Host-Pathogen Protein-Protein Interaction Prediction Using an in silico Model

Newcastle Disease (ND) is caused by Newcastle Disease Virus (NDV) and is a major problem in developing countries where vaccination against NDV is not easily achievable. A step required for NDV infection is the cleavage of the NDV fusion (F) protein. Using structural information of the NDV F protein and the only known host protein binding partner, protein disulfide isomerase A3 (PDIA3), we computer modeled the interaction between the two proteins by looking at a docked structure of these two proteins. With our docked structure, we visualized one of the catalytic domains of PDIA3 being near the cleavage site of the NDV F protein. We also discovered a novel binding pocket on the NDV F protein that interacts with the second catalytic domain of PDIA3. This new insight may provide additional molecular targets for NDV vaccine development

A conserved isoleucine maintains the inactive state of Bruton’s tyrosine kinase

Despite high homology among non-receptor tyrosine kinases, different kinase families employ a diverse array of regulatory mechanisms. For example, the catalytic kinase domains of the Tec family kinases are inactive without assembly of the adjacent regulatory domains, whereas the Src kinase domains are autoinhibited by the assembly of similar adjacent regulatory domains. Using molecular dynamic simulations, biochemical assays, and biophysical approaches, we have uncovered an isoleucine residue in the kinase domain of the Tec family member Btk that, when mutated to the closely related leucine, leads to a shift in the conformational equilibrium of the kinase domain toward the active state. The single amino acid mutation results in measureable catalytic activity for the Btk kinase domain in the absence of the regulatory domains. We suggest this isoleucine side chain in the Tec family kinases acts as a ‘wedge’ that restricts the conformational space available to key regions in the kinase domain, preventing activation until the kinase domain associates with its regulatory subunits and overcomes the energetic barrier to activation imposed by the isoleucine side chain

The Extent of Cooperativity of Protein Motions Observed with Elastic Network Models Is Similar for Atomic and Coarser-Grained Models

Coarse-grained elastic network models have been successful in determining functionally relevant collective motions. The level of coarse-graining, however, has usually focused on the level of one point per residue. In this work, we compare the applicability of elastic network models over a broader range of representational scales. We apply normal mode analysis for multiple scales on a highresolution protein data set using various cutoff radii to define the residues considered to be interacting, or the extent of cooperativity of their motions. These scales include the residue-, atomic-, proton-, and explicit solvent-levels. Interestingly, atomic, proton, and explicit solvent level calculations all provide similar results at the same cutoff value, with the computed mean-square fluctuations showing only a slightly higher correlation (0.61) with the experimental temperature factors from crystallography than the results of the residue-level coarse-graining. The qualitative behavior of each level of coarse graining is similar at different cutoff values. The correlations between these fluctuations and the number of internal contacts improve with increased cutoff values. Our results demonstrate that atomic level elastic network models provide an improved representation for the collective motions of proteins compared to the coarse-grained models

The Potential Trajectory of Carbapenem-Resistant Enterobacteriaceae, an Emerging Threat to Health-Care Facilities, and the Impact of the Centers for Disease Control and Prevention Toolkit.

Carbapenem-resistant Enterobacteriaceae (CRE), a group of pathogens resistant to most antibiotics and associated with high mortality, are a rising emerging public health threat. Current approaches to infection control and prevention have not been adequate to prevent spread. An important but unproven approach is to have hospitals in a region coordinate surveillance and infection control measures. Using our Regional Healthcare Ecosystem Analyst (RHEA) simulation model and detailed Orange County, California, patient-level data on adult inpatient hospital and nursing home admissions (2011-2012), we simulated the spread of CRE throughout Orange County health-care facilities under 3 scenarios: no specific control measures, facility-level infection control efforts (uncoordinated control measures), and a coordinated regional effort. Aggressive uncoordinated and coordinated approaches were highly similar, averting 2,976 and 2,789 CRE transmission events, respectively (72.2% and 77.0% of transmission events), by year 5. With moderate control measures, coordinated regional control resulted in 21.3% more averted cases (n = 408) than did uncoordinated control at year 5. Our model suggests that without increased infection control approaches, CRE would become endemic in nearly all Orange County health-care facilities within 10 years. While implementing the interventions in the Centers for Disease Control and Prevention's CRE toolkit would not completely stop the spread of CRE, it would cut its spread substantially, by half

SARS Clinical Features, United States, 2003

We compared the clinical features of 8 U.S. case-patients with laboratory-confirmed severe acute respiratory syndrome (SARS) to 65 controls who tested negative for SARS coronavirus (SARS-CoV) infection. Shortness of breath, vomiting, diarrhea, progressive bilateral infiltrates on chest radiograph, and need for supplemental oxygen were significantly associated with confirmed SARS-CoV infection

