Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature. The Seattle International Registry recruits patients from all over the world to investigate genetic causes of a wide variety of progeroid syndromes in order to contribute to the knowledge of basic mechanisms of human aging. Given the unusually high prevalence of WS patients and heterozygous carriers in Japan, the major goal of the Japanese Consortium is to develop effective therapies and to establish management guidelines for WS patients in Japan and elsewhere. This review will also discuss potential translational approaches to this disorder, including those currently under investigation.

No abstract

Objective-CCN3 belongs to the CCN family, which constitutes multifunctional secreted proteins that act as matrix cellular regulators. We investigated the pathophysiological roles of CCN3 in the vessels. Methods and Results-We examined the effects of CCN3 on the proliferation and migration of rat vascular smooth muscle cells (VSMC). CCN3 knockout mice were created, and vascular phenotypes and neointimal hyperplasia induced by photochemically induced thrombosis were investigated. CCN3 suppressed the VSMC proliferation induced by fetal bovine serum. The neutralizing antibody for transforming growth factor-␤ did not affect the growth inhibitory effect of CCN3. Moreover, CCN3 enhanced the mRNA expression of cyclin-dependent kinase inhibitors, p21 and p15. Gamma secretase inhibitor, an inhibitor of Notch signaling, partially inhibited the enhanced expression of p21 induced by CCN3. CCN3 also inhibited the VSMC migration. Finally, the histopathologic evaluation of the arteries 21 days after the endothelial injury revealed a 6-fold enhancement of neointimal thickening in the null mice compared with the wild-type mice. Conclusion-CCN3 See accompanying article on page 667Although other members of the CCN family, such as CCN1 and CCN2, are strongly expressed in a wide range of tissues, 6,7 CCN3 mRNA is highly and restrictively expressed in rat aortas and carotid arteries. 8 This specific expression pattern in vessels indicates that CCN3 plays an important role in vascular homeostasis. This article accompanies the DVT Series that was published in the March 2010 issue.The knockdown of CCN1/Cyr61 in mice suppresses neointimal hyperplasia in a rat artery balloon injury model. 9 CCN2/ CTGF also accumulates in the shoulders of human rupture-prone atherosclerotic plaques. 10 Because CTGF induces mononuclear cell chemotaxis in a dose-dependent manner in vitro, CTGF may also have a role in atherogenesis. However, despite the similarity of the amino acid sequence of CCN3 and CCN1 and CCN2, 4 the pathophysiological roles of CCN3 in vessels has not been fully elucidated. The present study confirmed the expression of CCN3 in medial layer of mouse aortas. Therefore, the effects of CCN3 on vascular smooth muscle cell (VSMC) proliferation and migration were investigated. Finally, CCN3-null mice were created and the physiological and pathological roles of CCN3 in vessels were determined. Materials and Methods ReagentsThe reagents used are described in the expanded Supplementary Materials and Methods section (available online at http://atvb.ahajournals.org). Cell CulturePrimary cultures of rat aortic smooth muscle cells were isolated from 250-to 300-gram Wister Rats (QLEA Japan, Inc.) as described previously. 11 See the Supplementary Materials and Methods section for details. Semiquantitative Reverse-Transcription Polymerases Chain ReactionReverse-transcription polymerase chain reaction is described in the Supplementary Materials and Methods section. Proliferation AssayVSMC proliferation was quantified by direct cell counting and by 5-bro...

