Non cell autonomous upregulation of CDKN2 transcription linked to progression of chronic hepatitis C disease

Chronic hepatitis C virus infection (C-HC) is associated with higher mortality arising from hepatic and extrahepatic disease. This may be due to accelerated biological aging; however, studies in C-HC have thus far been based solely on telomere length as a biomarker of aging (BoA). In this study, we have evaluated CDKN2 locus transcripts as alternative BoAs in C-HC. Our results suggest that C-HC induces non-cell-autonomous senescence and accelerates biological aging. The CDKN2 locus may provide a link between C-HC and increased susceptibility to age-associated diseases and provides novel biomarkers for assessing its impact on aging processes in man

Para-cresol production by Clostridium difficile affects microbial diversity and membrane integrity of Gram-negative bacteria

Clostridium difficile is a Gram-positive spore-forming anaerobe and a major cause of antibiotic-associated diarrhoea. Disruption of the commensal microbiota, such as through treatment with broad-spectrum antibiotics, is a critical precursor for colonisation by C. difficile and subsequent disease. Furthermore, failure of the gut microbiota to recover colonisation resistance can result in recurrence of infection. An unusual characteristic of C. difficile among gut bacteria is its ability to produce the bacteriostatic compound para-cresol (p-cresol) through fermentation of tyrosine. Here, we demonstrate that the ability of C. difficile to produce p-cresol in vitro provides a competitive advantage over gut bacteria including Escherichia coli, Klebsiella oxytoca and Bacteroides thetaiotaomicron. Metabolic profiling of competitive co-cultures revealed that acetate, alanine, butyrate, isobutyrate, p-cresol and p-hydroxyphenylacetate were the main metabolites responsible for differentiating the parent strain C. difficile (630Δerm) from a defined mutant deficient in p-cresol production. Moreover, we show that the p-cresol mutant displays a fitness defect in a mouse relapse model of C. difficile infection (CDI). Analysis of the microbiome from this mouse model of CDI demonstrates that colonisation by the p-cresol mutant results in a distinctly altered intestinal microbiota, and metabolic profile, with a greater representation of Gammaproteobacteria, including the Pseudomonales and Enterobacteriales. We demonstrate that Gammaproteobacteria are susceptible to exogenous p-cresol in vitro and that there is a clear divide between bacterial Phyla and their susceptibility to p-cresol. In general, Gram-negative species were relatively sensitive to p-cresol, whereas Gram-positive species were more tolerant. This study demonstrates that production of p-cresol by C. difficile has an effect on the viability of intestinal bacteria as well as the major metabolites produced in vitro. These observations are upheld in a mouse model of CDI, in which p-cresol production affects the biodiversity of gut microbiota and faecal metabolite profiles, suggesting that p-cresol production contributes to C. difficile survival and pathogenesis.Peer reviewedFinal Published versio

Diatom oxygen isotopes: evidence of a species effect in the sediment record

Diatom oxygen isotope measurements are commonly made on bulk mixed species assemblages due to the difficulty in purifying and separating individual taxa. As such, it is essential to understand processes in diatoms which may lead to isotope offsets both between and within individual species. Existing studies have suggested that mechanisms which may lead to isotopes offset in diatoms, such as vital effects, are either nonexistent or negligible. Here, we present a suite of diatom oxygen isotope data from the onset of major Northern Hemisphere Glaciation at ODP site 882 in the northwest Pacific Ocean which display large offsets (mean = 1.23%, max = 3.51%, error = 0.84%) between two different size fractions (75–150 um and >150 um) that are dominated by only two species: Coscinodiscus marginatus and Coscinodiscus radiatus. These offsets are most likely size related, although additional interspecies and intraspecies effects may also be important in determining the exact magnitude of the offsets. Consequently, considerable care is needed when interpreting bulk diatom oxygen isotope data in relation to paleoenvironmental change, especially when the amount of stratigraphical change within the isotopes is small

