Pollockbray0054

Visceral leishmaniasis (VL) is an important public health problem in the world, and control measures are insufficient to avoid the spread of this neglected disease. Dogs are important domestic reservoirs of Leishmania parasites in countries where VL is a zoonosis, representing a major source of infection between sand fly vectors and humans. In this context, a precise diagnosis of canine leishmaniasis (CanL) could help to reduce the number of human cases. Distinct approaches for the diagnosis of CanL have used recombinant proteins in serological assays. However, variable results of the antigens have been found, mainly to diagnosis asymptomatic cases. The present study used bioinformatics to select specific B-cell epitopes of four Leishmania infantum proteins, which had previously been proven to be antigenic in VL, aiming to produce a novel chimeric protein and to evaluate it for the diagnosis of CanL. Seven B-cell epitopes were identified and used to construct the chimera, which was analyzed in a recombinant format through an ELISA assay against a canine serological panel. A soluble Leishmania antigenic extract (SLA) was used as an antigen control. Results showed 100 % sensitivity and specificity for chimera, while when using SLA the values were 26.0 % and 96.4 %, respectively. The performance of chimera was compared with a commercial kit using asymptomatic and symptomatic dog sera, and the data showed that no false-negative result was found when the recombinant protein was used. However, when using the commercial kit, 40.0 % and 16.0 % of the false-negative results were found, respectively. In conclusion, the recombinant chimera showed an antigenic potential to be evaluated in new studies against a larger serological panel for the diagnosis of CanL.

While studies have reported increased post-operative pulmonary complications with SARS-CoV-2 infection, many are limited by use of historical controls or focus on less severe respiratory complications. We characterized the association between pre-operative SARS-CoV-2 infection and post-operative respiratory failure (PORF).

This was a single center retrospective cohort study in New York City between March 14-June 14, 2020.

Exclusion criteria were age<18-years, obstetric procedures, absence of SARS-CoV-2 PCR testing, and pre-operative respiratory failure. AS101 A total of 778 patients met criteria, of which 87 had SARS-CoV-2.

The primary outcome, PORF, included inability to extubate for ≥24h or unplanned re-intubation within 5days. Multiple exposures were measured including SARS-CoV-2 infection 4weeks before or 5days after surgery. Multivariable logistic regression was performed to adjust for pre-operative hypoxemia, oxygen use, and pneumonia as well as tachycardia, gender, Charlson Comorbidity Index (CCI)s such as oncologic surgery.

Detection of SARS-CoV-2 infection within 4 weeks before or 5 days after surgery is associated with increased odds of 5-day PORF and 30-day mortality. This supports delaying elective surgery, but questions remain regarding the applicability of this recommendation for asymptomatic patients needing urgent or semi-urgent procedures such as oncologic surgery.The Trier Social Stress Test (TSST) has been shown to reliably induce physiological stress responses in the hypothalamus-pituitary-adrenal (HPA) and in the sympathetic-adrenal-medullary (SAM) axis in cross-sectional studies. However, it was also reported that repeated exposure to the TSST might be associated with habituation, mainly of the HPA axis responsivity. Thus, in all longitudinal stress studies involving repeated TSST administration, potential habituation of the HPA axis response complicates the interpretation of results. The goal of the present study was therefore to assess stability and test-retest reliability of a number of different endocrinological stress markers as well as subjective stress responses after two exposures to the TSST four months apart. We assessed salivary and plasma cortisol profiles, plasma ACTH and noradrenaline profiles, as well as subjective stress ratings in healthy volunteers before, during, and after the TSST at six time-points both at test-day 1 (TSST_1, n = 42) and test-least reliable. A 4-month interval is a sufficient time interval between two repeated TSST exposures to largely reinstate the physiological stress response, which was also true for the initial psychological stress response. Thus, the TSST is well applicable in longitudinal studies.

Prader-Willi syndrome (PWS) is characterized by hypothalamic dysfunction. In children with PWS, stress-induced central adrenal insufficiency (CAI) has been described, however, daily life cortisol production may be normal. Hair cortisol concentration (HCC) is a marker of long-term systemic cortisol production. Cortisol awakening response (CAR) is the increase in cortisol level after awakening. A negative CAR might suggest hypothalamic-pituitary-adrenal (HPA)-axis reactivity problems. Little is known about HCC and CAR in children with PWS.

To investigate long-term cortisol levels in hair and CAR in children with PWS.

Cross-sectional study.

41 children with PWS.

Dutch PWS Reference Center.

HCC and salivary cortisol measured by LCMS.

Median (IQR) HCC was 1.90 (1.02-3.30)pg/mg at a median (IQR) age of 14.5 (8.20-19.0) years, with median HCC in age-matched references being 2.63pg/mg. Five patients (13.2%) had HCC <2.5th percentile for age and these patients had a repeatedly negative CAR. Median HCC was significantly lower in patients with negative CAR than in patients with normal CAR (1.00 (0.22-1.59) vs. 2.25 (1.47-3.26) pg/mg, p=0.007). One patient had both HCC <2.5th percentile and repeatedly low morning salivary cortisol levels and negative CAR, and was diagnosed with adrenal insufficiency by overnight metyrapone test.

