Lower vertebrates have an intrinsically-photosensitive iris and thus a local pupillary light reflex (PLR). In contrast, it has been a dogma that the PLR in mammals generally requires neuronal circuitry connecting the eye and the brain. We report here that an intrinsic component of the PLR is actually widespread in nocturnal and crepuscular mammals. In mouse, this intrinsic PLR requires the visual pigment, melanopsin. It also requires PLCβ4, the vertebrate homolog of the Drosophila NorpA phospholipase C mediating rhabdomeric phototransduction. The Plcβ4−/− genotype, besides removing the intrinsic PLR, also essentially eliminates the intrinsic light response of the M1-subtype of melanopsin-expressing, intrinsically-photosensitive retinal ganglion cells (M1-ipRGCs), by far the most photosensitive ipRGCs and with the largest responses. Ablating in mouse the expression of both TRPC6 and TRPC7, members of the TRP channel superfamily, likewise essentially eliminated the M1-ipRGC light response, but spared the intrinsic PLR. Thus, melanopsin signaling exists in both iris and retina, involving a PLCβ4-mediated pathway that nonetheless diverges in the two locations.

Japanese encephalitis virus (JEV) is a leading cause of viral encephalitis. However, the mechanisms of JEV penetration of the blood-brain-barrier (BBB) remain poorly understood. Mast cells (MCs) are granulated innate immune sentinels located perivascularly, including at the BBB. Here we show that JEV activates MCs, leading to the release of granule-associated proteases in vivo. MC-deficient mice display reduced BBB permeability during JEV infection compared to congenic wild-type (WT) mice, indicating that enhanced vascular leakage in the brain during JEV infection is MC-dependent. Moreover, MCs promoted increased JEV infection in the central nervous system (CNS), enhanced neurological deficits, and reduced survival in vivo. Mechanistically, chymase, a MC-specific protease, enhances JEV-induced breakdown of the BBB and cleavage of tight-junction proteins. Chymase inhibition reversed BBB leakage, reduced brain infection and neurological deficits during JEV infection, and prolonged survival, suggesting chymase is a novel therapeutic target to prevent JEV encephalitis.

Japanese encephalitis virus (JEV) is a positive-sense single-stranded RNA virus of the Flavivirus genus that is spread by Culex mosquitos. It is maintained in an enzootic cycle in pigs and wild birds in which humans are dead-end hosts [1]. Despite having effective vaccines, JEV is the leading cause of viral encephalitis in Asia [1]. As a neuroinvasive virus, it can effectively cross the blood-brain barrier (BBB) to cause acute encephalitis. Twenty-five percent to 30% of Japanese encephalitis (JE) cases are fatal, and 50% result in permanent neuropsychiatric complications [2]. There are currently no treatments for JE, partly due to an incomplete understanding of the mechanisms promoting encephalitis. The central nervous system (CNS) relies on the BBB, a tightly regulated barrier between the peripheral circulation and the CNS, to prevent entry of pathogens, including viruses. Yet, JEV and other neuroinvasive viruses can overcome the BBB, which usually excludes foreign substances. It is formed primarily by tight junctions (TJ) between endothelial cells, comprised of proteins such as claudin-5, zonula occludens (ZO)-1, and occludin. The BBB is sustained by supporting cell types, including astrocytes, pericytes, microglia, and mast cells (MCs) [1, 3]. Together, these cells form neurovascular units that maintain a barrier along the cerebrovascular microvessels to promote immune privilege and CNS homeostasis [3, 4]. Neuroinvasive viruses use several mechanisms to access the CNS: (1) direct infection of endothelial cells and subsequent transcellular release of virus into the brain parenchyma, (2) infection of peripheral immune cells that enter the CNS in a "Trojan Horse" mechanism, (3) paracellular entry following breakdown of the BBB, (4) retrograde transport of virus from the peripheral nervous system (PNS) into the CNS, and (5) translocation from the blood to the cerebral spinal fluid (CSF) [5, 6] (Fig 1). JEV infection through the natural subcutaneous route leads to widespread infection in various parts of the brain [7], suggesting a hematological route of infection, such as would occur for mechanisms 1-3. Here we provide an overview of a few described mechanisms of JEV penetration of the BBB and processes that amplify CNS infection. Transcellular infection of endothelial cells and activation of the neurovascular unit Some neurotropic viruses directly infect endothelial cells to reach the brain from the circulation and travel transcellularly to release viruses into the brain parenchyma [6]. JEV has been

BackgroundIntracerebral hemorrhage (ICH) accounts for 10–15% of all first time strokes and with incidence twice as high in the Asian compared to Western population. This study aims to investigate gender differences in ICH patient outcomes in a multi-ethnic Asian population.MethodData for 1,192 patients admitted for ICH were collected over a four-year period. Multivariate logistic regression was used to identify independent predictors and odds ratios were computed for 30-day mortality and Glasgow Outcome Scale (GOS) comparing males and females.ResultMales suffered ICH at a younger age than females (62.2 ± 13.2 years vs. 66.3 ± 15.3 years; P<0.001). The occurrence of ICH was higher among males than females at all ages until 80 years old, beyond which the trend was reversed. Females exhibited increased severity on admission as measured by Glasgow Coma Scale compared to males (10.9 ± 4.03 vs. 11.4 ± 4.04; P = 0.030). No difference was found in 30-day mortality between females and males (F: 30.5% [155/508] vs. M: 27.0% [186/688]), with unadjusted and adjusted odds ratio (F/M) of 1.19 (P = 0.188) and 1.21 (P = 0.300). At discharge, there was a non-statistically significant but potentially clinically relevant morbidity difference between the genders as measured by GOS (dichotomized GOS of 4–5: F: 23.7% [119/503] vs. M: 28.7% [194/677]), with unadjusted and adjusted odds ratio (F/M) of 0.77 (P = 0.055) and 0.87 (P = 0.434).ConclusionIn our multi-ethnic Asian population, males developed ICH at a younger age and were more susceptible to ICH than women at all ages other than the beyond 80-year old age group. In contrast to the Western population, neurological status of female ICH patients at admission was poorer and their 30-day mortality was not reduced. Although the study was not powered to detect significance, female showed a trend toward worse 30-day morbidity at discharge.