Genotyping, sequencing and analysis of 140,000 adults from Mexico City.

The Mexico City Prospective Study is a prospective cohort of more than 150,000 adults recruited two decades ago from the urban districts of Coyoacán and Iztapalapa in Mexico City1. Here we generated genotype and exome-sequencing data for all individuals and whole-genome sequencing data for 9,950 selected individuals. We describe high levels of relatedness and substantial heterogeneity in ancestry composition across individuals. Most sequenced individuals had admixed Indigenous American, European and African ancestry, with extensive admixture from Indigenous populations in central, southern and southeastern Mexico. Indigenous Mexican segments of the genome had lower levels of coding variation but an excess of homozygous loss-of-function variants compared with segments of African and European origin. We estimated ancestry-specific allele frequencies at 142 million genomic variants, with an effective sample size of 91,856 for Indigenous Mexican ancestry at exome variants, all available through a public browser. Using whole-genome sequencing, we developed an imputation reference panel that outperforms existing panels at common variants in individuals with high proportions of central, southern and southeastern Indigenous Mexican ancestry. Our work illustrates the value of genetic studies in diverse populations and provides foundational imputation and allele frequency resources for future genetic studies in Mexico and in the United States, where the Hispanic/Latino population is predominantly of Mexican descent.

Proton export upregulates aerobic glycolysis.

INTRODUCTION: Aggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or the "Warburg Effect." It is widely assumed that this is a consequence of the upregulation of glycolytic enzymes. Oncogenic drivers can increase the expression of most proteins in the glycolytic pathway, including the terminal step of exporting H+ equivalents from the cytoplasm. Proton exporters maintain an alkaline cytoplasmic pH, which can enhance all glycolytic enzyme activities, even in the absence of oncogene-related expression changes. Based on this observation, we hypothesized that increased uptake and fermentative metabolism of glucose could be driven by the expulsion of H+ equivalents from the cell. RESULTS: To test this hypothesis, we stably transfected lowly glycolytic MCF-7, U2-OS, and glycolytic HEK293 cells to express proton-exporting systems: either PMA1 (plasma membrane ATPase 1, a yeast H+-ATPase) or CA-IX (carbonic anhydrase 9). The expression of either exporter in vitro enhanced aerobic glycolysis as measured by glucose consumption, lactate production, and extracellular acidification rate. This resulted in an increased intracellular pH, and metabolomic analyses indicated that this was associated with an increased flux of all glycolytic enzymes upstream of pyruvate kinase. These cells also demonstrated increased migratory and invasive phenotypes in vitro, and these were recapitulated in vivo by more aggressive behavior, whereby the acid-producing cells formed higher-grade tumors with higher rates of metastases. Neutralizing tumor acidity with oral buffers reduced the metastatic burden. CONCLUSIONS: Therefore, cancer cells which increase export of H+ equivalents subsequently increase intracellular alkalization, even without oncogenic driver mutations, and this is sufficient to alter cancer metabolism towards an upregulation of aerobic glycolysis, a Warburg phenotype. Overall, we have shown that the traditional understanding of cancer cells favoring glycolysis and the subsequent extracellular acidification is not always linear. Cells which can, independent of metabolism, acidify through proton exporter activity can sufficiently drive their metabolism towards glycolysis providing an important fitness advantage for survival.

