Glucolipotoxicity initiates pancreatic beta-cell death through TNFR5/CD40-mediated STAT1 and NF-kappa B activation

Funded by Diabetes UK, NovoNordisk UK Research Foundation, and St. Bartholomew’s & The Royal London Charitable Foundation grant awards

A comparison of multidisciplinary team residential rehabilitation with conventional outpatient care for the treatment of non-arthritic intra-articular hip pain in UK Military personnel:a protocol for a randomised controlled trial

BACKGROUND: Non-arthritic hip disorders are defined as abnormalities of the articulating surfaces of the acetabulum and femur before the onset of osteoarthritis, including intra-articular structures such as the acetabular labrum and chondral surfaces. Abnormal femoroacetabular morphology is commonly seen in young men who constitute much of the UK military population. Residential multidisciplinary team (MDT) rehabilitation for patients with musculoskeletal injuries has a long tradition in the UK military, however, there are no studies presenting empirical data on the efficacy of a residential MDT approach compared with individualised conventional outpatient treatment. With no available data, the sustainability of this care pathway has been questioned. The purpose of this randomised controlled trial is to compare the effects of a residential multidisciplinary intervention, to usual outpatient care, on the clinical outcomes of young active adults undergoing treatment for non-arthritic intra-articular hip pain. METHODS/DESIGN: The trial will be conducted at the Defence Medical Rehabilitation Centre, Headley Court, UK. One hundred military male participants with clinical indicators of non-arthritic intra-articular hip pain will be randomly allocated to either: (1) 7-day residential multidisciplinary team intervention, n = 50; (2) 6-week physiotherapist-led outpatient intervention (conventional care), n = 50. Measurements will be taken at baseline, post-treatment (1-week MDT group; 6-weeks physiotherapy group), and 12-weeks. The primary outcome measures are the function in daily living sub-scale of the Copenhagen Hip and Groin Outcome Score (HAGOS), the physical function subscale of the Non-arthritic Hip Score (NAHS), and VAS pain scale. Secondary outcomes include objective measures of physical capacity and general health. An intention-to-treat analysis will be performed using linear and mixed models. DISCUSSION: This study will be the first to assess the efficacy of intensive MDT rehabilitation, versus conventional outpatient care, for the management of non-arthritic hip pain. The results from this study will add to the evidence-base and inform clinical practice for the management of intra-articular non-arthritic hip pain and femoroacetabular impingement in young active adults. TRIAL REGISTRATION: ISRCTN Reference: ISRCTN 59255714 dated 11-Nov-2015 ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12891-016-1309-z) contains supplementary material, which is available to authorized users

Attachment, infidelity, and loneliness in college students involved in a romantic relationship: the role of relationship satisfaction, morbidity and prayer for partner

This study examined the mediating effects of relationship satisfaction, prayer for a partner, and morbidity in the relationship between attachment and loneliness, infidelity and loneliness, and psychological morbidity and loneliness, in college students involved in a romantic relationship. Participants were students in an introductory course on family development. This study examined only students (n = 345) who were involved in a romantic relationship. The average age of participants was 19.46 (SD = 1.92) and 25 % were males. Short-form UCLA Loneliness Scale (ULS-8), (Hays and DiMatteo in J Pers Assess 51:69–81, doi:10.1207/s15327752jpa5101_6, 1987); Relationship Satisfaction Scale (Funk and Rogge in J Fam Psychol 21:572–583, doi:10.1037/0893-3200.21.4.572, 2007); Rotterdam Symptom Checklist (De Haes et al. in Measuring the quality of life of cancer patients with the Rotterdam Symptom Checklist (RSCL): a manual, Northern Centre for Healthcare Research, Groningen, 1996); Prayer for Partner Scale, (Fincham et al. in J Pers Soc Psychol 99:649–659, doi:10.1037/a0019628, 2010); Infidelity Scale, (Drigotas et al. in J Pers Soc Psychol 77:509–524, doi:10.1037/0022-3514.77.3.509, 1999); and the Experiences in Close Relationship Scale-short form (Wei et al. in J Couns Psychol 52(4):602–614, doi:10.1037/0022-0167.52.4.602, 2005). Results showed that relationship satisfaction mediated the relationship between avoidance attachment and loneliness and between infidelity and loneliness. Physical morbidity mediated the relationship between anxious attachment and psychological morbidity. Psychological morbidity mediated the relationship between anxious attachment and physical morbidity. The present results expand the literature on attachment by presenting evidence that anxious and avoidant partners experience loneliness differently. Implications for couple’s therapy are addressed. Future research should replicate these results with older samples and married couples.Acknowledgments This research was supported by Grant Number 90FE0022 from the United States Department of Health and Human Services awarded to the last author

