Phenotypic Landscape of Schizophrenia-Associated Genes Defines Candidates and Their Shared Functions.

Genomic studies have identified hundreds of candidate genes near loci associated with risk for schizophrenia. To define candidates and their functions, we mutated zebrafish orthologs of 132 human schizophrenia-associated genes. We created a phenotype atlas consisting of whole-brain activity maps, brain structural differences, and profiles of behavioral abnormalities. Phenotypes were diverse but specific, including altered forebrain development and decreased prepulse inhibition. Exploration of these datasets identified promising candidates in more than 10 gene-rich regions, including the magnesium transporter cnnm2 and the translational repressor gigyf2, and revealed shared anatomical sites of activity differences, including the pallium, hypothalamus, and tectum. Single-cell RNA sequencing uncovered an essential role for the understudied transcription factor znf536 in the development of forebrain neurons implicated in social behavior and stress. This phenotypic landscape of schizophrenia-associated genes prioritizes more than 30 candidates for further study and provides hypotheses to bridge the divide between genetic association and biological mechanism.

Codon optimality is a major determinant of mRNA stability.

mRNA degradation represents a critical regulated step in gene expression. Although the major pathways in turnover have been identified, accounting for disparate half-lives has been elusive. We show that codon optimality is one feature that contributes greatly to mRNA stability. Genome-wide RNA decay analysis revealed that stable mRNAs are enriched in codons designated optimal, whereas unstable mRNAs contain predominately non-optimal codons. Substitution of optimal codons with synonymous, non-optimal codons results in dramatic mRNA destabilization, whereas the converse substitution significantly increases stability. Further, we demonstrate that codon optimality impacts ribosome translocation, connecting the processes of translation elongation and decay through codon optimality. Finally, we show that optimal codon content accounts for the similar stabilities observed in mRNAs encoding proteins with coordinated physiological function. This work demonstrates that codon optimization exists as a mechanism to finely tune levels of mRNAs and, ultimately, proteins.

Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: Mirikizumab, a p19-directed antibody against interleukin-23, showed efficacy in the treatment of ulcerative colitis in a phase 2 trial. METHODS: We conducted two phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab in adults with moderately to severely active ulcerative colitis. In the induction trial, patients were randomly assigned in a 3:1 ratio to receive mirikizumab (300 mg) or placebo, administered intravenously, every 4 weeks for 12 weeks. In the maintenance trial, patients with a response to mirikizumab induction therapy were randomly assigned in a 2:1 ratio to receive mirikizumab (200 mg) or placebo, administered subcutaneously, every 4 weeks for 40 weeks. The primary end points were clinical remission at week 12 in the induction trial and at week 40 (at 52 weeks overall) in the maintenance trial. Major secondary end points included clinical response, endoscopic remission, and improvement in bowel-movement urgency. Patients who did not have a response in the induction trial were allowed to receive open-label mirikizumab during the first 12 weeks of the maintenance trial as extended induction. Safety was also assessed. RESULTS: A total of 1281 patients underwent randomization in the induction trial, and 544 patients with a response to mirikizumab underwent randomization again in the maintenance trial. Significantly higher percentages of patients in the mirikizumab group than in the placebo group had clinical remission at week 12 of the induction trial (24.2% vs. 13.3%, P<0.001) and at week 40 of the maintenance trial (49.9% vs. 25.1%, P<0.001). The criteria for all the major secondary end points were met in both trials. Adverse events of nasopharyngitis and arthralgia were reported more frequently with mirikizumab than with placebo. Among the 1217 patients treated with mirikizumab during the controlled and uncontrolled periods (including the open-label extension and maintenance periods) in the two trials, 15 had an opportunistic infection (including 6 with herpes zoster infection) and 8 had cancer (including 3 with colorectal cancer). Among the patients who received placebo in the induction trial, 1 had herpes zoster infection and none had cancer. CONCLUSIONS: Mirikizumab was more effective than placebo in inducing and maintaining clinical remission in patients with moderately to severely active ulcerative colitis. Opportunistic infection or cancer occurred in a small number of patients treated with mirikizumab. (Funded by Eli Lilly; LUCENT-1 and LUCENT-2 ClinicalTrials.gov numbers, NCT03518086 and NCT03524092, respectively.).