Hunger in Maine

Hunger and food insecurity is on the rise in Maine. Mainers are experiencing a food emergency made graver by the economic recession and rising health costs. The authors of this article discuss hunger in Maine, focusing on private efforts to alleviate it

Viral genotype correlates with distinct liver gene transcription signatures in chronic hepatitis C virus infection

BACKGROUND: Chronic hepatitis C virus (HCV) infection of the liver with either genotype 1 or genotype 3 gives rise to distinct pathologies, and the two viral genotypes respond differently to antiviral therapy. METHODS: To understand these clinical differences, we compared gene transcription profiles in liver biopsies from patients infected with either gt1 or gt3, and uninfected controls. RESULTS: Gt1-infected biopsies displayed elevated levels of transcripts regulated by type I and type III interferons (IFN), including genes that predict response to IFN-α therapy. In contrast, genes controlled by IFN-γ were induced in gt3-infected biopsies. Moreover, IFN-γ levels were higher in gt3-infected biopsies. Analysis of hepatocyte-derived cell lines confirmed that the genes upregulated in gt3 infection were preferentially induced by IFN-γ. The transcriptional profile of gt3 infection was unaffected by IFNL4 polymorphisms, providing a rationale for the reduced predictive power of IFNL genotyping in gt3-infected patients. CONCLUSIONS: The interactions between HCV genotypes 1 and 3 and hepatocytes are distinct. These unique interactions provide avenues to explore the biological mechanisms that drive viral genotype-specific differences in disease progression and treatment response. A greater understanding of the distinct host-pathogen interactions of the different HCV genotypes is required to facilitate optimal management of HCV infection

Effects of coastal urbanization on salt-marsh faunal assemblages in the northern Gulf of Mexico

Author Posting. © American Fisheries Society, 2014. This article is posted here by permission of American Fisheries Society for personal use, not for redistribution. The definitive version was published in Marine and Coastal Fisheries: Dynamics, Management, and Ecosystem Science 6 (2014): 89-107, doi:10.1080/19425120.2014.893467.Coastal landscapes in the northern Gulf of Mexico, specifically the Mississippi coast, have undergone rapid urbanization that may impact the suitability of salt-marsh ecosystems for maintaining and regulating estuarine faunal communities. We used a landscape ecology approach to quantify the composition and configuration of salt-marsh habitats and developed surfaces at multiple spatial scales surrounding three small, first-order salt-marsh tidal creeks arrayed along a gradient of urbanization in two river-dominated estuaries. From May 3 to June 4, 2010, nekton and macroinfauna were collected weekly at all six sites. Due to the greater abundance of grass shrimp Palaemonetes spp., brown shrimp Farfantepenaeus aztecus, blue crab Callinectes sapidus, Gulf Menhaden Brevoortia patronus, and Spot Leiostomus xanthurus, tidal creeks in intact natural (IN) salt-marsh landscapes supported a nekton assemblage that was significantly different from those in partially urbanized (PU) or completely urbanized (CU) salt-marsh landscapes. However, PU landscapes still supported an abundant nekton assemblage. In addition, the results illustrated a linkage between life history traits and landscape characteristics. Resident and transient nekton species that have specific habitat requirements are more likely to be impacted in urbanized landscapes than more mobile species that are able to exploit multiple habitats. Patterns were less clear for macroinfaunal assemblages, although they were comparatively less abundant in CU salt-marsh landscapes than in either IN or PU landscapes. The low abundance or absence of several macroinfaunal taxa in CU landscapes may be viewed as an additional indicator of poor habitat quality for nekton. The observed patterns also suggested that benthic sediments in the CU salt-marsh landscapes were altered in comparison with IN or PU landscapes. The amount of developed shoreline and various metrics related to salt marsh fragmentation were important drivers of observed patterns in nekton and macroinfaunal assemblages

The use of the six-minute walk test (6-MWT) to screen for symptoms of acute mountain sickness and predict susceptibility during a long-term exposure in normobaric hypoxia within young to middle-aged adults

