Characterization of the AI-2-dependent quorum sensing pathway in Aggregatibacter actinomycetemcomitans.

Quorum sensing in the oral pathogen Aggregatibacter actinomycetemcomitans is dependent upon the soluble signaling molecule AI-2, but it is not known how the initial detection of AI-2 is coupled to the downstream regulation of gene expression that confers complex phenotypes such as biofilm formation and iron acquisition. Here we show that expression of a two-component system encoded by qseBC is induced by AI-2 in A. actinomycetemcomitans and that induction of qseBC requires the AI-2 receptors, LsrB and/or RbsB. Inactivation of the sensor kinase gene qseC resulted in a significant reduction of in vitro biofilm growth and in vivo virulence using a murine model of periodontitis. We also show that qseBC regulates the expression of several operons encoding iron acquisition pathways, consistent with previous studies showing that AI-2 regulates iron uptake in A. actinomycetemcomitans. However, some AI-2 regulated iron uptake operons were not controlled by QseBC, suggesting that only a subset of iron acquisition systems are co-regulated by AI-2 and QseBC. Interestingly, the toxin-antitoxin system mqsRA is involved in AI-2 and QseBCdependent regulation of biofilm growth of some strains of Escherichia coli. The genome sequence of A. actinomycetemcomitans was searched and open reading frames Aa00672 and Aa00673 were shown to exhibit sequence similarity to MqsRA and MazEF, two toxin-antitoxin systems encoding mRNA interferases. Aa00673 was shown by RT-PCR to be co-expressed with Aa00672 and the expression of Aa00672-Aa00673 was decreased in A. actinomycetemcomitans strains lacking functional AI-2-receptors or QseC, suggesting that Aa00672-Aa00673 functions downstream from the AI-2 receptors and QseBC in the AI-2 response circuit of A. actinomycetemcomitans. We also demonstrate that Aa00673 encodes a toxin, which causes reversible growth inhibition and may function as an RNase; whereas Aa00672 encodes its cognate antitoxin, negating the effects of the toxin. Thus, our results suggest that the QseBC two-component system is part of the AI-2 regulon and in concert with Aa00673, a putative paralog of MqsR, link the detection of AI-2 to the regulation of genes controlling biofilm formation, iron acquisition, and in vivo virulence of A. actinomycetemcomitans

Experiences of Violence and Association with Decreased Drug Abstinence Among Women in Cape Town, South Africa

Drug abuse is a contributing factor in women’s HIV risk in low-income communities in Cape Town, South Africa. This study assessed whether experiencing violence is associated with reduced drug abstinence among adult women (n = 603) participating in a randomized field trial for an HIV prevention study in Cape Town. In relation to drug abstinence at 12-month follow-up, multivariable regression models were used to assess (1) baseline partner and non-partner victimization, and (2) victimization at 12-month follow-up among participants reporting baseline victimization. Baseline partner (AOR = 0.6; 95 % CI 0.4–0.9) and non-partner victimization (AOR = 0.6; 95 % CI 0.4–0.9) were associated with a reduced likelihood of drug abstinence at follow-up. Among participants who reported victimization at baseline, those no longer reporting victimization at follow-up did not differ significantly in drug abstinence compared with those who reported victimization at follow-up. The study findings highlight the lasting impact of victimization on women’s drug use outcomes, persisting regardless of whether violence was no longer reported at follow-up. Overall, the findings support the need for the primary prevention of violence to address the cycle of violence, drug use, and HIV among women in this setting

Biochar research activities and their relation to development and environmental quality. A meta-analysis

