Pandemics, public health emergencies and antimicrobial resistance - putting the threat in an epidemiologic and risk analysis context

Public health messaging about antimicrobial resistance (AMR) sometimes conveys the problem as an epidemic. We outline why AMR is a serious endemic problem manifested in hospital and community-acquired infections.

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Cancer survival disparities worsening by socio-economic disadvantage over the last 3 decades in new South Wales, Australia

Public concerns are commonly expressed about widening health gaps. This cohort study examines variations and trends in cancer survival by socio-economic disadvantage, geographical remoteness and country of bir...

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A socio-ecological analysis of barriers to the adoption, sustainablity and consistent use of sanitation facilities in rural Ethiopia

Despite evidence showing that access to and use of improved sanitation is associated with healthier households and communities, barriers influencing the adoption and sustainablity of sanitation facilities rema...

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Modelling the effects of booster dose vaccination schedules and recommendations for public health immunization programs: the case of Haemophilus influenzae serotype b

Haemophilus influenzae serotype b (Hib) has yet to be eliminated despite the implementation of routine infant immunization programs. There is no consensus regarding the number of prima...

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09/13/17 PHD comic: 'Impostor Attack'

Piled Higher & Deeper by Jorge Cham		www.phdcomics.com
title: "Impostor Attack" - originally published 9/13/2017 For the latest news in PHD Comics, CLICK HERE!

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Biodegradable Viral Nanoparticle/Polymer Implants Prepared via Melt-Processing

ACS Nano

DOI: 10.1021/acsnano.7b02786

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Controlling Protein Surface Orientation by Strategic Placement of Oligo-Histidine Tags

ACS Nano

DOI: 10.1021/acsnano.7b03717

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Serum 8-hydroxydeoxyguanosine and aldose reductase C-106T polymorphism in type 2 diabetes mellitus and its relation to complications in Egyptian patients

Abstract

Diabetes mellitus (DM) is an inherited disease, which can affect every organ in the body. 8-hydroxydeoxyguanosine (8-OHdG) is a biomarker for oxidative DNA damage. Occurrence of C-106T polymorphism of the aldose reductase (ALR) gene in type II diabetic patients suffering from diabetic microvascular complications has been reported. The aim of the present work was to assess the association between oxidative stress and C(-106)T ALR gene polymorphism and the incident of type 2 diabetes (T2D) and its complications. The current study was conducted on 200 subjects classified into 150 T2D patients and 50 healthy control subjects. Quantitative determination of human 8-OHdG was done using enzyme-linked immunosorbent assay (ELISA) technique. ALR C(-106)T polymorphism was assessed by PCR/RFLP method. Levels of 8-OHdG were significantly increased in diabetic patients when compared to control subjects and in diabetic patients with complications when compared to those without complications (P < 0.001 or all). CT genotype was associated with susceptibility to development of T2D in Egyptian population. Nevertheless, this association has not been observed in diabetic complications. 8-OHdG level is significantly increased in diabetic group when compared to the control group and in diabetic patients with complications when compared to diabetic patients without complications. C(-106)T gene polymorphisms were associated with susceptibility to development diabetes, but it has no associations in development of complications.

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Phenotypic variation of thymic epithelial cells and partial spontaneous regression in thymoma of a cow

