Intracellular sterol dynamics

We review the cellular mechanisms implicated in cholesterol trafficking and distribution. Recent studies have provided new information about the distribution of sterols within cells, including analysis of its transbilayer distribution. The cholesterol interaction with other lipids and its engagement in various trafficking processes will determine its proper level in a specific membrane; making the cholesterol distribution uneven among the various intracellular organelles. The cholesterol content is important since cholesterol plays an essential role in membranes by controlling their physicochemical properties as well as key cellular events such as signal transduction and protein trafficking. Cholesterol movement between cellular organelles is highly dynamic, and can be achieved by vesicular and non-vesicular processes. Various studies have analyzed the proteins that play a significant role in these processes, giving us new information about the relative importance of these two trafficking pathways in cholesterol transport. Although still poorly characterized in many trafficking routes, several potential sterol transport proteins have been described in detail; as a result, molecular mechanisms for sterol transport among membranes start to be appreciated.     

High Resolution NMR-based Model for the Structure of a scFv-IL-1�� Complex: POTENTIAL FOR NMR AS A KEY TOOL IN THERAPEUTIC ANTIBODY DESIGN AND DEVELOPMENT*

Monoclonal antibodies have recently started to deliver on their promise as highly specific and active drugs; however, a more effective, knowledge-based approach to the selection, design, and optimization of potential therapeutic antibodies is currently limited by the surprising lack of detailed structural information for complexes formed with target proteins. Here we show that complexes formed with minimal antigen binding single chain variable fragments (scFv) reliably reflect all the features of the binding interface present in larger Fab fragments, which are commonly used as therapeutics, and report the development of a robust, reliable, and relatively rapid approach to the determination of high resolution models for scFv-target protein complexes. This NMR spectroscopy-based approach combines experimental determination of the interaction surfaces and relative orientations of the scFv and target protein, with NMR restraint-driven, semiflexible docking of the proteins to produce a reliable and highly informative model of the complex. Experience with scFvs and Fabs targeted at a number of secreted regulatory proteins suggests that the approach will be applicable to many therapeutic antibodies targeted at proteins, and its application is illustrated for a potential therapeutic antibody targeted at the cytokine IL-1β. The detailed structural information that can be obtained by this approach has the potential to have a major impact on the rational design and development of an increasingly important class of biological pharmaceuticals.     

Modeling the effect of information quality on risk behavior change and the transmission of infectious diseases

How the quality of information about the prevalence of an infectious disease affects individuals’ incentives to adopt self-protective actions to reduce the risk of infection is studied using an economic/game-theoretic model of epidemics. In the model, agents make inferences regarding the current prevalence of a disease by observing the health status of a subset of the population. Therefore, the higher the number of agents whose infection status can be observed, the better one’s information about the current prevalence is. In particular, it is assumed that an agent’s estimate of the current prevalence depends on observations of the current health status of other agents and on the agent’s estimate of past prevalence, and that the agent places more weight on the current observations in forming an estimate of the prevailing prevalence when the number of observations increases. It is shown that the likelihood of eradicating an infectious disease through behavioral changes depends critically on the amount of information that individuals have access to, which also determines whether prevalence will be relatively stable or will exhibit cyclical patterns over time. Increasing the amount of information that individuals possess may lower the likelihood of eradication.     

Choosing the right path: enhancement of biologically relevant sets of genes or proteins using pathway structure

A method is proposed that finds enriched pathways relevant to a studied condition using the measured molecular data and also the structural information of the pathway viewed as a network of nodes and edges. Tests are performed using simulated data and genomic data sets and the method is compared to two existing approaches. The analysis provided demonstrates the method proposed is very competitive with the current approaches and also provides biologically relevant results.     

