Herpes Simplex Virus 1 (HSV-1) Infected Cell Protein 0 (ICP0) Targets of Ubiquitination during Productive Infection of Primary Adult Sensory Neurons

Herpes simplex virus 1 (HSV-1) enters sensory neurons with the potential for productive or latent infection. For either outcome, HSV-1 must curtail the intrinsic immune response, regulate viral gene expression, and remove host proteins that could restrict viral processes. Infected cell protein 0 (ICP0), a virus-encoded E3 ubiquitin ligase, supports these processes by mediating the transfer of ubiquitin to target proteins to change their location, alter their function, or induce their degradation. To identify ubiquitination targets of ICP0 during productive infection in sensory neurons, we immunoprecipitated ubiquitinated proteins from primary adult sensory neurons infected with HSV-1 KOS (wild-type), HSV-1 n212 (expressing truncated, defective ICP0), and uninfected controls using anti-ubiquitin antibody FK2 (recognizing K29, K48, K63 and monoubiquitinated proteins), followed by LC-MS/MS and comparative analyses. We identified 40 unique proteins ubiquitinated by ICP0 and 17 ubiquitinated by both ICP0 and host mechanisms, of which High Mobility Group Protein I/Y (HMG I/Y) and TAR DNA Binding Protein 43 (TDP43) were selected for further analysis. We show that ICP0 ubiquitinates HMG I/Y and TDP43, altering protein expression at specific time points during productive HSV-1 infection, demonstrating that ICP0 manipulates the sensory neuronal environment in a time-dependent manner to regulate infection outcome in neurons

Incorporating Reflective Writing into the Clerkship

During the last decade, medical schools have turned to writing exercises as a means for encouraging students to reflect on their learning experiences during clinical clerkships. The reasons for the increased popularity of reflective writing are broad. Approaches to encouraging reflective writing are quite varied. Recently, three internal medicine clerkships (University of Chicago Pritzker School of Medicine, University of Florida College of Medicine, and University of Massachusetts Medical School) independently implemented reflective writing activities in the clerkship curriculum

Questions to Ask Before You Join a Club

Despite the recent flurry of large transactions in which a consortium of private equity firms have teamed up to make joint bids and acquisitions, “club deals” themselves are not breaking news. In fact, they have been a staple of small- and middle-sized private equity M&A transactions for years. Recently, however, there has been a growing trend toward large club deals with enterprise values over $1 billion.1 Due to their size, complexity and, often, international dimension, these transactions have generated considerable attention in the business press and have prompted much discussion among private equity professionals and the limited partners whose money they manage

Questions to Ask Before You Join a Club

Despite the recent flurry of large transactions in which a consortium of private equity firms have teamed up to make joint bids and acquisitions, “club deals” themselves are not breaking news. In fact, they have been a staple of small- and middle-sized private equity M&A transactions for years. Recently, however, there has been a growing trend toward large club deals with enterprise values over $1 billion.1 Due to their size, complexity and, often, international dimension, these transactions have generated considerable attention in the business press and have prompted much discussion among private equity professionals and the limited partners whose money they manage

Ellipsometric study of Si(0.5)Ge(0.5)/Si strained-layer superlattices

An ellipsometric study of two Si(0.5)Ge(0.5)/Si strained-layer super lattices grown by MBE at low temperature (500 C) is presented, and results are compared with x ray diffraction (XRD) estimates. Excellent agreement is obtained between target values, XRD, and ellipsometry when one of two available Si(x)Ge(1-x) databases is used. It is shown that ellipsometry can be used to nondestructively determine the number of superlattice periods, layer thicknesses, Si(x)Ge(1-x) composition, and oxide thickness without resorting to additional sources of information. It was also noted that we do not observe any strain effect on the E(sub 1) critical point

Neurotrophic Factors NGF, GDNF and NTN Selectively Modulate HSV1 and HSV2 Lytic Infection and Reactivation in Primary Adult Sensory and Autonomic Neurons

