Notes

Cell Colistin Resistance Chemical MCR-3 Makes it possible for Microbial Evasion associated with Host Phagocytosis.
HpaR is a transcription regulator in the MarR family that controls the expression of the gene cluster responsible for conversion of p-hydroxyphenylacetate to pyruvate and succinate for cellular metabolism. Here, we report the biochemical and structural characterization of Acinetobacter baumannii HpaR (AbHpaR) and its complex with cognate DNA. Our study revealed that AbHpaR binds upstream of the divergently transcribed hpaA gene and the meta-cleavage operon, as well as the hpaR gene, thereby repressing their transcription by blocking access of RNA polymerase. Structural analysis of AbHpaR-DNA complex revealed that the DNA binding specificity can be achieved via a combination of both direct and indirect DNA sequence readouts. DNA binding of AbHpaR is weakened by 3,4-dihydroxyphenylacetate (DHPA), which is the substrate of the meta-cleavage reactions; this likely leads to expression of the target genes. Based on our findings, we propose a model for how A. baumannii controls transcription of HPA-metabolizing genes, which highlights the independence of global catabolite repression and could be beneficial for metabolic engineering toward bioremediation applications. DATABASES The structural data that support these findings are openly available in the wwPDB at https//doi.org/10.2210/pdb7EL2/pdb and https//doi.org/10.2210/pdb7EL3/pdb for AbHpaR and AbHpaR-DNA complex, respectively.
WHO has recommended rapid antiretroviral therapy (ART) initiation, including same-day ART (SDART). However, data on the feasibility in real-world settings are limited. We implemented a cohort study at a stand-alone HIV testing centre to examine its applicability and effectiveness.

Data were collected from the Thai Red Cross Anonymous Clinic in Bangkok, Thailand, between July 2017 and July 2018 from clients who were ART-naïve and could return for follow-up visits. Baseline laboratory tests and chest X-ray were performed according to national guidelines, and clinical eligibility was determined based on physical examination and chest X-ray findings. Primary outcomes were retention in care and viral load suppression at 3, 6 and 12 months.

During the study period, 2427 people tested HIV positive. Of these, 2107 (2207/2427, 86.8%) met logistical criteria, and 1904 (1904/2427, 78.5%) agreed to SDART. One thousand seven hundred and twenty-nine (1729/2427, 71.2%) were placed on ART, with 1257 received same-day initiation and 1576 initiated ART within 7 days; 1198 clients were successfully referred to free, sustained ART sites. Retention among eligible clients who accepted SDART service at months 3, 6 and 12 was 79.8%, 75.2% and 75.3%, respectively.

Same-day ART initiation hub model at a stand-alone HIV testing centre in an urban setting in Bangkok, Thailand, is highly feasible and has a potential for scaling up.

NCT04032028.
NCT04032028.
Bipolar disorder (BD) is a chronic psychiatric disorder characterized by recurrent mood episodes interspersed with euthymic periods. A growing number of studies have indicated that zinc plays an important role in coordinating immune responses, as well as being involved in synaptic transmission. In the current study, we set out to measure serum levels of zinc in a meticulously phenotyped cohort of 121 euthymic BD subjects and 30 matched controls.

Serum levels of zinc were measured by photometry. To assess the interplay between zinc levels and immune activation in BD, we measured serum levels of high-sensitive C-reactive protein (hsCRP) levels by immunoturbidimetric assay, and serum levels of monocyte chemoattractant protein-1 (MCP-1), chitinase 3-like protein 1 (YKL-40), and soluble cluster of differentiation 14 (sCD14) by electrochemiluminescence enzyme-linked immunosorbent assays. The baseline clinical diagnostic instrument for BD was the Affective Disorder Evaluation, and executive functioning was assessed by using the Delis-Kaplan Executive Function System.

Controlling for potential confounding factors, BD patients displayed increased serum levels of zinc unrelated to hsCRP, MCP-1, YKL-40, and sCD14 levels. Serum levels of zinc did not associate with executive functioning or measurements of disease severity.