Comparative analysis of the complete sequence of the plastid genome of Parthenium argentatum and identification of DNA barcodes to differentiate Parthenium species and lines

Background  

Parthenium argentatum (guayule) is an industrial crop that produces latex, which was recently commercialized as a source of latex rubber safe for people with Type I latex allergy. The complete plastid genome of P. argentatum was sequenced. The sequence provides important information useful for genetic engineering strategies. Comparison to the sequences of plastid genomes from three other members of the Asteraceae, Lactuca sativa, Guitozia abyssinica and Helianthus annuus revealed details of the evolution of the four genomes. Chloroplast-specific DNA barcodes were developed for identification of Parthenium species and lines.     

Distribution and ecology of the assemblages of myxomycetes associated with major vegetation types in Big Bend National Park,USA

The distribution and ecology of the assemblages of myxomycetes associated with four different microhabitats were studied in Big Bend National Park in Texas. During Mar. 2005, twelve plots (30 × 30 m) were established along an elevational gradient that extended from 564 to 1807 m. Samples of aerial bark from dead and living trees, aerial litter (dead but still attached plant parts), ground litter (fallen dead plant parts) and ground bark (fragments of fallen bark) were collected from these plots, which encompassed all of the major vegetation types found in the Park. Four hundred forty-seven moist chambers were prepared, and 95.8 % (428) produced some evidence (either fruit bodies or plasmodia) of myxomycetes. A total of 71 species were recorded, with ground litter yielding most (45 species). Aerial litter, aerial bark and ground bark yielded 44, 39 and 37 species, respectively. Species abundance distribution measures (diversity, dominance and similarities) varied among the four microhabitats as well as among the major vegetation types. Canonical Correspondence Analysis (CCA) showed that species distribution patterns were closely related to: (1) the major environmental-complex gradients associated with differences in elevation/temperature/moisture conditions that occur from one locality to another; and (2) the different types of microhabitat.     

Dynamic equilibria in an epidemic model with voluntary vaccinations

The dynamics of an epidemic model with voluntary vaccinations are studied. Individual vaccination decisions are modelled using an economic/game-theoretic approach: agents in the model decide whether to vaccinate or not by weighing the cost and benefit of vaccination and choose the action that maximizes their net benefit. It is shown that, when vaccine efficacy is low, there are parameter values for which multiple steady-state equilibria and periodic equilibria coexist. When multiplicity of steady states is obtained, which one the population reaches in some cases depends entirely on agents' expectations concerning the future course of an epidemic and not on the initial conditions of the model. (?)Comments and suggestions from anonymous referees of the journal are gratefully acknowledged. This paper is dedicated to the loving memory of Lucy Hauser.     

Best Practice Updates for Surgical Care in Weight Loss Surgery

To update evidence‐based best practice guidelines for surgical care in weight loss surgery (WLS). Systematic search of English‐language literature on WLS in MEDLINE, EMBASE, and the Cochrane Library between April 2004 and May 2007. Use of key words to narrow the search for a selective review of abstracts, retrieval of full articles, and grading of evidence according to systems used in established evidence‐based models. Evidence‐based best practice recommendations from the most recent literature on surgical methods and technologies, risks and benefits, outcomes, and surgeon qualifications and credentialing. We identified >135 articles; the 65 most relevant were reviewed in detail. Regular updates of evidence‐based recommendations for best practices in WLS are required to address rapid changes in surgical techniques and patient demographics. Key factors in patient safety include surgical risk factors, type of procedure, surgeon training, and facility certification.     

Vasoregression Linked to Neuronal Damage in the Rat with Defect of Polycystin-2

Background

Neuronal damage is correlated with vascular dysfunction in the diseased retina, but the underlying mechanisms remain controversial because of the lack of suitable models in which vasoregression related to neuronal damage initiates in the mature retinal vasculature. The aim of this study was to assess the temporal link between neuronal damage and vascular patency in a transgenic rat (TGR) with overexpression of a mutant cilia gene polycystin-2.

