VAMP7 modulates ciliary biogenesis in kidney cells

Epithelial cells elaborate specialized domains that have distinct protein and lipid compositions, including the apical and basolateral surfaces and primary cilia. Maintaining the identity of these domains is required for proper cell function, and requires the efficient and selective SNARE-mediated fusion of vesicles containing newly synthesized and recycling proteins with the proper target membrane. Multiple pathways exist to deliver newly synthesized proteins to the apical surface of kidney cells, and the post-Golgi SNAREs, or VAMPs, involved in these distinct pathways have not been identified. VAMP7 has been implicated in apical protein delivery in other cell types, and we hypothesized that this SNARE would have differential effects on the trafficking of apical proteins known to take distinct routes to the apical surface in kidney cells. VAMP7 expressed in polarized Madin Darby canine kidney cells colocalized primarily with LAMP2-positive compartments, and siRNA-mediated knockdown modulated lysosome size, consistent with the known function of VAMP7 in lysosomal delivery. Surprisingly, VAMP7 knockdown had no effect on apical delivery of numerous cargoes tested, but did decrease the length and frequency of primary cilia. Additionally, VAMP7 knockdown disrupted cystogenesis in cells grown in a three-dimensional basement membrane matrix. The effects of VAMP7 depletion on ciliogenesis and cystogenesis are not directly linked to the disruption of lysosomal function, as cilia lengths and cyst morphology were unaffected in an MDCK lysosomal storage disorder model. Together, our data suggest that VAMP7 plays an essential role in ciliogenesis and lumen formation. To our knowledge, this is the first study implicating an R-SNARE in ciliogenesis and cystogenesis. © 2014 Szalinski et al

Cognitive and psychological science insights to improve climate change data visualization

Visualization of climate data plays an integral role in the communication of climate change findings to both expert and non-expert audiences. The cognitive and psychological sciences can provide valuable insights into how to improve visualization of climate data based on knowledge of how the human brain processes visual and linguistic information. We review four key research areas to demonstrate their potential to make data more accessible to diverse audiences: directing visual attention, visual complexity, making inferences from visuals, and the mapping between visuals and language. We present evidence-informed guidelines to help climate scientists increase the accessibility of graphics to non-experts, and illustrate how the guidelines can work in practice in the context of Intergovernmental Panel on Climate Change graphics

Activation of the p53 pathway by the MDM2 inhibitor nutlin-3a overcomes BCL2 overexpression in a preclinical model of diffuse large B-cell lymphoma associated with t(14;18)(q32;q21)

p53 is frequently wild type (wt) in diffuse large B-cell lymphoma (DLBCL) associated with t(14;18)(q32;q21) that overexpresses BCL2. Nutlin-3a is a small molecule that activates the p53 pathway by disrupting p53–MDM2 interaction. We show that nutlin-3a activates p53 in DLBCL cells associated with t(14;18)(q32;q21), BCL2 overexpression and wt p53, resulting in cell cycle arrest and apoptosis. Nutlin-3a treatment had similar effects on DLBCL cells of activated B-cell phenotype with wt p53. Cell cycle arrest was associated with upregulation of p21. Nutlin-3a-induced apoptosis was accompanied by BAX and PUMA upregulation, BCL-XL downregulation, serine-70 dephosphorylation of BCL2, direct binding of BCL2 by p53, caspase-9 upregulation and caspase-3 cleavage. Cell death was reduced when p53-dependent transactivation activity was inhibited by pifithrin-α (PFT-α), or PFT-μ inhibited direct p53 targeting of mitochondria. Nutlin-3a sensitized activation of the intrinsic apoptotic pathway by BCL2 inhibitors in t(14;18)-positive DLBCL cells with wt p53, and enhanced doxorubicin cytotoxicity against t(14;18)-positive DLBCL cells with wt or mutant p53, the latter in part via p73 upregulation. Nutlin-3a treatment in a xenograft animal lymphoma model inhibited growth of t(14;18)-positive DLBCL tumors, associated with increased apoptosis and decreased proliferation. These data suggest that disruption of the p53–MDM2 interaction by nutlin-3a offers a novel therapeutic approach for DLBCL associated with t(14;18)(q32;q21)