Blood Pressure and Spot Sign in Spontaneous Supratentorial Subcortical Intracerebral Hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage is a potentially devastating cause of brain injury, often occurring secondary to hypertension. Contrast extravasation on computed tomography angiography (CTA), known as the spot sign, has been shown to predict hematoma expansion and worse outcomes. Although hypertension has been associated with an increased rate of the spot sign being present, the relationship between spot sign and blood pressure has not been fully explored. METHODS: We retrospectively analyzed data from 134 patients (40 women and 94 men, mean age 62.3 ± 15.73 years) presenting to a tertiary academic medical center with spontaneous supratentorial subcortical intracerebral hemorrhage from 1/1/2018 to 1/4/2021. RESULTS: A spot sign was demonstrated in images of 18 patients (13.43%) and correlated with a higher intracerebral hemorrhage score (2.61 ± 1.42 vs. 1.31 ± 1.25, p = 0.002), larger hematoma volume (53.49cm3 ± 32.08 vs. 23.45cm3 ± 25.65, p = 0.001), lower Glasgow Coma Scale on arrival (9.06 ± 4.56 vs. 11.74 ± 3.65, p = 0.027), increased risk of hematoma expansion (16.67% vs. 5.26%, p = 0.042), and need for surgical intervention (66.67% vs. 15.52%, p < 0.001). We did not see a correlation with age, sex, or underlying comorbidities. The presence of spot sign correlated with higher modified Rankin scores at discharge (4.94 ± 1.00 vs. 3.92 ± 1.64, p < 0.001). We saw significantly higher systolic blood pressure at the time of CTA in patients with a spot sign (184 mm Hg ± 43.11 vs. 153 mm Hg ± 36.99, p = 0.009) and the highest recorded blood pressure (p = 0.019), although not blood pressure on arrival (p = 0.081). Performing CTA early in the process of blood pressure lowering was associated with a spot sign (p < 0.001). CONCLUSIONS: The presence of spot sign correlates with larger hematomas, worse outcomes, and increased surgical intervention. There is a significant association between spot sign and systolic blood pressure at the time of CTA, with the highest systolic blood pressure being recorded prior to CTA. Although the role of intensive blood pressure management in spontaneous intracerebral hemorrhage remains a subject of debate, patients with a spot sign may be a subgroup that could benefit from this.

Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease.

BACKGROUND: Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease. METHODS: We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. We performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from four population studies. We also tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol. RESULTS: In the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. Loss-of-function variants were found in 0.33% of case patients with coronary artery disease and in 0.45% of controls (adjusted odds ratio, 0.59; 95% confidence interval, 0.41 to 0.85; P=0.004). These results were confirmed in the follow-up studies. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%. CONCLUSIONS: Genetic and therapeutic antagonism of ANGPTL3 in humans and of Angptl3 in mice was associated with decreased levels of all three major lipid fractions and decreased odds of atherosclerotic cardiovascular disease. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT01749878 .).

Correction to: Ant-mediated ecosystem processes are driven by trophic community structure but mainly by the environment.

Unfortunately, the given and family names of author "Mickal Houadria" was incorrectly published in the original.

"Housing Insecurity Seems to Almost Go Hand in Hand with Being Trans": Housing Stress among Transgender and Gender Non-conforming Individuals in New Orleans.

Housing is an important social determinant of physical and mental health. Transgender and gender non-conforming individuals (T/GNCI) face a unique constellation of discrimination and compromised social services, putting them at risk for housing insecurity, homelessness, and its associated public health concerns. This study explores housing insecurity among T/GNCI in New Orleans, LA, where the infrastructural landscape is marked by an underinvestment in housing stock and disaster capitalism. In-depth interviews were conducted with T/GNCI (n = 17) living in New Orleans, identified through purposive sampling. Semi-structured guides were used to elicit personal stories and peer accounts of insecure housing experiences and coping strategies. Interviews were audio recorded and transcribed. Data was coded, sorted, and analyzed for key themes using NVIVO 11. Respondents discussed an array of circumstances that contribute to housing insecurity, including intersectional stigma and discrimination coupled with gentrification and a changing housing landscape in the city. Housing was intricately intertwined with employment and other structural issues; vulnerability in one realm was closely tied to insecurity in the others. Social support and queer family structures emerged as a key source of resilience, coping, and survival. The study supports an increase of resources for T/GNC housing access and interventions that address the cyclical discrimination, housing, and employment issues this population faces with a consideration of the historical and current structural barriers impeding their access to safe, stable, long-term housing.

Ant-mediated ecosystem processes are driven by trophic community structure but mainly by the environment.

The diversity and functional identity of organisms are known to be relevant to the maintenance of ecosystem processes but can be variable in different environments. Particularly, it is uncertain whether ecosystem processes are driven by complementary effects or by dominant groups of species. We investigated how community structure (i.e., the diversity and relative abundance of biological entities) explains the community-level contribution of Neotropical ant communities to different ecosystem processes in different environments. Ants were attracted with food resources representing six ant-mediated ecosystem processes in four environments: ground and vegetation strata in cropland and forest habitats. The exploitation frequencies of the baits were used to calculate the taxonomic and trophic structures of ant communities and their contribution to ecosystem processes considered individually or in combination (i.e., multifunctionality). We then investigated whether community structure variables could predict ecosystem processes and whether such relationships were affected by the environment. We found that forests presented a greater biodiversity and trophic complementarity and lower dominance than croplands, but this did not affect ecosystem processes. In contrast, trophic complementarity was greater on the ground than on vegetation and was followed by greater resource exploitation levels. Although ant participation in ecosystem processes can be predicted by means of trophic-based indices, we found that variations in community structure and performance in ecosystem processes were best explained by environment. We conclude that determining the extent to which the dominance and complementarity of communities affect ecosystem processes in different environments requires a better understanding of resource availability to different species.

