RNA interference approaches for treatment of HIV-1 infection.

HIV/AIDS is a chronic and debilitating disease that cannot be cured with current antiretroviral drugs. While combinatorial antiretroviral therapy (cART) can potently suppress HIV-1 replication and delay the onset of AIDS, viral mutagenesis often leads to viral escape from multiple drugs. In addition to the pharmacological agents that comprise cART drug cocktails, new biological therapeutics are reaching the clinic. These include gene-based therapies that utilize RNA interference (RNAi) to silence the expression of viral or host mRNA targets that are required for HIV-1 infection and/or replication. RNAi allows sequence-specific design to compensate for viral mutants and natural variants, thereby drastically expanding the number of therapeutic targets beyond the capabilities of cART. Recent advances in clinical and preclinical studies have demonstrated the promise of RNAi therapeutics, reinforcing the concept that RNAi-based agents might offer a safe, effective, and more durable approach for the treatment of HIV/AIDS. Nevertheless, there are challenges that must be overcome in order for RNAi therapeutics to reach their clinical potential. These include the refinement of strategies for delivery and to reduce the risk of mutational escape. In this review, we provide an overview of RNAi-based therapies for HIV-1, examine a variety of combinatorial RNAi strategies, and discuss approaches for ex vivo delivery and in vivo delivery

Quantum Walks with Entangled Coins

We present a mathematical formalism for the description of unrestricted quantum walks with entangled coins and one walker. The numerical behaviour of such walks is examined when using a Bell state as the initial coin state, two different coin operators, two different shift operators, and one walker. We compare and contrast the performance of these quantum walks with that of a classical random walk consisting of one walker and two maximally correlated coins as well as quantum walks with coins sharing different degrees of entanglement. We illustrate that the behaviour of our walk with entangled coins can be very different in comparison to the usual quantum walk with a single coin. We also demonstrate that simply by changing the shift operator, we can generate widely different distributions. We also compare the behaviour of quantum walks with maximally entangled coins with that of quantum walks with non-entangled coins. Finally, we show that the use of different shift operators on 2 and 3 qubit coins leads to different position probability distributions in 1 and 2 dimensional graphs.Comment: Two new sections and several changes from referees' comments. 12 pages and 12 (colour) figure

Analysis of high quality superconducting resonators: consequences for TLS properties in amorphous oxides

$1/f$ noise caused by microscopic Two-Level Systems (TLS) is known to be very detrimental to the performance of superconducting quantum devices but the nature of these TLS is still poorly understood. Recent experiments with superconducting resonators indicates that interaction between TLS in the oxide at the film-substrate interface is not negligible. Here we present data on the loss and $1/f$ frequency noise from two different Nb resonators with and without Pt capping and discuss what conclusions can be drawn regarding the properties of TLS in amorphous oxides. We also estimate the concentration and dipole moment of the TLS.Comment: 8 pages, 5 figure

Municipal Water Works Operating Data for Tennessee

This is a tabulation and interpretation of the results of a survey made by MTAS in the spring of 1964 designed to obtain statistical information on the operation of municipally-owned water utilities in the State

EBSD mapping of herringbone domain structures in tetragonal piezoelectrics

Herringbone domain structures have been mapped using electron backscatter diffraction (EBSD) in two tetragonal piezoelectrics, lead zirconate titanate, [Pb(Zr,Ti)O<sub>3</sub>] and bismuth ferrite – lead titanate, [(PbTi)<sub>0.5</sub>(BiFe)<sub>0.5</sub>O<sub>3</sub>]. Analysis of the domain misorientations across the band junctions shows that the structures correspond very well to crystallographic models. High resolution mapping with a 20 nm step size allowed the crystal rotation across one of these band junctions in lead zirconate titanate to be studied in detail and allowed an improved estimation of the peak strain at the junction, of 0.56 GPa. The significance of this for crack nucleation and propagation in such materials is discussed

Nucleolar Localization of HIV-1 Rev Is Required, Yet Insufficient for Production of Infectious Viral Particles.

