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Detecting when and how much of a protein molecule is synthesized is important for understanding cell function, but current methods either cannot be performed in vivo or have poor temporal resolution. Here, we developed a technique to detect and quantify subcellular protein synthesis events in real time in vivo. This Protein Translation Reporting (PTR) technique uses a genetic tag that produces a stoichiometric ratio of a small peptide portion of a split fluorescent protein and the protein of interest during protein synthesis. We show that the split fluorescent protein peptide can generate fluorescence within milliseconds upon binding the larger portion of the fluorescent protein, and that the fluorescence intensity is directly proportional to the number of molecules of the protein of interest synthesized. Using PTR, we tracked and measured protein synthesis events in single cells over time in vivo. We use different color split fluorescent proteins to detect multiple genes or alleles in single cells simultaneously. We also split a photoswitchable fluorescent protein to photoconvert the reconstituted fluorescent protein to a different channel to continually reset the time of detection of synthesis events. [ABSTRACT FROM AUTHOR]

Data makes the world go round. Now more than ever, routine police work depends on the collection and analysis of digital information. Law enforcement agencies possess vast sums of intel on who we are, where we go, and what we do. The proliferation of digital technology has transformed federal criminal procedure—from how police investigate crimes to how prosecutors prove them at trial. Courts and commentators have written much about the first part, but less so about the second. Together, they represent two sides of the same problem: constitutional doctrine lagging behind new technology, leading to suboptimal constraints on law enforcement conduct. This Note explores the effects of digital technology on the nature and scope of federal prosecutors’ disclosure obligations under Brady v. Maryland. As police pass along more data to prosecutors—usually terabytes at a time—prosecutors face the difficult task of sifting through mountains of evidence to determine what is exculpatory or otherwise favorable to the defense. Often, prosecutors turn over their entire case file, knowing full well that defense counsel will fare no better. This state of affairs puts our adversarial system on shaky ground. This Note urges district courts to exercise greater oversight of the discovery process, requiring prosecutors to take reasonable precautions so exculpatory evidence comes to light. [ABSTRACT FROM AUTHOR]

Background: Existing evidence regarding the impact of the COVID-19 pandemic on postpartum mental health is mixed, with disparate studies showing increased, stable, or even reduced risk of postpartum depression (PPD) amid the pandemic. Furthermore, although it is plausible that the pandemic impacted the mental health of mothers from vulnerable and underserved communities differentially, few studies have characterized racial and ethnic differences in the impact of the COVID-19 pandemic on PPD. Materials and Methods: Pregnancy Risk Assessment Monitoring System data for 2018–2019 (pre-pandemic period) and 2020 (peri-pandemic period) from 40 sites (n = 110,779, representing 5,485,137 postpartum women) were used to determine whether rates of PPD changed during the first year of the pandemic. Postpartum depressive symptoms were assessed using the Patient Health Questionnaire 2-item. Average marginal effects and contrasts of predictive margins derived from a multivariable logistic regression model were used to compare the risk of PPD before and during the pandemic in the overall sample and across racial/ethnic subgroups. Results: Adjusting for sociodemographic and clinical characteristics, we found that the overall risk for PPD remained stable (0.0 percentage points [pp]; 95% confidence interval [CI]: −0.7, 0.6 pp) in the first year of the pandemic. We detected no statistically significant changes in risk for PPD across seven of eight racial/ethnic groups considered; however, the risk of PPD among non-Hispanic Black women fell by 2.0 pp (95% CI: −3.5, −0.4 pp) relative to the pre-pandemic period. Conclusion: We identified important subgroup differences in pandemic-related changes in risk for PPD. [ABSTRACT FROM AUTHOR]

BACKGROUND: Sex hormones are implicated in the development of diabetes. However, whether genetic variations in sex hormone pathways (SHPs) contribute to the risk of type 2 diabetes mellitus (T2DM) remains to be determined. This study investigated associations between genetic variations in all candidate genes in SHPs and T2DM risk among a cohort of women participating in the Womens Health Initiative (WHI). METHODS: Single nucleotide polymorphisms (SNPs) located within 30 kb upstream and downstream of SHP genes were comprehensively examined in 8180 African American, 3498 Hispanic American, and 3147 European American women in the WHI. In addition, whether significant SNPs would be replicated in independent populations was examined. RESULTS: After adjusting for age, region, and ancestry estimates and correcting for multiple testing, seven SNPs were significantly associated with the risk of T2DM among Hispanic American women were identified in the progesterone receptor (PGR) gene, with rs948516 showing the greatest significance (odds ratio 0.67; 95% confidence interval 0.57-0.78; P = 8.8 × 10-7 ; false discovery rate, Q = 7.8 × 10-4 ). These findings were not replicated in other ethnic groups in the WHI or in sex-combined analyses in replication studies. CONCLUSION: Significant signals were identified implicating the PGR gene in T2DM development in Hispanic American women in the WHI, which are consistent with genome-wide association studies findings linking PGR to glucose homeostasis. Nevertheless, the PGR SNPs-T2DM association was not statistically significant in other ethnic populations. Further studies, especially sex-specific analyses, are needed to confirm the findings and clarify the role of SHPs in T2DM.

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P

Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. VIDEO ABSTRACT.

BackgroundThe link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain.Methods and findingsWe conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination.ConclusionsWe present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases.