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Environmental mercury (Hg) contamination of the global tropics outpaces our understanding of its consequences for biodiversity. Knowledge gaps of pollution exposure could obscure conservation threats in the Neotropics: a region that supports over half of the worlds species, but faces ongoing land-use change and Hg emission via artisanal and small-scale gold mining (ASGM). Due to their global distribution and sensitivity to pollution, birds provide a valuable opportunity as bioindicators to assess how accelerating Hg emissions impact an ecosystems ability to support biodiversity, and ultimately, global health. We present the largest database on Neotropical bird Hg concentrations (n = 2316) and establish exposure baselines for 322 bird species spanning nine countries across Central America, South America, and the West Indies. Patterns of avian Hg exposure in the Neotropics broadly align with those in temperate regions: consistent bioaccumulation across functional groups and high spatiotemporal variation. Bird species occupying higher trophic positions and aquatic habitats exhibited elevated Hg concentrations that have been previously associated with reductions in reproductive success. Notably, bird Hg concentrations were over four times higher at sites impacted by ASGM activities and differed by season for certain trophic niches. We developed this synthesis via a collaborative research network, the Tropical Research for Avian Conservation and Ecotoxicology (TRACE) Initiative, which exemplifies inclusive, equitable, and international data-sharing. While our findings signal an urgent need to assess sampling biases, mechanisms, and consequences of Hg exposure to tropical avian communities, the TRACE Initiative provides a meaningful framework to achieve such goals. Ultimately, our collective efforts support and inform local, scientific, and government entities, including Parties of the United Nations Minamata Convention on Mercury, as we continue working together to understand how Hg pollution impacts biodiversity conservation, ecosystem function, and public health in the tropics.

Biallelic hypomorphic variants in PRORP have been recently described as causing the autosomal recessive disorder combined oxidative phosphorylation deficiency type 54 (COXPD54). COXPD54 encompasses a phenotypic spectrum of sensorineural hearing loss and ovarian insufficiency (Perrault syndrome) to leukodystrophy. Here, we report three additional families with homozygous missense PRORP variants with pleiotropic phenotypes. Each missense variant altered a highly conserved residue within the metallonuclease domain. In vitro mitochondrial tRNA processing assays with recombinant TRMT10C, SDR5C1 and PRORP indicated two COXPD54-associated PRORP variants, c.1159A>G (p.Thr387Ala) and c.1241C>T (p.Ala414Val), decreased pre-tRNAIle cleavage, consistent with both variants impacting tRNA processing. No significant decrease in tRNA processing was observed with PRORP c.1093T>C (p.Tyr365His), which was identified in an individual with leukodystrophy. These data provide independent evidence that PRORP variants are associated with COXPD54 and that the assessment of 5 leader mitochondrial tRNA processing is a valuable assay for the functional analysis and clinical interpretation of novel PRORP variants.

The COVID-19 pandemic produced a dramatic nationwide shift in K-12 education from in-person classroom learning to remote online learning. This shift left teachers and parents facing the challenge of finding engaging online resources to motivate students to become deeply involved in science learning. The pandemic also left educators and researchers, whose work focuses on providing students with experiential learning opportunities in the sciences, with the challenge of adapting to virtual and remote models to continue engaging students in STEM learning activities. In this article we describe: 1) the Health Quest project, which centers on the development of technology-rich learning resources to promote middle grade students' interest in health science careers, with a focus on girls and underrepresented racial and ethnic minorities; and 2) how the project has responded to the challenges presented by the COVID-19 pandemic. In Health Quest, through engaging narrative-based learning scenarios, students work with virtual characters to experience health science careers from multiple perspectives. Although originally envisioned for in-person classroom learning, we discuss how the team is adapting the Health Quest Career Adventure Game to remote learning, including highlighting the role science plays in addressing public health outbreaks. We describe new gameplay features that have been added to support career modeling and how we have adapted the core technology underpinning Health Quest to support broad dissemination to meet the project's broader goal of increasing adolescents' interest in and self-efficacy for pursuing health science careers. We conclude with a discussion of how our evaluation strategies have changed from in-person focus groups and testing to an online data collection model and lessons learned.