Introduction: Individuals travelling to altitudes of &gt;2000-2500m are at increased risk of acute mountain sickness (AMS) and may benefit from undergoing a standardised screening assessment prior to departure. As such, a simple and time-efficient tool for predicting human physiological responses to altitude exposure (both simulated and real), is the 6-minute walking test (6-MWT). The 6-MWT also demonstrates acceptable construct validity when monitoring acclimatisation at terrestrial altitude of ~3400m, however, it is unknown if this test can predict symptoms of AMS during a prolonged exposure to normobaric hypoxia. Therefore, the aim of this study was to: 1) compare the performance outcome and humans responses of the 6-MWT between normoxia and normobaric hypoxia; and 2) investigate if the 6-MWT in normobaric hypoxia can predict symptoms of AMS during an 8-hour normobaric hypoxia exposure.Methods: Forty-four healthy participants (25 males, 19 females, 31±10 years, 73.9±14.6 kg 174.1±8.0 cm) visited the laboratories on 3 occasions to complete a normoxic and normobaric hypoxic 6-MWT, and then an 8-hour exposure to normobaric hypoxia at rest. Participants underwent a familiarisation trial and 30-mins rest in each condition before starting the 6-MWT, which was completed in a randomised order. Normobaric hypoxia occurred within an environment simulating an altitude of 4500 m (FiO2 12.5%). Results: A significantly impaired performance (668±83 vs. 725±90m, p&lt;0.05), lower pulse oxygen saturation (SpO2: 75±8 vs. 97±2%, p&lt;0.05) and higher AMS scores via the Lake Louise Questionnaire (1±1 vs. 0±0 arbitrary units, p&lt;0.05) were observed following the 6-MWT in normobaric hypoxia compared to normoxia. During the 8-hour normobaric hypoxic exposure, a reduction in resting SpO2 (mean: 81±4%, end: 82±6%, pre-to-post change:-16±6%) and an increase in AMS scores were observed (mean: +1±4, end: +2±2 pre-to-post change: +2±2 arbitrary units). Low correlation coefficient values were found for post-test and pre-to-post test changes in SpO2 (r = 0.3 and 0.0) and AMS scores (r = 0.3 and 0.2) between the 6-MWT and 8-hour prolonged exposure in normobaric hypoxia, respectively.Conclusion: The 6-MWT demonstrates impairments to performance, increased physiological strain and the occurrence of AMS symptoms in response to normobaric hypoxia compared to normoxia. However, it appears the 6-MWT is unable to predict AMS susceptibility, nor impairment to SpO2 within a prolonged exposure. Whilst the 6-MWT is useful for monitoring acclimatisation progress and provides a good tool for educational purposes to improve individuals’ knowledge on the effect hypoxia has on performance and health outcomes prior to departing for an altitude sojourn, it is currently not possible to be used in screening for or, predicting AMS susceptibility. <br/

The use of the six-minute walk test (6-MWT) to screen for symptoms of acute mountain sickness and predict susceptibility during a long-term exposure in normobaric hypoxia within young to middle-aged adults