Abstract

Thymoma was recognized in a 12-year-old Holstein dairy cow presenting with no significant clinical signs. The animal was conventionally slaughtered at an abattoir and, on postmortem examination, a spherical tumor mass was found in the anterior region of the mediastinum. Histologically, the tumor was fibrously encapsulated and exhibiting varying-sized cystoid cavities containing serous fluid and necrotic and hemorrhagic foci. No architectural features showing distinct characteristics to a sufficient degree to allow identification of the thymus or other organs could be seen. The tumor showed diffuse solid sheet-like or nodular patterns of proliferation and consisted of a dual cell population: one was neoplastic epithelial cells that were immunohistochemically positive for cytokeratin, and the other was T lymphocytes that exhibited positive immunohistochemical staining with CD3. This finding enabled a diagnosis of mixed thymoma to be made. Neoplastic epithelial cells represented a wide spectrum of phenotypic expression, including (1) spindle shaped cells with a chiasmus-like, interlacing fascicular, or storiform growth pattern; (2) small, round to oval cells with scant cytoplasm showing indistinct boundary of cells; (3) large cells arranged in a solid sheet-like pattern; (4) vacuolated cells similar to signet ring cells; (5) clear cells that had defined cell membranes; and (6) occasional formation of micronodules composed of neoplastic epithelial cells. In addition, some areas of the tumor exhibited features of partial spontaneous regression characterized by collapse or disintegration of tumor tissues in close association with fibrocollagenous connective tissue deposition. Even if the morphology of thymic epithelial cells in thymoma is known to display variable appearance, it is likely to be unusual that, in the current bovine case, such thymic epithelial cells exhibited a wider spectrum of phenotypic expression within a single tumor. This salient histomorphological heterogeneity shown by thymic epithelial cells might have presumably been associated with innate characteristics specific to pluripotent thymic epithelial cells during thymoma tumorigenesis.

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Limited proteolysis as a tool to probe the tertiary conformation of dysferlin and structural consequences of patient missense variant L344P [Molecular Biophysics]

Dysferlin is a large transmembrane protein that plays a key role in cell membrane repair, and underlies a recessive form of inherited muscular dystrophy. Dysferlinopathy is characterized by absence or marked reduction of dysferlin protein, with 43% of reported pathogenic variants being missense variants that span the length of the dysferlin protein. The unique structure of dysferlin, with seven tandem C2-domains separated by linkers, suggest dysferlin may dynamically associate with phospholipid membranes in response to Ca2+ signaling. However, the overall conformation of the dysferlin protein is uncharacterized. To dissect the structural architecture of dysferlin, we have applied the method of limited proteolysis that allows non-specific digestion of unfolded peptides by trypsin. Using five antibodies spanning the dysferlin protein, we identified a highly reproducible jigsaw map of dysferlin fragments protected from digestion. Our data infers a modular architecture of four tertiary domains; 1) C2A which is readily removed as a solo domain, 2) mid-region C2B-C2C-Fer-DysF, commonly excised as an intact module, with sub-digestion to different fragments suggesting several dynamic folding options 3) C-terminal four C2 domain module and 4) calpain-cleaved mini-dysferlinC72, which is particularly resistant to proteolysis. Importantly, we reveal a patient missense variant L344P which largely escapes proteosomal surveillance, shows subtle but clear changes in tertiary conformation. Accompanying evidence from immunohisto-chemistry and flow cytometry, using antibodies with conformationally sensitive epitopes, supports proteolysis data. Collectively, we provide insight into the structural topology of dysferlin and show how a single missense mutation within dysferlin can exert local changes in tertiary conformation.

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The crystal structure of the AhRR/ARNT heterodimer reveals the structural basis of the repression of AhR-mediated transcription [Gene Regulation]

2,3,7,8-Tetrachlorodibenzo-p-dioxin and related compounds (TCDDs) are extraordinarily potent environmental toxic pollutants. Most of the TCDD toxicities are mediated by aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor belonging to the basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) family. Upon ligand binding, AhR forms a heterodimer with AhR nuclear translocator (ARNT) and induces the expression of genes involved in various biological responses. One of the genes induced by AhR encodes AhR repressor (AhRR), which also forms a heterodimer with ARNT and represses the activation of AhR-dependent transcription. The control of AhR activation is critical for managing AhR-mediated diseases, but the mechanisms by which AhRR represses AhR activation remain poorly understood, due to the lack of structural information. Here, we determined the structure of the AhRR/ARNT heterodimer by X-ray crystallography, which revealed an asymmetric intertwined domain organization presenting structural features that are both conserved and distinct among bHLH-PAS family members. The structures of AhRR/ARNT and AhR/ARNT were similar in the bHLH-PAS-A region, while the PAS-B of ARNT in the AhRR/ARNT complex exhibited a different domain arrangement in this family reported so far. The structure clearly disclosed that AhRR competitively represses AhR binding to ARNT and target DNA, and further suggested the existence of an AhRR/ARNT-specific repression mechanism. This study provides a structural basis for understanding the mechanism by which AhRR represses AhR-mediated gene transcription.