DNA methylation occurs predominantly on cytosine-phosphate-guanine (CpG) dinucleotides in the mammalian genome, and the methylation landscape is maintained over mitotic cell division. It has been posited that coupling of maintenance methylation activity among neighbouring CpGs is critical to stability over cellular generations; however, the mechanism is unclear. We used mathematical models and stochastic simulation to analyse data from experiments that probe genome-wide methylation of nascent DNA post-replication in cells. We find that DNA methylation maintenance rates on individual CpGs are locally correlated, and the degree of this correlation varies by genomic regional context. By using theory of protein diffusion along DNA, we show that exponential decay of methylation rate correlation with genomic distance is consistent with enzyme processivity. Our results provide quantitative evidence of genome-wide methyltransferase processivity in vivo. We further developed a method to disentangle different mechanistic sources of kinetic correlations. From the experimental data, we estimate that an individual methyltransferase methylates neighbour CpGs processively if they are 36 basepairs apart, on average. But other mechanisms of coupling dominate for longer inter-CpG distances. Our study demonstrates that quantitative insights into enzymatic mechanisms can be obtained from replication-associated, cell-based genome-wide measurements, by combining data-driven statistical analyses with hypothesis-driven mathematical modelling.

The activation of T cells, key players of the immune system, involves local evacuation of phosphatase CD45 from a region of the T cell's surface, segregating it from the T cell receptor. What drives this evacuation? In the presence of antigen, what ensures evacuation happens in the subsecond timescales necessary to initiate signaling? In the absence of antigen, what mechanisms ensure that evacuation does not happen spontaneously, which could cause signaling errors? Phenomena known to influence spatial organization of CD45 or similar surface molecules include diffusive motion in the lipid bilayer, oligomerization reactions, and mechanical compression against a nearby surface, such as that of the cell presenting the antigen. Computer simulations can investigate hypothesized spatiotemporal mechanisms of T cell signaling. The challenge to computational studies of evacuation is that the base process, spontaneous evacuation by simple diffusion, is in the extreme rare event limit, meaning direct stochastic simulation is unfeasible. Here, we combine particle-based spatial stochastic simulation with the weighted ensemble method for rare events to compute the mean first passage time for cell surface availability by surface reorganization of CD45. We confirm mathematical estimates that, at physiological concentrations, spontaneous evacuation is extremely rare, roughly 300 years. We find that dimerization decreases the time required for evacuation. A weak bimolecular interaction (dissociation constant estimate 460 μM) is sufficient for an order of magnitude reduction of spontaneous evacuation times, and oligomerization to hexamers reduces times to below 1 s. This introduces a mechanism whereby externally induced CD45 oligomerization could significantly modify T cell function. For large regions of close contact, such as those induced by large microvilli, molecular size and compressibility imply a nonzero reentry probability of 60%, decreasing evacuation times. Simulations show that these reduced evacuation times are still unrealistically long (even with a fourfold variation centered around previous estimates of parameters), suggesting that a yet-to-be-described mechanism, besides compressional exclusion at a close contact, drives evacuation.

Writing a college-application essay has become a rite of passage for high-school seniors in the United States, one whose importance has expanded over time due to an increasingly competitive admissions process. Various commentators have noted the disturbing evolution of these essays over the years, with an ever-greater emphasis placed on obstacles overcome and traumas survived. How have we gotten to the point where college-application essays are all too frequently competitive-victimhood displays? Colleges have an understandable interest in the disadvantages their applicants may have suffered, but this interest -- and the awareness of it among both applicants and their advisors -- has led to a 'race to the bottom': in order to thrive (or even survive) in a particular competitive context, participants are forced to continuously lower relevant standards in a game of one-upmanship. With college essays, the competition is among high-school seniors for admission, the one-upmanship is an ever-escalating effort to persuade admission committees of one's greater disadvantage, and the relevant standards being lowered are "honesty," "privacy," and "dignity" -- or so I shall argue. As we will see, this particular race to the bottom imposes unequal costs on certain groups and has implications stretching well beyond collegiate admissions.