The relation between circadian asynchrony, functional redundancy, and trophic performance in tropical ant communities.

The diversity-stability relationship has been under intense scrutiny for the past decades, and temporal asynchrony is recognized as an important aspect of ecosystem stability. In contrast to relatively well-studied interannual and seasonal asynchrony, few studies investigate the role of circadian cycles for ecosystem stability. Here, we studied multifunctional redundancy of diurnal and nocturnal ant communities in four tropical rain forest sites. We analyzed how it was influenced by species richness, functional performance, and circadian asynchrony. In two neotropical sites, species richness and functional redundancy were lower at night. In contrast, these parameters did not differ in the two paleotropical sites we studied. Circadian asynchrony between species was pronounced in the neotropical sites, and increased circadian functional redundancy. In general, species richness positively affected functional redundancy, but the effect size depended on the temporal and spatial breadth of the species with highest functional performance. Our analysis shows that high levels of trophic performance were only reached through the presence of such high-performing species, but not by even contributions of multiple, less-efficient species. Thus, these species can increase current functional performance, but reduce overall functional redundancy. Our study highlights that diurnal and nocturnal ecosystem properties of the very same habitat can markedly differ in terms of species richness and functional redundancy. Consequently, like the need to study multiple ecosystem functions, multiple periods of the circadian cycle need to be assessed in order to fully understand the diversity-stability relationship in an ecosystem.

Temperature-Controlled Switchable Photochromism in Solid Materials.

A novel strategy to achieve thermally switchable photochromism in solid materials is reported, which relies on the preparation of polymeric core-shell capsules containing solutions of photochromic dyes in acidic phase-change materials. Upon changing the phase (solid or liquid) of the encapsulated medium, one of the two photochromic states of the system is selectively stabilized on demand, allowing for reversible interconversion between direct and reverse photochromism when thermally scanning through the melting temperature of the phase-change material. This strategy, which does not require the addition of external agents or chemical modification of the dyes, proved to be general for different spiropyran photochromes and to be applicable to the fabrication of a variety of functional materials by simply embedding the capsules obtained into a solid matrix of choice.

Nanoparticles use magnetoelectricity to target and eradicate cancer cells.

This study presents the first in vivo and in vitro evidence of an externally controlled, predictive, MRI-based nanotheranostic agent capable of cancer cell specific targeting and killing via irreversible electroporation (IRE) in solid tumors. The rectangular-prism-shaped magnetoelectric nanoparticle is a smart nanoparticle that produces a local electric field in response to an externally applied magnetic field. When externally activated, MENPs are preferentially attracted to the highly conductive cancer cell membranes, which occurs in cancer cells because of dysregulated ion flux across their membranes. In a pancreatic adenocarcinoma murine model, MENPs activated by external magnetic fields during magnetic resonance imaging (MRI) resulted in a mean three-fold tumor volume reduction (62.3% vs 188.7%; P < .001) from a single treatment. In a longitudinal confirmatory study, 35% of mice treated with activated MENPs achieved a durable complete response for 14 weeks after one treatment. The degree of tumor volume reduction correlated with a decrease in MRI T 2 * relaxation time ( r = .351; P = .039) which suggests that MENPs have a potential to serve as a predictive nanotheranostic agent at time of treatment. There were no discernable toxicities associated with MENPs at any timepoint or on histopathological analysis of major organs. MENPs are a noninvasive alternative modality for the treatment of cancer. Summary: We investigated the theranostic capabilities of magnetoelectric nanoparticles (MENPs) combined with MRI via a murine model of pancreatic adenocarcinoma. MENPs leverage the magnetoelectric effect to convert an applied magnetic field into local electric fields, which can induce irreversible electroporation of tumor cell membranes when activated by MRI. Additionally, MENPs modulate MRI relaxivity, which can be used to predict the degree of tumor ablation. Through a pilot study (n=21) and a confirmatory study (n=27), we demonstrated that, ≥300 µg of MRI-activated MENPs significantly reduced tumor volumes, averaging a three-fold decrease as compared to controls. Furthermore, there was a direct correlation between the reduction in tumor T 2 relaxation times and tumor volume reduction, highlighting the predictive prognostic value of MENPs. Six of 17 mice in the confirmatory study's experimental arms achieved a durable complete response, showcasing the potential for durable treatment outcomes. Importantly, the administration of MENPs was not associated with any evident toxicities. This study presents the first in vivo evidence of an externally controlled, MRI-based, theranostic agent that effectively targets and treats solid tumors via irreversible electroporation while sparing normal tissues, offering a new and promising approach to cancer therapy.

