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Παρασκευή, 4 Νοεμβρίου 2016

IJERPH, Vol. 13, Pages 1083: The Association between Environmental Factors and Scarlet Fever Incidence in Beijing Region: Using GIS and Spatial Regression Models

(1) Background: Evidence regarding scarlet fever and its relationship with meteorological, including air pollution factors, is not very available. This study aimed to examine the relationship between ambient air pollutants and meteorological factors with scarlet fever occurrence in Beijing, China. (2) Methods: A retrospective ecological study was carried out to distinguish the epidemic characteristics of scarlet fever incidence in Beijing districts from 2013 to 2014. Daily incidence and corresponding air pollutant and meteorological data were used to develop the model. Global Moran’s I statistic and Anselin’s local Moran’s I (LISA) were applied to detect the spatial autocorrelation (spatial dependency) and clusters of scarlet fever incidence. The spatial lag model (SLM) and spatial error model (SEM) including ordinary least squares (OLS) models were then applied to probe the association between scarlet fever incidence and meteorological including air pollution factors. (3) Results: Among the 5491 cases, more than half (62%) were male, and more than one-third (37.8%) were female, with the annual average incidence rate 14.64 per 100,000 population. Spatial autocorrelation analysis exhibited the existence of spatial dependence; therefore, we applied spatial regression models. After comparing the values of R-square, log-likelihood and the Akaike information criterion (AIC) among the three models, the OLS model (R2 = 0.0741, log likelihood = −1819.69, AIC = 3665.38), SLM (R2 = 0.0786, log likelihood = −1819.04, AIC = 3665.08) and SEM (R2 = 0.0743, log likelihood = −1819.67, AIC = 3665.36), identified that the spatial lag model (SLM) was best for model fit for the regression model. There was a positive significant association between nitrogen oxide (p = 0.027), rainfall (p = 0.036) and sunshine hour (p = 0.048), while the relative humidity (p = 0.034) had an adverse association with scarlet fever incidence in SLM. (4) Conclusions: Our findings indicated that meteorological, as well as air pollutant factors may increase the incidence of scarlet fever; these findings may help to guide scarlet fever control programs and targeting the intervention.

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Troubled families, troubled policy making

Last month, an independent evaluation of the first four years of the coalition government’s flagship Troubled Families Programme reported no discernible benefits for participating families, a failure...
recent?d=yIl2AUoC8zA recent?d=dnMXMwOfBR0 recent?i=LUCxFU6asLs:Z6iVahL4OFY:V_sGLiP recent?d=qj6IDK7rITs recent?i=LUCxFU6asLs:Z6iVahL4OFY:gIN9vFw recent?d=l6gmwiTKsz0 recent?d=7Q72WNTAKBA recent?i=LUCxFU6asLs:Z6iVahL4OFY:F7zBnMy recent?i=LUCxFU6asLs:Z6iVahL4OFY:-BTjWOF


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The nature of early-stage endometrial cancer recurrence—A national cohort study

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Publication date: December 2016
Source:European Journal of Cancer, Volume 69
Author(s): Mette Moustgaard Jeppesen, Pernille Tine Jensen, Dorte Gilså Hansen, Maria Iachina, Ole Mogensen
Background and aimsThe aim of the study was to present a comprehensive analysis of disease recurrence in a large Danish cohort of women with early-stage endometrial cancer treated according to national guidelines.MethodsAll women diagnosed with stage I or II endometrial cancer in 2005–2009 were included in a population-based historical cohort derived from the Danish Gynaecological Cancer Database. Disease recurrence up to 3 years after the primary diagnosis was identified using national registers and hospital charts. Follow-up on survival ended on 31st December 2014. We evaluated the predictive value of clinico-pathological and sociodemographic variables using multivariate logistic regression.ResultsRecurrence within 3 years of the primary treatment was diagnosed in 183 (7%) of the included 2612 women. Site of recurrence significantly impacted on overall survival as the 5-year survival rate was 64.8% for women with vaginal recurrence and 17.5% in women with distant recurrence. Factors predictive of recurrence included the International Federation of Gynaecology and Obstetrics (FIGO) stage (OR: IB = 1.91, stage II = 3.91), Charlson comorbidity index of 3 (OR 1.86), non-endometrioid histology (OR 1.81) and being outside of the workforce (OR 1.81). Vaginal recurrence was predicted by FIGO stage only (OR: IB = 1.88, II = 2.79), while extra-vaginal recurrence was predicted by FIGO stage (OR: IB = 2.12, II = 3.31), Charlson comorbidity index of 3 (OR 1.88) and non-endometrioid histology (OR 2.51).ConclusionsFuture research should seek to understand the underlying mechanisms of the identified predictive factors to improve recurrence prediction and to reduce morbidity and mortality.