There is growing diversity within the Black population in the U.S., but limited understanding of ethnic and nativity differences in the mental health treatment needs of Black women. This study examined differences in the prevalence of psychiatric disorders, their persistence, and unmet treatment needs among Black women in the U.S. Data were from the National Survey of American Life, a nationally representative survey that assessed lifetime and twelve-month mood, anxiety, and substance use disorders according to the Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV) criteria, and mental health service use among those meeting disorder criteria. One in three African American women met criteria for a lifetime disorder, compared to one in three Caribbean women born within the U.S. and one in five Caribbean women born outside the U.S. About half of African American women with a lifetime disorder had a persistent psychiatric disorder, compared to two in five Caribbean women born within the U.S. and two in three Caribbean women born outside the U.S. African Americans had more persisting dysthymia and panic disorder and less persisting social phobia compared to foreign-born Caribbean women. Of the three groups, Caribbean women born within the U.S. were most likely to seek mental health treatment during their lifetime. These results demonstrate, despite a lower prevalence of psychiatric disorders in Black women, that there is a great likelihood their disorders will be marked by persistence and underscores the need for culturally specific treatment approaches. As Black immigrants in the United States are increasing in number, adequate mental health services are needed.

Genome-wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (eg, ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWAS of DSM-IV AD (primary analysis), DSM-IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7418 (1121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans-ancestral meta-analyses combined these results with data from 3175 (585 families) African-American (AA) individuals from COGA. In the EA GWAS, three loci were genome-wide significant: rs1229984 in ADH1B for AD criterion count (P = 4.16E-11) and Desire to cut drinking (P = 1.21E-11); rs188227250 (chromosome 8, Drinking more than intended, P = 6.72E-09); rs1912461 (chromosome 15, Time spent drinking, P = 1.77E-08). In the trans-ancestral meta-analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome-wide significant: rs61826952 (chromosome 1, DSM-IV AD, P = 8.42E-11); rs7597960 (chromosome 2, Time spent drinking, P = 1.22E-08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (P

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P

In the original version of this Article, the genotype of the M30 mutant presented in Fig. 3b was given incorrectly as Y288V/A232S, and the M31 mutant was given incorrectly as M1/A232S. The correct genotype of the M30 mutant is Y288A/A232S and for M31 it is Y288V/A232S. In addition, to keep consistency in genotype formatting, the genotype of the M27 mutant should be Y288V/G286S. The errors have been corrected in both the PDF and HTML versions of the Article.

Prenylation of natural compounds adds structural diversity, alters biological activity, and enhances therapeutic potential. Because prenylated compounds often have a low natural abundance, alternative production methods are needed. Metabolic engineering enables natural product biosynthesis from inexpensive biomass, but is limited by the complexity of secondary metabolite pathways, intermediate and product toxicities, and substrate accessibility. Alternatively, enzyme catalyzed prenyl transfer provides excellent regio- and stereo-specificity, but requires expensive isoprenyl pyrophosphate substrates. Here we develop a flexible cell-free enzymatic prenylating system that generates isoprenyl pyrophosphate substrates from glucose to prenylate an array of natural products. The system provides an efficient route to cannabinoid precursors cannabigerolic acid (CBGA) and cannabigerovarinic acid (CBGVA) at >1 g/L, and a single enzymatic step converts the precursors into cannabidiolic acid (CBDA) and cannabidivarinic acid (CBDVA). Cell-free methods may provide a powerful alternative to metabolic engineering for chemicals that are hard to produce in living organisms.