Effects of changing reference values on the interpretation of spirometry for rubber workers.

Introduction: The National Health and Nutrition Assessment Survey (NHANES) is being adopted for interpreting spirometry in occupational examinations. Rubber workers have an elevated risk of respiratory health issues due to industrial exposure, and changes in the equations would affect spirometry monitoring programs. Objective: To determine the differences in the use of the Knudson and NHANES III equations in nonsmoking workers in the rubber industry. Method: A cross-sectional study was conducted with 75 nonsmoking workers with occupational exposure to rubber for at least two years. The factory had engineered protection controls and provided respiratory protection to the workers. Spirometry was conducted according to Spirometry Testing in Occupational Health Programs and Standardization of Spirometry: American Thoracic Society/European Respiratory Society. Result: Spirometric prediction differences were present in the restrictive pattern assessment based on forced vital capacity (FVC), in which three individuals (4%) classified as normal according to Knudson presented restrictive disease according to NHANES III; only in the record of one participant was there restrictive disease using both equations. There was an 8% discrepancy for small airway obstruction in which six workers classified as normal using NHANES III were classified as diseased (FEF 25-75 <50%) using the Knudson equation. Conclusion: In the respiratory examination of workers exposed to rubber, the NHANES III equation is better able to detect restrictive diseases than is the Knudson equation; however, the Knudson equation is more sensitive to obstructive patterns.

An Analysis of Nectin-4 (PVRL4) in Penile Squamous Cell Carcinoma.

Penile squamous cell carcinoma (PSCC) remains a worldwide healthcare concern with poor outcomes and inadequate therapeutic options. Molecular characterization continues to describe the intricacies of PSCC biology, which vary by human papillomavirus (HPV) infection. Despite these advancements in our understanding, utilization of targeted therapies remains limited and underexplored. In this study, we evaluated the transcript and protein expression of Nectin-4 (PVRL4) in PSCC tumors and evaluated whether this is related to tumor features or clinical outcomes. Using two separate PSCC cohorts, we demonstrate that the majority of tumors have active transcription of Nectin-4. We then validated our findings using immunohistochemistry in a tissue microarray representing 57 patients with PSCC. We identified that Nectin-4 was expressed at higher levels in patients with high-risk HPV infection. No significant differences were identified in tumor characteristics or various clinical endpoints when comparing tumors with high and low Nectin-4 expression. This study demonstrates that Nectin-4 is expressed in PSCC and may represent a novel therapeutic target. Patient summary: In this study, we evaluated the expression of Nectin-4, a cell surface protein, in tumors from patients with nonmetastatic penile squamous cell carcinoma (PSCC). To our knowledge, this is the first study to describe elevated expression of Nectin-4 in PSCC, which may suggest its utility as a therapeutic target.

Classifying Malignancy in Prostate Glandular Structures from Biopsy Scans with Deep Learning.

Histopathological classification in prostate cancer remains a challenge with high dependence on the expert practitioner. We develop a deep learning (DL) model to identify the most prominent Gleason pattern in a highly curated data cohort and validate it on an independent dataset. The histology images are partitioned in tiles (14,509) and are curated by an expert to identify individual glandular structures with assigned primary Gleason pattern grades. We use transfer learning and fine-tuning approaches to compare several deep neural network architectures that are trained on a corpus of camera images (ImageNet) and tuned with histology examples to be context appropriate for histopathological discrimination with small samples. In our study, the best DL network is able to discriminate cancer grade (GS3/4) from benign with an accuracy of 91%, F1-score of 0.91 and AUC 0.96 in a baseline test (52 patients), while the cancer grade discrimination of the GS3 from GS4 had an accuracy of 68% and AUC of 0.71 (40 patients).

