Synthesis and Assay of Vibrio Quorum Sensing Inhibitors.

Bacteria detect local population numbers using quorum sensing, a method of cell-cell communication broadly utilized to control bacterial behaviors. In Vibrio species, the master quorum sensing regulators LuxR/HapR control hundreds of quorum sensing genes, many of which influence virulence, metabolism, motility, and more. Thiophenesulfonamides are potent inhibitors of LuxR/HapR that bind the ligand pocket in these transcription factors and block downstream quorum sensing gene expression. This class of compounds served as the basis for the development of a set of simple, robust, and educational procedures for college students to assimilate their chemistry and biology skills using a CURE model: course-based undergraduate research experience. Optimized protocols are described that comprise three learning stages in an iterative and multi-disciplinary platform to engage students in a year-long CURE: (1) design and synthesize new small molecule inhibitors based on the thiophenesulfonamide core, (2) use structural modeling to predict binding affinity to the target, and (3) assay the compounds for efficacy in microbiological assays against specific Vibrio LuxR/HapR proteins. The described reporter assay performed in E. coli successfully predicts the efficacy of the compounds against target proteins in the native Vibrio species.

Cardiac Disease Related to Primary Hyperthyroidism in a 20-Year-Old Mule.

Primary hyperthyroidism is a rarely diagnosed endocrinopathy in equids and there have been no previous reports of structural and functional cardiac changes associated with hyperthyroidism in these species. This case report investigates a 20-year-old mule gelding that presented for a three-month history of thin body condition despite polyphagia, with a heart murmur and elevated free and total thyroid hormone concentrations. On presentation, physical exam revealed a body condition score of two out of nine, persistent tachycardia, pansystolic heart murmur and firm bilateral ventral proximal cervical masses. Bloodwork confirmed markedly elevated free T4, total T4 and T3 concentrations. Echocardiogram demonstrated left ventricular concentric hypertrophy with increased ventricular and atrial systolic function. Bilateral thyroidectomy was performed under standing sedation without complications. Histopathology demonstrated adenocarcinoma of the left thyroid gland and multiple adenomas with osseous metaplasia within the right thyroid. The mule was supplemented with levothyroxine sodium two weeks post-op after a thyroid panel demonstrated undetectable concentrations. Polyphagia resolved following surgery and the mule began gaining weight. Echocardiographic changes improved but did not resolve at two years post-operative. Continued bi-annual follow up and monitoring of thyroid levels was recommended. This case represents the first documentation of hemodynamically relevant cardiac remodeling in an equid associated with primary hyperthyroidism.

The Targeted Motor Control Screening Tool is Valid for Four-Year-Old Children.

OBJECTIVE: The objective was to determine the validity of the Targeted Motor Control (TMC) screening tool with the Neurosensory Motor Developmental Assessment (NSMDA) in 4-year-old children. METHODS: In this single cohort observational study, children (3 years 9 months to 4 years 5 months) completed the TMC and the NSMDA in a randomized order 5 to 14 days apart. RESULTS: Seventy-six children (mean age = 4 years 2 months; SD = 2.5 months; n = 35 male) completed both assessments. Forty-two children performed within the normal range on the NSMDA. There were significant and positive moderate correlations between item totals overall and for each area on the NSMDA and the TMC (r = 0.40 to 0.61) and between the NSMDA functional grade for each area and the corresponding TMC areas (r = 0.47 to 0.67). However, the correlation between the NSMDA sensorimotor functional grade and the TMC sensory score was significant but low and positive (r = 0.35). The optimal cut-off score for detecting children at risk of atypical development on the TMC was a score of <9 (n = 42) (sensitivity = 82.4%; specificity = 66.7%) with a positive likelihood ratio of 2.47 (95% CI = 1.57 to 3.89) and a negative likelihood ratio of 0.26 (95% CI = 0.12 to 0.56). CONCLUSIONS: The TMC is a valid screening tool to identify 4-year-old children at risk of motor delay. IMPACT: Early identification of developmental concerns using a validated screening tool is recommended. The TMC is a valid performance-based screening tool that can be used to identify children at risk of atypical motor development who would benefit from further developmental assessment so that, if indicated, timely intervention can be implemented.