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Splice variants of cytosolic polyadenylation element binding protein 2 (CPEB2) differentially regulate pathways linked to cancer metastasis [Cell Biology]

The translational regulator cytosolic polyadenylation element binding protein 2 has two isoforms, CPEB2A and CPEB2B, derived by alternative splicing of RNA into a mature form that either includes or excludes exon 4. Previously, we reported that this splicing event is highly dysregulated in aggressive forms of breast cancers, which overexpress CPEB2B. The loss of CPEB2A with a concomitant increase in CPEB2B was also required for breast cancer cells to resist cell death due to detachment (anoikis resistance) and metastasize in vivo. To examine the mechanism by which CPEB2 isoforms mediate opposing effects on cancer-related phenotypes, we used next-generation sequencing of triple-negative breast cancer cells in which the isoforms were specifically downregulated. Downregulation of the CPEB2B isoform inhibited pathways driving the epithelial-to-mesenchymal transition and hypoxic response, whereas downregulation of the CPEB2A isoform did not have this effect. Examining key nodes of these pathways showed that CPEB2B induced the expression of regulatory DNA trans- factors (e.g., HIF1α and TWIST1). Specifically, CPEB2B functioned as a translational activator of TWIST1 and HIF1α. Functional studies showed that specific downregulation of either HIF1α or TWIST1 inhibited the ability of CPEB2B to induce the acquisition of anoikis resistance and drive metastasis. Overall, this study demonstrates that CPEB2 alternative splicing is a major regulator of key cellular pathways linked to anoikis resistance and metastasis.

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BaP exposure causes oocyte meiotic arrest and fertilization failure to weaken female fertility [Research]

Benzo[a]pyrene (BaP) is a ubiquitous environmental pollutant and carcinogen that is frequently found in particulate matter, with a diameter of ≤2.5 μm (PM2.5). It has been reported to interrupt the normal reproductive system, but the exact molecular basis has not been clearly defined. To understand the underlying mechanisms regarding how BaP exposure disrupts female fertility, we evaluated oocyte quality by assessing the critical regulators and events during oocyte meiotic maturation and fertilization. We found that BaP exposure compromised the mouse oocyte meiotic progression by disrupting normal spindle assembly, chromosome alignment, and kinetochore–microtubule attachment, consequently leading to the generation of aneuploid eggs. In addition, BaP administration significantly decreased the fertilization rate of mouse eggs by reducing the number of sperm binding to the zona pellucida, which was consistent with the premature cleavage of N terminus of zona pellucida sperm–binding protein 2 and precocious exocytosis of ovastacin. Furthermore, BaP exposure interfered with the gamete fusion process by perturbing the localization and protein level of Juno. Notably, we found that BaP exposure induced oxidative stress with an increased level of reactive oxygen species and apoptosis in oocytes and thereby led to the deterioration of critical regulators and events during oocyte meiotic progression and fertilization. Our data document that BaP exposure reduces female fertility via impairing oocyte maturation and fertilization ability induced by oxidative stress and early apoptosis in murine models.—Zhang, M., Miao, Y., Chen, Q., Cai, M., Dong, W., Dai, X., Lu, Y., Zhou, C., Cui, Z., Xiong, B. BaP exposure causes oocyte meiotic arrest and fertilization failure to weaken female fertility.

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PI3K{gamma} ablation does not promote diabetes in db/db mice, but improves insulin sensitivity and reduces pancreatic {beta}-cell apoptosis [Research]