Cannabis-assisted psychotherapy for complex dissociative posttraumatic stress disorder: A case report.

Background: A dissociative subtype of posttraumatic stress disorder, known as "D-PTSD", has been included in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. In addition to meeting criteria for PTSD, patients endorse prominent dissociative symptoms, namely depersonalization and derealization, or detachment from one's self and surroundings. At present, this population is supported by a highly heterogeneous and undeveloped literature. Targeted interventions are therefore lacking, and those indicated for PTSD are limited by poor efficacy, delayed onset of action, and low patient engagement. Here, we introduce cannabis-assisted psychotherapy (CAP) as a novel treatment for D-PTSD, drawing parallels to psychedelic therapy. Case presentation: A 28-year-old female presented with complex D-PTSD. In a naturalistic setting, she underwent 10 sessions of CAP, scheduled twice monthly over 5 months, coupled with integrative cognitive behavioral therapy. An autonomic and relational approach to CAP was leveraged, specifically psychedelic somatic interactional psychotherapy. Acute effects included oceanic boundlessness, ego dissolution, and emotional breakthrough. From baseline to post-treatment, the patient showed a 98.5% reduction in pathological dissociation, as measured by the Multidimensional Inventory of Dissociation, no longer meeting criteria for D-PTSD. This was accompanied by decreased cognitive distractibility and emotional suffering, as well as increased psychosocial functioning. Anecdotally, the patient has sustained improvements for over 2 years to date. Conclusions: There is urgency to identify treatments for D-PTSD. The present case, while inherently limited, underscores the potential of CAP as a therapeutic option, leading to robust and sustained improvement. Subjective effects were comparable to those produced by classic and non-classic psychedelics, such as psilocybin and ketamine. Further research is warranted to explore, establish, and optimize CAP in D-PTSD, and to characterize its role in the pharmacological landscape.

An Assessment of the Penile Squamous Cell Carcinoma Surfaceome for Biomarker and Therapeutic Target Discovery.

Penile squamous cell carcinoma (PSCC) is a rare malignancy in most parts of the world and the underlying mechanisms of this disease have not been fully investigated. About 30-50% of cases are associated with high-risk human papillomavirus (HPV) infection, which may have prognostic value. When PSCC becomes resistant to upfront therapies there are limited options, thus further research is needed in this venue. The extracellular domain-facing protein profile on the cell surface (i.e., the surfaceome) is a key area for biomarker and drug target discovery. This research employs computational methods combined with cell line translatomic (n = 5) and RNA-seq transcriptomic data from patient-derived tumors (n = 18) to characterize the PSCC surfaceome, evaluate the composition dependency on HPV infection, and explore the prognostic impact of identified surfaceome candidates. Immunohistochemistry (IHC) was used to validate the localization of select surfaceome markers. This analysis characterized a diverse surfaceome within patient tumors with 25% and 18% of the surfaceome represented by the functional classes of receptors and transporters, respectively. Significant differences in protein classes were noted by HPV status, with the most change being seen in transporter proteins (25%). IHC confirmed the robust surface expression of select surfaceome targets in the top 85% of expression and a superfamily immunoglobulin protein called BSG/CD147 was prognostic of survival. This study provides the first description of the PSCC surfaceome and its relation to HPV infection and sets a foundation for novel biomarker and drug target discovery in this rare cancer.

T2 Protect AD: Achieving a rapid recruitment timeline in a multisite clinical trial for individuals with mild to moderate Alzheimer's disease.

Introduction: The reporting of approaches facilitating the most efficient and timely recruitment of Alzheimer's disease (AD) patients into pharmacologic trials is fundamental to much-needed therapeutic progress. Methods: T2 Protect AD (T2), a phase 2 randomized placebo-controlled trial of troriluzole in mild to moderate AD, used multiple recruitment strategies. Results: T2 exceeded its recruitment target, enrolling 350 participants between July 2018 and December 2019 (randomization rate: 0.87 randomizations/site/month, or 3-fold greater than recent trials of mild to moderate AD). The vast majority (98%) of participants were enrolled during a 10-month window of intense promotion in news media, TV and radio advertisements, and social media. The distribution of primary recruitment sources included: existing patient lists at participating sites (72.3%), news media (12.3%), physician referral (6.0%), word of mouth (3.1%), and paid advertising (2.9%). Discussion: The rapid recruitment of participants with mild to moderate AD was achieved through a range of approaches with varying success.