HCC were normal in the majority of children with PWS. Our data suggest that children with HCC <2.5th percentile and (repeatedly) negative CAR might possibly have adrenal insufficiency or delayed HPA-axis responsiveness.

HCC were normal in the majority of children with PWS. Our data suggest that children with HCC less then 2.5th percentile and (repeatedly) negative CAR might possibly have adrenal insufficiency or delayed HPA-axis responsiveness.

Cushing's disease (CD) is a rare and severe endocrine disease characterized by hypercortisolemia. Previous studies have found structural brain alterations in remitted CD patients compared to healthy controls, specifically in the anterior cingulate cortex (ACC). However, potential mechanisms through which these persistent alterations may have occurred are currently unknown.

Structural 3T MRI's from 25 remitted CD patients were linked with gene expression data from neurotypical donors, derived from the Allen Human Brain Atlas. Differences in gene expression between the ACC and an unaffected control cortical region were examined, followed by a Gene Ontology (GO) enrichment analysis. A cell type enrichment analysis was conducted on the differentially expressed genes, and a disease association enrichment analysis was conducted to determine possible associations between differentially expressed genes and specific diseases. Subsequently, cortisol sensitivity of these genes in existing datasets was examined.

Th these cell types against the long-term effects of cortisol overexposure.Bacteria carrying New Delhi metallo-β-lactamase-1 (New Delhi metallo-β-lactamase, NDM-1) resistance gene is a new type of "superbug", which can hydrolyze almost all β-lactam antibiotics, rapidly spread among the same species and even spread among different species. NDM-1 belongs to the class B1 broad-spectrum enzyme of β-lactamase. The two positively charged zinc ions in the active center have electrostatic interaction with the hydroxyl ions in them to seize the hydrogen atom near the water molecule to form a bridging ring water molecule, which strengthens its nucleophilicity and attacks the carbonyl group on the lactam ring; thus, catalyzing the hydrolysis of β-lactam antibiotics. Since NDM-1 has an open active site and unique electrostatic structure, it essentially provides a wider range of substrate specificity. Due to its flexible hydrolysis mechanism and more and more variants also aggravate the threat of drug-resistant bacteria infection, there is still no effective inhibitor in clinic, which is a serious threat to human health and public health safety. The electron-rich substituents of NDM-1 inhibitors coordinate with two positively charged zinc ions in the active center of the enzyme through ion-dipole interaction to produce NDM-1 inhibitory activity. In this review, the research progress of NDM-1 enzyme and its inhibitors in the past 5 years was reviewed. The crystal structure, active center structure, surrounding important amino acid residues, newly discovered inhibitors and their action mechanism are classified and summarized in detail, which can be used as a reference for the development of effective drugs against drug-resistant bacteria targeting NDM-1.We have obtained the X-ray crystal structure of the galectin-8 N-terminal domain (galectin-8N) with a previously reported quinoline-galactoside ligand at a resolution of 1.6 Å. Based on this X-ray structure, a collection of galactosides derivatised at O3 with triazole, benzimidazole, benzothiazole, and benzoxazole moieties were designed and synthesised. This led to the discovery of a 3-O-(N-methylbenzimidazolylmethyl)-galactoside with a Kd of 1.8 μM for galectin-8N, the most potent selective synthetic galectin-8N ligand to date. Molecular dynamics simulations showed that benzimidazole-galactoside derivatives bind the non-conserved amino acid Gln47, accounting for the higher selectivity for galectin-8N. Galectin-8 is a carbohydrate-binding protein that plays a key role in pathological lymphangiogenesis, modulation of the immune system, and autophagy. Thus, the benzimidazole-derivatised galactosides represent promising compounds for studies of the pathological implications of galectin-8, as well as a starting point for the development of anti-tumour and anti-inflammatory therapeutics targeting galectin-8.MLL1-WDR5 interaction is essential for the formation of MLL core complex and its H3K4 methyltransferase activity. Disrupting MLL1-WDR5 interaction has been proposed as a potential therapeutic approach in the treatment of leukemia. A "toolkit" of well-characterized chemical probe will allow exploring animal studies. Based on a specific MLL1-WDR5 PPI inhibitor (DDO-2117), which was previously reported by our group, we conducted a bioisosterism approach by click chemistry to discover novel phenyltriazole scaffold MLL1-WDR5 interaction blockers. Here, our efforts resulted in the best inhibitor 24 (DDO-2093) with high binding affinity (Kd = 11.6 nM) and with improved drug-like properties. Both in vitro and in vivo assays revealed 24 could efficiently block the MLL1-WDR5 interaction. Furthermore, 24 significantly suppressed tumor growth in the MV4-11 xenograft mouse model and showed a favorable safety profile. We propose 24 as a chemical probe that is suitable for in vivo pharmacodynamic and biological studies of MLL1-WDR5 interaction.