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Adjuvant ipilimumab in stage III melanoma: New landscape, new questions

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Publication date: December 2016
Source:European Journal of Cancer, Volume 69
Author(s): Alexander M.M. Eggermont
The recently reported significant prolongation of overall survival with ipilimumab as adjuvant in high-risk stage III melanoma patients represents an important event in the adjuvant treatment landscape. The European Organisation for Research and Treatment of Cancer 18071 trial demonstrated a 28% reduction in risk of death in patients treated with ipilimumab at 10 mg/kg (hazard ratio for death, 0.72; 95.1% CI, 0.58−0.88; P = 0.001) compared with placebo. All end-points—recurrence-free survival (RFS), distant-metastasis-free survival (DMFS) and overall survival (OS)—showed similar benefits. Survival rates at 5 years in ipilimumab-treated patients were OS 11%, DMFS 9% and RFS 11% higher than in placebo-treated patients. Global Health quality-of-life scores were not significantly different between treatment arms, in spite of significant adverse event rates that resulted in only 42% of patients receiving more than four doses of ipilimumab and only 28.9% of patients going beyond 1 year of treatment. Grades 3–4 immune-related adverse events occurred in 41.6% of ipilimumab-treated patients and in 2.7% of placebo-treated patients. One can speculate on dose and duration of treatment, as well as on the requirement for complete lymph-node dissection in sentinel-node-positive patients. The remaining role of interferons will be discussed regarding differences in sensitivity profiles—such as in ulcerated melanoma versus non-ulcerated melanoma—and access to new drugs. Ongoing trials with targeted agents and with anti programmed cell death protein 1 (anti-PD-1) agents may bring significant additional results in the next few years that will redefine how we treat stage III patients. Overall, pricing of new treatments will determine access and whether patients will actually benefit from new treatment options.



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Health-related quality of life 10 years after oesophageal cancer surgery

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Publication date: December 2016
Source:European Journal of Cancer, Volume 69
Author(s): Anna Schandl, Jesper Lagergren, Asif Johar, Pernilla Lagergren
PurposeTo determine whether oesophageal cancer survivors recover in health-related quality of life (HRQOL) within 10 years of surgery.MethodsA prospective, nationwide, population-based cohort study including 90% of all oesophageal cancer surgery patients in Sweden in 2001–2005, with follow-up through 2015. HRQOL was assessed 5 and 10 years postoperatively, using questionnaires for cancer in general (EORTC QLQ-C30) and oesophageal cancer specifically (EORTC QLQ-OES18). The HRQOL measures at 10 years after surgery were compared with the 5-year assessment. The 10-year HRQOL scores were compared with a population-based reference population (4910 individuals), individually matched for age, sex and comorbidity, by means of mean score differences with 95% confidence intervals.ResultsAmong 616 patients, 104 (17%) survived at least 10 years. Of these, 92 (88%) responded to the HRQOL questionnaires at 5 and 10 years after surgery. Among the responders, 71% were older than 70 years. Patients did not improve in HRQOL between 5 and 10 years. Instead, the scores for 23 out of 25 HRQOL aspects declined, with clinically relevant and statistically significant deterioration in role function and appetite loss. Compared to the reference population, the 10 year-survivors had worse scores in all 25 HRQOL aspects, with significant deterioration in global quality of life, role functioning, social functioning and most symptoms. The most severe problems compared to the reference population were reflux, eating difficulties, diarrhoea and appetite loss.ConclusionPatients who have undergone curative treatment for oesophageal cancer experience reduced HRQOL with persisting symptoms 10 years after surgery.



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Diet, body size, physical activity and risk of prostate cancer: An umbrella review of the evidence

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Publication date: December 2016
Source:European Journal of Cancer, Volume 69
Author(s): Georgios Markozannes, Ioanna Tzoulaki, Dimitra Karli, Evangelos Evangelou, Evangelia Ntzani, Marc J. Gunter, Teresa Norat, John P. Ioannidis, Konstantinos K. Tsilidis
The existing literature on the relationship between diet, body size, physical activity and prostate cancer risk was summarised by the World Cancer Research Fund Continuous Update Project (CUP). An evaluation of the robustness of this evidence is required to help inform public health policy. The robustness of this evidence was evaluated using several criteria addressing evidence strength and validity, including the statistical significance of the random effects summary estimate and of the largest study in a meta-analysis, number of prostate cancer cases, between-study heterogeneity, 95% prediction intervals, small-study effects bias, excess significance bias and sensitivity analyses with credibility ceilings. A total of 248 meta-analyses were extracted from the CUP, which studied associations of 23 foods, 31 nutrients, eight indices of body size and three indices of physical activity with risk of total prostate cancer development, mortality or cancer development by stage and grade. Of the 176 meta-analyses using a continuous scale to measure the exposures, no association presented strong evidence by satisfying all the aforementioned criteria. Only the association of height with total prostate cancer incidence and mortality presented highly suggestive evidence with a 4% higher risk per 5 cm greater height (95% confidence interval, 1.03, 1.05). Associations for body mass index, weight, height, dietary calcium and spirits intake were supported by suggestive evidence. Overall, the association of diet, body size, physical activity and prostate cancer has been extensively studied, but no association was graded with strong evidence.



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Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation

