Hepatitis C virus (HCV) infection is a global health concern affecting an estimated 3% of the world's population. Recently, cell culture systems have been established, allowing recapitulation of the complete virus life cycle for the first time. Since the HCV proteins p7 and NS2 are not predicted to be major components of the virion, nor are they required for RNA replication, we investigated whether they might have other roles in the viral life cycle. Here we utilize the recently described infectious J6/JFH chimera to establish that the p7 and NS2 proteins are essential for HCV infectivity. Furthermore, unprocessed forms of p7 and NS2 were not required for this activity. Mutation of two conserved basic residues, previously shown to be important for the ion channel activity of p7 in vitro, drastically impaired infectious virus production. The protease domain of NS2 was required for infectivity, whereas its catalytic active site was dispensable. We conclude that p7 and NS2 function at an early stage of virion morphogenesis, prior to the assembly of infectious virus.Hepatitis C virus (HCV) is a major causative agent of severe liver disease, with an estimated 170 million people infected worldwide (36). HCV is the sole member of the genus Hepacivirus, which, together with the Flavivirus and Pestivirus genera, comprise the family Flaviviridae (reviewed in reference 21). The HCV genome is approximately 9,600 nucleotides in length and is translated from an internal ribosome entry site (IRES) to generate a polyprotein in the order NH 2 -C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COOH. Co-and posttranslational processing of the polyprotein by viral and cellular proteases yields the individual viral proteins. Core (C) and envelope proteins (E1 and E2) are the major structural proteins, which, together with a host derived lipid bilayer and the viral RNA, comprise the virion. The nonstructural (NS) proteins, NS3 to NS5B, are essential components of the viral replicase. NS3 possesses helicase and NTPase activities and, along with its cofactor NS4A, comprises the major viral protease. NS4B and NS5A play essential, but as yet undefined roles in RNA replication. NS5B is the RNA-dependent RNA polymerase (RdRp). p7 and NS2 are dispensable for RNA replication, since subgenomic replicons that lack the entire C to NS2 coding region replicate autonomously (2, 22). p7 is a small (63 amino acids) hydrophobic protein that is predicted to span the membrane twice. Both the N and C termini of p7 reside within the endoplasmic reticulum (ER) lumen, with a short, basic intervening loop exposed to the cytoplasm (4). The N and C termini of p7 are released from the polyprotein by host signal peptidase. Incomplete and delayed processing leads to the accumulation of E2-p7 and p7-NS2 precursors, respectively. (10,19,25). While sequence determinants within both p7 and NS2 have been shown to modulate E2-p7 and p7-NS2 cleavage efficiencies (3), the functional importance of these precursors is not known. In chimpanzees, p7 was found to be essential for HCV i...

Final outcomes include associations between early and late life cognition and integrity of key white matter tracts, volume of gray and white matter, myelination, brain water content, and visible abnormalities such as white matter lesions and mineral deposits; and influences of vascular risk factors, diet, environment, social metrics, education and genetics on healthy brain aging. It is intended that this information will help to inform and develop strategies for successful cognitive aging.

Human white matter integrity has been related to information processing speed, but it is unknown whether impaired integrity results from localized processes or is a general property shared across white matter tracts. Based on diffusion MRI scans of 132 healthy individuals with a narrow age range around 72 years, the integrity of eight major white matter tracts was quantified using probabilistic neighborhood tractography. Principal component analyses (PCAs) were conducted on the correlations between the eight tracts, separately for four tract-averaged integrity parameters: fractional anisotropy, mean diffusivity, and radial and axial diffusivity. For all four parameters, the PCAs revealed a single general factor explaining ϳ45% of the individual differences across all eight tracts. Individuals' scores on a general factor that captures the common variance in white matter integrity had significant associations with a general factor of information processing speed for fractional anisotropy (r ϭ Ϫ0.24, p ϭ 0.007) and radial diffusivity (r ϭ 0.21, p ϭ 0.016), but not with general intelligence or memory factors. Individual tracts showed no associations beyond what the common integrity factor explained. Just as different types of cognitive ability tests share much of their variance, these novel findings show that a substantial amount of variance in white matter integrity is shared between different tracts. Therefore, impaired cortical connection is substantially a global process affecting various major tracts simultaneously. Further studies should investigate whether these findings relate more to the role of tract integrity and information processing speed in nonpathological cognitive aging or in lifelong-stable processes.