Biochar is the solid product that results from pyrolysis of organic materials. Its addition to highly weathered soils changes physico-chemical soil properties, improves soil functions and enhances crop yields. Highly weathered soils are typical of humid tropics where agricultural productivity is low and needs to be raised to reduce human hunger and poverty. However, impact of biochar research on scientists, politicians and end-users in poor tropical countries remains unknown; assessing needs and interests on biochar is essential to develop reliable knowledge transfer/translation mechanisms. The aim of this publication is to present results of a meta-analysis conducted to (1) survey global biochar research published between 2010 and 2014 to assess its relation to human development and environmental quality, and (2) deduce, based on the results of this analysis, priorities required to assess and promote the role of biochar in the development of adapted and sustainable agronomic methods. Our main findings reveal for the very first time that: (1) biochar research associated with less developed countries focused on biochar production technologies (26.5 ± 0.7%), then on biochars’ impact on chemical soil properties (18.7 ± 1.2%), and on plant productivity (17.1 ± 2.6%); (2) China dominated biochar research activities among the medium developed countries focusing on biochar production technologies (26.8 ± 0.5%) and on use of biochar as sorbent for organic and inorganic compounds (29.1 ± 0.4%); and (3) the majority of biochar research (69.0±2.9%) was associated with highly developed countries that are able to address a higher diversity of questions. Evidently, less developed countries are eager to improve soil fertility and agricultural productivity, which requires transfer and/or translation of biochar knowledge acquired in highly developed countries. Yet, improving local research capacities and encouraging synergies across scientific disciplines and countries are crucial to foster development of sustainable agronomy in less developed countries. © 2017, The Author(s)

A Phase 1a/1b Clinical Trial Design to Assess Safety, Acceptability, Pharmacokinetics and Tolerability of Intranasal Q-Griffithsin for COVID-19 Prophylaxis

Background: The COVID-19 pandemic remains an ongoing threat to global public health. Q-Griffithsin (Q-GRFT) is a lectin that has demonstrated potent broad-spectrum inhibitory activity in preclinical studies in models of Nipah virus and the beta coronaviruses SARS-CoV, MERS-CoV, and SARS-CoV-2. Methods: Here, we propose a clinical trial design to test the safety, pharmacokinetics (PK), and tolerability of intranasally administered Q-GRFT for the prevention of SARS-CoV-2 infection as a prophylaxis strategy. The initial Phase 1a study will assess the safety and PK of a single dose of intranasally administered Q-GRFT. If found safe, the safety, PK, and tolerability of multiple doses of intranasal Q-GRFT will be assessed in a Phase 1b study. Group 1 participants will receive 3 mg of intranasal Q-GRFT (200 μL/nostril) once daily for 7 days. If this dose is tolerated, participants will be enrolled in Group 2 to receive 3 mg twice daily for 7 days. Secondary endpoints of the study will be user perceptions, acceptability, and the impact of product use on participants’ olfactory sensation and quality of life. Discussion: Results from this study will support further development of Q-GRFT as a prophylactic against respiratory viral infections in future clinical trials

A national harmonised data collection network for neurodevelopmental disorders: A transdiagnostic assessment protocol for neurodevelopment, mental health, functioning and well-being

BACKGROUND: Children with neurodevelopmental disorders share common phenotypes, support needs and comorbidities. Such overlap suggests the value of transdiagnostic assessment pathways that contribute to knowledge about research and clinical needs of these children and their families. Despite this, large transdiagnostic data collection networks for neurodevelopmental disorders are not well developed. This paper describes the development of a nationally supported transdiagnostic clinical and research assessment protocol across Australia. The vision is to establish a harmonised network for data collection and collaboration that promotes transdiagnostic clinical practice and research. METHODS: Clinicians, researchers and community groups across Australia were consulted using surveys and national summits to identify assessment instruments and unmet needs. A national research committee was formed and, using a consensus approach, selected assessment instruments according to pre-determined criteria to form a harmonised transdiagnostic assessment protocol. RESULTS: Identified assessment instruments were clustered into domains of transdiagnostic assessment needs, which included child functioning/quality of life, child mental health, caregiver mental health, and family background information. From this, the research committee identified a core set of nine measures and an extended set of 14 measures that capture these domains with potential for further modifications as recommended by clinicians, researchers and community members. CONCLUSION: The protocol proposed here was established through a strong partnership between clinicians, researchers and the community. It will enable (i) consensus driven transdiagnostic clinical assessments for children with neurodevelopmental disorders, and (ii) research studies that will inform large transdiagnostic datasets across neurodevelopmental disorders and that can be used to inform research and policy beyond narrow diagnostic groups. The long-term vision is to use this framework to facilitate collaboration across clinics to enable large-scale data collection and research. Ultimately, the transdiagnostic assessment data can be used to inform practice and improve the lives of children with neurodevelopmental disorders and their families

