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[This corrects the article DOI: 10.1371/journal.ppat.1006219.].

Zika virus (ZIKV), an emerging flavivirus, has recently spread explosively through the Western hemisphere. In addition to symptoms including fever, rash, arthralgia, and conjunctivitis, ZIKV infection of pregnant women can cause microcephaly and other developmental abnormalities in the fetus. We report herein the results of ZIKV infection of adult rhesus macaques. Following subcutaneous infection, animals developed transient plasma viremia and viruria from 1-7 days post infection (dpi) that was accompanied by the development of a rash, fever and conjunctivitis. Animals produced a robust adaptive immune response to ZIKV, although systemic cytokine response was minimal. At 7 dpi, virus was detected in peripheral nervous tissue, multiple lymphoid tissues, joints, and the uterus of the necropsied animals. Notably, viral RNA persisted in neuronal, lymphoid and joint/muscle tissues and the male and female reproductive tissues through 28 to 35 dpi. The tropism and persistence of ZIKV in the peripheral nerves and reproductive tract may provide a mechanism of subsequent neuropathogenesis and sexual transmission.

Discussions and practices focused on Black boys' literacy development and equity in U.S. classrooms require serious thought and interrogation if the aim is to move these boys toward advanced levels of reading, writing, intellectual development, and human development. Sorely, Black boys have become subjects of educational, programming, and policy experimentation endorsed by school boards that lead to instructional and curricular shortcomings in elementary classrooms. In this article, I call for a need to bring order to the literacy development of Black boys in the elementary grades by focusing on advanced literacy outcomes and the intellectual tradition. Order is needed to counter the random nature of literacy development that results in chaos and disorder as evidenced by reading outcomes and many Black boys, both high-academically performing and low-academically performing, being underserved in U.S. classrooms.

Cytomegaloviruses (CMV) are highly species-specific due to millennia of co-evolution and adaptation to their host, with no successful experimental cross-species infection in primates reported to date. Accordingly, full genome phylogenetic analysis of multiple new CMV field isolates derived from two closely related nonhuman primate species, Indian-origin rhesus macaques (RM) and Mauritian-origin cynomolgus macaques (MCM), revealed distinct and tight lineage clustering according to the species of origin, with MCM CMV isolates mirroring the limited genetic diversity of their primate host that underwent a population bottleneck 400 years ago. Despite the ability of Rhesus CMV (RhCMV) laboratory strain 68-1 to replicate efficiently in MCM fibroblasts and potently inhibit antigen presentation to MCM T cells in vitro, RhCMV 68-1 failed to productively infect MCM in vivo, even in the absence of host CD8+ T and NK cells. In contrast, RhCMV clone 68-1.2, genetically repaired to express the homologues of the HCMV anti-apoptosis gene UL36 and epithelial cell tropism genes UL128 and UL130 absent in 68-1, efficiently infected MCM as evidenced by the induction of transgene-specific T cells and virus shedding. Recombinant variants of RhCMV 68-1 and 68-1.2 revealed that expression of either UL36 or UL128 together with UL130 enabled productive MCM infection, indicating that multiple layers of cross-species restriction operate even between closely related hosts. Cumulatively, these results implicate cell tropism and evasion of apoptosis as critical determinants of CMV transmission across primate species barriers, and extend the macaque model of human CMV infection and immunology to MCM, a nonhuman primate species with uniquely simplified host immunogenetics.

The natural killer cell receptor NKG2D activates NK cells by engaging one of several ligands (NKG2DLs) belonging to either the MIC or ULBP families. Human cytomegalovirus (HCMV) UL16 and UL142 counteract this activation by retaining NKG2DLs and US18 and US20 act via lysomal degradation but the importance of NK cell evasion for infection is unknown. Since NKG2DLs are highly conserved in rhesus macaques, we characterized how NKG2DL interception by rhesus cytomegalovirus (RhCMV) impacts infection in vivo. Interestingly, RhCMV lacks homologs of UL16 and UL142 but instead employs Rh159, the homolog of UL148, to prevent NKG2DL surface expression. Rh159 resides in the endoplasmic reticulum and retains several NKG2DLs whereas UL148 does not interfere with NKG2DL expression. Deletion of Rh159 releases human and rhesus MIC proteins, but not ULBPs, from retention while increasing NK cell stimulation by infected cells. Importantly, RhCMV lacking Rh159 cannot infect CMV-naïve animals unless CD8+ cells, including NK cells, are depleted. However, infection can be rescued by replacing Rh159 with HCMV UL16 suggesting that Rh159 and UL16 perform similar functions in vivo. We therefore conclude that cytomegaloviral interference with NK cell activation is essential to establish but not to maintain chronic infection.

