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Plant-pathogenic Xanthomonas bacteria inject transcription activator-like effector proteins (TALEs) into host cells to specifically induce transcription of plant genes and enhance susceptibility. Although the DNA-binding mode is well-understood it is still ambiguous how TALEs initiate transcription and whether additional promoter elements are needed to support this. To systematically dissect prerequisites for transcriptional initiation the activity of one TALE was compared on different synthetic Bs4 promoter fragments. In addition, a large collection of artificial TALEs spanning the OsSWEET14 promoter was compared. We show that the presence of a TALE alone is not sufficient to initiate transcription suggesting the requirement of additional supporting promoter elements. At the OsSWEET14 promoter TALEs can initiate transcription from various positions, in a synergistic manner of multiple TALEs binding in parallel to the promoter, and even by binding in reverse orientation. TALEs are known to shift the transcriptional start site, but our data show that this shift depends on the individual position of a TALE within a promoter context. Our results implicate that TALEs function like classical enhancer-binding proteins and initiate transcription in both orientations which has consequences for in planta target gene prediction and design of artificial activators.

[This corrects the article DOI: 10.1371/journal.pone.0173580.].

mTORC1 is a central regulator of cell growth that is directly activated by the small GTPase Rheb on the lysosomal membrane in response to growth factors. We recently reported that polyubiquitinated Rheb facilitates its interaction with mTORC1, leading to mTORC1 activation. However, the molecular mechanisms underlying the ubiquitination of Rheb and its interaction with mTORC1 for activation are not fully understood. In this study, we demonstrate that HUWE1, an E3 ubiquitin ligase, preferentially interacts with ubiquitinated Rheb and is essential for the interaction between Rheb and mTOR, as well as for mTORC1 activation. Additionally, HUWE1 is necessary for Rheb to interact with CAD, a crucial enzyme involved in de novo pyrimidine biosynthesis, and for its activation through the mTORC1-S6K1 pathway. Knocking down HUWE1 in cultured cells or in the liver tissues of mice inhibits mTORC1 activity without affecting the phosphorylation of Akt or TSC2, nor does it affect the lysosomal localization of TSC2 or mTORC1. Furthermore, HUWE1 specifically enhances the expression of CAD without influencing other enzymes involved in de novo pyrimidine synthesis and maintains UMP levels in the hepatocytes of liver tissues. These findings indicate that HUWE1 serves as a key organizer of the Rheb ubiquitin complex, amplifying mTORC1 activity and playing a vital role in stimulating de novo pyrimidine synthesis by enhancing CAD expression and activity. HUWE1 and CAD preferentially interact with ubiquitinated Rheb. HUWE1 further ubiquitinates Rheb and supports Rheb interaction with mTORC1 and CAD. HUWE1 stimulates mTORC1 activity through its E3 ligase activity. HUWE1 also supports pyrimidine synthesis by enhancing CAD expression.

Determine if cocaine use impacts gut permeability, promotes microbial translocation and immune activation in people living with HIV (PLWH) using effective antiretroviral therapy (ART). Cross-sectional analysis of 100 PLWH (ART ≥6 months, HIV-RNA <200 copies/mL) from the Miami Adult Studies on HIV (MASH) cohort. Cocaine use was assessed by self-report, urine screen, and blood benzoylecgonine (BE). Blood samples were collected to assess gut permeability (intestinal fatty acid-binding protein, I-FABP), microbial translocation (lipopolysaccharide, LPS), immune activation (sCD14, sCD27, and sCD163) and markers of inflammation (hs-CRP, TNF-α and IL-6). Multiple linear regression models were used to analyze the relationships of cocaine use. A total of 37 cocaine users and 63 cocaine non-users were evaluated. Cocaine users had higher levels of I-FABP (7.92±0.35 vs. 7.69±0.56 pg/mL, P = 0.029) and LPS (0.76±0.24 vs. 0.54±0.27 EU/mL, P<0.001) than cocaine non-users. Cocaine use was also associated with the levels of LPS (P<0.001), I-FABP (P = 0.033), and sCD163 (P = 0.010) after adjusting for covariates. Cocaine users had 5.15 times higher odds to exhibit higher LPS levels than non-users (OR: 5.15 95% CI: 1.89-13.9; P<0.001). Blood levels of BE were directly correlated with LPS (rho = 0.276, P = 0.028), sCD14 (rho = 0.274, P = 0.031), and sCD163 (rho = 0.250, P = 0.049). Cocaine use was associated with markers of gut permeability, microbial translocation, and immune activation in virally suppressed PLWH. Mitigation of cocaine use may prevent further gastrointestinal damage and immune activation in PLWH.

