Recent publications from TDC/Clinical Epidemiology authors

High frequency of Taenia solium antigen positivity in patients admitted for neurological disorders in the Rural Hospital of Mosango, Democratic Republic of Congo

Sun, 04/18/2021 - 06:00

BMC Infect Dis. 2021 Apr 17;21(1):359. doi: 10.1186/s12879-021-06032-8.


BACKGROUND: The epidemiology of human cysticercosis and neurocysticercosis, caused by the larval stage of the pork tapeworm Taenia solium, is not well known in the Democratic Republic of Congo (DRC). Within a multicenter etiological and diagnostic study conducted by the NIDIAG consortium ("Better Diagnosis for Neglected Infections") and investigating several challenging syndromes, we consecutively evaluated from 2012 to 2015 all patients older than 5 years presenting with neurological disorders (neurology cohort) and with fever > 7 days (persistent fever cohort) at the rural hospital of Mosango, province of Kwilu, DRC. In both cohorts, etiological diagnosis relied on a systematic set of reference laboratory assays and on pre-established clinical case definitions. No neuroimaging was available in the study hospital. In this study, we determined the frequency of T. solium infection in both cohorts and explored in the neurology cohort its association with specific neurological presentations and final etiological diagnoses.

METHODS: We conducted a post-hoc descriptive and analytic study on cysticercosis in the neurology and persistent fever cohorts, based on the presence in serum samples of circulating T. solium antigen using the B158/B60 enzyme-linked immunosorbent assay (ELISA) and of cysticercosis IgG using the LDBIO Cysticercosis Western Blot IgG assay.

RESULTS: For the neurology cohort, 340 samples (of 351 enrolled patients) were available for analysis (males: 46.8%; mean age: 38.9 years). T. solium antigen positivity was found in 43 participants (12.6%; 95% confidence interval [CI] 9.3-16.7%), including 9 of 60 (15%) patients with epilepsy. Among the 148 samples available from the persistent fever cohort (males: 39.9%; mean age: 19.9 years), 7 were positive in the T. solium antigen ELISA (4.7%; 95% CI 1.9-9.5%; P = 0.009 when compared to the neurology cohort). No significant association was found within the neurology cohort between positivity and clinical presentation or final diagnoses. Of note, the IgG antibody-detecting assay was found positive in only four (1.3%) of the participants of the neurology cohort and in none of the persistent fever cohort.

CONCLUSIONS: T. solium antigen positivity was found in at least 10% of patients admitted with neurological disorders in the Kwilu province, DRC, with no specific pattern of presentation. Further neuroimaging studies should be used to confirm whether neurocysticercosis is prevalent in this region.

PMID:33865327 | DOI:10.1186/s12879-021-06032-8

Direct and specific binding of cholesterol to the mitochondrial translocator protein (TSPO) using PhotoClick cholesterol analogue

Tue, 04/13/2021 - 06:00

J Biochem. 2021 Apr 12:mvab031. doi: 10.1093/jb/mvab031. Online ahead of print.


The translocator protein (TSPO) is a five-helix transmembrane protein localized to the outer mitochondria membrane. Radioligand binding assays and chemical crosslinking showed TSPO to be a high affinity cholesterol-binding protein. In this report, we show that TSPO in mitochondrial fractions from MA-10 mouse tumour Leydig cells can interact directly and competitively with the clickable photoreactive cholesterol analogue. PhotoClick cholesterol showed saturable photoaffinity labelling of TSPO that could be specifically immunoprecipitated with anti-TSPO antibody, following the click reaction with the fluorescent-azide probe, tetramethylrhodamine (TAMRA)-azide. Moreover, excess cholesterol reduced the photolabelling of both total mitochondrial proteins and TSPO. Together, the results of this study demonstrated direct binding of PhotoClick cholesterol to TSPO and that this interaction occurs at physiologically relevant site(s).

PMID:33846725 | DOI:10.1093/jb/mvab031

Whole-Genome Sequencing Reveals the Presence of the <em>bla</em><sub>CTX-M-65</sub> Gene in Extended-Spectrum β-Lactamase-Producing and Multi-Drug-Resistant Clones of <em>Salmonella</em> Serovar Infantis Isolated from Broiler Chicken Environments in...

