Nephrin Regulates Lamellipodia Formation by Assembling a Protein Complex That Includes Ship2, Filamin and Lamellipodin

Actin dynamics has emerged at the forefront of podocyte biology. Slit diaphragm junctional adhesion protein Nephrin is necessary for development of the podocyte morphology and transduces phosphorylation-dependent signals that regulate cytoskeletal dynamics. The present study extends our understanding of Nephrin function by showing in cultured podocytes that Nephrin activation induced actin dynamics is necessary for lamellipodia formation. Upon activation Nephrin recruits and regulates a protein complex that includes Ship2 (SH2 domain containing 5′ inositol phosphatase), Filamin and Lamellipodin, proteins important in regulation of actin and focal adhesion dynamics, as well as lamellipodia formation. Using the previously described CD16-Nephrin clustering system, Nephrin ligation or activation resulted in phosphorylation of the actin crosslinking protein Filamin in a p21 activated kinase dependent manner. Nephrin activation in cell culture results in formation of lamellipodia, a process that requires specialized actin dynamics at the leading edge of the cell along with focal adhesion turnover. In the CD16-Nephrin clustering model, Nephrin ligation resulted in abnormal morphology of actin tails in human podocytes when Ship2, Filamin or Lamellipodin were individually knocked down. We also observed decreased lamellipodia formation and cell migration in these knock down cells. These data provide evidence that Nephrin not only initiates actin polymerization but also assembles a protein complex that is necessary to regulate the architecture of the generated actin filament network and focal adhesion dynamics

A cross-sectional study of the number and frequency of terms used to refer to knowledge translation in a body of health literature in 2006: a Tower of Babel?

<p/> <p>Background</p> <p>The study of implementing research findings into practice is rapidly growing and has acquired many competing names (<it>e.g</it>., dissemination, uptake, utilization, translation) and contributing disciplines. The use of multiple terms across disciplines pose barriers to communication and progress for applying research findings. We sought to establish an inventory of terms describing this field and how often authors use them in a collection of health literature published in 2006.</p> <p>Methods</p> <p>We refer to this field as knowledge translation (KT). Terms describing aspects of KT and their definitions were collected from literature, the internet, reports, textbooks, and contact with experts. We compiled a database of KT and other articles by reading 12 healthcare journals representing multiple disciplines. All articles published in these journals in 2006 were categorized as being KT or not. The KT articles (all KT) were further categorized, if possible, for whether they described KT projects or implementations (KT application articles), or presented the theoretical basis, models, tools, methods, or techniques of KT (KT theory articles). Accuracy was checked using duplicate reading. Custom designed software determined how often KT terms were used in the titles and abstracts of articles categorized as being KT.</p> <p>Results</p> <p>A total of 2,603 articles were assessed, and 581 were identified as KT articles. Of these, 201 described KT applications, and 153 included KT theory. Of the 100 KT terms collected, 46 were used by the authors in the titles or abstracts of articles categorized as being KT. For all 581 KT articles, eight terms or term variations used by authors were highly discriminating for separating KT and non-KT articles (p < 0.001): implementation, adoption, quality improvement, dissemination, complex intervention (with multiple endings), implementation (within three words of) research, and complex intervention. More KT terms were associated with KT application articles (n = 13) and KT theory articles (n = 18).</p> <p>Conclusions</p> <p>We collected 100 terms describing KT research. Authors used 46 of them in titles and abstracts of KT articles. Of these, approximately half discriminated between KT and non-KT articles. Thus, the need for consolidation and consistent use of fewer terms related to KT research is evident.</p

