-
Frontiers in Immunology 2021The immune system is unique among all biological sub-systems in its usage of DNA-editing enzymes to introduce targeted gene mutations and double-strand DNA breaks to...
Evolutionary Comparative Analyses of DNA-Editing Enzymes of the Immune System: From 5-Dimensional Description of Protein Structures to Immunological Insights and Applications to Protein Engineering.
The immune system is unique among all biological sub-systems in its usage of DNA-editing enzymes to introduce targeted gene mutations and double-strand DNA breaks to diversify antigen receptor genes and combat viral infections. These processes, initiated by specific DNA-editing enzymes, often result in mistargeted induction of genome lesions that initiate and drive cancers. Like other molecules involved in human health and disease, the DNA-editing enzymes of the immune system have been intensively studied in humans and mice, with little attention paid (< 1% of published studies) to the same enzymes in evolutionarily distant species. Here, we present a systematic review of the literature on the characterization of one such DNA-editing enzyme, activation-induced cytidine deaminase (AID), from an evolutionary comparative perspective. The central thesis of this review is that although the evolutionary comparative approach represents a minuscule fraction of published works on this and other DNA-editing enzymes, this approach has made significant impacts across the fields of structural biology, immunology, and cancer research. Using AID as an example, we highlight the value of the evolutionary comparative approach in discoveries already made, and in the context of emerging directions in immunology and protein engineering. We introduce the concept of 5-dimensional (5D) description of protein structures, a more nuanced view of a structure that is made possible by evolutionary comparative studies. In this higher dimensional view of a protein's structure, the classical 3-dimensional (3D) structure is integrated in the context of real-time conformations and evolutionary time shifts (4 dimension) and the relevance of these dynamics to its biological function (5 dimension).
Topics: Animals; Biological Evolution; Cytidine Deaminase; DNA; Humans; Protein Conformation; Protein Engineering
PubMed: 34135887
DOI: 10.3389/fimmu.2021.642343 -
Fertility and Sterility Sep 2021To evaluate the effect of varicocelectomy on sperm deoxyribonucleic acid fragmentation (SDF) rates in infertile men with clinical varicocele. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To evaluate the effect of varicocelectomy on sperm deoxyribonucleic acid fragmentation (SDF) rates in infertile men with clinical varicocele.
DESIGN
Systematic review and meta-analysis.
SETTING
Not applicable.
PATIENT(S)
Infertile men with clinical varicocele subjected to varicocelectomy.
INTERVENTION(S)
Systematic search using PubMed/Medline, EMBASE, Cochrane's central database, Scielo, and Google Scholar to identify relevant studies published from inception until January 2021. We included studies comparing SDF rates before and after varicocelectomy in infertile men with clinical varicocele.
MAIN OUTCOME MEASURE(S)
The primary outcome was the difference between the SDF rates before and after varicocelectomy. A meta-analysis of weighted data using random-effects models was performed. Results were reported as weighted mean differences (WMD) with 95% confidence intervals (CIs). Subgroup analyses were performed on the basis of the SDF assay, varicocelectomy technique, preoperative SDF levels, varicocele grade, follow-up time, and study design.
RESULT(S)
Nineteen studies involving 1,070 patients provided SDF data. Varicocelectomy was associated with reduced postoperative SDF rates (WMD -7.23%; 95% CI: -8.86 to -5.59; I = 91%). The treatment effect size was moderate (Cohen's d = 0.68; 95% CI: 0.77 to 0.60). The pooled results were consistent for studies using sperm chromatin structure assay, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling, sperm chromatin dispersion test, and microsurgical varicocele repair. Subgroup analyses showed that the treatment effect was more pronounced in men with elevated vs. normal preoperative SDF levels, but the impact of varicocele grade remained equivocal. Meta-regression analysis demonstrated that SDF decreased after varicocelectomy as a function of preoperative SDF levels (coefficient: 0.23; 95% CI: 0.07 to 0.39).