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Publication date: Available online 4 November 2016
Source:European Journal of Cancer
Author(s): David Miles, David Cameron, Igor Bondarenko, Lyudmila Manzyuk, Juan Carlos Alcedo, Roberto Ivan Lopez, Seock-Ah Im, Jean-Luc Canon, Yaroslav Shparyk, Denise A. Yardley, Norikazu Masuda, Jungsil Ro, Neelima Denduluri, Stanislas Hubeaux, Cheng Quah, Carlos Bais, Joyce O'Shaughnessy
AimMERiDiAN evaluated plasma vascular endothelial growth factor-A (pVEGF-A) prospectively as a predictive biomarker for bevacizumab efficacy in metastatic breast cancer (mBC).MethodsIn this double-blind placebo-controlled randomised phase III trial, eligible patients had HER2-negative mBC previously untreated with chemotherapy. pVEGF-A was measured before randomisation to paclitaxel 90 mg/m2 on days 1, 8 and 15 with either placebo or bevacizumab 10 mg/kg on days 1 and 15, repeated every 4 weeks until disease progression, unacceptable toxicity or consent withdrawal. Stratification factors were baseline pVEGF-A, prior adjuvant chemotherapy, hormone receptor status and geographic region. Co-primary end-points were investigator-assessed progression-free survival (PFS) in the intent-to-treat and pVEGF-Ahigh populations.ResultsOf 481 patients randomised (242 placebo–paclitaxel; 239 bevacizumab–paclitaxel), 471 received study treatment. The stratified PFS hazard ratio was 0.68 (99% confidence interval, 0.51–0.91; log-rank p = 0.0007) in the intent-to-treat population (median 8.8 months with placebo–paclitaxel versus 11.0 months with bevacizumab–paclitaxel) and 0.64 (96% confidence interval, 0.47–0.88; log-rank p = 0.0038) in the pVEGF-Ahigh subgroup. The PFS treatment-by-VEGF-A interaction p value (secondary end-point) was 0.4619. Bevacizumab was associated with increased incidences of bleeding (all grades: 45% versus 27% with placebo), neutropenia (all grades: 39% versus 29%; grade ≥3: 25% versus 13%) and hypertension (all grades: 31% versus 13%; grade ≥3: 11% versus 4%).ConclusionThe significant PFS improvement with bevacizumab is consistent with previous placebo-controlled first-line trials in mBC. Results do not support using baseline pVEGF-A to identify patients benefitting most from bevacizumab.Clinical trials registrationClinicalTrials.gov NCT01663727.



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IJERPH, Vol. 13, Pages 1084: Prevalence and Occupational and Environmental Risk Factors of Self-Reported Asthma: Evidence from a Cross-Sectional Survey in Seven Chinese Cities

Objective: Asthma is one of the most common chronic diseases and associated with significant morbidity and mortality. However, few data on occupational and environmental risk factors of asthma are available, particularly in Asian adults. Based on a national cross-sectional survey, we assessed the prevalence and risk factors of asthma in Chinese adults. Methods: A total of 9974 participants aged 15 years and over in seven Chinese cities were selected using a stratified four-stage random sampling. All participants were interviewed face-to-face in their homes using a standardized self-administered questionnaire. Multivariate logistic regression analyses were adopted to determine various risk factors for asthma. Results: The prevalence of self-reported lifetime asthma was 2.46% among the entire adult population, 3.02% among males and 1.93% among females. The prevalence varied by age group, ethnicity, marital status, education, and floor space per person (p < 0.05). After adjusting for socio-demographic variables and smoking, we found independent occupational and environmental determinants of asthma, including a clearance-related job (OR = 2.28, 95%CI: 1.07–4.89), occupational exposure to industrial or occupational poisonous gas (OR = 4.21, 95%CI: 2.43–7.30), having large amounts of carpet in the workplace (OR = 2.61, 95%CI: 1.20–5.69) and using coal for cooking (OR = 2.65, 95%CI: 1.26–5.57). Conclusions: Asthma is a serious public health problem in China. Our study provides important updated information on the prevalence of asthma and its associated risk factors, which may help us better understand the epidemiology of asthma and prevent this disorder.

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IJERPH, Vol. 13, Pages 1087: A Spatial Hierarchical Analysis of the Temporal Influences of the El Niño-Southern Oscillation and Weather on Dengue in Kalutara District, Sri Lanka

Dengue is the major public health burden in Sri Lanka. Kalutara is one of the highly affected districts. Understanding the drivers of dengue is vital in controlling and preventing the disease spread. This study focuses on quantifying the influence of weather variability on dengue incidence over 10 Medical Officer of Health (MOH) divisions of Kalutara district. Weekly weather variables and data on dengue notifications, measured at 10 MOH divisions in Kalutara from 2009 to 2013, were retrieved and analysed. Distributed lag non-linear model and hierarchical-analysis was used to estimate division specific and overall relationships between weather and dengue. We incorporated lag times up to 12 weeks and evaluated models based on the Akaike Information Criterion. Consistent exposure-response patterns between different geographical locations were observed for rainfall, showing increasing relative risk of dengue with increasing rainfall from 50 mm per week. The strongest association with dengue risk centred around 6 to 10 weeks following rainfalls of more than 300 mm per week. With increasing temperature, the overall relative risk of dengue increased steadily starting from a lag of 4 weeks. We found similarly a strong link between the Oceanic Niño Index to weather patterns in the district in Sri Lanka and to dengue at a longer latency time confirming these relationships. Part of the influences of rainfall and temperature can be seen as mediator in the causal pathway of the Ocean Niño Index, which may allow a longer lead time for early warning signals. Our findings describe a strong association between weather, El Niño-Southern Oscillation and dengue in Sri Lanka.

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IJERPH, Vol. 13, Pages 1088: Changes in Composition and Function of Human Intestinal Microbiota Exposed to Chlorpyrifos in Oil as Assessed by the SHIME® Model

The presence of pesticide residues in food is a public health problem. Exposure to these substances in daily life could have serious effects on the intestine—the first organ to come into contact with food contaminants. The present study investigated the impact of a low dose (1 mg/day in oil) of the pesticide chlorpyrifos (CPF) on the community structure, diversity and metabolic response of the human gut microbiota using the SHIME® model (six reactors, representing the different parts of the gastrointestinal tract). The last three reactors (representing the colon) were inoculated with a mixture of feces from human adults. Three time points were studied: immediately before the first dose of CPF, and then after 15 and 30 days of CPF-oil administration. By using conventional bacterial culture and molecular biology methods, we showed that CPF in oil can affect the gut microbiota. It had the greatest effects on counts of culturable bacteria (with an increase in Enterobacteria, Bacteroides spp. and clostridia counts, and a decrease in bifidobacterial counts) and fermentative activity, which were colon-segment-dependent. Our results suggest that: (i) CPF in oil treatment affects the gut microbiota (although there was some discordance between the culture-dependent and culture-independent analyses); (ii) the changes are “SHIME®-compartment” specific; and (iii) the changes are associated with minor alterations in the production of short-chain fatty acids and lactate.