Proton Pump Inhibitor Use and Iron Deficiency Anemia in Celiac Patients.

INTRODUCTION: We sought to evaluate the effect of proton pump inhibitor (PPI) use on the development and severity of iron deficiency anemia (IDA) in celiac disease (CD). METHODS: We conducted a retrospective chart review of patients older than 18 years of age at Milton S. Hershey Medical Center who were diagnosed with CD. We analyzed four cohorts of celiac patients: (1) IDA diagnosis with PPI usage, (2) no IDA diagnosis with PPI usage, (3) IDA diagnosis with no PPI usage, and (4) no IDA diagnosis with no PPI usage. We also stratified celiac patients with IDA by anemia severity. RESULTS: Of 366 celiac patients, 92 (25.1%) were diagnosed with IDA, of which 60 (65.2%) were on a PPI. The mean Hgb of celiac patients with IDA on a PPI was 11.1 g/dL and 12.1 g/dL for those without PPI (p = 0.04). For all celiac patients on a PPI without IDA, the mean was 13.3 g/dL and 13.7 g/dL for those without PPI (p = 0.02). PPI use occurred in 12 (70.6%) of the 17 patients with low severity anemia, 11 (64.7%) of the 17 patients with medium severity and 6 (85.7%) of the 7 patients with severe (p = 0.55). CONCLUSIONS: There is significant association between PPI use and IDA in celiac patients (p < 0.0001). Of those with IDA on PPIs, the distribution of the severity of anemia is not statistically different compared to those not on PPI. Discontinuation of PPIs or usage of alternative acid suppressive treatments may be indicated in patients with CD and iron deficiency anemia.

Mobile Affinity Selection Chromatography Analysis of Therapeutic Monoclonal Antibodies.

Federal regulatory agencies require continuous verification of recombinant therapeutic monoclonal antibody (mAb) quality that is commonly achieved in a two-step process. First, the host-cell proteome and metabolome are removed from the production medium by protein A affinity chromatography. Second, following recovery from the affinity column with an acidic wash, mAb quality is assessed in multiple ways by liquid chromatography-mass spectrometry (LC-MS). However, lengthy sample preparation and the lack of higher-order structure analyses are limitations of this approach. To address these issues, this report presents an integrated approach for the analysis of two critical quality attributes of mAbs, namely titer and relative aggregate content. Integration of sample preparation and molecular-recognition-based analyses were achieved in a single step utilizing an isocratically eluted mobile affinity selection chromatography (MASC) column. MASC circumvents the protein A step, simplifying sample preparation. Within 10 min, (i) mAbs are fluorescently coded for specific detection, (ii) monomers and aggregates are resolved, (iii) the mAb titer is quantified, (iv) relative aggregate content is determined, (v) analytes are detected, and (vi) the column is ready for the next sample. It is suggested herein that this mode of rapid quality assessment will be of value at all stages of discovery (screening, clone selection, characterization), process R&D, and manufacturing. Rapid monitoring of variant formation is a critical element of quality evaluation.

Estuarine Sediment Microbiomes from a Chronosequence of Restored Urban Salt Marshes.

Salt marshes play an important role in the global nutrient cycle. The sediments in these systems harbor diverse and complex bacterial communities possessing metabolic capacities that provide ecosystem services such as nutrient cycling and removal. On the East Coast of the USA, salt marshes have been experiencing degradation due to anthropogenic stressors. Salt marsh islands within Jamaica Bay, New York City (USA), are surrounded by a large highly urbanized watershed and have declined in area. Restoration efforts have been enacted to reduce further loss, but little is known about how microbial communities develop following restoration activities, or how processes such as nitrogen cycling are impacted. Sediment samples were collected at two sampling depths from five salt marsh islands to characterize the bacterial communities found in marsh sediment including a post-restoration chronosequence of 3-12 years. We used 16s rRNA amplicon sequencing to define alpha and beta diversity, taxonomic composition, and predicted metabolic profile of each sediment sample. We found significant differences in alpha diversity between sampling depths, and significant differences in beta diversity, taxonomic composition, and predicted metabolic capacity among the five sampling locations. The youngest restored site and the degraded natural sampling site exhibited the most distinct communities among the five sites. Our findings suggest that while the salt marsh islands are located in close proximity to each other, they harbor distinct bacterial communities that can be correlated with post-restoration age, marsh health, and other environmental factors such as availability of organic carbon. IMPORTANCE: Salt marshes play a critical role in the global nutrient cycle due to sediment bacteria and their metabolic capacities. Many East Coast salt marshes have experienced significant degradation over recent decades, thought largely to be due to anthropogenic stressors such as nitrogen loading, urban development, and sea-level rise. Salt marsh islands in Jamaica Bay (Queens/Brooklyn NY) are exposed to high water column nitrogen due to wastewater effluent. Several receding marsh islands have been subjected to restoration efforts to mitigate this loss. Little is known about the effect marsh restoration has on bacterial communities, their metabolic capacity, or how they develop post-restoration. Here, we describe the bacterial communities found in marsh islands including a post-restoration chronosequence of 3-12 years and one degraded marsh island that remains unrestored. We found distinct communities at marsh sites, despite their geographic proximity. Differences in diversity and community composition were consistent with changes in organic carbon availability that occur during marsh development, and may result in differences in ecosystem function among sites.

