Garrod's concept of 'chemical individuality' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth ...snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.25 × 10
) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.
The muscular dystrophies encompass a broad range of pathologies with varied clinical outcomes. In the case of patients carrying defects in fukutin-related protein (FKRP), these diverse pathologies ...arise from mutations within the same gene. This is surprising as FKRP is a glycosyltransferase, whose only identified function is to transfer ribitol-5-phosphate to α-dystroglycan (α-DG). Although this modification is critical for extracellular matrix attachment, α-DG's glycosylation status relates poorly to disease severity, suggesting the existence of unidentified FKRP targets. Here we reveal that FKRP directs sialylation of fibronectin, a process essential for collagen recruitment to the muscle basement membrane. Thus, our results reveal that FKRP simultaneously regulates the two major muscle-ECM linkages essential for fibre survival, and establishes a new disease axis for the muscular dystrophies.
The Ensembl project (http://www.ensembl.org) is a comprehensive genome information system featuring an integrated set of genome annotation, databases and other information for chordate and selected ...model organism and disease vector genomes. As of release 47 (October 2007), Ensembl fully supports 35 species, with preliminary support for six additional species. New species in the past year include platypus and horse. Major additions and improvements to Ensembl since our previous report include extensive support for functional genomics data in the form of a specialized functional genomics database, genome-wide maps of protein-DNA interactions and the Ensembl regulatory build; support for customization of the Ensembl web interface through the addition of user accounts and user groups; and increased support for genome resequencing. We have also introduced new comparative genomics-based data mining options and report on the continued development of our software infrastructure.
Campus interpersonal violence - defined as sexual assault, sexual harassment, intimate partner violence, and stalking - is a social problem that has received widespread attention due to its high ...prevalence and devastating consequences, especially for students facing multiple forms of minoritization. Research on campus interpersonal violence prioritizes certain types of institutions; violence; victims, perpetrators, and bystanders; and intervention goals. This prioritization fails to challenge underlying systems of oppression and makes invisible minoritized students who are most affected by campus interpersonal violence. Historically, there has been an emphasis on acquaintance sexual assault against White heterosexual women at residential four-year predominantly White institutions. Far less studied are other types of violence and harm; violence experienced by gender and sexual minorities, and students of color; and students in online or commuter programs. In this commentary, we propose centering minoritized students to better situate campus interpersonal violence research within broader systems of oppression. We describe challenges to centering minoritized students in researching the problem, prevalence, and risk, as well as prevention and response interventions. We also provide recommendations for overcoming these barriers.
Background
In a previously reported CoFAR study, 55 subjects with egg allergy underwent randomized, placebo‐controlled egg oral immunotherapy (eOIT). Active treatment induced desensitization in most ...and sustained unresponsiveness (SU) in a smaller subset. We hypothesized that component‐resolved analysis of IgE, IgG4, IgA, IgA1, and IgA2 may identify potential biomarkers of SU in OIT subjects.
Methods
Longitudinal samples for 51 egg‐allergic subjects (37 active and 14 placebo) were available. Egg white (EW)‐, ovalbumin (OVA)‐, and ovomucoid (OVM)‐specific levels of IgA, IgA1, and IgA2 were quantified by ELISA. IgE and IgG4 to these antigens were quantified using ImmunoCAP®. Clinical responders achieved SU to egg; all others were considered nonresponders. Between‐group comparisons were made among active and placebo, as well as responders and nonresponders.
Results
No placebo subjects achieved responder status. Through month 48, among the 37 active subjects, baseline IgE‐OVM was lower in responders (median 3.97 kU/l, n = 19) than in nonresponders (10.9 kU/l, n = 18, P = 0.010). Logistic regression analysis revealed that lower baseline IgE‐EW (P = 0.038), IgE‐OVM (P = 0.032), and a higher IgG4/IgE‐OVM ratio (P = 0.013) were associated with clinical response. Relative increases in IgG4‐EW, IgA‐EW, and IgA2‐EW were observed in responders (P = 0.024, 0.024, and 0.029, respectively). IgG4/IgE, IgA/IgE, and IgA2/IgE ratios for EW and IgA/IgE ratio for OVA were found to be significantly elevated among responders (P = 0.004, 0.009, 0.028, and 0.008, respectively).