Background and study aims: Techniques to optimize endoscopic ultrasound-guided tissue acquisition (EUS-TA) in a variety of lesion types have not yet been established. The primary aim of this study was to compare the diagnostic yield (DY) of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) to endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) for pancreatic and non-pancreatic masses. Patients and methods: Consecutive patients referred for EUS-TA underwent randomization to EUS-FNA or EUS-FNB at four tertiary-care medical centers. A maximum of three passes were allowed for the initial method of EUS-TA and patients were crossed over to the other arm based on on-site specimen adequacy. Results: A total of 140 patients were enrolled. The overall DY was significantly higher with specimens obtained by EUS-FNB compared to EUS-FNA (90.0 % vs. 67.1 %, P = 0.002). While there was no difference in the DY between the two groups for pancreatic masses (FNB: 91.7 % vs. FNA: 78.4 %, P = 0.19), the DY of EUS-FNB was higher than the EUS-FNA for non-pancreatic lesions (88.2 % vs. 54.5 %, P = 0.006). Specimen adequacy was higher for EUS-FNB compared to EUS-FNA for all lesions (P = 0.006). There was a significant rescue effect of crossover from failed FNA to FNB in 27 out of 28 cases (96.5 %, P = 0.0003). Decision analysis showed that the strategy of EUS-FNB was cost saving compared to EUS-FNA over a wide range of cost and outcome probabilities. Conclusions: Results of this RCT and decision analysis demonstrate superior DY and specimen adequacy for solid mass lesions sampled by EUS-FNB.

BACKGROUND:In recent years large bibliographic databases have made much of the published literature of biology available for searches. However, the capabilities of the search engines integrated into these databases for text-based bibliographic searches are limited. To enable searches that deliver the results expected by comparative anatomists, an underlying logical structure known as an ontology is required. DEVELOPMENT AND TESTING OF THE ONTOLOGY:Here we present the Mammalian Feeding Muscle Ontology (MFMO), a multi-species ontology focused on anatomical structures that participate in feeding and other oral/pharyngeal behaviors. A unique feature of the MFMO is that a simple, computable, definition of each muscle, which includes its attachments and innervation, is true across mammals. This construction mirrors the logical foundation of comparative anatomy and permits searches using language familiar to biologists. Further, it provides a template for muscles that will be useful in extending any anatomy ontology. The MFMO is developed to support the Feeding Experiments End-User Database Project (FEED, https://feedexp.org/), a publicly-available, online repository for physiological data collected from in vivo studies of feeding (e.g., mastication, biting, swallowing) in mammals. Currently the MFMO is integrated into FEED and also into two literature-specific implementations of Textpresso, a text-mining system that facilitates powerful searches of a corpus of scientific publications. We evaluate the MFMO by asking questions that test the ability of the ontology to return appropriate answers (competency questions). We compare the results of queries of the MFMO to results from similar searches in PubMed and Google Scholar. RESULTS AND SIGNIFICANCE:Our tests demonstrate that the MFMO is competent to answer queries formed in the common language of comparative anatomy, but PubMed and Google Scholar are not. Overall, our results show that by incorporating anatomical ontologies into searches, an expanded and anatomically comprehensive set of results can be obtained. The broader scientific and publishing communities should consider taking up the challenge of semantically enabled search capabilities.

