROUND: Quantifying infection intensity is a common goal in parasitological studies. We have previously shown that the amount of parasite DNA in faecal samples can be a biologically meaningful measure of infection intensity, even if it does not agree well with complementary counts of transmission stages (oocysts in the case of Coccidia). Parasite DNA can be quantified at relatively high throughput using quantitative polymerase chain reaction (qPCR), but amplification needs a high specificity and does not simultaneously distinguish between parasite species. Counting of amplified sequence variants (ASVs) from high-throughput marker gene sequencing using a relatively universal primer pair has the potential to distinguish between closely related co-infecting taxa and to uncover the community diversity, thus being both more specific and more open-ended.

METHODS: We here compare qPCR to the sequencing-based amplification using standard PCR and a microfluidics-based PCR to quantify the unicellular parasite Eimeria in experimentally infected mice. We use multiple amplicons to differentially quantify Eimeria spp. in a natural house mouse population.

RESULTS: We show that sequencing-based quantification has high accuracy. Using a combination of phylogenetic analysis and the co-occurrence network, we distinguish three Eimeria species in naturally infected mice based on multiple marker regions and genes. We investigate geographical and host-related effects on Eimeria spp. community composition and find, as expected, prevalence to be largely explained by sampling locality (farm). Controlling for this effect, the novel approach allowed us to find body condition of mice to be negatively associated with Eimeria spp. abundance.

CONCLUSIONS: We conclude that amplicon sequencing provides the underused potential for species distinction and simultaneous quantification of parasites in faecal material. The method allowed us to detect a negative effect of Eimeria infection on the body condition of mice in the natural environment.

PMID:37330545 | DOI:10.1186/s13071-023-05800-6

Trends Mol Med. 2023 Jun 7:S1471-4914(23)00115-6. doi: 10.1016/j.molmed.2023.06.001. Online ahead of print.

ABSTRACT

A recent publication by Barreto and colleagues showed that SARS-CoV-2 directly triggers hyperglycemia by infecting hepatocytes and inducing phosphoenolpyruvate carboxykinase (PEPCK)-dependent gluconeogenesis. Here, we discuss the biological importance of these findings, including the hepatic tropism of SARS-CoV-2. We also comment on the clinical implications of the bidirectional connection between COVID-19 and noncommunicable diseases.

PMID:37330366 | DOI:10.1016/j.molmed.2023.06.001

Immunity. 2023 Jun 12:S1074-7613(23)00234-0. doi: 10.1016/j.immuni.2023.05.017. Online ahead of print.

ABSTRACT

It is currently not well known how necroptosis and necroptosis responses manifest in vivo. Here, we uncovered a molecular switch facilitating reprogramming between two alternative modes of necroptosis signaling in hepatocytes, fundamentally affecting immune responses and hepatocarcinogenesis. Concomitant necrosome and NF-κB activation in hepatocytes, which physiologically express low concentrations of receptor-interacting kinase 3 (RIPK3), did not lead to immediate cell death but forced them into a prolonged "sublethal" state with leaky membranes, functioning as secretory cells that released specific chemokines including CCL20 and MCP-1. This triggered hepatic cell proliferation as well as activation of procarcinogenic monocyte-derived macrophage cell clusters, contributing to hepatocarcinogenesis. In contrast, necrosome activation in hepatocytes with inactive NF-κB-signaling caused an accelerated execution of necroptosis, limiting alarmin release, and thereby preventing inflammation and hepatocarcinogenesis. Consistently, intratumoral NF-κB-necroptosis signatures were associated with poor prognosis in human hepatocarcinogenesis. Therefore, pharmacological reprogramming between these distinct forms of necroptosis may represent a promising strategy against hepatocellular carcinoma.

PMID:37329888 | DOI:10.1016/j.immuni.2023.05.017

Cell Host Microbe. 2023 Jun 12:S1931-3128(23)00220-2. doi: 10.1016/j.chom.2023.05.027. Online ahead of print.