Extreme Heat and Adverse Cardiovascular Outcomes in Australia and New Zealand: What Do We Know?

Extreme heat events are a leading natural hazard risk to human health. Under all future climate change models, extreme heat events will continue to increase in frequency, duration, and intensity. Evidence from previous extreme heat events across the globe demonstrates that adverse cardiovascular events are the leading cause of morbidity and mortality, particularly amongst the elderly and those with pre-existing cardiovascular disease. However, less is understood about the adverse effects of extreme heat amongst specific cardiovascular diseases (i.e., heart failure, dysrhythmias) and demographics (sex, ethnicity, age) within Australia and New Zealand. Furthermore, although Australia has implemented regional and state heat warning systems, most personal heat-health protective advice available in public health policy documents is either insufficient, not grounded in scientific evidence, and/or does not consider clinical factors such as age or co-morbidities. Dissemination of evidence-based recommendations and enhancing community resilience to extreme heat disasters within Australia and New Zealand should be an area of critical focus to reduce the burden and negative health effects associated with extreme heat. This narrative review will focus on five key areas in relation to extreme heat events within Australia and New Zealand: 1) the potential physiological mechanisms that cause adverse cardiovascular outcomes during extreme heat events; 2) how big is the problem within Australia and New Zealand?; 3) what the heat-health response plans are; 4) research knowledge and translation; and, 5) knowledge gaps and areas for future research.

Hot weather and heat extremes: health risks.

Hot ambient conditions and associated heat stress can increase mortality and morbidity, as well as increase adverse pregnancy outcomes and negatively affect mental health. High heat stress can also reduce physical work capacity and motor-cognitive performances, with consequences for productivity, and increase the risk of occupational health problems. Almost half of the global population and more than 1 billion workers are exposed to high heat episodes and about a third of all exposed workers have negative health effects. However, excess deaths and many heat-related health risks are preventable, with appropriate heat action plans involving behavioural strategies and biophysical solutions. Extreme heat events are becoming permanent features of summer seasons worldwide, causing many excess deaths. Heat-related morbidity and mortality are projected to increase further as climate change progresses, with greater risk associated with higher degrees of global warming. Particularly in tropical regions, increased warming might mean that physiological limits related to heat tolerance (survival) will be reached regularly and more often in coming decades. Climate change is interacting with other trends, such as population growth and ageing, urbanisation, and socioeconomic development, that can either exacerbate or ameliorate heat-related hazards. Urban temperatures are further enhanced by anthropogenic heat from vehicular transport and heat waste from buildings. Although there is some evidence of adaptation to increasing temperatures in high-income countries, projections of a hotter future suggest that without investment in research and risk management actions, heat-related morbidity and mortality are likely to increase.

Reducing the health effects of hot weather and heat extremes: from personal cooling strategies to green cities.