CONCLUSION(S)
We concluded that pooled results from studies including infertile men with clinical varicocele indicated that varicocelectomy reduced the SDF rates. The treatment effect was greater in men with elevated (vs. normal) preoperative SDF levels. Further research is required to determine the full clinical implications of SDF reduction for these men.
Topics: Adult; DNA Fragmentation; Fertility; Humans; Infertility, Male; Male; Spermatozoa; Treatment Outcome; Urologic Surgical Procedures, Male; Varicocele
PubMed: 33985792
DOI: 10.1016/j.fertnstert.2021.04.003 -
PloS One 2021Nontuberculous mycobacteria (NTM) infection is similar to Mycobacterium tuberculosis (MTB) infection. Early clinical identification and differentiation of NTM and MTB... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Nontuberculous mycobacteria (NTM) infection is similar to Mycobacterium tuberculosis (MTB) infection. Early clinical identification and differentiation of NTM and MTB infections continues to be a major challenge. Nucleic acid amplification tests (NAATs) have the ability to efficiently and rapidly detect pathogens and are widely used in mycobacterial infections. The objective of this study is to estimate the diagnostic accuracy of NAATs for NTM.
METHODS
We will search candidate studies that assessing the accuracy of NAATs for diagnosis of NTM through PubMed, Embase and the Cochrane Library until May 2021. Studies with full text that meet the inclusion criteria will be included. Following a revised tool for Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2), two researchers will independently evaluate the study quality. The STATA software (version 15.0) will be used to carry out meta-analyses. When heterogeneity is observed, subgroup analyses and meta-regression analyses will be used to explore sources of heterogeneity. Sensitivity analyses will be used to check the robustness of analyses.
CONCLUSION
We hope that this study will provide meaningful evidence for the early and rapid diagnosis of NAATs for NTM, which will help to guide the treatment of NTM and improve the prognosis of patients.
Topics: DNA, Bacterial; Diagnostic Tests, Routine; Humans; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Nucleic Acid Amplification Techniques
PubMed: 33886648
DOI: 10.1371/journal.pone.0250470 -
Social Science & Medicine (1982) Mar 2021We systematically review the literature on social epigenetics, examining how empirical research to date has conceptualized and operationalized social determinants of... (Review)
Review
OBJECTIVE
We systematically review the literature on social epigenetics, examining how empirical research to date has conceptualized and operationalized social determinants of health (SDOH).
METHODS
Using comprehensive search procedures, we identified studies that consider the impact of SDOH on DNA methylation (DNAm), the most common measure of epigenetic change in research on human adult populations. We analyzed the studies to determine: 1) which populations and environments have been investigated in the literature; 2) how SDOH are defined and operationalized; 3) which SDOH have been linked to DNAm; and 4) what lessons from the SDOH literature can be better integrated into future studies exploring the social determinants of health and epigenetic outcomes.
RESULTS
We identified 67 studies, with 39 to 8397 participants. The SDOH most commonly considered were early life socioeconomic exposures and early life trauma or mental health. Our review highlights four broad challenges: a) high dependence on convenience sampling, b) limited racial/ethnic, and geographic diversity in sampling frames, c) overreliance on individual sociodemographic characteristics as proxies for broader stratification processes, and d) a focus on downstream social determinants of health and individualized experiences with social stressors.
CONCLUSIONS
Future social epigenetics research should prioritize larger, more diverse and representative population-based samples and employ the SDOH framework to better inform the conceptualization of research questions and interpretation of findings. In particular, the simplified depiction of race/ethnicity, gender, and socioeconomic status as individual-level characteristics should be updated with an explicit acknowledgement that these characteristics are more accurately interpreted as cues used by society to differentiate subpopulations. Social epigenetics research can then more clearly elucidate the biological consequences of these social exposures for patterns of gene expression, subsequent disease etiology, and health inequities.
Topics: Adult; Epigenesis, Genetic; Humans; Social Determinants of Health
PubMed: 33610974
DOI: 10.1016/j.socscimed.2021.113738 -
Antimicrobial Agents and Chemotherapy Feb 2021Molecular testing is rapidly becoming an integral component of global tuberculosis (TB) control. Uncommon mechanisms of resistance escape detection by these platforms...
