The Unfolded Protein Response Regulates Multiple Aspects of Secretory and Membrane Protein Biogenesis and Endoplasmic Reticulum Quality Control

The unfolded protein response (UPR) is an intracellular signaling pathway that relays signals from the lumen of the ER to activate target genes in the nucleus. We devised a genetic screen in the yeast Saccharomyces cerevisiae to isolate mutants that are dependent on activation of the pathway for viability. Using this strategy, we isolated mutants affecting various aspects of ER function, including protein translocation, folding, glycosylation, glycosylphosphatidylinositol modification, and ER-associated protein degradation (ERAD). Extending results gleaned from the genetic studies, we demonstrate that the UPR regulates trafficking of proteins at the translocon to balance the needs of biosynthesis and ERAD. The approach also revealed connections of the UPR to other regulatory pathways. In particular, we identified SON1/RPN4, a recently described transcriptional regulator for genes encoding subunits of the proteasome. Our genetic strategy, therefore, offers a powerful means to provide insight into the physiology of the UPR and to identify novel genes with roles in many aspects of secretory and membrane protein biogenesis

Sequentially based analysis versus image based analysis of Intima Media Thickness in common carotid arteries studies - Do major IMT studies underestimate the true relations for cardio- and cerebrovascular risk?

<p>Abstract</p> <p>Background</p> <p>Image-based B-mode ultrasound has gained popularity in major studies as a non-invasive method of measuring cardio- and cerebrovascular risk factors. However, none of the major studies appears to have paid sufficient attention to the variation in end diastolic wall process. By using sequentially based analyses (SBA) of Intima-Media Thickness (IMT), the general purpose of this study was to show that the current image based (ECG tracked) analysis (IBA) has some major variations and might underestimate the true relations for cardiovascular events and stroke for IMT measurement.</p> <p>Method</p> <p>The study group consisted of 2500 healthy male subjects aged between 35 to 55 years. 4 sequences (300 images) were analyzed per subject. 750,000 images were analysed throughout the course of this study.</p> <p>Results</p> <p>IBA showed significantly lower mean, maximal, and minimal values for IMT in CCA than for SBA. The correlation analysis between IBA and SBA with the cardio- and cerebrovascular risk factors showed a higher correlation of SBA for all risk factors. The Pearson coefficient was 0.81, p < 0.01, for SBA versus Framingham CHD risk level (FCRL) and 0.49, p = 0.01, for IBA versus FCRL.</p> <p>Conclusion</p> <p>IBA did not measure the true maximal values of the IMT in this study. Together with the correlation analysis, this indicates that IBA might underestimate the true relations for IMT and risk factors.</p

Transcranial Doppler ultrasonography predicts cardiovascular events after TIA

<p>Abstract</p> <p>Background</p> <p>Transient ischemic attack (TIA) patients are at high vascular risk. We assessed the value of extracranial (ECD) and transcranial (TCD) Doppler and duplex ultrasonography to predict clinical outcome after TIA.</p> <p>Methods</p> <p>176 consecutive TIA patients admitted to the Stroke Unit were recruited in the study. All patients received diffusion-weighted imaging, standardized ECD and TCD. At a median follow-up of 27 months, new vascular events were recorded.</p> <p>Results</p> <p>22 (13.8%) patients experienced an ischemic stroke or TIA, 5 (3.1%) a myocardial infarction or acute coronary syndrome, and 5 (3.1%) underwent arterial revascularization. ECD revealed extracranial ≥ 50% stenosis or occlusions in 34 (19.3%) patients, TCD showed intracranial stenosis in 15 (9.2%) and collateral flow patterns due to extracranial stenosis in 5 (3.1%) cases. Multivariate analysis identified these abnormal ECD and TCD findings as predictors of new cerebral ischemic events (ECD: hazard ratio (HR) 4.30, 95% confidence interval (CI) 1.75 to 10.57, P = 0.01; TCD: HR 4.73, 95% CI 1.86 to 12.04, P = 0.01). Abnormal TCD findings were also predictive of cardiovascular ischemic events (HR 18.51, 95% CI 3.49 to 98.24, P = 0.001).</p> <p>Conclusion</p> <p>TIA patients with abnormal TCD findings are at high risk to develop further cerebral and cardiovascular ischemic events.</p

