Altered expression of caspases-4 and -5 during inflammatory bowel disease and colorectal cancer : diagnostic and therapeutic potential

Caspases are a group of proteolytic enzymes involved in the co-ordination of cellular processes, including cellular homeostasis, inflammation and apoptosis. Altered activity of caspases, particularly caspase-1, has been implicated in the development of intestinal diseases, such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). However, the involvement of two related inflammatory caspase members, caspases-4 and -5, during intestinal homeostasis and disease has not yet been established. This study demonstrates that caspases-4 and -5 are involved in IBD-associated intestinal inflammation. Furthermore, we found a clear correlation between stromal caspase-4 and -5 expression levels, inflammation and disease activity in ulcerative colitis patients. Deregulated intestinal inflammation in IBD patients is associated with an increased risk of developing CRC. We found robust expression of caspases-4 and -5 within intestinal epithelial cells, exclusively within neoplastic tissue, of colorectal tumours. An examination of adjacent normal, inflamed and tumour tissue from patients with colitis-associated CRC confirmed that stromal expression of caspases-4 and -5 is increased in inflamed and dysplastic tissue, while epithelial expression is restricted to neoplastic tissue. In addition to identifying caspases-4 and -5 as potential targets for limiting intestinal inflammation, this study has identified epithelial-expressed caspases-4 and -5 as biomarkers with diagnostic and therapeutic potential in CRC

A nurse-led clinic for patients consulting with osteoarthritis in general practice: development and impact of training in a cluster randomised controlled trial

Background: Despite a lack of service provision for people with osteoarthritis (OA), each year 1 in 5 of the general population consults a GP about a musculoskeletal condition such as OA. Consequently this may provide an opportunity for practice nurses to take an active role in helping patients manage their condition. A nurse led clinic for supporting patients with OA was developed for the MOSAICS study investigating how to implement the NICE 2014 OA Guideline core recommendations. This paper has two main objectives, firstly to provide an overview of the nurse-led OA clinic, and secondly to describe the development, key learning objectives, content and impact of the training to support its delivery. Methods: A training programme was developed and delivered to provide practice nurses with the knowledge and skill set needed to run the nurse-led OA clinic. The impact of the training programme on knowledge, confidence and OA management was evaluated using case report forms and pre and post training questionnaires. Results: The pre-training questionnaire identified a gap between what practice nurses feel they can do and what they should be doing in line with NICE OA guidelines. Evaluation of the training suggests that it enabled practice nurses to feel more knowledgeable and confident in supporting patients to manage their OA and this was reflected in the clinical management patients received in the nurse-led OA clinics. Conclusions: A significant gap between what is recommended and what practice nurses feel they can currently provide in terms of OA management was evident. The development of a nurse training programme goes some way to develop a system in primary care for delivering the core recommendations by NICE

Autonomy support, basic need satisfaction and the optimal functioning of adult male and female sport participants: A test of basic needs theory

Grounded in Basic Needs Theory (BNT; Ryan and Deci, American Psychologist, 55, 68–78, 2000a), the present study aimed to: (a) test a theoretically-based model of coach autonomy support, motivational processes and well-/ill being among a sample of adult sport participants, (b) discern which basic psychological need(s) mediate the link between autonomy support and well-/ill-being, and (c) explore gender invariance in the hypothesized model. Five hundred and thirty nine participants (Male = 271;Female = 268; Mage = 22.75) completed a multi-section questionnaire tapping the targeted variables. Structural Equation Modeling (SEM) analysis revealed that coach autonomy support predicted participants’ basic need satisfaction for autonomy, competence and relatedness. In turn, basic need satisfaction predicted greater subjective vitality when engaged in sport. Participants with low levels of autonomy were more susceptible to feeling emotionally and physically exhausted from their sport investment. Autonomy and competence partially mediated the path from autonomy support to subjective vitality. Lastly, the results supported partial invariance of the model with respect to gender

A mycorrhizal revolution.

It has long been postulated that symbiotic fungi facilitated plant migrations onto land through enhancing the scavenging of mineral nutrients and exchanging these for photosynthetically fixed organic carbon. Today, land plant-fungal symbioses are both widespread and diverse. Recent discoveries show that a variety of potential fungal associates were likely available to the earliest land plants, and that these early partnerships were probably affected by changing atmospheric CO2 concentrations. Here, we evaluate current hypotheses and knowledge gaps regarding early plant-fungal partnerships in the context of newly discovered fungal mutualists of early and more recently evolved land plants and the rapidly changing views on the roles of plant-fungal symbioses in the evolution and ecology of the terrestrial biosphere

Selective expansion of viral variants following experimental transmission of a reconstituted feline immunodeficiency virus quasispecies