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Codon optimality and mRNA decay

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Breast-friendly, radiation-free alternative to mammogram in the making

Each year around a million women in the Netherlands undergo mammograms for early detection of possible breast cancer. It's an unpleasant procedure that uses X-rays. Researchers at TU Eindhoven are working on a 'breast-friendly' method, without...

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Seven substances added to 14th Report on Carcinogens

Today's release of the U.S. Department of Health and Human Services 14th Report on Carcinogens includes seven newly reviewed substances, bringing the cumulative total to 248 listings. The chemical trichloroethylene (TCE), and the metallic element cobalt...

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IJMS, Vol. 17, Pages 1837: Comparative Transcriptional Analysis of Loquat Fruit Identifies Major Signal Networks Involved in Fruit Development and Ripening Process

Loquat (Eriobotrya japonica Lindl.) is an important non-climacteric fruit and rich in essential nutrients such as minerals and carotenoids. During fruit development and ripening, thousands of the differentially expressed genes (DEGs) from various metabolic pathways cause a series of physiological and biochemical changes. To better understand the underlying mechanism of fruit development, the Solexa/Illumina RNA-seq high-throughput sequencing was used to evaluate the global changes of gene transcription levels. More than 51,610,234 high quality reads from ten runs of fruit development were sequenced and assembled into 48,838 unigenes. Among 3256 DEGs, 2304 unigenes could be annotated to the Gene Ontology database. These DEGs were distributed into 119 pathways described in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. A large number of DEGs were involved in carbohydrate metabolism, hormone signaling, and cell-wall degradation. The real-time reverse transcription (qRT)-PCR analyses revealed that several genes related to cell expansion, auxin signaling and ethylene response were differentially expressed during fruit development. Other members of transcription factor families were also identified. There were 952 DEGs considered as novel genes with no annotation in any databases. These unigenes will serve as an invaluable genetic resource for loquat molecular breeding and postharvest storage.

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IJMS, Vol. 17, Pages 1836: The Chemical Composition of Essential Oils from Cinnamomum camphora and Their Insecticidal Activity against the Stored Product Pests

To investigate the chemical composition and insecticidal activity of the essential oils of certain Chinese medicinal herbs and spices, the essential oils were extracted from the stem barks, leaves, and fruits of Cinnamomum camphora (L.) Presl, which were found to possess strong fumigant toxicity against Tribolium castaneum and Lasioderma serricorne adults. The essential oils of the plants were extracted by the method of steam distillation using a Clavenger apparatus. Their composition was determined by gas chromatography/mass spectrometric (GC-MS) analyses (HP-5MS column), and their insecticidal activity was measured by seal-spaced fumigation. D-camphor (51.3%), 1,8-cineole (4.3%), and α-terpineol (3.8%), while D-camphor (28.1%), linalool (22.9%), and 1,8-cineole (5.3%) were the main constituents of its fruits. The essential oils of the C. camphora all showed fumigant and contact toxicity. Other compounds exhibited various levels of bioactivities. The results indicate that the essential oils of C. camphora and its individual compounds can be considered a natural resource for the two stored-product insect management.

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IJMS, Vol. 17, Pages 1841: Lipidomics—Reshaping the Analysis and Perception of Type 2 Diabetes

As a consequence of a sedentary lifestyle as well as changed nutritional behavior, today’s societies are challenged by the rapid propagation of metabolic disorders. A common feature of diseases, such as obesity and type 2 diabetes (T2D), is the dysregulation of lipid metabolism. Our understanding of the mechanisms underlying these diseases is hampered by the complexity of lipid metabolic pathways on a cellular level. Furthermore, overall lipid homeostasis in higher eukaryotic organisms needs to be maintained by a highly regulated interplay between tissues, such as adipose tissue, liver and muscle. Unraveling pathological mechanisms underlying metabolic disorders therefore requires a diversified approach, integrating basic cellular research with clinical research, ultimately relying on the analytical power of mass spectrometry-based techniques. Here, we discuss recent progress in the development of lipidomics approaches to resolve the pathological mechanisms of metabolic diseases and to identify suitable biomarkers for clinical application. Due to its growing impact worldwide, we focus on T2D to highlight the key role of lipidomics in our current understanding of this disease, discuss remaining questions and suggest future strategies to address them.

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IJMS, Vol. 17, Pages 1840: Transcriptional and Posttranslational Regulation of Nucleotide Excision Repair: The Guardian of the Genome against Ultraviolet Radiation

Ultraviolet (UV) radiation from sunlight represents a constant threat to genome stability by generating modified DNA bases such as cyclobutane pyrimidine dimers (CPD) and pyrimidine-pyrimidone (6-4) photoproducts (6-4PP). If unrepaired, these lesions can have deleterious effects, including skin cancer. Mammalian cells are able to neutralize UV-induced photolesions through nucleotide excision repair (NER). The NER pathway has multiple components including seven xeroderma pigmentosum (XP) proteins (XPA to XPG) and numerous auxiliary factors, including ataxia telangiectasia and Rad3-related (ATR) protein kinase and RCC1 like domain (RLD) and homologous to the E6-AP carboxyl terminus (HECT) domain containing E3 ubiquitin protein ligase 2 (HERC2). In this review we highlight recent data on the transcriptional and posttranslational regulation of NER activity.