Cancer has surpassed heart disease as the leading cause of death among Hispanics in the U.S., yet data on cancer prevalence and risk factors in Hispanics in regard to ancestry remain scarce. This study sought to describe (a) the prevalence of cancer among Hispanics from four major U.S. metropolitan areas, (b) cancer prevalence across Hispanic ancestry, and (c) identify correlates of self-reported cancer prevalence. Participants were 16,415 individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), who self-identified as Cuban, Dominican, Mexican, Puerto Rican, Central or South American. All data were collected at a single time point during the HCHS/SOL baseline clinic visit. The overall self-reported prevalence rate of cancer for the population was 4%. The rates varied by Hispanic ancestry group, with individuals of Cuban and Puerto Rican ancestry reporting the highest cancer prevalence. For the entire population, older age (OR = 1.47, p < .001, 95% CI, 1.26-1.71) and having health insurance (OR = 1.93, p < .001, 95% CI, 1.42-2.62) were all significantly associated with greater prevalence, whereas male sex was associated with lower prevalence (OR = 0.56, p < .01, 95% CI, .40-.79). Associations between study covariates and cancer prevalence also varied by Hispanic ancestry. Findings underscore the importance of sociodemographic factors and health insurance in relation to cancer prevalence for Hispanics and highlight variations in cancer prevalence across Hispanic ancestry groups. Characterizing differences in cancer prevalence rates and their correlates is critical to the development and implementation of effective prevention strategies across distinct Hispanic ancestry groups.

PURPOSE:To create a standardized method for evaluating the video recordings of patients self-instilling eye drops and to determine the level of agreement of eye drop instillation efficacy, safety and efficiency ratings by three masked graders. DESIGN:Prospective cross-sectional study. PARTICIPANTS:78 patients with open-angle glaucoma or ocular hypertension who had at least 6 months of experience with the use of eye drop medications. METHODS:Participants were video recorded while self-instilling artificial tears sequentially to both eyes. Three masked observers graded these video recordings on three criteria: efficacy (the determination of whether an eye drop was instilled on the ocular surface), safety (assessment of whether the tip of the medication bottle made contact with the ocular surface or eyelids), and efficiency (the number of eye drops expressed from the bottle). MAIN OUTCOME MEASURES:After grading the video recordings based on efficacy, safety, and efficiency, kappa statistics were used to estimate inter-rater agreement. RESULTS:The mean kappa level of agreement for efficacy, safety, and efficiency was 0.64 (95% confidence interval (CI), 0.42-0.87), 0.73 (95% CI, 0.58-0.88), and 0.62 (95% CI, 0.42-0.81), respectively. CONCLUSIONS:We demonstrated good inter-rater reproducibility of the masked analysis of video recordings of patients self-instilling eye drops based on three criteria: efficiency, safety, and efficacy.

Little is known about the tolerance mechanisms that reduce the negative effects of microbial infection on host fitness. Here, we demonstrate that the histone H3 lysine 9 methyltransferase G9a regulates tolerance to virus infection by shaping the response of the evolutionary conserved Jak-Stat pathway in Drosophila. G9a-deficient mutants are more sensitive to RNA virus infection and succumb faster to infection than wild-type controls, which was associated with strongly increased Jak-Stat dependent responses, but not with major differences in viral load. Genetic experiments indicate that hyperactivated Jak-Stat responses are associated with early lethality in virus-infected flies. Our results identify an essential epigenetic mechanism underlying tolerance to virus infection.

To gain insight into female-to-male HIV sexual transmission and how male circumcision protects against this mode of transmission, we visualized HIV-1 interactions with foreskin and penile tissues in ex vivo tissue culture and in vivo rhesus macaque models utilizing epifluorescent microscopy. 12 foreskin and 14 cadaveric penile specimens were cultured with R5-tropic photoactivatable (PA)-GFP HIV-1 for 4 or 24 hours. Tissue cryosections were immunofluorescently imaged for epithelial and immune cell markers. Images were analyzed for total virions, proportion of penetrators, depth of virion penetration, as well as immune cell counts and depths in the tissue. We visualized individual PA virions breaching penile epithelial surfaces in the explant and macaque model. Using kernel density estimated probabilities of localizing a virion or immune cell at certain tissue depths revealed that interactions between virions and cells were more likely to occur in the inner foreskin or glans penis (from local or cadaveric donors, respectively). Using statistical models to account for repeated measures and zero-inflated datasets, we found no difference in total virions visualized at 4 hours between inner and outer foreskins from local donors. At 24 hours, there were more virions in inner as compared to outer foreskin (0.0495 +/- 0.0154 and 0.0171 +/- 0.0038 virions/image, p = 0.001). In the cadaveric specimens, we observed more virions in inner foreskin (0.0507 +/- 0.0079 virions/image) than glans tissue (0.0167 +/- 0.0033 virions/image, p

