Recent Submissions

  • Incorporating NTCP into randomized trials of proton versus photon therapy

    Scherman, J. (Allen Press, 2019-03-21)
    Purpose: We propose and simulate a model-based methodology to incorporate heterogeneous treatment benefit of proton therapy (PrT) versus photon therapy into randomized trial designs. We use radiation-induced pneumonitis (RP) as an exemplar. The aim is to obtain an unbiased estimate of how predicted difference in normal tissue complications probability (DNTCP) converts into clinical outcome on the patient level. Materials and Methods: DNTCP data from in silico treatment plans for photon therapy and PrT for patients with locally advanced lung cancer as well as randomly sampled clinical risk factors were included in simulations of trial outcomes. The model used at point of analysis of the trials was an iQUANTEC model. Trial outcomes were examined with Cox proportional hazards models, both in case of a correctly specified model and in a scenario where there is discrepancy between the dose metric used for DNTCP and the dose metric associated with the "true" clinical outcome, that is, when the model is misspecified. We investigated how outcomes from such a randomized trial may feed into a model-based estimate of the patient-level benefit from PrT, by creating patient-specific predicted benefit probability distributions. Results: Simulated trials showed benefit in accordance with that expected when the NTCP model was equal to the model for simulating outcome. When the model was misspecified, the benefit changed and we observed a reversal when the driver of outcome was high-dose dependent while the NTCP model was mean-dose dependent. By converting trial results into probability distributions, we demonstrated large heterogeneity in predicted benefit, and provided a randomized measure of the precision of individual benefit estimates. Conclusions: The design allows for quantifying the benefit of PrT referral, based on the combination of NTCP models, clinical risk factors, and traditional randomization. A misspecified model can be detected through a lower-than-expected hazard ratio per predicted DNTCP. © 2019 International Journal of Particle Therapy.
  • Racial/ethnic disparities in prevalence, treatment, and control of hypertension among US adults following application of the 2017 American College of Cardiology/American Heart Association guideline

    Al Kibria, G. (Elsevier Inc., 2019-03-14)
    The 2017 American College of Cardiology/American Heart Association (ACC/AHA) Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults recommends reduced systolic/diastolic blood pressure (SBP/DBP)cutoffs to define hypertension (i.e., by changing these from ≥140/90 to ≥130/80 mmHg), including new recommendations about indications and goals of antihypertensive treatment. This study reported the differences in age-adjusted prevalence and treatment status of hypertension according to race among US adults per the 2017 ACC/AHA guideline. The National Health and Nutrition Examination Survey 2011–16 data was analyzed. The main outcomes were age-adjusted prevalence and treatment status of hypertension among adults aged ≥20 years. After prevalence estimation, other proportions were obtained. The analysis included 16,103 adults (mean age: 47.6 years, 51.8% women). The age-adjusted proportions of adults with hypertension (59.0%, 95% confidence interval [CI]: 57.4%–60.6%), treatment-eligible for hypertension (49.3%, 95% CI: 47.7%–50.8%), and unmet treatment goals (63.8%, 95% CI: 60.0%–67.5%)among the treated were highest among non-Hispanic blacks. A large proportion of Mexican-Americans (46.5%, 95% CI: 42.0%–51.0%)and people of other races/ethnicities (49.3%, 95% CI: 45.5%–53.0%)were not receiving treatment despite having indication. Non-Hispanic blacks also had the highest prevalence of stage 2 hypertension. Among all races, prevalence, treatment-eligibility, and unmet treatment goals were higher among people with older age, male gender, diabetes, higher body weight, and higher cardiovascular disease risk while the majority of younger, lower/normal body weight, or non-diabetic people were untreated despite being eligible for treatment. The prevalence, treatment-eligibility, and unmet goals were substantially higher among non-Hispanic blacks. Moreover, disparities exist in treatment where Mexican-Americans and people of ‘other races/ethnicities’ were largely untreated despite having indication. © 2019 The Author
  • Sex differences in the expression of calcitonin gene-related peptide receptor components in the spinal trigeminal nucleus

