Development of the preterm gut microbiome in twins at risk of necrotising enterocolitis and sepsis

The preterm gut microbiome is a complex dynamic community influenced by genetic and environmental factors and is implicated in the pathogenesis of necrotising enterocolitis (NEC) and sepsis. We aimed to explore the longitudinal development of the gut microbiome in preterm twins to determine how shared environmental and genetic factors may influence temporal changes and compared this to the expressed breast milk (EBM) microbiome. Stool samples (n = 173) from 27 infants (12 twin pairs and 1 triplet set) and EBM (n = 18) from 4 mothers were collected longitudinally. All samples underwent PCR-DGGE (denaturing gradient gel electrophoresis) analysis and a selected subset underwent 454 pyrosequencing. Stool and EBM shared a core microbiome dominated by Enterobacteriaceae, Enterococcaceae, and Staphylococcaceae. The gut microbiome showed greater similarity between siblings compared to unrelated individuals. Pyrosequencing revealed a reduction in diversity and increasing dominance of Escherichia sp. preceding NEC that was not observed in the healthy twin. Antibiotic treatment had a substantial effect on the gut microbiome, reducing Escherichia sp. and increasing other Enterobacteriaceae. This study demonstrates related preterm twins share similar gut microbiome development, even within the complex environment of neonatal intensive care. This is likely a result of shared genetic and immunomodulatory factors as well as exposure to the same maternal microbiome during birth, skin contact and exposure to EBM. Environmental factors including antibiotic exposure and feeding are additional significant determinants of community structure, regardless of host genetics

Dietary fiber showed no preventive effect against colon and rectal cancers in Japanese with low fat intake: an analysis from the results of nutrition surveys from 23 Japanese prefectures

BACKGROUND: Since Fuchs' report in 1999, the reported protective effect of dietary fiber from colorectal carcinogenesis has led many researchers to question its real benefit. The aim of this study is to evaluate the association between diet, especially dietary fiber and fat and colorectal cancer in Japan. METHODS: A multiple regression analysis (using the stepwise variable selection method) was performed using the standardized mortality ratios (SMRs) of colon and rectal cancer in 23 Japanese prefectures as objective variables and dietary fiber, nutrients and food groups as explanatory variables. RESULTS: As for colon cancer, the standardized partial correlation coefficients were positively significant for fat (1,13, P = 0.000), seaweeds (0.41, P = 0.026) and beans (0.45, P = 0.017) and were negatively significant for vitamin A (-0.63, P = 0.003), vitamin C (-0.42, P = 0.019) and yellow-green vegetables (-0.37, P = 0.046). For rectal cancer, the standardized partial correlation coefficient in fat (0.60, P = 0.002) was positively significant. Dietary fiber was not found to have a significant relationship with either colon or rectal cancers. CONCLUSIONS: This study failed to show any protective effect of dietary fiber in subjects with a low fat intake (Japanese) in this analysis, which supports Fuchs' findings in subjects with a high fat intake (US Americans)

Spatio-Temporal Credit Assignment in Neuronal Population Learning

In learning from trial and error, animals need to relate behavioral decisions to environmental reinforcement even though it may be difficult to assign credit to a particular decision when outcomes are uncertain or subject to delays. When considering the biophysical basis of learning, the credit-assignment problem is compounded because the behavioral decisions themselves result from the spatio-temporal aggregation of many synaptic releases. We present a model of plasticity induction for reinforcement learning in a population of leaky integrate and fire neurons which is based on a cascade of synaptic memory traces. Each synaptic cascade correlates presynaptic input first with postsynaptic events, next with the behavioral decisions and finally with external reinforcement. For operant conditioning, learning succeeds even when reinforcement is delivered with a delay so large that temporal contiguity between decision and pertinent reward is lost due to intervening decisions which are themselves subject to delayed reinforcement. This shows that the model provides a viable mechanism for temporal credit assignment. Further, learning speeds up with increasing population size, so the plasticity cascade simultaneously addresses the spatial problem of assigning credit to synapses in different population neurons. Simulations on other tasks, such as sequential decision making, serve to contrast the performance of the proposed scheme to that of temporal difference-based learning. We argue that, due to their comparative robustness, synaptic plasticity cascades are attractive basic models of reinforcement learning in the brain