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IJMS, Vol. 17, Pages 1844: Anti-Melanogenic Activities of Heracleum moellendorffii via ERK1/2-Mediated MITF Downregulation

In this study, the anti-melanogenic effects of Heracleum moellendorffii Hance extract (HmHe) and the mechanisms through which it inhibits melanogenesis in melan-a cells were investigated. Mushroom tyrosinase (TYR) activity and melanin content as well as cellular tyrosinase activity were measured in the cells. mRNA and protein expression of microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), TYR-related protein-1 (TYRP-1) and -2 were also examined. The results demonstrate that treatment with HmHe significantly inhibits mushroom tyrosinase activity. Furthermore, HmHe also markedly inhibits melanin production and intracellular tyrosinase activity. By suppressing the expression of TYR, TYRP-1, TYRP-2, and MITF, HmHe treatment antagonized melanin production in melan-a cells. Additionally, HmHe interfered with the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, with reversal of HmHe-induced melanogenesis inhibition after treatment with specific inhibitor U0126. In summary, HmHe can be said to stimulate ERK1/2 phosphorylation and subsequent degradation of MITF, resulting in suppression of melanogenic enzymes and melanin production, possibly due to the presence of polyphenolic compounds.

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Autophagy suppression sensitizes glioma cells to IMP dehydrogenase inhibition-induced apoptotic death

Publication date: Available online 4 November 2016
Source:Experimental Cell Research
Author(s): Andjelka M. Isakovic, Marija Dulovic, Ivanka Markovic, Tamara Kravic-Stevovic, Vladimir Bumbasirevic, Vladimir Trajkovic, Aleksandra Isakovic
We investigated the role of autophagy, a process of controlled self-digestion, in the in vitro anticancer action of the inosine monophosphate dehydrogenase (IMPDH) inhibitor ribavirin. Ribavirin-triggered oxidative stress, caspase activation, and apoptotic death in U251 human glioma cells were associated with the induction of autophagy, as confirmed by intracellular acidification, appearance of autophagic vesicles, conversion of microtubule associated protein 1 light chain 3 (LC3)-I to autophagosome-associated LC3-II, and degradation of autophagic target p62/sequestosome 1. Ribavirin downregulated the activity of autophagy-inhibiting mammalian target of rapamycin complex 1 (mTORC1), as indicated by a decrease in phosphorylation of the mTORC1 substrate ribosomal p70S6 kinase and reduction of the mTORC1-activating Src/Akt signaling. Guanosine supplementation inhibited, while IMPDH inhibitor tiazofurin mimicked ribavirin-mediated autophagy induction, suggesting the involvement of IMPDH blockade in the observed effect. Autophagy suppression by ammonium chloride, bafilomycin A1, or RNA interference-mediated knockdown of LC3 sensitized glioma cells to ribavirin-induced apoptosis. Ribavirin also induced cytoprotective autophagy associated with Akt/mTORC1 inhibition in C6 rat glioma cells. Our data demonstrate that ribavirin-triggered Akt/mTORC1-dependent autophagy counteracts apoptotic death of glioma cells, indicating autophagy suppression as a plausible therapeutic strategy for sensitization of cancer cells to IMPDH inhibition.



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If You Want to Buy a Camel or Zebra, Go to Africa--or Missouri

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A livestock auction house in the town of Macon has more in common with an exotic African market than you might think

-- Read more on ScientificAmerican.com
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Viruses, Vol. 8, Pages 301: Recombinant Marek’s Disease Virus as a Vector-Based Vaccine against Avian Leukosis Virus Subgroup J in Chicken

Avian leukosis virus subgroup J (ALV-J) is an immunosuppressive virus that causes considerable economic losses to the chicken industry in China. However, there is currently no effective vaccine to prevent ALV-J infection. In order to reduce the losses caused by ALV-J, we constructed two effective ALV-J vaccines by inserting the ALV-J (strain JL093-1) env or gag+env genes into the US2 gene of the Marek’s disease herpesviruses (MDV) by transfection of overlapping fosmid DNAs, creating two recombinant MDVs, rMDV/ALV-gag+env and rMDV/ALV-env. Analysis of cultured chicken embryo fibroblasts infected with the rMDVs revealed that Env and Gag were successfully expressed and that there was no difference in growth kinetics in cells infected with rMDVs compared with that of cells infected with the parent MDV. Chickens vaccinated with either rMDV revealed that positive serum antibodies were induced. Both rMDVs also effectively reduced the rate of positive viremia in chicken flocks challenged with ALV-J. The protective effect provided by rMDV/ALV-env inoculation was slightly stronger than that provided by rMDV/ALV-gag+env. This represents the first study where a potential rMDV vaccine, expressing ALV-J antigenic genes, has been shown to be effective in the prevention of ALV-J. Our study also opens new avenues for the control of MDV and ALV-J co-infection.