Epithelial NAD+ depletion drives mitochondrial dysfunction and contributes to intestinal inflammation

IntroductionWe have previously demonstrated that a pathologic downregulation of peroxisome proliferator-activated receptor–gamma coactivator 1-alpha (PGC1α) within the intestinal epithelium contributes to the pathogenesis of inflammatory bowel disease (IBD). However, the mechanism underlying downregulation of PGC1α expression and activity during IBD is not yet clear.MethodsMice (male; C57Bl/6, Villincre/+;Pgc1afl/fl mice, and Pgc1afl/fl) were subjected to experimental colitis and treated with nicotinamide riboside. Western blot, high-resolution respirometry, nicotinamide adenine dinucleotide (NAD+) quantification, and immunoprecipitation were used to in this study.ResultsWe demonstrate a significant depletion in the NAD+ levels within the intestinal epithelium of mice undergoing experimental colitis, as well as humans with ulcerative colitis. While we found no decrease in the levels of NAD+-synthesizing enzymes within the intestinal epithelium of mice undergoing experimental colitis, we did find an increase in the mRNA level, as well as the enzymatic activity, of the NAD+-consuming enzyme poly(ADP-ribose) polymerase-1 (PARP1). Treatment of mice undergoing experimental colitis with an NAD+ precursor reduced the severity of colitis, restored mitochondrial function, and increased active PGC1α levels; however, NAD+ repletion did not benefit transgenic mice that lack PGC1α within the intestinal epithelium, suggesting that the therapeutic effects require an intact PGC1α axis.DiscussionOur results emphasize the importance of PGC1α expression to both mitochondrial health and homeostasis within the intestinal epithelium and suggest a novel therapeutic approach for disease management. These findings also provide a mechanistic basis for clinical trials of nicotinamide riboside in IBD patients

Relationships between Levels of Serum IgE, Cell-Bound IgE, and IgE-Receptors on Peripheral Blood Cells in a Pediatric Population

Background: Elevated serum immunoglobulin (Ig) E is a diagnostic marker of immediate-type allergic reactions. We hypothesize that serum IgE does not necessarily reflect total body IgE because in vivo IgE can be bound to cell surface receptors such as FcεRI and FcεRII (CD23). The aim of this study was to analyze the relationships between levels of serum IgE, cell-bound IgE, and IgE-receptors on peripheral blood cells in a pediatric population. Methodology: Whole blood samples from 48 children (26 boys, 22 girls, mean age 10,3±5,4 years) were analyzed by flow cytometry for FcεRI, CD23, and cell-bound IgE on dendritic cells (CD11c+MHC class II+), monocytes (CD14+), basophils (CD123+MHC class II-) and neutrophils (myeloperoxidase+). Total serum IgE was measured by ELISA and converted into z-units to account for age-dependent normal ranges. Correlations were calculated using Spearman rank correlation test. Principal Findings: Dendritic cells, monocytes, basophils, and neutrophils expressed the high affinity IgE-receptor FcεRI. Dendritic cells and monocytes also expressed the low affinity receptor CD23. The majority of IgE-receptor positive cells carried IgE on their surface. Expression of both IgE receptors was tightly correlated with cell-bound IgE. In general, cell-bound IgE on FcεRI+ cells correlated well with serum IgE. However, some patients carried high amounts of cell-bound IgE despite low total serum IgE levels. Conclusion/Significance: In pediatric patients, levels of age-adjusted serum IgE, cell-bound IgE, and FcεRI correlate. Even in the absence of elevated levels of serum IgE, cell-bound IgE can be detected on peripheral blood cells in a subgroup of patients