Herpes simplex viruses (HSV1 and HSV2) establish latency in peripheral ganglia after ocular or genital infection, and can reactivate to produce different patterns and frequencies of recurrent disease. Previous studies showed that nerve growth factor (NGF) maintains HSV1 latency in embryonic sympathetic and sensory neurons. However, adult sensory neurons are no longer dependent on NGF for survival, some populations cease expression of NGF receptors postnatally, and the viruses preferentially establish latency in different populations of sensory neurons responsive to other neurotrophic factors (NTFs). Thus, NGF may not maintain latency in adult sensory neurons. To identify NTFs important for maintaining HSV1 and HSV2 latency in adult neurons, we investigated acute and latently-infected primary adult sensory trigeminal (TG) and sympathetic superior cervical ganglia (SCG) after NTF removal. NGF and glial cell line-derived neurotrophic factor (GDNF) deprivation induced HSV1 reactivation in adult sympathetic neurons. In adult sensory neurons, however, neurturin (NTN) and GDNF deprivation induced HSV1 and HSV2 reactivation, respectively, while NGF deprivation had no effects. Furthermore, HSV1 and HSV2 preferentially reactivated from neurons expressing GFRα2 and GFRα1, the high affinity receptors for NTN and GDNF, respectively. Thus, NTN and GDNF play a critical role in selective maintenance of HSV1 and HSV2 latency in primary adult sensory neurons

Resonances Width in Crossed Electric and Magnetic Fields

We study the spectral properties of a charged particle confined to a two-dimensional plane and submitted to homogeneous magnetic and electric fields and an impurity potential. We use the method of complex translations to prove that the life-times of resonances induced by the presence of electric field are at least Gaussian long as the electric field tends to zero.Comment: 3 figure

A public health vs a risk-based intervention to improve cardiovascular health in elementary school children : The cardiovascular health in children study

Objectives. This study sought to determine the population effects of both classroom-based and risk-based interventions designed to reduce cardiovascular disease risk factors in children. Methods. Elemenary school children (n = 2109; age range 7-12 years) were randomized by school to a classroom-based intervention for all third and fourth graders, a risk-based intervention only for those with 1 or more cardiovascular disease risk factors, or a control group. The 8-week interventions involved both knowledge-attitude and physical activity components. Results. School-level analyses showed that physical activity in the risk-based group and posttest knowledge in the classroom-based groups were significantly higher than in the control group. With regard to trends shown by individual-level analyses, cholesterol dropped more in the classroom-based than in the control group, and skinfold thickness decreased 2,9% in the classroom-based group and 3.2% in the risk-based group (as compared with a 1.1% increase in the control group). Conclusions. Both classroom-based and risk-based interventions had positive effects on physical activity and knowledge, with trends toward reduced body fat and cholesterol. However, the classroom-based approach was easier to implement and evidenced stronger results than the risk-based intervention

Comparison of techniques for handling missing covariate data within prognostic modelling studies: a simulation study

Background: There is no consensus on the most appropriate approach to handle missing covariate data within prognostic modelling studies. Therefore a simulation study was performed to assess the effects of different missing data techniques on the performance of a prognostic model. Methods: Datasets were generated to resemble the skewed distributions seen in a motivating breast cancer example. Multivariate missing data were imposed on four covariates using four different mechanisms; missing completely at random (MCAR), missing at random (MAR), missing not at random (MNAR) and a combination of all three mechanisms. Five amounts of incomplete cases from 5% to 75% were considered. Complete case analysis (CC), single imputation (SI) and five multiple imputation (MI) techniques available within the R statistical software were investigated: a) data augmentation (DA) approach assuming a multivariate normal distribution, b) DA assuming a general location model, c) regression switching imputation, d) regression switching with predictive mean matching (MICE-PMM) and e) flexible additive imputation models. A Cox proportional hazards model was fitted and appropriate estimates for the regression coefficients and model performance measures were obtained. Results: Performing a CC analysis produced unbiased regression estimates, but inflated standard errors, which affected the significance of the covariates in the model with 25% or more missingness. Using SI, underestimated the variability; resulting in poor coverage even with 10% missingness. Of the MI approaches, applying MICE-PMM produced, in general, the least biased estimates and better coverage for the incomplete covariates and better model performance for all mechanisms. However, this MI approach still produced biased regression coefficient estimates for the incomplete skewed continuous covariates when 50% or more cases had missing data imposed with a MCAR, MAR or combined mechanism. When the missingness depended on the incomplete covariates, i.e. MNAR, estimates were biased with more than 10% incomplete cases for all MI approaches. Conclusion: The results from this simulation study suggest that performing MICE-PMM may be the preferred MI approach provided that less than 50% of the cases have missing data and the missing data are not MNAR