Firearms on College Campuses: Research Evidence nad Policy Implications

This report reviews the evidence surrounding the relationship between civilian gun carrying and violent crime and mass shootings and factors that are unique to public safety on college campuses. Policies removing restrictions on civilian gun carrying are based on claims or assumptions about civilian gun use, the impact of state Right-to-Carry (RTC) laws, and the nature of mass shootings that are not supported by or are contrary to the best available research. The incidence of civilian self-defensive gun use (SDGU) is difficult to discern as available data are based on self-report, and distinguishing aggressor from victim in interpersonal altercations can be highly subjective. Nonetheless, data from the National Crime Victimization Survey indicate that SDGU is relatively rare (about 102,000 self-reported incidents per year affecting 0.9% of all violent crime victimizations) and is no more effective in reducing victims' risk of injury than other victim responses to attempted violent crimes. Research led by John Lott, author of More Guns, Less Crime, suggesting that RTC laws prevent violent crime has important flaws that biased his findings. The most recent and rigorous research on RTC laws that corrects for these flaws consistently finds that RTC laws are associated with more violent crime. These findings may seem counterintuitive because concealed-carry permit holders have, as a group, low rates of criminal offending and must pass a background check to ensure that they do not have any condition, such as a felony conviction, that prohibits firearm ownership. But, in states with low standards for legal gun ownership, legal gun owners account for the majority of persons incarcerated for committing violent crimes with firearms

Effect of daily chlorhexidine bathing on hospital-acquired infection

BACKGROUND Results of previous single-center, observational studies suggest that daily bathing of patients with chlorhexidine may prevent hospital-acquired bloodstream infections and the acquisition of multidrug-resistant organisms (MDROs). METHODS We conducted a multicenter, cluster-randomized, nonblinded crossover trial to evaluate the effect of daily bathing with chlorhexidine-impregnated washcloths on the acquisition of MDROs and the incidence of hospital-acquired bloodstream infections. Nine intensive care and bone marrow transplantation units in six hospitals were randomly assigned to bathe patients either with no-rinse 2% chlorhexidine– impregnated washcloths or with nonantimicrobial washcloths for a 6-month period, exchanged for the alternate product during the subsequent 6 months. The incidence rates of acquisition of MDROs and the rates of hospital-acquired bloodstream infections were compared between the two periods by means of Poisson regression analysis. RESULTS A total of 7727 patients were enrolled during the study. The overall rate of MDRO acquisition was 5.10 cases per 1000 patient-days with chlorhexidine bathing versus 6.60 cases per 1000 patient-days with nonantimicrobial washcloths (P=0.03), the equivalent of a 23% lower rate with chlorhexidine bathing. The overall rate of hospital-acquired bloodstream infections was 4.78 cases per 1000 patient-days with chlorhexidine bathing versus 6.60 cases per 1000 patient-days with nonantimicrobial washcloths (P=0.007), a 28% lower rate with chlorhexidine-impregnated washcloths. No serious skin reactions were noted during either study period. CONCLUSIONS Daily bathing with chlorhexidine-impregnated washcloths significantly reduced the risks of acquisition of MDROs and development of hospital-acquired bloodstream infections. (Funded by the Centers for Disease Control and Prevention and Sage Products; ClinicalTrials.gov number, NCT00502476.

Multicenter study of the impact of community-onset Clostridium difficile infection on surveillance for C. difficile infection

OBJECTIVE: To evaluate the influence of community-onset/healthcare facility-associated cases on Clostridium difficile infection (CDI) incidence and outbreak detection. DESIGN: Retrospective cohort. SETTING: Five acute-care healthcare facilities in the United States. METHODS: Positive stool C. difficile toxin assays from July 2000 through June 2006 and healthcare facility exposure information were collected. CDI cases were classified as hospital-onset (HO) if they were diagnosed > 48 hours after admission or community-onset/healthcare facility-associated if they were diagnosed ≤ 48 hours from admission and had recently been discharged from the healthcare facility. Four surveillance definitions were compared: HO cases only and HO plus community-onset/healthcare facility-associated cases diagnosed within 30 (HCFA-30), 60 (HCFA-60) and 90 (HCFA-90) days after discharge from the study hospital. Monthly CDI rates were compared. Control charts were used to identify potential CDI outbreaks. RESULTS: The HCFA-30 rate was significantly higher than the HO rate at two healthcare facilities (p<0.01). The HCFA-30 rate was not significantly different from the HCFA-60 or HCFA-90 rates at any healthcare facility. The correlations between each healthcare facility’s monthly rates of HO and HCFA-30 CDI were almost perfect (range, 0.94–0.99, p<0.001). Overall, 12 time points had a CDI rate >3 SD above the mean, including 11 by the HO definition and 9 by the HCFA-30 definition, with discordant results at 4 time points (κ = 0.794, p<0.001). CONCLUSIONS: Tracking community-onset/healthcare facility-associated cases in addition to HO cases captures significantly more CDI cases but surveillance of HO CDI alone is sufficient to detect an outbreak