    Ji, Y. (Elsevier B.V., 2019-04-23)
    Background and purpose: Calcitonin gene-related peptide (CGRP)plays an important role in migraine pathophysiology. CGRP acts primarily by activating a receptor composed of 3 proteins: calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and receptor component protein (RCP). We tested the hypothesis that sex differences exist in protein levels of two key components of this CGRP receptor: CLR and RCP. Methods: We used specific antibodies to assess baseline protein levels of CLR and RCP in the spinal trigeminal nucleus caudalis (SpVc)and upper cervical spinal cord of both male and female rats. We also tested if manipulations that knock-down the expression of RCP in SpVc, using locally-mediated gene transfer of short hairpin RNA (shRNA), ameliorate pain in an animal model of intracranial migraine-like pain induced by chemical noxious stimulation of the meninges. To assess pain, we used tests of ongoing pain (rat face grimace test and freezing behavior)and tests of facial mechanical hypersensitivity and allodynia. Results: There was no difference in CLR levels between male and female animals (p > 0.11)in SpVc and the upper cervical cord. However, female animals exhibited greater baseline levels of RCP (up to 3-fold higher)compared to males (p < 0.002). The knock-down of RCP expression in SpVc attenuated mechanical facial allodynia induced by chemical noxious stimulation of the meninges, but had little effect on ongoing pain behaviors in female and male animals. Conclusions: RCP is an integral component of the CGRP receptor and may play a key role in mediating CGRP induced central sensitization after noxious stimulation of the meninges. RCP expression in the SpVc and upper cervical cord is sexually dimorphic, with higher levels of expression in females. This dimorphism may be related to the increased incidence of migraines in females–a hypothesis that should be tested in the future. © 2019 The Authors
  • Multi-platform discovery of haplotype-resolved structural variation in human genomes

    Chaisson, M. (Nature Publishing Group, 2019-04-16)
    The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (<50 bp) and 27,622 SVs (≥50 bp) per genome. We also discover 156 inversions per genome and 58 of the inversions intersect with the critical regions of recurrent microdeletion and microduplication syndromes. Taken together, our SV callsets represent a three to sevenfold increase in SV detection compared to most standard high-throughput sequencing studies, including those from the 1000 Genomes Project. The methods and the dataset presented serve as a gold standard for the scientific community allowing us to make recommendations for maximizing structural variation sensitivity for future genome sequencing studies. © 2019, The Author(s).
  • ALDH1A1 regulates postsynaptic μ–opioid receptor expression in dorsal striatal projection neurons and mitigates dyskinesia through transsynaptic retinoic acid signaling

    Pan, J.; Yu, J.; Sun, L. (Springer Nature, 2019)
    Aldehyde dehydrogenase 1A1 (ALDH1A1), a retinoic acid (RA) synthase, is selectively expressed by the nigrostriatal dopaminergic (nDA) neurons that preferentially degenerate in Parkinson’s disease (PD). ALDH1A1–positive axons mainly project to the dorsal striatum. However, whether ALDH1A1 and its products regulate the activity of postsynaptic striatal neurons is unclear. Here we show that μ–type opioid receptor (MOR1) levels were severely decreased in the dorsal striatum of postnatal and adult Aldh1a1 knockout mice, whereas dietary supplement of RA restores its expression. Furthermore, RA treatment also upregulates striatal MOR1 levels and signaling and alleviates L-DOPA–induced dyskinetic movements in pituitary homeobox 3 (Pitx3)–defcient mice that lack of ALDH1A1–expressing nDA neurons. Therefore, our fndings demonstrate that ALDH1A1–synthesized RA is required for postsynaptic MOR1 expression in the postnatal and adult dorsal striatum, supporting potential therapeutic benefts of RA supplementation in moderating L-DOPA–induced dyskinesia.
  • Association study in African-admixed populations across the Americas recapitulates asthma risk loci in non-African populations