Heat extremes (ie, heatwaves) already have a serious impact on human health, with ageing, poverty, and chronic illnesses as aggravating factors. As the global community seeks to contend with even hotter weather in the future as a consequence of global climate change, there is a pressing need to better understand the most effective prevention and response measures that can be implemented, particularly in low-resource settings. In this Series paper, we describe how a future reliance on air conditioning is unsustainable and further marginalises the communities most vulnerable to the heat. We then show that a more holistic understanding of the thermal environment at the landscape and urban, building, and individual scales supports the identification of numerous sustainable opportunities to keep people cooler. We summarise the benefits (eg, effectiveness) and limitations of each identified cooling strategy, and recommend optimal interventions for settings such as aged care homes, slums, workplaces, mass gatherings, refugee camps, and playing sport. The integration of this information into well communicated heat action plans with robust surveillance and monitoring is essential for reducing the adverse health consequences of current and future extreme heat.

Translation elongation and mRNA stability are coupled through the ribosomal A-site.

Messenger RNA (mRNA) degradation plays a critical role in regulating transcript levels in eukaryotic cells. Previous work by us and others has shown that codon identity exerts a powerful influence on mRNA stability. In Saccharomyces cerevisiae, studies using a handful of reporter mRNAs show that optimal codons increase translation elongation rate, which in turn increases mRNA stability. However, a direct relationship between elongation rate and mRNA stability has not been established across the entire yeast transcriptome. In addition, there is evidence from work in higher eukaryotes that amino acid identity influences mRNA stability, raising the question as to whether the impact of translation elongation on mRNA decay is at the level of tRNA decoding, amino acid incorporation, or some combination of each. To address these questions, we performed ribosome profiling of wild-type yeast. In good agreement with other studies, our data showed faster codon-specific elongation over optimal codons and faster transcript-level elongation correlating with transcript optimality. At both the codon-level and transcript-level, faster elongation correlated with increased mRNA stability. These findings were reinforced by showing increased translation efficiency and kinetics for a panel of 11 HIS3 reporter mRNAs of increasing codon optimality. While we did observe that elongation measured by ribosome profiling is composed of both amino acid identity and synonymous codon effects, further analyses of these data establish that A-site tRNA decoding rather than other steps of translation elongation is driving mRNA decay in yeast.

Plasma glycomics predict cardiovascular disease in patients with ART-controlled HIV infections.

Despite effective control of HIV infection with antiretroviral drugs, individuals with HIV have high incidences of secondary diseases. These sequelae, such as cardiovascular disease (CVD), are poorly understood and represent a major health burden. To date, predictive biomarkers of HIV-associated secondary disease have been elusive, making preventative clinical management essentially impossible. Here, we applied a newly developed and easy to deploy, multitarget, and high-throughput glycomic analysis to banked HIV+ human plasma samples to determine whether the glycome may include biomarkers that predict future HIV-associated cardiovascular events or CVD diagnoses. Using 324 patient samples, we identified a glycomic fingerprint that was predictive of future CVD events but independent of CD4 counts, diabetes, age, and birth sex, suggesting that the plasma glycome may serve as a biomarker for specific HIV-associated sequelae. Our findings constitute the discovery of novel glycan biomarkers that could classify patients with HIV with elevated risk for CVD and reveal the untapped prognostic potential of the plasma glycome in human disease.-Oswald, D. M., Sim, E. S., Baker, C., Farhan, O., Debanne, S. M., Morris, N. J., Rodriguez, B. G., Jones, M. B., Cobb, B. A. Plasma glycomics predict cardiovascular disease in patients with ART-controlled HIV infections.

Sustainable solutions to mitigate occupational heat strain - an umbrella review of physiological effects and global health perspectives.

BACKGROUND: Climate change is set to exacerbate occupational heat strain, the combined effect of environmental and internal heat stress on the body, threatening human health and wellbeing. Therefore, identifying effective, affordable, feasible and sustainable solutions to mitigate the negative effects on worker health and productivity, is an increasingly urgent need. OBJECTIVES: To systematically identify and evaluate methods that mitigate occupational heat strain in order to provide scientific-based guidance for practitioners. METHODS: An umbrella review was conducted in biomedical databases employing the following eligibility criteria: 1) ambient temperatures > 28 °C or hypohydrated participants, 2) healthy adults, 3) reported psychophysiological (thermal comfort, heart rate or core temperature) and/or performance (physical or cognitive) outcomes, 4) written in English, and 5) published before November 6, 2019. A second search for original research articles was performed to identify interventions of relevance but lacking systematic reviews. All identified interventions were independently evaluated by all co-authors on four point scales for effectiveness, cost, feasibility and environmental impact. RESULTS: Following screening, 36 systematic reviews fulfilled the inclusion criteria. The most effective solutions at mitigating occupational heat strain were wearing specialized cooling garments, (physiological) heat acclimation, improving aerobic fitness, cold water immersion, and applying ventilation. Although air-conditioning and cooling garments in ideal settings provide best scores for effectiveness, the limited applicability in certain industrial settings, high economic cost and high environmental impact are drawbacks for these solutions. However, (physiological) acclimatization, planned breaks, shading and optimized clothing properties are attractive alternative solutions when economic and ecological sustainability aspects are included in the overall evaluation. DISCUSSION: Choosing the most effective solution or combinations of methods to mitigate occupational heat strain will be scenario-specific. However, this paper provides a framework for integrating effectiveness, cost, feasibility (indoors and outdoor) and ecologic sustainability to provide occupational health and safety professionals with evidence-based guidelines.