A systems approach to prion disease

Prions cause transmissible neurodegenerative diseases and replicate by conformational conversion of normal benign forms of prion protein (PrPC) to disease-causing PrPSc isoforms. A systems approach to disease postulates that disease arises from perturbation of biological networks in the relevant organ. We tracked global gene expression in the brains of eight distinct mouse strain–prion strain combinations throughout the progression of the disease to capture the effects of prion strain, host genetics, and PrP concentration on disease incubation time. Subtractive analyses exploiting various aspects of prion biology and infection identified a core of 333 differentially expressed genes (DEGs) that appeared central to prion disease. DEGs were mapped into functional pathways and networks reflecting defined neuropathological events and PrPSc replication and accumulation, enabling the identification of novel modules and modules that may be involved in genetic effects on incubation time and in prion strain specificity. Our systems analysis provides a comprehensive basis for developing models for prion replication and disease, and suggests some possible therapeutic approaches

Patient and public involvement in designing and conducting doctoral research: the whys and the hows

YesPublic and patient involvement (PPI) has been shown to have a positive impact on health and social care research. However, adequate examples describing how to operationalise effective PPI, especially in doctoral studies, are lacking. Hence, doctoral researchers new to research, or those with limited experience, can be discouraged from facilitating PPI in their research. This paper aims to describe and discuss in detail the approaches used by four doctoral researchers to incorporate PPI at different stages of their research studies from study design to disseminating findings. We aim to inform other doctoral researchers about the challenges and limitations relating to PPI that we faced. Through these, we share pragmatic recommendations for facilitating PPI during doctoral studies. The description of four case studies demonstrated that PPI could be incorporated at various stages during doctoral research. This has had a beneficial impact on our research study progression, researcher self-esteem and lastly, helped alleviate researcher isolation during doctoral studies.Supported by Research Design Service Yorkshire and the Humber (RDSYH), the National Institute for Health Research (NIHR) Yorkshire and Humber Patient Safety Translational Research Centre (NIHR Yorkshire and Humber PSTRC). This paper presents independent research funded by NIHR under its Research for Patient Benefit (RfPB) Programme (Grant Reference Number PB-PG-0317-20010).Research Development Fund Publication Prize Award winner, July 2019

Factors perceived to influence risky sexual behaviours among university students in the United Kingdom: a qualitative telephone interview study

Background In the United Kingdom people under the age of 25 years are at increased risk of contracting sexually transmitted infections. Most university students belong to this age group but little is known about their sexual behaviours. The aim of the study was to explore university students’ perspectives of factors and mechanisms that influence risky sexual behaviours among university students in the United Kingdom. Methods All students at a university in a northern city of England were invited via email to participate in qualitative telephone interviews. Interviews were audio recorded and transcribed verbatim. Framework analytical approach was used. Results Twenty interviews were conducted with a diverse sample of students. The social context of university lifestyle was perceived to affect risky sex through high levels of alcohol consumption, increased sexual opportunities, liberation from moral surveillance and expectations of the stereotypical highly sexually active student. Individual and cultural differences were also perceived to account for some patterns of risky sex with older students, overseas students and religious students perceived to be less likely to engage in risky sex due to academic priorities and a tendency to be more likely to adhere to moral values. Risk denial was also a key factor that led students to engage in risky sex. Poor access to sexual health services including inconvenient opening times, lack of confidentiality and stigma were perceived to contribute to the limited use of sexually transmitted infections testing and contraceptive services. Conclusions Lifestyle, individual and structural factors seem to play an important role in influencing the risky sexual behaviours of university students. Therefore preventive interventions that focus on these factors could be very useful in this sub-population of young people. This study provides useful baseline information that helps us understand how and why some United Kingdom university students engage in risky sexual behaviours that puts them at risk of contracting sexually transmitted infections

A Role in Immunity for Arabidopsis Cysteine Protease RD21, the Ortholog of the Tomato Immune Protease C14

Secreted papain-like Cys proteases are important players in plant immunity. We previously reported that the C14 protease of tomato is targeted by cystatin-like EPIC proteins that are secreted by the oomycete pathogen Phytophthora infestans (Pinf) during infection. C14 has been under diversifying selection in wild potato species coevolving with Pinf and reduced C14 levels result in enhanced susceptibility for Pinf. Here, we investigated the role C14-EPIC-like interactions in the natural pathosystem of Arabidopsis with the oomycete pathogen Hyaloperonospora arabidopsidis (Hpa). In contrast to the Pinf-solanaceae pathosystem, the C14 orthologous protease of Arabidopsis, RD21, does not evolve under diversifying selection in Arabidopsis, and rd21 null mutants do not show phenotypes upon compatible and incompatible Hpa interactions, despite the evident lack of a major leaf protease. Hpa isolates express highly conserved EPIC-like proteins during infections, but it is unknown if these HpaEPICs can inhibit RD21 and one of these HpaEPICs even lacks the canonical cystatin motifs. The rd21 mutants are unaffected in compatible and incompatible interactions with Pseudomonas syringae pv. tomato, but are significantly more susceptible for the necrotrophic fungal pathogen Botrytis cinerea, demonstrating that RD21 provides immunity to a necrotrophic pathogen

