Highlights•The killed oral ETEC vaccine ETVAX ± dmLT adjuvant was safe in Bangladeshi adults. •All vaccinees responded to all 5 primary vaccine antigens in ALS specimens. •A majority of vaccinees ...responded to ≥4 antigens in plasma specimens. •A sensitive electrochemiluminescence assay was established for small sample volumes. •ALS responses measured by electrochemiluminescence and ELISA assays correlated well.
Enterotoxigenic Escherichia coli causes diarrhoea, leading to substantial mortality and morbidity in children, but no specific vaccine exists. This trial tested an oral, inactivated, enterotoxigenic ...E coli vaccine (ETVAX), which has been previously shown to be safe and highly immuongenic in Swedish and Bangladeshi adults. We tested the safety and immunogenicity of ETVAX, consisting of four E coli strains overexpressing the most prevalent colonisation factors (CFA/I, CS3, CS5, and CS6) and a toxoid (LCTBA) administered with or without a double-mutant heat-labile enterotoxin (dmLT) as an adjuvant, in Bangladeshi children.
We did a randomised, double-blind, placebo-controlled, dose-escalation, age-descending, phase 1/2 trial in Dhaka, Bangladesh. Healthy children in one of three age groups (24–59 months, 12–23 months, and 6–11 months) were eligible. Children were randomly assigned with block randomisation to receive either ETVAX, with or without dmLT, or placebo. ETVAX (half 5·5 × 1010 cells, quarter 2·5 × 1010 cells, or eighth 1·25 × 1010 cells adult dose), with or without dmLT adjuvant (2·5 μg, 5·0 μg, or 10·0 μg), or placebo were administered orally in two doses 2 weeks apart. Investigators and participants were masked to treatment allocation. The primary endpoint was safety and tolerability, assessed in all children who received at least one dose of vaccine. Antibody responses to vaccine antigens, defined as at least a two-times increase in antibody levels between baseline and post-immunisation, were assessed as secondary endpoints. This trial is registered with ClinicalTrials.gov, NCT02531802.
Between Dec 7, 2015, and Jan 10, 2017, we screened 1500 children across the three age groups, of whom 430 were enrolled and randomly assigned to the different treatment groups (130 aged 24–59 months, 100 aged 12–23 months, and 200 aged 6–11 months). All participants received at least one dose of vaccine. No solicited adverse events occurred that were greater than moderate in severity, and most were mild. The most common solicited event was vomiting (ten 8% of 130 patients aged 24–59 months, 13 13% of 100 aged 12–23 months, and 29 15% of 200 aged 6–11 months; mostly of mild severity), which appeared related to dose and age. The addition of dmLT did not modify the safety profile. Three serious adverse events occurred but they were not considered related to the study drug. Mucosal IgA antibody responses in lymphocyte secretions were detected against all primary vaccine antigens (CFA/I, CS3, CS5, CS6, and the LCTBA toxoid) in most participants in the two older age groups, whereas such responses to four of the five antigens were less frequent and of lower magnitude in infants aged 6–11 months than in older children. Faecal secretory IgA immune responses were recorded against all vaccine antigens in infants aged 6–11 months. 78 (56%) of 139 infants aged 6–11 months who were vaccinated developed mucosal responses against at least three of the vaccine antigens versus 14 (29%) of 49 of the infants given placebo. Addition of the adjuvant dmLT enhanced the magnitude, breadth, and kinetics (based on number of responders after the first dose of vaccine) of immune responses in infants.
The encouraging safety and immunogenicity of ETVAX and benefit of dmLT adjuvant in young children support its further assessment for protective efficacy in children in enterotoxigenic E coli-endemic areas.
PATH (Bill & Melinda Gates Foundation and the UK's Department for International Development), the Swedish Research Council, and The Swedish Foundation for Strategic Research.