Cultivating cultural capitals in introductory algebra-based physics through reflective journaling.

At a large, diverse, hispanic-serving, master's-granting university, the Alma Project was created to support the rich connections of life experiences of science, technology, engineering, and mathematics (STEM) students that come from racially diverse backgrounds through reflective journaling. Utilizing frameworks in ethnic studies and social psychology, the Alma Project aims to make learning STEM inclusive by affirming the intersectional identities and cultural wealth that students bring into STEM classrooms. Approximately once per month students who participate in the Alma Project spend 5-10 min at the beginning of class responding to questions designed to affirm their values and purpose for studying STEM in college. Students then spend time in class sharing their responses with their peers, to the extent that they feel comfortable, including common struggles and successes in navigating through college and STEM spaces. For this study, we analyze 180 reflective journaling essays of students enrolled in General Physics I, an algebra-based introductory physics course primarily for life science majors. Students were enrolled in a required lab, a self-selected community-based learning program (Supplemental Instruction), or in a small number of instances, both. Using the community cultural wealth framework to anchor our analysis, we identified 11 cultural capitals that students often expressed within these physics spaces. Students in both populations frequently expressed aspirational, attainment, and navigational capital, while expressions of other cultural capitals, such as social capital, differ in the two populations. Our findings suggest that students bring rich and diverse perspectives into physics classrooms when asked to reflect about their lived experiences. Moreover, our study provides evidence that reflective journaling can be used as an asset-based teaching tool. By using reflective journaling in physics spaces, recognizing students' assets has the potential for physics educators to leverage students' lived experiences, goals, and values to make physics learning more meaningful and engaging.

Temporal regulation of Cat-1 (cationic amino acid transporter-1) gene transcription during endoplasmic reticulum stress.

Expression of the Cat-1 gene (cationic amino acid transporter-1) is induced in proliferating cells and in response to a variety of stress conditions. The expression of the gene is mediated via a TATA-less promoter. In the present study we show that an Sp1 (specificity protein 1)-binding site within a GC-rich region of the Cat-1 gene controls its basal expression and is important for induction of the gene during the UPR (unfolded protein response). We have shown previously that induction of Cat-1 gene expression during the UPR requires phosphorylation of the translation initiation factor eIF2alpha (eukaryotic initiation factor 2alpha) by PERK (protein-kinase-receptor-like endoplasmic reticulum kinase), one of the signalling pathways activated during the UPR. This leads to increased translation of the transcription factor ATF4 (activating transcription factor 4). We also show that a second signalling pathway is required for sustained transcriptional induction of the Cat-1 gene during the UPR, namely activation of IRE1 (inositol-requiring enzyme 1) leading to alternative splicing of the mRNA for the transcription factor XBP1 (X-box-binding protein 1). The resulting XBP1s (spliced XBP1) can bind to an ERSE (endoplasmic-reticulum-stress-response-element), ERSE-II-like, that was identified within the Cat-1 promoter. Surprisingly, eIF2alpha phosphorylation is required for accumulation of XBP1s. We propose that the signalling via phosphorylated eIF2alpha is required for maximum induction of Cat-1 transcription during the UPR by inducing the accumulation of both ATF4 and XBP1s.

Advancing human genetics research and drug discovery through exome sequencing of the UK Biobank.

The UK Biobank Exome Sequencing Consortium (UKB-ESC) is a private-public partnership between the UK Biobank (UKB) and eight biopharmaceutical companies that will complete the sequencing of exomes for all ~500,000 UKB participants. Here, we describe the early results from ~200,000 UKB participants and the features of this project that enabled its success. The biopharmaceutical industry has increasingly used human genetics to improve success in drug discovery. Recognizing the need for large-scale human genetics data, as well as the unique value of the data access and contribution terms of the UKB, the UKB-ESC was formed. As a result, exome data from 200,643 UKB enrollees are now available. These data include ~10 million exonic variants-a rich resource of rare coding variation that is particularly valuable for drug discovery. The UKB-ESC precompetitive collaboration has further strengthened academic and industry ties and has provided teams with an opportunity to interact with and learn from the wider research community.