Potential therapeutic effect of alkaline reduced water in polycystic ovarian syndrome

Publication date: Available online 24 May 2017
Source:Medical Hypotheses
Author(s): Jesmin Ara, Selikem Abla Nuwormegbe, Ma. Easter Joy Sajo, Kwang-Yong Shim, Kyu-Jae Lee
Polycystic ovarian syndrome (PCOS) is an endocrine-metabolic disorder characterized by hormonal disturbances including hyperandrogenemia, insulin resistance, and hyperinsulinemia culminating into obesity, multiple ovarian cysts and anovulatory infertility in women. There has been no effective medication against PCOS and its complication. However, weight loss can reduce insulin resistance, which in turn helps to restore hormonal balance and ovulation resulting to improved fertility. Previously, we reported that alkaline reduced water (ARW) could significantly reduce obesity by alleviating adiposity, regulating the levels of adipokines/pro-inflammatory cytokines and by inducing cholesterol homeostasis. Herein, we hypothesize that ARW might ameliorate the pathophysiological (hormonal, metabolic, and immunological) imbalances incurred by PCOS, thereby improving the infertility of PCOS patients.



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Cover Figure

Publication date: June 2017
Source:Cortex, Volume 91





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Editorial Board/Title Page

Publication date: June 2017
Source:Cortex, Volume 91





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Appendiceal Goblet Cell Carcinoid: Common Errors in Staging and Clinical Interpretation with a Proposal for an Improved Terminology

Publication date: Available online 24 May 2017
Source:Human Pathology
Author(s): Kwun Wah Wen, Gillian Hale, Nafis Shafizadeh, Mojgan Hosseini, Anne Huang, Sanjay Kakar
Goblet cell carcinoid (GCC) is staged and treated as adenocarcinoma (AC) and not as neuroendocrine tumor (NET) or neuroendocrine carcinoma. The term 'carcinoid' may lead to incorrect interpretation as NET. To explore pitfalls in staging and clinical interpretation of GCC and mixed GCC-AC, and propose strategies to avoid common errors. Diagnostic terminology, staging and clinical interpretation were evaluated in 58 cases (27 GCC, 31 mixed GCC-AC). Opinions were collected from 23 pathologists using a survey. Clinical notes were reviewed to assess the interpretation of pathology diagnoses by oncologists. NET staging was incorrectly used for 25% GCC and 5% mixed GCC-AC. In the survey, 43% of pathologists incorrectly indicated that NET staging is applicable to GCC and 43% incorrectly responded that Ki-67 proliferation index is necessary for GCC grading. Two cases each of GCC and mixed GCC-AC were incorrectly interpreted as neuroendocrine neoplasms by oncologists, and platinum-based therapy was considered for 2 GCC-AC cases due to the mistaken impression of neuroendocrine carcinoma created by use of the World Health Organization (WHO) 2010 term 'mixed adenoneuroendocrine carcinoma' (MANEC). The term 'carcinoid' in GCC and use of MANEC for mixed GCC-AC leads to errors in staging and treatment. We propose that 'goblet cell carcinoid' should be changed to 'goblet cell carcinoma', while GCC with AC should be referred to as 'mixed GCC-AC' with a comment about the proportion of each component and the histologic subtype of AC. This terminology will facilitate appropriate staging and clinical management, and avoid errors in interpretation.



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Synthesis and Evaluation of Symmetric Acyclic Nucleoside Bisphosphonates as Inhibitors of the Plasmodium falciparum, Plasmodium vivax and Human 6-Oxopurine Phosphoribosyltransferases and the Antimalarial Activity of Their Prodrugs

Publication date: Available online 24 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Petr Špaček, Dianne T. Keough, Marina Chavchich, Martin Dračínský, Zlatko Janeba, Lieve Naesens, Michael D. Edstein, Luke W. Guddat, Dana Hocková
Two new series of symmetric acyclic nucleoside bisphosphonates (ANbPs) have been synthesised as potential inhibitors of the Plasmodium falciparum (Pf) and vivax (Pv) 6-oxopurine phosphoribosyltransferases. The structural variability between these symmetric ANbPs lies in the number of atoms in the two acyclic linkers connecting the N⁹ atom of the purine base to each of two phosphonate groups and the branching point of the acyclic moiety relative to the purine base, which occurs at either the alpha or beta positions. Within each series, six different 6-oxopurine bases have been attached. In general, the ANbPs with either guanine or hypoxanthine have lower Ki values than for those containing either the 8-bromo or 7-deaza 6-oxopurine bases. The lowest Ki values obtained for the two parasite enzymes were 0.1 μM (Pf) and 0.2 μM (Pv) for this series of compounds. Two phosphoramidate prodrugs of these inhibitors exhibited antimalarial activity against Pf in infected erythrocyte cell culture with IC50 values of 0.8 and 1.5 μM. These two compounds exhibited low cytotoxicity in human A549 cells having CC50 values of >300 μM resulting in an excellent selectivity index.

Graphical abstract

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The IL-33/ST2 axis is crucial in type 2 airway responses induced by the Staphylococcus aureus protease SplD.

Related Articles

The IL-33/ST2 axis is crucial in type 2 airway responses induced by the Staphylococcus aureus protease SplD.

J Allergy Clin Immunol. 2017 May 19;:

Authors: Teufelberger AR, Nordengrün M, Braun H, Maes T, De Grove K, Holtappels G, O'Brien C, Provoost S, Hammad H, Gonçalves A, Beyaert R, Declercq W, Vandenabeele P, Krysko DV, Bröker BM, Bachert C, Krysko O

Abstract
BACKGROUND: Chronic airway inflammatory diseases such as chronic rhinosinusitis with nasal polyps and asthma showed increased nasal Staphylococcus aureus (S. aureus) colonization. Serine protease like protein D (SplD) and other closely related proteases secreted by S. aureus have recently been identified as inducers of allergic asthma in humans and mice but their mechanism of action is largely unknown.
OBJECTIVE: We investigated the role of recombinant SplD in driving Th2-biased responses and IgE formation in a murine model of allergic asthma.
METHODS: Allergic asthma was induced in C57BL/6 J wild type mice, TLR4 knockout mice (TLR4(-/-)) and Rag2 knockout mice (Rag2(-/-)) by repeated intratracheal applications of SplD. Inflammatory parameters in the airways were assessed by flow cytometry, ELISA, Luminex and immunohistochemistry. Serum SplD-specific IgE levels were analysed by ELISA.
RESULTS: We observed that repeated intratracheal exposure to SplD led to IL-33 and eotaxin production, eosinophilia, bronchial hyperreactivity and goblet cell hyperplasia in the airways. Blocking the IL-33 activity using a soluble ST2 receptor (sST2) significantly decreased the numbers of eosinophils, IL-13(+)ILC2s, IL-13(+)CD4(+) T cells, and IL-5 and IL-13 production by lymph node cells but had no effect on IgE production. SplD-induced airway inflammation and IgE production were largely dependent on the presence of the functional adaptive immune system and independent of TLR4 signalling.
CONCLUSION: The S. aureus-derived protein SplD is a potent allergen of S. aureus and induces a Th2-biased inflammatory response in the airways in an IL-33-dependent, but TRL4-independent manner. sST2 could be an efficient strategy to interfere with SplD-induced Th2 inflammation, but does not prevent the allergic sensitization.

PMID: 28532656 [PubMed - as supplied by publisher]

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The adaptive immune system in atopic dermatitis and implications on therapy.

Related Articles

The adaptive immune system in atopic dermatitis and implications on therapy.

Expert Rev Clin Immunol. 2016 Jul;12(7):787-96

Authors: Roesner LM, Werfel T, Heratizadeh A

Abstract
In atopic dermatitis (AD), the skin inflammation is believed to occur due to a misdirected immune reaction against harmless antigens on the one hand, and to a disturbed skin barrier on the other. In recent years, vast efforts have been made to investigate the relevance and details of the immune response to allergens. Clinically, it was demonstrated for the first time that aeroallergen exposure leads to worsening of AD symptoms. An overexpression of Th2 cytokines has been observed in acute and subacute lesions of AD. The clinical impact of the key Th2 cytokines IL-4 and IL-13 on atopic dermatitis has recently been shown in clinical studies with dupilumab, a monoclonal antibody which blocks the IL-4/IL-13 receptor. In vitro data indicate, however, that the T cell response is not solely Th2-polarized but may lead to heterogeneous cytokine production involving IFN-γ and IL-17 in an allergen-dependent manner. Classical thymus-derived Foxp3 T cells have interestingly been detected in elevated numbers in the circulation of AD patients. Therapeutic approaches with allergen specific immunotherapy aim to induce regulatory T cells of the Tr1 type. The strikingly altered microbiome of AD skin with diminished diversity of bacteria on lesional skin but increases of S. aureus colonization and the sensitization against microbial allergens and homologue self-proteins deserve special attention. For the treatment of itch symptoms, which still represent a challenge in daily practice, promising data have been published on the relevance of the H(histamine)4-receptor and on mediators such as IL-31, TSLP.

PMID: 26967382 [PubMed - indexed for MEDLINE]

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Intensity-modulated proton therapy and osteoradionecrosis in oropharyngeal cancer

Publication date: Available online 23 May 2017
Source:Radiotherapy and Oncology
Author(s): Wencheng Zhang, Xiaodong Zhang, Pei Yang, Pierre Blanchard, Adam S. Garden, Brandon Gunn, C. David Fuller, Mark Chambers, Katherine A. Hutcheson, Rong Ye, Stephen Y. Lai, Mohamed Abdallah Sherif Radwan, X. Ron Zhu, Steven J. Frank
PurposeWe compared mandibular doses and osteoradionecrosis in patients with oropharyngeal cancer after intensity-modulated radiation therapy (IMRT) or intensity-modulated proton therapy (IMPT).Methods and materialsWe identified 584 patients who received definitive radiotherapy for oropharyngeal cancer from January 2011 through June 2014 at MD Anderson Cancer Center (534 IMRT and 50 IMPT). The dosimetric variables and osteoradionecrosis were compared with Chi-square test or Fisher's exact test.ResultsMedian follow-up time for all patients (534 IMRT and IMPT) was 33.8months (33.8months IMRT vs. 34.6months IMPT, P=0.854), and median time to osteoradionecrosis was 11.4months (range 6.74–16.1months). Mandibular doses were lower for patients treated with IMPT (minimum 0.8 vs. 7.3Gy; mean 25.6 vs. 41.2Gy; P<0.001), and osteoradionecrosis rates were lower as well: 2% IMPT (1 grade 1), 7.7% IMRT (12 grade 4, 5 grade 3, 1 grade 2 and 23 grade 1). Osteoradionecrosis location depended on the primary tumor site and high-dose field in the mandible.ConclusionsOsteoradionecrosis events were significantly associated with higher dose irradiation to mandibular. Use of IMPT minimized excess irradiation of the mandible and consequently reduced the risk of osteoradionecrosis for oropharyngeal cancer.