Systematic Review of Mutations Associated with Isoniazid Resistance Points to Continuing Evolution and Subsequent Evasion of Molecular Detection, and Potential for Emergence of Multidrug Resistance in Clinical Strains of Mycobacterium tuberculosis.
Molecular testing is rapidly becoming an integral component of global tuberculosis (TB) control. Uncommon mechanisms of resistance escape detection by these platforms and undermine our ability to contain outbreaks. This article is a systematic review of published articles that reported isoniazid (INH) resistance-conferring mutations between September 2013 and December 2019. The genes , , and , and the intergenic region '- were considered in this review. Fifty-two articles were included that described 9,306 clinical isolates (5,804 INH resistant [INH] and 3,502 INH susceptible [INH]) from 31 countries. The three most frequently mutated loci continue to be locus 315 of (315; = 4,271), locus -15 of (-15; = 787), and locus -8 of (-8; 106). However, the diagnostic value of -8 is far lower than previously thought, as it only appears in 25 (0.4%) of the INH isolates lacking the first two mutations. I catalogued 45 new loci (29 , nine , and seven ) associated with INH resistance and identified 59 loci (common to this and previous reviews) as a reliable basis for molecular diagnostics. Including all observed mutations provides a cumulative sensitivity of 85.6%. In 14.4% of resistant isolates, no mechanism of resistance was detected, making them likely to escape molecular detection, and in the case of INH monoresistance, likely to convert to multidrug-resistant TB (MDR-TB). Integrating the information cataloged in this study into current diagnostic tools is essential for combating the emergence of MDR-TB, and its exclusion can lead to an unintended selection against common mechanisms and to diversifying evolution. Observation of many low-frequency resistance-conferring mutations points to an advantage of whole-genome sequencing (WGS) for diagnostics. Finally, I provide five recommendations for future diagnostic platforms.
Topics: Antitubercular Agents; Bacterial Proteins; DNA, Bacterial; Drug Resistance, Multiple; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 33361298
DOI: 10.1128/AAC.02091-20 -
Journal of Pediatric Gastroenterology... Mar 2021It is important to identify patients with monogenic IBD as management may differ from classical IBD. In this position statement we formulate recommendations for the use...
Clinical Genomics for the Diagnosis of Monogenic Forms of Inflammatory Bowel Disease: A Position Paper From the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition.
BACKGROUND
It is important to identify patients with monogenic IBD as management may differ from classical IBD. In this position statement we formulate recommendations for the use of genomics in evaluating potential monogenic causes of IBD across age groups.
METHODS
The consensus included paediatric IBD specialists from the Paediatric IBD Porto group of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and specialists from several monogenic IBD research consortia. We defined key topics and performed a systematic literature review to cover indications, technologies (targeted panel, exome and genome sequencing), gene panel setup, cost-effectiveness of genetic screening, and requirements for the clinical care setting. We developed recommendations that were voted upon by all authors and Porto group members (32 voting specialists).
RESULTS
We recommend next-generation DNA-sequencing technologies to diagnose monogenic causes of IBD in routine clinical practice embedded in a setting of multidisciplinary patient care. Routine genetic screening is not recommended for all IBD patients. Genetic testing should be considered depending on age of IBD-onset (infantile IBD, very early-onset IBD, paediatric or young adult IBD), and further criteria, such as family history, relevant comorbidities, and extraintestinal manifestations. Genetic testing is also recommended in advance of hematopoietic stem cell transplantation. We developed a diagnostic algorithm that includes a gene panel of 75 monogenic IBD genes. Considerations are provided also for low resource countries.
CONCLUSIONS
Genomic technologies should be considered an integral part of patient care to investigate patients at risk for monogenic forms of IBD.
