Pegylated alpha interferon and ribavirin therapy for hepatitis C virus (HCV) genotype 1 infection fails for half of Caucasian American patients (CA) and more often for African Americans (AA). The reasons for these low response rates are unknown. HCV is highly genetically variable, but it is unknown how this variability affects response to therapy. To assess effects of viral diversity on response to therapy, the complete pretreatment genotype 1 HCV open reading frame was sequenced using samples from 94 participants in the Virahep-C study. Sequences from patients with >3.5 log declines in viral RNA levels by day 28 (marked responders) were more variable than those from patients with declines of <1.4 log (poor responders) in NS3 and NS5A for genotype 1a and in core and NS3 for genotype 1b. These correlations remained when all T-cell epitopes were excluded, indicating that these differences were not due to differential immune selection. When the sequences were compared by race of the patients, higher diversity in CA patients was found in E2 and NS2 but only for genotype 1b. Core, NS3, and NS5A can block the action of alpha interferon in vitro; hence, these genetic patterns are consistent with multiple amino acid variations independently impairing the function of HCV proteins that counteract interferon responses in humans, resulting in HCV strains with variable sensitivity to therapy. No evidence was found for novel HCV strains in the AA population, implying that AA patients may be infected with a higher proportion of the same resistant strains that are found in CA patients.Chronic infection with hepatitis C virus (HCV) is a major cause of cirrhosis, liver disease, and hepatocellular carcinoma (reviewed in reference 37). About 3.1 million Americans are chronically infected with HCV, causing 8,000 to 10,000 deaths annually (3). Due to the slow progression of hepatitis C virus infections and the increasing prevalence of HCV in the American population, HCV-associated deaths are expected to more than triple over the next two decades, eventually exceeding those from AIDS (45).HCV is a hepatotropic Flavivirus (reviewed in reference 40). The virion contains a lipid envelope with two envelope proteins surrounding a capsid. Within the capsid is a positivepolarity RNA genome about 9,600 nucleotides long that contains an open reading frame (ORF) that encodes a polyprotein of ϳ3,000 amino acids (Fig. 1). The structural proteins include the core protein that forms the capsid and the E1 and E2 surface glycoproteins. The nonstructural proteins include P7 (ion channel), NS2 (protease), NS3 (protease and helicase), NS4A (cofactor for NS3), NS4B (putative organizer of the viral replicase complex), NS5A (implicated in viral replication and pathogenesis), and NS5B (RNA polymerase). An 11th viral protein, the alternate reading frame (ARF) protein, is encoded in the ϩ1 frame within the core region and is of unknown function (7).Six HCV genotypes that are less than 72% identical at the nucleotide level have been identified, and within thes...

Mimicking the pressure-sensing behavior of biological skins using electronic devices has profound implications for prosthetics and medicine. The developed electronic skins based on single response mode for pressure sensing suffer from a rapid decrease in sensitivity with the increase of pressure. Their highly sensitive range covers a narrow part of tolerable pressure range of the human skin and has a weak response to the injurious high pressures. Herein, inspired by a bioluminescent jellyfish, we develop an electronic skin with dual-mode response characteristics, which is able to quantify and map the static and dynamic pressures by combining electrical and optical responses. The electronic skin shows notable changes in capacitance in the low-pressure regime and can emit bright luminescence in the high-pressure regime, which, respectively, imitates the functions of the mechanoreceptors and nociceptors in the biological skin, enabling it to sense gentle tactile and injurious pressure with sensitivities up to 0.66 and 0.044 kPa, respectively. The complementary highly sensitive sensing ranges of the electronic skin realize a reliable perception to different levels of pressure, and its mechanically robust and stretchable properties may find a wide range of applications in intelligent robots.

each collected data on ≥80% of violent deaths in the state, in accordance with requirements under which the state was funded for NVDRS; therefore, presented data likely underestimate suicide deaths and rates.