Trends in broad-spectrum antibiotic prescribing for children with acute otitis media in the United States, 1998–2004

<p>Abstract</p> <p>Background</p> <p>Overuse of broad-spectrum antibiotics is associated with antibiotic resistance. Acute otitis media (AOM) is responsible for a large proportion of antibiotics prescribed for US children. Rates of broad-spectrum antibiotic prescribing for AOM are unknown.</p> <p>Methods</p> <p>Analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, 1998 to 2004 (N = 6,878). Setting is office-based physicians, hospital outpatient departments, and emergency departments. Patients are children aged 12 years and younger prescribed antibiotics for acute otitis media. Main outcome measure is percentage of broad-spectrum antibiotics, defined as amoxicillin/clavulanate, macrolides, cephalosporins and quinolones.</p> <p>Results</p> <p>Broad-spectrum prescribing for acute otitis media increased from 34% of visits in 1998 to 45% of visits in 2004 (P < .001 for trend). The trend was primarily attributable to an increase in prescribing of amoxicillin/clavulanate (8% to 15%; P < .001 for trend) and macrolides (9% to 15%; P < .001 for trend). Prescribing remained stable for amoxicillin and cephalosporins while decreasing for narrow-spectrum agents (12% to 3%; P < .001 for trend) over the study period. Independent predictors of broad-spectrum antibiotic prescribing were ear pain, non-white race, public and other insurance (compared to private), hospital outpatient department setting, emergency department setting, and West region (compared to South and Midwest regions), each of which was associated with lower rates of broad-spectrum prescribing. Age and fever were not associated with prescribing choice.</p> <p>Conclusion</p> <p>Prescribing of broad-spectrum antibiotics for acute otitis media has steadily increased from 1998 to 2004. Associations with non-clinical factors suggest potential for improvement in prescribing practice.</p

Rod and Cone Pathway Signalling Is Altered in the P2X7 Receptor Knock Out Mouse

The P2X7 receptor (P2X7-R) is expressed in the retina and brain and has been implicated in neurodegenerative diseases. However, whether it is expressed by neurons and plays a role as a neurotransmitter receptor has been the subject of controversy. In this study, we first show that the novel vesicular transporter for ATP, VNUT, is expressed in the retina, verifying the presence of the molecular machinery for ATP to act as neurotransmitter at P2X7-Rs. Secondly we show the presence of P2X7-R mRNA and protein in the retina and cortex and absence of the full length variant 1 of the receptor in the P2X7-R knock out (P2X7-KO) mouse. The role of the P2X7-R in neuronal function of the retina was assessed by comparing the electroretinogram response of P2X7-KO with WT mice. The rod photoreceptor response was found to be similar, while both rod and cone pathway post-photoreceptor responses were significantly larger in P2X7-KO mice. This suggests that activation of P2X7-Rs modulates output of second order retinal neurons. In line with this finding, P2X7-Rs were found in the outer plexiform layer and on inner retinal cell classes, including horizontal, amacrine and ganglion cells. The receptor co-localized with conventional synapses in the IPL and was expressed on amacrine cells post-synaptic to rod bipolar ribbon synapses. In view of the changes in visual function in the P2X7-KO mouse and the immunocytochemical location of the receptor in the normal retina, it is likely the P2X7-R provides excitatory input to photoreceptor terminals or to inhibitory cells that shape both the rod and cone pathway response

The STRATOB study: design of a randomized controlled clinical trial of Cognitive Behavioral Therapy and Brief Strategic Therapy with telecare in patients with obesity and binge-eating disorder referred to residential nutritional rehabilitation