    Daya, M. (Nature Publishing Group, 2019-02-20)
    Asthma is a complex disease with striking disparities across racial and ethnic groups. Despite its relatively high burden, representation of individuals of African ancestry in asthma genome-wide association studies (GWAS) has been inadequate, and true associations in these underrepresented minority groups have been inconclusive. We report the results of a genome-wide meta-analysis from the Consortium on Asthma among African Ancestry Populations (CAAPA; 7009 asthma cases, 7645 controls). We find strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations, including the chromosome 17q12–q21 locus and the chr12q13 region, a novel (and not previously replicated) asthma locus recently identified by the Trans-National Asthma Genetic Consortium (TAGC). An additional seven loci reported by TAGC show marginal evidence for association in CAAPA. We also identify two novel loci (8p23 and 8q24) that may be specific to asthma risk in African ancestry populations. © 2019, The Author(s).
  • Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids

    Jeffrey R., O'Connell; Bentley, Amy R.; Sung, Yun J. (Nature Publishing Group, 2019-03-29)
    The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene–smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings. © 2019, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
  • The assessment of resistance to antidepressant treatment: Rationale for the Antidepressant Treatment History Form: Short Form (ATHF-SF)

    Sackeim, H. (Elsevier Inc., 2019-03-21)
    There is considerable diversity in how treatment-resistant depression (TRD) is defined. However, every definition incorporates the concept that patients with TRD have not benefited sufficiently from one or more adequate trials of antidepressant treatment. This review examines the issues fundamental to the systematic evaluation of antidepressant treatment adequacy and resistance. These issues include the domains of interventions deemed effective in treatment of major depressive episodes (e.g., pharmacotherapy, brain stimulation, and psychotherapy), the subgroups of patients for whom distinct adequacy criteria are needed (e.g., bipolar vs. unipolar depression, psychotic vs. nonpsychotic depression), whether trials should be rated dichotomously as adequate or inadequate or on a potency continuum, whether combination and augmentation strategies require specific consideration, and the criteria used to evaluate the adequacy of treatment delivery (e.g., dose, duration), trial adherence, and clinical outcome. This review also presents the Antidepressant Treatment History Form: Short-Form (ATHF-SF), a completely revised version of an earlier instrument, and details how these fundamental issues were addressed in the ATHF-SF. © 2019 The Authors
  • Factors affecting interpretation of national biomonitoring data from multiple countries: BPA as a case study

    LaKind, J. (Elsevier Inc., 2019-03-19)
    Introduction: The use of biomonitoring data as an indicator of national levels of human exposure to environmental chemicals has grown in importance and prevalence. Nationally representative urinary bisphenol A (BPA) data are now available for Canada, the United States and Korea. Here we address the following questions: Are urinary BPA data from these countries comparable? What can be discerned regarding geographic and/or temporal similarities or differences? Are there generalizable lessons to be learned regarding comparison of biomonitoring results from different countries? Methods: We examined underlying methods and resultant urinary BPA data from national surveys of three countries: Canada (Canadian Health Measures Survey, CHMS, 2009-2015); United States (National Health and Nutrition Examination Survey, NHANES, 2009–2014); and Korea (Korean National Environmental Health Survey, KoNEHS, 2009–2014). We estimated BPA daily intakes on both a volume- and creatinine-adjusted basis. Results: The three countries use similar methods for analyzing urine samples for BPA and participate in external proficiency testing with acceptable results. Field blanks are only used in the CHMS program. There were program-specific differences in fasting times of participants. Median urinary BPA levels in Canada remained relatively constant over the three cycles (1.1–1.2 ng/ml), while US levels decreased (from 1.9 to 1.3 ng/ml) and Korean levels increased (from 0.7 to 1.1 ng/ml) over similar time periods. The most recent survey year data indicate that levels do not differ substantially across countries. Canadian urinary BPA levels have been stable; the subtle, non-significant decrease in intakes may be due to higher body weight in the more recent Canadian surveys. In contrast, the decrease in intakes in the US appears to be due to decreases in urinary BPA as body weights in the US have been stable. Estimated 95th percentile intakes are over an order of magnitude below current health-based guidance values. Discussion: Our assessment of urinary BPA data from Canada, the US and Korea indicates that methodological differences, methods for dilution adjustment, and population characteristics should be carefully considered when interpreting biomonitoring data. Despite the plethora of publications describing issues with use of creatinine levels for urinary dilution adjustment, there have been no major methodological advances that would assist in interpreting urinary chemical data. A combination of biomonitoring and traditional exposure assessment approaches may be needed to fully assess human exposures to BPA and other chemicals. Conclusions: National biomonitoring surveys provide important information on population levels of chemicals such as BPA and can assist in understanding temporal and geographic similarities, differences, and trends. However, caution must be exercised when using these data to draw anything but broad conclusions, due to both intercountry methodological differences and factors affecting urinary chemical levels that are still poorly understood. While the issues raised in this paper do not appear to be a major concern specifically for the national-scale monitoring of BPA described here, they must be considered when comparing data for other chemicals measured as part of both national and smaller-scale biomonitoring-based research as well as for BPA data from other studies. © 2019
  • Chronic pain after blast-induced traumatic brain injury in awake rats

