Data Brief. 2021 Jan 30;35:106803. doi: 10.1016/j.dib.2021.106803. eCollection 2021 Apr.

ABSTRACT

Temporal data on how the mycobacterium infection establishes itself inside the host cell is not available. We differentiated human THP1 cell line with PMA and infected them with different laboratory (H37Ra and H37Rv) and clinical strains (BND433 and JAL2287) of mycobacterium tuberculosis (Mtb). Uninfected differentiated THP1 cells were used as infection control. Host proteome was investigated at four different time points to understand the dynamics of host response to mycobacterial infection with time. The investigated time points included 6 hrs, 18 hrs, 30 hrs and 42 hrs of infection with all the Mtb strains. SWATH-MS method was used to quantitate the host proteome in response to Mtb infection and the data thus obtained are available via PRIDE repository with the dataset identifier PXD022352 (https://www.ebi.ac.uk/pride/archive/projects/PXD022352).

PMID:33659582 | PMC:PMC7892794 | DOI:10.1016/j.dib.2021.106803

Bio Protoc. 2020 Mar 5;10(5):e3546. doi: 10.21769/BioProtoc.3546. eCollection 2020 Mar 5.

ABSTRACT

The plant cell wall is a complex network of polysaccharides and proteins that provides strength and structural integrity to plant cells, as well as playing a vital role in growth, development, and defense response. Cell wall polysaccharides can be broadly grouped into three categories: cellulose, pectins, and hemicelluloses. Dynamic interactions between polysaccharides and cell wall-associated proteins contribute to regions of flexibility and rigidity within the cell wall, allowing for remodeling when necessary during growth, environmental adaptation, or stress response activation. These polysaccharide interactions are vital to plant growth, however they also contribute to the level of difficulty encountered when attempting to analyze cell wall structure and composition. In the past, lengthy protocols to quantify cell wall monosaccharides contributing to cellulose as well as neutral and acidic cell wall polysaccharides have been used. Recently, a streamlined approach for monosaccharide quantification was described. This protocol combines a simplified hydrolysis method followed by several runs of high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD). Here, we present an updated version of this protocol in which we can analyze all nine cell wall monosaccharides in a single high-performance liquid chromatography HPAEC-PAD gradient profile. The inclusion of an enzymatic starch degradation, as well as alternate internal standards for added quantification accuracy, and a ready-to-use Python script facilitating data analysis adds a broadened scope of utility to this protocol. This protocol was used to analyze Arabidopsis light-grown seedlings and dark-grown hypocotyls, but is suitable for any plant tissues.

PMID:33659520 | PMC:PMC7842735 | DOI:10.21769/BioProtoc.3546

Bio Protoc. 2020 Jul 20;10(14):e3692. doi: 10.21769/BioProtoc.3692. eCollection 2020 Jul 20.

ABSTRACT

Potato virus Y (PVY), the type member of the genus Potyvirus (family Potyviridae), is the most widespread virus affecting potato and is included in the top five most economically detrimental plant viruses. Recently, the structure of the PVY virion has been determined by cryo-electron microscopy, which has opened the doors to functional studies that explore the involvement of selected amino acids in different stages of the viral cycle. The only way to functionally challenge in planta the role of particular amino acids in the coat protein of PVY, or in other viral proteins, is by using cDNA clones. The use and manipulation of PVY cDNA clones, unlike those of other potyviruses, has been traditionally impaired by the toxicity that certain sequences within the PVY genome pose to Escherichia coli. Here, we describe the use of a published PVY cDNA clone, which harbours introns that overcome the aforementioned toxicity, to explore the effects of different coat protein modifications on viral infection. The protocol includes manipulation of the cDNA clone in E. coli, biolistic inoculation of plants with the constructed clones, observation of the biological effects on plants, quantification of cDNA clones by reverse transcription quantitative PCR, and confirmation of virion formation by transmission electron microscopy. Future possibilities involve the use of PVY cDNA clones tagged with fluorescent protein reporters to allow further insights into the effects of coat protein mutations on the cell-to-cell movement of PVY virions.

