Swimming in curved space or The Baron and the cat

We study the swimming of non-relativistic deformable bodies in (empty) static curved spaces. We focus on the case where the ambient geometry allows for rigid body motions. In this case the swimming equations turn out to be geometric. For a small swimmer, the swimming distance in one stroke is determined by the Riemann curvature times certain moments of the swimmer.Comment: 19 pages 6 figure

JNKs function as CDK4-activating kinases by phosphorylating CDK4 and p21

Cyclin D-CDK4/6 are the first cyclin-dependent kinase (CDK) complexes to be activated by mitogenic/oncogenic pathways. They have a central role in the cell multiplication decision and in its deregulation in cancer cells. We identified T172 phosphorylation of CDK4 rather than cyclin D accumulation as the distinctly regulated step determining CDK4 activation. This finding challenges the view that the only identified metazoan CDK-activating kinase, cyclin H-CDK7-Mat1 (CAK), which is constitutively active, is responsible for the activating phosphorylation of all cell cycle CDKs. We previously showed that T172 phosphorylation of CDK4 is conditioned by an adjacent proline (P173), which is not present in CDK6 and CDK1/2. Although CDK7 activity was recently shown to be required for CDK4 activation, we proposed that proline-directed kinases might specifically initiate the activation of CDK4. Here, we report that JNKs, but not ERK1/2 or CAK, can be direct CDK4-activating kinases for cyclin D-CDK4 complexes that are inactivated by p21-mediated stabilization. JNKs and ERK1/2 also phosphorylated p21 at S130 and T57, which might facilitate CDK7-dependent activation of p21-bound CDK4, however, mutation of these sites did not impair the phosphorylation of CDK4 by JNKs. In two selected tumor cells, two different JNK inhibitors inhibited the phosphorylation and activation of cyclin D1-CDK4-p21 but not the activation of cyclin D3-CDK4 that is mainly associated to p27. Specific inhibition by chemical genetics in MEFs confirmed the involvement of JNK2 in cyclin D1-CDK4 activation. Therefore, JNKs could be activating kinases for cyclin D1-CDK4 bound to p21, by independently phosphorylating both CDK4 and p21

Homozygous staggerer (sg/sg) mice display improved insulin sensitivity and enhanced glucose uptake in skeletal muscle

Homozygous staggerer (sg/sg) mice, which have decreased and dysfunctional Ror alpha (also known as Rora) expression in all tissues, display a lean and dyslipidaemic phenotype. They are also resistant to (high fat) diet-induced obesity. We explored whether retinoic acid receptor-related orphan receptor (ROR) alpha action in skeletal muscle was involved in the regulation of glucose metabolism

Co-designing inflammatory bowel disease (Ibd) services in Scotland : findings from a nationwide survey

Background: The Scottish Government’s ambition is to ensure that health services are co-designed with the communities they serve. Crohn’s and Colitis UK and the Scottish Government acknowledged the need to review and update the current IBD care model. An online survey was conducted asking IBD patients about their experiences of the NHS care they receive. This survey was the first step of co-designing and developing a national strategy for IBD service improvement in Scotland. Aim: To explore IBD patients’ experiences of current services and make recommendations for future service development. Methods: This study was part of a wider cross-sectional on-line survey. Participants were patients with IBD across Scotland. 777 people with IBD took part in the survey. Thematic analysis of all data was conducted independently by two researchers. Results: Three key themes emerged: Quality of life: Participants highlighted the impact the disease has on quality of life and the desperate need for IBD services to address this more holistically. IBD clinicians and access: Participants recognised the need for more IBD nurses and gastroenterologists along with better access to them. Those with a named IBD nurse reported to be more satisfied with their care. An explicit IBD care pathway: Patients with IBD identified the need of making the IBD care pathway more explicit to service users. Conclusions: Participants expressed the need for a more holistic approach to their IBD care. This includes integrating psychological, counselling and dietetic services into IBD care with better access to IBD clinicians and a more explicit IBD care pathway. Keywords: Inflammatory bowel disease, Co-designing, Qualitative study, Patient survey, Crohn’s disease, Ulcerative coliti

The population-based oncological health care study OVIS – recruitment of the patients and analysis of the non-participants

<p>Abstract</p> <p>Background</p> <p>The ageing of the population is expected to bring an enormous growth in demand for oncological health care. In order to anticipate and respond to future trends, cancer care needs to be critically evaluated. The present study explores the possibility of conducting representative and population-based research on cancer care on the basis of data drawn from the Cancer Registry.</p> <p>Methods</p> <p>A population-based state-wide cohort study (OVIS) has been carried out in Schleswig-Holstein, Germany. All patients with malignant melanoma, breast, or prostate cancer were identified in the Cancer Registry. Epidemiological data were obtained for all the patients and screened for study eligibility. A postal questionnaire requesting information on diagnosis, therapy, QoL and aftercare was sent to eligible patients.</p> <p>Results</p> <p>A total of 11,489 persons diagnosed with the cancer types of interest in the period from January 2002 to July 2004 were registered in the Cancer Registry. Of the 5,354 (47%) patients who gave consent for research, 4,285 (80% of consenters) completed the questionnaire. In terms of relevant epidemiological variables, participants with melanoma were not found to be different from non-participants with the same diagnosis. However, participants with breast or prostate cancer were slightly younger and had smaller tumours than patients who did not participate in our study.</p> <p>Conclusion</p> <p>Population-based cancer registry data proved to be an invaluable resource for both patient recruitment and non-participant analysis. It can help improve our understanding of the strength and nature of differences between participants and non-respondents. Despite minor differences observed in breast and prostate cancer, the OVIS-sample seems to represent the source population adequately.</p