"Something we can all share": Exploring the social significance of food insecurity for young people in KwaZulu-Natal, South Africa.

Food insecurity remains a pressing global issue and South Africa continues to face socioeconomic inequalities that make securing food a challenge for many young people. To address this challenge, we need better understanding of the social context of food and its importance in driving perceptions and behaviours about food and its scarcity. In this study, we examine the meaning of food for young people living in urban informal settlements and rural villages in KwaZulu-Natal, and investigate how they exert agency in the face of food insecurity. We use qualitative data from 17 photo/video elicitation interviews conducted from December 2020-January 2021 with young people experiencing food insecurity. The sample consisted of 9 women and 8 men who were part of the Siyaphambili Youth ("Youth Moving Forward") project. Data were analysed using thematic analysis. Themes included the challenges young people face in securing food and money for food. However, in exploring young people's agency, food also plays a critical role in shaping their identities and social networks. Relevant themes included the use of food as a means of bonding with others; solidifying relationships; and as a signifier of social status and gender roles. Despite the challenges of food insecurity, young people demonstrated resilience and agency, utilising social and gendered coping strategies to secure food and to maintain their social networks. Our study contributes to the understanding of food insecurity amongst young people in South Africa and highlights the need for a comprehensive and culturally sensitive approach to addressing this issue. We argue that interventions aimed at addressing food insecurity should prioritise the empowerment of local communities and consider the sociocultural and gendered context of food in their design and implementation.

Steric Control of Luminescence in Phenyl-Substituted Trityl Radicals.

Triphenylmethyl (trityl) radicals have shown potential for use in organic optoelectronic applications, but the design of practical trityl structures has been limited to donor/radical charge-transfer systems due to the poor luminescence of alternant symmetry hydrocarbons. Here, we circumvent the symmetry-forbidden transition of alternant hydrocarbons via excited-state symmetry breaking in a series of phenyl-substituted tris(2,4,6-trichlorophenyl)methyl (TTM) radicals. We show that 3-fold phenyl substitution enhances the emission of the TTM radical and that steric control modulates the optical properties in these systems. Simple ortho-methylphenyl substitution boosts the photoluminescence quantum efficiency from 1% (for TTM) to 65% at a peak wavelength of 612 nm (for 2-T3TTM) in solution. In the crystalline solid state, the neat 2-T3TTM radical shows a remarkably high photoluminescence quantum efficiency of 25% for emission peaking at 706 nm. This has implications in the design of aryl-substituted radical structures where the electronic coupling of the substituents influences variables such as emission, charge transfer, and spin interaction.

Voices of the unhoused from Santa Fe, New Mexico: A mixed methods study of health status, substance use, and community harm reduction program perspectives.

No published studies have examined the community service priorities and harm reduction perspectives of unhoused people in Santa Fe, New Mexico. We conducted a mixed methods pilot study of 56 unhoused people at community locations in Santa Fe to: (1) assess the current prevalence of chronic medical conditions and substance use; (2) highlight community service priorities; and (3) explore views of innovative community harm reduction programs. Our first hypothesis was there would be high prevalence of chronic medical conditions, for which we found high prevalence of post-traumatic stress disorder, major depression, substance use disorders, chronic pain, and hypertension. Our second hypothesis was that we would find top community service priorities of housing, food, and health care. We found long- and short-term housing and food, but not healthcare, top priorities. Our third hypothesis was that we would find mixed support for community harm reduction initiatives like managed alcohol programs and overdose prevention centers. We found positive, not mixed, support for these community harm reduction programs among Santa Fe's unhoused. Unhoused study participants ranged in age 27-77 years, with lifetime years unhoused from less than one year to 63 years. Study limitations included small sample size, convenience sampling, and descriptive results. Policies and program initiatives supporting additional Housing First options, managed alcohol programs, and overdose prevention centers in the Santa Fe community are clearly indicated to increase engagement with this vulnerable population. Future research should focus on inclusion of the perspectives of the unhoused in the design, conduct, evaluation, and dissemination of community programs to meet the needs of the unhoused, with re-defined outcomes to include changes in quality of life, program engagement, demarginalization, and future goals and plans, beyond currently utilized health and social service program outcome measures.