PI3K has emerged as a promising target for the treatment of obesity and insulin resistance; however, previous studies have indicated that PI3K activity in pancreatic β-cells is required for normal insulin secretion in response to glucose. Hence, a possible deterioration of insulin secretion capacity in patients who are predisposed to the failure of pancreatic β-cell function is a major concern for the pharmacologic inhibition of PI3K. To address this issue, we investigated the effects of PI3K ablation in db/db diabetic mice, a genetic model of obesity-driven β-cell failure and diabetes. Mice that lacked PI3K were backcrossed into db/+ mice C57BL/KS (>10 generations) to obtain db/db–PI3K^–/– mice. db/db–PI3K^–/– mice and control db/db mice were phenotyped for glucose homeostasis, insulin sensitivity, insulin secretion, steatosis, metabolic inflammation, pancreatic islet morphometry, islet cellular composition, and inflammation. Pancreatic β-cell apoptosis and proliferation were also evaluated. db/db–PI3K^–/– mice and control db/db mice developed similar body weight, steatosis, glycaemia, and insulin levels after a glucose load; however, db/db–PI3K^–/– mice displayed improved insulin tolerance, higher levels of fasting serum insulin, and lower pancreatic insulin content. In db/db–PI3K^–/– mice, the number of adipose tissue macrophages was similar to control, but displayed reduced adipose tissue neutrophils and M2-polarized adipose tissue gene expression. Finally, db/db–PI3K^–/– mice have more pancreatic β-cells and larger islets than db/db mice, despite displaying similar islet inflammation. This phenotype could be explained by reduced β-cell apoptosis in db/db–PI3K^–/– mice compared with control db/db mice. Our results are consistent with the concept that the beneficial action of PI3K ablation in obesity-driven glucose intolerance is largely a result of its leptin-dependent effects on adiposity and, to a lesser extent, the promotion of adipose tissue neutrophil recruitment and M1 polarization of gene expression. Of importance, our data challenge the concept that PI3K is required for insulin secretion in response to glucose in vivo, and indicate that PI3K ablation protects db/db mice from β-cell apoptosis and improves fasting insulin levels. We conclude that PI3K inhibition in obese patients who are predisposed to β-cell failure is not expected to produce adverse effects on insulin secretion.—Breasson, L., Sardi, C., Becattini, B., Zani, F., Solinas, G. PI3K ablation does not promote diabetes in db/db mice, but improves insulin sensitivity and reduces pancreatic β-cell apoptosis.

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GTRAP3-18 regulates food intake and body weight by interacting with pro-opiomelanocortin [Research]

Pro-opiomelanocortin (POMC)-expressing neurons provide α-melanocyte–stimulating hormone (α-MSH), which stimulates melanocortin 4 receptor to induce hypophagia by AMPK inhibition in the hypothalamus. α-MSH is produced by POMC cleavage in secretory granules and released. However, it is not known yet whether any posttranscriptional regulatory mechanism of POMC signaling exists upstream of the secretory granules in neurons. Here we show that glutamate transporter–associated protein 3-18 (GTRAP3-18), an anchor protein that retains interacting proteins in the endoplasmic reticulum, is a critical regulator of food intake and body weight by interacting with POMC. GTRAP3-18-deficient mice showed hypophagia, lean bodies, and lower blood glucose, insulin, and leptin levels with increased serum and brain α-MSH levels, leading to AMPK inhibition. Intraperitoneal glucose tolerance tests revealed significantly decreased blood glucose levels and areas under the curve in GTRAP3-18-deficient mice compared to wild-type mice. An intracerebroventricular infusion of a selective melanocortin 4 receptor antagonist to GTRAP3-18-deficient mice significantly increased their food intake and body weight. A fluorescence resonance energy transfer study showed an interaction between GTRAP3-18 and POMC in vitro. These findings suggest that activation of the melanocortin pathway by modulating GTRAP3-18/POMC interaction could be an alternative strategy for obesity and/or type 2 diabetes.—Aoyama, K., Bhadhprasit, W., Watabe, M., Wang, F., Matsumura, N., Nakaki, T. GTRAP3-18 regulates food intake and body weight by interacting with pro-opiomelanocortin.