Ad libitum water consumption off-sets the thermal and cardiovascular strain exacerbated by dehydration during a 3-h simulated heatwave.

PURPOSE: To assess whether ad libitum water ingestion of different temperatures is sufficient to prevent dehydration-related exacerbations of thermal and cardiovascular strain, during exposure to conditions representative of a heatwave. METHODS: Twelve participants (mean ± SD; 25 ± 4 years) exercised for 180 min at 3 METs in 40.1 ± 0.6 °C, 40.4 ± 2.1%RH four times: (i) consuming 20 °C water ad libitum (AL20); (ii) consuming 4 °C water ad libitum (AL4); (iii) replacing no fluids (NOFR); (iv) replacing sweat losses (FULLFR). Fluid consumption (FC), dehydration (%DEH), rectal temperature (Tre), rate-pressure product (RPP), forearm blood flow (FBF), mean skin temperature (Tsk), and local sweat rate (LSR) were measured/determined. RESULTS: FC was greater in AL20 (1.30 ± 0.41 L) than AL4 (1.03 ± 0.32 L; P = 0.003). %DEH was lower (P < 0.001) in AL20 (0.11 ± 0.76%), AL4 (0.43 ± 0.64%), and FULLFR (0.01 ± 0.12%) compared to NOFR (1.93 ± 0.28%). %DEH was lower in AL20 than AL4 (P = 0.003). In NOFR, end-trial changes in Tre were greater (P < 0.001) (1.05 ± 0.27 °C) compared to all other trials, but similar among AL20 (0.72 ± 0.30 °C), AL4 (0.76 ± 0.25 °C) and FULLFR (0.74 ± 0.35 °C). End-trial RPP was higher (P < 0.001) in NOFR (12,389 ± 1578 mmHg·bpm) compared to all other trials, but similar among FULLFR (11,067 ± 1292 mmHg·bpm), AL20 (11,214 ± 2078 mmHg·bpm) and AL4 (11,089 ± 1795 mmHg·bpm). No differences in Tsk or LSR were observed among trials, but FBF was lower in NOFR compared to FULLFR (2.84 ± 0.69 vs. 3.52 ± 0.96 ml/100 ml/min; P = 0.029). CONCLUSION: 4 °C or 20 °C ad libitum water ingestion prevented dehydration levels that exacerbate thermal/cardiovascular strain, despite blunted fluid intake with 4 °C water. Higher core temperatures with NOFR are attributed to impaired internal heat distribution secondary to a lower FBF.

Widespread epistasis regulates glucose homeostasis and gene expression.

The relative contributions of additive versus non-additive interactions in the regulation of complex traits remains controversial. This may be in part because large-scale epistasis has traditionally been difficult to detect in complex, multi-cellular organisms. We hypothesized that it would be easier to detect interactions using mouse chromosome substitution strains that simultaneously incorporate allelic variation in many genes on a controlled genetic background. Analyzing metabolic traits and gene expression levels in the offspring of a series of crosses between mouse chromosome substitution strains demonstrated that inter-chromosomal epistasis was a dominant feature of these complex traits. Epistasis typically accounted for a larger proportion of the heritable effects than those due solely to additive effects. These epistatic interactions typically resulted in trait values returning to the levels of the parental CSS host strain. Due to the large epistatic effects, analyses that did not account for interactions consistently underestimated the true effect sizes due to allelic variation or failed to detect the loci controlling trait variation. These studies demonstrate that epistatic interactions are a common feature of complex traits and thus identifying these interactions is key to understanding their genetic regulation.