Deregulation of MUC4 in gastric adenocarcinoma: potential pathobiological implication in poorly differentiated non-signet ring cell type gastric cancer

MUC4 is a large, heavily glycosylated transmembrane mucin, that is implicated in the pathogenesis of various types of cancers. To date, no extensive study has been done to check the expression and functional significance of MUC4 in different types of gastric adenocarcinomas. Here, we report the expression profile of MUC4 in gastric adenocarcinomas and its function in poorly differentiated gastric non-signet ring cell carcinoma (non-SRCC) type cells. Immunohistochemical analysis using tissue microarray (TMA) showed a significant difference in MUC4 expression between normal adjacent (n=45) and gastric adenocarcinoma (n=83; P<0.001). MUC4 expression was not associated with tumour type, stage or with the degree of differentiation. To gain further insight into the significance of MUC4 expression in gastric non-SRCC cells, MUC4 was ectopically expressed in AGS, a poorly differentiated gastric non-signet ring cell line. The MUC4 overexpressing cells (AGS-MUC4) showed a significant increase (P<0.005) in cell motility and a decrease in cellular aggregation as compared with the vector-transfected cells. Furthermore, in vivo tumorigenicity analysis revealed that animals transplanted with the MUC4 overexpressing cells (AGS-MUC4) had a greater incidence of tumours (83%) in comparison to empty vector control (17%). In addition, the expression of MUC4 resulted in enhanced expression of total cellular ErbB2 and phosphorylated ErbB2. In conclusion, our results showed that MUC4 is overexpressed in gastric adenocarcinoma tissues, and that it has a role in promoting aggressive properties in poorly differentiated gastric non-SRCC cells through the activation of the ErbB2 oncoprotein

PI3K Signaling in Normal B Cells and Chronic Lymphocytic Leukemia (CLL).

B cells provide immunity to extracellular pathogens by secreting a diverse repertoire of antibodies with high affinity and specificity for exposed antigens. The B cell receptor (BCR) is a transmembrane antibody, which facilitates the clonal selection of B cells producing secreted antibodies of the same specificity. The diverse antibody repertoire is generated by V(D)J recombination of heavy and light chain genes, whereas affinity maturation is mediated by activation-induced cytidine deaminase (AID)-mediated mutagenesis. These processes, which are essential for the generation of adaptive humoral immunity, also render B cells susceptible to chromosomal rearrangements and point mutations that in some cases lead to cancer. In this chapter, we will review the central role of PI3K s in mediating signals from the B cell receptor that not only facilitate the development of functional B cell repertoire, but also support the growth and survival of neoplastic B cells, focusing on chronic lymphocytic leukemia (CLL) B cells. Perhaps because of the central role played by PI3K in BCR signaling, B cell leukemia and lymphomas are the first diseases for which a PI3K inhibitor has been approved for clinical use

The effects of IQPLUS Focus on cognitive function, mood and endocrine response before and following acute exercise

