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

Treatment with Helicobacter pylori-derived VacA attenuates allergic airway disease

BACKGROUND: Asthma is an incurable heterogeneous disease with variations in clinical and underlying immunological phenotype. New approaches could help to support existing therapy concepts. Neonatal infection of mice with Helicobacter pylori or administration of H. pylori-derived extracts or molecules after birth have been shown to prevent the development of allergic airway disease later in life. This study evaluated the potential therapeutic efficacy of H. pylori vacuolating cytotoxin A (VacA) in allergic airway inflammation and investigated the underlying immunological mechanisms for its actions. METHODS: Murine models of allergic airway diseases, and murine and human in vitro models were used. RESULTS: In both an acute model and a therapeutic house dust mite model of allergic airway disease, treatment with H. pylori-derived VacA reduced several asthma hallmarks, including airway hyperresponsiveness, inflammation and goblet cell metaplasia. Flow cytometry and ELISA analyses revealed induction of tolerogenic dendritic cells (DC) and FoxP3 positive regulatory T cells (Tregs), and a shift in the composition of allergen-specific immunoglobulins. Depletion of Tregs during treatment with VacA reversed treatment-mediated suppression of allergic airway disease. Human monocyte derived DCs (moDC) that were exposed to VacA induced Tregs in co-cultured naïve autologous T cells, replicating key observations made in vivo. CONCLUSION: H. pylori-derived VacA suppressed allergic airway inflammation via induction of Tregs in both allergic airway disease models. These data suggest that the immunomodulatory activity of VacA could potentially be exploited for the prevention and treatment of allergic airway disease

Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy

A major function of proteasomes and macroautophagy is to eliminate misfolded potentially toxic proteins. Mammalian proteasomes, however, cannot cleave polyglutamine (polyQ) sequences and seem to release polyQ-rich peptides. Puromycin-sensitive aminopeptidase (PSA) is the only cytosolic enzyme able to digest polyQ sequences. We tested whether PSA can protect against accumulation of polyQ fragments. In cultured cells, Drosophila and mouse muscles, PSA inhibition or knockdown increased aggregate content and toxicity of polyQ-expanded huntingtin exon 1. Conversely, PSA overexpression decreased aggregate content and toxicity. PSA inhibition also increased the levels of polyQ-expanded ataxin-3 as well as mutant α-synuclein and superoxide dismutase 1. These protective effects result from an unexpected ability of PSA to enhance macroautophagy. PSA overexpression increased, and PSA knockdown or inhibition reduced microtubule-associated protein 1 light chain 3-II (LC3-II) levels and the amount of protein degradation sensitive to inhibitors of lysosomal function and autophagy. Thus, by promoting autophagic protein clearance, PSA helps protect against accumulation of aggregation-prone proteins and proteotoxicity

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

Prevalence of low back pain and associated occupational factors among Chinese coal miners

<p>Abstract</p> <p>Background</p> <p>Very few studies have evaluated the association between occupational factors and low back pain (LBP) among miners. The epidemiological data on LBP in Chinese miners are limited. The aim of this study was to measure the prevalence of low back pain in Chinese coal miners and to investigate the role of occupational factors.</p> <p>Methods</p> <p>A cross-sectional survey was conducted to examine 1573 coal miners in northern China. The prevalence of LBP over a 12-month period was assessed using the Nordic Musculoskeletal Questionnaire. Odds ratios were calculated to examine the association between the prevalence of LBP over a 12-month period and occupational factors using logistic regression.</p> <p>Results</p> <p>Among the coal miners, 64.9% self-reported LBP in a 12-month period. Occupational factors associated with LBP were identified, including tasks with a high degree of repetitiveness (OR 1.3, 95%CI 1.0-1.6), tasks characterized by a high level of physical demand (OR 1.4, 95% CI 1.1-1.8), posture requiring extreme bending (OR 1.6, 95% CI 1.2-1.7) and insufficient recovery time (OR 1.4, 95% CI 1.0-1.8).</p> <p>Conclusion</p> <p>Low back pain is common among Chinese miners. There were strong associations with occupational factors.</p

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

Case management for the treatment of patients with major depression in general practices – rationale, design and conduct of a cluster randomized controlled trial – PRoMPT (Primary care Monitoring for depressive Patient's Trial) [ISRCTN66386086] – Study protocol

BACKGROUND: Depression is a disorder with high prevalence in primary health care and a significant burden of illness. The delivery of health care for depression, as well as other chronic illnesses, has been criticized for several reasons and new strategies to address the needs of these illnesses have been advocated. Case management is a patient-centered approach which has shown efficacy in the treatment of depression in highly organized Health Maintenance Organization (HMO) settings and which might also be effective in other, less structured settings. METHODS/DESIGN: PRoMPT (PRimary care Monitoring for depressive Patients Trial) is a cluster randomised controlled trial with General Practice (GP) as the unit of randomisation. The aim of the study is to evaluate a GP applied case-management for patients with major depressive disorder. 70 GPs were randomised either to intervention group or to control group with the control group delivering usual care. Each GP will include 10 patients suffering from major depressive disorder according to the DSM-IV criteria. The intervention group will receive treatment based on standardized guidelines and monthly telephone monitoring from a trained practice nurse. The nurse investigates the patient's status concerning the MDD criteria, his adherence to GPs prescriptions, possible side effects of medication, and treatment goal attainment. The control group receives usual care – including recommended guidelines. Main outcome measure is the cumulative score of the section depressive disorders (PHQ-9) from the German version of the Prime MD Patient Health Questionnaire (PHQ-D). Secondary outcome measures are the Beck-Depression-Inventory, self-reported adherence (adapted from Moriskey) and the SF-36. In addition, data are collected about patients' satisfaction (EUROPEP-tool), medication, health care utilization, comorbidity, suicide attempts and days out of work. The study comprises three assessment times: baseline (T0) , follow-up after 6 months (T1) and follow-up after 12 months (T2). DISCUSSION: Depression is now recognized as a disorder with a high prevalence in primary care but with insufficient treatment response. Case management seems to be a promising intervention which has the potential to bridge the gap of the usually time-limited and fragmented provision of care. Case management has been proven to be effective in several studies but its application in the private general medical practice setting remains unclear