Introduction: Individuals travelling to altitudes of &gt;2000-2500m are at increased risk of acute mountain sickness (AMS) and may benefit from undergoing a standardised screening assessment prior to departure. As such, a simple and time-efficient tool for predicting human physiological responses to altitude exposure (both simulated and real), is the 6-minute walking test (6-MWT). The 6-MWT also demonstrates acceptable construct validity when monitoring acclimatisation at terrestrial altitude of ~3400m, however, it is unknown if this test can predict symptoms of AMS during a prolonged exposure to normobaric hypoxia. Therefore, the aim of this study was to: 1) compare the performance outcome and humans responses of the 6-MWT between normoxia and normobaric hypoxia; and 2) investigate if the 6-MWT in normobaric hypoxia can predict symptoms of AMS during an 8-hour normobaric hypoxia exposure.Methods: Forty-four healthy participants (25 males, 19 females, 31±10 years, 73.9±14.6 kg 174.1±8.0 cm) visited the laboratories on 3 occasions to complete a normoxic and normobaric hypoxic 6-MWT, and then an 8-hour exposure to normobaric hypoxia at rest. Participants underwent a familiarisation trial and 30-mins rest in each condition before starting the 6-MWT, which was completed in a randomised order. Normobaric hypoxia occurred within an environment simulating an altitude of 4500 m (FiO2 12.5%). Results: A significantly impaired performance (668±83 vs. 725±90m, p&lt;0.05), lower pulse oxygen saturation (SpO2: 75±8 vs. 97±2%, p&lt;0.05) and higher AMS scores via the Lake Louise Questionnaire (1±1 vs. 0±0 arbitrary units, p&lt;0.05) were observed following the 6-MWT in normobaric hypoxia compared to normoxia. During the 8-hour normobaric hypoxic exposure, a reduction in resting SpO2 (mean: 81±4%, end: 82±6%, pre-to-post change:-16±6%) and an increase in AMS scores were observed (mean: +1±4, end: +2±2 pre-to-post change: +2±2 arbitrary units). Low correlation coefficient values were found for post-test and pre-to-post test changes in SpO2 (r = 0.3 and 0.0) and AMS scores (r = 0.3 and 0.2) between the 6-MWT and 8-hour prolonged exposure in normobaric hypoxia, respectively.Conclusion: The 6-MWT demonstrates impairments to performance, increased physiological strain and the occurrence of AMS symptoms in response to normobaric hypoxia compared to normoxia. However, it appears the 6-MWT is unable to predict AMS susceptibility, nor impairment to SpO2 within a prolonged exposure. Whilst the 6-MWT is useful for monitoring acclimatisation progress and provides a good tool for educational purposes to improve individuals’ knowledge on the effect hypoxia has on performance and health outcomes prior to departing for an altitude sojourn, it is currently not possible to be used in screening for or, predicting AMS susceptibility. <br/

Exploring flow occurrence in elite golf

Research on flow (Csikszentmihalyi, 1975) has traditionally focused on reactive, externally-paced sports (e.g., tennis) without exploring those that are self-paced and stopstart in nature. This study investigated the occurrence of flow in a sample of thirteen elite golfers by conducting semi-structured interviews discussing: (i) their experiences of flow, (ii) factors that influenced flow occurrence, and (iii) the controllability of these experiences. Results shared similarity with existing research in terms of the majority of influencing factors reported, including motivation, preparation, focus, psychological state, environmental and situational conditions, and arousal, and that flow was reported to be at least potentially controllable. Golf-specific influences were also noted, including pre-shot routines, use of psychological interventions, standard of performance, and maintenance of physical state, suggesting that flow may have occurred differently for this sample. Findings are discussed and applied recommendations are made that may help golfers put relevant factors in place to increase the likelihood of experiencing flow

NKG2D function protects the host from tumor initiation

The activation NKG2D receptor has been shown to play an important role in the control of experimental tumor growth and metastases expressing ligands for NKG2D; however, a function for this recognition pathway in host protection from de novo tumorigenesis has never been demonstrated. We show that neutralization of NKG2D enhances the sensitivity of wild-type (WT) C57BL/6 and BALB/c mice to methylcholanthrene (MCA)-induced fibrosarcoma. The importance of the NKG2D pathway was additionally illustrated in mice deficient for either IFN-γ or tumor necrosis factor–related apoptosis-inducing ligand, whereas mice depleted of natural killer cells, T cells, or deficient for perforin did not display any detectable NKG2D phenotype. Furthermore, IL-12 therapy preventing MCA-induced sarcoma formation was also largely dependent on the NKG2D pathway. Although NKG2D ligand expression was variable or absent on sarcomas emerging in WT mice, sarcomas derived from perforin-deficient mice were Rae-1+ and immunogenic when transferred into WT syngeneic mice. These findings suggest an important early role for the NKG2D in controlling and shaping tumor formation