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{alpha}-Linolenic acid-derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40 [Research]

Among dietary fatty acids with immunologic effects, -3 polyunsaturated fatty acids, such as α-linolenic acid (ALA), have been considered as factors that contribute to the differentiation of M2-type macrophages (M2 macrophages). In this study, we examined the effect of ALA and its gut lactic acid bacteria metabolites 13-hydroxy-9(Z),15(Z)-octadecadienoic acid (13-OH) and 13-oxo-9(Z),15(Z)-octadecadienoic acid (13-oxo) on the differentiation of M2 macrophages from bone marrow–derived cells (BMDCs) and investigated the underlying mechanisms. BMDCs were stimulated with ALA, 13-OH, or 13-oxo in the presence of IL-4 or IL-13 for 24 h, and significant increases in M2 macrophage markers CD206 and Arginase-1 (Arg1) were observed. In addition, M2 macrophage phenotypes were less prevalent following cotreatment with GPCR40 antagonists or inhibitors of PLC-β and MEK under these conditions, suggesting that GPCR40 signaling is involved in the regulation of M2 macrophage differentiation. In further experiments, remarkable M2 macrophage accumulation was observed in the lamina propria of the small intestine of C57BL/6 mice after intragastric treatments with ALA, 13-OH, or 13-oxo at 1 g/kg of body weight per day for 3 d. These findings suggest a novel mechanism of M2 macrophage differentiation involving fatty acids from gut lactic acid bacteria and GPCR40 signaling.—Ohue-Kitano, R., Yasuoka, Y., Goto, T., Kitamura, N., Park, S.-B., Kishino, S., Kimura, I., Kasubuchi, M., Takahashi, H., Li, Y., Yeh, Y.-S., Jheng, H.-F., Iwase, M., Tanaka, M., Masuda, S., Inoue, T., Yamakage, H., Kusakabe, T., Tani, F., Shimatsu, A., Takahashi, N., Ogawa, J., Satoh-Asahara, N., Kawada, T. α-Linolenic acid–derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40.

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Cathepsin B-mediated CD18 shedding regulates leukocyte recruitment from angiogenic vessels [Research]

Cathepsin B (CtsB) contributes to atherosclerosis and cancer progression by processing the extracellular matrix and promoting angiogenesis. Although CtsB was reported to promote and reduce angiogenesis, there is no mechanistic explanation that reconciles this apparent discrepancy. CtsB cleaves CD18 from the surface of immune cells, but its contribution to angiogenesis has not been studied. We developed an in vivo technique for visualization of immune cell transmigration from corneal vessels toward implanted cytokines. Wild-type (WT) leukocytes extravasated from limbal vessels, angiogenic stalks, and growing tip vessels and migrated toward the cytokines, indicating immune competence of angiogenic vessels. Compared to WT leukocytes, CtsB^–/– leukocytes accumulated in a higher number in angiogenic vessels, but extravasated less toward the implanted cytokine. The accumulated CtsB^–/– leukocytes in angiogenic vessels expressed more CD18. CD18^–/– leukocytes extravasated later than WT leukocytes. However, once extravasated, CD18^–/– leukocytes transmigrated more rapidly than their WT counterparts. These results suggest that, although CD18 facilitates efficient extravasation, outside of the vessel CD18 interaction with the extracellular matrix, it reduced transmigration velocity. Our results reveal an unexpected role for CtsB in leukocyte extravasation and transmigration, which advances our understanding of the complex contribution of CtsB to angiogenesis.—Nakao, S., Zandi, S., Sun, D., Hafezi-Moghadam, A. Cathepsin B-mediated CD18 shedding regulates leukocyte recruitment from angiogenic vessels.

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Dyslipidemia impairs mitochondrial trafficking and function in sensory neurons [Research]