    Uddin, O. (Elsevier Inc., 2019-04-01)
    Explosive blast-induced traumatic brain injury (blast-TBI) in military personnel is a leading cause of injury and persistent neurological abnormalities, including chronic pain. We previously demonstrated that chronic pain after spinal cord injury results from central sensitization in the posterior thalamus (PO). The presence of persistent headaches and back pain in veterans with blast-TBI suggests a similar involvement of thalamic sensitization. Here, we tested the hypothesis that pain after blast-TBI is associated with abnormal increases in activity of neurons in PO thalamus. We developed a novel model with two unique features: (1) blast-TBI was performed in awake, un-anesthetized rats, to simulate the human experience and to eliminate confounds of anesthesia and surgery inherent in other models; (2) only the cranium, rather than the entire body, was exposed to a collimated blast wave, with the blast wave striking the posterior cranium in the region of the occipital crest and foramen magnum. Three weeks after blast-TBI, rats developed persistent, ongoing spontaneous pain. Contrary to our hypothesis, we found no significant differences in the activity of PO neurons, or of neurons in the spinal trigeminal nucleus. There were also no significant changes in gliosis in either of these structures. This novel model will allow future studies on the pathophysiology of chronic pain after blast-TBI. © 2019 The Authors
  • Ten questions concerning the built environment and mental health

    Hoisington, A. (2019-05-15)
    Most people spend the majority of their lives indoors. Research over the last thirty years has focused on investigating the mechanisms through which specific elements of the built environment, such as indoor air quality, influence the physical health of occupants. However, similar effort has not been expended in regard to mental health, a significant public health concern. One in five Americans has been diagnosed with a mental health disorder in the past year, and, in the United States, the number of suicide deaths are similar to the number of deaths due to breast cancer. Increases in mental health disorders in Western societies may be due, in part, to increased systemic inflammation, secondary to decreased exposures to a diverse microbial environment (i.e., the hygiene hypothesis, “Old Friends” hypothesis, “missing microbes” hypothesis, or biodiversity hypothesis), as well as increased environmental exposures that lead to chronic low-grade inflammation. In this review, we provide an assessment that integrates historical research across disciplines. We offer ten questions that highlight the importance of current lessons learned regarding the built environment and mental health, including a potential role for the microbiome of the built environment to influence mental health. Suggested areas for future investigation are also highlighted. © 2019
  • Measurement of lactate levels in postmortem brain, iPSCs, and animal models of schizophrenia.