White matter hyperintensities (WMH) of presumed vascular origin are a common finding in brain magnetic resonance imaging of older individuals and contribute to cognitive and functional decline. It is unknown how WMH form, although white matter degeneration is characterized pathologically by demyelination, axonal loss, and rarefaction, often attributed to ischemia. Changes within normal-appearing white matter (NAWM) in subjects with WMH have also been reported but have not yet been fully characterized. Here, we describe the in vivo imaging signatures of both NAWM and WMH in a large group of community-dwelling older people of similar age using biomarkers derived from magnetic resonance imaging that collectively reflect white matter integrity, myelination, and brain water content. Fractional anisotropy (FA) and magnetization transfer ratio (MTR) were significantly lower, whereas mean diffusivity (MD) and longitudinal relaxation time (T1) were significantly higher, in WMH than NAWM (p < 0.0001), with MD providing the largest difference between NAWM and WMH. Receiver operating characteristic analysis on each biomarker showed that MD differentiated best between NAWM and WMH, identifying 94.6% of the lesions using a threshold of 0.747 × 10−9 m2s−1 (area under curve, 0.982; 95% CI, 0.975–0.989). Furthermore, the level of deterioration of NAWM was strongly associated with the severity of WMH, with MD and T1 increasing and FA and MTR decreasing in NAWM with increasing WMH score, a relationship that was sustained regardless of distance from the WMH. These multimodal imaging data indicate that WMH have reduced structural integrity compared with surrounding NAWM, and MD provides the best discriminator between the 2 tissue classes even within the mild range of WMH severity, whereas FA, MTR, and T1 only start reflecting significant changes in tissue microstructure as WMH become more severe.

General intelligence is a robust predictor of important life outcomes, including educational and occupational attainment, successfully managing everyday life situations, good health and longevity. Some neuronal correlates of intelligence have been discovered, mainly indicating that larger cortices in widespread parieto-frontal brain networks and efficient neuronal information processing support higher intelligence. However, there is a lack of established associations between general intelligence and any basic structural brain parameters that have a clear functional meaning. Here, we provide evidence that lower brain-wide white matter tract integrity exerts a substantial negative effect on general intelligence through reduced information-processing speed. Structural brain magnetic resonance imaging scans were acquired from 420 older adults in their early 70s. Using quantitative tractography, we measured fractional anisotropy and two white matter integrity biomarkers that are novel to the study of intelligence: longitudinal relaxation time (T1) and magnetisation transfer ratio. Substantial correlations among 12 major white matter tracts studied allowed the extraction of three general factors of biomarker-specific brain-wide white matter tract integrity. Each was independently associated with general intelligence, together explaining 10% of the variance, and their effect was completely mediated by information-processing speed. Unlike most previously established neurostructural correlates of intelligence, these findings suggest a functionally plausible model of intelligence, where structurally intact axonal fibres across the brain provide the neuroanatomical infrastructure for fast information processing within widespread brain networks, supporting general intelligence.

Viruses of the Flaviviridae family, including hepatitis C, dengue, and bovine viral diarrhoea, are responsible for significant morbidity and mortality worldwide. Recent advances in understanding virion assembly have uncovered commonalities among distantly related members of this family. We discuss the emerging hypothesis that physical virion components are not alone in forming the infectious particle, but that nonstructural proteins are intimately involved in orchestrating morphogenesis. Pinpointing the roles of Flaviviridae proteins in virion production could reveal new avenues for antiviral therapeutics.

In this large, narrow-age sample of adults in their 70s, physical activity was associated with less atrophy and WML. Its role as a potential neuroprotective factor is supported; however, the direction of causation is unclear from this observational study.

Hepatitis C virus (HCV) is an important human pathogen affecting an estimated 3% of the world's population. Recent advances have enabled in vitro propagation of the virus and allow assembly and egress to be investigated for the first time. As a component of the virion, the HCV core protein likely functions primarily in infectious virus production, although little is known about the determinants of this activity. To investigate the roles of core in the viral life cycle, we performed a comprehensive deletion and alanine scanning mutagenesis study of this protein in the context of a genotype 2a reporter virus. We have confirmed that core protein is essential for infectious virion production and have identified numerous residues required for this role. The infectivity of several assembly-defective core mutants could be rescued by compensatory mutations identified in p7 and NS2, suggesting genetic interactions with core and highlighting the importance of these nonstructural proteins in infectious virion morphogenesis.