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Glycemic Control in the Treatment of Psoriasis

Psoriasis is a common chronic inflammatory skin disease that manifests as scaly erythematous plaques as a consequence of keratinocyte hyperproliferation and inflammation. It is commonly associated with diabetes, obesity, and the metabolic syndrome. While there are numerous approved treatment options available, they have limitations including availability, toxicities such as immunosuppression, and high cost. There is increasing evidence to suggest that several hypoglycemic agents used in the treatment of type 2 diabetes, including glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, thiazolidinediones and biguanides, exert beneficial effects in psoriasis. In this review, we summarize the growing evidence supporting the therapeutic role of hypoglycemic agents in psoriasis and discuss the potential underlying mechanisms. We suggest that dermatologists consider the use of hypoglycemic agents in psoriasis especially in cases with coexisting diabetes and in cases in which immunosuppression is contraindicated. Earlier referral to endocrinology in patients with concomitant diabetes may be appropriate.
Dermatology

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Thyroid hormone treatment activates protective pathways in both in vivo and in vitro models of neuronal injury

Publication date: Available online 23 May 2017
Source:Molecular and Cellular Endocrinology
Author(s): Jianrong Li, Ines Donangelo, Kiyomi Abe, Oscar Scremin, Sujie Ke, Feng Li, Anna Milanesi, Yan-Yun Liu, Gregory A. Brent
Thyroid hormone plays an important role in brain development and adult brain function, and may influence neuronal recovery after Traumatic Brain Injury (TBI). We utilized both animal and cell culture models to determine the effects of thyroid hormone treatment, post TBI or during hypoxia, on genes important for neuronal survival and neurogenesis. We show that TBI in rats is associated with a reduction in serum thyroxine (T4) and triiodothyronine (T3). A single dose of levothyroxine (T4), one hour after injury, increased serum T4 and normalized serum T3 levels. Expression of genes important for thyroid hormone action in the brain, MCT8 and Type 2 deiodinase (Dio2) mRNA, diminished after injury, but were partially restored with T4 treatment. mRNA from the Type 3 deiodinase (Dio3) gene, which inactivates T4 to reverse T3 (rT3), was induced 2.7 fold by TBI, and further stimulated 6.7-fold by T4 treatment. T4 treatment significantly increased the expression of mRNA from Bcl2, VEGFA, Sox2 and neurotrophin, genes important for neuronal survival and recovery. The cortex, compared to the hippocampus and cerebellum, sustained the greatest injury and had the most significant change in gene expression as a result of injury and the greatest response to T4 treatment. We utilized hypoxia to study the effect of neuronal injury in vitro. Neuroblastoma cells were exposed to reduced oxygen tension, 0.2%, and were compared to cells grown at control oxygen levels of 21%. T3 treatment significantly increased hypoxia inducible factor (HIF)-2α protein, but not HIF-1α. In a hypoxia time course exposure, expression of hypoxia-mediated genes (VEGF, Enolase, HIF2α, c-Jun) peaked at least 8 h earlier with T3-treatment, compared to cells grown without T3. The early induction of these genes may promote cellular growth after injury. After hypoxic injury, T3 induced mRNA from the genes, KLF9 and hairless, important for T3-mediated brain function. The findings from both in vitro and in vivo studies support a role of thyroid hormone in activating pathways important for neuronal protection and promotion of neuronal recovery after injury.



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Early transcriptome responses of the bovine midcycle corpus luteum to prostaglandin F2α includes cytokine signaling

Publication date: Available online 23 May 2017
Source:Molecular and Cellular Endocrinology
Author(s): Heather Talbott, Xiaoying Hou, Fang Qiu, Pan Zhang, Chittibabu Guda, Fang Yu, Robert A. Cushman, Jennifer R. Wood, Cheng Wang, Andrea S. Cupp, John S. Davis
In ruminants, prostaglandin F2alpha (PGF2α)-mediated luteolysis is essential prior to estrous cycle resumption, and is a target for improving fertility. To deduce early PGF2α-provoked changes in the corpus luteum a short time-course (0.5–4 h) was performed on cows at midcycle. A microarray-determined transcriptome was established and examined by bioinformatic pathway analysis. Classic PGF2α effects were evident by changes in early response genes (FOS, JUN, ATF3) and prediction of active pathways (PKC, MAPK). Several cytokine transcripts were elevated and NF-κB and STAT activation were predicted by pathway analysis. Self-organizing map analysis grouped differentially expressed transcripts into ten mRNA expression patterns indicative of temporal signaling cascades. Comparison with two analogous datasets revealed a conserved group of 124 transcripts similarly altered by PGF2α treatment, which both, directly and indirectly, indicated cytokine activation. Elevated levels of cytokine transcripts after PGF2α and predicted activation of cytokine pathways implicate inflammatory reactions early in PGF2α-mediated luteolysis.



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Pancreatic-derived factor impaired glucagon-like Peptide-1 production from GLUTag enterendorine L-cell line and intestines

Publication date: Available online 24 May 2017
Source:Molecular and Cellular Endocrinology
Author(s): Fenghua Lai, Yan Chen, Huimei Lin, Xuelan Wang, Xiaonan Zhu, Yanbing Li, Haipeng Xiao, Xiaopei Cao
PurposePancreatic-derived factor (PANDER) is a pancreatic islet-specific cytokine that co-secretes with insulin. However, its biological function remains largely unknown. We have recently shown that the intestine might be its novel target tissue. The aim of this study was to clarify whether PANDER impacts the production of glucagon-like peptide-1 (GLP-1).MethodsWe treated GLUTag cells from the mouse intestine L cell line with recombinant PANDER protein and hepatic overexpression of PANDER in an obese murine model.ResultsIn GLUTag cells, PANDER exposure led to decreased proglucagon gene mRNA expression and GLP-1 secretion without affecting cell viability or caspase-3 activation. Overexpression of PANDER in mice induced glucose intolerance and impaired glucose-stimulated GLP-1 secretion Moreover, PANDER blocked insulin-induced GLP-1 secretion by inhibiting the insulin signalling-Wnt pathway and directly inhibited the cAMP/PKA pathway.ConclusionsOur findings indicate that intestinal L cells are responsive to PANDER, and elevated PANDER levels impair GLP-1 production in vitro and in vivo.



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Evolution of thyroid hormone signaling in animals: Non-genomic and genomic modes of action

Publication date: Available online 23 May 2017
Source:Molecular and Cellular Endocrinology
Author(s): Elias Taylor, Andreas Heyland
Much research has focused on vertebrate thyroid hormone (TH) synthesis and their function in development and metabolism. While important differences in TH synthesis and signaling exist, comparative studies between vertebrates fail to explain the evolutionary origins of this important regulatory axis. For that, one needs to make sense out of the diverse TH effects which have been described in invertebrate phyla but for which a mechanistic understanding is largely missing. Almost every major group of non-vertebrate animals possesses the capability to synthesize and metabolize thyroid hormones and there is evidence for a nuclear thyroid hormone receptor mediated mechanism in the bilateria, especially in molluscs, echinoderms, cephalochordates and ascidians. Still, genomic pathways cannot fully explain many observed effects of thyroid hormones in groups such as cnidarians, molluscs, and echinoderms and it is therefore possible that TH may signal via other mechanisms, such as non-genomic signaling systems via membrane bound or cytoplasmic receptors. Here we provide a brief review of TH actions in selected invertebrate species and discuss the hypothesis that non-genomic TH action may have played a critical role in TH signaling throughout animal evolution.



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LL-37-induced human mast cell activation through G protein-coupled receptor MrgX2

Publication date: August 2017
Source:International Immunopharmacology, Volume 49
Author(s): Yangyang Yu, Yuanyuan Zhang, Yarui Zhang, Yihong Lai, Wenwen Chen, Zhangang Xiao, Wei Zhang, Meiling Jin, Bo Yu
Human LL-37 is an important class of cationic antimicrobial peptide (CAP) that is known to stimulate mast cell activation. While many studies have been conducted on LL-37, to date little is known about the functional receptors for LL-37-induced human mast cell activation, in particular in terms of the release of de novo synthesized mediators. Thus, the aim of the present study is to identify the functional receptors for LL-37-induced human mast cell activation in terms of the degranulation and release of de novo synthesized mediators and investigate the downstream signalling pathways involved in mast cell activation. Overall, our study importantly demonstrates that LL-37-induced human mast cell degranulation and release of de novo synthesized mediators function primarily through the activation of MrgX2. We furthermore show that LL-37-induced human mast cell line LAD2 cells are involved in the degranulation and release of IL-8, and that FPRL1 and P2X7 have only a partial effect on IL-8 release, and no effect on mast cell degranulation triggered by LL-37. Instead, we find that silencing the expression of MrgX2 in human mast cell significantly inhibits the LL-37-induced degranulation and release of IL-8. Overall, this effect is associated with the activation of the Gi protein, PLC/PKC/Calcium/NFAT, PI3K/Akt and MAPKs signalling pathways.

Graphical abstract

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Effects of androgen deprivation therapy on telomere length

Abstract

Objective

Recent evidence suggests that androgens either directly or via aromatisation to oestradiol may regulate telomere length, hence providing a mechanism whereby reproductive steroids are linked to biological aging in men. Using men with prostate cancer initiating androgen deprivation therapy (ADT), we tested the hypothesis that severe sex steroid deprivation would accelerate telomere shortening.

Design

We conducted a secondary analysis of a 2-year prospective controlled study among 65 men with non-metastatic prostate cancer newly commencing adjuvant ADT (n=40) and age- and radiotherapy-matched prostate cancer controls (n=25).

Methods

We measured leukocyte telomere length (LTL) expressed as telomeric/single copy control gene (T/S) ratio at baseline, 6, 12 and 24 months. Generalised linear models determined the mean adjusted difference (MAD) [95% confidence interval] between groups during follow-up.