This study suggests that the zinc homeostasis is disturbed in BD and that this dyshomeostasis is not related to ongoing mood symptoms or immune activation. Of note, serum levels were increased and hence do not support continuous zinc supplementation in BD.
This study suggests that the zinc homeostasis is disturbed in BD and that this dyshomeostasis is not related to ongoing mood symptoms or immune activation. Of note, serum levels were increased and hence do not support continuous zinc supplementation in BD.Secretagogin (SCGN) is a calcium-sensor protein with a regulatory role in glucose metabolism and the secretion of several peptide hormones. Many, but not all, functions of SCGN can be explained by its intracellular manifestation. Despite early data on SCGN secretion, the secretory mechanism, biological fate, physiological implications and trans-cellular signalling of extracellular SCGN remain unknown. We here report that extracellular SCGN is readily internalized into the C2C12 cells in an energy-dependent manner. Using endocytosis inhibitors, we demonstrate that SCGN internalizes via clathrin-mediated endocytosis, following which, SCGN localizes largely in the cytosol. Exogenous SCGN treatment induces a global proteomic reprogramming in C2C12 cells. Gene ontology search suggests that SCGN-induced proteomic reprogramming favours protein synthesis and cellular growth. We thus validated the cell proliferative action of SCGN using C2C12, HepG2 and NIH-3T3 cell lines. Based on the data, we propose that circulatory SCGN is internalized into the target cells and modulates the expression of cell growth-related proteins. The work suggests that extracellular SCGN is a functional protein, which communicates with specific cell types and directly modulates cell proliferation.Xanthohumol is the main prenylflavonoid in hops and has been associated with a wide range of health benefits, due to its anti-inflammatory, anti-oxidative, and cancer-preventive properties. Increasing evidence suggests that xanthohumol positively affects biomarkers associated with metabolic syndrome and cardiovascular diseases (CVDs). This review summarizes the effects of xanthohumol supplementation on body weight, lipid and glucose metabolism, systemic inflammation, and redox status. In addition, it provides insights into the pharmacokinetics of xanthohumol intake. Animal studies show that xanthohumol exerts beneficial effects on body weight, lipid profile, glucose metabolism, and other biochemical parameters associated with metabolic syndrome and CVDs. Although in vitro studies are increasingly elucidating the responsible mechanisms, the overall in vivo results are currently inconsistent and quantitatively insufficient. Pharmacokinetic and safety studies confirm that intake of xanthohumol is safe and well tolerated in both animals and humans. However, little is known about the metabolism of xanthohumol in the human body, and even less about its effects on body weight and CVD risk factors. There is an urgent need for studies investigating whether the effects of xanthohumol on body weight and cardiometabolic parameters observe in animal studies are reproducible in humans, and what dosage, formulation, and intervention period are required.
It was proposed that peripheral blood (PB) monocyte profiles evaluated by flow cytometry, called "monocyte assay," could rapidly and efficiently distinguish chronic myelomonocytic leukemia (CMML) from other causes of monocytosis by highlighting an increase in the classical monocyte (cMo) fraction above 94%. JAK cancer However, the robustness of this assay requires a large multicenter validation and the assessment of its feasibility on bone marrow (BM) samples, as some centers may not have access to PB.

PB and/or BM samples from patients displaying monocytosis were assessed with the "monocyte assay" by 10 ELN iMDS Flow working group centers with harmonized protocols. The corresponding files were reanalyzed in a blind fashion and the cMo percentages obtained by both analyses were compared. Confirmed diagnoses were collected when available.

The comparison between cMo percentages from 267 PB files showed a good global significant correlation (r= 0.88) with no bias. Confirmed diagnoses, available for 212 patients, achiBM samples.The third PDZ domain of the postsynaptic density protein 95 (PSD95-PDZ3; 11 kDa, 103 residues) has a propensity to form amyloid fibrils at high temperatures. At neutral pH, PDZ3 is natively folded, but it exhibits a peculiar three-state thermal unfolding with a reversible oligomerization (RO) equilibrium at high temperatures, which is uncharacteristic in the unfolding of a small globular protein as PDZ3 is. Here, we examined the RO's role in PDZ3's amyloidogenesis at high-temperature using two variants (F340A and L342A) that suppress the high-temperature RO and five single-alanine-mutated variants, where we mutated surface-exposed hydrophobic residues to alanine. Circular Dichroism (CD), Analytical Ultracentrifuge (AUC), and other spectroscopic measurements confirmed the retention of the native structure at ambient temperature. Differential Scanning Calorimetry (DSC) was used to assess the presence or absence of the high-temperature RO, and the amyloidogenicity of the variants was measured by Thioflavin T (ThT) fluorescence and Transmission Electron Microscopy (TEM). By comparing the fraction of RO and the ThT signal, we found that mutations that suppressed the high-temperature RO strongly inhibited amyloidogenesis. On the other hand, all variants forming RO also formed amyloids under the same conditions as the wild-type PDZ3.In biopharmaceutical process development time, cost and reliability are the relevant keywords. During the development of chromatographic processes these targets are challenged by many possible scaffolds, ligands and process parameters. The common response to this diversity is the establishment of platform processes in the development of chromatographic unit operations. However, while developing a platform library to simplify and accelerate chromatographic processes, the potential combination of scaffold, ligands and process parameters need to be characterized. This challenge is addressed in a case study on novel mixed mode (MM) adsorber for the removal of monoclonal antibody (mAb) aggregates. We propose a rigorous strategy to reduce the various experimental design space resulting from possible combinations in scaffolds, backbones and ligands. This strategy is based on theoretical considerations, identification of adsorber selectivity and capacity for the identification of a suitable membrane system. For this system, each potential MM membrane adsorber candidate is investigated in its high molecular weight species reduction potential for a given mAb feed stream and referenced to the performance of Capto™ Adhere. The introduced strategy can reduce the developmental effort in an early stage from three to two possible stationary phases. Thereafter, initial examinations at different ionic capacities enlighten one favorable stationary phase. Finalizing the development strategy procedure by studying five different MM ligands by HTS and confirming the study with a 2-3 MV higher dynamic breakthrough capacity in benchtop experiments and provides an insight in the benefits of a living process platform library.
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