Topics: Child; Child Nutritional Physiological Phenomena; Colitis; Gastroenterology; Genomics; Humans; Inflammatory Bowel Diseases
PubMed: 33346580
DOI: 10.1097/MPG.0000000000003017 -
PloS One 2020Abdominal tuberculosis is a severe extrapulmonary tuberculosis, which can lead to serious complications. Early diagnosis and treatment are very important for the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Abdominal tuberculosis is a severe extrapulmonary tuberculosis, which can lead to serious complications. Early diagnosis and treatment are very important for the prognosis and the diagnosis of abdominal tuberculosis is still difficult. This study aims to evaluate the diagnostic accuracy of nucleic acid amplification tests (NAATs) for abdominal tuberculosis using meta-analysis method.
METHODS
We will search PubMed, the Cochrane Library, Embase, China National Knowledge Infrastructure, and the Wanfang database for studies evaluating the diagnostic accuracy of NAATs for abdominal tuberculosis until May 2020. We will include a systematic review and meta-analysis that evaluated the accuracy of NAATs for abdominal tuberculosis. Any types of study design with full text will be sought and included. The risk of bias will be assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. Stata version 15.0 with the midas command packages will be used to carry out meta-analyses.
RESULTS
The results will provide clinical evidence for diagnostic accuracy of NAATs for abdominal tuberculosis, and this systematic review and meta-analysis will be submitted to a peer-reviewed journal for publication.
CONCLUSION
This overview will provide evidence of NAATs for diagnosis of abdominal tuberculosis.
SYSTEMATIC REVIEW REGISTRATION
INPLASY202060030.
Topics: Abdomen; DNA, Bacterial; Databases, Factual; Humans; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Reference Standards; Tuberculosis
PubMed: 33315919
DOI: 10.1371/journal.pone.0243765 -
The Lancet. Infectious Diseases May 2021Cryptosporidiosis is a common cause of diarrhoea in young children (aged younger than 24 months) in low-resource settings but is currently challenging to diagnose....
BACKGROUND
Cryptosporidiosis is a common cause of diarrhoea in young children (aged younger than 24 months) in low-resource settings but is currently challenging to diagnose. Light-emitting diode fluorescence microscopy with auramine-phenol staining (LED-AP), recommended for tuberculosis testing, can also detect Cryptosporidium species. A lateral-flow test not requiring refrigerator storage (by contrast with most immunochromatographic lateral-flow assays) has also recently been developed for Cryptosporidium spp detection. We aimed to evaluate the diagnostic accuracy and operational feasibility of LED-AP and the lateral-flow test strip for cryptosporidiosis in children.
METHODS
We did a prospective diagnostic accuracy study in two health-care facilities in Ethiopia, in a consecutive series of children younger than 5 years of age with diarrhoea (three or more loose stools within the previous 24 h) or dysentery (at least one loose stool with stains of blood within the previous 24 h). Stool samples were tested for Cryptosporidium spp by LED-AP and the lateral-flow test strip; accuracy of each test was estimated by independent and blind comparison with a composite reference standard comprising quantitative immunofluorescent antibody test (qIFAT), ELISA, and quantitative PCR (qPCR). Quantitative cutoff values for diarrhoea-associated infection were established in an embedded case-control substudy, with cases of cryptosporidiosis coming from the 15 districts in and around Jimma and the eight districts surrounding Serbo, and community controls without diarrhoea in the previous 48 h recruited by weekly frequency matching by geographical district of the household, age group, and enrolment week.
FINDINGS
Stool samples from 912 children with diarrhoea or dysentery and 706 controls from the case-control substudy were tested between Dec 22, 2016, and July 6, 2018. Estimated reference-standard cutoff values for cryptosporidiosis positivity were 2·3 × 10 DNA copies per g of wet stool for qPCR, and 725 oocysts per g for qIFAT. LED-AP had a sensitivity for cryptosporidiosis of 88% (95% CI 79-94; 66 of 75 samples) and a specificity of 99% (98-99; 717 of 726 samples); the lateral-flow test strip had a sensitivity of 89% (79-94; 63 of 71 samples) and a specificity of 99% (97-99; 626 of 635 samples).