Results

Compared to controls over 24 months, men receiving ADT had no change in LTL, MAD for T/S ratio (0.105 [-0.004; 0.213], p=0.235).

Conclusions

Using men with prostate cancer receiving ADT as a model we found no evidence that prolonged and profound sex steroid deprivation is associated with accelerated telomerase shortening Larger studies will be required to confirm, or refute these findings.

This article is protected by copyright. All rights reserved.

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Proliferation Drives Aging-Related Functional Decline in a Subpopulation of the Hematopoietic Stem Cell Compartment

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Kristina Kirschner, Tamir Chandra, Vladimir Kiselev, David Flores-Santa Cruz, Iain C. Macaulay, Hyun Jun Park, Juan Li, David G. Kent, Rupa Kumar, Dean C. Pask, Tina L. Hamilton, Martin Hemberg, Wolf Reik, Anthony R. Green
Aging of the hematopoietic stem cell (HSC) compartment is characterized by lineage bias and reduced stem cell function, the molecular basis of which is largely unknown. Using single-cell transcriptomics, we identified a distinct subpopulation of old HSCs carrying a p53 signature indicative of stem cell decline alongside pro-proliferative JAK/STAT signaling. To investigate the relationship between JAK/STAT and p53 signaling, we challenged HSCs with a constitutively active form of JAK2 (V617F) and observed an expansion of the p53-positive subpopulation in old mice. Our results reveal cellular heterogeneity in the onset of HSC aging and implicate a role for JAK2V617F-driven proliferation in the p53-mediated functional decline of old HSCs.

Graphical abstract

Teaser

Kirschner et al. describe heterogeneous aging of hematopoietic stem cells (HSCs), with a subset of old HSCs displaying signs of functional exhaustion. An increase in proliferation expands the aged HSC subgroup, linking prolonged proliferation to functional decline in HSCs.


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Using hESCs to Probe the Interaction of the Diabetes-Associated Genes CDKAL1 and MT1E

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Min Guo, Tuo Zhang, Xue Dong, Jenny Zhaoying Xiang, Minxiang Lei, Todd Evans, Johannes Graumann, Shuibing Chen
Genome-wide association studies (GWASs) have identified many disease-associated variant alleles, but understanding whether and how different genes/loci interact requires a platform for probing how the variant alleles act mechanistically. Isogenic mutant human embryonic stem cells (hESCs) provide an unlimited resource to derive and study human disease-relevant cells. Here, we focused on CDKAL1, linked by GWASs to diabetes. Through transcript profiling, we find that expression of the metallothionein (MT) gene family, also linked by GWASs to diabetes, is significantly downregulated in CDKAL1^−/− cells that have been differentiated to insulin-expressing pancreatic beta-like cells. Forced MT1E expression rescues both hypersensitivity of CDKAL1 mutant cells to glycolipotoxicity and pancreatic beta-cell dysfunction in vitro and in vivo. MT1E functions at least in part through relief of ER stress. This study establishes an isogenic hESC-based platform to study the interaction of GWAS-identified diabetes gene variants and illuminate the molecular network impacting disease progression.

Graphical abstract

Teaser

Guo et al. use an isogenic hESC-based platform to study the interaction of diabetes-associated genes identified by GWASs. The authors find that biallelic mutations of CDKAL1 cause impaired insulin section and hypersensitivity to glucolipotoxicity, which can be rescued by expression of MT1E, at least in part, through suppression of ER stress.


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Cortico-Accumbens Regulation of Approach-Avoidance Behavior Is Modified by Experience and Chronic Pain

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Neil Schwartz, Catriona Miller, Howard L. Fields
Although optimizing decisions between drives to avoid pain and to obtain reward are critical for survival, understanding the neuronal circuit activity that regulates choice during approach-avoidance conflicts is limited. Here, we recorded neuronal activity in the infralimbic (IL) cortex and nucleus accumbens (NAc) during an approach-avoidance task. In this task, disruption of approach by a pain-predictive cue (PPC-avoidance) is extinguished by experience and reinstated in a model of chronic pain. In the IL-NAc circuit, the activity of distinct subpopulations of neurons predicts the extent of PPC-avoidance observed. Furthermore, chemogenetic and optogenetic manipulations establish that IL-NAc circuitry regulates PPC-avoidance behavior. Our results indicate that IL-NAc circuitry is engaged during approach-avoidance conflicts, and modifications of this circuit by experience and chronic pain determine whether approach or avoidance occurs.

Graphical abstract

Teaser

Schwartz et al. establish that an approach-avoidance choice is regulated by cortico-accumbens activity, and that learning, chronic pain, or targeted manipulations of this circuit determine whether approach or avoidance occurs.


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Schizophrenia-Related Microdeletion Impairs Emotional Memory through MicroRNA-Dependent Disruption of Thalamic Inputs to the Amygdala

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Tae-Yeon Eom, Ildar T. Bayazitov, Kara Anderson, Jing Yu, Stanislav S. Zakharenko
Individuals with 22q11.2 deletion syndrome (22q11DS) are at high risk of developing psychiatric diseases such as schizophrenia. Individuals with 22q11DS and schizophrenia are impaired in emotional memory, anticipating, recalling, and assigning a correct context to emotions. The neuronal circuits responsible for these emotional memory deficits are unknown. Here, we show that 22q11DS mouse models have disrupted synaptic transmission at thalamic inputs to the lateral amygdala (thalamo-LA projections). This synaptic deficit is caused by haploinsufficiency of the 22q11DS gene Dgcr8, which is involved in microRNA processing, and is mediated by the increased dopamine receptor Drd2 levels in the thalamus and by reduced probability of glutamate release from thalamic inputs. This deficit in thalamo-LA synaptic transmission is sufficient to cause fear memory deficits. Our results suggest that dysregulation of the Dgcr8–Drd2 mechanism at thalamic inputs to the amygdala underlies emotional memory deficits in 22q11DS.

Graphical abstract

Teaser

Eom et al. show that mouse models of schizophrenia-associated 22q11.2 deletion syndrome are deficient in synaptic transmission at thalamic inputs to the lateral amygdala (LA). Thalamo-LA synaptic deficits impair fear memory and are mediated by Dgcr8 haploinsufficiency and Drd2 elevation in the auditory thalamus.


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Extracellular Vesicles from a Helminth Parasite Suppress Macrophage Activation and Constitute an Effective Vaccine for Protective Immunity

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Gillian Coakley, Jana L. McCaskill, Jessica G. Borger, Fabio Simbari, Elaine Robertson, Marissa Millar, Yvonne Harcus, Henry J. McSorley, Rick M. Maizels, Amy H. Buck
Recent studies have demonstrated that many parasites release extracellular vesicles (EVs), yet little is known about the specific interactions of EVs with immune cells or their functions during infection. We show that EVs secreted by the gastrointestinal nematode Heligmosomoides polygyrus are internalized by macrophages and modulate their activation. EV internalization causes downregulation of type 1 and type 2 immune-response-associated molecules (IL-6 and TNF, and Ym1 and RELMα) and inhibits expression of the IL-33 receptor subunit ST2. Co-incubation with EV antibodies abrogated suppression of alternative activation and was associated with increased co-localization of the EVs with lysosomes. Furthermore, mice vaccinated with EV-alum generated protective immunity against larval challenge, highlighting an important role in vivo. In contrast, ST2-deficient mice are highly susceptible to infection, and they are unable to clear parasites following EV vaccination. Hence, macrophage activation and the IL-33 pathway are targeted by H. polygyrus EVs, while neutralization of EV function facilitates parasite expulsion.

Graphical abstract

Teaser

Coakley et al. find that extracellular vesicles (EVs) from a nematode parasite can suppress host macrophage activation and the alarmin receptor ST2 and that this can be blocked by antibodies. Vaccination with EVs drives strong antibody responses, conferring protection against infection. The authors thus highlight a role for EVs in parasite-host crosstalk.


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YAP Regulates Actin Dynamics through ARHGAP29 and Promotes Metastasis

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Yiting Qiao, Jianxiang Chen, Ying Bena Lim, Megan Louise Finch-Edmondson, Veerabrahma Pratap Seshachalam, Lei Qin, Tingting Jiang, Boon Chuan Low, Himanshu Singh, Chwee Teck Lim, Marius Sudol
Yes-associated protein (YAP) is regulated by mechanical cues via the interaction of the Hippo pathway with cytoskeleton. Previous studies showed that YAP plays a role in regulating the actomyosin network by suppressing Rho GTPase in medaka fish. Here, we identify Rho GTPase activating protein 29 (ARHGAP29) as a transcriptional target of YAP in a human gastric cancer cell line. YAP promotes the expression of ARHGAP29 to suppress the RhoA-LIMK-cofilin pathway, destabilizing F-actin. The overexpression of YAP causes cytoskeletal rearrangement by altering the dynamics of F-actin/G-actin turnover, thus promoting migration. In a mouse model, circulating tumor cells (CTCs) exhibit an increased ARHGAP29 RNA level compared with cells at primary tumor sites, and the metastatic potential of CTCs is positively correlated with ARHGAP29 expression. Moreover, increased ARHGAP29 expression is correlated with shortened survival of human gastric cancer patients. Our study provides a model to understand YAP's contribution to cancer metastasis via regulation of actin dynamics.

Graphical abstract

Teaser

Qiao et al. discover a role for YAP in regulating actin dynamics. YAP activates the transcription of ARHGAP29 to suppress RhoA activity, resulting in F-actin depolymerization, which reduces cytoskeletal rigidity and promotes a metastatic phenotype.


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Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Darienne R. Myers, Tannia Lau, Evan Markegard, Hyung W. Lim, Herbert Kasler, Minghua Zhu, Andrea Barczak, John P. Huizar, Julie Zikherman, David J. Erle, Weiguo Zhang, Eric Verdin, Jeroen P. Roose
CD4⁺ T cells differentiate into T helper cell subsets in feedforward manners with synergistic signals from the T cell receptor (TCR), cytokines, and lineage-specific transcription factors. Naive CD4⁺ T cells avoid spontaneous engagement of feedforward mechanisms but retain a prepared state. T cells lacking the adaptor molecule LAT demonstrate impaired TCR-induced signals yet cause a spontaneous lymphoproliferative T helper 2 (TH2) cell syndrome in mice. Thus, LAT constitutes an unexplained maintenance cue. Here, we demonstrate that tonic signals through LAT constitutively export the repressor HDAC7 from the nucleus of CD4⁺ T cells. Without such tonic signals, HDAC7 target genes Nur77 and Irf4 are repressed. We reveal that Nur77 suppresses CD4⁺ T cell proliferation and uncover a suppressive role for Irf4 in TH2 polarization; halving Irf4 gene-dosage leads to increases in GATA3⁺ and IL-4⁺ cells. Our studies reveal that naive CD4⁺ T cells are dynamically tuned by tonic LAT-HDAC7 signals.