Human metapneumovirus (hMPV) is a recently described member of the Paramyxoviridae family/Pneumovirinae subfamily and shares many common features with respiratory syncytial virus (RSV), another member of the same subfamily. hMPV causes respiratory tract illnesses that, similar to human RSV, occur predominantly during the winter months and have symptoms that range from mild to severe cough, bronchiolitis, and pneumonia. Like RSV, the hMPV virus can be subdivided into two genetic subgroups, A and B. With RSV, a single monoclonal antibody directed at the fusion (F) protein can prevent severe lower respiratory tract RSV infection. Because of the high level of sequence conservation of the F protein across all the hMPV subgroups, this protein is likely to be the preferred antigenic target for the generation of cross-subgroup neutralizing antibodies. Here we describe the generation of a panel of neutralizing monoclonal antibodies that bind to the hMPV F protein. A subset of these antibodies has the ability to neutralize prototypic strains of both the A and B hMPV subgroups in vitro. Two of these antibodies exhibited high-affinity binding to the F protein and were shown to protect hamsters against infection with hMPV. The data suggest that a monoclonal antibody could be used prophylactically to prevent lower respiratory tract disease caused by hMPV.Respiratory viruses account for a large proportion of upper and lower respiratory tract illness in humans. In the past few decades, many etiological agents of respiratory tract illness have been identified. Of these, respiratory syncytial virus (RSV) is the single most important cause of respiratory infections during infancy and early childhood (29). However, only 60% of clinically attended respiratory infections of infants and children are of a known etiology (21). Recently, van den Hoogen et al. (26) discovered and described human metapneumovirus (hMPV) and revealed that it may account for a portion of these previously unclassified infections. Prospective and retrospective studies suggest that hMPV infections account for between 3% and 15% of respiratory tract infections (5,6,8

Empty virions are inadvertent by-products of recombinant adeno-associated virus (rAAV) packaging process, resulting in vector lots with mixtures of full and empty virions at variable ratios. Impact of empty virions on the efficiency and side-effects of rAAV transduction has not been well characterized. Here, we generated partially and completely empty AAV8 virions, fully packaged rAAV8 lots as well as mixtures of empty and fully packaged virions with variable ratios of empty virions (REVs). The aforementioned dosing formulations of rAAV8 expressing either cellular (EGFP or nuclear-targeted (n) LacZ) or secreted (human α1-antitrypsin, hA1AT) reporter genes were intravenously injected into two different mouse strains, followed by analyses of transgene expressions and serum alanine aminotransferase (ALT) levels at different time points. We found that addition of empty particles to the fixed doses of rAAV8 preparations repressed liver transduction up to 64% (serum hA1AT) and 44% (nLacZ) in C57BL/6 mice, respectively. The similar trend in inhibiting EGFP expression together with concurrent elevations of serum ATL levels were observed in the BALB/c mice, indicating that empty particles may also exacerbate side-effects of rAAV8EGFP transduction. Our results suggest that removal of empty particles from rAAV preparations may improve efficacy and safety of AAV in clinical applications.

African American women with lower VDN exhibit increased depressive symptoms. Research on vitamin D supplementation for reducing antenatal depressive symptoms is needed.

Short hairpin (sh)RNAs delivered by recombinant adeno-associated viruses (rAAVs) are valuable tools to study gene function in vivo and a promising gene therapy platform. Our data show that incorporation of shRNA transgenes into rAAV constructs reduces vector yield and produces a population of truncated and defective genomes. We demonstrate that sequences with hairpins or hairpin-like structures drive the generation of truncated AAV genomes through a polymerase redirection mechanism during viral genome replication. Our findings reveal the importance of genomic secondary structure when optimizing viral vector designs. We also discovered that shDNAs could be adapted to act as surrogate mutant inverted terminal repeats (mTRs), sequences that were previously thought to be required for functional self-complementary AAV vectors. The use of shDNAs as artificial mTRs opens the door to engineering a new generation of AAV vectors with improved potency, genetic stability, and safety for both preclinical studies and human gene therapy.

1 Typeset by A.NfS--'!EX ABSTRACTA heterosexually active population is e>...1>osed to two competing strains or two distinct sexually-transmitted pathogens. It is assumed that a host cannot be invaded simultaneously by both disease agents and that when symptoms appear, a function of the pathogen or strain virulence, individuals recover. We conclude that in a behaviorally and genetically homogeneous population coexistence is not possible but under very special circumstances. The mathematical qualitatively analysis of our model is complete; that is, we provide a global stability analysis of the stationary states. We conclude this manuscript with two extensions. The first allows for the possibility that a host may face multiple competing strains while the second looks at the effects on coexistence of the host's age-of-infection when two strains compete for the same host.