ABSTRACT

Longitudinal microbiome data provide valuable insight into disease states and clinical responses, but they are challenging to mine and view collectively. To address these limitations, we present TaxUMAP, a taxonomically informed visualization for displaying microbiome states in large clinical microbiome datasets. We used TaxUMAP to chart a microbiome atlas of 1,870 patients with cancer during therapy-induced perturbations. Bacterial density and diversity were positively associated, but the trend was reversed in liquid stool. Low-diversity states (dominations) remained stable after antibiotic treatment, and diverse communities had a broader range of antimicrobial resistance genes than dominations. When examining microbiome states associated with risk for bacteremia, TaxUMAP revealed that certain Klebsiella species were associated with lower risk for bacteremia localize in a region of the atlas that is depleted in high-risk enterobacteria. This indicated a competitive interaction that was validated experimentally. Thus, TaxUMAP can chart comprehensive longitudinal microbiome datasets, enabling insights into microbiome effects on human health.

PMID:37329880 | DOI:10.1016/j.chom.2023.05.027

Pathol Res Pract. 2023 Jun 13;248:154614. doi: 10.1016/j.prp.2023.154614. Online ahead of print.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a cancer that is usually diagnosed at late stages. This highly aggressive tumor is resistant to most therapeutic approaches, necessitating identification of differentially expressed genes to design new therapies. Herein, we have analyzed single cell RNA-seq data with a systems biology approach to identify important differentially expressed genes in PDAC samples compared to adjacent non-cancerous samples. Our approach revealed 1462 DEmRNAs, including 1389 downregulated DEmRNAs (like PRSS1 and CLPS) and 73 upregulated DEmRNAs (like HSPA1A and SOCS3), 27 DElncRNAs, including 26 downregulated DElncRNAs (like LINC00472 and SNHG7) and 1 upregulated DElncRNA (SNHG5). We also listed a number of dysregulated signaling pathways, abnormally expressed genes and aberrant cellular functions in PDAC which can be used as possible biomarkers and therapeutic targets in this type of cancer.

PMID:37329816 | DOI:10.1016/j.prp.2023.154614

J Chromatogr B Analyt Technol Biomed Life Sci. 2023 Apr 14;1226:123676. doi: 10.1016/j.jchromb.2023.123676. Online ahead of print.

ABSTRACT

Functional dyspepsia (FD) is one of the more common functional disorders, with a prevalence of 20-25 %. It seriously affects the quality life of patients. Xiaopi Hewei Capsule (XPHC) is a classic formula originated from the Chinese Miao minority. Clinical studies have demonstrated that XPHC can effectively alleviate the symptoms of FD, but the molecular mechanism has not been elucidated. The purpose of this work is to investigate the mechanism of XPHC on FD by integrating metabolomics and network pharmacology. The mice models of FD were established, and gastric emptying rate, small intestine propulsion rate, serum level of motilin and gastrin were evaluate to study the interventional effect of XPHC on FD. Next, a metabolomics strategy has been developed to screen differential metabolites and related metabolic pathways induced by XPHC. Then, prediction of active compounds, targets and pathways of XPHC in treating FD were carried out by commonly used network pharmacological method. Finally, two parts of the results were integrated to investigate therapeutic mechanism of XPHC on FD, which were preliminary validated based on molecular docking. Thus, twenty representative different metabolites and thirteen related pathways of XPHC in treating FD were identified. Most of these metabolites were restored using modulation after XPHC treatment. The results of the network pharmacology analysis showed ten crucial compounds and nine hub genes related to the treatment of FD with XPHC. The further integrated analysis focused on four key targets, such as albumin (ALB), epidermal growth factor receptor (EGFR), tumor necrosis factor (TNF) and roto-oncogene tyrosine-protein kinase Src (SRC), and three representative biomarkers such as citric acid, L-leucine and eicosapentaenoic acid. Furthermore, molecular docking results showed that ten bioactive compounds from XPHC have good binding interactions with the four key genes. The functional enrichment analysis indicated that the potential mechanism of XPHC in treating FD was mainly associated with energy metabolism, amino acid metabolism, lipid metabolism, inflammatory reactions and mucosal repair. Our work confirms that network pharmacology-integrated metabolomics strategyis a powerful means to reveal the therapeutic mechanisms of XPHC improves FD, which contribute its further scientific research.

PMID:37329776 | DOI:10.1016/j.jchromb.2023.123676

Comp Immunol Microbiol Infect Dis. 2023 Jun 1;98:102002. doi: 10.1016/j.cimid.2023.102002. Online ahead of print.