Graphical abstract

Teaser

Myers et al. find that tonic signals through the adaptor LAT are critical to maintain naive T cell homeostasis. They delineate a tonic LAT-PLCγ-HDAC7 pathway that controls expression of HDAC7 targets. Disruption of the pathway leads to reduced expression of targets Nur77 and Irf4 and aberrant lymphocyte proliferation and differentiation.


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Chemokine Signaling and the Regulation of Bidirectional Leukocyte Migration in Interstitial Tissues

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Davalyn Powell, Sebastien Tauzin, Laurel E. Hind, Qing Deng, David J. Beebe, Anna Huttenlocher
Motile cells navigate through complex tissue environments that include both attractive and repulsive cues. In response to tissue wounding, neutrophils, primary cells of the innate immune response, exhibit bidirectional migration that is orchestrated by chemokines and their receptors. Although progress has been made in identifying signals that mediate the recruitment phase, the mechanisms that regulate neutrophil reverse migration remain largely unknown. Here, we visualize bidirectional neutrophil migration to sterile wounds in zebrafish larvae and identify specific roles for the chemokine receptors Cxcr1 and Cxcr2 in neutrophil recruitment to sterile injury and infection. Notably, we also identify Cxcl8a/Cxcr2 as a specific ligand-receptor pair that orchestrates neutrophil chemokinesis in interstitial tissues during neutrophil reverse migration and resolution of inflammation. Taken together, our findings identify distinct receptors that mediate bidirectional leukocyte motility during interstitial migration depending on the context and type of tissue damage in vivo.

Graphical abstract

Teaser

Powell et al. describe disparate roles for the chemokine receptors Cxcr1 and Cxcr2 in neutrophil recruitment to, and resolution from, tail-transection wounding in larval zebrafish. Their work suggests that Cxcl8-Cxcr2 signaling drives neutrophil reverse migration from the wound by promoting random migration after exposure to Cxcl8.


http://ift.tt/2qaMJug

Wolf-Hirschhorn Syndrome Candidate 1 Is Necessary for Correct Hematopoietic and B Cell Development

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Elena Campos-Sanchez, Nerea Deleyto-Seldas, Veronica Dominguez, Enrique Carrillo-de-Santa-Pau, Kiyoe Ura, Pedro P. Rocha, JungHyun Kim, Arafat Aljoufi, Anna Esteve-Codina, Marc Dabad, Marta Gut, Holger Heyn, Yasufumi Kaneda, Keisuke Nimura, Jane A. Skok, Maria Luisa Martinez-Frias, Cesar Cobaleda
Immunodeficiency is one of the most important causes of mortality associated with Wolf-Hirschhorn syndrome (WHS), a severe rare disease originated by a deletion in chromosome 4p. The WHS candidate 1 (WHSC1) gene has been proposed as one of the main genes responsible for many of the alterations in WHS, but its mechanism of action is still unknown. Here, we present in vivo genetic evidence showing that Whsc1 plays an important role at several points of hematopoietic development. Particularly, our results demonstrate that both differentiation and function of Whsc1-deficient B cells are impaired at several key developmental stages due to profound molecular defects affecting B cell lineage specification, commitment, fitness, and proliferation, demonstrating a causal role for WHSC1 in the immunodeficiency of WHS patients.

Graphical abstract

Teaser

Campos-Sanchez et al. show that Whsc1 plays an important function in hematopoiesis in vivo, demonstrating a role for Whsc1 in the immunodeficiency in Wolf-Hirschhorn syndrome. Whsc1-deficient blood cells are impaired at several developmental stages due to defects in hematopoietic stem cell fitness and B cell lineage specification and commitment, among other problems.


http://ift.tt/2qb7ne5

HAND2 Target Gene Regulatory Networks Control Atrioventricular Canal and Cardiac Valve Development

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Frédéric Laurent, Ausra Girdziusaite, Julie Gamart, Iros Barozzi, Marco Osterwalder, Jennifer A. Akiyama, Joy Lincoln, Javier Lopez-Rios, Axel Visel, Aimée Zuniga, Rolf Zeller
The HAND2 transcriptional regulator controls cardiac development, and we uncover additional essential functions in the endothelial to mesenchymal transition (EMT) underlying cardiac cushion development in the atrioventricular canal (AVC). In Hand2-deficient mouse embryos, the EMT underlying AVC cardiac cushion formation is disrupted, and we combined ChIP-seq of embryonic hearts with transcriptome analysis of wild-type and mutants AVCs to identify the functionally relevant HAND2 target genes. The HAND2 target gene regulatory network (GRN) includes most genes with known functions in EMT processes and AVC cardiac cushion formation. One of these is Snai1, an EMT master regulator whose expression is lost from Hand2-deficient AVCs. Re-expression of Snai1 in mutant AVC explants partially restores this EMT and mesenchymal cell migration. Furthermore, the HAND2-interacting enhancers in the Snai1 genomic landscape are active in embryonic hearts and other Snai1-expressing tissues. These results show that HAND2 directly regulates the molecular cascades initiating AVC cardiac valve development.

Graphical abstract

Teaser

Laurent et al. combine ChIP-seq with transcriptome analysis to identify the HAND2 target gene network that controls the EMT and mesenchymal cell migration during cardiac cushion formation in the atrioventricular canal (AVC). The HAND2 transcriptional targets include Snai1, whose re-expression in Hand2-deficient AVC explants partially restores mesenchymal cell migration.


http://ift.tt/2qaGKWl

Regnase-1 Maintains Iron Homeostasis via the Degradation of Transferrin Receptor 1 and Prolyl-Hydroxylase-Domain-Containing Protein 3 mRNAs

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Masanori Yoshinaga, Yoshinari Nakatsuka, Alexis Vandenbon, Daisuke Ori, Takuya Uehata, Tohru Tsujimura, Yutaka Suzuki, Takashi Mino, Osamu Takeuchi
Iron metabolism is regulated by transcriptional and post-transcriptional mechanisms. The mRNA of the iron-controlling gene, transferrin receptor 1 (TfR1), has long been believed to be negatively regulated by a yet-unidentified endonuclease. Here, we show that the endonuclease Regnase-1 is critical for the degradation of mRNAs involved in iron metabolism in vivo. First, we demonstrate that Regnase-1 promotes TfR1 mRNA decay. Next, we show that Regnase-1^−/− mice suffer from severe iron deficiency anemia, although hepcidin expression is downregulated. The iron deficiency anemia is induced by a defect in duodenal iron uptake. We reveal that duodenal Regnase-1 controls the expression of PHD3, which impairs duodenal iron uptake via HIF2α suppression. Finally, we show that Regnase-1 is a HIF2α-inducible gene and thus provides a positive feedback loop for HIF2α activation via PHD3. Collectively, these results demonstrate that Regnase-1-mediated regulation of iron-related transcripts is essential for the maintenance of iron homeostasis.

Graphical abstract

Teaser

Iron homeostasis is regulated by post-transcriptional mechanisms. Yoshinaga et al. demonstrate that an endoribonuclease, Regnase-1, destabilizes mRNAs related to iron metabolism, including TfR1 and PHD3. A positive feedback circuit of Regnase-1, PHD3, and HIF2α is critical for iron uptake in the duodenal epithelium and facilitates proper erythropoiesis.


http://ift.tt/2qaTBI8

Malate and Aspartate Increase L-Arginine and Nitric Oxide and Attenuate Hypertension

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Entai Hou, Na Sun, Fuchang Zhang, Chenyang Zhao, Kristie Usa, Mingyu Liang, Zhongmin Tian
Fumarase catalyzes the interconversion of fumarate and L-malate in the tricarboxylic acid cycle. The Dahl salt-sensitive (SS) rat, a model of salt-sensitive hypertension, exhibits fumarase insufficiencies. To investigate the mechanism mediating the effect of fumarase-related metabolites on hypertension, we considered the pathway in which L-malate can be converted to oxaloacetate, aspartate, argininosuccinate, and L-arginine, the substrate of nitric oxide (NO) synthase. The levels of aspartate, citrulline, L-arginine, and NO were significantly decreased in the kidneys of SS rats compared to salt-insensitive consomic SS.13^BN rats. Knockdown of fumarase in human kidney cells and vascular endothelial cells resulted in decreased levels of malate, aspartate, L-arginine, and NO. Supplementation of aspartate or malate increased renal levels of L-arginine and NO and attenuated hypertension in SS rats. These findings reveal a multi-step metabolic pathway important for hypertension in which malate and aspartate may modulate blood pressure by altering levels of L-arginine and NO.

Graphical abstract

Teaser

Hou et al. discovered a multi-step metabolic pathway involved in the regulation of blood pressure in a model of salt-sensitive hypertension. In this pathway, fumarase insufficiencies and lower levels of malate result in decreased levels of aspartate, leading to decreased L-arginine regeneration and NO production and contributing to hypertension.


http://ift.tt/2qaQAry

Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Heather S. Smallwood, Susu Duan, Marie Morfouace, Svetlana Rezinciuc, Barry L. Shulkin, Anang Shelat, Erika E. Zink, Sandra Milasta, Resha Bajracharya, Ajayi J. Oluwaseum, Martine F. Roussel, Douglas R. Green, Ljiljana Pasa-Tolic, Paul G. Thomas
Influenza is a worldwide health and financial burden posing a significant risk to the immune-compromised, obese, diabetic, elderly, and pediatric populations. We identified increases in glucose metabolism in the lungs of pediatric patients infected with respiratory pathogens. Using quantitative mass spectrometry, we found metabolic changes occurring after influenza infection in primary human respiratory cells and validated infection-associated increases in c-Myc, glycolysis, and glutaminolysis. We confirmed these findings with a metabolic drug screen that identified the PI3K/mTOR inhibitor BEZ235 as a regulator of infectious virus production. BEZ235 treatment ablated the transient induction of c-Myc, restored PI3K/mTOR pathway homeostasis measured by 4E-BP1 and p85 phosphorylation, and reversed infection-induced changes in metabolism. Importantly, BEZ235 reduced infectious progeny but had no effect on the early stages of viral replication. BEZ235 significantly increased survival in mice, while reducing viral titer. We show metabolic reprogramming of host cells by influenza virus exposes targets for therapeutic intervention.

