An Alphavirus nsP1 Determinant Modulates Type I Interferon Induction

Alphaviruses are mosquito-transmitted viruses that can cause severe disease in both animals and humans. The host type I Interferon (IFN) response plays a critical role in limiting alphavirus infections. However, the specific interactions of type I IFN with that of the alphaviruses remain largely uncharacterized. Therefore, to gain insight into these early interactions, this study addresses the role of genetic virulence determinants in modulating the host type I IFN response. These analyses are based upon previous detailed mapping studies that identified a virulence determinant within the nsP1/nsP2 cleavage domain of the mouse adapted, neurovirulent Sindbis AR86 alphavirus that is critical for AR86 pathogenesis in vivo. We demonstrate that a Threonine to Isoleucine change at this position, leads to a mutant virus that robustly induces IFN independently of effects on viral replication or viral mediated shutoff of host macromolecular syntheses. Furthermore, we demonstrate that the modulation in type I IFN induction is not specific to the Sindbis AR86 virus, as a similar mutation within the Ross River Virus, also leads to robust type I IFN responses, suggesting that the nsP1/nsP2 determinant may be fundamentally important for all alphaviruses. Additional work has established that the nsP1/nsP2 determinant modulates type I IFN induction through the IPS-1 signaling pathway, primarily mediated by the RIG-I and PKR receptors. As RIG-I and PKR recognize specific RNA ligands, such as free 5' triphosphates on uncapped viral RNAs, we next determined whether the nsP1/nsP2 determinant would disrupt the viral capping apparatus. We found increased synthesis of uncapped viral 26S subgenomic RNAs made within infected cells containing the nsP1/nsP2 mutation. Furthermore, the uncapped 26S RNAs differentially activated RIG-I which was phosphatase dependent. Therefore, altogether, our data presents a novel mechanism in which a genetic determinant specifically enhances the viral capping apparatus in order to evade the host type I IFN receptors. And disruption of the capping apparatus leads to the synthesis of uncapped RNAs that are efficiently recognized by the RIG-I and PKR host sensors to induce IFN to aid in the clearance of the viral infection

Distribution and associated factors of optic disc diameter and cup-to-disc ratio in an elderly Chinese population

AbstractBackgroundGlaucoma is the second leading cause of blindness worldwide and East Asian people account for almost half of those affected. Vertical elongation of the optic cup is a characteristic feature of glaucoma. However, there is a significant overlap in the vertical cup-to-disc ratio (VCDR) between normal eyes and eyes affected by glaucoma. The purpose of this study was to determine the distribution of VCDR and vertical disc diameter (VDD) and their predictive factors in a population of elderly Chinese residents in Taiwan.MethodsFour hundred and sixty elderly Chinese residents aged 72 years and older in the Shihpai district, Taipei, Taiwan participated in this study. Slit lamp biomicroscopic measurement of the VCDR and VDD after pupil dilation with a 78 diopter lens was performed by one glaucoma specialist. Multiple linear regression analyses were used to fit the best model for independent variables.ResultsThe VCDR was recorded for 438 right eyes and 430 left eyes. After excluding participants with glaucoma, the mean ± SD VCDR was 0.44 ± 0.17 for both eyes, and the 97.5th percentile was 0.8. A greater VCDR was associated with a longer axial length [VCDR = −0.47 + 0.04(axial length)] under multiple regression analysis. The VDD was obtained for 420 right eyes and 406 left eyes. The mean ± SD VDD for all participants was 1.77 ± 0.22 mm for the right eye and 1.79 ± 0.22 mm for the left eye. A higher body mass index (BMI) and a longer axial length were significantly associated with a larger VDD under multiple regression analysis. [VDD = −0.05 + 0.07 (axial length) + 0.06 (obesity); if BMI <24, then obesity = 0; if BMI ≥24, then obesity = 1]. A larger VDD was associated with a larger VCDR (p < 0.001) and the VCDR could be predicted by the equation VCDR = −0.07 + 0.3VDD.ConclusionA greater VCDR was related to a longer axial length. A greater VDD was related to a higher BMI and a longer axial length

Adolescents negotiating romantic relationships in a culturally diverse, urban community

Sherpa Romeo blue journal. Open access article. Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0) appliesIn this study we examined the negotiation of romantic relationships by urban youth, as discussed in focus groups, in a multicultural community. We compared these urban-student findings for an emergent fit with previously reported findings from more homogeneous groups of rural students. The unifying category, wrestling with gender expectations, which was identified in the rural studies, also emerged in the present study. A new unifying category represented urban participants’ balancing cultural expectations in the contexts of their families and social groups. Three categories from the former rural studies emerged in the present urban study: making sacrifices, showing respect, and standing up for oneself; and a new category emerged: communicating. While the rural students identified media as critical contextual conditions for romantic relationships, the current urban teens identified digital and social media as crucial contextual conditions in dating relationships. Together, these findings suggest the importance of considering cultural and contextual aspects of youths’ dating processes for developing a grounded theory that reflects aspects of teens’ relational lives. Implications of this emergent theory are explored, and directions for future research are suggested.Ye

Safety and Immunogenicity of the Live Attenuated Varicella Vaccine Following T Replete or T Cell-Depleted Related and Unrelated Allogeneic Hematopoietic Cell Transplantation (alloHCT)