To evaluate the role of fish larvae as a Link between the microbial loop and higher trophic levels, predation of protozoan zooplankton by young larvae was investigated. More than 400 individual fish larvae with total lengths of less than ca 10 mm in 52 different taxonomic groups were collected at different sampling times from several coastal regions, and the gut contents of larvae were exarnined under epifluorescence microscopy after staining with DAPI. Among numerous fragments of copepod nauplii, many flagellate-like cells with a size of 5 pm and ciliate-like cells with a size of 20 to 30 pm were frequently recognized. The number of protozoan cells varied significantly from one larva to another. Some individuals had more than 60 protozoa. while others contained none at all. The amount of protists contained in the gut of larvae depended on the fish species and did not show any trend with the body or rnouth sizes of larvae, nor the sampling site or season. Fish taxa were divided into 3 groups depending on the amount of protists in the gut: 'abundant', 'moderate', and 'none' The Acanthopterygii group contained the highest concentration of protozoa. Results of the present study suggested that fish larvae of some taxonon~ical groups were important predators of protozoa and may be an important link between the microbial loop and the grazing food chain.

Loss of motor coordination is one of the main problems for patients after stroke. Muscle synergy is widely accepted as an indicator of motor coordination. Recently, the characteristics of muscle synergy were quantitatively evaluated using nonnegative matrix factorization (NNMF) with surface electromyography. Previous studies have identified that the number and structure of synergies were associated with motor function in patients after stroke. However, most of these studies had a cross-sectional design, and the changes in muscle synergy during recovery process are not clear. In present study, two consecutive measurements were conducted for subacute patients after stroke and the change of number and structure of muscle synergies during gait were determined using NNMF. Results showed that functional change did not rely on number of synergies in patients after subacute stroke. However, the extent of merging of the synergies was negatively associated with an increase in muscle strength and the range of angle at ankle joint. Our results suggest that the neural changes represented by NNMF were related to the longitudinal change of function and gait pattern and that the merging of synergy is an important marker in patients after subacute stroke.

No abstract

There is no detailed information on the association between age, time of disease, and HIV-associated neurocognitive disorders (HAND). In this prospective study involving 17 medical facilities across Japan, we recruited HIV-infected patients to complete a 14-test neuropsychological battery that assess eight neurocognitive domains. HAND were diagnosed by the Frascati criteria. Of 1399 recruited patients, 728 were enrolled. The prevalence of HAND was 25.3% [13.5% asymptomatic neurocognitive impairment, 10.6% mild neurocognitive disorder (MND), and 1.2% HIV-associated dementia (HAD)]. Tests that assess executive and visuospatial functions showed better diagnostic accuracy than other tests for HAND. Multivariate analysis identified age (≥ 50 years) and incomplete virological suppression as risk factors for MND and HAD and current ART as a protective factor. The prevalence of MND and HAD was low in the early stage of infection (6.3% in ≥ 2 to < 6 years), then increased in the later stage [17.3% in ≥ 11 years, p = 0.001 (vs. ≥ 2 to < 6 years)], independent of age or treatment. Older patients were more likely to show MND or HAD in the early stage of HIV infection (26.7 vs. 8.7% for < 2 years and 17.4 vs. 3.1% for ≥ 2 to < 6 years, p = 0.040 and 0.004, respectively) compared to younger ones. In conclusion, MND and HAD were more commonly found in later years since diagnosis of HIV infection and older patients are at risk of neurocognitive impairment at the early stage of HIV infection. Tests for executive and visuospatial functions seem more sensitive than other tests for diagnosing HAND.

Syngnathid fish (pipefish and seahorses) are unique among teleost fish in that their ovary consists of a rolled sheet with germinal ridge(s) on the dorsal side running along the entire length of the sheet. A distinct difference is seen in the ovarian structure between polygamous Syngnathus pipefish and monogamous seahorses ( Hippocampus spp.), the former having one germinal ridge and the latter with two ridges. This study examined the ovarian structure and the mode of egg production in a monogamous pipefish Corythoichthys haematopterus . The ovary of C. haematopterus had two germinal ridges like that observed in monogamous seahorses. There were two distinct groups of follicles in the ovary, one being a cohort of extremely small follicles and the other a cohort of follicles developing and increasing in size with the passage of time. We suggest that the ovarian structure and the mode of egg production in this pipefish are adaptations to monogamy.