Ten Years of Screening and Testing for Acute HIV Infection in North Carolina

Objective: To describe demographic and behavioral characteristics of persons with acute HIV infection (AHI) over time. Methods: We conducted a retrospective assessment of AHI identified through the Screening and Tracing Active Transmission (STAT) program from 2003 to 2012 in North Carolina (NC). AHI was identified using pooled nucleic acid amplification for antibody negative samples and individual HIV-1 RNA for antibody indeterminate samples. The STAT program provides rapid notification and evaluation. We compared STAT-collected demographic and risk characteristics with all persons requesting tests and all non-AHI diagnoses from the NC State Laboratory of Public Health. Results: The STAT Program identified 236 AHI cases representing 3.4% (95% confidence interval: 3.0% to 3.9%) of all HIV diagnoses. AHI cases were similar to those diagnosed during established HIV. On pretest risk-assessments, AHI cases were predominately black (69.1%), male (80.1%), young (46.8% < 25 years), and men who have sex with men (MSM) (51.7%). Per postdiagnosis interviews, the median age decreased from 35 (interquartile range 25-42) to 27 (interquartile range 22-37) years, and the proportion <25 years increased from 23.8% to 45.2% (trend P 0.04) between 2003 and 2012. AHI men were more likely to report MSM risk post-diagnosis than on pretest risk-assessments (64%-82.9%; P < 0.0001). Post-diagnosis report of MSM risk in men with AHI increased from 71.4% to 96.2%. Conclusions: In NC, 3.4% of individuals diagnosed with HIV infection have AHI. AHI screening provides a real-time source of incidence trends, improves the diagnostic yield of HIV testing, and offers an opportunity to limit onward transmission

Immunogenicity of AGS-004 Dendritic Cell Therapy in Patients Treated during Acute HIV Infection

AGS-004 consists of matured autologous dendritic cells co-electroporated with in vitro transcribed RNA encoding autologous HIV antigens. In an open-label, single arm sub-study of AGS-004-003, AGS-004 was administered monthly to suppressed participants who started antiretroviral therapy (ART) during acute HIV infection. HIV-1 specific T cell responses were measured by multicolor flow cytometry after 3-4 doses. The frequency of resting CD4+ T-cell infection (RCI) was measured by quantitative viral outgrowth assay. Participants demonstrating increased immune response postvaccination were eligible for analytic treatment interruption (ATI). AGS-004 induced a positive immune response defined as ≥2-fold increase from baseline in the number of multifunctional HIV-1 specific CD28+/CD45RA- CD8+ effector/memory cytoxic T-lymphocytes (CTLs) in all six participants. All participants underwent ATI with rebound viremia at a median of 29 days. Immune correlates between time to viral rebound and the induction of effector CTLs were determined. Baseline RCI was low in most participants (0.043-0.767 IUPM). One participant had a &gt;2-fold decrease (0.179-0.067 infectious units per million [IUPM]) in RCI at week 10. One participant with the lowest RCI had the longest ATI. AGS-004 dendritic cell administration increased multifunctional HIV-specific CD28+/CD45RA- CD8+ memory T cell responses in all participants, but did not permit sustained ART interruption. However, greater expansion of CD28-/CCR7-/CD45RA- CD8+ effector T cell responses correlated with a longer time to viral rebound. AGS-004 may be a useful tool to augment immune responses in the setting of latency reversal and eradication strategies

The PHENIX Experiment at RHIC

The physics emphases of the PHENIX collaboration and the design and current status of the PHENIX detector are discussed. The plan of the collaboration for making the most effective use of the available luminosity in the first years of RHIC operation is also presented.Comment: 5 pages, 1 figure. Further details of the PHENIX physics program available at http://www.rhic.bnl.gov/phenix

Phylogeny of snakes (Serpentes): combining morphological and molecular data in likelihood Bayesian and parsimony analyses