Mitochondrial respiration is lower in the intrauterine growth-restricted fetal sheep heart.

Fetuses affected by intrauterine growth restriction have an increased risk of developing heart disease and failure in adulthood. Compared with controls, late gestation intrauterine growth-restricted (IUGR) fetal sheep have fewer binucleated cardiomyocytes, reflecting a more immature heart, which may reduce mitochondrial capacity to oxidize substrates. We hypothesized that the late gestation IUGR fetal heart has a lower capacity for mitochondrial oxidative phosphorylation. Left (LV) and right (RV) ventricles from IUGR and control (CON) fetal sheep at 90% gestation were harvested. Mitochondrial respiration (states 1-3, LeakOmy, and maximal respiration) in response to carbohydrates and lipids, citrate synthase (CS) activity, protein expression levels of mitochondrial oxidative phosphorylation complexes (CI-CV), and mRNA expression levels of mitochondrial biosynthesis regulators were measured. The carbohydrate and lipid state 3 respiration rates were lower in IUGR than CON, and CS activity was lower in IUGR LV than CON LV. However, relative CII and CV protein levels were higher in IUGR than CON; CV expression level was higher in IUGR than CON. Genes involved in lipid metabolism had lower expression in IUGR than CON. In addition, the LV and RV demonstrated distinct differences in oxygen flux and gene expression levels, which were independent from CON and IUGR status. Low mitochondrial respiration and CS activity in the IUGR heart compared with CON are consistent with delayed cardiomyocyte maturation, and CII and CV protein expression levels may be upregulated to support ATP production. These insights will provide a better understanding of fetal heart development in an adverse in utero environment. KEY POINTS: Growth-restricted fetuses have a higher risk of developing and dying from cardiovascular diseases in adulthood. Mitochondria are the main supplier of energy for the heart. As the heart matures, the substrate preference of the mitochondria switches from carbohydrates to lipids. We used a sheep model of intrauterine growth restriction to study the capacity of the mitochondria in the heart to produce energy using either carbohydrate or lipid substrates by measuring how much oxygen was consumed. Our data show that the mitochondria respiration levels in the growth-restricted fetal heart were lower than in the normally growing fetuses, and the expression levels of genes involved in lipid metabolism were also lower. Differences between the right and left ventricles that are independent of the fetal growth restriction condition were identified. These results indicate an impaired metabolic maturation of the growth-restricted fetal heart associated with a decreased capacity to oxidize lipids postnatally.

IGF-1 infusion increases growth in fetal sheep when euinsulinemia is maintained.

Insulin-like growth factor 1 (IGF-1) is a critical fetal anabolic hormone. IGF-1 infusion to the normally growing sheep fetus increases the weight of some organs but does not consistently increase body weight. However, IGF-1 infusion profoundly decreases fetal plasma insulin concentrations, which may limit fetal growth potential. In this study, normally growing late-gestation fetal sheep received an intravenous infusion of either: IGF-1 (IGF), IGF-1 with insulin and dextrose to maintain fetal euinsulinemia and euglycemia (IGF+INS), or vehicle control (CON) for 1 week. The fetus underwent a metabolic study immediately prior to infusion start and after 1 week of the infusion to measure uterine and umbilical uptake rates of nutrients and oxygen. IGF+INS fetuses were 23% heavier than CON (P = 0.0081) and had heavier heart, liver, and adrenal glands than IGF and CON (P < 0.01). By design, final fetal insulin concentrations in IGF were 62% and 65% lower than IGF+INS and CON, respectively. Final glucose concentrations were similar in all groups. IGF+INS had lower final oxygen content than IGF and CON (P < 0.0001) and lower final amino acid concentrations than CON (P = 0.0002). Final umbilical oxygen uptake was higher in IGF+INS compared to IGF and CON (P < 0.05). Final umbilical uptake of several essential amino acids was higher in IGF+INS compared to CON (P < 0.05). In summary, maintaining euinsulinemia and euglycemia during fetal IGF-1 infusion is necessary to maximally support body growth. We speculate that IGF-1 and insulin stimulate placental nutrient transport to support fetal growth.