ABSTRACT

This study is an attempt to extract and analyse the microsatellites or simple sequence repeats (SSRs) from the genomes of eight species of the genus Orthopoxvirus. The average size of genomes included in the study was 205 kb while the GC% was 33% for all but one. A total of 10,584 SSRs and 854 cSSRs were observed. POX2 with the largest genome of 224.499 kb had maximum of 1493 SSRs and 121 cSSRs (compound SSR) while POX7 with the smallest genome of 185.578 kb had minimum incident SSRs and cSSRs at 1181 and 96, respectively. There was significant correlation between genome size and SSR incidence. Di-nucleotide repeats were the most prevalent (57.47%) followed by mono- at 33% and tri- at 8.6%. Mono-nucleotide SSRs were predominantly T (51%) and A (48.4%). A majority of 80.32% SSRs were in the coding region. The three most similar genomes as per heat map POX1, POX7 and POX5 (93% similarity) are adjacent to one another in the phylogenetic tree. Ankyrin/Ankyrin like protein and Kelch protein which are associated with host determination and divergence have the highest SSR density in almost all studied viruses. Thus, SSRs are involved in genome evolution and host determination of viruses.

PMID:37329681 | DOI:10.1016/j.cimid.2023.102002

Nat Commun. 2023 Jun 16;14(1):3576. doi: 10.1038/s41467-023-39252-4.

ABSTRACT

Resource competition can be the cause of unintended coupling between co-expressed genetic constructs. Here we report the quantification of the resource load imposed by different mammalian genetic components and identify construct designs with increased performance and reduced resource footprint. We use these to generate improved synthetic circuits and optimise the co-expression of transfected cassettes, shedding light on how this can be useful for bioproduction and biotherapeutic applications. This work provides the scientific community with a framework to consider resource demand when designing mammalian constructs to achieve robust and optimised gene expression.

PMID:37328476 | DOI:10.1038/s41467-023-39252-4

Nat Commun. 2023 Jun 16;14(1):3481. doi: 10.1038/s41467-023-38958-9.

ABSTRACT

Loss of a kidney results in compensatory growth of the remaining kidney, a phenomenon of considerable clinical importance. However, the mechanisms involved are largely unknown. Here, we use a multi-omic approach in a unilateral nephrectomy model in male mice to identify signaling processes associated with renal compensatory hypertrophy, demonstrating that the lipid-activated transcription factor peroxisome proliferator-activated receptor alpha (PPARα) is an important determinant of proximal tubule cell size and is a likely mediator of compensatory proximal tubule hypertrophy.

PMID:37328470 | DOI:10.1038/s41467-023-38958-9

Sci Total Environ. 2023 Jun 14:164834. doi: 10.1016/j.scitotenv.2023.164834. Online ahead of print.

ABSTRACT

Climate change threatens freshwater fish species due to predicted changes in thermal, sedimentary and hydrological properties of stream ecosystems. Gravel-spawning fish are particularly sensitive to such alterations as warming, higher inputs of fine sediment and low-flow all have potentially negative effects on the functionality of their reproductive habitat, the hyporheic zone. Multiple stressors can interact in synergistic and antagonistic manners, causing surprise-effects that cannot be predicted from the additive consideration of individual stressors. For obtaining reliable, yet realistic data on the climate change stressor effects warming (+3-4 °C), fine sediment (increase in <0.85 mm by 22 %) and low-flow (eightfold discharge-reduction), we constructed a unique large-scale outdoor-mesocosm facility consisting of 24 flumes to study individual and combined stressor responses in a fully-crossed, 3-way-replicated design. To acquire representative results reflecting individual susceptibilities of gravel-spawning fish species due to taxonomic affiliation or spawning seasonality, we studied hatching success and embryonic development in the three fish species brown trout (Salmo trutta L.), common nase (Chondrostoma nasus L.) and Danube salmon (Hucho hucho L.). Fine sediment had the most significant single negative effect on both hatching rates and embryonic development (-80 % in brown trout, -50 % in nase, -60 % in Danube salmon). When fine sediment was combined with one or both of the other stressors, we observed strongly synergistic stressor responses, being distinctly stronger in the two salmonid species than in the cyprinid nase. Danube salmon was most susceptible to synergistic effects due to warmer spring water temperatures exacerbating the fine sediment-induced hypoxia, hence leading to complete mortality of fish eggs. This study highlights that individual and multiple-stressor effects depend strongly on life-history traits of respective species and that climate change stressors have to be assessed in combination to obtain representative results due to the high level of synergisms and antagonisms detected in this study.