PMID:33659360 | PMC:PMC7842295 | DOI:10.21769/BioProtoc.3692

Bio Protoc. 2020 May 20;10(10):e3620. doi: 10.21769/BioProtoc.3620. eCollection 2020 May 20.

ABSTRACT

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that arises from transformation of T-cell primed hematopoietic progenitors. Although T-ALL is a heterogenous and molecularly complex disease, more than 65% of T-ALL patients carry activating mutations in the NOTCH1 gene. The majority of T-ALL-associated NOTCH1 mutations either disrupt the negative regulatory region, allowing signal activation in the absence of ligand binding, or result in truncation of the C-terminal PEST domain involved in the termination of NOTCH1 signaling by proteasomal degradation. To date, retroviral transduction models have relied heavily on the overexpression of aggressively truncated variants of NOTCH1 (such as ICN1 or ΔE-NOTCH1), which result in supraphysiological levels of signaling activity and are rarely found in human T-ALL. The current protocol describes the method for mouse bone marrow isolation, hematopoietic stem and progenitor cell (HSC) enrichment, followed by retroviral transduction with an oncogenic mutant form of the NOTCH1 receptor (NOTCH1-L1601P-ΔP) that closely resembles the gain-of-function mutations most commonly found in patient samples. A hallmark of this forced expression of constitutively active NOTCH1 is a transient wave of extrathymic immature T-cell development, which precedes oncogenic transformation to T-ALL. Furthermore, this approach models leukemic transformation and progression in vivo by allowing for crosstalk between leukemia cells and the microenvironment, an aspect unaccounted for in cell-line based in vitro studies. Thus, the HSC transduction and transplantation model more faithfully recapitulates development of the human disease, providing a highly comprehensive and versatile tool for further in vivo and ex vivo functional studies.

PMID:33659293 | PMC:PMC7842547 | DOI:10.21769/BioProtoc.3620

Front Cell Infect Microbiol. 2021 Feb 15;11:610348. doi: 10.3389/fcimb.2021.610348. eCollection 2021.

ABSTRACT

Antimicrobial resistance prediction from whole genome sequencing data (WGS) is an emerging application of machine learning, promising to improve antimicrobial resistance surveillance and outbreak monitoring. Despite significant reductions in sequencing cost, the availability and sampling diversity of WGS data with matched antimicrobial susceptibility testing (AST) profiles required for training of WGS-AST prediction models remains limited. Best practice machine learning techniques are required to ensure trained models generalize to independent data for optimal predictive performance. Limited data restricts the choice of machine learning training and evaluation methods and can result in overestimation of model performance. We demonstrate that the widely used random k-fold cross-validation method is ill-suited for application to small bacterial genomics datasets and offer an alternative cross-validation method based on genomic distance. We benchmarked three machine learning architectures previously applied to the WGS-AST problem on a set of 8,704 genome assemblies from five clinically relevant pathogens across 77 species-compound combinations collated from public databases. We show that individual models can be effectively ensembled to improve model performance. By combining models via stacked generalization with cross-validation, a model ensembling technique suitable for small datasets, we improved average sensitivity and specificity of individual models by 1.77% and 3.20%, respectively. Furthermore, stacked models exhibited improved robustness and were thus less prone to outlier performance drops than individual component models. In this study, we highlight best practice techniques for antimicrobial resistance prediction from WGS data and introduce the combination of genome distance aware cross-validation and stacked generalization for robust and accurate WGS-AST.

PMID:33659219 | PMC:PMC7917081 | DOI:10.3389/fcimb.2021.610348

Oncotarget. 2021 Feb 16;12(4):316-332. doi: 10.18632/oncotarget.27875. eCollection 2021 Feb 16.