Rare variant association test in family-based sequencing studies.

The objective of this article is to introduce valid and robust methods for the analysis of rare variants for family-based exome chips, whole-exome sequencing or whole-genome sequencing data. Family-based designs provide unique opportunities to detect genetic variants that complement studies of unrelated individuals. Currently, limited methods and software tools have been developed to assist family-based association studies with rare variants, especially for analyzing binary traits. In this article, we address this gap by extending existing burden and kernel-based gene set association tests for population data to related samples, with a particular emphasis on binary phenotypes. The proposed approach blends the strengths of kernel machine methods and generalized estimating equations. Importantly, the efficient generalized kernel score test can be applied as a mega-analysis framework to combine studies with different designs. We illustrate the application of the proposed method using data from an exome sequencing study of autism. Methods discussed in this article are implemented in an R package 'gskat', which is available on CRAN and GitHub.

Temperature of water ingested before exercise alters the onset of physiological heat loss responses.

This study sought to determine whether the temperature of water ingested before exercise alters the onset threshold and subsequent thermosensitivity of local vasomotor and sudomotor responses after exercise begins. Twenty men [24 (SD 4) yr of age, 75.8 (SD 8.1) kg body mass, 52.3 (SD 7.7) ml·min-1·kg-1 peak O2 consumption (V̇o2peak)] ingested 1.5°C, 37°C, or 50°C water (3.2 ml/kg), rested for 5 min, and then cycled at 50% V̇o2peak for 15 min at 23.0 (SD 0.9) °C and 32 (SD 10) % relative humidity. Mean body temperature (Tb), local sweat rate (LSR), and skin blood flow (SBF) were measured. In a subset of eight men [25 (SD 5) yr of age, 78.6 (SD 8.3) kg body mass, 48.9 (SD 11.1) ml·min-1·kg-1 V̇o2peak], blood pressure was measured and cutaneous vascular conductance (CVC) was determined. The change in Tb was greater at the onset of LSR measurement with ingestion of 1.5°C than 50°C water [ΔTb = 0.19 (SD 0.15) vs. 0.11 (SD 0.12) °C, P = 0.04], but not 37°C water [ΔTb = 0.14 (SD 0.14) °C, P = 0.23], but did not differ between trials for SBF measurement [ΔTb = 0.18 (SD 0.15) °C, 0.11 (SD 0.13) °C, and 0.09 (SD 0.09) °C with 1.5°C, 37°C, and 50°C water, respectively, P = 0.07]. Conversely, the thermosensitivity of LSR and SBF was not different [LSR = 1.11 (SD 0.75), 1.11 (SD 0.75), and 1.34 (SD 1.11) mg·min-1·cm-2·°C-1 with 1.5°C, 37°C, and 50°C ingested water, respectively ( P = 0.46); SBF = 717 (SD 882), 517 (SD 606), and 857 (SD 904) %baseline arbitrary units (AU)/°C with 1.5°C, 37°C, and 50°C ingested water, respectively ( P = 0.95)]. After 15 min of exercise, LSR and SBF were greater with ingestion of 50°C than 1.5°C water [LSR = 0.40 (SD 0.17) vs. 0.31 (SD 0.19) mg·min-1·cm-2 ( P = 0.02); SBF = 407 (SD 149) vs. 279 (SD 117) %baseline AU ( P < 0.001)], but not 37°C water [LSR = 0.50 (SD 0.22) mg·min-1·cm-2; SBF = 324 (SD 169) %baseline AU]. CVC was statistically unaffected [275 (SD 81), 340 (SD 114), and 384 (SD 160) %baseline CVC with 1.5°C, 37°C, and 50°C ingested water, respectively, P = 0.30]. Collectively, these results support the concept that visceral thermoreceptors modify the central drive for thermoeffector responses.

Cord Blood Antiparasite Interleukin 10 as a Risk Marker for Compromised Vaccine Immunogenicity in Early Childhood.