INTERPRETATION
LED-AP has high sensitivity and specificity for cryptosporidiosis and should be considered as a dual-use technology that can be easily integrated with existing laboratory infrastructures in low-resource settings. The lateral-flow test strip has similar sensitivity and specificity and provides an alternative that does not require microscopy, although purchase cost of the test strip is unknown as it is not yet available on the market.
FUNDING
Norwegian Research Council GLOBVAC fund, The Bill & Melinda Gates Foundation, Norwegian Society for Medical Microbiology, University of Bergen, and Vestfold Hospital Trust.
Topics: Child; Cryptosporidiosis; Cryptosporidium; Databases, Factual; Diagnostic Tests, Routine; Diarrhea; Ethiopia; Feasibility Studies; Feces; Humans; Immunoassay; Prospective Studies; Real-Time Polymerase Chain Reaction; Sensitivity and Specificity
PubMed: 33278916
DOI: 10.1016/S1473-3099(20)30556-9 -
Frontiers in Physiology 2020Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder affecting up to 15% of women at reproductive age. The main features of PCOS are hyperandrogenism...
Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder affecting up to 15% of women at reproductive age. The main features of PCOS are hyperandrogenism and irregular menstrual cycles together with metabolic dysfunctions including hyperinsulinemia and insulin resistance and a 4-fold increased risk of developing type 2 diabetes. Despite the high prevalence the pathophysiology of the syndrome is unclear. Insulin resistance in women with PCOS likely affect the skeletal muscle and recently it was demonstrated that changes in DNA methylation affects the gene expression in skeletal muscle that in part can explain their metabolic abnormalities. The objective of this work was to combine gene expression array data from different datasets to improve statistical power and thereby identify novel biomarkers that can be further explored. In this narrative review, we performed a meta-analysis of skeletal muscle arrays available from Gene Expression Omnibus and from publications. The eligibility criteria were published articles in English, and baseline (no treatment) skeletal muscle samples from women with PCOS and controls. The R package Metafor was used for integration of the datasets. One hundred and fourteen unique transcripts were differentially expressed in skeletal muscle from women with PCOS vs. controls ( < 0.05), 87% of these transcripts have not been previously identified as altered in PCOS muscle. , and had the largest differential increase in expression, and , and had the largest decrease in expression. Two genes, and were consistently upregulated ( < 0.05) in the individual analyses and meta-analysis. Based on the meta-analysis, we identified several dysregulated immunometabolic pathways as a part of the molecular mechanisms of insulin resistance in the skeletal muscle of women with PCOS. The transcriptomic data need to be verified by functional analyses as well as proteomics to advance our understanding of PCOS specific insulin resistance in skeletal muscle.
PubMed: 33192572
DOI: 10.3389/fphys.2020.573505 -
Frontiers in Oncology 2020Breast cancer is the most common malignancy diagnosed during pregnancy. Strong data on the genomic profile of pregnancy-associated breast cancer are lacking. This...
Breast cancer is the most common malignancy diagnosed during pregnancy. Strong data on the genomic profile of pregnancy-associated breast cancer are lacking. This systematic review aims to integrate and analyze all existing data from the literature regarding the genomic background and the gene mutational patterns of pregnancy-associated breast cancer. Using various genomic analysis methods, multiple differentially expressed genes and numerous non-silent mutations have been detected. More particularly, our review demonstrates the aberrant expression of several oncogenes (e.g., ), tumor suppressor genes (e.g., ), apoptosis regulators (e.g., ), transcription regulators (e.g., ), genes involved in DNA repair mechanisms (e.g., Sig20, ), in cell proliferation (e.g., ), in the immune response (e.g., ), and in other significant biological processes (e.g., protein modification, internal cell motility). Further research on the genomic profile of pregnancy-associated breast cancer is urgently required in order to identify potential biomarkers facilitating early-stage diagnosis and individualized therapy.
PubMed: 33014874
DOI: 10.3389/fonc.2020.01773