Sat, 04/03/2021 - 06:00

Antibiotics (Basel). 2021 Mar 5;10(3):267. doi: 10.3390/antibiotics10030267.


Salmonella Infantis, a common contaminant of poultry products, is known to harbor mobile genetic elements that confer multi-drug resistance (MDR) and have been detected in many continents. Here, we report four MDR S. Infantis strains recovered from poultry house environments in Santa Cruz Island of the Galapagos showing extended-spectrum β-lactamase (ESBL) resistance and reduced fluoroquinolone susceptibility. Whole-genome sequencing (WGS) revealed the presence of the ESBL-conferring blaCTX-M-65 gene in an IncFIB-like plasmid in three S. Infantis isolates. Multi-locus sequence typing (MLST) and single nucleotide variant/polymorphism (SNP) SNVPhyl analysis showed that the S. Infantis isolates belong to sequence type ST32, likely share a common ancestor, and are closely related (1-3 SNP difference) to blaCTX-M-65-containing clinical and veterinary S. Infantis isolates from the United States and Latin America. Furthermore, phylogenetic analysis of SNPs following core-genome alignment (i.e., ParSNP) inferred close relatedness between the S. Infantis isolates from Galapagos and the United States. Prophage typing confirmed the close relationship among the Galapagos S. Infantis and was useful in distinguishing them from the United States isolates. This is the first report of MDR blaCTX-M-65-containing S. Infantis in the Galapagos Islands and highlights the need for increased monitoring and surveillance programs to determine prevalence, sources, and reservoirs of MDR pathogens.

PMID:33807748 | DOI:10.3390/antibiotics10030267

Development of a Comprehensive Toxicity Pathway Model for 17α-Ethinylestradiol in Early Life Stage Fathead Minnows (<em>Pimephales promelas</em>)

Tue, 03/23/2021 - 06:00

Environ Sci Technol. 2021 Mar 23. doi: 10.1021/acs.est.0c05942. Online ahead of print.


There is increasing pressure to develop alternative ecotoxicological risk assessment approaches that do not rely on expensive, time-consuming, and ethically questionable live animal testing. This study aimed to develop a comprehensive early life stage toxicity pathway model for the exposure of fish to estrogenic chemicals that is rooted in mechanistic toxicology. Embryo-larval fathead minnows (FHM; Pimephales promelas) were exposed to graded concentrations of 17α-ethinylestradiol (water control, 0.01% DMSO, 4, 20, and 100 ng/L) for 32 days. Fish were assessed for transcriptomic and proteomic responses at 4 days post-hatch (dph), and for histological and apical end points at 28 dph. Molecular analyses revealed core responses that were indicative of observed apical outcomes, including biological processes resulting in overproduction of vitellogenin and impairment of visual development. Histological observations indicated accumulation of proteinaceous fluid in liver and kidney tissues, energy depletion, and delayed or suppressed gonad development. Additionally, fish in the 100 ng/L treatment group were smaller than controls. Integration of omics data improved the interpretation of perturbations in early life stage FHM, providing evidence of conservation of toxicity pathways across levels of biological organization. Overall, the mechanism-based embryo-larval FHM model showed promise as a replacement for standard adult live animal tests.

PMID:33755441 | DOI:10.1021/acs.est.0c05942

Ultrafast functional profiling of RNA-seq data for nonmodel organisms

Thu, 03/18/2021 - 06:00

Genome Res. 2021 Mar 17. doi: 10.1101/gr.269894.120. Online ahead of print.


Computational time and cost remain a major bottleneck for RNA-seq data analysis of nonmodel organisms without reference genomes. To address this challenge, we have developed Seq2Fun, a novel, all-in-one, ultrafast tool to directly perform functional quantification of RNA-seq reads without transcriptome de novo assembly. The pipeline starts with raw read quality control: sequencing error correction, removing poly(A) tails, and joining overlapped paired-end reads. It then conducts a DNA-to-protein search by translating each read into all possible amino acid fragments and subsequently identifies possible homologous sequences in a well-curated protein database. Finally, the pipeline generates several informative outputs including gene abundance tables, pathway and species hit tables, an HTML report to visualize the results, and an output of clean reads annotated with mapped genes ready for downstream analysis. Seq2Fun does not have any intermediate steps of file writing and loading, making I/O very efficient. Seq2Fun is written in C++ and can run on a personal computer with a limited number of CPUs and memory. It can process >2,000,000 reads/min and is >120 times faster than conventional workflows based on de novo assembly, while maintaining high accuracy in our various test data sets.

