Genome-wide association study meta-analysis for quantitative ultrasound parameters of bone identifies five novel loci for broadband ultrasound attenuation.

Osteoporosis is a common and debilitating bone disease that is characterised by low bone mineral density, typically assessed using dual-energy X-ray absorptiometry. Quantitative ultrasound (QUS), commonly utilising the two parameters velocity of sound (VOS) and broadband ultrasound attenuation (BUA), is an alternative technology used to assess bone properties at peripheral skeletal sites. The genetic influence on the bone qualities assessed by QUS remains an under-studied area. We performed a comprehensive GWAS including low-frequency variants (MAF ≥0.005) for BUA and VOS using a discovery population of individuals with whole-genome sequence (WGS) data from the UK10K project (n=1,268). These results were then meta-analysed with those from two deeply imputed GWAS replication cohorts (n=1,610 and 13,749). In the gender-combined analysis, we identified eight loci associated with BUA and five with VOS at the genome-wide significance level, including three novel loci for BUA at 8p23.1 (PPP1R3B), 11q23.1 (LOC387810) and 22q11.21 (SEPT5) (P = 2.4 × 10-8-1.6 × 10-9). Gene-based association testing in the gender-combined dataset revealed eight loci associated with BUA and seven with VOS at the genome-wide significance level, with one novel locus for BUA at FAM167A (8p23.1) (P = 1.4 × 10-6). An additional novel locus for BUA was seen in the male-specific analysis at DEFB103B (8p23.1) (P = 1.8 × 10-6). Fracture analysis revealed significant associations between variation at the WNT16 and RSPO3 loci and fracture risk (P = 0.004 and 4.0 × 10-4 respectively). In conclusion, by performing a large GWAS meta-analysis for QUS parameters of bone using a combination of WGS and deeply imputed genotype data, we have identified five novel genetic loci associated with BUA

Quantitative nanoscale vortex-imaging using a cryogenic quantum magnetometer

Microscopic studies of superconductors and their vortices play a pivotal role in our understanding of the mechanisms underlying superconductivity. Local measurements of penetration depths or magnetic stray-fields enable access to fundamental aspects of superconductors such as nanoscale variations of superfluid densities or the symmetry of their order parameter. However, experimental tools, which offer quantitative, nanoscale magnetometry and operate over the large range of temperature and magnetic fields relevant to address many outstanding questions in superconductivity, are still missing. Here, we demonstrate quantitative, nanoscale magnetic imaging of Pearl vortices in the cuprate superconductor YBCO, using a scanning quantum sensor in form of a single Nitrogen-Vacancy (NV) electronic spin in diamond. The sensor-to-sample distance of ~10nm we achieve allows us to observe striking deviations from the prevalent monopole approximation in our vortex stray-field images, while we find excellent quantitative agreement with Pearl's analytic model. Our experiments yield a non-invasive and unambiguous determination of the system's local London penetration depth, and are readily extended to higher temperatures and magnetic fields. These results demonstrate the potential of quantitative quantum sensors in benchmarking microscopic models of complex electronic systems and open the door for further exploration of strongly correlated electron physics using scanning NV magnetometry.Comment: Main text (5 pages, 4 figures) plus supplementary material (5 pages, 6 figures). Comments welcome. Further information under http://www.quantum-sensing.c

Myofibrillogenesis regulator 1 induces hypertrophy by promoting sarcomere organization in neonatal rat cardiomyocytes