Combination antiretroviral therapy fails in complete suppression of HIV-1 due to drug resistance and persistent latency. Novel therapeutic intervention requires knowledge of intracellular pathways responsible for viral replication, specifically those untargeted by antiretroviral drugs. An understudied phenomenon is the nucleolar localization of Rev phosphoprotein, which completes nucleocytoplasmic transport of unspliced/partially spliced HIV mRNA through multimerization with intronic cis-acting targets-the Rev-response element (RRE). Rev contains a nucleolar localization signal (NoLS) comprising the COOH terminus of the arginine-rich motif for accumulation within nucleoli-speculated as the interaction ground for Rev with cellular proteins mediating mRNA-independent nuclear export and splicing. Functionality of Rev nucleolar access during HIV-1 production and infection was investigated in the context of deletion and single-point mutations within Rev-NoLS. Mutations induced upon Rev-NoLS are hypothesized to inactivate the HIV-1 infectious cycle. HIV-1HXB2 replication ceased with Rev mutations lacking nucleolar access due to loss or replacement of multiple arginine residues. Rev mutations missing single arginine residues remained strictly nucleolar in pattern and participated in proviral production, however, with reduced efficiency. Viral RNA packaging also decreased in efficiency after expression of nucleolar-localizing mutations. These results were observed during propagation of variant HIV-1NL4-3 containing nucleolar-localizing mutations within the viral backbone (M4, M5, and M6). Lentiviral particles produced with Rev single-point mutations were transducible at extremely low frequency. Similarly, HIV-1NL4-3 Rev-NoLS variants lost infectivity, unlike virulent WT (wild type) HIV-1NL4-3. HIV-1NL4-3 variants were capable of CD4+ host entry and reverse transcription as WT HIV-1NL4-3, but lacked ability to complete a full infectious cycle. We currently reveal that viral integration is deregulated in the presence of Rev-NoLS mutations

Replication of Molluscum Contagiosum Virus

AbstractMolluscum contagiosum virus (MCV) infects preadolescent children and sexually active adults, frequently causing a disfiguring cutaneous disease in immunosuppressed HIV-infected individuals. The development of an efficacious treatment regime has been hampered by the failure to replicate the virus in the laboratory. Here we report the first demonstration of MCV replication in an experimental system. In human foreskin grafts to athymic mice, MCV induced morphological changes which were indistinguishable from patient biopsies and included the development and migration of molluscum bodies containing mature virions to the epidermal surface

Concept for a distributed processor computer

Future generation computer utilizes cell of single metal oxide semiconductor wafer containing general purpose processor section and small memory of approximately 512 words of 16 bits each. Cells are organized into groups and groups interconnected to form computer

Nutrient Estimation from 24-Hour Food Recalls Using Machine Learning and Database Mapping: A Case Study with Lactose.

The Automated Self-Administered 24-Hour Dietary Assessment Tool (ASA24) is a free dietary recall system that outputs fewer nutrients than the Nutrition Data System for Research (NDSR). NDSR uses the Nutrition Coordinating Center (NCC) Food and Nutrient Database, both of which require a license. Manual lookup of ASA24 foods into NDSR is time-consuming but currently the only way to acquire NCC-exclusive nutrients. Using lactose as an example, we evaluated machine learning and database matching methods to estimate this NCC-exclusive nutrient from ASA24 reports. ASA24-reported foods were manually looked up into NDSR to obtain lactose estimates and split into training (n = 378) and test (n = 189) datasets. Nine machine learning models were developed to predict lactose from the nutrients common between ASA24 and the NCC database. Database matching algorithms were developed to match NCC foods to an ASA24 food using only nutrients ("Nutrient-Only") or the nutrient and food descriptions ("Nutrient + Text"). For both methods, the lactose values were compared to the manual curation. Among machine learning models, the XGB-Regressor model performed best on held-out test data (R2 = 0.33). For the database matching method, Nutrient + Text matching yielded the best lactose estimates (R2 = 0.76), a vast improvement over the status quo of no estimate. These results suggest that computational methods can successfully estimate an NCC-exclusive nutrient for foods reported in ASA24

Neck exercises compared to muscle activation during aerial combat maneuvers

Introduction: Performing specific neck strengthening exercises has been proposed to decrease the incidence of neck injury and pain in high performance combat pilots. However, there is little known about these exercises in comparison to the demands on the neck musculature in flight. Methods: Eight male non-pilots performed specific neck exercises using two different modalities (elastic band and resistance machine) at six different intensities in flexion, extension, and lateral bending. Six Royal Australian Air Force Hawk pilots flew a sortie that included combinations of three +Gz levels and four head positions. Surface electromyography (EMG) from selected neck and shoulder muscles was recorded in both activities. Results: Muscle activation levels recorded during the three elastic band exercises were similar to in-flight EMG collected at +1 Gz (15% MVIC). EMG levels elicited during the 50% resistance machine exercises were between the +3 Gz (9-40% MVIC) and +5 Gz (16-53% MVIC) ranges of muscle activations in most muscles. EMG recorded during 70% and 90% resistance machine exercises were generally higher than in-flight EMG at +5 Gz. Discussion: Elastic band exercises could possibly be useful to pilots who fly low +Gz missions while 50% resistance machine mimicked neck loads experienced by combat pilots flying high +Gz ACM. The 70% and 90% resistance machine intensities are known to optimize maximal strength but should be administered with care because of the unknown spinal loads and diminished muscle force generating capacity after exercise.<br /