PMID:33731361 | DOI:10.1101/gr.269894.120

Maternal postpartum deworming and infant milk intake: Secondary outcomes from a trial

Wed, 03/17/2021 - 06:00

Matern Child Nutr. 2021 Mar 17:e13183. doi: 10.1111/mcn.13183. Online ahead of print.


The World Health Organization recommends deworming to reduce soil-transmitted helminth (STH)-attributable morbidity in women of reproductive age, including pregnant and lactating women, to reduce blood loss, iron deficiency anaemia and nutrient malabsorption. This study assessed the impact of maternal postpartum deworming with albendazole approximately 1 day after delivery on infant milk intake among a subset of 216 randomly selected mother-infant pairs recruited into a large trial in Peru. Infant milk intake was measured using the deuterium-oxide method at 1- and 6-month postpartum. Maternal STH infection was measured at 6-month postpartum. At 1-month postpartum, mean intake was 756 ± 16 and 774 ± 18 mL day-1 in the albendazole and placebo groups, respectively (mean difference: -18 mL day-1 ; 95% CI: -65, 30). At 6-month postpartum, mean intake was 903 ± 16 and 908 ± 18 mL day-1 in the albendazole and placebo groups, respectively (mean difference: -5 mL day-1 ; 95% CI: -52, 43). There was no statistically significant difference in milk intake between groups at either time point. At 6-month postpartum, mothers infected with Trichuris trichiura had infants with higher milk intakes (adjusted mean difference: 70 mL day-1 ; 95% CI: 20, 120) compared with uninfected mothers. However, there was no statistically significant difference in infant milk intake between mothers who had moderate-and-heavy intensity infection compared with the comparison group (mothers with no and light intensity infection). A lower prevalence and intensity of infection, and inclusion of uninfected mothers in both arms of the trial, resulting in effect dilution, may explain the null findings.

PMID:33729674 | DOI:10.1111/mcn.13183

Viral hepatitis C cascade of care: A population-level comparison of immigrant and long-term residents

Wed, 03/03/2021 - 06:00

Liver Int. 2021 Mar 2. doi: 10.1111/liv.14840. Online ahead of print.


BACKGROUND & AIMS: Viral hepatitis C represents a major global burden, particularly among immigrant-receiving countries such as Canada, where knowledge of disparities in hepatitis C virus among immigrant groups for micro-elimination efforts is lacking. We quantify the hepatitis C cascades of care among immigrants and long-term residents prior to the introduction of direct-acting antiviral medications.

METHODS: Using laboratory and health administrative records, we described the hepatitis C virus cascades of care in terms of diagnosis, engagement with care, treatment initiation, and clearance in Ontario, Canada (1997-2014). We stratified the cascade by immigrant and long-term resident groups and identify drivers at each stage using multivariable Poisson regression.

RESULTS: We included 940,245 individuals in the study with an estimated hepatitis C prevalence of 167,923 (1.4%) overall, 23,759 (0.7%) among all immigrants, and 6,019 (1.1%) among immigrants from hepatitis C endemic countries. Overall there were 104,616 individuals with reactive antibody results, 73,861 tested for viral RNA, 52,388 with viral RNA detected, 50,805 genotyped, 13,159 on treatment, and 3,919 with evidence of viral clearance. Compared to long-term residents, immigrants showed increased nucleic-acid testing (aRR: 1.09 [95%CI: 1.08, 1.10]), treatment initiation (aRR: 1.46 [95%CI: 1.38, 1.54]), and higher clearance rates (aRR: 1.07 [95%CI: 1.03, 1.11]).