Verifiable Registration-Based Encryption

In a recent work, Garg, Hajiabadi, Mahmoody, and Rahimi (TCC 18) introduced a new encryption framework, which they referred to as Registration-Based Encryption (RBE). The central motivation behind RBE was to provide a novel methodology for solving the well-known key-escrow problem in Identity-Based Encryption (IBE) systems. Informally, in an RBE system there is no private-key generator unlike IBE systems, but instead it is replaced with a public key accumulator. Every user in an RBE system samples its own public-secret key pair, and sends the public key to the accumulator for registration. The key accumulator has no secret state, and is only responsible for compressing all the registered user identity-key pairs into a short public commitment. Here the encryptor only requires the compressed parameters along with the target identity, whereas a decryptor requires supplementary key material along with the secret key associated with the registered public key. The initial construction by Garg et al. (TCC 18) based on standard assumptions only provided weak efficiency properties. In a follow-up work by Garg, Hajiabadi, Mahmoody, Rahimi, and Sekar (PKC 19), they gave an efficient RBE construction from standard assumptions. However, both these works considered the key accumulator to be honest which might be too strong an assumption in real-world scenarios. In this work, we initiate a formal study of RBE systems with malicious key accumulators. To that end, we introduce a strengthening of the RBE framework which we call Verifiable RBE (VRBE). A VRBE system additionally gives the users an extra capability to obtain short proofs from the key accumulator proving correct (and unique) registration for every registered user as well as proving non-registration for any yet unregistered identity. We construct VRBE systems which provide succinct proofs of registration and non-registration from standard assumptions (such as CDH, Factoring, LWE). Our proof systems also naturally allow a much more efficient audit process which can be perfomed by any non-participating third party as well. A by-product of our approach is that we provide a more efficient RBE construction than that provided in the prior work of Garg et al. (PKC 19). And, lastly we initiate a study on extension of VRBE to a wider range of access and trust structures

Viremic HIV Infected Individuals with High CD4 T Cells and Functional Envelope Proteins Show Anti-gp41 Antibodies with Unique Specificity and Function

BACKGROUND: CD4 T-cell decay is variable among HIV-infected individuals. In exceptional cases, CD4 T-cell counts remain stable despite high plasma viremia. HIV envelope glycoprotein (Env) properties, namely tropism, fusion or the ability to induce the NK ligand NKp44L, or host factors that modulate Env cytopathic mechanisms may be modified in such situation. METHODS: We identified untreated HIV-infected individuals showing non-cytopathic replication (VL>10,000 copies/mL and CD4 T-cell decay<50 cells/µL/year, Viremic Non Progressors, VNP) or rapid progression (CD4 T-cells<350 cells/µL within three years post-infection, RP). We isolated full-length Env clones and analyzed their functions (tropism, fusion activity and capacity to induce NKp44L expression on CD4 cells). Anti-Env humoral responses were also analyzed. RESULTS: Env clones isolated from VNP or RP individuals showed no major phenotypic differences. The percentage of functional clones was similar in both groups. All clones tested were CCR5-tropic and showed comparable expression and fusogenic activity. Moreover, no differences were observed in their capacity to induce NKp44L expression on CD4 T cells from healthy donors through the 3S epitope of gp41. In contrast, anti- Env antibodies showed clear functional differences: plasma from VNPs had significantly higher capacity than RPs to block NKp44L induction by autologous viruses. Consistently, CD4 T-cells isolated from VNPs showed undetectable NKp44L expression and specific antibodies against a variable region flanking the highly conserved 3S epitope were identified in plasma samples from these patients. Conversely, despite continuous antigen stimulation, VNPs were unable to mount a broad neutralizing response against HIV. CONCLUSIONS: Env functions (fusion and induction of NKp44L) were similar in viremic patients with slow or rapid progression to AIDS. However, differences in humoral responses against gp41 epitopes nearby 3S sequence may contribute to the lack of CD4 T cell decay in VNPs by blocking the induction of NKp44L by gp41

High fat diet modifies the association of lipoprotein lipase gene polymorphism with high density lipoprotein cholesterol in an Asian Indian population

Background Single nucleotide polymorphisms (SNPs) in lipoprotein lipase gene (LPL) have been shown to influence metabolism related to lipid phenotypes. Dietary factors have been shown to modify the association between LPL SNPs and lipids; however, to date, there are no studies in South Asians. Hence, we tested for the association of four common LPL SNPs with plasma lipids and examined the interactions between the SNPs and dietary factors on lipids in 1,845 Asian Indians. Methods The analysis was performed in 788 Type 2 diabetes cases and 1,057 controls randomly chosen from the cross-sectional Chennai Urban Rural Epidemiological Study. Serum triacylglycerol (TAG), serum total cholesterol, and high-density lipoprotein cholesterol (HDL-C) were measured using a Hitachi-912 autoanalyzer (Roche Diagnostics GmbH, Mannheim, Germany). Dietary intake was assessed using a semi-quantitative food frequency questionnaire. The SNPs (rs1121923, rs328, rs4922115 and rs285) were genotyped by polymerase chain reaction followed by restriction enzyme digestion and 20% of samples were sequenced to validate the genotypes obtained. Statistical Package for Social Sciences for Windows version 22.0 (SPSS, Chicago, IL) was used for statistical analysis. Results After correction for multiple testing and adjusting for potential confounders, SNPs rs328 and rs285 showed association with HDL-C (P = 0.0004) and serum TAG (P = 1×10−5), respectively. The interaction between SNP rs1121923 and fat intake (energy %) on HDL-C (P = 0.003) was also significant, where, among those who consumed a high fat diet (28.4 ± 2.5%), the T allele carriers (TT + XT) had significantly higher HDL-C concentrations (P = 0.0002) and 30% reduced risk of low HDL-C levels compared to the CC homozygotes. None of the interactions on other lipid traits were statistically significant. Conclusion Our findings suggest that individuals carrying T allele of the SNP rs1121923 have increased HDL-C levels when consuming a high fat diet compared to CC homozygotes. Our finding warrants confirmation in prospective studies and randomized controlled trials