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Anal itching

What you need to knowAsk about frequent stools and leaking because faeces are a known irritant of the perianal skinA symptom diary can help to identify foods, allergens, or washing practices...
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Placebo for treating depression . . . and other stories

The drug that works for depressionA systematic review of 252 trials of drugs for depression published between 1978 and 2016 has found one drug that consistently works for 35-40% of participants...
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How Old Brains Got New Neurons

Publication date: 3 November 2016
Source:Cell, Volume 167, Issue 4
Author(s): Rusty Gage




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Breaking Down Walls

Publication date: 3 November 2016
Source:Cell, Volume 167, Issue 4

In five days, there will be an election in the United States with immigration as a signature issue. We ask scientists their experiences as immigrants.

Teaser

In five days, there will be an election in the United States with immigration as a signature issue. We ask scientists their experiences as immigrants.


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Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity

Publication date: 3 November 2016
Source:Cell, Volume 167, Issue 4
Author(s): Melanie Schirmer, Sanne P. Smeekens, Hera Vlamakis, Martin Jaeger, Marije Oosting, Eric A. Franzosa, Trees Jansen, Liesbeth Jacobs, Marc Jan Bonder, Alexander Kurilshikov, Jingyuan Fu, Leo A.B. Joosten, Alexandra Zhernakova, Curtis Huttenhower, Cisca Wijmenga, Mihai G. Netea, Ramnik J. Xavier
Gut microbial dysbioses are linked to aberrant immune responses, which are often accompanied by abnormal production of inflammatory cytokines. As part of the Human Functional Genomics Project (HFGP), we investigate how differences in composition and function of gut microbial communities may contribute to inter-individual variation in cytokine responses to microbial stimulations in healthy humans. We observe microbiome-cytokine interaction patterns that are stimulus specific, cytokine specific, and cytokine and stimulus specific. Validation of two predicted host-microbial interactions reveal that TNFα and IFNγ production are associated with specific microbial metabolic pathways: palmitoleic acid metabolism and tryptophan degradation to tryptophol. Besides providing a resource of predicted microbially derived mediators that influence immune phenotypes in response to common microorganisms, these data can help to define principles for understanding disease susceptibility. The three HFGP studies presented in this issue lay the groundwork for further studies aimed at understanding the interplay between microbial, genetic, and environmental factors in the regulation of the immune response in humans.PaperClip

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Teaser

As part of the Human Functional Genomics Project, this study investigates the relationship between the gut microbiome and inter-individual variation in cytokine responses in humans, providing a resource of predicted microbially derived mediators that influence immune phenotypes in response to common microorganisms.


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On the Necessity of Ethical Guidelines for Novel Neurotechnologies

Publication date: 3 November 2016
Source:Cell, Volume 167, Issue 4
Author(s): Sara Goering, Rafael Yuste
Because novel neurotechnologies may alter human identity and society in profound ways, we advocate for the early integration of ethics into neurotechnology. We recommend developing and adopting a set of guidelines, like the Belmont Report on human subject research, as a framework for development and use of brain-related technologies.

Teaser

Because novel neurotechnologies may alter human identity and society in profound ways, we advocate for the early integration of ethics into neurotechnology. We recommend developing and adopting a set of guidelines, like the Belmont Report on human subject research, as a framework for development and use of brain-related technologies.


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For Motor Adjustments, Serotonin Steps In

Publication date: 3 November 2016
Source:Cell, Volume 167, Issue 4
Author(s): Hitoshi Okamoto
To adapt to their environment, animals subconsciously calculate how motor commands can be efficiently translated into the actual movements. Kawashima et al. discovered that serotonergic neurons in the dorsal raphe nucleus regulate the transient memory of such efficacy; thus, successive behaviors do not require repeated cumbersome readjustment of efficacy.

Teaser

To adapt to their environment, animals subconsciously calculate how motor commands can be efficiently translated into the actual movements. Kawashima et al. discovered that serotonergic neurons in the dorsal raphe nucleus regulate the transient memory of such efficacy; thus, successive behaviors do not require repeated cumbersome readjustment of efficacy.


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Illuminating the Neuronal Architecture Underlying Context in Fear Memory

Publication date: 3 November 2016
Source:Cell, Volume 167, Issue 4
Author(s): Mark S. Cembrowski, Nelson Spruston
Context plays a foundational role in determining how to interpret potentially fear-producing stimuli, yet the precise neurobiological substrates of context are poorly understood. In this issue of Cell, Xu et al. elegantly show that parallel neuronal circuits are necessary for two distinct roles of context in fear conditioning.

Teaser

Context plays a foundational role in determining how to interpret potentially fear-producing stimuli, yet the precise neurobiological substrates of context are poorly understood. In this issue of Cell, Xu et al. elegantly show that parallel neuronal circuits are necessary for two distinct roles of context in fear conditioning.


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Firing Up in Anticipation

Publication date: 3 November 2016
Source:Cell, Volume 167, Issue 4
Author(s): Marta Koch




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MIS12/MIND Control at the Kinetochore

Publication date: 3 November 2016
Source:Cell, Volume 167, Issue 4
Author(s): Rene Ladurner, Aaron F. Straight
Kinetochores are complex multiprotein machines that link chromosomes to dynamic microtubules for chromosome segregation. Two studies in Cell reveal the structure of the human MIS12 and budding yeast MIND kinetochore complexes and the regulatory mechanisms that enable them to link chromosomes to microtubules during mitosis.

Teaser

Kinetochores are complex multiprotein machines that link chromosomes to dynamic microtubules for chromosome segregation. Two studies in Cell reveal the structure of the human MIS12 and budding yeast MIND kinetochore complexes and the regulatory mechanisms that enable them to link chromosomes to microtubules during mitosis.