CONCLUSIONS: Hepatitis C virus is more prevalent among long-term residents compared to immigrants overall, however immigrants from endemic countries are an important subgroup to consider for future screening and linkage to care initiatives. These findings are prior to the introduction of newer medications and provide a population-based benchmark for follow-up studies and evaluation of treatment programs and surveillance activities.

PMID:33655665 | DOI:10.1111/liv.14840

Distinct Changes Occur in the Human Breast Milk Microbiome Between Early and Established Lactation in Breastfeeding Guatemalan Mothers

Mon, 03/01/2021 - 06:00

Front Microbiol. 2021 Feb 12;12:557180. doi: 10.3389/fmicb.2021.557180. eCollection 2021.


Human breast milk contains a diverse community of bacteria, but as breast milk microbiome studies have largely focused on mothers from high income countries where few women breastfeed to 6 months, the temporal changes in the breast milk microbiome that occur during later lactation stages have not been explored. For this cross-sectional study, microbiota from breast milk samples of Mam-Mayan mothers living in eight remote rural communities in the Western Highlands of Guatemala were analyzed. All mothers delivered vaginally and breastfed their infants for 6 months. Breast milk from 76 unrelated mothers was used to compare two lactation stages, either "early" (6-46 days post-partum, n = 33) or "late" (109-184 days post-partum, n = 43). Breast milk microbial communities were assessed using 16S ribosomal RNA gene sequencing and lactation stages were compared using DESeq2 differential abundance analysis. A total of 1,505 OTUs were identified, including 287 which could be annotated as putative species. Among several maternal factors, lactation stage explained microbiome variance and inertia in ordination with the most significance (p < 0.001). Differential abundance analysis identified 137 OTUs as significantly higher in either early or late lactation. These included a general shift from Staphylococcus and Streptococcus species in early lactation to Sphingobium and Pseudomonas species in late lactation. Species enriched in early lactation included putative commensal bacteria known to colonize the infant oral and intestinal tracts whereas species enriched in late lactation had a uniform functional trait associated with aromatic compound degradation. Differentially abundant species also included several species which have not previously been reported within breast milk, such as Janthinobacterium agaricidamnosum, Novosphingobium clariflavum, Ottowia beijingensis, and Flavobacterium cucumis. These discoveries describe temporal changes to the breast milk microbiome of healthy Guatemalan mothers from early to late lactation. Collectively, these findings illustrate how studying under-represented human populations might advance our understanding of factors that modulate the human milk microbiome in low and middle income countries (LMIC).

PMID:33643228 | PMC:PMC7907006 | DOI:10.3389/fmicb.2021.557180

Vaccine-associated enhanced disease: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data

Sat, 02/27/2021 - 06:00

Vaccine. 2021 Feb 23:S0264-410X(21)00094-3. doi: 10.1016/j.vaccine.2021.01.055. Online ahead of print.


This is a Brighton Collaboration Case Definition of the term "Vaccine Associated Enhanced Disease" to be utilized in the evaluation of adverse events following immunization. The Case Definition was developed by a group of experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of vaccines for SARS-CoV-2 vaccines and other emerging pathogens. The case definition format of the Brighton Collaboration was followed to develop a consensus definition and defined levels of certainty, after an exhaustive review of the literature and expert consultation. The document underwent peer review by the Brighton Collaboration Network and by selected Expert Reviewers prior to submission.

PMID:33637387 | DOI:10.1016/j.vaccine.2021.01.055

Management of Coronavirus Disease 2019 (COVID-19) Pandemic: From Diagnosis to Treatment Strategies

Mon, 02/22/2021 - 06:00

Adv Ther (Weinh). 2020 Dec 16:2000173. doi: 10.1002/adtp.202000173. Online ahead of print.