Graphical abstract

Teaser

Influenza infection is a significant burden on public health, with increased morbidity and mortality in pediatric patients, as well as diabetic, obese, and elderly populations. Smallwood et al. define the metabolic response in infected humans and primary human respiratory cells ex vivo and use this information for targeted drug discovery.


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RUNX1-ETO and RUNX1-EVI1 Differentially Reprogram the Chromatin Landscape in t(8;21) and t(3;21) AML

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Justin Loke, Salam A. Assi, Maria Rosaria Imperato, Anetta Ptasinska, Pierre Cauchy, Yura Grabovska, Natalia Martinez Soria, Manoj Raghavan, H. Ruud Delwel, Peter N. Cockerill, Olaf Heidenreich, Constanze Bonifer
Acute myeloid leukemia (AML) is a heterogeneous disease caused by mutations in transcriptional regulator genes, but how different mutant regulators shape the chromatin landscape is unclear. Here, we compared the transcriptional networks of two types of AML with chromosomal translocations of the RUNX1 locus that fuse the RUNX1 DNA-binding domain to different regulators, the t(8;21) expressing RUNX1-ETO and the t(3;21) expressing RUNX1-EVI1. Despite containing the same DNA-binding domain, the two fusion proteins display distinct binding patterns, show differences in gene expression and chromatin landscape, and are dependent on different transcription factors. RUNX1-EVI1 directs a stem cell-like transcriptional network reliant on GATA2, whereas that of RUNX1-ETO-expressing cells is more mature and depends on RUNX1. However, both types of AML are dependent on the continuous expression of the fusion proteins. Our data provide a molecular explanation for the differences in clinical prognosis for these types of AML.

Graphical abstract

Teaser

Loke et al. compare the regulatory signature of two related types of acute myeloid leukemia, t(8;21) expressing RUNX1-ETO and t(3;21) expressing RUNX1-EVI1. Each fusion protein displays a distinct binding pattern and cooperates with different transcription factors to impact the epigenome, but both downregulate the myeloid differentiation regulator C/EBPα.


http://ift.tt/2qaRyUM

Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Maithili P. Dalvi, Lei Wang, Rui Zhong, Rahul K. Kollipara, Hyunsil Park, Juan Bayo, Paul Yenerall, Yunyun Zhou, Brenda C. Timmons, Jaime Rodriguez-Canales, Carmen Behrens, Barbara Mino, Pamela Villalobos, Edwin R. Parra, Milind Suraokar, Apar Pataer, Stephen G. Swisher, Neda Kalhor, Natarajan V. Bhanu, Benjamin A. Garcia, John V. Heymach, Kevin Coombes, Yang Xie, Luc Girard, Adi F. Gazdar, Ralf Kittler, Ignacio I. Wistuba, John D. Minna, Elisabeth D. Martinez
Although non-small cell lung cancer (NSCLC) patients benefit from standard taxane-platin chemotherapy, many relapse, developing drug resistance. We established preclinical taxane-platin-chemoresistance models and identified a 35-gene resistance signature, which was associated with poor recurrence-free survival in neoadjuvant-treated NSCLC patients and included upregulation of the JumonjiC lysine demethylase KDM3B. In fact, multi-drug-resistant cells progressively increased the expression of many JumonjiC demethylases, had altered histone methylation, and, importantly, showed hypersensitivity to JumonjiC inhibitors in vitro and in vivo. Increasing taxane-platin resistance in progressive cell line series was accompanied by progressive sensitization to JIB-04 and GSK-J4. These JumonjiC inhibitors partly reversed deregulated transcriptional programs, prevented the emergence of drug-tolerant colonies from chemo-naive cells, and synergized with standard chemotherapy in vitro and in vivo. Our findings reveal JumonjiC inhibitors as promising therapies for targeting taxane-platin-chemoresistant NSCLCs.

Graphical abstract

Teaser

Taxane-platin chemotherapy for non-small cell lung cancer (NSCLC) is beneficial, yet most tumors become drug resistant. Dalvi et al. find upregulation of JumonjiC demethylases in clinical NSCLC samples and preclinical models of resistance. Resistant cells and tumors show hypersensitivity to JumonjiC inhibitors, suggesting a therapeutic opportunity for targeting taxane-platin resistance.


http://ift.tt/2qayuWG

Regulation of Active DNA Demethylation through RAR-Mediated Recruitment of a TET/TDG Complex

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Haider M. Hassan, Bart Kolendowski, Majdina Isovic, Kerstin Bose, Helen J. Dranse, Arthur V. Sampaio, T. Michael Underhill, Joseph Torchia
Retinoic acid (RA) plays important roles in development, growth, and homeostasis through regulation of the nuclear receptors for RA (RARs). Herein, we identify Hypermethylated in Cancer 1 (Hic1) as an RA-inducible gene. HIC1 encodes a tumor suppressor, which is often silenced by promoter hypermethylation in cancer. Treatment of cells with an RAR agonist causes a rapid recruitment of an RAR/RXR complex consisting of TDG, the lysine acetyltransferase CBP, and TET 1/2 to the Hic1 promoter. Complex binding coincides with a transient accumulation of 5fC/5caC and concomitant upregulation of Hic1 expression, both of which are TDG dependent. Furthermore, conditional deletion of Tdg in vivo is associated with Hic1 silencing and DNA hypermethylation of the Hic1 promoter. These findings suggest that the catalytic and scaffolding activities of TDG are essential for RA-dependent gene expression and provide important insights into the mechanisms underlying targeting of TET-TDG complexes.

Graphical abstract

Teaser

Hassan et al. report that DNA methylation and expression of Hypermethylated in Cancer 1 (Hic1) are regulated by the retinoic acid receptor (RAR) in a TDG dependent manner. Failure to recruit TDG and TETs may contribute to aberrant silencing of HIC1 in cancer.


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An Engineered Virus Library as a Resource for the Spectrum-wide Exploration of Virus and Vector Diversity

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Wenli Zhang, Jun Fu, Jing Liu, Hailong Wang, Maren Schiwon, Sebastian Janz, Lukas Schaffarczyk, Lukas von der Goltz, Eric Ehrke-Schulz, Johannes Dörner, Manish Solanki, Philip Boehme, Thorsten Bergmann, Andre Lieber, Chris Lauber, Andreas Dahl, Andreas Petzold, Youming Zhang, A. Francis Stewart, Anja Ehrhardt
Adenoviruses (Ads) are large human-pathogenic double-stranded DNA (dsDNA) viruses presenting an enormous natural diversity associated with a broad variety of diseases. However, only a small fraction of adenoviruses has been explored in basic virology and biomedical research, highlighting the need to develop robust and adaptable methodologies and resources. We developed a method for high-throughput direct cloning and engineering of adenoviral genomes from different sources utilizing advanced linear-linear homologous recombination (LLHR) and linear-circular homologous recombination (LCHR). We describe 34 cloned adenoviral genomes originating from clinical samples, which were characterized by next-generation sequencing (NGS). We anticipate that this recombineering strategy and the engineered adenovirus library will provide an approach to study basic and clinical virology. High-throughput screening (HTS) of the reporter-tagged Ad library in a panel of cell lines including osteosarcoma disease-specific cell lines revealed alternative virus types with enhanced transduction and oncolysis efficiencies. This highlights the usefulness of this resource.

Graphical abstract

Teaser

Zhang et al. develop a direct cloning strategy to incorporate viral genomes into an easy-to-handle plasmid, thereby generating a library consisting of cloned adenovirus plasmids and reporter-tagged vectors. This library, together with the homologous recombineering technique, offers a resource to study pathogenesis and to establish therapeutic applications.


http://ift.tt/2qaQwI5

Bivariate Genomic Footprinting Detects Changes in Transcription Factor Activity

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Songjoon Baek, Ido Goldstein, Gordon L. Hager
In response to activating signals, transcription factors (TFs) bind DNA and regulate gene expression. TF binding can be measured by protection of the bound sequence from DNase digestion (i.e., footprint). Here, we report that 80% of TF binding motifs do not show a measurable footprint, partly because of a variable cleavage pattern within the motif sequence. To more faithfully portray the effect of TFs on chromatin, we developed an algorithm that captures two TF-dependent effects on chromatin accessibility: footprinting and motif-flanking accessibility. The algorithm, termed bivariate genomic footprinting (BaGFoot), efficiently detects TF activity. BaGFoot is robust to different accessibility assays (DNase-seq, ATAC-seq), all examined peak-calling programs, and a variety of cut bias correction approaches. BaGFoot reliably predicts TF binding and provides valuable information regarding the TFs affecting chromatin accessibility in various biological systems and following various biological events, including in cases where an absolute footprint cannot be determined.

Graphical abstract

Teaser

Baek et al. describe a method to identify changes in transcription factor activity based on telltale signs they leave on chromatin. This approach reliably predicts the activity of various transcription factors from chromatin accessibility information. The method provides an unbiased way to isolate relevant factors without assays targeting specific factors.


http://ift.tt/2qaPGLp

Identification and Characterization of a Class of MALAT1-like Genomic Loci

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): Bin Zhang, Yuntao S. Mao, Sarah D. Diermeier, Irina V. Novikova, Eric P. Nawrocki, Tom A. Jones, Zsolt Lazar, Chang-Shung Tung, Weijun Luo, Sean R. Eddy, Karissa Y. Sanbonmatsu, David L. Spector
The MALAT1 (Metastasis-Associated Lung Adenocarcinoma Transcript 1) gene encodes a noncoding RNA that is processed into a long nuclear retained transcript (MALAT1) and a small cytoplasmic tRNA-like transcript (mascRNA). Using an RNA sequence- and structure-based covariance model, we identified more than 130 genomic loci in vertebrate genomes containing the MALAT1 3′ end triple-helix structure and its immediate downstream tRNA-like structure, including 44 in the green lizard Anolis carolinensis. Structural and computational analyses revealed a co-occurrence of components of the 3′ end module. MALAT1-like genes in Anolis carolinensis are highly expressed in adult testis, thus we named them testis-abundant long noncoding RNAs (tancRNAs). MALAT1-like loci also produce multiple small RNA species, including PIWI-interacting RNAs (piRNAs), from the antisense strand. The 3′ ends of tancRNAs serve as potential targets for the PIWI-piRNA complex. Thus, we have identified an evolutionarily conserved class of long noncoding RNAs (lncRNAs) with similar structural constraints, post-transcriptional processing, and subcellular localization and a distinct function in spermatocytes.