ABSTRACT

Around 3-7% of patients with non-small cell lung cancer (NSCLC), which represent 85% of diagnosed lung cancers, have a rearrangement in the ALK gene that produces an abnormal activity of the ALK protein cell signaling pathway. The developed ALK tyrosine kinase inhibitors (TKIs), such as crizotinib, ceritinib, alectinib, brigatinib and lorlatinb present good performance treating ALK+ NSCLC, although all patients invariably develop resistance due to ALK secondary mutations or bypass mechanisms. In the present study, we compare the potential differences between brigatinib and alectinib's mechanisms of action as first-line treatment for ALK+ NSCLC in a systems biology-based in silico setting. Therapeutic performance mapping system (TPMS) technology was used to characterize the mechanisms of action of brigatinib and alectinib and the impact of potential resistances and drug interferences with concomitant treatments. The analyses indicate that brigatinib and alectinib affect cell growth, apoptosis and immune evasion through ALK inhibition. However, brigatinib seems to achieve a more diverse downstream effect due to a broader cancer-related kinase target spectrum. Brigatinib also shows a robust effect over invasiveness and central nervous system metastasis-related mechanisms, whereas alectinib seems to have a greater impact on the immune evasion mechanism. Based on this in silico head to head study, we conclude that brigatinib shows a predicted efficacy similar to alectinib and could be a good candidate in a first-line setting against ALK+ NSCLC. Future investigation involving clinical studies will be needed to confirm these findings. These in silico systems biology-based models could be applied for exploring other unanswered questions.

PMID:33659043 | PMC:PMC7899557 | DOI:10.18632/oncotarget.27875

Front Endocrinol (Lausanne). 2021 Feb 15;11:619989. doi: 10.3389/fendo.2020.619989. eCollection 2020.

ABSTRACT

BACKGROUND: Graves' ophthalmopathy (GO) is a frequent extrathyroidal complication of Graves' hyperthyroidism. Orbital fibroblasts contribute to both orbital tissue inflammation and remodeling in GO, and as such are crucial cellular elements in active GO and inactive GO. However, so far it is largely unknown whether GO disease progression is associated with functional reprogramming of the orbital fibroblast effector function. Therefore, the aim of this study was to compare both the proteome and global DNA methylation patterns between orbital fibroblasts isolated from active GO, inactive GO and healthy controls.

METHODS: Orbital fibroblasts from inactive GO (n=5), active GO (n=4) and controls (n=5) were cultured and total protein and DNA was isolated. Labelled and fractionated proteins were analyzed with a liquid chromatography tandem-mass spectrometer (LC-MS/MS). Data are available via ProteomeXchange with identifier PXD022257. Furthermore, bisulphite-treated DNA was analyzed for methylation pattern with the Illumina Infinium Human Methylation 450K beadchip. In addition, RNA was isolated from the orbital fibroblasts for real-time quantitative (RQ)-PCR. Network and pathway analyses were performed.

RESULTS: Orbital fibroblasts from active GO displayed overexpression of proteins that are typically involved in inflammation, cellular proliferation, hyaluronan synthesis and adipogenesis, while various proteins associated with extracellular matrix (ECM) biology and fibrotic disease, were typically overexpressed in orbital fibroblasts from inactive GO. Moreover, orbital fibroblasts from active GO displayed hypermethylation of genes that linked to inflammation and hypomethylated genes that linked to adipogenesis and autoimmunity. Further analysis revealed networks that contained molecules to which both hypermethylated and hypomethylated genes were linked, including NF-κB, ERK1/2, Alp, RNA polymerase II, Akt and IFNα. In addition, NF-κB, Akt and IFNα were also identified in networks that were derived from the differentially expressed proteins. Generally, poor correlation between protein expression, DNA methylation and mRNA expression was observed.

CONCLUSIONS: Both the proteomics and DNA methylation data support that orbital fibroblasts from active GO are involved in inflammation, adipogenesis, and glycosaminoglycan production, while orbital fibroblasts from inactive disease are more skewed towards an active role in extracellular matrix remodeling. This switch in orbital fibroblast effector function may have therapeutic implications and further studies into the underlying mechanism are thus warranted.