Copyright © 2007 The Natural history MuseumThe phylogeny of living and fossil snakes is assessed using likelihood and parsimony approaches and a dataset combining 263 morphological characters with mitochondrial (2693 bp) and nuclear (1092 bp) gene sequences. The ‘no common mechanism’ (NCMr) and ‘Markovian’ (Mkv) models were employed for the morphological partition in likelihood analyses; likelihood scores in the NCMr model were more closely correlated with parsimony tree lengths. Both models accorded relatively less weight to the molecular data than did parsimony, with the effect being milder in the NCMr model. Partitioned branch and likelihood support values indicate that the mtDNA and nuclear gene partitions agree more closely with each other than with morphology. Despite differences between data partitions in phylogenetic signal, analytic models, and relative weighting, the parsimony and likelihood analyses all retrieved the following widely accepted groups: scolecophidians, alethinophidians, cylindrophiines, macrostomatans (sensu lato) and caenophidians. Anilius alone emerged as the most basal alethinophidian; the combined analyses resulted in a novel and stable position of uropeltines and cylindrophiines as the second-most basal clade of alethinophidians. The limbed marine pachyophiids, along with Dinilysia and Wonambi, were always basal to all living snakes. Other results stable in all combined analyses include: Xenopeltis and Loxocemus were sister taxa (fide morphology) but clustered with pythonines (fide molecules), and Ungaliophis clustered with a boine-erycine clade (fide molecules). Tropidophis remains enigmatic; it emerges as a basal alethinophidian in the parsimony analyses (fide molecules) but a derived form in the likelihood analyses (fide morphology), largely due to the different relative weighting accorded to data partitions.Michael S. Y. Lee, Andrew F. Hugall, Robin Lawson & John D. Scanlo

Toward a Multifaceted Heuristic of Digital Reading to Inform Assessment, Research, Practice, and Policy

In this commentary, the author explores the tension between almost 30 years of work that has embraced increasingly complex conceptions of digital reading and recent studies that risk oversimplifying digital reading as a singular entity analogous with reading text on a screen. The author begins by tracing a line of theoretical and empirical work that both informs and complicates our understanding of digital literacy and, more specifically, digital reading. Then, a heuristic is proposed to systematically organize, label, and define a multifaceted set of increasingly complex terms, concepts, and practices that characterize the spectrum of digital reading experiences. Research that informs this heuristic is used to illustrate how more precision in defining digital reading can promote greater clarity across research methods and advance a more systematic study of promising digital reading practices. Finally, the author discusses implications for assessment, research, practice, and policy

Systematics of the Neotropical Genus Leptodactylus Fitzinger, 1826 (Anura: Leptodactylidae): Phylogeny, the Relevance of Non-molecular Evidence, and Species Accounts