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Differences in carotid arterial morphology and composition between individuals with and without obstructive coronary artery disease: A cardiovascular magnetic resonance study

Objective: We sought to determine differences with cardiovascular magnetic resonance (CMR) in the morphology and composition of the carotid arteries between individuals with angiographically-defined obstructive coronary artery disease (CAD, = 50% stenosis, cases) and those with angiographically normal coronaries (no lumen irregularities, controls). Methods and results: 191 participants (50.3% female; 50.8% CAD cases) were imaged with a multi-sequence, carotid CMR protocol at 1.5T. For each segment of the carotid, lumen area, wall area, total vessel area (lumen area + wall area), mean wall thickness and the presence or absence of calcification and lipid-rich necrotic core were recorded bilaterally. In male CAD cases compared to male controls, the distal bulb had a significantly smaller lumen area (60.0 [plus or minus] 3.1 vs. 79.7 [plus or minus] 3.2 mm[super]2, p less than 0.001) and total vessel area (99.6 [plus or minus] 4.0 vs. 119.8 [plus or minus] 4.1 mm[super]2; p less than 0.001), and larger mean wall thickness (1.25 [plus or minus] 0.03 vs. 1.11 [plus or minus] 0.03 mm; p = 0.002). Similarly, the internal carotid had a smaller lumen area (37.5 [plus or minus] 1.8 vs. 44.6 [plus or minus] 1.8 mm[super]2; p = 0.006) and smaller total vessel area (64.0 [plus or minus] 2.3 vs. 70.9 [plus or minus] 2.4 mm[super]2; p = 0.04). These metrics were not significantly different between female groups in the distal bulb and internal carotid or for either gender in the common carotid. Male CAD cases had an increased prevalence of lipid-rich necrotic core (49.0% vs. 19.6%; p = 0.003), while calcification was more prevalent in both male (46.9% vs. 17.4%; p = 0.002) and female (33.3% vs. 14.6%; p = 0.031) CAD cases compared to controls. Conclusion: Males with obstructive CAD compared to male controls had carotid bulbs and internal carotid arteries with smaller total vessel and lumen areas, and an increased prevalence of lipid-rich necrotic core. Carotid calcification was related to CAD status in both males and females. Carotid CMR identifies distinct morphological and compositional differences in the carotid arteries between individuals with and without angiographically-defined obstructive CAD.Carotid Atherosclerosis (MRI) Progression Study (CAMPS, HL076378) and Cardiovascular Research Training Program (T-32, HL07838); and the General Clinical Research Center at the Wake Forest University School of Medicine (M01 RR-07122)

Modelling Strategies for Predicting the Residual Strength of Impacted Composite Aircraft Fuselages

Aeronautic Certification rules established for the metallic materials are not convenient for the composite structures concerning the resistance against impact. The computerbased design is a new methodology that is thought about to replace the experimental tests. It becomes necessary for numerical methods to be robust and predictive for impact. Three questions are addressed in this study: (i) can a numerical model be “mechanically intrinsic” to predict damage after impact, (ii) can this model be the same for a lab sample and a large structure, and (iii) can the numerical model be predictive enough to predict the Compression After Impact (CAI)? Three different computational strategies are used and compared: a Cohesive Model (CM), a Continuous Damage Model (CDM) coupling failure modes and damage, and a Mixed Methodology (MM) using the CDM for delamination initiation and the CM for cracks propagation. The first attempts to use the Smooth Particle Hydrodynamics method are presented. Finally, impact on a fuselage is modelled and a numerical two-stage strategy is developed to predict the CAI

Structural Characteristics and Stellar Composition of Low Surface Brightness Disk Galaxies