Graphical abstract

Teaser

Zhang et al. find that vertebrate genomes have more than 130 genomic loci with a unique 3′ end structure similar to that of MALAT1. This class of MALAT1-like noncoding RNAs in green lizard is expressed in testis, and it recruits piRNAs derived from the opposite strands to meiotic chromatin in spermatocytes.


http://ift.tt/2qaNnrU

Scholar : These new articles for AIDS Care are available online

The online platform for Taylor & Francis Online content New for AIDS Care and online now on Taylor & Francis Online: Original Articles Positive smoking cessation-related interactions with HIV care providers increase the likelihood of interest in cessation among HIV-positive cigarette smokers Lauren R. Pacek, Olga Rass & Matthew W. Johnson Pages: 1-6 | DOI: 10.1080/09540121.2017.1330532 Free access World Diabetes Day research collection – Eyes on Diabetes. To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Radio-opaque polyethylene for personalized craniomaxillofacial implants

Abstract

Objective

This study aimed to present a new possibility to create radio-opaque implant material for craniomaxillofacial reconstruction.

Materials and methods

The test disks made of the own compound of polyethylenes with addiction of 2, 4, and 6 % of weight TiO₂ was investigated for cytotoxicity [each group 15 disks respectively]. Next, computed tomography of the disks was performed in environment of muscle and fat. Hardness, tensile modulus and strength, and compressive modulus and strength were tested too.

Results

Deterioration of mechanical properties of the composites containing titanium dioxide was observed [hardness, tensile modulus and strength, compressive modulus and strength, respectively: 56.7 ± 1.6 shore D, 354 ± 52, 22.5 ± 1.3, 21.8 ± 1.1, and 2995 ± 327 MPa as addiction of 2 % TiO₂; 52.0 ± 0.9 shore D, 347 ± 66, 18.0 ± 0.7, 14.2 ± 0.9, and 1396 ± 477 MPa as 4 % TiO₂; 51.3 ± 1.3 shore D, 316 ± 9, 17.4 ± 0.2, 13.6 ± 0.6, and 1100 ± 144 MPa as 6 % TiO₂ added]. The test disks revealed no cytotoxicity effect on human osteoblasts. The new material presents mild radio-opacity which was enough to observe the implant in relation to fat and muscle, but with no visible effect of beam hardening.

Conclusion

In view of the performed tests, the polyethylene enriched by titanium dioxide seems to be a proper material to consider manufacturing of craniomaxillofacial implants.

Clinical relevance

Maxilloafacial surgery is still looking for new implantologic materials. The proposed one is a new way to manufacture an implant visible in computed tomography which does not interfere with its shape in radiological examination and makes it possible to observe the surrounding soft tissues.

http://ift.tt/2rPD21K

Effect of the addition of nano-sized sodium hexametaphosphate to fluoride toothpastes on tooth demineralization: an in vitro study

Abstract

Objective

This study evaluated the effect of toothpastes containing 1100 ppm F associated with nano-sized sodium hexametaphosphate (HMPnano) on enamel demineralization in vitro using a pH-cycling model.

Design

Bovine enamel blocks (4 mm × 4 mm, n = 72) selected by initial surface hardness (SHi) were randomly allocated into six groups (n = 12), according to the test toothpastes: without fluoride or HMPnano (Placebo), 550 ppm F (550F), 1100 ppm F (1100F), 1100F plus HMPnano at concentrations of 0.25% (1100F/0.25%HMPnano), 0.5% (1100F/0.5%HMPnano), and 1.0% (1100F/1.0%HMPnano). Blocks were treated 2×/day with slurries of toothpastes and submitted to five pH cycles (demineralizing/remineralizing solutions) at 37 °C. Next, final surface hardness (SHf), integrated loss subsurface hardness (ΔKHN), integrated mineral loss (g_HAp × cm⁻³), and enamel fluoride (F) concentrations were determined. Data were analyzed by ANOVA and Student-Newman-Keuls test (p < 0.001).

Results

Toothpaste with 1100F/0.5%HMPnano led to the lowest mineral loss and the highest mineral concentration among all groups, which were 26% (SHf) and 21% (ΔKHN) lower and ~58% higher (g_HAp × cm⁻³) when compared to 1100F (p < 0.001). Similar values of enamel F were observed for all fluoridated toothpastes (p > 0.001).

Conclusion

The addition of 0.5%HMPnano to a 1100 F toothpaste significantly enhances its effects against enamel demineralization when compared to its counterpart without HMPnano in vitro.

Clinical significance

Toothpaste containing 1100 ppm F associated with HMPnano has a higher potential to reduce the demineralization compared to 1100 ppm F. This toothpaste could be a viable alternative to patients at high risk of caries.

http://ift.tt/2rgeZMg

Recombinant human bone morphogenetic protein (rhBMP)9 induces osteoblast differentiation when combined with demineralized freeze-dried bone allografts (DFDBAs) or biphasic calcium phosphate (BCP)

Abstract

Objectives

Recently, recombinant human bone morphogenetic protein 9 (rhBMP9) has been characterized as one of the most osteogenic growth factors among the 15 human BMPs. The aim of the present study was to investigate the effects of rhBMP9 in comparison to the clinically utilized rhBMP2 on in vitro cell behavior when combined with two bone graft materials including demineralized freeze-dried bone allografts (DFDBAs) and biphasic calcium phosphate (BCP).

Materials and methods

The absorption and release kinetics of rhBMPs from DFDBA and BCP were investigated by ELISA. Moreover, murine bone stromal ST2 cell behavior was investigated on DFDBA or BCP seeded on (1) graft only, (2) rhBMP2 (10 ng/ml), (3) rhBMP2 (100 ng/ml), (4) rhBMP9 (10 ng/ml), and (5) rhBMP9 (100 ng/ml). The effects of rhBMPs on DFDBA and BCP were assessed for cell adhesion, proliferation, and osteoblast differentiation by alkaline phosphatase (ALP) activity, alizarin red staining, and real-time PCR for genes encoding Runx2, ALP, and bone sialoprotein (BSP).

Results

While both BMPs were gradually released from DFDBA and BCP over time, significantly higher adsorption was observed on BCP when compared to DFDBA. Cell attachment and proliferation was higher on BCP with little influence of either rhBMP2/9. Despite rhBMPs having relatively no effect on cell attachment/proliferation, a pronounced and marked effect was observed on osteoblast differentiation for both rhBMP2/9. Interestingly, it was observed that rhBMP9 induced significantly higher ALP activity, alizarin red staining, and messenger RNA (mRNA) levels of ALP and BSP when compared to rhBMP2. Our results also revealed higher differentiation for rhBMP2/9 with BCP when compared to DFDBA most likely as a result of higher growth factor adsorption.

Conclusion

While both rhBMP2/9 combined with DFDBA or BCP induced osteoblast differentiation, rhBMP9 induced greater osteoblast differentiation when compared to rhBMP2.

Clinical relevance

rhBMP9 may be a recombinant growth factor with higher potential to induce new bone formation when compared to rhBMP2. Further in vivo studies are necessary to characterize its regenerative potential in various animal models.

http://ift.tt/2rPkxKU

A retrospective study of osteomyelitis and osteonecrosis of the jaws and its etiologic implication of bisphosphonate in Asians

Abstract

Objective

The objective of this study were to find the annual case trend of inflammatory jawbone diseases and to investigate the impact of medication-related osteonecrosis of the jaws (MRONJ).

Material and methods

A retrospective study of 372 patients diagnosed with inflammatory jawbone condition except for alveolar osteitis from 2007 to 2015 was initiated. History taking and investigation of etiologic factors MRONJ, osteoradionecrosis (ORN), odontogenic infection, foreign body, and trauma were investigated. A separate analysis showed the number of MRONJ cases in two age groups (under 70 years; 70 years and over) and serum C-terminal peptide (s-CTX) values that were found.

Results

The results showed that the number of MRONJ cases was significantly larger in the older age group (p < 0.05). Regarding gender and sites of lesions, MRONJ was significantly frequent in the female and the mandible (p < 0.05). The R ² values for the regression analysis for MRONJ (R ² = 0.9234) and odontogenic etiology (R ² = 0.0427) signified linear increase in the number of MRONJ cases, whereas bone lesions due to traditional odontogenic etiology stayed stationary.

Conclusion

The number of MRONJ has escalated, and most of the patients are elderly people. The current trend of inflammatory conditions of the jaw may have changed since the advent of MRONJ.

Clinical relevance

Long-term bisphosphonate therapy became a major risk factor for the osteomyelitis and osteonecrosis of the jaws. Thorough medical history, taking would be essential and communication with prescribing physicians should be emphasized during the dental treatment planning.

http://ift.tt/2rghIVX

Efficacy of various side-to-side toothbrushes and impact of brushing parameters on noncontact biofilm removal in an interdental space model

Abstract

Objectives

The objective of this study was to evaluate the efficacy of four different side-to-side toothbrushes and the impact of various brushing parameters on noncontact biofilm removal in an adjustable interdental space model.

Materials and methods

A three-species biofilm, consisting of Porphyromonas gingivalis, Fusobacterium nucleatum, and Streptococcus sanguinis, was formed in vitro on protein-coated titanium disks using a flow chamber combined with a static biofilm growth model. Subsequently, the biofilm-coated disks were exposed to four different powered toothbrushes (A, B, C, D). The parameters distance (0 and 1 mm), brushing time (2, 4, and 6 s), interdental space width (1, 2, and 3 mm), and toothbrush angulation (45° and 90°) were tested. The biofilm volumes were determined using volumetric analyses with confocal laser scanning microscope (Zeiss LSM700) images and Imaris version 7.7.2 software.

Results

The median percentages of simulated interdental biofilm reduction by the tested toothbrushes ranged from 7 to 64 %. The abilities of the analyzed toothbrushes to reduce the in vitro biofilm differed significantly (p < 0.05). Three of the tested toothbrushes (A, B, C) were able to significantly reduce a simulated interdental biofilm by noncontact brushing (p ≤ 0.005). The brushing parameters and their combinations tested in the experiments revealed only minor effects on in vitro interdental biofilm reduction (p > 0.05).

Conclusions

A three-species in vitro biofilm could be altered by noncontact brushing with toothbrushes A, B, and C in an artificial interdental space model.