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Did a Single Amino Acid Change Make Ebola Virus More Virulent?

Publication date: 3 November 2016
Source:Cell, Volume 167, Issue 4
Author(s): Trevor Bedford, Harmit S. Malik
A mutation in the Ebola virus glycoprotein arose early during the 2013–2016 epidemic and dominated the viral population. Two studies by Diehl et al. and Urbanowicz et al. now reveal that this mutation is associated with higher infectivity to human cells, representing the clearest example of Ebola’s functional adaptation to human hosts.

Teaser

A mutation in the Ebola virus glycoprotein arose early during the 2013–2016 epidemic and dominated the viral population. Two studies by Diehl et al. and Urbanowicz et al. now reveal that this mutation is associated with higher infectivity to human cells, representing the clearest example of Ebola’s functional adaptation to human hosts.


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The Human Functional Genomics Project: Understanding Generation of Diversity

Publication date: 3 November 2016
Source:Cell, Volume 167, Issue 4
Author(s): Jenna L. Pappalardo, David A. Hafler
Generation of biologic diversity is a cornerstone of immunity, yet the tools to investigate the causal influence of genetic and environmental factors have been greatly limited. Studies from the Human Functional Genomics Project, presented in Cell and other Cell Press journals, integrate environmental and genetic factors with the direction and magnitude of immune responses to decipher inflammatory disease pathogenesis.

Teaser

Generation of biologic diversity is a cornerstone of immunity, yet the tools to investigate the causal influence of genetic and environmental factors have been greatly limited. Studies from the Human Functional Genomics Project, presented in Cell and other Cell Press journals, integrate environmental and genetic factors with the direction and magnitude of immune responses to decipher inflammatory disease pathogenesis.


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Adult Neurogenesis in the Hippocampus: From Stem Cells to Behavior

Publication date: 3 November 2016
Source:Cell, Volume 167, Issue 4
Author(s): J. Tiago Gonçalves, Simon T. Schafer, Fred H. Gage
The dentate gyrus of the mammalian hippocampus continuously generates new neurons during adulthood. These adult-born neurons become functionally active and are thought to contribute to learning and memory, especially during their maturation phase, when they have extraordinary plasticity. In this Review, we discuss the molecular machinery involved in the generation of new neurons from a pool of adult neural stem cells and their integration into functional hippocampal circuits. We also summarize the potential functions of these newborn neurons in the adult brain, their contribution to behavior, and their relevance to disease.

Teaser

The dentate gyrus of the mammalian hippocampus continuously generates new neurons during adulthood. Understanding the molecular mechanisms underlying the generation, integration, and functions of these newborn neurons in the adult brain may help design future regenerative approaches for treating neurological disease.


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The Central Nervous System and the Gut Microbiome

Publication date: 3 November 2016
Source:Cell, Volume 167, Issue 4
Author(s): Gil Sharon, Timothy R. Sampson, Daniel H. Geschwind, Sarkis K. Mazmanian
Neurodevelopment is a complex process governed by both intrinsic and extrinsic signals. While historically studied by researching the brain, inputs from the periphery impact many neurological conditions. Indeed, emerging data suggest communication between the gut and the brain in anxiety, depression, cognition, and autism spectrum disorder (ASD). The development of a healthy, functional brain depends on key pre- and post-natal events that integrate environmental cues, such as molecular signals from the gut. These cues largely originate from the microbiome, the consortium of symbiotic bacteria that reside within all animals. Research over the past few years reveals that the gut microbiome plays a role in basic neurogenerative processes such as the formation of the blood-brain barrier, myelination, neurogenesis, and microglia maturation and also modulates many aspects of animal behavior. Herein, we discuss the biological intersection of neurodevelopment and the microbiome and explore the hypothesis that gut bacteria are integral contributors to development and function of the nervous system and to the balance between mental health and disease.

Teaser

Emerging evidence points toward an important role of the gut-brain axis in neuropsychiatric diseases, suggesting that gut bacteria may be integral contributors to development and function of the nervous system and to the balance between mental health and disease.


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From Whole-Brain Data to Functional Circuit Models: The Zebrafish Optomotor Response

Publication date: 3 November 2016
Source:Cell, Volume 167, Issue 4
Author(s): Eva A. Naumann, James E. Fitzgerald, Timothy W. Dunn, Jason Rihel, Haim Sompolinsky, Florian Engert
Detailed descriptions of brain-scale sensorimotor circuits underlying vertebrate behavior remain elusive. Recent advances in zebrafish neuroscience offer new opportunities to dissect such circuits via whole-brain imaging, behavioral analysis, functional perturbations, and network modeling. Here, we harness these tools to generate a brain-scale circuit model of the optomotor response, an orienting behavior evoked by visual motion. We show that such motion is processed by diverse neural response types distributed across multiple brain regions. To transform sensory input into action, these regions sequentially integrate eye- and direction-specific sensory streams, refine representations via interhemispheric inhibition, and demix locomotor instructions to independently drive turning and forward swimming. While experiments revealed many neural response types throughout the brain, modeling identified the dimensions of functional connectivity most critical for the behavior. We thus reveal how distributed neurons collaborate to generate behavior and illustrate a paradigm for distilling functional circuit models from whole-brain data.

Graphical abstract

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Teaser

Whole-brain imaging and behavioral analysis combined with network modeling reveal key circuit elements contributing to a complex sensorimotor behavior in zebrafish larvae and provide a framework for building brain-level circuit models.


