Phenotypic Characteristics of Mucosally Transmitted HIV-1

Mucosal transmission accounts for the majority of new human immunodeficiency virus type 1 (HIV-1) infections and results in a genetically and phenotypically homogenous founder virus population in 60-80 percent of cases. Biological properties common to these transmitted and founder (T/F) viruses but not chronic control (CC) viruses would define key targets for microbicides and vaccines. To identify such properties, we tested 45 T/F and 52 CC envelope glycoproteins (Envs) from the best studied and most prevalent HIV-1 subtypes (B and C, respectively) in various pseudotype assays to determine their receptor and coreceptor interaction, tropism for primary CD4+ T cell subsets, and sensitivity to neutralizing antibodies. T/F Envs were unable to mediate entry into cells expressing low amounts of CD4, thus macrophages and other CD4low cells likely do not support their replication during mucosal transmission. In contrast, T/F Env pseudoviruses efficiently infected primary memory CD4+ T cells with a preference for the effector rather than central memory subset, as did CC pseudoviruses. There was a trend towards increased sensitivity of T/F viruses to neutralization by antibodies targeting the CD4 binding site. All T/F Envs were able to use the coreceptor CCR5 for cell entry, whereas some CC Envs used CXCR4 alone. However, one bona fide T/F virus entered and replicated very poorly in CCR5+ cells in vitro, so efficient use of CCR5 as tested is not absolutely required for transmission. To extend these studies beyond intrinsic Env functions, we characterized the Env content, infectivity, dendritic cell interaction, and interferon alpha (IFN-α) sensitivity of 27 T/F and 14 CC infectious molecular clones from subtypes B and C. T/F viruses contained more Env and were more infectious than CC viruses. T/F viruses also readily attached to DCs and were effectively transferred to CD4+ T cells. T/F viruses were more resistant to the inhibitory effect of IFN-α on virus spread than CC viruses, suggesting that selective pressure imposed by the innate immune response may in part mediate the bottleneck associated with mucosal transmission. Future work is needed to define the mechanistic basis of these phenomena in order to target them to prevent HIV-1 transmission

Identifying Factors that Impact the Educational Success of Veterans at IUPUI

poster abstractIncreased post-secondary enrollment among US military veterans using benefits from the Post-9/11 Veterans Educational Assistance Act of 2008 has led to a newfound emphasis on expanded student services on college campuses. We examined academic performance, social support, and mental health through a cross-sectional survey of 101 Veterans who were enrolled in at least one course at IUPUI in the last 12 months in order to identify barriers and facilitators to academic success. In addition to educational outcomes, we also assessed a variety of measures related to community reintegration, quality of life, and resilience. We conceptualized academic success as higher GPA, student status, and lower levels of reported difficulty in reintegration, concentrating in the classroom, and completing coursework. We hypothesized that use of student services and financial aid, involvement with student affairs, perceived social support, encountered barriers, and completion of transition assistance programs were expected to influence success variables. More than half of participants reported experiencing educational barriers unique to their Veteran status, including moderate difficulties with concentration and completing tasks for school. Although high mean scores of grit, resilience, and perceived social support were recorded, high scores of reintegration difficulty suggest that the sample may be at probable risk for post-traumatic stress disorder and substance abuse. Despite these difficulties, most student Veterans did not report using Veteran specific resources, with only one in ten participants reporting any use of campus-based adaptive education services and psychological services. No significant difference was found between groups utilizing or failing to utilize 6 separate sources of financial aid, 6 services, and 9 types of student affairs. Our findings suggest potential ways to enhance current support programs. Future research that tracks longitudinal change and explores student experience in-depth may help explore mechanisms related to the academic success of military Veterans