Following the emergence of severe acute respiratory syndrome (SARS) in 2002 and the Middle East respiratory syndrome (MERS) in 2012, the world is now combating a third large-scale outbreak caused by a coronavirus, the coronavirus disease 2019 (COVID-19). After the rapid spread of SARS-coronavirus (CoV)-2 (the virus causing COVID-19) from its origin in China, the World Health Organization (WHO) declared a Public Health Emergency of International Concern (PHEIC) on January 30, 2020. From the beginning of the COVID-19 pandemic, a significant number of studies have been conducted to better understand the biology and pathogenesis of the novel coronavirus, and to aid in developing effective treatment regimens, therapeutics, and vaccines. This review focuses on the recent advancements in the rapidly evolving areas of clinical care and management of COVID-19. The emerging strategies for the diagnosis and treatment of this disease are explored, and the development of effective vaccines is reviewed.

PMID:33614905 | PMC:PMC7883285 | DOI:10.1002/adtp.202000173

Serodiagnostics for SARS-CoV-2

Mon, 02/15/2021 - 06:00

Ann Intern Med. 2021 Feb;174(2):287-288. doi: 10.7326/L20-1396.


PMID:33587882 | DOI:10.7326/L20-1396

Phase III: Randomized observer-blind trial to evaluate lot-to-lot consistency of a new plant-derived quadrivalent virus like particle influenza vaccine in adults 18-49 years of age

Sun, 02/14/2021 - 06:00

Vaccine. 2021 Feb 10:S0264-410X(21)00004-9. doi: 10.1016/j.vaccine.2021.01.004. Online ahead of print.


BACKGROUND: The global reliance on eggs to produce most influenza vaccines has several limitations and new approaches to influenza vaccine production are needed. Herein we describe a phase 3, lot-to-lot consistency trial (NCT03321968) of a quadrivalent, recombinant, virus-like particle (VLP) influenza vaccine produced in plants. This platform is based on transient expression of proteins in Nicotiana benthamiana and yields VLPs bearing hemagglutinin (HA) protein trimers that are combined in a quadrivalent vaccine (QVLP).

METHODS: The HAs targeted in this study were A/California/07/2009 H1N1, A/Hong Kong/4801/2014 H3N2, B/Brisbane/60/08 and B/Phuket/3073/2013: recommended for the 2016-2017 Northern Hemisphere season. Healthy adults 18-49 years of age (n = 1200) were randomized 1:1:1 to receive a 0.5 mL intramuscular injection of QVLP (30 μg HA/strain) from three sequential lots. Local and systemic reactions were monitored for 21 days post-vaccination and blood was collected pre-vaccination and at day 21 (D21) after vaccination to measure hemagglutination inhibition (HI) antibodies.

RESULTS: Subject demographics were similar between groups and compliance with study procedures was 96.3%. The study population was 54.8% female, the mean age (±SD) was 29.9 ± 9.01 and the racial distribution was 77.8% Caucasian, 15.6% Asian, 5.8% Black/African American and 0.8% other. The HI responses met the Center for Biologics Evaluation and Research criteria for seroconversion (SCR ≥ 40%) and seroprotection rates (SPR ≥ 70%). The geometric mean fold rise in HI titers was ≥ 2.5 for all 4 strains for each lot. Lot-to-lot consistency was met with the 95% confidence intervals of the D21 mean geometric titre ratios falling between 0.67 and 1.5 for all four strains. No safety concerns were identified. Solicited adverse events were generally mild and transient: typical for what is reported after inactivated influenza vaccines.

CONCLUSIONS: This study supported earlier findings of the safety profile and immunogenicity of the plant-derived QVLP and demonstrated the consistency with which it can be produced.

PMID:33581920 | DOI:10.1016/j.vaccine.2021.01.004

When Secretomes Meet Anthelmintics: Lessons for Therapeutic Interventions

Wed, 02/10/2021 - 06:00

Trends Parasitol. 2021 Feb 6:S1471-4922(21)00010-6. doi: 10.1016/ Online ahead of print.


Helminth secretomes comprise many potential immunomodulators. The molecular and functional diversity of these entities and their importance at the host-parasite interface have been increasingly recognized. It is now common to hypothesize that parasite-derived molecules (PDMs) are essential mediators used by parasites to establish and remain in their hosts. Suppression of PDM release has been reported for two anthelmintic drug classes, the benzimidazoles and macrocyclic lactones, the mechanisms of action of which remain incompletely resolved. We propose that bringing together recent insights from different streams of parasitology research, for example, immunoparasitology and pharmacology, will stimulate the development of new ways to alter the host-parasite interface in the search for novel anthelmintic strategies.