Human myofibrillogenesis regulator 1, a novel 17-kDa protein, is closely involved in cardiac hypertrophy. We studied the molecular mechanism that links MR-1 to hypertrophic response. Hypertrophic hallmarks such as cell size and [3H]-leucine incorporation were significantly increased when MR-1 was transfected into cardiomyocytes for 48 h. However, sarcomere organization was promoted when MR-1 was transfected for 8 h. The finding that cardiac hypertrophy was induced long after increase of sarcomere organization indicates that the promoted sarcomere organization may be one of the crucial factors causing hypertrophy. Furthermore, when MR-1 was transfected into cardiomyocytes, the nuclear localization of myomesin-1 was shifted to the cytoplasm. Transfection with small ubiquitin-like modifier-1 (SUMO-1) mimicked the effect of MR-1 inducing translocation of myomesin-1. However, transfection with SUMO-1 in MR-1-silenced cardiomyocytes failed to induce translocation and sarcomere organization, even though SUMO-1 expression was at the same level. Overexpression of MR-1 may induce cardiomyocyte hypertrophy via myomesin-1-mediated sarcomere organization

Antimetastatic Effects of Norcantharidin on Hepatocellular Carcinoma by Transcriptional Inhibition of MMP-9 through Modulation of NF-kB Activity

The rate of morbidity and mortality of hepatocellular carcinoma (HCC) in Taiwan has not lessened because of difficulty in treating tumor metastasis. Norcantharidin (NCTD) is currently used as an anticancer drug for hepatoma, breast cancer, and colorectal adenocarcinoma. NCTD possesses various biological anticancer activities, including apoptosis. However, detailed effects and molecular mechanisms of NCTD on metastasis are unclear. Thus, HCC cells were subjected to treatment with NCTD and then analyzed to determine the effects of NCTD on cell metastasis.Modified Boyden chamber assays revealed that NCTD treatment inhibited cell migration and invasion capacities of HCC cells substantially. Results of zymography and western blotting showed that activities and protein levels of matrix metalloproteinase-9 (MMP-9) and urokinase plasminogen activator (u-PA) were inhibited by NCTD. Western blot analysis showed that NCTD inhibits phosphorylation of ERK1/2. Testing of mRNA level, quantitative real-time PCR, and promoter assays evaluated the inhibitory effects of NCTD on MMP-9 and u-PA expression in HCC cells. The chromatin immunoprecipitation (ChIP) assay for analyzing the genomic DNA sequences bound to these proteins was reactive to the transcription protein nuclear factor (NF)-kappaB, which was inhibited by NCTD. The expression of NF-kappa B was measured by western blot analysis, which revealed decreased nuclear-factor DNA-binding activity after NCTD treatment.NCTD inhibited MMP-9 and u-PA expression through the phosphorylation of ERK1/2 and NF-kappaB signaling pathway which serves as a powerful chemopreventive agent in HCC cell metastasis

Effects of Irritant Chemicals on Aedes aegypti Resting Behavior: Is There a Simple Shift to Untreated “Safe Sites”?

Aedes aegypti, the primary vector mosquito of dengue virus, typically lives near or inside human dwellings, and feeds preferentially on humans. The control of this mosquito vector remains the most important dengue prevention method. The use of chemicals at levels toxic to mosquitoes is currently the only confirmed effective adult vector control strategy with interventions usually applied following epidemic onset. However, research indicates that sub-lethal chemical approaches to prevent human-vector contact at the house level exist: contact irritancy and spatial repellency. The optimum efficacy of an intervention based on contact irritant actions of chemicals will, however, require full knowledge of variables that will influence vector resting behavior and thereby chemical uptake from treated sources. Here we characterize the resting patterns of female Ae. aegypti on two material types at various dark:light surface area coverage ratios and contrast configurations under chemical-free and treated conditions using a laboratory behavioral assay. Change in resting behavior between baseline and treatment conditions was quantified to determine potential negative effects of untreated surfaces (“safe sites”) when irritant responses are elicited. We show that treatment of preferred resting sites with known irritant compounds do not stimulate mosquitoes to move to safe sites after making contact with treated surfaces

Pesan Moral Islami Dalam Film Le Grand Voyage Karya Ismael Ferroukhi: Sebuah Tinjauan Struktural

