Increasing Hydrophobicity of Residues in an Anti-HIV-1 Env Peptide Synergistically Improves Potency

AbstractT-20/Fuzeon/Enfuvirtide (ENF), a peptide inhibitor of HIV-1 infection, targets the grooves created by heptad repeat 2 (HR2) of Env's coiled-coil, but mutants resistant to ENF emerge. In this study, ENF-resistant mutants—V38A, N43D, N43D/S138A, Q40H/L45M—were combined with modified inhibitory peptides to identify what we believe to be novel ways to improve peptide efficacy. V38A did not substantially reduce infectivity, but was relatively resistant to inhibitory peptides. N43D was more resistant to inhibitory peptides than wild-type, but infectivity was reduced. The additional mutation S138A (N43D/S138A) increased infectivity and further reduced peptide inhibitory potency. It is concluded that S138A increased binding of HR2/ENF into grooves and that S138A compensated for electrostatic repulsion between N43D and HR2. The six-helix bundle structure indicated that E148A should increase hydrophobic interactions between the coiled-coil and peptide. Importantly, the modifications S138A and E148A in the same peptide retained potency against ENF-escape mutants. The double mutant's increase in potency was greater than the increases from the sum of S138A and E148A individually, showing that these two altered residues synergistically contributed to peptide binding. Isothermal titration calorimetry established that hydrophobic substitutions at positions S138 and E148 improved potency of inhibitory peptides against escape mutants by increasing enthalpic release of energy upon peptide binding

Paper Session II-B - Optical Diagnostics: Reagentless Chemistry for Extended Space Flights

Maintaining the health and safety of the crews of spacecraft remain the highest priorities. Health monitoring requires at least two overlapping activities: (1) frequent or continuous monitoring of bodily functions to determine normalcy or deviation from normalcy, and (2) specific diagnosis and treatment of diseases. Thus, with a broad mandate and limited resources, the spacecraft must provide the diagnostic capabilities for quickly and accurately diagnosing a wide range of diseases. Optical devices, though still in the early developmental stages, diagnose diseases by analyzing and quantitating the spectra of metabolites and other substances non-invasively and without using chemical reagents. Once commercially available, optical devices will replace many clinical tests that use chemical reagents for diagnostics

Direct Loan and FFEL: One School Compares Student Satisfaction with the Programs

New York University (NYU) began selective participation in the Federal Direct Student Loan Program during the 1995-96 academic year. In order to inform campus decision makers about possible expansion, a study was instituted at the same time to evaluate and compare the effects of the Direct Loan and the Federal Family Education Loan Programs on students, families, and campus administrators. The study was designed to investigate each program and compare them. Also, since the FFEL Program delivery system in New York has been streamlined and automated for some time, comparison of best practices in the two programs was possible. The study is ongoing and in the future will include longitudinal follow-up to explore possible influences on choice of major, retention, and default rates. At this stage, the initial survey of student satisfaction and interviews with campus administrators have been evaluated. Our findings suggest that participation in both programs, rather than just one, may pose some challenges for campus administrators and staff, but not for students. Also, while student reactions to the two programs were similar and positive for the most part, there were some troubling differences among students of different ethnicities and income levels

Paper Session III-B - Measurements of Oxygen in Biological & Medical Experiments

Since the maintenance of the appropriate levels of oxygen is essential for ensuring the success of many of the specialized experiments in space missions, such as tissue culture experiments, the continuous monitoring of partial pressures of oxygen provides important data. We are developing optical methods of monitoring not only oxygen but also many dissolved constituents in blood and tissue culture solutions. The optical system uses tiny optical fibers, which easily fit inside a fine-gauged needle, for monitoring each specimen. Moreover, the beam can be split so that multiple specimens can be monitored simultaneously. The same optical technology can also be used for monitoring the blood chemistry of humans and animals; it is minimally invasive. It has a medical application for measuring tissue partial pressures of oxygen