Sexual and reproductive health (SRH) care often excludes the needs and experiences of transgender, non-binary, and gender-expansive (TGE) individuals. This study aimed to collect diverse stakeholder perspectives on barriers and facilitators to contraception and abortion for TGE individuals assigned female at birth (AFAB), assess knowledge and attitudes about unintended pregnancy prevention in these populations, and identify recommendations for improving SRH services for people of all genders. Between October 2017 and January 2018, we conducted 27 in-depth interviews with SRH stakeholders, including five TGE individuals who had obtained contraception or abortion care, and 22 clinicians, researchers, and advocates experienced in transgender healthcare. We iteratively developed a codebook and conducted thematic analysis to capture the spectrum of perspectives across interviews. Stakeholders reported a range of barriers to contraception and abortion access for TGE people AFAB, including inability to afford services, lack of gender-affirming clinicians, difficulty obtaining insurance coverage, and misconceptions about fertility and unplanned pregnancy risk. Deterrents to care-seeking included gendered healthcare environments, misgendering, and discrimination. Stakeholders described provider knowledge gaps and a perceived lack of medical education relevant to the SRH needs of TGE people. Recommendations included using gender-inclusive language and gender-affirming patient education materials and improving provider training on gender-affirming SRH care. Stakeholders identified substantial barriers to high-quality contraception and abortion care for TGE AFAB people in the U.S. They recommended specific interventions at the provider and institutional levels to improve experiences with care for TGE people and ensure broader access to gender-affirming SRH services.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA‐Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega‐analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between‐country transfer of subject‐level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega‐analyses. This report summarizes the background information and rationale for the various methodological decisions made by the ENIGMA—GAD group. The aim of this work is to help guide other research groups working with large brain imaging data sets.

Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60–0·87 for MACE; 0·79, 0·64–0·98 for the heart failure composite endpoint; 0·76, 0·59–0·97 for cardiovascular death; and 0·81, 0·66–1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49–0·87 for MACE; 0·79, 0·58–1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51–0·91 for MACE; 0·75, 0·52–1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. Novo Nordisk.

Background Accurately measuring stigmatized experiences is a challenge across reproductive health research. In this study, we tested a novel method – the list experiment – that aims to reduce underreporting of sensitive events by asking participants to report how many of a list of experiences they have had, not which ones. We applied the list experiment to measure “self-managed abortion” - any attempt by a person to end a pregnancy on one’s own, outside of a clinical setting – a phenomenon that may be underreported in surveys due to a desire to avoid judgement. Methods We administered a double list experiment on self-managed abortion to a Texas-wide representative sample of 790 women of reproductive age in 2015. Participants were asked how many of a list of health experiences they had experienced; self-managed abortion was randomly added as an item to half of the lists. A difference in the average number of items reported by participants between lists with and without self-managed abortion provided a population level estimate of self-managed abortion. In 2017, we conducted cognitive interviews with women of reproductive age in four states to understand how women (1) interpreted the list experiment question format, and (2) interpreted the list item on prior experiences attempting to self-manage an abortion. Results Results from this list experiment estimated that 8% of women of reproductive age in Texas have ever self-managed an abortion. This number was higher than expected, thus, the researchers conducted cognitive interviews to better understand how people interpreted the list experiment on self-managed abortion. Some women interpreted “on your own” to mean “without the knowledge of friends or family”, as opposed to “without medical assistance”, as intended. Conclusion The list experiment may have reduced under-reporting of self-managed abortion; however, the specific phrasing of the list item may also have unintentionally increased reporting of abortion experiences not considered “self-managed.” High participation in and comprehension of the list experiment, however, suggests that this method is worthy of further exploration as tool for measuring stigmatized experiences.

Determine if cocaine use impacts gut permeability, promotes microbial translocation and immune activation in people living with HIV (PLWH) using effective antiretroviral therapy (ART). Cross-sectional analysis of 100 PLWH (ART [greater than or equal to]6 months, HIV-RNA <200 copies/mL) from the Miami Adult Studies on HIV (MASH) cohort. Cocaine use was assessed by self-report, urine screen, and blood benzoylecgonine (BE). Blood samples were collected to assess gut permeability (intestinal fatty acid-binding protein, I-FABP), microbial translocation (lipopolysaccharide, LPS), immune activation (sCD14, sCD27, and sCD163) and markers of inflammation (hs-CRP, TNF-[alpha] and IL-6). Multiple linear regression models were used to analyze the relationships of cocaine use. A total of 37 cocaine users and 63 cocaine non-users were evaluated. Cocaine users had higher levels of I-FABP (7.92±0.35 vs. 7.69±0.56 pg/mL, P = 0.029) and LPS (0.76±0.24 vs. 0.54±0.27 EU/mL, P<0.001) than cocaine non-users. Cocaine use was also associated with the levels of LPS (P<0.001), I-FABP (P = 0.033), and sCD163 (P = 0.010) after adjusting for covariates. Cocaine users had 5.15 times higher odds to exhibit higher LPS levels than non-users (OR: 5.15 95% CI: 1.89-13.9; P<0.001). Blood levels of BE were directly correlated with LPS (rho = 0.276, P = 0.028), sCD14 (rho = 0.274, P = 0.031), and sCD163 (rho = 0.250, P = 0.049). Cocaine use was associated with markers of gut permeability, microbial translocation, and immune activation in virally suppressed PLWH. Mitigation of cocaine use may prevent further gastrointestinal damage and immune activation in PLWH.