PMID:33658982 | PMC:PMC7919747 | DOI:10.3389/fendo.2020.619989

Front Neurol. 2021 Feb 15;12:587771. doi: 10.3389/fneur.2021.587771. eCollection 2021.

ABSTRACT

Non-invasive low-intensity transcranial electrical stimulation (tES) of the brain is an evolving field that has brought remarkable attention in the past few decades for its ability to directly modulate specific brain functions. Neurobiological after-effects of tES seems to be related to changes in neuronal and synaptic excitability and plasticity, however mechanisms are still far from being elucidated. We aim to review recent results from in vitro and in vivo studies that highlight molecular and cellular mechanisms of transcranial direct (tDCS) and alternating (tACS) current stimulation. Changes in membrane potential and neural synchronization explain the ongoing and short-lasting effects of tES, while changes induced in existing proteins and new protein synthesis is required for long-lasting plastic changes (LTP/LTD). Glial cells, for decades supporting elements, are now considered constitutive part of the synapse and might contribute to the mechanisms of synaptic plasticity. This review brings into focus the neurobiological mechanisms and after-effects of tDCS and tACS from in vitro and in vivo studies, in both animals and humans, highlighting possible pathways for the development of targeted therapeutic applications.

PMID:33658972 | PMC:PMC7917202 | DOI:10.3389/fneur.2021.587771

Sci Rep. 2021 Mar 3;11(1):5022. doi: 10.1038/s41598-021-83185-1.

ABSTRACT

We hypothesized that epigenetics is a link between smoking/allergen exposures and the development of Asthma and chronic obstructive pulmonary disease (ACO). A total of 75 of 228 COPD patients were identified as ACO, which was independently associated with increased exacerbations. Microarray analysis identified 404 differentially methylated loci (DML) in ACO patients, and 6575 DML in those with rapid lung function decline in a discovery cohort. In the validation cohort, ACO patients had hypermethylated PDE9A (+ 30,088)/ZNF323 (- 296), and hypomethylated SEPT8 (- 47) genes as compared with either pure COPD patients or healthy non-smokers. Hypermethylated TIGIT (- 173) gene and hypomethylated CYSLTR1 (+ 348)/CCDC88C (+ 125,722)/ADORA2B (+ 1339) were associated with severe airflow limitation, while hypomethylated IFRD1 (- 515) gene with frequent exacerbation in all the COPD patients. Hypermethylated ZNF323 (- 296) / MPV17L (+ 194) and hypomethylated PTPRN2 (+ 10,000) genes were associated with rapid lung function decline. In vitro cigarette smoke extract and ovalbumin concurrent exposure resulted in specific DNA methylation changes of the MPV17L / ZNF323 genes, while 5-aza-2'-deoxycytidine treatment reversed promoter hypermethylation-mediated MPV17L under-expression accompanied with reduced apoptosis and decreased generation of reactive oxygen species. Aberrant DNA methylations may constitute a determinant for ACO, and provide a biomarker of airflow limitation, exacerbation, and lung function decline.

PMID:33658578 | DOI:10.1038/s41598-021-83185-1

Sci Rep. 2021 Mar 3;11(1):5050. doi: 10.1038/s41598-021-83974-8.