Clinical relevance

Certain side-to-side toothbrushes demonstrate in vitro a high efficacy in interdental biofilm removal without bristle-to-biofilm contact.

http://ift.tt/2rPD0XG

Neural oscillations demonstrate that general anesthesia and sedative states are neurophysiologically distinct from sleep

Publication date: June 2017
Source:Current Opinion in Neurobiology, Volume 44
Author(s): Oluwaseun Akeju, Emery N Brown
General anesthesia is a man-made neurophysiological state comprised of unconsciousness, amnesia, analgesia, and immobility along with maintenance of physiological stability. Growing evidence suggests that anesthetic-induced neural oscillations are a primary mechanism of anesthetic action. Each anesthetic drug class produces distinct oscillatory dynamics that can be related to the circuit mechanisms of drug action. Sleep is a naturally occurring state of decreased arousal that is essential for normal health. Physiological measurements (electrooculogram, electromyogram) and neural oscillatory (electroencephalogram) dynamics are used to empirically characterize sleep into rapid eye movement sleep and the three stages of non-rapid eye movement sleep. In this review, we discuss the differences between anesthesia- and sleep-induced altered states from the perspective of neural oscillations.



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REM sleep and memory

Publication date: June 2017
Source:Current Opinion in Neurobiology, Volume 44
Author(s): Richard Boyce, Sylvain Williams, Antoine Adamantidis
Memory consolidation, a process which stabilizes recently acquired information into long-term storage, is thought to be optimized during sleep. Although recent evidence indicates that non-rapid-eye movement sleep (NREMs) is directly involved in memory consolidation, the role of rapid-eye movement sleep (REMs) in this process has remained controversial due to the extreme difficulty in experimentally isolating neural activity during REMs. Using a combination of electrophysiological recording and optogenetic techniques, recent work demonstrated for the first time that neural activity occurring specifically during REMs is required for spatial and contextual memory consolidation. Identifying the underlying mechanisms behind these observations, precisely how they translate to humans, and clarifying the extent of REMs' role in other modalities of memory are important challenges of future research with implications for human health.

Graphical abstract

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Freeze artifact on full-field optical coherence tomography skin imaging

Abstract

Background/Purpose

Full-field optical coherence tomography (FFOCT) is an emerging imaging technique for rapid histological analysis. As FFOCT is introduced into the Mohs workflow, it is important to document the effect of tissue freezing on FFOCT images and any effect FFOCT has on frozen sections. Our study aimed to evaluate the changes on FFOCT images after tissue freezing as well as FFOCT imaging effects on frozen sectioning.

Methods

Six normal skin specimens were imaged using FFOCT and subsequently frozen using a cryostat. The specimens were then reimaged using FFOCT and compared for any differences. To evaluate the effect of FFOCT imaging on frozen sections, five normal skin specimens were bisected and one half was imaged using FFOCT. Both halves underwent frozen sectioning and analysis.

Results

Significant changes in the fat, sebaceous glands, eccrine glands, and dermal collage and minimal changes in the epidermis were seen after freezing. No effect on frozen sectioning was seen after FFOCT imaging.

Conclusion

As FFOCT is studied for use in Mohs, clinicians should be aware that freezing prior to imaging introduces significant artifact in the FFOCT image. If possible, specimens should undergo imaging prior to being frozen.

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Scholar : These new articles for Journal of the Institute of Conservation are available online

The online platform for Taylor & Francis Online content New for Journal of the Institute of Conservation and online now on Taylor & Francis Online: Original Articles Conservation in an era of participation Hélia Pereira Marçal Pages: 1-8 | DOI: 10.1080/19455224.2017.1319872 3D4Ever: why is it so hard to talk about the preservation of 3D data? William Kilbride Pages: 1-7 | DOI: 10.1080/19455224.2017.1317006 326—Conservation in the age of the robot Alastair McCapra Pages: 1-8 | DOI: 10.1080/19455224.2017.1317007 Cross-disciplinary conservation—is this the way forward? Emily M. Williams Pages: 1-11 | DOI: 10.1080/19455224.2017.1320298 Contemporary art, contemporary issues—conservation at Tate Louise Lawson & Deborah Potter Pages: 1-12 | DOI: 10.1080/19455224.2017.1318079 Visionary design practices: preserving plastics and designers' intent in collections of modern and contemporary fashion Leanne Tonkin Pages: 1-16 | DOI: 10.1080/19455224.2017.1321561 To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

In vivo exfoliating efficacy of biodegradable beads and the correlation with user's satisfaction

Abstract

Background/purpose

By the end of 2017, non-biodegradable microbeads will be prohibited in USA, UK and Europe, due to their environmental issue. There are biodegradable beads available, but their effect on skin desquamation has not been evaluated yet. This study aimed to understand the skin renewal time, moisturizing effect and user's satisfaction of gel scrubs containing different exfoliating beads.

Methods

Gel scrubs, containing polyethylene, mannan or wax beads, were used in this study. The stratum corneum turnover time (SCTT) and skin hydration were evaluated by dansyl chloride staining technique and Corneometer^®, respectively. The self-assessment was also performed after a 3-week home use trial.

Results

The SCTTs of three different gel scrubs were not significantly different. A numerical increase in the skin hydration level was found in all groups. Satisfaction scores for the appearance and usability attributes were similar, but scores for improvement in the skin hydration and skin smoothness were higher in the gel scrubs with mannan or wax beads.

Conclusion

All three gel scrubs provided a similar effect on the SCTT and skin hydration, but gel scrubs with mannan or wax beads were more favorable. Thus, these two biodegradable exfoliating beads may be good substitutes in scrubbing products.

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Assessment of Competence in EVAR Procedures: A Novel Rating Scale Developed by the Delphi Technique

Publication date: Available online 23 May 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): M. Strøm, L. Lönn, B. Bech, T.V. Schroeder, L. Konge
Objective/BackgroundTo develop a procedure specific global rating scale for assessment of operator competence in endovascular aortic repair (EVAR).MethodsA Delphi approach was used to achieve expert consensus. A panel of 32 international experts (median 300 EVAR procedures, range 200–3000) from vascular surgery (n = 21) and radiology (n = 11) was established. The first Delphi round was based on a review of endovascular skills assessment papers, stent graft instructions for use, and structured interviews. It led to a primary pool of 83 items that were formulated as global rating scale items with tentative anchors. Iterative Delphi rounds were executed. The panellists rated the importance of each item on a 5 point Likert scale. Consensus was defined as 80% of the panel rating an item 4 or 5 in the primary round and 90% in subsequent rounds. Consensus on the final assessment tool was defined as Cronbach's alpha > .8 after a minimum of three rounds.ResultsThirty-two of 35 invited experts participated. Three rounds of surveys were completed with a completion rate of 100% in the first two rounds and 91% in round three. The 83 primary assessment items were supplemented with five items suggested by the panel and reduced to seven pivotal assessment items that reached consensus, Cronbach's alpha = 0.82. The seven item rating scale covers key elements of competence in EVAR stent placement and deployment. Each item has well defined grades with explicit anchors at unacceptable, acceptable, and superior performance on a 5 point Likert scale.ConclusionThe Delphi methodology allowed for international consensus on a new procedure specific global rating scale for assessment of competence in EVAR. The resulting scale, EndoVascular Aortic Repair Assessment of Technical Expertise (EVARATE), represents key elements in the procedure. EVARATE constitutes an assessment tool for providing structured feedback to endovascular operators in training.



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The conserved domain in MORF proteins has distinct affinities to the PPR and E elements in PPR RNA editing factors

Publication date: Available online 23 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Eszter Bayer-Császár, Sascha Haag, Anja Jörg, Franziska Glass, Barbara Härtel, Toshihiro Obata, Etienne H. Meyer, Axel Brennicke, Mizuki Takenaka
In plant organelles specific nucleotide motifs at C to U RNA editing sites are recognized by the PLS-class of pentatricopeptide repeat (PPR) proteins, which are additionally characterized by a C-terminal E domain. The PPR elements bind the nucleotides in the target RNA, while the function of the E domain has remained unknown. At most sites RNA editing also requires multiple organellar RNA editing factor (MORF) proteins. To understand how these two types of proteins are involved in RNA editing complexes, we systematically analyzed their protein-protein interactions. In vivo pull-down and yeast two-hybrid assays show that MORF proteins connect with selected PPR proteins. In a loss of function mutant of MORF1, a single amino acid alteration in the conserved MORF domain abrogates interactions with many PLS-class PPR proteins, implying the requirement of direct interaction to PPR proteins for the RNA editing function of MORF1. Subfragment analyses show that predominantly the N-terminal/central regions of the MORF domain in MORF1 and MORF3 bind the PPR proteins. Within the PPR proteins, the E domains in addition to PPR elements contact MORF proteins. In chimeric PPR proteins, different E domains alter the specificity of the interaction with MORF proteins. The selective interactions between E domain containing PPR and MORF proteins suggest that the E domains and MORF proteins play a key role for specific protein complexes to assemble at different RNA editing sites.



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Combination Liposomal Amphotericin B, Posaconazole and Oral Amphotericin B for Treatment of Gastrointestinal Mucorales in an Immunocompromised Patient

Publication date: Available online 24 May 2017
Source:Medical Mycology Case Reports
Author(s): Anthony Anderson, Dayna McManus, Sarah Perreault, Ying-Chun Lo, Stuart Seropian, Jeffrey E. Topal
Mucormycosis is a life threatening infection caused by fungi in the order Mucorales. Mucormycosis can affect any organ system with rhino-orbital-cerebral and pulmonary infections being the most predominant infection types. Gastrointestinal mucormycosis is rare and accounts for only 4–7% of all cases. Here, we present a case of invasive gastrointestinal mucormycosis in an immunocompromised host treated with systemic and topical anti-mold therapy.



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Microstructure, texture and mechanical properties of friction stir processed Mg-14Gd alloys

Publication date: 15 September 2017
Source:Materials & Design, Volume 130
Author(s): Jingyu Han, Juan Chen, Liming Peng, Shuai Tan, Yujuan Wu, Feiyan Zheng, Hong Yi
Mg-14wt% Gd alloys in both as cast and as quenched conditions (T4) were subjected to friction stir processing (FSP). The microstructure evolution, texture modification, mechanical enhancement, as well as subsequent aging performance for both of the two conditions were studied. Supplementary FSP experiments with cold air-cooling (CFSP) were conducted for microstructure evolution comparison. During FSP, the thermal histories are similar in regions away from the top center for both conditions. The primary coarse grains were initially refined through repetition of geometric dynamic recrystallization (GDRX). The refined grains then experienced subsequent recovery and grain growth. Compared with as cast condition, generally larger grain size, lower high angle grain boundary fractions, as well as much stronger texture intensities leading to poorer ductility were generated in T4 condition after FSP. The differences mainly lie on the pinning effect exerted by the Mg5Gd particle remnants. The texture distribution depends on the final position strains and aging has little effect on it.