bstract BACKGROUND: Overweight and obesity are linked with binge eating disorder (BED). Effective interventions to significantly reduce weight, maintain weight loss and manage associated pathologies like BED are typically combined treatment options (dietetic, nutritional, physical, behavioral, cognitive-behavioral, pharmacological, surgical). Significant difficulties with regard to availability, costs, treatment adherence and long-term efficacy are present. Particularly Cognitive Behavioral Therapy (CBT) is the therapeutic approach indicated both in in-patient and in out-patient settings for BED. In recent years systemic and systemic-strategic psychotherapies have been implemented to treat patients with obesity and BED involved in familiar problems. Particularly a brief protocol for the systemic-strategic treatment of BED, using overall the strategic dialogue, has been recently developed. Moreover telemedicine, a new promising low cost method, has been used for obesity with BED in out-patient settings in order to avoid relapse after the in-patient step of treatment and to keep on a continuity of care with the involvement of the same clinical in-patient team. METHODS: The comparison between CBT and Brief Strategic Therapy (BST) will be assessed in a two-arm randomized controlled clinical trial. Due to the novelty of the application of BST in BED treatment (no other RCTs including BST have been carried out), a pilot study will be carried out before conducting a large scale randomized controlled clinical trial (RCT). Both CBT and BST group will follow an in-hospital treatment (diet, physical activity, dietitian counseling, 8 psychological sessions) plus 8 out-patient telephone-based sessions of psychological support and monitoring with the same in-patient psychotherapists. Primary outcome measure of the randomized trial will be the change in the Global Index of the Outcome Questionnaire (OQ-45.2). Secondary outcome measures will be the percentage of BED patients remitted considering the number of weekly binge episodes and the weight loss. Data will be collected at baseline, at discharge from the hospital (c.a. 1 month after) and after 6-12-24 months from the end of the in-hospital treatment. Data at follow-up time points will be collected through tele-sessions. DISCUSSION: The STRATOB (Systemic and STRATegic psychotherapy for OBesity), a comprehensive two-phase stepped down program enhanced by telepsychology for the medium-term treatment of obese people with BED seeking intervention for weight loss, will shed light about the comparison of the effectiveness of the BST with the gold standard CBT and about the continuity of care at home using a low-level of telecare (mobile phones). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0109625

Syndromics: A Bioinformatics Approach for Neurotrauma Research

Substantial scientific progress has been made in the past 50 years in delineating many of the biological mechanisms involved in the primary and secondary injuries following trauma to the spinal cord and brain. These advances have highlighted numerous potential therapeutic approaches that may help restore function after injury. Despite these advances, bench-to-bedside translation has remained elusive. Translational testing of novel therapies requires standardized measures of function for comparison across different laboratories, paradigms, and species. Although numerous functional assessments have been developed in animal models, it remains unclear how to best integrate this information to describe the complete translational “syndrome” produced by neurotrauma. The present paper describes a multivariate statistical framework for integrating diverse neurotrauma data and reviews the few papers to date that have taken an information-intensive approach for basic neurotrauma research. We argue that these papers can be described as the seminal works of a new field that we call “syndromics”, which aim to apply informatics tools to disease models to characterize the full set of mechanistic inter-relationships from multi-scale data. In the future, centralized databases of raw neurotrauma data will enable better syndromic approaches and aid future translational research, leading to more efficient testing regimens and more clinically relevant findings

A search for rare B → Dμ+μ− decays

A search for rare B→Dμ+μ− decays is performed using proton-proton collision data collected by the LHCb experiment, corresponding to an integrated luminosity of 9 fb−1. No significant signals are observed in the non-resonant μ+μ− modes, and upper limits of B(B0→D ̄ ̄ ̄ ̄0μ+μ−)&lt;5.1×10−8, B(B+→D+sμ+μ−)&lt;3.2×10−8, B(B0s→D ̄ ̄ ̄ ̄0μ+μ−)&lt;1.6×10−7 and fc/fu⋅B(B+c→D+sμ+μ−)&lt;9.6×10−8 are set at the 95\% confidence level, where fc and fu are the fragmentation fractions of a B meson with a c and u quark respectively in proton-proton collisions. Each result is either the first such measurement or an improvement by three orders of magnitude on an existing limit. Separate upper limits are calculated when the muon pair originates from a J/ψ→μ+μ− decay. The branching fraction of B+c→D+sJ/ψ multiplied by the fragmentation-fraction ratio is measured to be fc/fu⋅B(B+c→D+sJ/ψ)=(1.63±0.15±0.13)×10−5, where the first uncertainty is statistical and the second systematic