    Sullivan, Courtney R.; Mielnik, Catharine A.; Funk, Adam; Rowland, Laura M. (Nature Publishing Group, 2019-03-25)
    Converging evidence suggests bioenergetic defects contribute to the pathophysiology of schizophrenia and may underlie cognitive dysfunction. The transport and metabolism of lactate energetically couples astrocytes and neurons and supports brain bioenergetics. We examined the concentration of lactate in postmortem brain (dorsolateral prefrontal cortex) in subjects with schizophrenia, in two animal models of schizophrenia, the GluN1 knockdown mouse model and mutant disrupted in schizophrenia 1 (DISC1) mouse model, as well as inducible pluripotent stem cells (iPSCs) from a schizophrenia subject with the DISC1 mutation. We found increased lactate in the dorsolateral prefrontal cortex (p = 0.043, n = 16/group) in schizophrenia, as well as in frontal cortical neurons differentiated from a subject with schizophrenia with the DISC1 mutation (p = 0.032). We also found a decrease in lactate in mice with induced expression of mutant human DISC1 specifically in astrocytes (p = 0.049). These results build upon the body of evidence supporting bioenergetic dysfunction in schizophrenia, and suggests changes in lactate are a key feature of this often devastating severe mental illness. © 2019, The Author(s).
  • Adaptation of the Drug and Drug Problems Perception Questionnaire to assess healthcare provider attitudes toward adolescent substance use

    Connors, E. (Elsevier Inc., 2019-03-14)
    Although preventive screening, brief intervention and referral to treatment for adolescent substance use is recommended by the American Academy of Pediatrics, primary care providers inconsistently address substance use with their pediatric patients (AAP Committee on Practice and Ambulatory Medicine and AAP Bright Futures Periodicity Schedule Workgroup, 2017). Further research on provider perceptions about addressing adolescent substance use may help identify and address some barriers to screening. However, there are few validated measures of provider perceptions toward patient substance, and none are specific to pediatric patients. This study (conducted in Maryland, 2015–2017) examines the internal consistency and factor structure of an adapted measure to assess perceptions of adolescent substance use. Internal consistency was assessed using responses from a sample of 276 healthcare practitioners (87.7% women, 12.3% men). Their professions included the following: Certified Medical Assistants (10.9%), Registered Nurses (17.8%), Nurse Practitioners (8.3%), Physician Assistants (3.6%), Medical Doctors (13.8%), Clinical Therapists (10.9%) and Other (21.0%). A four-factor solution was identified and initial evidence suggests the adapted measure is appropriate for use with health care providers. A subsample of 181 participants who reported direct interaction with adolescent patients in a provider role was also used to assess convergent validity with self-reported screening practices and effectiveness. Provider-reported frequency of alcohol and drug use assessment for pediatric patients was significantly related to positive perceptions about adolescent substance use on all subscales. The adapted measure could prove useful for assessing provider readiness to receive adolescent substance use screening training and could be further adapted to include items unique to adolescent care, including parental involvement. © 2019 The Authors
  • Specific inhibition of myostatin activation is beneficial in mouse models of SMA therapy

    Long, K. (Oxford University Press., 2019-04-01)
    Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by loss of α-motor neurons, leading to profound skeletal muscle atrophy. Patients also suffer from decreased bone mineral density and increased fracture risk. The majority of treatments for SMA, approved or in clinic trials, focus on addressing the underlying cause of disease, insufficient production of full-length SMN protein. While restoration of SMN has resulted in improvements in functional measures, significant deficits remain in both mice and SMA patients following treatment. Motor function in SMA patients may be additionally improved by targeting skeletal muscle to reduce atrophy and improve muscle strength. Inhibition of myostatin, a negative regulator of muscle mass, offers a promising approach to increase muscle function in SMA patients. Here we demonstrate that muSRK-015P, a monoclonal antibody which specifically inhibits myostatin activation, effectively increases muscle mass and function in two variants of the pharmacological mouse model of SMA in which pharmacologic restoration of SMN has taken place either 1 or 24 days after birth to reflect early or later therapeutic intervention. Additionally, muSRK-015P treatment improves the cortical and trabecular bone phenotypes in these mice. These data indicate that preventing myostatin activation has therapeutic potential in addressing muscle and bone deficiencies in SMA patients. An optimized variant of SRK-015P, SRK-015, is currently in clinical development for treatment of SMA. © The Author(s) 2018.
  • Cervicovaginal microbiota and local immune response modulate the risk of spontaneous preterm delivery