PMID:33563557 | DOI:10.1016/

Biochemical and cellular characterisation of the Plasmodium falciparum M1 alanyl aminopeptidase (PfM1AAP) and M17 leucyl aminopeptidase (PfM17LAP)

Thu, 02/04/2021 - 06:00

Sci Rep. 2021 Feb 3;11(1):2854. doi: 10.1038/s41598-021-82499-4.


The Plasmodium falciparum M1 alanyl aminopeptidase and M17 leucyl aminopeptidase, PfM1AAP and PfM17LAP, are potential targets for novel anti-malarial drug development. Inhibitors of these aminopeptidases have been shown to kill malaria parasites in culture and reduce parasite growth in murine models. The two enzymes may function in the terminal stages of haemoglobin digestion, providing free amino acids for protein synthesis by the rapidly growing intra-erythrocytic parasites. Here we have performed a comparative cellular and biochemical characterisation of the two enzymes. Cell fractionation and immunolocalisation studies reveal that both enzymes are associated with the soluble cytosolic fraction of the parasite, with no evidence that they are present within other compartments, such as the digestive vacuole (DV). Enzyme kinetic studies show that the optimal pH of both enzymes is in the neutral range (pH 7.0-8.0), although PfM1AAP also possesses some activity (< 20%) at the lower pH range of 5.0-5.5. The data supports the proposal that PfM1AAP and PfM17LAP function in the cytoplasm of the parasite, likely in the degradation of haemoglobin-derived peptides generated in the DV and transported to the cytosol.

PMID:33536500 | DOI:10.1038/s41598-021-82499-4

A Practical Guide to Metabolomics Software Development

Wed, 01/20/2021 - 06:00

Anal Chem. 2021 Jan 19. doi: 10.1021/acs.analchem.0c03581. Online ahead of print.


A growing number of software tools have been developed for metabolomics data processing and analysis. Many new tools are contributed by metabolomics practitioners who have limited prior experience with software development, and the tools are subsequently implemented by users with expertise that ranges from basic point-and-click data analysis to advanced coding. This Perspective is intended to introduce metabolomics software users and developers to important considerations that determine the overall impact of a publicly available tool within the scientific community. The recommendations reflect the collective experience of an NIH-sponsored Metabolomics Consortium working group that was formed with the goal of researching guidelines and best practices for metabolomics tool development. The recommendations are aimed at metabolomics researchers with little formal background in programming and are organized into three stages: (i) preparation, (ii) tool development, and (iii) distribution and maintenance.

PMID:33467846 | DOI:10.1021/acs.analchem.0c03581

Sorting and detection of COVID-19 by low-dose thoracic CT scan in patients consulting the radiology department of Fann hospital (Dakar-Senegal)

Mon, 01/18/2021 - 06:00

Pan Afr Med J. 2020 Oct 13;37(Suppl 1):22. doi: 10.11604/pamj.supp.2020.37.22.26140. eCollection 2020.


INTRODUCTION: COVID-19 has spread rapidly since its emergence in China and is currently a global health issue. Its definitive diagnosis is made by PCR on nasopharyngeal swabs. However, this diagnostic test has low sensitivity with delayed results. Hence, thoracic computed tomography represents an interesting alternative. The aims of this study were to assess the frequency of computed tomography (CT) lesions suggestive of COVID-19 and to compare the results of CT and PCR test.

METHODS: a prospective study carried out over15 working days and involved 47 patients. These patients were recruited based on the presence of at least 2 clinical signs of COVID-19. Chest CT without contrast according to the "LOW-DOSE" protocol was performed. A PCR test on nasopharyngeal swabs was done in patients with signs suggestive of COVID on CT. A serological test was performed in case of a discrepancy between the CT and PCR results.