Following long-term infection with virus derived from the pathogenic GL8 molecular clone of feline immunodeficiency virus (FIV), a range of viral variants emerged with distinct modes of interaction with the viral receptors CD134 and CXCR4, and sensitivities to neutralizing antibodies. In order to assess whether this viral diversity would be maintained following subsequent transmission, a synthetic quasispecies was reconstituted comprising molecular clones bearing envs from six viral variants and its replicative capacity compared in vivo with a clonal preparation of the parent virus. Infection with either clonal (Group 1) or diverse (Group 2) challenge viruses, resulted in a reduction in CD4+ lymphocytes and an increase in CD8+ lymphocytes. Proviral loads were similar in both study groups, peaking by 10 weeks post-infection, a higher plateau (set-point) being achieved and maintained in study Group 1. Marked differences in the ability of individual viral variants to replicate were noted in Group 2; those most similar to GL8 achieved higher viral loads while variants such as the chimaeras bearing the B14 and B28 Envs grew less well. The defective replication of these variants was not due to suppression by the humoral immune response as virus neutralising antibodies were not elicited within the study period. Similarly, although potent cellular immune responses were detected against determinants in Env, no qualitative differences were revealed between animals infected with either the clonal or the diverse inocula. However, in vitro studies indicated that the reduced replicative capacity of variants B14 and B28 in vivo was associated with altered interactions between the viruses and the viral receptor and co-receptor. The data suggest that viral variants with GL8-like characteristics have an early, replicative advantage and should provide the focus for future vaccine development

Acquisition of aluminium tolerance by modification of a single gene in barley

Originating from the Fertile Crescent in the Middle East, barley has now been cultivated widely on different soil types including acid soils, where aluminium toxicity is a major limiting factor. Here we show that the adaptation of barley to acid soils is achieved by the modification of a single gene (HvAACT1) encoding a citrate transporter. We find that the primary function of this protein is to release citrate from the root pericycle cells to the xylem to facilitate the translocation of iron from roots to shoots. However, a 1-kb insertion in the upstream of the HvAACT1 coding region occurring only in the Al-tolerant accessions, enhances its expression and alters the location of expression to the root tips. The altered HvAACT1 has an important role in detoxifying aluminium by secreting citrate to the rhizosphere. Thus, the insertion of a 1-kb sequence in the HvAACT1 upstream enables barley to adapt to acidic soils

Long-time Low-latency Quantum Memory by Dynamical Decoupling

Quantum memory is a central component for quantum information processing devices, and will be required to provide high-fidelity storage of arbitrary states, long storage times and small access latencies. Despite growing interest in applying physical-layer error-suppression strategies to boost fidelities, it has not previously been possible to meet such competing demands with a single approach. Here we use an experimentally validated theoretical framework to identify periodic repetition of a high-order dynamical decoupling sequence as a systematic strategy to meet these challenges. We provide analytic bounds-validated by numerical calculations-on the characteristics of the relevant control sequences and show that a "stroboscopic saturation" of coherence, or coherence plateau, can be engineered, even in the presence of experimental imperfection. This permits high-fidelity storage for times that can be exceptionally long, meaning that our device-independent results should prove instrumental in producing practically useful quantum technologies.Comment: abstract and authors list fixe

The novel CXCR4 antagonist POL5551 mobilizes hematopoietic stem and progenitor cells with greater efficiency than Plerixafor

Mobilized blood has supplanted bone marrow (BM) as the primary source of hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Pharmacologically enforced egress of hematopoietic stem cells from BM, or mobilization, has been achieved by directly or indirectly targeting the CXCL12/CXCR4 axis. Shortcomings of the standard mobilizing agent, granulocyte colony-stimulating factor (G-CSF), administered alone or in combination with the only approved CXCR4 antagonist, Plerixafor, continue to fuel the quest for new mobilizing agents. Using Protein Epitope Mimetics technology, a novel peptidic CXCR4 antagonist, POL5551, was developed. In vitro data presented herein indicate high affinity to and specificity for CXCR4. POL5551 exhibited rapid mobilization kinetics and unprecedented efficiency in C57BL/6 mice, exceeding that of Plerixafor and at higher doses also of G-CSF. POL5551-mobilized stem cells demonstrated adequate transplantation properties. In contrast to G-CSF, POL5551 did not induce major morphological changes in the BM of mice. Moreover, we provide evidence of direct POL5551 binding to hematopoietic stem and progenitor cells (HSPCs) in vivo, strengthening the hypothesis that CXCR4 antagonists mediate mobilization by direct targeting of HSPCs. In summary, POL5551 is a potent mobilizing agent for HSPCs in mice with promising therapeutic potential if these data can be orroborated in humans

Assessment of the frequency of Mycobacterium bovis shedding in the faeces of naturally and experimentally TB infected cattle.

AIMS: Assess the prevalence of Mycobacterium bovis bacilli in faecal samples of tuberculous cattle, to better understand the risk of environmental dissemination of bovine tuberculosis (TB) through the spreading of manure or slurry. METHODS AND RESULTS: Faecal samples were collected from 72 naturally infected cattle with visible lesions of TB that had reacted to the tuberculin skin test and 12 cattle experimentally infected with M. bovis. These were examined by microbial culture and PCR to assess the presence of M. bovis bacilli. There were no positive cultures from any naturally infected test reactor animal. A single M. bovis colony was cultured from a faecal sample from one of the experimentally infected animals. A single PCR positive result was obtained from the faecal sample of one naturally infected test reactor. CONCLUSION: The prevalence of M. bovis in the faecal samples of TB-infected cattle was extremely low. SIGNIFICANCE AND IMPACT OF STUDY: The results suggest that the risk of spreading TB through the use of slurry or manure as an agricultural fertiliser is lower than suggested in some historical literature. The results could inform a reconsideration of current risk assessments and guidelines on the disposal of manure and slurry from TB-infected herds