    Elovitz, M. (Nature Publishing Group, 2019-03-21)
    Failure to predict and understand the causes of preterm birth, the leading cause of neonatal morbidity and mortality, have limited effective interventions and therapeutics. From a cohort of 2000 pregnant women, we performed a nested case control study on 107 well-phenotyped cases of spontaneous preterm birth (sPTB) and 432 women delivering at term. Using innovative Bayesian modeling of cervicovaginal microbiota, seven bacterial taxa were significantly associated with increased risk of sPTB, with a stronger effect in African American women. However, higher vaginal levels of β-defensin-2 lowered the risk of sPTB associated with cervicovaginal microbiota in an ethnicity-dependent manner. Surprisingly, even in Lactobacillus spp. dominated cervicovaginal microbiota, low β-defensin-2 was associated with increased risk of sPTB. These findings hold promise for diagnostics to accurately identify women at risk for sPTB early in pregnancy. Therapeutic strategies could include immune modulators and microbiome-based therapeutics to reduce this significant health burden. © 2019, The Author(s).
  • 2018 American College of Rheumatology/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis

    Singh, J.A.; Guyatt, G.; Ogdie, A. (John Wiley and Sons Inc., 2019)
    Objective: To develop an evidence-based guideline for the pharmacologic and nonpharmacologic treatment of psoriatic arthritis (PsA), as a collaboration between the American College of Rheumatology (ACR) and the National Psoriasis Foundation (NPF). Methods: We identified critical outcomes in PsA and clinically relevant PICO (population/intervention/comparator/outcomes) questions. A Literature Review Team performed a systematic literature review to summarize evidence supporting the benefits and harms of available pharmacologic and nonpharmacologic therapies for PsA. GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to rate the quality of the evidence. A voting panel, including rheumatologists, dermatologists, other health professionals, and patients, achieved consensus on the direction and the strength of the recommendations. Results: The guideline covers the management of active PsA in patients who are treatment-naive and those who continue to have active PsA despite treatment, and addresses the use of oral small molecules, tumor necrosis factor inhibitors, interleukin-12/23 inhibitors (IL-12/23i), IL-17 inhibitors, CTLA4-Ig (abatacept), and a JAK inhibitor (tofacitinib). We also developed recommendations for psoriatic spondylitis, predominant enthesitis, and treatment in the presence of concomitant inflammatory bowel disease, diabetes, or serious infections. We formulated recommendations for a treat-to-target strategy, vaccinations, and nonpharmacologic therapies. Six percent of the recommendations were strong and 94% conditional, indicating the importance of active discussion between the health care provider and the patient to choose the optimal treatment. Conclusion: The 2018 ACR/NPF PsA guideline serves as a tool for health care providers and patients in the selection of appropriate therapy in common clinical scenarios. Best treatment decisions consider each individual patient situation. The guideline is not meant to be proscriptive and should not be used to limit treatment options for patients with PsA. © 2018, American College of Rheumatology
  • Minimum information about an uncultivated virus genome (MIUVIG)

    Roux, S.; Adriaenssens, E.M.; Dutilh, B.E. (Nature Publishing Group, 2019)
    We present an extension of the Minimum Information about any (x) Sequence (MIxS) standard for reporting sequences of uncultivated virus genomes. Minimum Information about an Uncultivated Virus Genome (MIUViG) standards were developed within the Genomic Standards Consortium framework and include virus origin, genome quality, genome annotation, taxonomic classification, biogeographic distribution and in silico host prediction. Community-wide adoption of MIUViG standards, which complement the Minimum Information about a Single Amplified Genome (MISAG) and Metagenome-Assembled Genome (MIMAG) standards for uncultivated bacteria and archaea, will improve the reporting of uncultivated virus genomes in public databases. In turn, this should enable more robust comparative studies and a systematic exploration of the global virosphere. © 2019, Nature Publishing Group. All rights reserved.
  • Colonization factors among enterotoxigenic Escherichia coli isolates from children with moderate-to-severe diarrhea and from matched controls in the Global Enteric Multicenter Study (GEMS)