RESULTS: thoracic CT was abnormal in 38 patients and normal in 9 patients. Lesions suggestive of COVID-19 have been identified in 32 patients. Two patients had lesions of non-specific pneumonia. Tuberculosis lesions were visualized in 3 patients. One patient had lesions of interstitial pneumonia. The mean DLP was 59 with extremes of 25 and 95 Ground-glass opacity was present in 100% of COVID-19 suspects on CT. The results of the PCR test were the same than CT in 12 patients. The positive predictive value for CT was 37.5%. In 20 patients with COVID lesions on CT, the PCR test was negative with a false positive rate of 62.5%. In the patients with negative PCR test, 4 had a serological test for COVID-19 and this test was positive in 3.

CONCLUSION: low-dose chest CT can reduce radiation exposure in COVID-19 patients who are at risk of cumulative dose due to repetitive exam. CT can identify lesions suggestive of COVID-19. It also enables the triage of patients by identifying other diagnoses.

PMID:33456646 | PMC:PMC7796847 | DOI:10.11604/pamj.supp.2020.37.22.26140

Comprehensive Meta-Analysis of COVID-19 Global Metabolomics Datasets

Wed, 01/13/2021 - 06:00

Metabolites. 2021 Jan 9;11(1):E44. doi: 10.3390/metabo11010044.


The novel coronavirus SARS-CoV-2 has spread across the world since 2019, causing a global pandemic. The pathogenesis of the viral infection and the associated clinical presentations depend primarily on host factors such as age and immunity, rather than the viral load or its genetic variations. A growing number of omics studies have been conducted to characterize the host immune and metabolic responses underlying the disease progression. Meta-analyses of these datasets have great potential to identify robust molecular signatures to inform clinical care and to facilitate therapeutics development. In this study, we performed a comprehensive meta-analysis of publicly available global metabolomics datasets obtained from three countries (United States, China and Brazil). To overcome high heterogeneity inherent in these datasets, we have (a) implemented a computational pipeline to perform consistent raw spectra processing; (b) conducted meta-analyses at pathway levels instead of individual feature levels; and (c) performed visual data mining on consistent patterns of change between disease severities for individual studies. Our analyses have yielded several key metabolic signatures characterizing disease progression and clinical outcomes. Their biological interpretations were discussed within the context of the current literature. To the best of our knowledge, this is the first comprehensive meta-analysis of global metabolomics datasets of COVID-19.

PMID:33435351 | DOI:10.3390/metabo11010044

ATR Kinase Is a Crucial Player Mediating the DNA Damage Response in <em>Trypanosoma brucei</em>

Fri, 01/08/2021 - 06:00

Front Cell Dev Biol. 2020 Dec 22;8:602956. doi: 10.3389/fcell.2020.602956. eCollection 2020.


DNA double-strand breaks (DSBs) are among the most deleterious lesions that threaten genome integrity. To address DSBs, eukaryotic cells of model organisms have evolved a complex network of cellular pathways that are able to detect DNA damage, activate a checkpoint response to delay cell cycle progression, recruit the proper repair machinery, and resume the cell cycle once the DNA damage is repaired. Cell cycle checkpoints are primarily regulated by the apical kinases ATR and ATM, which are conserved throughout the eukaryotic kingdom. Trypanosoma brucei is a divergent pathogenic protozoan parasite that causes human African trypanosomiasis (HAT), a neglected disease that can be fatal when left untreated. The proper signaling and accuracy of DNA repair is fundamental to T. brucei not only to ensure parasite survival after genotoxic stress but also because DSBs are involved in the process of generating antigenic variations used by this parasite to evade the host immune system. DSBs trigger a strong DNA damage response and efficient repair process in T. brucei, but it is unclear how these processes are coordinated. Here, by knocking down ATR in T. brucei using two different approaches (conditional RNAi and an ATR inhibitor), we show that ATR is required to mediate intra-S and partial G1/S checkpoint responses. ATR is also involved in replication fork stalling, is critical for H2A histone phosphorylation in a small group of cells and is necessary for the recruitment and upregulation of the HR-mediated DNA repair protein RAD51 after ionizing radiation (IR) induces DSBs. In summary, this work shows that apical ATR kinase plays a central role in signal transduction and is critical for orchestrating the DNA damage response in T. brucei.

PMID:33415107 | PMC:PMC7783291 | DOI:10.3389/fcell.2020.602956

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