We present UBVI surface photometry of a sample of low surface brightness (LSB) disk galaxies. LSB disk galaxies are fairly well described as exponential disks with no preferred value for either scale length, central surface brightness, or rotational velocity. Indeed, the distribution of scale lengths is indistinguishable from that of high surface brightness spirals, indicating that dynamically similar galaxies (e.g., those with comparable Rv^2) exist over a large range in surface density. These LSB galaxies are strikingly blue. The complete lack of correlation between central surface brightness and color rules out any fading scenario. Similarly, the oxygen abundances inferred from HII region spectra are uncorrelated with color so the low metallicities are not the primary cause of the blue colors. While these are difficult to interpret in the absence of significant star formation, the most plausible scenario is a stellar population with a young mean age stemming from late formation and subsequent slow evolution. These properties suggest that LSB disks formed from low initial overdensities with correspondingly late collapse times.Comment: Astronomical Journal, in press 45 pages uuencoded postscript (368K) including 9 multipart figures also available by anonymous ftp @ ftp.ast.cam.ac.uk /pub/ssm/phot.uu CAP-30-210442962983742937

Clear and independent associations of several HLA-DRB1 alleles with differential antibody responses to hepatitis B vaccination in youth

To confirm and refine associations of human leukocyte antigen (HLA) genotypes with variable antibody (Ab) responses to hepatitis B vaccination, we have analyzed 255 HIV-1 seropositive (HIV+) youth and 80 HIV-1 seronegatives (HIV−) enrolled into prospective studies. In univariate analyses that focused on HLA-DRB1, -DQA1, and -DQB1 alleles and haplotypes, the DRB1*03 allele group and DRB1*0701 were negatively associated with the responder phenotype (serum Ab concentration ≥ 10 mIU/mL) (P = 0.026 and 0.043, respectively). Collectively, DRB1*03 and DRB1*0701 were found in 42 (53.8%) out of 78 non-responders (serum Ab <10 mIU/mL), 65 (40.6%) out of 160 medium responders (serum Ab 10–1,000 mIU/mL), and 27 (27.8%) out of 97 high responders (serum Ab >1,000 mIU/mL) (P < 0.001 for trend). Meanwhile, DRB1*08 was positively associated with the responder phenotype (P = 0.010), mostly due to DRB1*0804 (P = 0.008). These immunogenetic relationships were all independent of non-genetic factors, including HIV-1 infection status and immunodeficiency. Alternative analyses confined to HIV+ youth or Hispanic youth led to similar findings. In contrast, analyses of more than 80 non-coding, single nucleotide polymorphisms within and beyond the three HLA class II genes revealed no clear associations. Overall, several HLA-DRB1 alleles were major predictors of differential Ab responses to hepatitis B vaccination in youth, suggesting that T-helper cell-dependent pathways mediated through HLA class II antigen presentation are critical to effective immune response to recombinant vaccines

Antibacterial activity of sucralfate versus aluminum chloride in simulated gastric fluid

Studies have previously demonstrated that sucralfate possesses intrinsic antibacterial activity. This study was designed to indirectly assess whether aluminum is the active antibacterial component of sucralfate and to further evaluate factors that may influence this agent's antibacterial activity. Utilizing an in vitro model, the antibacterial activity of sucralfate, an equivalent quantity of aluminum in the form of aluminum chloride, and a control were compared. In addition, the influences of bacterial species ( Enterobacter cloacae and Pseudomonas aeruginosa ), time (0–24 h) and environmental pH (3, 5, 7) on the agents' antibacterial activities were evaluated. Equivalent quantities of aluminum, as either sucralfate or aluminum chloride, were added to two of three flasks containing approximately 10 5 cfu/ml of bacteria in pH-adjusted simulated gastric fluid. The third flask served as a control. Samples were obtained over 24 h, diluted and subcultured onto agar plates. The experiments demonstrated that bacterial growth was influenced by pH, time and treatment (aluminum chloride or sucralfate). Regardless of pH or bacterial species, bacterial death occurred within 20 min following the addition of aluminum chloride. In contrast, bacterial death following the addition of sucralfate was more variable and appeared to be pH dependent. In conclusion, sucralfate and aluminum chloride both possess antibacterial activity, even at pH values that normally support bacterial growth in gastric fluid. Although differences in the antibacterial activity of the two agents may in part be related to drug-induced changes in pH, these differences also support data suggesting that aluminum release from sucralfate is incomplete and is dependent on pH.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47895/1/10096_2005_Article_BF02111825.pd