A phylogeny of the species-rich clade of the Neotropical frog genus Leptodactylus sensu stricto is presented on the basis of a total evidence analysis of molecular (mitochondrial and nuclear markers) and non-molecular (adult and larval morphological and behavioral characters) sampled from > 80% of the 75 currently recognized species. Our results support the monophyly of Leptodactylus sensu stricto, with Hydrolaetare placed as its sister group. The reciprocal monophyly of Hydrolaetare and Leptodactylus sensu stricto does not require that we consider Hydrolaetare as either a subgenus or synonym of Leptodactylus sensu lato. We recognize Leptodactylus sensu stricto, Hydrolaetare, Adenomera, and Lithodytes as valid monophyletic genera. Our results generally support the traditionally recognized Leptodactylus species groups, with exceptions involving only a few species that are easily accommodated without proposing new groups or significantly altering contents. The four groups form a pectinate tree, with the Leptodactylus fuscus group diverging first, followed by the L. pentadactylus group, which is sister to the L. latrans and L. melanonotus groups. To evaluate the impact of non-molecular evidence on our results, we compared our total evidence results with results obtained from analyses using only molecular data. Although non-molecular evidence comprised only 3.5% of the total evidence matrix, it had a strong impact on our total evidence results. Only one species group was monophyletic in the molecular-only analysis, and support differed in 86% of the 54 Leptodactylus clades that are shared by the results of the two analyses. Even though no non-molecular evidence was included for Hydrolaetare, exclusion of that data partition resulted in that genus being nested within Leptodactylus, demonstrating that the inclusion of a small amount of non-molecular evidence for a subset of species can alter not only the placement of those species, but also species that were not scored for those data. The evolution of several natural history and reproductive traits is considered in the light of our phylogenic framework. Invasion of rocky outcrops, larval oophagy, and use of underground reproductive chambers are restricted to species of the Leptodactylus fuscus and L. pentadactylus groups. In contrast, larval schooling, larval attendance, and more complex parental care are restricted to the L. latrans and L. melanonotus groups. Construction of foam nests is plesiomorphic in Leptodactylus but their placement varies extensively (e.g., underground chambers, surface of waterbodies, natural or excavated basins). Information on species synonymy, etymology, adult and larval morphology, advertisement call, and geographic distribution is summarized in species accounts for the 30 species of the Leptodactylus fuscus group, 17 species of the L. pentadactylus group, eight species of the L. latrans group, and 17 species of the L. melanonotus group, as well as the three species that are currently unassigned to any species group.Se presenta una filogenia del género Leptodactylus, un ciado neotropical rico en especies, basada en análises combinados de datos moleculares (marcadores nuclear y mitocondriales) y no moleculares (caracteres de la morfología de adultos y larvas así como de comportamiento) se muestrearon > 80% de las 75 especies reconocidas. Los resultados apoyan la monofília de Leptodactylus sensu stricto, con Hydrolaetare como su grupo hermano. La monofília recíproca de Hydrolaetare y Leptodactylus no requiere considerar a Hydrolaetare como un subgénero o sinónimo de Leptodactylus sensu lato. Se reconocen Leptodactylus sensu stricto, Hydrolaetare, Adenomera y Lithodytes como géneros monofiléticos válidos. Los resultados en general resuelven los grupos tradicionalmente reconocidos de Leptodactylus, con excepciones de algunas especies que son reasignadas sin la necesidad de proponer nuevos grupos o alterar significativamente el contenido de los grupos tradicionales. Los cuatro grupos de especies forman una topología pectinada donde el grupo de L. fuscus tiene una posición basal, seguido por el grupo de L. pentadactylus que es el grupo hermano al clado formado por los grupo de L. latrans y L. melanonotus. Se estimó el impacto de los datos no moleculares en los resultados, comparándose los resultados de evidencia total con los de los análises de datos moleculares solamente. Los datos no moleculares representan un 3.5% de la matriz de evidencia total, pero estos datos tuvieron un impacto significativo en los resultados del análisis de evidencia total. En el análisis estrictamente molecular solamente un grupo de especies resultó monofilético, y el apoyo difirió en 86% de los 54 ciados de Leptodactylus compartidos entre los dos análises. A pesar que datos no moleculares no fueron incluidos para Hydrolaetare, la exclusión de evidencia no molecular resultó en el género estar dentro de Leptodactylus, demostrando que la inclusión de evidencia no molecular pequeña para un subgrupo de especies altera no solamente la posición topológica de esas especies, sino tambien de las especies para las cuales dichos datos no fueron codificados. La evolución de patrones de historia natural y reprodución se evalúan en el contexto filogenético. La invasión de afloramientos rocosos y la construción de cámaras de reprodución subterraneas está limitada a los grupos de Leptodactylus fuscus y L. pentadactylus, mientras que la oofagia larval está restringida al grupo de L. pentadactylus. Por otro lado, los cárdumenes larvales, la proteción del cárdumen, y otros comportamientos parentales complejos carecterizan al clado formado por los grupos de especies de L. latrans y L. melanonotus. Los resúmenes de especies incluyen información de sinonimias, etimología, morfología de adultos y larvas, cantos, y distribución geográfica para las 30 especies del grupo de Leptodactylus fuscus, 17 especies del grupo L. pentadactylus, ocho especies del grupo de L. latrans, 17 especies del grupo de L. melanonotus, así como para las tres especies que actualmente no se encuentran asociadas a ninguno de los grupos de especies.Taran Grant was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico Proc. 307001/2011-3 and Fundação de Amparo à Pesquisa do Estado de São Paulo Proc. 2012/10000-5