Phenotypic properties of transmitted founder HIV-1

Defining the virus–host interactions responsible for HIV-1 transmission, including the phenotypic requirements of viruses capable of establishing de novo infections, could be important for AIDS vaccine development. Previous analyses have failed to identify phenotypic properties other than chemokine receptor 5 (CCR5) and CD4+ T-cell tropism that are preferentially associated with viral transmission. However, most of these studies were limited to examining envelope (Env) function in the context of pseudoviruses. Here, we generated infectious molecular clones of transmitted founder (TF; n = 27) and chronic control (CC; n = 14) viruses of subtypes B (n = 18) and C (n = 23) and compared their phenotypic properties in assays specifically designed to probe the earliest stages of HIV-1 infection. We found that TF virions were 1.7-fold more infectious (P = 0.049) and contained 1.9-fold more Env per particle (P = 0.048) compared with CC viruses. TF viruses were also captured by monocyte-derived dendritic cells 1.7-fold more efficiently (P = 0.035) and more readily transferred to CD4+ T cells (P = 0.025). In primary CD4+ T cells, TF and CC viruses replicated with comparable kinetics; however, when propagated in the presence of IFN-α, TF viruses replicated to higher titers than CC viruses. This difference was significant for subtype B (P = 0.000013) but not subtype C (P = 0.53) viruses, possibly reflecting demographic differences of the respective patient cohorts. Together, these data indicate that TF viruses are enriched for higher Env content, enhanced cell-free infectivity, improved dendritic cell interaction, and relative IFN-α resistance. These viral properties, which likely act in concert, should be considered in the development and testing of AIDS vaccines

A stochastic quantum Krylov protocol with double factorized Hamiltonians

We propose a class of randomized quantum Krylov diagonalization (rQKD) algorithms capable of solving the eigenstate estimation problem with modest quantum resource requirements. Compared to previous real-time evolution quantum Krylov subspace methods, our approach expresses the time evolution operator, $e^{-i\hat{H} \tau}$, as a linear combination of unitaries and subsequently uses a stochastic sampling procedure to reduce circuit depth requirements. While our methodology applies to any Hamiltonian with fast-forwardable subcomponents, we focus on its application to the explicitly double-factorized electronic-structure Hamiltonian. To demonstrate the potential of the proposed rQKD algorithm, we provide numerical benchmarks for a variety of molecular systems with circuit-based statevector simulators, achieving ground state energy errors of less than 1~kcal~mol$^{-1}$ with circuit depths orders of magnitude shallower than those required for low-rank deterministic Trotter-Suzuki decompositions

Chemical Study of the Interstitial Water Dissolved Organic Matter and Gases in Lake Erie, Cleveland Harbor, and Hamilton Harbour Bottom Sediments - Composition and Fluxes to Overlying Waters

The research on which this report is based was financed in part by the U.S. Department of the Interior, as authorized by the Water Research and Development Act of 1978 (P.L. 95-467).(print) iv, 167, [45] p. : ill., maps ; 29 cm.FINAL REPORT FOR OWRT GRANT A-O59-OHIOItem lacks publication date. Issue date supplied from hand-written year on coverIntroduction -- The Study Area -- Methods and Materials -- Results -- Discussion -- Conclusions -- Selected Bibliographic References -- Tables 1-32 -- Figures 1-36 -- Appendi

A Review of LIDAR Radiometric Processing: From Ad Hoc Intensity Correction to Rigorous Radiometric Calibration

In addition to precise 3D coordinates, most light detection and ranging (LIDAR) systems also record “intensity”, loosely defined as the strength of the backscattered echo for each measured point. To date, LIDAR intensity data have proven beneficial in a wide range of applications because they are related to surface parameters, such as reflectance. While numerous procedures have been introduced in the scientific literature, and even commercial software, to enhance the utility of intensity data through a variety of “normalization”, “correction”, or “calibration” techniques, the current situation is complicated by a lack of standardization, as well as confusing, inconsistent use of terminology. In this paper, we first provide an overview of basic principles of LIDAR intensity measurements and applications utilizing intensity information from terrestrial, airborne topographic, and airborne bathymetric LIDAR. Next, we review effective parameters on intensity measurements, basic theory, and current intensity processing methods. We define terminology adopted from the most commonly-used conventions based on a review of current literature. Finally, we identify topics in need of further research. Ultimately, the presented information helps lay the foundation for future standards and specifications for LIDAR radiometric calibration.Keywords: calibration, normalization, radiometric, correction, intensity, LIDAR, laser scanningThis is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by MDPI. The published article can be found at: http://www.mdpi.com/journal/sensor

Bordetella spp. block eosinophil recruitment to suppress the generation of early mucosal protection