Implication of the F-Box Protein FBXL21 in Circadian Pacemaker Function in Mammals

In mammals, the circadian clock relies on interlocked feedback loops involving clock genes and their protein products. Post-translational modifications control intracellular trafficking, functionality and degradation of clock proteins and are keys to the functioning of the clock as recently exemplified for the F-Box protein Fbxl3. The SCFFbxl3 complex directs degradation of CRY1/2 proteins and Fbxl3 murine mutants have a slower clock. To assess whether the role of Fbxl3 is phylogenetically conserved, we investigated its function in the sheep, a diurnal ungulate. Our data show that Fbxl3 function is conserved and further reveal that its closest homologue, the F-Box protein Fbxl21, also binds to CRY1 which impairs its repressive action towards the transcriptional activators CLOCK/BMAL1. However, while Fbxl3 appears to be ubiquitously expressed, Fbxl21 expression is tissue-specific. Furthermore, and in sharp contrast with Fbxl3, Fbxl21 is highly expressed within the suprachiasmatic nuclei, site of the master clock, where it displays marked circadian oscillations apparently driven by members of the PAR-bZIP family. Finally, for both Fbxl3 and Fbxl21 we identified and functionally characterized novel splice-variants, which might reduce CRY1 proteasomal degradation dependent on cell context. Altogether, these data establish Fbxl21 as a novel circadian clock-controlled gene that plays a specific role within the mammalian circadian pacemaker

Randomised controlled study in the primary healthcare sector to investigate the effectiveness and safety of auriculotherapy for the treatment of uncomplicated chronic rachialgia: a study protocol

<p>Abstract</p> <p>Background</p> <p>Uncomplicated chronic rachialgia is a highly prevalent complaint, and one for which therapeutic results are contradictory. The aim of the present study is to evaluate the effectiveness and safety of treatment with auriculopressure, in the primary healthcare sector, carried out by trained healthcare professionals via a 30-hour course.</p> <p>Methods/Design</p> <p>The design consists of a multi-centre randomized controlled trial, with placebo, with two parallel groups, and including an economic evaluation. Patients with chronic uncomplicated rachialgia, whose GP is considering referral for auriculopressure sensory stimulation, are eligible for inclusion. Sampling will be by consecutive selection, and randomised allocation to one of the two study arms will be determined using a centralised method, following a 1:1 plan (true auriculopressure; placebo auriculopressure). The implants (true and placebo) will be replaced once weekly, and the treatment will have a duration of 8 weeks. The primary outcome measure will be the change in pain intensity, measured on a visual analogue scale (VAS) of 100 mm, at 9 weeks after beginning the treatment. A follow up study will be performed at 6 months after beginning treatment. An assessment will also be made of the changes measured in the Spanish version of the McGill Pain Questionnaire, of the changes in the Lattinen test, and of the changes in quality of life (SF-12). Also planned is an analysis of cost-effectiveness and also, if necessary, a cost-benefit analysis.</p> <p>Discussion</p> <p>This study will contribute to developing evidence on the use of auriculotherapy using Semen vaccariae [wang bu liu xing] for the treatment of uncomplicated chronic rachialgia.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN01897462.</p

Regulation of Expression of Citrate Synthase by the Retinoic Acid Receptor-Related Orphan Receptor α (RORα)

The retinoic acid receptor-related orphan receptor α (RORα) is a member of the nuclear receptor superfamily of transcription factors that plays an important role in regulation of the circadian rhythm and metabolism. Mice lacking a functional RORα display a range of metabolic abnormalities including decreased serum cholesterol and plasma triglycerides. Citrate synthase (CS) is a key enzyme of the citric acid cycle that provides energy for cellular function. Additionally, CS plays a critical role in providing citrate derived acetyl-CoA for lipogenesis and cholesterologenesis. Here, we identified a functional RORα response element (RORE) in the promoter of the CS gene. ChIP analysis demonstrates RORα occupancy of the CS promoter and a putative RORE binds to RORα effectively in an electrophoretic mobility shift assay and confers RORα responsiveness to a reporter gene in a cotransfection assay. We also observed a decrease in CS gene expression and CS enzymatic activity in the staggerer mouse, which has a mutation of in the Rora gene resulting in nonfunctional RORα protein. Furthermore, we found that SR1001 a RORα inverse agonist eliminated the circadian pattern of expression of CS mRNA in mice. These data suggest that CS is a direct RORα target gene and one mechanism by which RORα regulates lipid metabolism is via regulation of CS expression