Bacterial multidrug transporter DrrAB exhibits overlapping substrate specificity with mammalian P-glycoprotein. DrrA hydrolyzes ATP, and the energy is transduced to carrier DrrB resulting in export ...of drugs. Previous studies suggested that DrrB contains a large and flexible drug-binding pocket made of aromatic residues contributed by several transmembrane helices with different drugs binding to both specific and shared residues in this pocket. However, direct binding of drugs to DrrAB or the mechanism of substrate-induced conformational changes between DrrA and DrrB has so far not been investigated. We used two fluorescence-based approaches to determine substrate binding to purified DrrAB. Our analysis shows that DrrB binds drugs with variable affinities and contains multiple drug binding sites. This work also provides evidence for two asymmetric nucleotide binding sites in DrrA with strikingly different binding affinities. Using targeted fluorescence labeling, we provide clear evidence of long-range conformational changes occurring between DrrA and DrrB. It is proposed that the transduction pathway from the nucleotide-binding DrrA subunit to the substrate binding DrrB subunit includes Q-loop and CREEM motifs in DrrA and EAA-like motif in DrrB. This study lays a solid groundwork for examining roles of various conserved regions of DrrA and DrrB in transduction of conformational changes.
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•Fluorescence-based approaches were used to determine substrate binding to DrrAB.•DrrB exhibits variable drug affinities and contains multiple drug binding sites.•DrrA contains two nucleotide binding sites with strikingly different affinities.•ATP binding to DrrA reduced affinity of DrrB for drugs.•Substrate-induced crosstalk between DrrB and two subdomains of DrrA was observed.
Head and neck cancer encompass different malignancies that develop in and around the throat, larynx, nose, sinuses and mouth. Most head and neck cancers are squamous cell carcinomas (HNSCC) that ...arise in the flat squamous cells that makeup the thin layer of tissue on the surface of anatomical structures in the head and neck. Each year, HNSCC is diagnosed in more than 600,000 people worldwide, with about 50,000 new cases. HNSCC is considered extremely curable if detected early. But the problem remains in treatment of inoperable cases, residues or late stages. Circadian rhythm regulation has a big role in developing various carcinomas, and head and neck tumors are no exception. A number of studies have reported that alteration in clock gene expression is associated with several cancers, including HNSCC. Analyses on circadian clock genes and their association with HNSCC have shown that expression of
,
and
are deregulated in HNSCC tissues. This review paper comprehensively presents data on deregulation of circadian genes in HNSCC and critically evaluates their potential diagnostics and prognostics role in this type of pathology.
Homelessness, a long-standing societal problem, appears to be on the rise, fueled in part by the Covid-19 pandemic. Looking at the homelessness system as a network of interconnected services which ...individuals traverse over time, we seek to shed light on their progression toward securing stable housing. We formalize the concept of stability upon exit and show that regardless of starting conditions, the ultimate goal is either reached quickly or not at all, indicating the importance of addressing the homeless' needs early on to avoid them "giving up." To better understand the causes that may contribute to positive outcomes for certain individuals versus others, we computationally analyze their pathways through the network of homeless services. We confirm the intuition that some individuals face more challenges than others based on their initial living conditions and initial placement to homelessness services. At the same time, we discover that simple signals can act as good indicators of individuals at risk of "falling through the cracks." Being able to predict such outcomes is critical to design assistive technology that can retain individuals who would otherwise falter.
Mucosa-associated invariant T (MAIT) cells are recently characterized as a novel subset of innate-like T cells that recognize microbial metabolites as presented by the MHC-1b-related protein MR1. The ...significance of MAIT cells in anti-bacterial defense is well-understood but not clear in viral infections such as SIV/HIV infection. Here we studied the phenotype, distribution, and function of MAIT cells and their association with plasma viral levels during chronic SHIV infection in rhesus macaques (RM). Two groups of healthy and chronic SHIV-infected macaques were characterized for MAIT cells in blood and mucosal tissues. Similar to human, we found a significant fraction of macaque T cells co-expressing MAIT cell markers CD161 and TCRVα-7.2 that correlated directly with macaque MR1 tetramer. These cells displayed memory phenotype and expressed high levels of IL-18R, CCR6, CD28, and CD95. During chronic infection, the frequency of MAIT cells are enriched in the blood but unaltered in the rectum; both blood and rectal MAIT cells displayed higher proliferative and cytotoxic phenotype post-SHIV infection. The frequency of MAIT cells in blood and rectum correlated inversely with plasma viral RNA levels and correlated directly with total CD4 T cells. MAIT cells respond to microbial products during chronic SHIV infection and correlated positively with serum immunoreactivity to flagellin levels. Tissue distribution analysis of MAIT cells during chronic infection showed significant enrichment in the non-lymphoid tissues (lung, rectum, and liver) compared to lymphoid tissues (spleen and LN), with higher levels of tissue-resident markers CD69 and CD103. Exogenous