    Vidal, R.M.; Muhsen, K.; Tennant, S.M. (Public Library of Science, 2019)
    Background: Enterotoxigenic Escherichia coli (ETEC) encoding heat-stable enterotoxin (ST) alone or with heat-labile enterotoxin (LT) cause moderate-to-severe diarrhea (MSD) in developing country children. The Global Enteric Multicenter Study (GEMS) identified ETEC encoding ST among the top four enteropathogens. Since the GEMS objective was to provide evidence to guide development and implementation of enteric vaccines and other interventions to diminish diarrheal disease morbidity and mortality, we examined colonization factor (CF) prevalence among ETEC isolates from children age <5 years with MSD and from matched controls in four African and three Asian sites. We also assessed strength of association of specific CFs with MSD. Methodology/Principal findings: MSD cases enrolled at healthcare facilities over three years and matched controls were tested in a standardized manner for many enteropathogens. To identify ETEC, three E. coli colonies per child were tested by polymerase chain reaction (PCR) to detect genes encoding LT, ST; confirmed ETEC were examined by PCR for major CFs (Colonization Factor Antigen I [CFA/I] or Coli Surface [CS] antigens CS1-CS6) and minor CFs (CS7, CS12, CS13, CS14, CS17, CS18, CS19, CS20, CS21, CS30). ETEC from 806 cases had a single toxin/CF profile in three tested strains per child. Major CFs, components of multiple ETEC vaccine candidates, were detected in 66.0% of LT/ST and ST-only cases and were associated with MSD versus matched controls by conditional logistic regression (p?0.006); major CFs detected in only 25.0% of LT-only cases weren't associated with MSD. ETEC encoding exclusively CS14, identified among 19.9% of 291 ST-only and 1.5% of 259 LT/ST strains, were associated with MSD (p = 0.0011). No other minor CF exhibited prevalence ?5% and significant association with MSD. Conclusions/Significance: Major CF-based efficacious ETEC vaccines could potentially prevent up to 66% of pediatric MSD cases due to ST-encoding ETEC in developing countries; adding CS14 extends coverage to ~77%. © 2019, Public Library of Science. All rights reserved.
  • The Gene Ontology Resource: 20 years and still GOing strong

    Carbon, S.; Douglass, E.; Dunn, N. (Oxford University Press, 2019)
    The Gene Ontology resource (GO; provides structured, computable knowledge regarding the functions of genes and gene products. Founded in 1998, GO has become widely adopted in the life sciences, and its contents are under continual improvement, both in quantity and in quality. Here, we report the major developments of the GO resource during the past two years. Each monthly release of the GO resource is now packaged and given a unique identifier (DOI), enabling GO-based analyses on a specific release to be reproduced in the future. The molecular function ontology has been refactored to better represent the overall activities of gene products, with a focus on transcription regulator activities. Quality assurance efforts have been ramped up to address potentially out-of-date or inaccurate annotations. New evidence codes for high-Throughput experiments now enable users to filter out annotations obtained from these sources. GO-CAM, a new framework for representing gene function that is more expressive than standard GO annotations, has been released, and users can now explore the growing repository of these models. We also provide the 'GO ribbon' widget for visualizing GO annotations to a gene; the widget can be easily embedded in any web page. © The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.
  • Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

    Kraja, A.T.; Liu, C.; Fetterman, J.L. (Cell Press, 2019)
    Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E−04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E−03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia’s genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E−06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.

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