Completion of hepatitis C virus replication cycle in heterokaryons excludes dominant restrictions in human non-liver and mouse liver cell lines

Hepatitis C virus (HCV) is hepatotropic and only infects humans and chimpanzees. Consequently, an immunocompetent small animal model is lacking. The restricted tropism of HCV likely reflects specific host factor requirements. We investigated if dominant restriction factors expressed in non-liver or non-human cell lines inhibit HCV propagation thus rendering these cells non-permissive. To this end we explored if HCV completes its replication cycle in heterokaryons between human liver cell lines and non-permissive cell lines from human non-liver or mouse liver origin. Despite functional viral pattern recognition pathways and responsiveness to interferon, virus production was observed in all fused cells and was only ablated when cells were treated with exogenous interferon. These results exclude that constitutive or virus-induced expression of dominant restriction factors prevents propagation of HCV in these cell types, which has important implications for HCV tissue and species tropism. In turn, these data strongly advocate transgenic approaches of crucial human HCV cofactors to establish an immunocompetent small animal model.     

The influence of physiological aging and atrophy on brain viscoelastic properties in humans

Physiological aging of the brain is accompanied by ubiquitous degeneration of neurons and oligodendrocytes. An alteration of the cellular matrix of an organ impacts its macroscopic viscoelastic properties which can be detected by magnetic resonance elastography (MRE) – to date the only method for measuring brain mechanical parameters without intervention. However, the wave patterns detected by MRE are affected by atrophic changes in brain geometry occurring in an individual''s life span. Moreover, regional variability in MRE-detected age effects is expected corresponding to the regional variation in atrophy. Therefore, the sensitivity of brain MRE to brain volume and aging was investigated in 66 healthy volunteers aged 18–72. A linear decline in whole-brain elasticity was observed (−0.75%/year, R-square = 0.59, p<0.001); the rate is three times that determined by volume measurements (−0.23%/year, R-square = 0.4, p<0.001). The highest decline in elasticity (−0.92%/year, R-square = 0.43, p<0.001) was observed in a region of interest placed in the frontal lobe with minimal age-related shrinkage (−0.1%, R-square = 0.06, p = 0.043). Our results suggest that cerebral MRE can measure geometry-independent viscoelastic parameters related to intrinsic tissue structure and altered by age.     

MRI pattern recognition in multiple sclerosis normal-appearing brain areas

Objective

Here, we use pattern-classification to investigate diagnostic information for multiple sclerosis (MS; relapsing­remitting type) in lesioned areas, areas of normal­appearing grey matter (NAGM), and normal-appearing white matter (NAWM) as measured by standard MR techniques.

Methods

A lesion mapping was carried out by an experienced neurologist for Turbo Inversion Recovery Magnitude (TIRM) images of individual subjects. Combining this mapping with templates from a neuroanatomic atlas, the TIRM images were segmented into three areas of homogenous tissue types (Lesions, NAGM, and NAWM) after spatial standardization. For each area, a linear Support Vector Machine algorithm was used in multiple local classification analyses to determine the diagnostic accuracy in separating MS patients from healthy controls based on voxel tissue intensity patterns extracted from small spherical subregions of these larger areas. To control for covariates, we also excluded group-specific biases in deformation fields as a potential source of information.

Results

Among regions containing lesions a posterior parietal WM area was maximally informative about the clinical status (96% accuracy, p<10⁻¹³). Cerebellar regions were maximally informative among NAGM areas (84% accuracy, p<10⁻⁷). A posterior brain region was maximally informative among NAWM areas (91% accuracy, p<10⁻¹⁰).

Interpretation

We identified regions indicating MS in lesioned, but also NAGM, and NAWM areas. This complements the current perception that standard MR techniques mainly capture macroscopic tissue variations due to focal lesion processes. Compared to current diagnostic guidelines for MS that define areas of diagnostic information with moderate spatial specificity, we identified hotspots of MS associated tissue alterations with high specificity defined on a millimeter scale.     

Molar macrowear reveals Neanderthal eco-geographic dietary variation

Neanderthal diets are reported to be based mainly on the consumption of large and medium sized herbivores, while the exploitation of other food types including plants has also been demonstrated. Though some studies conclude that early Homo sapiens were active hunters, the analyses of faunal assemblages, stone tool technologies and stable isotopic studies indicate that they exploited broader dietary resources than Neanderthals. Whereas previous studies assume taxon-specific dietary specializations, we suggest here that the diet of both Neanderthals and early Homo sapiens is determined by ecological conditions. We analyzed molar wear patterns using occlusal fingerprint analysis derived from optical 3D topometry. Molar macrowear accumulates during the lifespan of an individual and thus reflects diet over long periods. Neanderthal and early Homo sapiens maxillary molar macrowear indicates strong eco-geographic dietary variation independent of taxonomic affinities. Based on comparisons with modern hunter-gatherer populations with known diets, Neanderthals as well as early Homo sapiens show high dietary variability in Mediterranean evergreen habitats but a more restricted diet in upper latitude steppe/coniferous forest environments, suggesting a significant consumption of high protein meat resources.     

