Caveolin-1 enhances resveratrol-mediated cytotoxicity and transport in a hepatocellular carcinoma model

<p>Abstract</p> <p>Background</p> <p>Resveratrol (RES), an estrogen analog, is considered as a potential cancer chemo-preventive agent. However, it remains unclear how RES is transported into cells. In this study, we observed that Caveolin-1(CAV1) expression can increase the cytotoxic and pro-apoptotic activity of RES in a dose- and time-dependent manner both <it>in vitro </it>and <it>in vivo </it>in a Hepatocellular Carcinoma animal model.</p> <p>Methods</p> <p>High performance liquid chromatography (HPLC) demonstrated that RES intra-cellular concentration is increased about 2-fold in cells stably expressing CAV1 or CAVM1 (a scaffolding domain (81-101AA)-defective CAV1 mutant) compared to the untransduced human Hepatoblastoma cell line (HepG2) or after transduction with the green fluorescent protein (GFP) control vector. The increased intra-cellular transport of RES was abolished in cells stably expressing CAVM2 (a cholesterol shuttle domain (143-156AA)-defective CAV1 mutant) or CAVRNAi. In order to further characterize CAV1-dependent RES transport, we synthesized RES-dansyl chloride derivatives as fluorescent probes to visualize the transport process, which demonstrated a distribution consistent with that of CAV1 in HepG2 cells.</p> <p>Results</p> <p>In addition, RES endocytosis was not mediated by estrogen receptor (ER) α and β, as suggested by lack of competitive inhibition by estrogen or Tamoxifen. Pathway analysis showed that RES can up-regulate the expression of endogenous CAV1; this activates further the MAPK pathway and caspase-3 expression.</p> <p>Discussion</p> <p>This study provides novel insights about the role played by CAV1 in modulating cellular sensitivity to RES through enhancement of its internalization and trafficking.</p

Diversification of Schistosoma japonicum in Mainland China Revealed by Mitochondrial DNA

Despite the existing threat of schistosomiasis in some rural areas along the Yangtze River, the genetic diversity of Schistosoma japonicum has not been investigated across its wide geographical distribution in China, and such information may provide insight into the disease epidemiology and the development of its control measures. In this study, the adult parasites, obtained through infecting mice with cercariae from snails of the genus Oncomelania collected from a wide range of localities in currently endemic areas of schistosomiasis in the middle and lower (ML) reaches of the Yangtze River, and in Sichuan and Yunnan provinces in the upper reaches of the river in southwest (SW) China, were sequenced individually for mitochondrial genes. In general, a relatively high degree of genetic variation was observed in populations in the ML reaches in terms of nucleotide and haplotype diversity, but a low level was observed in populations in the SW. The significant difference in genetic diversity as revealed by F-statistics, and the existence of no shared haplotypes, were observed between populations in the ML reaches and those in the SW, indicating the effect of geographical separation/isolation upon the schistosomes and probably the parasite-snail system in China

The genome and transcriptome of Japanese flounder provide insights into flatfish asymmetry

Flatfish have the most extreme asymmetric body morphology of vertebrates. During metamorphosis, one eye migrates to the contralateral side of the skull, and this migration is accompanied by extensive craniofacial transformations and simultaneous development of lopsided body pigmentation(1-5). The evolution of this developmental and physiological innovation remains enigmatic. Comparative genomics of two flatfish and transcriptomic analyses during metamorphosis point to a role for thyroid hormone and retinoic acid signaling, as well as phototransduction pathways. We demonstrate that retinoic acid is critical in establishing asymmetric pigmentation and, via cross-talk with thyroid hormones, in modulating eye migration. The unexpected expression of the visual opsins from the phototransduction pathway in the skin translates illumination differences and generates retinoic acid gradients that underlie the generation of asymmetry. Identifying the genetic underpinning of this unique developmental process answers long-standing questions about the evolutionary origin of asymmetry, but it also provides insight into the mechanisms that control body shape in vertebrates.National Natural Science Foundation of China [31130057, 31461163005, 31530078, 31472269, 31472262, 31472273]; State 863 High Technology R&D Project of China [2012AA092203, 2012AA10A408, 2012AA10A403-2]; Education and Research of Guangdong Province [2013B090800017]; Taishan Scholar Climb Project Fund of Shandong of China; Taishan Scholar Project Fund of Shandong of China for Young Scientists; Shanghai Universities First-class Disciplines Project of Fisheries; Program for Professor of Special Appointment (Eastern Scholar) at the Shanghai Institutions of Higher Learning; Shanghai Municipal Science, Special Project on the Integration of Industryinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/publishedVersio