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Host and Environmental Factors Influencing Individual Human Cytokine Responses

Publication date: 3 November 2016
Source:Cell, Volume 167, Issue 4
Author(s): Rob ter Horst, Martin Jaeger, Sanne P. Smeekens, Marije Oosting, Morris A. Swertz, Yang Li, Vinod Kumar, Dimitri A. Diavatopoulos, Anne F.M. Jansen, Heidi Lemmers, Helga Toenhake-Dijkstra, Antonius E. van Herwaarden, Matthijs Janssen, Renate G. van der Molen, Irma Joosten, Fred C.G.J. Sweep, Johannes W. Smit, Romana T. Netea-Maier, Mieke M.J.F. Koenders, Ramnik J. Xavier, Jos W.M. van der Meer, Charles A. Dinarello, Norman Pavelka, Cisca Wijmenga, Richard A. Notebaart, Leo A.B. Joosten, Mihai G. Netea
Differences in susceptibility to immune-mediated diseases are determined by variability in immune responses. In three studies within the Human Functional Genomics Project, we assessed the effect of environmental and non-genetic host factors of the genetic make-up of the host and of the intestinal microbiome on the cytokine responses in humans. We analyzed the association of these factors with circulating mediators and with six cytokines after stimulation with 19 bacterial, fungal, viral, and non-microbial metabolic stimuli in 534 healthy subjects. In this first study, we show a strong impact of non-genetic host factors (e.g., age and gender) on cytokine production and circulating mediators. Additionally, annual seasonality is found to be an important environmental factor influencing cytokine production. Alpha-1-antitrypsin concentrations partially mediate the seasonality of cytokine responses, whereas the effect of vitamin D levels is limited. The complete dataset has been made publicly available as a comprehensive resource for future studies.PaperClip

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Teaser

As part of the Human Functional Genomics Project, mapping of environmental and non-genetic host factors reveals critical associations between age, gender, and annual seasonality in inter-individual variability of immune cell function.


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The Colonic Crypt Protects Stem Cells from Microbiota-Derived Metabolites

Publication date: 3 November 2016
Source:Cell, Volume 167, Issue 4
Author(s): Gerard E. Kaiko, Stacy H. Ryu, Olivia I. Koues, Patrick L. Collins, Lilianna Solnica-Krezel, Edward J. Pearce, Erika L. Pearce, Eugene M. Oltz, Thaddeus S. Stappenbeck




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Hematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance

Publication date: 3 November 2016
Source:Cell, Volume 167, Issue 4
Author(s): Pingping Li, Shuainan Liu, Min Lu, Gautum Bandyopadhyay, Dayoung Oh, Takeshi Imamura, Andrew M.F. Johnson, Dorothy Sears, Zhufang Shen, Bing Cui, Lijuan Kong, Shaocong Hou, Xiao Liang, Salvatore Iovino, Steven M. Watkins, Wei Ying, Olivia Osborn, Joshua Wollam, Martin Brenner, Jerrold M. Olefsky
In obesity, macrophages and other immune cells accumulate in insulin target tissues, promoting a chronic inflammatory state and insulin resistance. Galectin-3 (Gal3), a lectin mainly secreted by macrophages, is elevated in both obese subjects and mice. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese mice. In vitro treatment with Gal3 directly enhanced macrophage chemotaxis, reduced insulin-stimulated glucose uptake in myocytes and 3T3-L1 adipocytes and impaired insulin-mediated suppression of glucose output in primary mouse hepatocytes. Importantly, we found that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These observations elucidate a novel role for Gal3 in hepatocyte, adipocyte, and myocyte insulin resistance, suggesting that Gal3 can link inflammation to decreased insulin sensitivity. Inhibition of Gal3 could be a new approach to treat insulin resistance.

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Teaser

A circulating lectin secreted by macrophages in obese individuals drives insulin resistance and glucose intolerance by directly binding the insulin receptor and antagonizing downstream metabolic responses.


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Inflammation Improves Glucose Homeostasis through IKKβ-XBP1s Interaction

Publication date: 3 November 2016
Source:Cell, Volume 167, Issue 4
Author(s): Junli Liu, Dorina Ibi, Koji Taniguchi, Jaemin Lee, Hilde Herrema, Bedia Akosman, Patrick Mucka, Mario Andres Salazar Hernandez, Muhemmet Fatih Uyar, Sang Won Park, Michael Karin, Umut Ozcan
It is widely believed that inflammation associated with obesity has an important role in the development of type 2 diabetes. IκB kinase beta (IKKβ) is a crucial kinase that responds to inflammatory stimuli such as tumor necrosis factor α (TNF-α) by initiating a variety of intracellular signaling cascades and is considered to be a key element in the inflammation-mediated development of insulin resistance. We show here, contrary to expectation, that IKKβ-mediated inflammation is a positive regulator of hepatic glucose homeostasis. IKKβ phosphorylates the spliced form of X-Box Binding Protein 1 (XBP1s) and increases the activity of XBP1s. We have used three experimental approaches to enhance the IKKβ activity in the liver of obese mice and observed increased XBP1s activity, reduced ER stress, and a significant improvement in insulin sensitivity and consequently in glucose homeostasis. Our results reveal a beneficial role of IKKβ-mediated hepatic inflammation in glucose homeostasis.

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Teaser

Inflammatory signaling via IKKβ in the liver is beneficial for glucose homeostasis, running counter to the prevailing view that inflammation caused by obesity leads to insulin resistance.


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