PMID:37327887 | DOI:10.1016/j.scitotenv.2023.164834

Cancer Cell. 2023 Jun 5:S1535-6108(23)00181-2. doi: 10.1016/j.ccell.2023.05.014. Online ahead of print.

ABSTRACT

The cell-autonomous balance of immune-inhibitory and -stimulatory signals is a critical process in cancer immune evasion. Using patient-derived co-cultures, humanized mouse models, and single-cell RNA-sequencing of patient melanomas biopsied before and on immune checkpoint blockade, we find that intact cancer cell-intrinsic expression of CD58 and ligation to CD2 is required for anti-tumor immunity and is predictive of treatment response. Defects in this axis promote immune evasion through diminished T cell activation, impaired intratumoral T cell infiltration and proliferation, and concurrently increased PD-L1 protein stabilization. Through CRISPR-Cas9 and proteomics screens, we identify and validate CMTM6 as critical for CD58 stability and upregulation of PD-L1 upon CD58 loss. Competition between CD58 and PD-L1 for CMTM6 binding determines their rate of endosomal recycling over lysosomal degradation. Overall, we describe an underappreciated yet critical axis of cancer immunity and provide a molecular basis for how cancer cells balance immune inhibitory and stimulatory cues.

PMID:37327789 | DOI:10.1016/j.ccell.2023.05.014

Curr Biol. 2023 Jun 11:S0960-9822(23)00683-8. doi: 10.1016/j.cub.2023.05.051. Online ahead of print.

ABSTRACT

Stomata are controllable micropores formed between two adjacent guard cells (GCs) that regulate gas flow across the plant surface.1 Grasses, among the most successful organisms on the planet and the main food crops for humanity, have GCs flanked by specialized lateral subsidiary cells (SCs).2,3,4 SCs improve performance by acting as a local pool of ions and metabolites to drive changes in turgor pressure within the GCs that open/close the stomatal pore.4,5,6,7,8 The 4-celled complex also involves distinctive changes in geometry, having dumbbell-shaped GCs compared with typical kidney-shaped stomata.2,4,9 However, the degree to which this distinctive geometry contributes to improved stomatal performance, and the underlying mechanism, remains unclear. To address this question, we created a finite element method (FEM) model of a grass stomatal complex that successfully captures experimentally observed pore opening/closure. Exploration of the model, including in silico and experimental mutant analyses, supports the importance of a reciprocal pressure system between GCs and SCs for effective stomatal function, with SCs functioning as springs to restrain lateral GC movement. Our results show that SCs are not essential but lead to a more responsive system. In addition, we show that GC wall anisotropy is not required for grass stomatal function (in contrast to kidney-shaped GCs10) but that a relatively thick GC rod region is needed to enhance pore opening. Our results demonstrate that a specific cellular geometry and associated mechanical properties are required for the effective functioning of grass stomata.

PMID:37327783 | DOI:10.1016/j.cub.2023.05.051

PLoS One. 2023 Jun 16;18(6):e0287230. doi: 10.1371/journal.pone.0287230. eCollection 2023.

ABSTRACT

INTRODUCTION: Geriatric co-management is known to improve treatment of older adults in various clinical settings, however, widespread application of the concept is limited due to restricted resources. Digitalization may offer options to overcome these shortages by providing structured, relevant information and decision support tools for medical professionals. We present the SURGE-Ahead project (Supporting SURgery with GEriatric co-management and Artificial Intelligence) addressing this challenge.