ABSTRACT

Non-alcoholic steatohepatitis (NASH) is the most rapidly growing liver disease that is nevertheless without approved pharmacological treatment. Despite great effort in developing novel NASH therapeutics, many have failed in clinical trials. This has raised questions on the adequacy of preclinical models. Elafibranor is one of the drugs currently in late stage development which had mixed results for phase 2/interim phase 3 trials. In the current study we investigated the response of elafibranor in APOE*3Leiden.CETP mice, a translational animal model that displays histopathological characteristics of NASH in the context of obesity, insulin resistance and hyperlipidemia. To induce NASH, mice were fed a high fat and cholesterol (HFC) diet for 15 weeks (HFC reference group) or 25 weeks (HFC control group) or the HFC diet supplemented with elafibranor (15 mg/kg/d) from week 15-25 (elafibranor group). The effects on plasma parameters and NASH histopathology were assessed and hepatic transcriptome analysis was used to investigate the underlying pathways affected by elafibranor. Elafibranor treatment significantly reduced steatosis and hepatic inflammation and precluded the progression of fibrosis. The underlying disease pathways of the model were compared with those of NASH patients and illustrated substantial similarity with molecular pathways involved, with 87% recapitulation of human pathways in mice. We compared the response of elafibranor in the mice to the response in human patients and discuss potential pitfalls when translating preclinical results of novel NASH therapeutics to human patients. When taking into account that due to species differences the response to some targets, like PPAR-α, may be overrepresented in animal models, we conclude that elafibranor may be particularly useful to reduce hepatic inflammation and could be a pharmacologically useful agent for human NASH, but probably in combination with other agents.

PMID:33658534 | DOI:10.1038/s41598-021-83974-8

Nat Commun. 2021 Mar 3;12(1):1411. doi: 10.1038/s41467-021-21654-x.

ABSTRACT

Genetically programmed circuits allowing bifunctional dynamic regulation of enzyme expression have far-reaching significances for various bio-manufactural purposes. However, building a bio-switch with a post log-phase response and reversibility during scale-up bioprocesses is still a challenge in metabolic engineering due to the lack of robustness. Here, we report a robust thermosensitive bio-switch that enables stringent bidirectional control of gene expression over time and levels in living cells. Based on the bio-switch, we obtain tree ring-like colonies with spatially distributed patterns and transformer cells shifting among spherical-, rod- and fiber-shapes of the engineered Escherichia coli. Moreover, fed-batch fermentations of recombinant E. coli are conducted to obtain ordered assembly of tailor-made biopolymers polyhydroxyalkanoates including diblock- and random-copolymer, composed of 3-hydroxybutyrate and 4-hydroxybutyrate with controllable monomer molar fraction. This study demonstrates the possibility of well-organized, chemosynthesis-like block polymerization on a molecular scale by reprogrammed microbes, exemplifying the versatility of thermo-response control for various practical uses.

PMID:33658500 | DOI:10.1038/s41467-021-21654-x

Proc Natl Acad Sci U S A. 2021 Mar 9;118(10):e2022312118. doi: 10.1073/pnas.2022312118.

ABSTRACT

Bacteria use intercellular signaling, or quorum sensing (QS), to share information and respond collectively to aspects of their surroundings. The autoinducers that carry this information are exposed to the external environment; consequently, they are affected by factors such as removal through fluid flow, a ubiquitous feature of bacterial habitats ranging from the gut and lungs to lakes and oceans. To understand how QS genetic architectures in cells promote appropriate population-level phenotypes throughout the bacterial life cycle requires knowledge of how these architectures determine the QS response in realistic spatiotemporally varying flow conditions. Here we develop and apply a general theory that identifies and quantifies the conditions required for QS activation in fluid flow by systematically linking cell- and population-level genetic and physical processes. We predict that when a subset of the population meets these conditions, cell-level positive feedback promotes a robust collective response by overcoming flow-induced autoinducer concentration gradients. By accounting for a dynamic flow in our theory, we predict that positive feedback in cells acts as a low-pass filter at the population level in oscillatory flow, allowing a population to respond only to changes in flow that occur over slow enough timescales. Our theory is readily extendable and provides a framework for assessing the functional roles of diverse QS network architectures in realistic flow conditions.

PMID:33658377 | DOI:10.1073/pnas.2022312118

Life Sci Alliance. 2021 Mar 3;4(5):e201900332. doi: 10.26508/lsa.201900332. Print 2021 May.

