A Protein‐Based Pentavalent Inhibitor of the Cholera Toxin B‐Subunit

Protein toxins produced by bacteria are the cause of many life-threatening diarrheal diseases. Many of these toxins, including cholera toxin (CT), enter the cell by first binding to glycolipids in the cell membrane. Inhibiting these multivalent protein/carbohydrate interactions would prevent the toxin from entering cells and causing diarrhea. Here we demonstrate that the site-specific modification of a protein scaffold, which is perfectly matched in both size and valency to the target toxin, provides a convenient route to an effective multivalent inhibitor. The resulting pentavalent neoglycoprotein displays an inhibition potency (IC50) of 104 pM for the CT B-subunit (CTB), which is the most potent pentavalent inhibitor for this target reported thus far. Complexation of the inhibitor and CTB resulted in a protein heterodimer. This inhibition strategy can potentially be applied to many multivalent receptors and also opens up new possibilities for protein assembly strategies

Logarithmic correction to BH entropy as Noether charge

We consider the role of the type-A trace anomaly in static black hole solutions to semiclassical Einstein equation in four dimensions. Via Wald's Noether charge formalism, we compute the contribution to the entropy coming from the anomaly induced effective action and unveil a logarithmic correction to the Bekenstein-Hawking area law. The corrected entropy is given by a seemingly universal formula involving the coefficient of the type-A trace anomaly, the Euler characteristic of the horizon and the value at the horizon of the solution to the uniformization problem for Q-curvature. Two instances are examined in detail: Schwarzschild and a four-dimensional massless topological black hole. We also find agreement with the logarithmic correction due to one-loop contribution of conformal fields in the Schwarzschild background.Comment: 14 pages, JHEP styl

Membrane Fusion Mediated by Non-covalent Binding of Re-engineered Cholera Toxin Assemblies to Glycolipids

Membrane fusion is essential for the transport of macromolecules and viruses across membranes. While glycan-binding proteins (lectins) often initiate cellular adhesion, subsequent fusion events require additional protein machinery. No mechanism for membrane fusion arising from simply a protein binding to membrane glycolipids has been described thus far. Herein, we report that a biotinylated protein derived from cholera toxin becomes a fusogenic lectin upon cross-linking with streptavidin. This novel reengineered protein brings about hemifusion and fusion of vesicles as demonstrated by mixing of fluorescently labeled lipids between vesicles as well as content mixing of liposomes filled with fluorescently labeled dextran. Exclusion of the complex at vesicle–vesicle interfaces could also be observed, indicating the formation of hemifusion diaphragms. Discovery of this fusogenic lectin complex demonstrates that new emergent properties can arise from simple changes in protein architecture and provides insights into new mechanisms of lipid-driven fusion

HIV Testing Practices by Clinical Service before and after Revised Testing Guidelines in a Swiss University Hospital

OBJECTIVES: To determine 1) HIV testing practices in a 1400-bed university hospital where local HIV prevalence is 0.4% and 2) the effect on testing practices of national HIV testing guidelines, revised in March 2010, recommending Physician-Initiated Counselling and Testing (PICT). METHODS: Using 2 hospital databases, we determined the number of HIV tests performed by selected clinical services, and the number of patients tested as a percentage of the number seen per service ('testing rate'). To explore the effect of the revised national guidelines, we examined testing rates for two years pre- and two years post-PICT guideline publication. RESULTS: Combining the clinical services, 253,178 patients were seen and 9,183 tests were performed (of which 80 tested positive, 0.9%) in the four-year study period. The emergency department (ED) performed the second highest number of tests, but had the lowest testing rates (0.9-1.1%). Of inpatient services, neurology and psychiatry had higher testing rates than internal medicine (19.7% and 9.6% versus 8%, respectively). There was no significant increase in testing rates, either globally or in the majority of the clinical services examined, and no increase in new HIV diagnoses post-PICT recommendations. CONCLUSIONS: Using a simple two-database tool, we observe no global improvement in HIV testing rates in our hospital following new national guidelines but do identify services where testing practices merit improvement. This study may show the limit of PICT strategies based on physician risk assessment, compared to the opt-out approach

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Morbidity and Risk of Subsequent Diagnosis of HIV: A Population Based Case Control Study Identifying Indicator Diseases for HIV Infection

BACKGROUND: Early identification of persons with undiagnosed HIV infection is an important health care issue. We examined associations between diseases diagnosed in hospitals and risk of subsequent HIV diagnosis. METHODS: In this population-based case control study, cases were persons with incident HIV infection diagnosed in Denmark between 1 January 1995 and 1 June 2008. Risk-set sampling was used to identify 19 age- and gender-matched population controls for each HIV case, using the HIV diagnosis date as the index date for both cases and controls. Prior hospital diagnoses obtained from Danish medical databases were first categorized into 22 major disease categories (excluding AIDS-defining diseases except tuberculosis) and then subdivided into 161 subcategories, allowing us to examine specific diseases as potential HIV indicators by conditional logistic regression. RESULTS: The study included 2,036 HIV cases and 35,718 controls. Persons with the following disease categories had a high risk of HIV diagnosis during the subsequent 5-year period: sexually transmitted infections and viral hepatitis (adjusted odds ratio [aOR] = 12.3, 95% CI: 9.60-15.7), hematological diseases (aOR = 4.28, 3.13-5.85), lower respiratory tract infections (aOR = 3.98, 3.14-5.04)), CNS infections (aOR = 3.44, 1.74-6.80), skin infections (aOR = 3.05, 2.47-3.75), other infections (aOR = 4.64, 3.89-5.54), and substance abuse (aOR = 2.60, 2.06-3.29). Several specific diseases were associated with aORs >20 including syphilis, hepatitis A, non "A" viral hepatitis, herpes zoster, candida infection, endocarditis, thrombocytopenia, and opioid abuse. CONCLUSIONS: Targeted testing for HIV in patients diagnosed with diseases associated with HIV may lead to earlier treatment and thereby reduced morbidity, mortality and HIV transmission

Azimuthal anisotropy of charged particles at high transverse momenta in PbPb collisions at sqrt(s[NN]) = 2.76 TeV

The azimuthal anisotropy of charged particles in PbPb collisions at nucleon-nucleon center-of-mass energy of 2.76 TeV is measured with the CMS detector at the LHC over an extended transverse momentum (pt) range up to approximately 60 GeV. The data cover both the low-pt region associated with hydrodynamic flow phenomena and the high-pt region where the anisotropies may reflect the path-length dependence of parton energy loss in the created medium. The anisotropy parameter (v2) of the particles is extracted by correlating charged tracks with respect to the event-plane reconstructed by using the energy deposited in forward-angle calorimeters. For the six bins of collision centrality studied, spanning the range of 0-60% most-central events, the observed v2 values are found to first increase with pt, reaching a maximum around pt = 3 GeV, and then to gradually decrease to almost zero, with the decline persisting up to at least pt = 40 GeV over the full centrality range measured.Comment: Replaced with published version. Added journal reference and DO