Methods

Vasoregression, neuroglial changes and expression of neurotrophic factors were assessed in TGR and control rats in a time course. Determination of neuronal changes was performed by quantitative morphometry of paraffin-embedded vertical sections. Vascular cell composition and patency were assessed by quantitative retinal morphometry of digest preparations. Glial activation was assessed by western blot and immunofluorescence. Expression of neurotrophic factors was detected by quantitative PCR.

Findings

At one month, number and thickness of the outer nuclear cell layers (ONL) in TGR rats were reduced by 31% (p<0.001) and 17% (p<0.05), respectively, compared to age-matched control rats. Furthermore, the reduction progressed from 1 to 7 months in TGR rats. Apoptosis was selectively detected in the photoreceptor in the ONL, starting after one month. Nevertheless, TGR and control rats showed normal responses in electroretinogram at one month. From the second month onwards, TGR retinas had significantly increased acellular capillaries (p<0.001), and a reduction of endothelial cells (p<0.01) and pericytes (p<0.01). Upregulation of GFAP was first detected in TGR retinas after 1 month in glial cells, in parallel with an increase of FGF2 (fourfold) and CNTF (60 %), followed by upregulation of NGF (40 %) at 3 months.

Interpretation

Our data suggest that TGR is an appropriate animal model for vasoregression related to neuronal damage. Similarities to experimental diabetic retinopathy render this model suitable to understand general mechanisms of maturity-onset vasoregression.     

Effects of Genital Ulcer Disease and Herpes Simplex Virus Type 2 on the Efficacy of Male Circumcision for HIV Prevention: Analyses from the Rakai Trials

Background

Randomized trials show that male circumcision (MC) reduces the incidence of HIV and herpes simplex virus type 2 (HSV-2) infections, and symptomatic genital ulcer disease (GUD). We assessed the role of GUD and HSV-2 in the protection against HIV afforded by MC.

Methods and Findings

HIV-uninfected men were randomized to immediate (n = 2,756) or delayed MC (n = 2,775) in two randomized trials in Rakai, Uganda. GUD symptoms, HSV-2 status, and HIV acquisition were determined at enrollment and at 6, 12, and 24 mo of follow up. Ulcer etiology was assessed by PCR. We estimated the prevalence and prevalence risk ratios (PRRs) of GUD in circumcised versus uncircumcised men and assessed the effects of HSV-2 serostatus as a risk-modifying factor for GUD. We estimated the proportion of the effect of MC on HIV acquisition that was mediated by symptomatic GUD, and by HSV-2 infection. Circumcision significantly reduced symptomatic GUD in HSV-2-seronegative men (PRR = 0.51, 95% [confidence interval] CI 0.43–0.74), HSV-2-seropositive men (PRR = 0.66, 95% CI 0.51–0.69), and in HSV-2 seroconverters (PRR = 0.48, 95% CI 0.30–0.79). The proportion of acute ulcers due to HSV-2 detected by PCR was 48.0% in circumcised men and 39.3% in uncircumcised men (χ² p = 0.62). Circumcision reduced the risk of HIV acquisition in HSV-2 seronegative men (incidence rate ratio [IRR] = 0.34, 95% CI 0.15–0.81), and potentially in HSV-2 seroconverters (IRR = 0.56, 95% CI 0.19–1.57; not significant), but not in men with prevalent HSV-2 at enrollment (IRR = 0.89, 95% CI 0.49–1.60). The proportion of reduced HIV acquisition in circumcised men mediated by reductions in symptomatic GUD was 11.2% (95% CI 5.0–38.0), and the proportion mediated by reduced HSV-2 incidence was 8.6% (95% CI −1.2 to 77.1).

Conclusions

Circumcision reduced GUD irrespective of HSV-2 status, but this reduction played only a modest role in the protective effect of circumcision on HIV acquisition.

NIH Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00425984","term_id":"NCT00425984"}}NCT00425984

Gates Foundation Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00124878","term_id":"NCT00124878"}}NCT00124878 Please see later in the article for the Editors'' Summary