ABSTRACT

The migrational propensity of neuroblastoma is affected by cell identity, but the mechanisms behind the divergence remain unknown. Using RNAi and time-lapse imaging, we show that ADRN-type NB cells exhibit RAC1- and kalirin-dependent nucleokinetic (NUC) migration that relies on several integral components of neuronal migration. Inhibition of NUC migration by RAC1 and kalirin-GEF1 inhibitors occurs without hampering cell proliferation and ADRN identity. Using three clinically relevant expression dichotomies, we reveal that most of up-regulated mRNAs in RAC1- and kalirin-GEF1-suppressed ADRN-type NB cells are associated with low-risk characteristics. The computational analysis shows that, in a context of overall gene set poverty, the upregulomes in RAC1- and kalirin-GEF1-suppressed ADRN-type cells are a batch of AU-rich element-containing mRNAs, which suggests a link between NUC migration and mRNA stability. Gene set enrichment analysis-based search for vulnerabilities reveals prospective weak points in RAC1- and kalirin-GEF1-suppressed ADRN-type NB cells, including activities of H3K27- and DNA methyltransferases. Altogether, these data support the introduction of NUC inhibitors into cancer treatment research.

PMID:33658318 | DOI:10.26508/lsa.201900332

mSphere. 2021 Mar 3;6(2):e00091-21. doi: 10.1128/mSphere.00091-21.

ABSTRACT

The human pathogen Clostridioides difficile has evolved into the leading cause of nosocomial diarrhea. The bacterium is capable of spore formation, which even allows survival of antibiotic treatment. Although C. difficile features an anaerobic lifestyle, we determined a remarkably high oxygen tolerance of the laboratory reference strain 630Δerm A mutation of a single nucleotide (single nucleotide polymorphism [SNP]) in the DNA sequence (A to G) of the gene encoding the regulatory protein PerR results in an amino acid substitution (Thr to Ala) in one of the helices of the helix-turn-helix DNA binding domain of this transcriptional repressor in C. difficile 630Δerm PerR is a sensor protein for hydrogen peroxide and controls the expression of genes involved in the oxidative stress response. We show that PerR of C. difficile 630Δerm has lost its ability to bind the promoter region of PerR-controlled genes. This results in a constitutive derepression of genes encoding oxidative stress proteins such as a rubrerythrin (rbr1) whose mRNA abundance under anaerobic conditions was increased by a factor of about 7 compared to its parental strain C. difficile 630. Rubrerythrin repression in strain 630Δerm could be restored by the introduction of PerR from strain 630. The permanent oxidative stress response of C. difficile 630Δerm observed here should be considered in physiological and pathophysiological investigations based on this widely used model strain.IMPORTANCE The intestinal pathogen Clostridioides difficile is one of the major challenges in medical facilities nowadays. In order to better combat the bacterium, detailed knowledge of its physiology is mandatory. C. difficile strain 630Δerm was generated in a laboratory from the patient-isolated strain C. difficile 630 and represents a reference strain for many researchers in the field, serving as the basis for the construction of insertional gene knockout mutants. In our work, we demonstrate that this strain is characterized by an uncontrolled oxidative stress response as a result of a single-base-pair substitution in the sequence of a transcriptional regulator. C. difficile researchers working with model strain 630Δerm should be aware of this permanent stress response.

PMID:33658275 | DOI:10.1128/mSphere.00091-21

IMA Fungus. 2021 Mar 3;12(1):4. doi: 10.1186/s43008-021-00057-z.