Expression of a malarial Hsp70 improves defects in chaperone-dependent activities in ssa1 mutant yeast

Plasmodium falciparum causes the most virulent form of malaria and encodes a large number of molecular chaperones. Because the parasite encounters radically different environments during its lifecycle, many members of this chaperone ensemble may be essential for P. falciparum survival. Therefore, Plasmodium chaperones represent novel therapeutic targets, but to establish the mechanism of action of any developed therapeutics, it is critical to ascertain the functions of these chaperones. To this end, we report the development of a yeast expression system for PfHsp70-1, a P. falciparum cytoplasmic chaperone. We found that PfHsp70-1 repairs mutant growth phenotypes in yeast strains lacking the two primary cytosolic Hsp70s, SSA1 and SSA2, and in strains harboring a temperature sensitive SSA1 allele. PfHsp70-1 also supported chaperone-dependent processes such as protein translocation and ER associated degradation, and ameliorated the toxic effects of oxidative stress. By introducing engineered forms of PfHsp70-1 into the mutant strains, we discovered that rescue requires PfHsp70-1 ATPase activity. Together, we conclude that yeast can be co-opted to rapidly uncover specific cellular activities mediated by malarial chaperones. © 2011 Bell et al

Memantine increases NMDA receptor level in the prefrontal cortex but fails to reverse apomorphine-induced conditioned place preference in rats

Studies have shown that inflammation and neurodegeneration may accompany the development of addiction to apomorphine and that the glutamate NMDA receptor antagonist, memantine, may be neuroprotective. The similarity between apomorphine and dopamine with regard to their chemical, pharmacological and toxicological properties provided a basis for investigating the mechanism of action of the former agent. In this study, we investigated whether memantine would suppress apomorphine-seeking behavior in rats subjected to apomorphine-induced place preference conditioning, through modulation of NMDA receptors in the prefrontal cortex. Repeated apomorphine (1 mg/kg) treatment induced conditioned place preference (CPP) and had no significant effect on NMDA receptor levels in the prefrontal cortex. Prior treatment with memantine (5 mg/kg or 10 mg/kg) increased the levels of NMDA receptors in the prefrontal cortex but did not suppress CPP induced by apomorphine. These data give further support to the addictive effect of apomorphine and demonstrate that blockade of NMDA receptors by memantine is unable to suppress apomorphine-seeking behavior

Multiple Histone Methyl and Acetyltransferase Complex Components Bind the HLA-DRA Gene

Major histocompatibility complex class II (MHC-II) genes are fundamental components that contribute to adaptive immune responses. While characterization of the chromatin features at the core promoter region of these genes has been studied, the scope of histone modifications and the modifying factors responsible for activation of these genes are less well defined. Using the MHC-II gene HLA-DRA as a model, the extent and distribution of major histone modifications associated with active expression were defined in interferon-γ induced epithelial cells, B cells, and B-cell mutants for MHC-II expression. With active transcription, nucleosome density around the proximal regulatory region was diminished and histone acetylation and methylation modifications were distributed throughout the gene in distinct patterns that were dependent on the modification examined. Irrespective of the location, the majority of these modifications were dependent on the binding of either the X-box binding factor RFX or the class II transactivator (CIITA) to the proximal regulatory region. Importantly, once established, the modifications were stable through multiple cell divisions after the activating stimulus was removed, suggesting that activation of this system resulted in an epigenetic state. A dual crosslinking chromatin immunoprecipitation method was used to detect histone modifying protein components that interacted across the gene. Components of the MLL methyltransferase and GCN5 acetyltransferase complexes were identified. Some MLL complex components were found to be CIITA independent, including MLL1, ASH2L and RbBP5. Likewise, GCN5 containing acetyltransferase complex components belonging to the ATAC and STAGA complexes were also identified. These results suggest that multiple complexes are either used or are assembled as the gene is activated for expression. Together the results define and illustrate a complex network of histone modifying proteins and multisubunit complexes participating in MHC-II transcription