Refreshing, necessary exposure to the problem with exposure therapies for trauma: Commentary on Rubenstein et al. (2024).

In this invited commentary, I address what I see as the major contributions Rubenstein et al. (2024) have made to challenging the hegemony of exposure therapies for trauma-exposed persons. These include a thorough review of the history of the rise of exposure therapies, the identification of posttrauma responses as forms of anxiety disorders, and an extensive discussion of the neurobiology of the trauma response. Additionally, Rubenstein et al. expose the very high dropout rates in studies of exposure therapies and ways in which many traumatized people have not found them helpful. This article brings the so-called "gold standard" back to its rightful position as one possible, occasionally helpful way of assisting some, but not all, traumatized people. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Stable and robust Xi and Y transcriptomes drive cell-type-specific autosomal and Xa responses in vivo and in vitro in four human cell types.

Recent in vitro studies of human sex chromosome aneuploidy showed that the Xi ("inactive" X) and Y chromosomes broadly modulate autosomal and Xa ("active" X) gene expression in two cell types. We tested these findings in vivo in two additional cell types. Using linear modeling in CD4+ T cells and monocytes from individuals with one to three X chromosomes and zero to two Y chromosomes, we identified 82 sex-chromosomal and 344 autosomal genes whose expression changed significantly with Xi and/or Y dosage in vivo . Changes in sex-chromosomal expression were remarkably constant in vivo and in vitro across all four cell types examined. In contrast, autosomal responses to Xi and/or Y dosage were largely cell-type-specific, with up to 2.6-fold more variation than sex-chromosomal responses. Targets of the X- and Y-encoded transcription factors ZFX and ZFY accounted for a significant fraction of these autosomal responses both in vivo and in vitro . We conclude that the human Xi and Y transcriptomes are surprisingly robust and stable across the four cell types examined, yet they modulate autosomal and Xa genes - and cell function - in a cell-type-specific fashion. These emerging principles offer a foundation for exploring the wide-ranging regulatory roles of the sex chromosomes across the human body.

Absence of Metformin in Fetal Circulation Following Maternal Administration in Late Gestation Pregnant Sheep.

In human pregnancy, metformin administered to the mother crosses the placenta resulting in metformin exposure to the fetus. However, the effects of metformin exposure on the fetus are poorly understood and difficult to study in humans. Pregnant sheep are a powerful large animal model for studying fetal physiology. The objective of this study was to determine if maternally administered metformin at human dose-equivalent concentrations crosses the ovine placenta and equilibrates in the fetal circulation. To test this, metformin was administered to the pregnant ewe via continuous intravenous infusion or supplementation in the drinking water. Both administration routes increased maternal metformin concentrations to human dose-equivalent concentrations of ~ 10 µM, yet metformin was negligible in the fetus even after 3-4 days of maternal administration. In cotyledon and caruncle tissue, expression levels of the major metformin uptake transporter organic cation transporter 1 (OCT1) were < 1% of expression levels in the fetal liver, a tissue with abundant expression. Expression of other putative uptake transporters OCT2 and OCT3, and efflux transporters multidrug and toxin extrusion (MATE)1 and MATE2were more abundant. These results demonstrate that the ovine placenta is impermeable to maternal metformin administration. This is likely due to anatomical differences and increased interhaemal distance between the maternal and umbilical circulations in the ovine versus human placenta limiting placental metformin transport.