Conclusions
Increased IgG4‐EW, IgA‐EW, and IgA2‐EW during eOIT are associated with clinical response to eOIT. Lower pretreatment IgE‐EW and IgE‐OVM are also associated with SU. Future studies are needed to evaluate and validate these potential biomarkers.
In sickle cell disease (SCD), oxygen delivery is impaired due to anemia, especially during times of increased metabolic demand, and cerebral blood flow (CBF) must increase to meet changing ...physiologic needs. But hyperemia limits cerebrovascular reserve (CVR) and ischemic risk prevails despite elevated CBF. The cerebral metabolic rate of oxygen (CMRO2) directly reflects oxygen supply and consumption and may therefore be more insightful than flow‐based CVR measures for ischemic risk in SCD. We hypothesized that adults with SCD have impaired CMRO2 at rest and that a vasodilatory challenge with acetazolamide would improve CMRO2. CMRO2 was calculated from CBF and oxygen extraction fraction (OEF), measured with arterial spin labeling and T2‐prepared tissue relaxation with inversion recovery (T2‐TRIR) MRI. We studied 36 adults with SCD without a clinical history of overt stroke, and nine healthy controls. As expected, CBF was higher in patients with SCD versus controls (mean ± SD: 74 ± 16 versus 46 ± 5 mL/100 g/min, P < .001), resulting in similar oxygen delivery (SCD: 377 ± 67 versus controls: 368 ± 42 μmol O2/100g/min, P = .69). OEF was lower in patients versus controls (27 ± 4 versus 35 ± 4%, P < .001), resulting in lower CMRO2 in patients versus controls (102 ± 24 versus 127 ± 20 μmol O2/100g/min, P = .002). After acetazolamide, CMRO2 declined further in patients (P < .01) and did not decline significantly in controls (P = .78), indicating that forcing higher CBF worsened oxygen utilization in SCD patients. This lower CMRO2 could reflect variation between healthy and unhealthy vascular beds in terms of dilatory capacity and resistance whereby dysfunctional vessels become more oxygen‐deprived, hence increasing the risk of localized ischemia.
Mechanical cues influence tissue regeneration, and although vasculature is known to be mechanically sensitive, little is known about the effects of bulk extracellular matrix deformation on the ...nascent vessel networks found in healing tissues. Previously, we found that dynamic matrix compression in vivo potently regulated revascularization during bone tissue regeneration; however, whether matrix deformations directly regulate angiogenesis remained unknown. Here, we demonstrated that load initiation time, magnitude, and mode all regulate microvascular growth, as well as upstream angiogenic and mechanotransduction signaling pathways. Immediate load initiation inhibited angiogenesis and expression of early sprout tip cell selection genes, while delayed loading enhanced microvascular network formation and upstream signaling pathways. This research provides foundational understanding of how extracellular matrix mechanics regulate angiogenesis and has critical implications for clinical translation of new regenerative medicine therapies and physical rehabilitation strategies designed to enhance revascularization during tissue regeneration.
While the equivalence between online and traditional classrooms has been well researched, very little effort has been expended to do such comparisons for college level introductory chemistry. The ...existing literature has only one study that investigated chemistry lectures at an entire course level as opposed to particular course components such as individual topics or exams. Regarding lab courses, only one study is available and it involves moderating variables that are largely uncontrolled. In this work, we compared the student pass rates, withdrawal rates, and grade distributions between asynchronous online and traditional formats of an introductory chemistry lecture as well as its associated lab course. The study was based on the 823 university records available for the 2015-2016 academic year. Student pass and withdrawal rates between the two modes were quite similar and did not appear to be statistically significant. However, grade distributions for both the lecture and lab differed between the two learning modes, showing significant statistical associations. Online students were more likely to earn As in both lecture and lab while traditional in-person students were more likely to earn Cs or Ds. Further research should include replication of this study with a larger data set. Additionally, this study should be repeated in three to five years to determine if advances in course design, standardization and delivery platforms further reduce or eliminate differences between learning modes. Future studies should also use qualitative tools for a better understanding of why students fail or withdraw from courses.
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