BACKGROUND: Phosphatidylserine (PS) is a phospholipid found in cell membranes of most animals and plants. PS has been shown to reduce stress and increase performance in runners, cyclists and golfers. The purpose of this study was to investigate the effects of a PS containing formulation on cognitive function, mood and endocrine response before and after intense resistance exercise. METHODS: 18 lower body, resistance trained, college aged males ingested 14 days of supplement (IQPLUS Focus, providing 400 mg of soy-derived PS) and a Placebo (PL), in a randomized, double-blind, placebo controlled, cross-over manner. Following 14 days of supplementation, participants performed an acute bout of lower body resistance training. Mood (Profile of Mood States, POMS) and cognitive function (Serial Subtraction Test, SST) were measured prior to, 5 minutes after, and 60 minutes after exercise. Venous blood samples were collected prior to, and 5, 15, 25, 40 and 60 minutes after exercise. Blood samples were analyzed for plasma cortisol and testosterone. Data were analyzed using repeated measures ANOVA. RESULTS: PS supplementation significantly reduced the time needed for a correct calculation on the SST by 20% (reduced by 1.27 s per calculation; PL: 6.4 s, PS: 5.13 s; p = 0.001), and reduced the total amount of errors by 39% (PL: 1.28 + .69, PS: .78 + .27, p = 0.53), and increased the amount of correct calculations by 13% (PL: 22.1 + 2.24, PS: 24.9 + 1.52, p = 0.07) prior to or in response to exercise compared to PL. Following exercise, there was no difference in SST scores between PS and PL. There were no significant changes in regards to mood or endocrine response to exercise as a result of PS supplementation. CONCLUSION: PS supplementation significantly increased cognitive function prior to exercise. Improved cognitive function could benefit athletes and non-athletes alike. PS did not appear to affect mood or endocrine response prior to or following resistance exercise

Identification and genomic location of a reniform nematode (Rotylenchulus reniformis) resistance locus (Renari) introgressed from Gossypium aridum into upland cotton (G. hirsutum)

In this association mapping study, a tri-species hybrid, [Gossypium arboreum × (G. hirsutum × G. aridum)2], was crossed with MD51ne (G. hirsutum) and progeny from the cross were used to identify and map SSR markers associated with reniform nematode (Rotylenchulus reniformis) resistance. Seventy-six progeny (the 50 most resistant and 26 most susceptible) plants were genotyped with 104 markers. Twenty-five markers were associated with a resistance locus that we designated Renari and two markers, BNL3279_132 and BNL2662_090, mapped within 1 cM of Renari. Because the SSR fragments associated with resistance were found in G. aridum and the bridging line G 371, G. aridum is the likely source of this resistance. The resistance is simply inherited, possibly controlled by a single dominant gene. The markers identified in this project are a valuable resource to breeders and geneticists in the quest to produce cotton cultivars with a high level of resistance to reniform nematode

Macoilin, a Conserved Nervous System–Specific ER Membrane Protein That Regulates Neuronal Excitability

Genome sequence comparisons have highlighted many novel gene families that are conserved across animal phyla but whose biological function is unknown. Here, we functionally characterize a member of one such family, the macoilins. Macoilins are characterized by several highly conserved predicted transmembrane domains towards the N-terminus and by coiled-coil regions C-terminally. They are found throughout Eumetazoa but not in other organisms. Mutants for the single Caenorhabditis elegans macoilin, maco-1, exhibit a constellation of behavioral phenotypes, including defects in aggregation, O2 responses, and swimming. MACO-1 protein is expressed broadly and specifically in the nervous system and localizes to the rough endoplasmic reticulum; it is excluded from dendrites and axons. Apart from subtle synapse defects, nervous system development appears wild-type in maco-1 mutants. However, maco-1 animals are resistant to the cholinesterase inhibitor aldicarb and sensitive to levamisole, suggesting pre-synaptic defects. Using in vivo imaging, we show that macoilin is required to evoke Ca2+ transients, at least in some neurons: in maco-1 mutants the O2-sensing neuron PQR is unable to generate a Ca2+ response to a rise in O2. By genetically disrupting neurotransmission, we show that pre-synaptic input is not necessary for PQR to respond to O2, indicating that the response is mediated by cell-intrinsic sensory transduction and amplification. Disrupting the sodium leak channels NCA-1/NCA-2, or the N-,P/Q,R-type voltage-gated Ca2+ channels, also fails to disrupt Ca2+ responses in the PQR cell body to O2 stimuli. By contrast, mutations in egl-19, which encodes the only Caenorhabditis elegans L-type voltage-gated Ca2+ channel α1 subunit, recapitulate the Ca2+ response defect we see in maco-1 mutants, although we do not see defects in localization of EGL-19. Together, our data suggest that macoilin acts in the ER to regulate assembly or traffic of ion channels or ion channel regulators

Cell-specific microarray profiling experiments reveal a comprehensive picture of gene expression in the C. elegans nervous system

A novel strategy for profiling Caenorhabditis elegans cells identifies transcripts highly enriched in either the embryonic or larval C. elegans nervous system, including 19 conserved transcripts of unknown function that are also expressed in the mammalian brain