METHODS: A digital application with a dashboard-style user interface will be developed, displaying 1) evidence-based recommendations for geriatric co-management and 2) artificial intelligence-enhanced suggestions for continuity of care (COC) decisions. The development and implementation of the SURGE-Ahead application (SAA) will follow the Medical research council framework for complex medical interventions. In the development phase a minimum geriatric data set (MGDS) will be defined that combines parametrized information from the hospital information system with a concise assessment battery and sensor data. Two literature reviews will be conducted to create an evidence base for co-management and COC suggestions that will be used to display guideline-compliant recommendations. Principles of machine learning will be used for further data processing and COC proposals for the postoperative course. In an observational and AI-development study, data will be collected in three surgical departments of a University Hospital (trauma surgery, general and visceral surgery, urology) for AI-training, feasibility testing of the MGDS and identification of co-management needs. Usability will be tested in a workshop with potential users. During a subsequent project phase, the SAA will be tested and evaluated in clinical routine, allowing its further improvement through an iterative process.

DISCUSSION: The outline offers insights into a novel and comprehensive project that combines geriatric co-management with digital support tools to improve inpatient surgical care and continuity of care of older adults.

TRIAL REGISTRATION: German clinical trials registry (Deutsches Register für klinische Studien, DRKS00030684), registered on 21st November 2022.

PMID:37327245 | DOI:10.1371/journal.pone.0287230

PLoS Comput Biol. 2023 Jun 16;19(6):e1011163. doi: 10.1371/journal.pcbi.1011163. Online ahead of print.

ABSTRACT

BACKGROUND: Microbiome research is providing important new insights into the metabolic interactions of complex microbial ecosystems involved in fields as diverse as the pathogenesis of human diseases, agriculture and climate change. Poor correlations typically observed between RNA and protein expression datasets make it hard to accurately infer microbial protein synthesis from metagenomic data. Additionally, mass spectrometry-based metaproteomic analyses typically rely on focused search sequence databases based on prior knowledge for protein identification that may not represent all the proteins present in a set of samples. Metagenomic 16S rRNA sequencing only targets the bacterial component, while whole genome sequencing is at best an indirect measure of expressed proteomes. Here we describe a novel approach, MetaNovo, that combines existing open-source software tools to perform scalable de novo sequence tag matching with a novel algorithm for probabilistic optimization of the entire UniProt knowledgebase to create tailored sequence databases for target-decoy searches directly at the proteome level, enabling metaproteomic analyses without prior expectation of sample composition or metagenomic data generation and compatible with standard downstream analysis pipelines.

RESULTS: We compared MetaNovo to published results from the MetaPro-IQ pipeline on 8 human mucosal-luminal interface samples, with comparable numbers of peptide and protein identifications, many shared peptide sequences and a similar bacterial taxonomic distribution compared to that found using a matched metagenome sequence database-but simultaneously identified many more non-bacterial peptides than the previous approaches. MetaNovo was also benchmarked on samples of known microbial composition against matched metagenomic and whole genomic sequence database workflows, yielding many more MS/MS identifications for the expected taxa, with improved taxonomic representation, while also highlighting previously described genome sequencing quality concerns for one of the organisms, and identifying an experimental sample contaminant without prior expectation.

CONCLUSIONS: By estimating taxonomic and peptide level information directly on microbiome samples from tandem mass spectrometry data, MetaNovo enables the simultaneous identification of peptides from all domains of life in metaproteome samples, bypassing the need for curated sequence databases to search. We show that the MetaNovo approach to mass spectrometry metaproteomics is more accurate than current gold standard approaches of tailored or matched genomic sequence database searches, can identify sample contaminants without prior expectation and yields insights into previously unidentified metaproteomic signals, building on the potential for complex mass spectrometry metaproteomic data to speak for itself.

PMID:37327214 | DOI:10.1371/journal.pcbi.1011163

Bioinformatics. 2023 Jun 16:btad384. doi: 10.1093/bioinformatics/btad384. Online ahead of print.

ABSTRACT

MOTIVATION: Biomarker discovery is one of the most frequent pursuits in bioinformatics and is crucial for precision medicine, disease prognosis, and drug discovery. A common challenge of biomarker discovery applications is the low ratio of samples over features for the selection of a reliable not-redundant subset of features, but despite the development of efficient tree-based classification methods, such as the extreme gradient boosting (XGBoost), this limitation is still relevant. Moreover, existing approaches for optimizing XGBoost do not deal effectively with the class imbalance nature of the biomarker discovery problems, and the presence of multiple conflicting objectives, since they focus on the training of a single-objective model. In the current work, we introduce MEvA-X, a novel hybrid ensemble for feature selection and classification, combining a niche-based multi-objective evolutionary algorithm (EA) with the XGBoost classifier. MEvA-X deploys a multi-objective EA to optimize the hyper-parameters of the classifier and perform feature selection, identifying a set of Pareto-optimal solutions and optimizing multiple objectives, including classification and model simplicity metrics.