ABSTRACT

The systematic position of the enigmatically mycoparasitic genus Squamanita (Agaricales, Basidiomycota) together with Cystoderma, Phaeolepiota, Floccularia, and Leucopholiota is largely unknown. Recently they were recognized as Squamanitaceae, but previous studies used few DNA markers from a restricted sample of taxa from the family and lacked a formal taxonomic treatment. In this study, with newly generated sequences of the type of the genus Squamanita, S. schreieri, and several additional species of the family, the phylogeny is reinvestigated with a concatenated (18S-5.8S-nrLSU-RPB2-TEF1-α) dataset. This study reveals that Cystoderma, Phaeolepiota, Squamanita, Floccularia, and Leucopholiota are a monophyletic clade with strong statistical support in Bayesian analysis and form Squamanitaceae. Phaeolepiota nested within Cystoderma; Squamanita, Leucopholiota, and Floccularia clustered together as two monophyletic subclades; and Squamanita was present as a monophyletic clade with strong statistical support in both Maximum Likelihood and Bayesian analyses. The family name Squamanitaceae is formally emended and a detailed taxonomic treatment is presented to accommodate the five genera. Meanwhile, another concatenated (18S-ITS-nrLSU-RPB2-TEF1-α) dataset is used to investigate phylogenetic relationships and species delimitation in Squamanita. Our data indicates that "S. umbonata" from the Northern hemisphere forms two species complexes, one complex includes six specimens from North America, Europe, and East Asia, the other includes two specimens from Central America and North America respectively. Futhermore, species of Squamanita can parasitize species of Amanita, besides other fungal species. Squamanita mira parasitizes A. kitamagotake (A. sect. Caesareae), while S. orientalis and S. sororcula are parasites of species belonging to the A. sepiacea complex (A. sect. Validae). "Squamanita umbonata" from Italy occurs on A. excelsa (A. sect. Validae). Three new species of Squamanita from East Asia, viz. S. mira, S. orientalis and S. sororcula are documented with morphological, multi-gene phylogenetic, and ecological data, along with line drawings and photographs, and compared with similar species. A key for identification of the global Squamanita species is provided.

PMID:33658081 | DOI:10.1186/s43008-021-00057-z

J Bioinform Comput Biol. 2021 Mar 3:2150002. doi: 10.1142/S0219720021500025. Online ahead of print.

ABSTRACT

A central problem of systems biology is the reconstruction of Gene Regulatory Networks (GRNs) by the use of time series data. Although many attempts have been made to design an efficient method for GRN inference, providing a best solution is still a challenging task. Existing noise, low number of samples, and high number of nodes are the main reasons causing poor performance of existing methods. The present study applies the ensemble Kalman filter algorithm to model a GRN from gene time series data. The inference of a GRN is decomposed with p genes into p subproblems. In each subproblem, the ensemble Kalman filter algorithm identifies the weight of interactions for each target gene. With the use of the ensemble Kalman filter, the expression pattern of the target gene is predicted from the expression patterns of all the remaining genes. The proposed method is compared with several well-known approaches. The results of the evaluation indicate that the proposed method improves inference accuracy and demonstrates better regulatory relations with noisy data.

PMID:33657986 | DOI:10.1142/S0219720021500025

Cell Metab. 2021 Mar 2;33(3):455-456. doi: 10.1016/j.cmet.2021.02.012.

ABSTRACT

Many of the gut-microbiome-derived signatures for liver cirrhosis, especially the important ones, were likely under the influence of proton pump inhibitors (PPIs). Wu et al. suggest that drug usage is a confounding factor in metagenomics analysis that should be controlled for.

PMID:33657385 | DOI:10.1016/j.cmet.2021.02.012

Cell Rep. 2021 Mar 2;34(9):108789. doi: 10.1016/j.celrep.2021.108789.

ABSTRACT

Harnessing the microbiota for beneficial outcomes is limited by our poor understanding of the constituent bacteria, as the functions of most of their genes are unknown. Here, we measure the growth of a barcoded transposon mutant library of the gut commensal Bacteroides thetaiotaomicron on 48 carbon sources, in the presence of 56 stress-inducing compounds, and during mono-colonization of gnotobiotic mice. We identify 516 genes with a specific phenotype under only one or a few conditions, enabling informed predictions of gene function. For example, we identify a glycoside hydrolase important for growth on type I rhamnogalacturonan, a DUF4861 protein for glycosaminoglycan utilization, a 3-keto-glucoside hydrolase for disaccharide utilization, and a tripartite multidrug resistance system specifically for bile salt tolerance. Furthermore, we show that B. thetaiotaomicron uses alternative enzymes for synthesizing nitrogen-containing metabolic precursors based on ammonium availability and that these enzymes are used differentially in vivo in a diet-dependent manner.