cytokine treatments during chronic SHIV infection revealed that IL-7 is important for the proliferation of MAIT cells, but IL-12 and IL-18 are important for their cytolytic function. Overall our results demonstrated that MAIT cells are enriched in blood but unaltered in the rectum during chronic SHIV infection, which displayed proliferative and functional phenotype that inversely correlated with SHIV plasma viral RNA levels. Treatment such as combined cytokine treatments could be beneficial for enhancing functional MAIT cells during chronic HIV infection
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The cohesin complex links DNA molecules and plays key roles in the organization, expression, repair, and segregation of eukaryotic genomes. In vertebrates the Esco1 and Esco2 acetyltransferases both ...modify cohesin’s Smc3 subunit to establish sister chromatid cohesion during S phase, but differ in their N-terminal domains and expression during development and across the cell cycle. Here we show that Esco1 and Esco2 also differ dramatically in their interaction with chromatin, as Esco1 is recruited by cohesin to over 11,000 sites, whereas Esco2 is infrequently enriched at REST/NRSF target genes. Esco1’s colocalization with cohesin occurs throughout the cell cycle and depends on two short motifs (the A-box and B-box) present in and unique to all Esco1 orthologs. Deleting either motif led to the derepression of Esco1-proximal genes and functional uncoupling of cohesion from Smc3 acetylation. In contrast, other mutations that preserved Esco1’s recruitment separated its roles in cohesion establishment and gene silencing. We conclude that Esco1 uses cohesin as both a substrate and a scaffold for coordinating multiple chromatinbased transactions in somatic cells.
What is the impact of China's official human rights stance on international human rights discourses/norms? Will China's ambition to change the international human rights framework succeed, resulting ...in a new normative order in the world of human rights? The article attempts to address these questions. First, it identifies the state's practice pursuing different standards when dealing with human rights issues internationally and domestically. Second, it argues that China is no different from other states when it behaves in a double standard way. The paper maintains, however, that China's double-standard human rights approach is critical for the future development of the international human rights regime since the CCP leadership intends to redefine human rights in its own interests. While China's interests align with most states in the third world, its pursuit of normative design is a threat to the current notion of universal human rights.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Introduction: In an unanticipated difficult airway or in an emergency situation of cannot-intubate-cannot-ventilate scenario, Supraglottic Airway Devices (SGD) are recommended as rescue devices for ...establishing airway quickly to prevent hypoxia. Aim: To compare efficacy of i-gel airway and Laryngeal Mask Airway supreme (LMA supreme) as ventilatory devices and the time taken for their insertion in anaesthetised and paralysed patients with simulated difficult airway. Materials and Methods: One hundred and eighty adult patients with simulated difficult airway were randomly allocated to two groups of 90 patients each. In group I: i-gel and in group S: LMA supreme was inserted. Primary outcome studied was time taken for insertion of SGD. Secondary outcomes were the number of attempts taken for insertion of device, oropharyngeal leak pressure, ease of gastric catheter insertion, fibreoptic bronchoscopic view of anatomical alignment of device with glottic opening. Quantitative variables were compared using unpaired t-test/Mann-Whitney Test, between the two groups. Qualitative variable were compared using Chi-Square test/Fisher’s-exact test. Results: Total time taken for successful insertion was significantly shorter with group i-gel as compared to group LMA supreme {median (IQR) {19 (18.25-21)} versus {24 (23-24)} with p-value ≤0.0001. Overall success rate of insertion (96.67% vs 97.78%, p=1.000) and oropharyngeal leak pressure (p-value=0.555) of i-gel and LMA-S were comparable. i-gel has better anatomic alignment with glottic opening as compared to LMA-S (p-value ≤0.0001). Gastric tube insertion was easy in all patients in both the groups. Conclusion: Shorter time for the insertion of i-gel was observed due to absence of inflatable cuff, although both LMA-S and i-gel are equally efficacious as ventilatory devices in patients with simulated difficult airway under general anaesthesia with controlled ventilation.
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