Increased hepatic glucose production with lower oxidative metabolism in the growth-restricted fetus.

Fetal growth restriction (FGR) is accompanied by early activation of hepatic glucose production (HGP), a hallmark of type 2 diabetes (T2D). Here, we used fetal hepatic catheterization to directly measure HGP and substrate flux in a sheep FGR model. We hypothesized that FGR fetuses would have increased hepatic lactate and amino acid uptake to support increased HGP. Indeed, FGR fetuses compared with normal (CON) fetuses had increased HGP and activation of gluconeogenic genes. Unexpectedly, hepatic pyruvate output was increased, while hepatic lactate and gluconeogenic amino acid uptake rates were decreased in FGR liver. Hepatic oxygen consumption and total substrate uptake rates were lower. In FGR liver tissue, metabolite abundance, 13C-metabolite labeling, enzymatic activity, and gene expression supported decreased pyruvate oxidation and increased lactate production. Isolated hepatocytes from FGR fetuses had greater intrinsic capacity for lactate-fueled glucose production. FGR livers also had lower energy (ATP) and redox state (NADH/NAD+ ratio). Thus, reduced hepatic oxidative metabolism may make carbons available for increased HGP, but also produces nutrient and energetic stress in FGR liver. Intrinsic programming of these pathways regulating HGP in the FGR fetus may underlie increased HGP and T2D risk postnatally.

The Effects of Pulmonary Risk Factors and Combination Thoracic Osseous Fractures on Mortality and Outcomes of Surgical Stabilization of Rib Fractures.

BACKGROUND: Rib fixation for traumatic rib fractures is advocated to decrease morbidity and mortality in select patient populations. We intended to investigate the effect of combination osseous thoracic injuries on mortality with the hypothesis that combination injuries will worsen overall mortality and that SSRF will improve outcomes in combination injuries and in high-risk patients. METHODS: Patients with rib fractures were identified from the Trauma Quality Improvement Project registry from 2019. Patients were then divided into rib fracture(s) alone or in combination with sternal, thoracic vertebra, or scapula fracture. Patients were also categorized into those with COPD and smokers. Patients with AIS >3 outside of thorax were excluded. Patients were subcategorized into those who had rib fixation verse nonoperative management for all subgroups. Analysis was performed to evaluate the efficacy of rib fixation. RESULTS: A total of 111,066 patients were included for analysis. The overall mortality was 1.4%. Patients with COPD had over double the mortality risk, with an overall mortality of 3.4%. Combination injuries did not appear to increase mortality. SSRF did not decrease mortality; however, the number of patients in this group was too small to complete statistical analysis. The overall complication rate was 0.43%. There was a trend towards an increase in extrapulmonary complications in the group that underwent surgical fixation. DISCUSSION: Mortality from rib fractures with concomitant osseous thoracic fracture appears to be low. However, mortality is increased in patients with COPD regardless of rib fracture pattern. The number of patients who underwent SSRF was too small to make a statistical comparison.

An Update on Gender Disparity in Critical Care Conferences.