RESULTS: The performance of the MEvA-X tool was benchmarked using one omics dataset coming from a microarray gene expression experiment, and one clinical questionnaire-based dataset combined with demographic information. MEvA-X tool outperformed the state-of-the-art methods in the balanced categorization of classes, creating multiple low-complexity models and identifying important non-redundant biomarkers. The best-performing run of MEvA-X for the prediction of weight loss using gene expression data yields a small set of blood circulatory markers which are sufficient for this precision nutrition application but need further validation.

AVAILABILITY: https://github.com/PanKonstantinos/MEvA-X.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:37326976 | DOI:10.1093/bioinformatics/btad384

Microb Ecol. 2023 Jun 16. doi: 10.1007/s00248-023-02253-3. Online ahead of print.

ABSTRACT

Biofilms are complex microecosystems with valuable ecological roles that can shelter a variety of microorganisms. Spirochetes from the genus Leptospira have been observed to form biofilms in vitro, in rural environments, and in the kidneys of reservoir rats. The genus Leptospira is composed of pathogenic and non-pathogenic species, and the description of new species is ongoing due to the advent of whole genome sequencing. Leptospires have increasingly been isolated from water and soil samples. To investigate the presence of Leptospira in environmental biofilms, we collected three distinct samples of biofilms formed in an urban setting with poor sanitation: Pau da Lima, in Salvador, Bahia, Brazil. All biofilm samples were negative for the presence of pathogenic leptospires via conventional PCR, but cultures containing saprophytic Leptospira were identified. Whole genomes were generated and analyzed for twenty isolates obtained from these biofilms. For species identification, we used digital DNA-DNA hybridization (dDDH) and average nucleotide identity (ANI) analysis. The obtained isolates were classified into seven presumptive species from the saprophytic S1 clade. ANI and dDDH analysis suggest that three of those seven species were new. Classical phenotypic tests confirmed the novel isolated bacteria as saprophytic Leptospira. The isolates presented typical morphology and ultrastructure according to scanning electron microscopy and formed biofilms under in vitro conditions. Our data indicate that a diversity of saprophytic Leptospira species survive in the Brazilian poorly sanitized urban environment, in a biofilm lifestyle. We believe our results contribute to a better understanding of Leptospira biology and ecology, considering biofilms as natural environmental reservoirs for leptospires.

PMID:37326636 | DOI:10.1007/s00248-023-02253-3

Elife. 2023 Jun 16;12:e79834. doi: 10.7554/eLife.79834.

ABSTRACT

Obesity is a major risk factor for cardiovascular disease, stroke, and type 2 diabetes (T2D). Excessive accumulation of fat in the abdomen further increases T2D risk. Abdominal obesity is measured by calculating the ratio of waist-to-hip circumference adjusted for the body-mass index (WHRadjBMI), a trait with a significant genetic inheritance. Genetic loci associated with WHRadjBMI identified in genome-wide association studies are predicted to act through adipose tissues, but many of the exact molecular mechanisms underlying fat distribution and its consequences for T2D risk are poorly understood. Further, mechanisms that uncouple the genetic inheritance of abdominal obesity from T2D risk have not yet been described. Here we utilize multi-omic data to predict mechanisms of action at loci associated with discordant effects on abdominal obesity and T2D risk. We find six genetic signals in five loci associated with protection from T2D but also with increased abdominal obesity. We predict the tissues of action at these discordant loci and the likely effector Genes (eGenes) at three discordant loci, from which we predict significant involvement of adipose biology. We then evaluate the relationship between adipose gene expression of eGenes with adipogenesis, obesity, and diabetic physiological phenotypes. By integrating these analyses with prior literature, we propose models that resolve the discordant associations at two of the five loci. While experimental validation is required to validate predictions, these hypotheses provide potential mechanisms underlying T2D risk stratification within abdominal obesity.

PMID:37326626 | DOI:10.7554/eLife.79834