O Transtorno de Estresse Pós-Traumático (TEPT) é um transtorno prevalente, associado a alterações neurobiológicas e cognitivas. O presente artigo é um estudo teórico sobre as aplicações da avaliação neuropsicológica no TEPT. Inicialmente são revisados aspectos conceituais do transtorno, bem como alterações neurobiológicas relacionadas aos prejuízos cognitivos comumente detectados. Finalmente, argumenta-se que a avaliação dos prejuízos nas funções de memória, atenção e, sobretudo, funções executivas são relevantes tanto para a intervenção clínica junto ao paciente quanto para o refinamento das teorias psicológicas do TEPT.Post Traumatic Stress Disorder (PTSD) is a prevalent disorder which is associated with neurobiological and cognitive impairments. This paper is a theoretical review of the uses of neuropsychological assessment in PTSD. Conceptual aspects of this disorder are reviewed, as well as the neurobiological alterations related to cognitive impairments. Finally, it is argued that the assessment of memory, attention, and executive function impairments is as relevant to the clinical intervention as it is to the refinement of the psychological theories of PTSD.

Aromatase inhibitors (AIs) are the most effective class of drugs in the endocrine treatment of breast cancer, with an approximate 50% treatment response rate. Our objective was to determine whether intratumoral expression levels of estrogen-related genes are predictive of AI responsiveness in postmenopausal women with breast cancer. Primary breast carcinomas were obtained from 112 women who received AI therapy after failing adjuvant tamoxifen therapy and developing recurrent breast cancer. Tumor ERα and PR protein expression were analyzed by immunohistochemistry (IHC). Messenger RNA (mRNA) levels of 5 estrogen-related genes-AKR1C3, aromatase, ERα, and 2 estradiol/ERα target genes, BRCA1 and PR-were measured by real-time PCR. Tumor protein and mRNA levels were compared with breast cancer progression rates to determine predictive accuracy. Responsiveness to AI therapy-defined as the combined complete response, partial response, and stable disease rates for at least 6 months-was 51%; rates were 56% in ERα-IHC-positive and 14% in ERα-IHC-negative tumors. Levels of ERα, PR, or BRCA1 mRNA were independently predictive for responsiveness to AI. In cross-validated analyses, a combined measurement of tumor ERα and PR mRNA levels yielded a more superior specificity (36%) and identical sensitivity (96%) to the current clinical practice (ERα/PR-IHC). In patients with ERα/PR-IHC-negative tumors, analysis of mRNA expression revealed either non-significant trends or statistically significant positive predictive values for AI responsiveness. In conclusion, expression levels of estrogen-related mRNAs are predictive for AI responsiveness in postmenopausal women with breast cancer, and mRNA expression analysis may improve patient selection.

RNA interference (RNAi) is a major antiviral pathway that shapes evolution of RNA viruses. We show here that Nora virus, a natural Drosophila pathogen, is both a target and suppressor of RNAi. We detected viral small RNAs with a signature of Dicer-2 dependent small interfering RNAs in Nora virus infected Drosophila. Furthermore, we demonstrate that the Nora virus VP1 protein contains RNAi suppressive activity in vitro and in vivo that enhances pathogenicity of recombinant Sindbis virus in an RNAi dependent manner. Nora virus VP1 and the viral suppressor of RNAi of Cricket paralysis virus (1A) antagonized Argonaute-2 (AGO2) Slicer activity of RNA induced silencing complexes pre-loaded with a methylated single-stranded guide strand. The convergent evolution of AGO2 suppression in two unrelated insect RNA viruses highlights the importance of AGO2 in antiviral defense.

The siRNA pathway is an essential antiviral mechanism in insects. Whether other RNA interference pathways are involved in antiviral defense remains unclear. Here, we report in cells derived from the two main vectors for arboviruses, Aedes albopictus and Aedes aegypti, the production of viral small RNAs that exhibit the hallmarks of ping-pong derived piwi-associated RNAs (piRNAs) after infection with positive or negative sense RNA viruses. Furthermore, these cells produce endogenous piRNAs that mapped to transposable elements. Our results show that these mosquito cells can initiate de novo piRNA production and recapitulate the ping-pong dependent piRNA pathway upon viral infection. The mechanism of viral-piRNA production is discussed.