Bordetella spp. are respiratory pathogens equipped with immune evasion mechanisms. We previously characterized a Bordetella bronchiseptica mutant (RB50DbtrS) that fails to suppress host responses, leading to rapid clearance and long-lasting immunity against reinfection. This work revealed eosinophils as an exclusive requirement for RB50DbtrS clearance. We also show that RB50DbtrS promotes eosinophil-mediated B/T cell recruitment and inducible bronchus-associated lymphoid tissue (iBALT) formation, with eosinophils being present throughout iBALT for Th17 and immunoglobulin A (IgA) responses. Finally, we provide evidence that XCL1 is critical for iBALT formation but not maintenance, proposing a novel role for eosinophils as facilitators of adaptive immunity against B. bronchiseptica. RB50DbtrS being incapable of suppressing eosinophil effector functions illuminates active, bacterial targeting of eosinophils to achieve successful persistence and reinfection. Overall, our discoveries contribute to understanding cellular mechanisms for use in future vaccines and therapies against Bordetella spp. and extension to other mucosal pathogens.Xunta de Galicia | Ref. ED431C 2020/02Xunta de Galicia | Ref.ED481A-2018/23

Drug design on quantum computers

Quantum computers promise to impact industrial applications, for which quantum chemical calculations are required, by virtue of their high accuracy. This perspective explores the challenges and opportunities of applying quantum computers to drug design, discusses where they could transform industrial research and elaborates on what is needed to reach this goal

Evolutionary History of Endogenous Human Herpesvirus 6 Reflects Human Migration out of Africa.

Human herpesvirus 6A and 6B (HHV-6) can integrate into the germline, and as a result, ∼70 million people harbor the genome of one of these viruses in every cell of their body. Until now, it has been largely unknown if 1) these integrations are ancient, 2) if they still occur, and 3) whether circulating virus strains differ from integrated ones. Here, we used next-generation sequencing and mining of public human genome data sets to generate the largest and most diverse collection of circulating and integrated HHV-6 genomes studied to date. In genomes of geographically dispersed, only distantly related people, we identified clades of integrated viruses that originated from a single ancestral event, confirming this with fluorescent in situ hybridization to directly observe the integration locus. In contrast to HHV-6B, circulating and integrated HHV-6A sequences form distinct clades, arguing against ongoing integration of circulating HHV-6A or "reactivation" of integrated HHV-6A. Taken together, our study provides the first comprehensive picture of the evolution of HHV-6, and reveals that integration of heritable HHV-6 has occurred since the time of, if not before, human migrations out of Africa

Transmitted/Founder and Chronic Subtype C HIV-1 Use CD4 and CCR5 Receptors with Equal Efficiency and Are Not Inhibited by Blocking the Integrin α4β7

Sexual transmission of human immunodeficiency virus type 1 (HIV-1) most often results from productive infection by a single transmitted/founder (T/F) virus, indicating a stringent mucosal bottleneck. Understanding the viral traits that overcome this bottleneck could have important implications for HIV-1 vaccine design and other prevention strategies. Most T/F viruses use CCR5 to infect target cells and some encode envelope glycoproteins (Envs) that contain fewer potential N-linked glycosylation sites and shorter V1/V2 variable loops than Envs from chronic viruses. Moreover, it has been reported that the gp120 subunits of certain transmitted Envs bind to the gut-homing integrin α4β7, possibly enhancing virus entry and cell-to-cell spread. Here we sought to determine whether subtype C T/F viruses, which are responsible for the majority of new HIV-1 infections worldwide, share biological properties that increase their transmission fitness, including preferential α4β7 engagement. Using single genome amplification, we generated panels of both T/F (n = 20) and chronic (n = 20) Env constructs as well as full-length T/F (n = 6) and chronic (n = 4) infectious molecular clones (IMCs). We found that T/F and chronic control Envs were indistinguishable in the efficiency with which they used CD4 and CCR5. Both groups of Envs also exhibited the same CD4+ T cell subset tropism and showed similar sensitivity to neutralization by CD4 binding site (CD4bs) antibodies. Finally, saturating concentrations of anti-α4β7 antibodies failed to inhibit infection and replication of T/F as well as chronic control viruses, although the growth of the tissue culture-adapted strain SF162 was modestly impaired. These results indicate that the population bottleneck associated with mucosal HIV-1 acquisition is not due to the selection of T/F viruses that use α4β7, CD4 or CCR5 more efficiently