PMID:33657378 | DOI:10.1016/j.celrep.2021.108789

Adv Exp Med Biol. 2021;1321:277-286. doi: 10.1007/978-3-030-59261-5_25.

ABSTRACT

There is data from individual clinical trials suggesting that procalcitonin (PCT) may be a prognostic factor in the severity of COVID-19 disease. Therefore, this systematic review and meta-analysis was performed to investigate PCT levels in severe COVID-19 patients. We searched Embase, ProQuest, MEDLINE/PubMed, Scopus, and ISI/Web of Science for studies that reported the level of PCT of patient with severe COVID-19. We included all studies regardless of design that reported the level of PCT in patients with severe COVID-19. We excluded articles not regarding COVID-19 or not reporting PCT level, studies not in severe patients, review articles, editorials or letters, expert opinions, comments, and animal studies. Nine studies were included in the analysis. The odds of having more severe COVID-19 disease was higher in subjects with elevated PCT (≥0.05 ng/mL) compared with those having low procalcitonin (<0.05 ng/mL) [n = 6, OR(95% CI) = 2.91(1.14, 7.42), p = 0.025). After estimating the mean and standard deviation values from the sample size, median, and interquartile range, a pooled effect analysis indicated higher serum PCT concentrations in patients with severe versus less severe disease [n = 6, SMD(95% CI) = 0.64(0.02, 1.26), p = 0.042]. The results of this study showed that PCT is increased in patients with severe COVID-19 infection.

PMID:33656733 | DOI:10.1007/978-3-030-59261-5_25

Adv Exp Med Biol. 2021;1321:199-210. doi: 10.1007/978-3-030-59261-5_17.

ABSTRACT

AIM: We aimed to describe the epidemiological and clinical characteristics of Iranian patients with COVID-19.

METHODS: In this single-center and retrospective study, patients with confirmed COVID-19 infections were enrolled. Univariate and multivariate logistic regression methods were used to explore the risk factors associated with outcomes.

RESULTS: Of 179 patients with confirmed COVID-19 infection, 12 remained hospitalized at the end of the study and 167 were included in the final analysis. Of these, 153 (91.6%) were discharged and 14 (8.38%) died in hospital. Approximately half (50.9%) of patients suffered from a comorbidity, with diabetes or coronary heart disease being the most common in 20 patients. The most common symptoms on admission were fever, dyspnea, and cough. The mean durations from first symptoms to hospital admission was 8.64 ± 4.14 days, whereas the mean hospitalization time to discharge or death was 5.19 ± 2.42 and 4.35 ± 2.70 days, respectively. There was a significantly higher age in non-survivor patients compared with survivor patients. Multivariate regression showed increasing odds ratio (OR) of in-hospital death associated with respiratory rates >20 breaths/min (OR: 5.14, 95% CI: 1.19-22.15, p = 0.028) and blood urea nitrogen (BUN) >19 mg/dL (OR: 4.54, 95% CI: 1.30-15.85, p = 0.017) on admission. In addition, higher respiratory rate was associated with continuous fever (OR: 4.08, 95% CI: 1.18-14.08, p = 0.026) and other clinical symptoms (OR: 3.52, 95% CI: 1.05-11.87, p = 0.04).

CONCLUSION: The potential risk factors including high respiratory rate and BUN levels could help to identify COVID-19 patients with poor prognosis at an early stage in the Iranian population.

PMID:33656725 | DOI:10.1007/978-3-030-59261-5_17