Mitochondrial trafficking plays a central role in dorsal root ganglion (DRG) neuronal cell survival and neurotransmission by transporting mitochondria from the neuronal cell body throughout the bundles of DRG axons. In type 2 diabetes (T2DM), dyslipidemia and hyperglycemia damage DRG neurons and induce mitochondrial dysfunction; however, the impact of free fatty acids and glucose on mitochondrial trafficking in DRG neurons remains unknown. To evaluate the impact of free fatty acids compared to hyperglycemia on mitochondrial transport, primary adult mouse DRG neuron cultures were treated with physiologic concentrations of palmitate and glucose and assessed for alterations in mitochondrial trafficking, mitochondrial membrane potential, and mitochondrial bioenergetics. Palmitate treatment significantly reduced the number of motile mitochondria in DRG axons, but physiologic concentrations of glucose did not impair mitochondrial trafficking dynamics. Palmitate-treated DRG neurons also exhibited a reduction in mitochondrial velocity, and impaired mitochondrial trafficking correlated with mitochondrial depolarization in palmitate-treated DRG neurons. Finally, we found differential bioenergetic effects of palmitate and glucose on resting and energetically challenged mitochondria in DRG neurons. Together, these results suggest that palmitate induces DRG neuron mitochondrial depolarization, inhibiting axonal mitochondrial trafficking and altering mitochondrial bioenergetic capacity.—Rumora, A. E., Lentz, S. I., Hinder, L. M., Jackson, S. W., Valesano, A., Levinson, G. E., Feldman, E. L. Dyslipidemia impairs mitochondrial trafficking and function in sensory neurons.

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lncRNA AK017368 promotes proliferation and suppresses differentiation of myoblasts in skeletal muscle development by attenuating the function of miR-30c [Research]

Long noncoding RNAs (lncRNAs) have been reported to play diverse roles in biologic and pathologic processes, including myogenesis. We found that lncRNA AK017368 is highly expressed in skeletal muscle cells. Functional analyses showed that overexpression of AK017368 promoted proliferation and restrained differentiation of myoblasts; whereas inhibition of AK017368 had completely opposite effects in vitro. In mice, knockdown of AK017368 promoted muscle hypertrophy in vivo. RNA molecules of AK017368 acted mechanistically as competing endogenous RNAs to target micro-RNA (miR)-30c, which was supported by the results of bioinformatics analyses and dual-luciferase reporter assays. It has been shown that lncRNA AK017368 competes with trinucleotide repeat containing-6A (Tnrc6a) for miR-30c. Tnrc6a was previously reported to promote proliferation and inhibit differentiation of myoblast cells, whereas miR-30c targets the 3'-UTR of Tnrc6a mRNA to weaken its function. Taken together, lncRNA AK017368 promotes proliferation and inhibits differentiation of myoblast cells by attenuating function of miR-30c.—Liang, T., Zhou, B., Shi, L., Wang, H., Chu, Q., Xu, F., Li, Y., Chen, R., Shen, C., Schinckel, A. P. lncRNA AK017368 promotes proliferation and suppresses differentiation of myoblasts in skeletal muscle development by attenuating the function of miR-30c.

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Eliciting improved antibacterial efficacy of host proteins in the presence of antibiotics [Research]

We recently reported the aptitude of a membrane-active lipopeptide (C₁₀OOc₁₂O) to sensitize gram-negative bacilli (GNB) to host antibacterial proteins. Here we explored the potential of harnessing such capacity in the presence of antibiotics. For this purpose, we compared Escherichia coli sensitization to antibiotics in broth and plasma; assessed inner and outer membrane damages using scanning electron microscopy, dyes, and mutant strains; and assessed the ability to affect disease course using the mouse peritonitis–sepsis model for mono- and combination therapies. We found that by altering permeability of both outer and inner membranes, subinhibitory concentrations of C₁₀OOc₁₂O can transiently sensitize GNB to diverse cytoplasm-targeting antibiotics in simple media. Sensitization was maintained in plasma, where C₁₀OOc₁₂O instigated greater bactericidal activities, including in the presence of a bacteriostatic antibiotic (erythromycin). Single-dose administrations of rifampin and C₁₀OOc₁₂O to E. coli–infected mice resulted in 55% vs. 0, and 36% viability, respectively, for combined and individual treatments. Combining C₁₀OOc₁₂O and erythromycin has similarly improved mice protection from developing fatal sepsis. Consequently, the data confirmed that C₁₀OOc₁₂O renders GNB sensitive to both endogenous and exogenous antibacterials, and suggested that the tripartite concomitant presence increases therapeutic efficacy synergistically. This approach might expand the available treatment options to comprise antimicrobials with low permeability and/or efflux issues.—Jammal, J., Zaknoon, F., Mor, A. Eliciting improved antibacterial efficacy of host proteins in the presence of antibiotics.

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