Regulatory Architecture of the Neuronal Cacng2/Tarpγ2 Gene Promoter: Multiple Repressive Domains, a Polymorphic Regulatory Short Tandem Repeat, and Bidirectional Organization with Co-regulated lncRNAs

CACNG2 (TARPγ2, Stargazin) is a multi-functional regulator of excitatory neurotransmission and has been implicated in the pathological processes of several brain diseases. Cacng2 function is dependent upon expression level, but currently, little is known about the molecular mechanisms that control expression of this gene. To address this deficit and investigate disease-related gene variants, we have cloned and characterized the rat Cacng2 promoter and have defined three major features: (i) multiple repressive domains that include an array of RE-1 silencing transcription factor (REST) elements, and a calcium regulatory element-binding factor (CaRF) element, (ii) a (poly-GA) short tandem repeat (STR), and (iii) bidirectional organization with expressed lncRNAs. Functional activity of the promoter was demonstrated in transfected neuronal cell lines (HT22 and PC12), but although selective removal of REST and CaRF domains was shown to enhance promoter-driven transcription, the enhanced Cacng2 promoter constructs were still about fivefold weaker than a comparable rat Synapsin-1 promoter sequence. Direct evidence of REST activity at the Cacng2 promoter was obtained through co-transfection with an established dominant-negative REST (DNR) construct. Investigation of the GA-repeat STR revealed polymorphism across both animal strains and species, and size variation was also observed in absence epilepsy disease model cohorts (Genetic Absence Epilepsy Rats, Strasbourg [GAERS] and non-epileptic control [NEC] rats). These data provide evidence of a genotype (STR)-phenotype correlation that may be unique with respect to proximal gene regulatory sequence in the demonstrated absence of other promoter, or 3′ UTR variants in GAERS rats. However, although transcriptional regulatory activity of the STR was demonstrated in further transfection studies, we did not find a GAERS vs. NEC difference, indicating that this specific STR length variation may only be relevant in the context of other (Cacna1h and Kcnk9) gene variants in this disease model. Additional studies revealed further (bidirectional) complexity at the Cacng2 promoter, and we identified novel, co-regulated, antisense rat lncRNAs that are paired with Cacng2 mRNA. These studies have provided novel insights into the organization of a synaptic protein gene promoter, describing multiple repressive and modulatory domains that can mediate diverse regulatory inputs

The Immune Landscape of Cancer

We performed an extensive immunogenomic anal-ysis of more than 10,000 tumors comprising 33diverse cancer types by utilizing data compiled byTCGA. Across cancer types, we identified six im-mune subtypes\u2014wound healing, IFN-gdominant,inflammatory, lymphocyte depleted, immunologi-cally quiet, and TGF-bdominant\u2014characterized bydifferences in macrophage or lymphocyte signa-tures, Th1:Th2 cell ratio, extent of intratumoral het-erogeneity, aneuploidy, extent of neoantigen load,overall cell proliferation, expression of immunomod-ulatory genes, and prognosis. Specific drivermutations correlated with lower (CTNNB1,NRAS,orIDH1) or higher (BRAF,TP53,orCASP8) leukocytelevels across all cancers. Multiple control modalitiesof the intracellular and extracellular networks (tran-scription, microRNAs, copy number, and epigeneticprocesses) were involved in tumor-immune cell inter-actions, both across and within immune subtypes.Our immunogenomics pipeline to characterize theseheterogeneous tumors and the resulting data areintended to serve as a resource for future targetedstudies to further advance the field