N-acetylglucosamine drives myelination by triggering oligodendrocyte precursor cell differentiation

Myelination plays an important role in cognitive development and in demyelinating diseases like multiple sclerosis (MS), where failure of remyelination promotes permanent neuro-axonal damage. Modification of cell surface receptors with branched N-glycans coordinates cell growth and differentiation by controlling glycoprotein clustering, signaling, and endocytosis. GlcNAc is a rate-limiting metabolite for N-glycan branching. Here we report that GlcNAc and N-glycan branching trigger oligodendrogenesis from precursor cells by inhibiting platelet-derived growth factor receptor-α cell endocytosis. Supplying oral GlcNAc to lactating mice drives primary myelination in newborn pups via secretion in breast milk, whereas genetically blocking N-glycan branching markedly inhibits primary myelination. In adult mice with toxin (cuprizone)-induced demyelination, oral GlcNAc prevents neuro-axonal damage by driving myelin repair. In MS patients, endogenous serum GlcNAc levels inversely correlated with imaging measures of demyelination and microstructural damage. Our data identify N-glycan branching and GlcNAc as critical regulators of primary myelination and myelin repair and suggest that oral GlcNAc may be neuroprotective in demyelinating diseases like MS.     

Optical Coherence Tomography Reveals Distinct Patterns of Retinal Damage in Neuromyelitis Optica and Multiple Sclerosis

Background

Neuromyelitis optica (NMO) and relapsing-remitting multiple sclerosis (RRMS) are difficult to differentiate solely on clinical grounds. Optical coherence tomography (OCT) studies investigating retinal changes in both diseases focused primarily on the retinal nerve fiber layer (RNFL) while rare data are available on deeper intra-retinal layers.

Objective

To detect different patterns of intra-retinal layer alterations in patients with NMO spectrum disorders (NMOSD) and RRMS with focus on the influence of a previous optic neuritis (ON).

Methods

We applied spectral-domain OCT in eyes of NMOSD patients and compared them to matched RRMS patients and healthy controls (HC). Semi-automatic intra-retinal layer segmentation was used to quantify intra-retinal layer thicknesses. In a subgroup low contrast visual acuity (LCVA) was assessed.

Results

NMOSD-, MS- and HC-groups, each comprising 17 subjects, were included in analysis. RNFL thickness was more severely reduced in NMOSD compared to MS following ON. In MS-ON eyes, RNFL thinning showed a clear temporal preponderance, whereas in NMOSD-ON eyes RNFL was more evenly reduced, resulting in a significantly lower ratio of the nasal versus temporal RNFL thickness. In comparison to HC, ganglion cell layer thickness was stronger reduced in NMOSD-ON than in MS-ON, accompanied by a more severe impairment of LCVA. The inner nuclear layer and the outer retinal layers were thicker in NMOSD-ON patients compared to NMOSD without ON and HC eyes while these differences were primarily driven by microcystic macular edema.

Conclusion

Our study supports previous findings that ON in NMOSD leads to more pronounced retinal thinning and visual function impairment than in RRMS. The different retinal damage patterns in NMOSD versus RRMS support the current notion of distinct pathomechanisms of both conditions. However, OCT is still insufficient to help with the clinically relevant differentiation of both conditions in an individual patient.     

La Crosse bunyavirus nonstructural protein NSs serves to suppress the type I interferon system of mammalian hosts

La Crosse virus (LACV) is a mosquito-transmitted member of the Bunyaviridae family that causes severe encephalitis in children. For the LACV nonstructural protein NSs, previous overexpression studies with mammalian cells had suggested two different functions, namely induction of apoptosis and inhibition of RNA interference (RNAi). Here, we demonstrate that mosquito cells persistently infected with LACV do not undergo apoptosis and mount a specific RNAi response. Recombinant viruses that either express (rLACV) or lack (rLACVdelNSs) the NSs gene similarly persisted and were prone to the RNAi-mediated resistance to superinfection. Furthermore, in mosquito cells overexpressed LACV NSs was unable to inhibit RNAi against Semliki Forest virus. In mammalian cells, however, the rLACVdelNSs mutant virus strongly activated the antiviral type I interferon (IFN) system, whereas rLACV as well as overexpressed NSs suppressed IFN induction. Consequently, rLACVdelNSs was attenuated in IFN-competent mouse embryo fibroblasts and animals but not in systems lacking the type I IFN receptor. In situ analyses of mouse brains demonstrated that wild-type and mutant LACV mainly infect neuronal cells and that NSs is able to suppress IFN induction in the central nervous system. Thus, our data suggest little relevance of the NSs-induced apoptosis or RNAi inhibition for growth or pathogenesis of LACV in the mammalian host and indicate that NSs has no function in the insect vector. Since deletion of the viral NSs gene can be fully complemented by inactivation of the host's IFN system, we propose that the major biological function of NSs is suppression of the mammalian innate immune response.     

Vitamin D in the treatment of pulmonary tuberculosis

Vitamin D was used to treat tuberculosis in the pre-antibiotic era. New insights into the immunomodulatory properties of 1alpha,25-dihydroxy-vitamin D have rekindled interest in vitamin D as an adjunct to antituberculous therapy. We describe the historical use of vitamin D in tuberculosis treatment; discuss the mechanisms by which it may modulate host response to infection with Mycobacterium tuberculosis; and review three clinical trials and ten case series in which vitamin D has been used in the treatment of pulmonary tuberculosis.