Understanding the yeast host cell response to recombinant membrane protein production

Membrane proteins are drug targets for a wide range of diseases. Having access to appropriate samples for further research underpins the pharmaceutical industry's strategy for developing new drugs. This is typically achieved by synthesizing a protein of interest in host cells that can be cultured on a large scale, allowing the isolation of the pure protein in quantities much higher than those found in the protein's native source. Yeast is a popular host as it is a eukaryote with similar synthetic machinery to that of the native human source cells of many proteins of interest, while also being quick, easy and cheap to grow and process. Even in these cells, the production of human membrane proteins can be plagued by low functional yields; we wish to understand why. We have identified molecular mechanisms and culture parameters underpinning high yields and have consolidated our findings to engineer improved yeast host strains. By relieving the bottlenecks to recombinant membrane protein production in yeast, we aim to contribute to the drug discovery pipeline, while providing insight into translational processes

Asteroseismology with the Roman Galactic Bulge Time-Domain Survey

Asteroseismology has transformed stellar astrophysics. Red giant asteroseismology is a prime example, with oscillation periods and amplitudes that are readily detectable with time-domain space-based telescopes. These oscillations can be used to infer masses, ages and radii for large numbers of stars, providing unique constraints on stellar populations in our galaxy. The cadence, duration, and spatial resolution of the Roman galactic bulge time-domain survey (GBTDS) are well-suited for asteroseismology and will probe an important population not studied by prior missions. We identify photometric precision as a key requirement for realizing the potential of asteroseismology with Roman. A precision of 1 mmag per 15-min cadence or better for saturated stars will enable detections of the populous red clump star population in the Galactic bulge. If the survey efficiency is better than expected, we argue for repeat observations of the same fields to improve photometric precision, or covering additional fields to expand the stellar population reach if the photometric precision for saturated stars is better than 1 mmag. Asteroseismology is relatively insensitive to the timing of the observations during the mission, and the prime red clump targets can be observed in a single 70 day campaign in any given field. Complementary stellar characterization, particularly astrometry tied to the Gaia system, will also dramatically expand the diagnostic power of asteroseismology. We also highlight synergies to Roman GBTDS exoplanet science using transits and microlensing.Comment: Roman Core Community Survey White Paper, 3 pages, 4 figure

Asteroseismology with the Roman Galactic Bulge Time-Domain Survey

Asteroseismology has transformed stellar astrophysics. Red giant asteroseismology is a prime example, with oscillation periods and amplitudes that are readily detectable with time-domain space-based telescopes. These oscillations can be used to infer masses, ages and radii for large numbers of stars, providing unique constraints on stellar populations in our galaxy. The cadence, duration, and spatial resolution of the Roman galactic bulge time-domain survey (GBTDS) are well-suited for asteroseismology and will probe an important population not studied by prior missions. We identify photometric precision as a key requirement for realizing the potential of asteroseismology with Roman. A precision of 1 mmag per 15-min cadence or better for saturated stars will enable detections of the populous red clump star population in the Galactic bulge. If the survey efficiency is better than expected, we argue for repeat observations of the same fields to improve photometric precision, or covering additional fields to expand the stellar population reach if the photometric precision for saturated stars is better than 1 mmag. Asteroseismology is relatively insensitive to the timing of the observations during the mission, and the prime red clump targets can be observed in a single 70 day campaign in any given field. Complementary stellar characterization, particularly astrometry tied to the Gaia system, will also dramatically expand the diagnostic power of asteroseismology. We also highlight synergies to Roman GBTDS exoplanet science using transits and microlensing

Validity of Resting Energy Expenditure Predictive Equations before and after an Energy-Restricted Diet Intervention in Obese Women

Background We investigated the validity of REE predictive equations before and after 12-week energy-restricted diet intervention in Spanish obese (30 kg/m2>BMI<40 kg/m2) women. Methods We measured REE (indirect calorimetry), body weight, height, and fat mass (FM) and fat free mass (FFM, dual X-ray absorptiometry) in 86 obese Caucasian premenopausal women aged 36.7±7.2 y, before and after (n = 78 women) the intervention. We investigated the accuracy of ten REE predictive equations using weight, height, age, FFM and FM. Results At baseline, the most accurate equation was the Mifflin et al. (Am J Clin Nutr 1990; 51: 241–247) when using weight (bias:−0.2%, P = 0.982), 74% of accurate predictions. This level of accuracy was not reached after the diet intervention (24% accurate prediction). After the intervention, the lowest bias was found with the Owen et al. (Am J Clin Nutr 1986; 44: 1–19) equation when using weight (bias:−1.7%, P = 0.044), 81% accurate prediction, yet it provided 53% accurate predictions at baseline. Conclusions There is a wide variation in the accuracy of REE predictive equations before and after weight loss in non-morbid obese women. The results acquire especial relevance in the context of the challenging weight regain phenomenon for the overweight/obese population.The present study was supported by the University of the Basque Country (UPV 05/80), Social Foundation of the Caja Vital- Kutxa and by the Department of Health of the Government of the Basque Country (2008/111062), and by the Spanish Ministry of Science and Innovation (RYC-2010-05957)

Community Violence Exposure and Conduct Problems in Children and Adolescents with Conduct Disorder and Healthy Controls

Exposure to community violence through witnessing or being directly victimized has been associated with conduct problems in a range of studies. However, the relationship between community violence exposure (CVE) and conduct problems has never been studied separately in healthy individuals and individuals with conduct disorder (CD). Therefore, it is not clear whether the association between CVE and conduct problems is due to confounding factors, because those with high conduct problems also tend to live in more violent neighborhoods, i.e., an ecological fallacy. Hence, the aim of the present study was: (1) to investigate whether the association between recent CVE and current conduct problems holds true for healthy controls as well as adolescents with a diagnosis of CD; (2) to examine whether the association is stable in both groups when including effects of aggression subtypes (proactive/reactive aggression), age, gender, site and socioeconomic status (SES); and (3) to test whether proactive or reactive aggression mediate the link between CVE and conduct problems. Data from 1178 children and adolescents (62% female; 44% CD) aged between 9 years and 18 years from seven European countries were analyzed. Conduct problems were assessed using the Kiddie-Schedule of Affective Disorders and Schizophrenia diagnostic interview. Information about CVE and aggression subtypes was obtained using self-report questionnaires (Social and Health Assessment and Reactive-Proactive aggression Questionnaire (RPQ), respectively). The association between witnessing community violence and conduct problems was significant in both groups (adolescents with CD and healthy controls). The association was also stable after examining the mediating effects of aggression subtypes while including moderating effects of age, gender and SES and controlling for effects of site in both groups. There were no clear differences between the groups in the strength of the association between witnessing violence and conduct problems. However, we found evidence for a ceiling effect, i.e., individuals with very high levels of conduct problems could not show a further increase if exposed to CVE and vice versa. Results indicate that there was no evidence for an ecological fallacy being the primary cause of the association, i.e., CVE must be considered a valid risk factor in the etiology of CD

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Erratum to 'Predominance of healthcare-associated cases among episodes of community-onset bacteraemia due to extended-spectrum β-lactamase-producing Enterobacteriaceae' [International Journal of Antimicrobial Agents 49/1 67-73]

International audienc