Cell–cell contact promotes Ebola virus GP-mediated infection

AbstractEbola virus (EBOV) is a highly pathogenic filovirus that causes hemorrhagic fever in humans and animals. Here we provide evidence that cell–cell contact promotes infection mediated by the glycoprotein (GP) of EBOV. Interestingly, expression of EBOV GP alone, even in the absence of retroviral Gag-Pol, is sufficient to transfer a retroviral vector encoding Tet-off from cell to cell. Cell-to-cell infection mediated by EBOV GP is blocked by inhibitors of actin polymerization, but appears to be less sensitive to KZ52 neutralization. Treatment of co-cultured cells with cathepsin B/L inhibitors, or an entry inhibitor 3.47 that targets the receptor NPC1 for virus binding, also blocks cell-to-cell infection. Cell–cell contact also enhances spread of rVSV bearing GP in monocytes and macrophages, the primary targets of natural EBOV infection. Altogether, our study reveals that cell–cell contact promotes EBOV GP-mediated infection, and provides new insight into understanding EBOV spread and viral pathogenesis

HashWires: Hyperefficient Credential-Based Range Proofs

This paper presents HashWires, a hash-based range proof protocol that is applicable in settings for which there is a trusted third party (typically a credential issuer) that can generate commitments. We refer to these as credential-based range proofs (CBRPs). HashWires improves upon hashchain solutions that are typically restricted to micro-payments for small interval ranges, achieving an exponential speedup in proof generation and verification time. In terms of proof size and computational cost, we show that HashWires compares favorably against Bulletproofs for both 32- and 64-bit numeric values. Although CBRPs are inherently less flexible than general zero-knowledge range proofs, we provide a number of applications in which a credential issuer can leverage HashWires to provide range proofs for private values, without having to rely on heavyweight cryptographic tools and assumptions

Effect of a Lay Counselor Intervention on Prevention of Major Depression in Older Adults Living in Low- and Middle-Income Countries:A Randomized Clinical Trial

Importance: Preventing depression in older adults living in low- and middle-income countries is important because of the scarcity of treatment resources and the risk of disability, suicide, and dementia. Objective: To assess whether an intervention for depression prevention provided by lay counselors is effective in older adults from low- and middle-income countries. Design, Setting, and Participants: This parallel-group randomized clinical trial with masked outcome assessment was performed in 181 older adults (≥60 years) with subsyndromal depressive symptoms at rural and urban primary care clinics in Goa, India. The first participant entered the trial on March 31, 2015, and the last exited on June 2, 2017. Data analysis used the intention-to-treat approach. Interventions: Lay counselors provided problem-solving therapy, brief behavioral treatment for insomnia, education in self-care of common medical disorders such as diabetes, and assistance in accessing medical and social programs. Main Outcomes and Measures: The main outcome was incidence of major depressive episodes. The study also assessed symptom change during 12 months (12-item General Health Questionnaire [GHQ-12]; score range of 0 to 12, with higher scores indicating greater symptoms of depression and anxiety), functional status (World Health Organization Disability Assessment Schedule 2.0; score range of 12 to 60, with higher scores indicating greater disability), cognition (Hindi Mini-Mental State Examination; score range of 0 to 30, with higher scores indicating better cognitive functioning), blood pressure, and body mass index to provide further clinical context. Results: The study enrolled 181 participants (mean [SD] age, 69.6 [7.2] years; 114 [63.0%] female): 91 to the intervention arm (depression in later life [DIL] intervention) and 90 to care as usual (CAU). Incident episodes of major depression were lower in the DIL intervention than in the CAU group (4.40% vs 14.44%; log-rank P =.04; number needed to treat, 9.95; 95% CI, 5.12-182.43). The 12-month Kaplan-Meier estimates of percentage of depression-free participants were 95.1% (95% CI, 90.5%-99.9%) in the DIL group vs 87.4% (95% CI, 80.4%-95.1%) in the CAU group. The incidence of depressive symptoms (GHQ-12) was also less (12-month mean difference, -1.18; 95% CI, -2.03 to -0.31; group × time interaction P <.001). There were no changes in measures of disability or cognition. The DIL intervention was associated with a significantly greater lowering of systolic blood pressure (12-month mean difference, -6.98; 95% CI, -11.96 to -2.01; group × time interaction P <.001) and change in body mass index (12-month mean difference, 0.23; 95% CI, -0.97 to 1.43; P =.04). Conclusions and Relevance: The DIL intervention is effective for preventing episodes of major depression in older persons with subsyndromal symptoms. If replicated, the DIL intervention may be effective in older adults living in low- and middle-income countries