A multimodal cell census and atlas of the mammalian primary motor cortex

ABSTRACT We report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex (MOp or M1) as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties, and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Together, our results advance the collective knowledge and understanding of brain cell type organization: First, our study reveals a unified molecular genetic landscape of cortical cell types that congruently integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a unified taxonomy of transcriptomic types and their hierarchical organization that are conserved from mouse to marmoset and human. Third, cross-modal analysis provides compelling evidence for the epigenomic, transcriptomic, and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types and subtypes. Fourth, in situ single-cell transcriptomics provides a spatially-resolved cell type atlas of the motor cortex. Fifth, integrated transcriptomic, epigenomic and anatomical analyses reveal the correspondence between neural circuits and transcriptomic cell types. We further present an extensive genetic toolset for targeting and fate mapping glutamatergic projection neuron types toward linking their developmental trajectory to their circuit function. Together, our results establish a unified and mechanistic framework of neuronal cell type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties

Values of the Minimal Clinically Important Difference for the Neuropsychiatric Inventory Questionnaire in Individuals with Dementia

ObjectivesTo estimate the minimal clinically important difference (MCID) for the Neuropsychiatric Inventory Questionnaire (NPI-Q), a widely used measure of behavioral and psychological symptoms of dementia (BPSDs) and associated caregiver stress. ;DesignTen registered nurses rated the severity of BPSDs and caregiver distress using the NPI-Q during six monthly assessments and an external reference, a 7-point Likert-type global rating of BPSDs change during five monthly assessments from the second to the sixth month. An anchor-based (global ratings of change) approach and a distribution-based (standard error of measurement) approach were used to determine the MCID for the NPI-Q severity and distress subscales. ;SettingLong-term care facility. ;ParticipantsNonbedridden residents with dementia (n=45) and registered nurses (n=10). ;MeasurementsNPI-Q (severity and caregiver distress subscales) and global ratings of changes in BPSDs on a 7-point Likert-type scale. ;ResultsThe NPI-Q MCID ranges were 2.77 to 3.18 for severity and 3.10 to 3.95 for distress. Residents in the highest NPI-Q tertile at baseline had higher MCID severity (3.62) and distress (5.08) scores than those in the lowest tertile (severity (2.40), distress (3.10)). ;ConclusionThis study provides an estimate of the MCID for severity and distress subscales of the NPI-Q, which can help clinicians and researchers determine whether NPI-Q change scores within a group of individuals with dementia are beyond measurement error and are clinically important

Indicators of perceived useful dementia care assistive technology: Caregivers' perspectives

AimThe study aims to investigate the caregivers' context-specific perceived usefulness of available assistive technology (AT) devices and the professionals' perspectives on the usefulness indicators of AT devices for home-dwelling individuals with mild-to-moderate dementia. ;MethodsA total of 72 caregivers completed a questionnaire rating 82 AT devices with a high-perceived usefulness (HPU) or low-perceived usefulness (LPU). A total of 21 experts rated 10 usefulness indicators of these devices. We compared the mean of each indicator between the HPU and LPU groups. ;ResultsMost caregivers, who are generally amenable to using AT devices, thought they were useful for helping to care for home-dwelling older adults with mild-to-moderate dementia. The level of perceived usefulness from the experts' perspectives depends on specific design indicators (e.g. familiarity) and the context in which the AT is used (e.g. in everyday life or in emergencies). Indicators for HPU devices were: allows selective accident prevention, has an intuitive interface, is familiar, offers ease of use and simplifies activities. LPU devices featured client prompting. There were no significant differences between HPU and LPU devices with indicators of: is automated, informs caregiver, preserves privacy and preserves autonomy. Safety issues were considered important, and sometimes overshadowed ethical dilemmas, such as privacy and autonomy concern. ;ConclusionsThe present study provides insight into how caregivers perceived the usefulness of AT devices, and how that varied with context. Indicators of devices perceived as useful can serve as guidelines for modifying existing devices and designing new devices. Future application could also incorporate the points of view from the persons with dementia. Geriatr Gerontol Int 2015; 15: 1049-1057