We describe the discovery and isolation of a paramyxovirus, feline morbillivirus (FmoPV), from domestic cat ( Felis catus ). FmoPV RNA was detected in 56 (12.3%) of 457 stray cats (53 urine, four rectal swabs, and one blood sample) by RT-PCR. Complete genome sequencing of three FmoPV strains showed genome sizes of 16,050 bases, the largest among morbilliviruses, because of unusually long 5′ trailer sequences of 400 nt. FmoPV possesses identical gene contents (3′-N-P/V/C-M-F-H-L-5′) and is phylogenetically clustered with other morbilliviruses. IgG against FmoPV N protein was positive in 49 sera (76.7%) of 56 RT-PCR–positive cats, but 78 (19.4%) of 401 RT-PCR–negative cats ( P < 0.0001) by Western blot. FmoPV was isolated from CRFK feline kidney cells, causing cytopathic effects with cell rounding, detachment, lysis, and syncytia formation. FmoPV could also replicate in subsequent passages in primate Vero E6 cells. Infected cell lines exhibited finely granular and diffuse cytoplasmic fluorescence on immunostaining for FmoPV N protein. Electron microscopy showed enveloped virus with typical “herringbone” appearance of helical N in paramyxoviruses. Histological examination of necropsy tissues in two FmoPV-positive cats revealed interstitial inflammatory infiltrate and tubular degeneration/necrosis in kidneys, with decreased cauxin expression in degenerated tubular epithelial cells, compatible with tubulointerstitial nephritis (TIN). Immunohistochemical staining revealed FmoPV N protein-positive renal tubular cells and mononuclear cells in lymph nodes. A case-control study showed the presence of TIN in seven of 12 cats with FmoPV infection, but only two of 15 cats without FmoPV infection ( P < 0.05), suggesting an association between FmoPV and TIN.

Sequential processing of amyloid precursor protein (APP) by membrane-bound proteases, BACE1 and ␥-secretase, plays a crucial role in the pathogenesis of Alzheimer disease. Much has been discovered on the properties of these proteases; however, regulatory mechanisms of enzyme-substrate interaction in neurons and their involvement in pathological changes are still not fully understood. It is mainly because of the membrane-associated cleavage of these proteases and the lack of information on new substrates processed in a similar way to APP. Here, using RNA interference-mediated BACE1 knockdown, mouse embryonic fibroblasts that are deficient in either BACE1 or presenilins, and BACE1-deficient mouse brain, we show clear evidence that ␤ subunits of voltage-gated sodium channels are sequentially processed by BACE1 and ␥-secretase. These results may provide new insights into the underlying pathology of Alzheimer disease.Alzheimer disease is a progressive neurodegenerative disorder and the most common form of age-dependent dementia. The major pathological features of Alzheimer disease are senile plaques and neurofibrillary tangles, which are the deposits of amyloid ␤ peptide (A␤) 1 and hyperphosphorylated tau, respectively. It is widely accepted that the sequential processing of APP, a type I membrane protein, by ␤-and ␥-secretases in the brain is crucial for the accumulation of A␤ and disease pathogenesis (1, 2). Although ␤-site APP-cleaving enzyme (BACE1) has been identified to be the ␤-secretase (3-6), a growing body of evidence favors presenilins-1 and -2 as the catalytic core of ␥-secretase (7). Although the properties of both proteases as APP processing enzymes are relatively well established, the regulatory mechanisms of sequential cleavage by both proteases in neurons are not completely clear. This is partly because of the fact that APP and its family proteins are still the only substrates identified for both ␤-and ␥-secretases, although a number of integral membrane proteins have been reported to be processed either by BACE1 (8, 9) or ␥-secretase (10). Identifying new substrates for both ␤-and ␥-secretases in neurons would therefore be useful to further explore the precise mechanism by which BACE1 and ␥-secretase function in cohort.Recently, our laboratory has been focusing on examining the role of voltage-gated sodium channel (VGSC) ␤ in the pathogenesis of Huntington disease and the regulation of APP processing in lipid rafts.2,3 VGSC is a large, multimeric complex that consists of an ␣ subunit and one or more ␤ subunits. To date, nine functional ␣ subunits and four ␤ subunits have been identified (11,12). Although VGSC␤ subunits are not essential to the basic operation of sodium channels, they are considered to be important auxiliary subunits, because co-expression of ␤ subunits are required to reconstitute full properties of the native sodium channel and to modify channel properties and intracellular localization (11,13). In the course of analyzing the VGSC␤, we found that these subunits are preferentially a...

Pathological angiogenesis-driven by an imbalance of pro-and antiangiogenic signaling-is a hallmark of many diseases, both malignant and benign. Unlike in the healthy adult in which angiogenesis is tightly regulated, such diseases are characterized by uncontrolled new vessel formation, resulting in a microvascular network characterized by vessel immaturity, with profound structural and functional abnormalities. The consequence of these abnormalities is further modification of the microenvironment, often serving to fuel disease progression and attenuate response to conventional therapies. In this article, we present the "vascular normalization" hypothesis, which states that antiangiogenic therapy, by restoring the balance between pro-and antiangiogenic signaling, can induce a more structurally and functionally normal vasculature in a variety of diseases. We present the preclinical and clinical evidence supporting this concept and discuss how it has contributed to successful treatment of both solid tumors and several benign conditions.

Alzheimer's disease (AD) is a multifactorial and fatal neurodegenerative disorder for which the mechanisms leading to profound neuronal loss are incompletely recognized. MicroRNAs (miRNAs) are recently discovered small regulatory RNA molecules that repress gene expression and are increasingly acknowledged as prime regulators involved in human brain pathologies. Here we identified two homologous miRNAs, miR-132 and miR-212, downregulated in temporal cortical areas and CA1 hippocampal neurons of human AD brains. Sequence-specific inhibition of miR-132 and miR-212 induces apoptosis in cultured primary neurons, whereas their overexpression is neuroprotective against oxidative stress. Using primary neurons and PC12 cells, we demonstrate that miR-132/212 controls cell survival by direct regulation of PTEN, FOXO3a and P300, which are all key elements of AKT signaling pathway. Silencing of these three target genes by RNAi abrogates apoptosis caused by the miR-132/212 inhibition. We further demonstrate that mRNA and protein levels of PTEN, FOXO3a, P300 and most of the direct pro-apoptotic transcriptional targets of FOXO3a are significantly elevated in human AD brains. These results indicate that the miR-132/miR-212/PTEN/FOXO3a signaling pathway contributes to AD neurodegeneration.