This commentary's objective was to identify whether female representation at critical care conferences has improved since our previous publication in 2018. We audited the scientific programs from three international (International Symposium on Intensive Care and Emergency Medicine [ISICEM], European Society of Intensive Care Medicine [ESICM], and Society of Critical Care Medicine [SCCM]) and two national (State of the Art [SOA] and Critical Care Canada Forum) critical care conferences from the years 2017 to 2022. We collected data on the number of female faculty members and categorized them into physicians, nurses, allied health professions (AHPs), and other. Across all conferences, there was an increased representation of females as speakers and moderators over the 6 years. However, at each conference, male speakers outnumbered female speakers. Only two conferences achieved gender parity in speakers, SCCM in 2021 (48% female) and 2022 and SOA in 2022 (48% female). These conferences also had the highest representation of female nursing and AHP speakers (25% in SCCM, 2021; 19% in SOA, 2022). While there was a statistically significant increase in female speakers (p < 0.01) in 2022 compared with 2016, there was a persistent gender gap in the representation of men and female physicians. While the proportion of female moderators increased in each conference every year, the increase was statistically only significant for ISICEM, ESICM, and SCCM (p < 0.05). The proportion of female nurses and AHP speakers increased in 2022 compared with 2016 (p < 0.0001) but their overall representation was low with the highest proportion (25%) in the 2022 SCCM conference and the lowest (0.5%) in the 2017 ISICEM conference. This follow-up study demonstrates a narrowing but persisting gender gap in the studied critical care conferences. Thus, a commitment toward minimizing gender inequalities is warranted.

What are the Correlates of Hearing Aid Use for People Living With Dementia?

OBJECTIVES: To identify correlates of hearing aid use in people with dementia and age-related hearing loss. METHODS: Bivariate and multivariate logistic regression analyses of predictor variables from 239 participants with dementia and hearing loss in the European SENSE-Cog Randomized Controlled Trial (Cyprus, England, France, Greece, and Ireland). RESULTS: In multivariate analysis, four variables were significantly associated with hearing aid use: greater self-perceived hearing difficulties (OR 2.61 [CI 1.04-6.55]), lower hearing acuity (OR .39 [CI .2-.56]), higher cognitive ability (OR 1.19 [CI 1.08-1.31]), and country of residence. Participants in England had significantly increased odds of use compared to Cyprus (OR .36 [CI .14-.96]), France (OR .12 [CI .04-.34]) or Ireland (OR .05 [CI .01-.56]) but not Greece (OR 1.13 [CI .42-3.00]). CONCLUSIONS: Adapting interventions to account for cognitive ability, country of residence, self-perceived hearing difficulties, and hearing acuity may support hearing aid use in people with dementia.

A study protocol to investigate if acipimox improves muscle function and sarcopenia: an open-label, uncontrolled, before-and-after experimental medicine feasibility study in community-dwelling older adults.

INTRODUCTION: Sarcopenia is the age-associated loss of muscle mass and strength. Nicotinamide adenine dinucleotide (NAD) plays a central role in both mitochondrial function and cellular ageing processes implicated in sarcopenia. NAD concentrations are low in older people with sarcopenia, and increasing skeletal muscle NAD concentrations may offer a novel therapy for this condition. Acipimox is a licensed lipid-lowering agent known to act as an NAD precursor. This open-label, uncontrolled, before-and-after proof-of-concept experimental medicine study will test whether daily supplementation with acipimox improves skeletal muscle NAD concentrations. METHODS AND ANALYSIS: Sixteen participants aged 65 and over with probable sarcopenia will receive acipimox 250 mg and aspirin 75 mg orally daily for 4 weeks, with the frequency of acipimox administration being dependent on renal function. Muscle biopsy of the vastus lateralis and MRI scanning of the lower leg will be performed at baseline before starting acipimox and after 3 weeks of treatment. Adverse events will be recorded for the duration of the trial. The primary outcome, analysed in a per-protocol population, is the change in skeletal muscle NAD concentration between baseline and follow-up. Secondary outcomes include changes in phosphocreatine recovery rate by 31P magnetic resonance spectroscopy, changes in physical performance and daily activity (handgrip strength, 4 m walk and 7-day accelerometry), changes in skeletal muscle mitochondrial respiratory function, changes in skeletal muscle mitochondrial DNA copy number and changes in NAD concentrations in whole blood as a putative biomarker for future participant selection. ETHICS AND DISSEMINATION: The trial is approved by the UK Medicines and Healthcare Products Regulatory Agency (EuDRACT 2021-000993-28) and UK Health Research Authority and Northeast - Tyne and Wear South Research Ethics Committee (IRAS 293565). Results will be made available to participants, their families, patients with sarcopenia, the public, regional and national clinical teams, and the international scientific community. PROTOCOL: Acipimox feasibility study Clinical Trial Protocol V.2 2/11/21. TRIAL REGISTRATION NUMBER: The ISRCTN trial database (ISRCTN87404878).