Background: Antenatal exposure to parasites can affect infants' subsequent responses to vaccination. The present study investigated how maternal prenatal infections and newborns' antiparasite cytokine profiles relate to immunoglobulin G (IgG) responses to standard vaccination during infancy. Methods: A total of 450 Kenyan women were tested for parasitic infections during pregnancy. Their newborns' responses to Plasmodium falciparum, schistosome, and filaria antigens were assessed in cord blood lymphocytes. Following standard neonatal vaccination, this infant cohort was followed biannually to age 30 months for measurement of circulating IgG levels against Haemophilus influenzae b (Hib), diphtheria toxoid (DT), hepatitis B virus (HBV), and tetanus toxoid. Results: Trajectories of postvaccination IgG levels were classified by functional principal component (PC) analysis to assess each child's response profile. Two main components, PC1, reflecting height of response over time, and PC2, reflecting crossover from high to low responses or from low to high responses, were identified. Cord blood cytokine responses to schistosome and filarial antigens showed a significant association between augmented antihelminth interleukin 10 and reduced antibody levels, particularly to DT and HBV, and a more rapid postvaccination decline in circulating IgG levels against Hib. Conclusion: Antenatal sensitization to schistosomiasis or filariasis and related production of antiparasite interleukin 10 at birth are associated with reduced antivaccine IgG levels in infancy, with possibly impaired protection.

Genome-wide survey in African Americans demonstrates potential epistasis of fitness in the human genome.

The role played by epistasis between alleles at unlinked loci in shaping population fitness has been debated for many years and the existing evidence has been mainly accumulated from model organisms. In model organisms, fitness epistasis can be systematically inferred by detecting nonindependence of genotypic values between loci in a population and confirmed through examining the number of offspring produced in two-locus genotype groups. No systematic study has been conducted to detect epistasis of fitness in humans owing to experimental constraints. In this study, we developed a novel method to detect fitness epistasis by testing the correlation between local ancestries on different chromosomes in an admixed population. We inferred local ancestry across the genome in 16,252 unrelated African Americans and systematically examined the pairwise correlations between the genomic regions on different chromosomes. Our analysis revealed a pair of genomic regions on chromosomes 4 and 6 that show significant local ancestry correlation (P-value = 4.01 × 10-8 ) that can be potentially attributed to fitness epistasis. However, we also observed substantial local ancestry correlation that cannot be explained by systemic ancestry inference bias. To our knowledge, this study is the first to systematically examine evidence of fitness epistasis across the human genome.

Who's the boss: determining the control pathways of cardiovascular and cellular immune responses to acute stress.

Acute stress responses are known to include increases in heart rate and blood pressure, as well as increases in the number of circulating immune cells, all of which are governed by the autonomic nervous system. This laboratory practical measures cardiovascular and circulating immune cell responses to a passive (cold pressor) and active (mental arithmetic) acute stress task in student participants. The results allow them to examine the different patterns of autonomic response they elicit (approximated by heart rate and blood pressure responses), and knowledge of these responses can then be used to infer the governing autonomic aspect of the increases in circulating immune cells from the results. This activity can be either adapted from teacher-led methods to inquiry, asking students to design the details of the acute stress tasks, or developed by asking students to design a follow-up experiment that could be used to provide direct evidence for their conclusions. Data collected provide a platform for teaching data analysis and interpretation, as well as critical thinking.

Heritability and longitudinal outcomes of spelling skills in individuals with histories of early speech and language disorders.

This study examined the spelling skills in middle childhood and adolescence in individuals with histories of early childhood speech sound disorders (SSD) with and without language impairment (LI). Youth without such histories were also included (No SSD/LI group). The heritability of spelling skills at each age level was estimated. Children with SSD were classified as SSD-only, SSD with LI but without childhood apraxia of speech (SSD + LI/ No CAS), and CAS and LI (CAS + LI). The SSD-only group did not differ in spelling from the No SSD/LI group, suggesting that SSD-only did not increase risk for poor spelling. The SSD + LI/No CAS and CAS + LI groups had poorer spelling skills than the SSD-only and No SSD/LI groups. Spelling was associated with phonological awareness in the middle childhood and adolescent samples and with rapid automatized naming in the adolescent sample. Heritability of spelling skills was stronger in adolescence than in middle childhood. Differences in the correlates of spelling and in heritability at the two ages suggest developmental changes in the factors contributing to spelling.