There are limited studies assessing the live attenuated varicella vaccine following allogeneic hematopoietic cell transplantation (alloHCT). Because of the morbidity of varicella acquired after childhood, we immunized and retrospectively analyzed the safety and immunogenicity of this vaccine in 46 varicella zoster virus (VZV) seronegative patients <20 years old at HCT who achieved a CD4 cell count ≥200/μL, were off immunosuppression, and responded to ≥1 post-HCT vaccines. Two vaccinated patients lacking follow-up titers were excluded from analysis. Stem cells were derived from an HLA-matched sibling (n = 18) or an alternative (HLA mismatched related or unrelated) donor (n = 26). Median time to vaccination was 4 years. Sixty-four percent of patients seroconverted following 1 immunization. There was no significant difference in response between recipients of a matched related or alternative donor graft (P = .2) or between those given a T cell-depleted or T-replete alternative donor graft (P = .27). Three of 44 patients developed a self-limited varicella-like rash within 2.5 weeks of immunization. With a median follow-up of 29.1 (range: 6.9-167.1) months, there were no subsequent cases of varicella-like rashes. No patient developed shingles. This study suggests that this vaccine is safe and immunogenic when given according to preset clinical and immunologic milestones, warranting larger prospective studies in patients ≥24 months following HCT as outlined in current post-HCT vaccine guidelines

Glycogen Storage Disease Type Ia in Canines: A Model for Human Metabolic and Genetic Liver Disease

A canine model of Glycogen storage disease type Ia (GSDIa) is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose-6-phosphatase-α. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including “lactic acidosis”, larger size, and longer lifespan compared to other animal models. Use of this model in preclinical trials of gene therapy is described and briefly compared to the murine model. Although the canine model offers a number of advantages for evaluating potential therapies for GSDIa, there are also some significant challenges involved in its use. Despite these challenges, the canine model of GSDIa should continue to provide valuable information about the potential for generating curative therapies for GSDIa as well as other genetic hepatic diseases

Elemental topological Dirac semimetal: {\alpha}-Sn on InSb(111)

Three-dimensional (3D) topological Dirac semimetals (TDSs) are rare but important as a versatile platform for exploring exotic electronic properties and topological phase transitions. A quintessential feature of TDSs is 3D Dirac fermions associated with bulk electronic states near the Fermi level. Using angle-resolved photoemission spectroscopy (ARPES), we have observed such bulk Dirac cones in epitaxially-grown {\alpha}-Sn films on InSb(111), the first such TDS system realized in an elemental form. First-principles calculations confirm that epitaxial strain is key to the formation of the TDS phase. A phase diagram is established that connects the 3D TDS phase through a singular point of a zero-gap semimetal phase to a topological insulator (TI) phase. The nature of the Dirac cone crosses over from 3D to 2D as the film thickness is reduced

Impacts of Social Distancing Policies on Mobility and COVID-19 Case Growth in the US

Social distancing remains an important strategy to combat the COVID-19 pandemic in the United States. However, the impacts of specific state-level policies on mobility and subsequent COVID-19 case trajectories have not been completely quantified. Using anonymized and aggregated mobility data from opted-in Google users, we found that state-level emergency declarations resulted in a 9.9% reduction in time spent away from places of residence. Implementation of one or more social distancing policies resulted in an additional 24.5% reduction in mobility the following week, and subsequent shelter-in-place mandates yielded an additional 29.0% reduction. Decreases in mobility were associated with substantial reductions in case growth 2 to 4 weeks later. For example, a 10% reduction in mobility was associated with a 17.5% reduction in case growth 2 weeks later. Given the continued reliance on social distancing policies to limit the spread of COVID-19, these results may be helpful to public health officials trying to balance infection control with the economic and social consequences of these policies.Comment: Co-first Authors: GAW, SV, VE, and AF contributed equally. Corresponding Author: Dr. Evgeniy Gabrilovich, [email protected] 32 pages (including supplemental material), 4 figures in the main text, additional figures in the supplemental materia

The impact of provider-initiated (opt-out) HIV testing and counseling of patients with sexually transmitted infection in Cape Town, South Africa: a controlled trial

<p>Abstract</p> <p>Background</p> <p>The effectiveness of provider-initiated HIV testing and counseling (PITC) for patients with sexually transmitted infection (STI) in resource-constrained settings are of particular concern for high HIV prevalence countries like South Africa. This study evaluated whether the PITC approach increased HIV testing amongst patients with a new episode of sexually transmitted infection, as compared to standard voluntary counseling and testing (VCT) at the primary care level in South Africa, a high prevalence and low resource setting.</p> <p>Methods</p> <p>The design was a pragmatic cluster-controlled trial with seven intervention and 14 control clinics in Cape Town. Nurses in intervention clinics integrated PITC into standard HIV care with few additional resources, whilst lay counselors continued with the VCT approach in control clinics. Routine data were collected for a six-month period following the intervention in 2007, on new STI patients who were offered and who accepted HIV testing. The main outcome measure was the proportion of new STI patients tested for HIV, with secondary outcomes being the proportions who were offered and who declined the HIV test.</p> <p>Results</p> <p>A significantly higher proportion of new STI patients in the intervention group tested for HIV as compared to the control group with (56.4% intervention versus 42.6% control, p = 0.037). This increase was achieved despite a significantly higher proportion intervention group declining testing when offered (26.7% intervention versus 13.5% control, p = 0.0086). Patients were more likely to be offered HIV testing in intervention clinics, where providers offered the HIV test to 76.8% of new STI patients versus 50.9% in the control group (p = 0.0029). There was significantly less variation in the main outcomes across the intervention clinics, suggesting that the intervention also facilitated more consistent performance.</p> <p>Conclusions</p> <p>PITC was successful in three ways: it increased the proportion of new STI patients tested for HIV; it increased the proportion of new STI patients offered HIV testing; and it delivered more consistent performance across clinics. Recommendations are made for increasing the impact and feasibility of PITC in high HIV prevalence and resource-constrained settings. These include more flexible use of clinical and lay staff, and combining PITC with VCT and other community-based approaches to HIV testing.</p> <p>Trial registration</p> <p>Controlled trial ISRCTN93692532</p