Biological response of an in vitro human 3D lung cell model exposed to brake wear debris varies based on brake pad formulation

Wear particles from automotive friction brake pads of various sizes, morphology, and chemical composition are significant contributors towards particulate matter. Knowledge concerning the potential adverse effects following inhalation exposure to brake wear debris is limited. Our aim was, therefore, to generate brake wear particles released from commercial low-metallic and non-asbestos organic automotive brake pads used in mid-size passenger cars by a full-scale brake dynamometer with an environmental chamber simulating urban driving and to deduce their potential hazard in vitro. The collected fractions were analysed using scanning electron microscopy via energy-dispersive X-ray spectroscopy (SEM-EDS) and Raman microspectroscopy. The biological impact of the samples was investigated using a human 3D multicellular model consisting of human epithelial cells (A549) and human primary immune cells (macrophages and dendritic cells) mimicking the human epithelial tissue barrier. The viability, morphology, oxidative stress, and (pro-)inflammatory response of the cells were assessed following 24 h exposure to similar to 12, similar to 24, and similar to 48 A mu g/cm(2) of non-airborne samples and to similar to 3.7 A mu g/cm(2) of different brake wear size fractions (2-4, 1-2, and 0.25-1 A mu m) applying a pseudo-air-liquid interface approach. Brake wear debris with low-metallic formula does not induce any adverse biological effects to the in vitro lung multicellular model. Brake wear particles from non-asbestos organic formulated pads, however, induced increased (pro-)inflammatory mediator release from the same in vitro system. The latter finding can be attributed to the different particle compositions, specifically the presence of anatase.Web of Science9272351233

Computerized clinical decision support systems for chronic disease management: A decision-maker-researcher partnership systematic review

<p>Abstract</p> <p>Background</p> <p>The use of computerized clinical decision support systems (CCDSSs) may improve chronic disease management, which requires recurrent visits to multiple health professionals, ongoing disease and treatment monitoring, and patient behavior modification. The objective of this review was to determine if CCDSSs improve the processes of chronic care (such as diagnosis, treatment, and monitoring of disease) and associated patient outcomes (such as effects on biomarkers and clinical exacerbations).</p> <p>Methods</p> <p>We conducted a decision-maker-researcher partnership systematic review. We searched MEDLINE, EMBASE, Ovid's EBM Reviews database, Inspec, and reference lists for potentially eligible articles published up to January 2010. We included randomized controlled trials that compared the use of CCDSSs to usual practice or non-CCDSS controls. Trials were eligible if at least one component of the CCDSS was designed to support chronic disease management. We considered studies 'positive' if they showed a statistically significant improvement in at least 50% of relevant outcomes.</p> <p>Results</p> <p>Of 55 included trials, 87% (n = 48) measured system impact on the process of care and 52% (n = 25) of those demonstrated statistically significant improvements. Sixty-five percent (36/55) of trials measured impact on, typically, non-major (surrogate) patient outcomes, and 31% (n = 11) of those demonstrated benefits. Factors of interest to decision makers, such as cost, user satisfaction, system interface and feature sets, unique design and deployment characteristics, and effects on user workflow were rarely investigated or reported.</p> <p>Conclusions</p> <p>A small majority (just over half) of CCDSSs improved care processes in chronic disease management and some improved patient health. Policy makers, healthcare administrators, and practitioners should be aware that the evidence of CCDSS effectiveness is limited, especially with respect to the small number and size of studies measuring patient outcomes.</p