Ligand binding determines proteolytic stability of Vibrio LuxR/HapR quorum sensing transcription factors.

In Vibrio species, quorum sensing signaling culminates in the production of a TetR-type master transcription factor collectively called the LuxR/HapR family, which regulates genes required for colonization and infection of host organisms. These proteins possess a solvent accessible putative ligand binding pocket. However, a native ligand has not been identified, and the role of ligand binding in LuxR/HapR function in Vibrionaceae is unknown. To probe the role of the ligand binding pocket, we utilize the small molecule thiophenesulfonamide inhibitor PTSP (3- p henyl-1-( t hiophen-2-yl s ulfonyl)-1 H - p yrazole) that we previously showed targets LuxR/HapR proteins. Amino acid conservation in the ligand binding pocket determines the specificity and efficacy of PTSP inhibition across Vibrio species. Here, we used structure-function analyses to identify PTSP-interacting residues in the ligand binding pocket of SmcR - the Vibrio vulnificus LuxR/HapR homolog - that are required for PTSP inhibition of SmcR activity in vivo . Forward genetic screening combined with X-ray crystallography structural determination of SmcR bound to PTSP identified substitutions at eight residues that were sufficient to reduce or eliminate PTSP-mediated SmcR inhibition. Small-angle X-ray scattering and computational modeling determined that PTSP drives allosteric unfolding at the N-terminal DNA binding domain. We discovered that SmcR is degraded by the ClpAP protease in the presence of PTSP in vivo ; substitution of key PTSP-interacting residues stabilized or increased SmcR levels in the cell. This mechanism of inhibition is observed for all thiophenesulfonamide compounds tested and against other Vibrio species. We conclude that thiophenesulfonamides specifically bind in the ligand binding pocket of LuxR/HapR proteins, promoting protein degradation and thereby suppressing downstream gene expression, implicating ligand binding as a mediator of LuxR/HapR protein stability and function to govern virulence gene expression in Vibrio pathogens. SIGNIFICANCE: LuxR/HapR proteins were discovered in the 1990s as central regulators of quorum sensing gene expression and later discovered to be conserved in all studied Vibrio species. LuxR/HapR homologs regulate a wide range of genes involved in pathogenesis, including but not limited to genes involved in biofilm production and toxin secretion. As archetypal members of the broad class of TetR-type transcription factors, each LuxR/HapR protein has a predicted ligand binding pocket. However, no ligand has been identified for LuxR/HapR proteins that control their function as regulators. Here, we used LuxR/HapR-specific chemical inhibitors to determine that ligand binding drives proteolytic degradation in vivo , the first demonstration of LuxR/HapR function connected to ligand binding for this historical protein family.

Enablers and Barriers to Hearing aid Use in People Living With Dementia.

Hearing loss is highly prevalent in dementia; however, people with dementia are less likely to use hearing aids consistently than people with intact cognition are. This qualitative study is the first of its kind to explore factors that influence hearing aid use from the perspective of community-living people with mild to moderate dementia and their care partners. Eleven UK-based dyads from the European SENSE-Cog Randomized Controlled Trial of a sensory intervention for people with dementia completed semi-structured interviews based on the Theoretical Domains Framework (TDF). Our findings suggest that the TDF domains environmental context and resources, behavioral regulation, reinforcement, and social influences are of greatest relevance to hearing aid use in dementia. Within these domains, we identified a range of factors that may influence the target behavior of hearing aid use. The findings suggest that adoption of multifaceted, flexible intervention approaches may support hearing aid use in dementia.