Graphical abstract

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Experimental and numerical investigation of influence of air-voids on the compressive behaviour of foamed concrete

Publication date: 15 September 2017
Source:Materials & Design, Volume 130
Author(s): Thang T. Nguyen, Ha H. Bui, Tuan D. Ngo, Giang D. Nguyen
A combined experimental and numerical approach is proposed in this study for the characterisation of the mechanical behaviour of foamed geopolymer concretes. Advanced experimental techniques employing X-Ray CT give both microstructures and mechanical responses of a range of geopolymer concretes with varying densities. In parallel with this, a numerical modelling technique based on the discrete element method (DEM) is developed for explicit descriptions of air-void distribution, while the mortar binder is described at the micro/meso scale with cohesive behaviour. The calibrated and validated DEM model is then used to systematically study the effects of air-void content, air-void distribution and microstructural parameters, including particle size and porosity on the compressive strength of foamed concretes. A non-linear relationship between the compressive strength and porosity of foamed concretes is found from DEM simulations, which are consistent with our experimental findings and existing strength-porosity models. Furthermore, it is found that the air-void distribution has a significant influence on the compressive strength of foamed concretes, while the micro-void structure has less effect on the loading bearing capacity of the material. The proposed combined approach demonstrates the tight correlations between experimental and numerical techniques in characterising the mechanical behaviour of foamed concretes for practical design purposes.

Graphical abstract

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Enzymatic-photocatalytic synergetic effect on the decolorization of dyes by single chloroperoxidase molecule immobilization on TiO2 mesoporous thin film

Publication date: 5 September 2017
Source:Materials & Design, Volume 129
Author(s): Jing Lu, Long Cheng, Yong Wang, Yu Ding, Mancheng Hu, Shuni Li, Quanguo Zhai, Yucheng Jiang
A chloroperoxidase (CPO) -TiO2 thin film type enzyme reactor was constructed by single chloroperoxidase molecule immobilization on TiO2 mesoporous thin film. The CPO-TiO2 enzyme reactor showed an enzymatic-photocatalytic synergetic effect, 1+1>2, when applied in the decolorization of azo dye crocein orange G. Moreover, the enzyme reactor made it possible that the photocatalytic catalysis was carried out under natural sunlight instead of ultraviolet radiation. The synergetic effect was studied by PL emission spectroscopy with terephthalic acid used as a probe molecule to investigate the formation of ·OH radicals.The mesoporous TiO2, prepared by a sol-gel and dip-coating method, being spherical form without interconnectivity in a 3D pore systems of 8nm ~15nm pore size, matched the size of CPO molecules. Such an architecture was suitable for single CPO molecule immobilization, which enabled easy access of the substrates to enzyme active sites.The CPO-TiO2 enzyme reactor was very efficient. 98.61% decolorization efficiency of crocein orange G was achieved in 5min. It can be reused for seven cycles with no loss in activity. Compared with free CPO, the stability of CPO-TiO2 enzyme reactor against thermal denaturation and deactivation by high concentration of oxidants or in a strong acid-base environment was enhanced.

Graphical abstract

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Synthesis of fluorescent hyperbranched enediynes and Bergman cyclization polymerization for generating spatially locked persistent radicals

Publication date: 16 June 2017
Source:Polymer, Volume 119
Author(s): Qiaoping Li, Shudan Chen, Peng Zhao, Aiguo Hu
A series of AB2 type monomers with terminal alkyne (A) and iodine (B) were synthesized from dichloromaleic anhydride by amidation with terminal alkynylamine followed by chlorine-iodine exchange reaction. Starting from these AB2 monomers, three kinds of fluorescent hyperbranched polymers with enediyne repeating units (HBEP1∼HBEP3) were synthesized via one-pot Sonogashira cross coupling polymerization reaction. The HBEPs was characterized by a variety of techniques and the degree of branching (DB) of the HBEPs were determined by ¹H NMR spectroscopy. The molecular weights (Mn) of HBEPs are up to 73 kDa and the DBs are up to 0.97, close to that for a dendrimer. Due to the different degree of conjugation of these HBEPs, the HBEPs display different photo-luminescence and excitation-dependent fluorescence behavior. These HBEPs were further subjected to thermal Bergman cyclization to generate crosslinked polymeric networks with spatially locked persistent radicals. EPR experiments showed that the free radicals in these materials were stable for a long time at room temperature and can be slowly quenched when exposed to air, providing a promising application as long-term free radical cleaner.

Graphical abstract

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Impact of Bis-(3-triethoxysilylpropyl)tetrasulphide on the properties of PMMA/Cellulose composite

Publication date: 16 June 2017
Source:Polymer, Volume 119
Author(s): V.P. Anju, Sunil K. Narayanankutty
Poly(methyl methacrylate) (PMMA)-microcrystalline cellulose composites with improved interfacial interaction were prepared by solution casting method using Bis-(3-triethoxysilylpropyl) tetrasulphide (Si69) as coupling agent. The incorporation of microcrystalline cellulose into PMMA enhanced the mechanical as well as thermal properties over that of base polymer but not remarkably. So in the current study Bis-(3-triethoxysilylpropyl) tetrasulphide (Si69) is used as a coupling agent to improve PMMA-Cellulose adhesion. The composites were characterized using FTIR, ¹³C NMR, UV–Vis, ²⁹Si NMR, XRD and SEM analysis. The results indicated that Si69 formed chemical bonds with both PMMA and cellulose. The effect of Si69 on the physical and mechanical properties of PMMA/Cellulose composite was investigated. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) studies showed that the degradation temperature and glass transition temperature of PMMA shifted to higher temperature. The addition of silane coupling agent in to the PMMA/Cellulose improved the mechanical properties. The impact strength increased up to 72%, flexural strength by 37%. The composite exhibited 49% higher tensile strength and 50% storage modulus than pristine PMMA. The addition of cellulose to PMMA increased the dielectric constant and attained an AC conductivity of 1.4*10⁻⁴ S/m. The result proved that Si69 is compactable to both PMMA and cellulose and can be used as an effective coupling agent for PMMA/Cellulose system.

Graphical abstract

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Synthesis of silicon-containing cycloaliphatic diepoxide from biomass-based α-terpineol and the decrosslinking behavior of cured network

Publication date: 16 June 2017
Source:Polymer, Volume 119
Author(s): Linni Zhao, Zhonggang Wang
The intractable after-treatment problem of thermosetting epoxy resins due to the insolubility and infusibility brings about an ever-increasing pressure on environment. In this work, new degradable silicon-containing cycloaliphatic diepoxide (Epo-Si) was designed and synthesized using biomass-based 2-(4-methylcyclohex-3-enyl)propan-2-ol (α-terpineol) as a major material. After curing with anhydride, large amounts of heat-labile tertiary carbon ester and tertiary C-O ether linkages in the network made the crosslinked Epo-Si degrade at a lower temperature of 269 °C. Moreover, its degradation temperatures could be readily tuned through co-curing with the commercial diepoxide ERL-4221. At room temperature, the shearing strength of the cured Epo-Si is 6.74 MPa, superior to that of ERL-4221 (5.24 MPa), exhibiting excellent adhesion property. More importantly, the cured Epo-Si maintains the high shearing strength up to 240 °C, but when further increasing temperature, the strength rapidly dropped and almost completely lost at around 285 °C. Therefore, if integrated circuits have been encapsulated with Epo-Si, their dismantlement or repair at a suitably lower temperature could be realized without damaging the PCB board. The thermal decrosslinking mechanism of the cured products were investigated by means of isothermal and temperature-programmed thermogravimetric and FTIR spectra in detail.

Graphical abstract

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27-Hydroxycholesterol upregulates the production of heat shock protein 60 of monocytic cells

Publication date: Available online 24 May 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Bo-Young Kim, Yonghae Son, Jeongyoon Choi, Seong-Kug Eo, Young Chul Park, Koanhoi Kim
Investigating differentially expressed proteins in a milieu rich in cholesterol oxidation products, we found via mass spectrometry-based proteomics that surface levels of heat shock protein 60 (HSP60) were upregulated on monocytic cells in the presence of 27-hydroxycholesterol (27OHChol). The elevated levels of cytoplasmic membrane HSP60 were verified via Western blot analysis and visualized by confocal microscopy. Treatment with 27OHChol also resulted in increased levels of cellular HSP60 without altering its transcription. Cholesterol, however, did not affect cell-surface levels and cellular amount of HSP60. GSK 2033, an LXR antagonist, inhibited expression of live X receptor α, but not of HSP60, induced by 27OHChol. Treatment with 27OHChol also resulted in increased release of HSP60 from monocytic cells, but the release was significantly reduced by inhibitors of endoplasmic reticulum-Golgi protein trafficking, brefeldin A and monensin. Results of the current study indicate that 27OHChol upregulates not only cell-surface and cellular levels of HSP60 but also its release from monocytic cells, thereby contributing to activation of the immune system.

Graphical abstract

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Disorder of thyroid hormone transport into the tissues

Publication date: Available online 24 May 2017
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): Stefan Groeneweg, W. Edward Visser, Theo J. Visser
Transport of thyroid hormone (TH) across the plasma membrane is essential for intracellular TH metabolism and action, and this is mediated by specific transporter proteins. During the last two decades several transporters capable of transporting TH have been identified, including monocarboxylate transporter 8 (MCT8), MCT10 and organic anion transporting polypeptide 1C1 (OATP1C1). In particular MCT8 and OATP1C1 are important for the regulation of local TH activity in the brain and thus for brain development. MCT8 is a protein containing 12 transmembrane domains, and is encoded by the SLC16A2 gene located on the X chromosome. It facilitates both TH uptake and efflux across the cell membrane. Male subjects with hemizygous mutations in MCT8 are afflicted with severe intellectual and motor disability, also known as the Allan-Herndon-Dudley syndrome (AHDS), which goes together with low serum T4 and high T3 levels. This review concerns molecular and clinical aspects of MCT8 function.



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