Kata kunci : Film, sastra, struktural, pesan moral, Islam.Film merupakan produk budaya yang tidak hanya menjadi hiburan di masyarakat, tetapi juga sebagai sarana penyampaian pesan moral yang mengarifkan. Salah satufilm Perancis yang dianggap menginspirasi adalah film berjudul Le grand voyageyang ditulis dan disutradarai oleh Ismaël Ferroukhi. Film ini bercerita tentang perjalanan seorang muslim keturunan Maroko dan anaknya yang bernama Reda.Mereka menempuh jarak ribuan mil dari Perancis menuju ke kota Makah untukmelaksanakan haji hanya dengan mengendarai sebuah mobil tua. Penelitian inibertujuan untuk mengetahui pesan moral islami apa saja yang terkandung dalamfilm Le grand voyage dan bagaimana pesan tersebut dimunculkan dalam film.Penelitian ini menggunakan teori Struktural untuk menjawab rumusan masalah.Penelitian ini merupakan penelitian kualitatif dengan menggunakan teknik studipustaka serta dokumentasi sebagai metode pengumpulan data, dan teknikdeskriptif dalam proses analisis data.Berdasarkan hasil penelitian ini, terdapat 13 pesan moral islami yang terkandungdalam film Le grand voyage. Semua pesan moral tersebut mengacu pada sebuahproses perbaikan moral dan spiritual antara manusia dengan manusia dan alam,serta antara manusia dengan TuhanPenulis menyarankan pada penelitian selanjutnya untuk meneliti film Le grandvoyage menggunakan pendekatan sosiologi sastra yang nantinya dapat mengupashal apa saja yang melatarbelakangi pembuatan film ini dan tujuan sebenarnyayang ingin dicapai oleh pembuat film Le grand voyage

Burden of Illness and Quality of Life in Tuberous Sclerosis Complex: Findings From the TOSCA Study

Research on tuberous sclerosis complex (TSC) to date has focused mainly on the physical manifestations of the disease. In contrast, the psychosocial impact of TSC has received far less attention. The aim of this study was therefore to examine the impact of TSC on health, quality of life (QoL), and psychosocial well-being of individuals with TSC and their families. Questionnaires with disease-specific questions on burden of illness (BOI) and validated QoL questionnaires were used. After completion of additional informed consent, we included 143 individuals who participated in the TOSCA (TuberOus SClerosis registry to increase disease Awareness) study. Our results highlighted the substantial burden of TSC on the personal lives of individuals with TSC and their families. Nearly half of the patients experienced negative progress in their education or career due to TSC (42.1%), as well as many of their caregivers (17.6% employed; 58.8% unemployed). Most caregivers (76.5%) indicated that TSC affected family life, and social and working relationships. Further, well-coordinated care was lacking: a smooth transition from pediatric to adult care was mentioned by only 36.8% of adult patients, and financial, social, and psychological support in 21.1, 0, and 7.9%, respectively. In addition, the moderate rates of pain/discomfort (35%) and anxiety/depression (43.4%) reported across all ages and levels of disease demonstrate the high BOI and low QoL in this vulnerable population

Neuroarchitecture of Peptidergic Systems in the Larval Ventral Ganglion of Drosophila melanogaster

Recent studies on Drosophila melanogaster and other insects have revealed important insights into the functions and evolution of neuropeptide signaling. In contrast, in- and output connections of insect peptidergic circuits are largely unexplored. Existing morphological descriptions typically do not determine the exact spatial location of peptidergic axonal pathways and arborizations within the neuropil, and do not identify peptidergic in- and output compartments. Such information is however fundamental to screen for possible peptidergic network connections, a prerequisite to understand how the CNS controls the activity of peptidergic neurons at the synaptic level. We provide a precise 3D morphological description of peptidergic neurons in the thoracic and abdominal neuromeres of the Drosophila larva based on fasciclin-2 (Fas2) immunopositive tracts as landmarks. Comparing the Fas2 “coordinates” of projections of sensory or other neurons with those of peptidergic neurons, it is possible to identify candidate in- and output connections of specific peptidergic systems. These connections can subsequently be more rigorously tested. By immunolabeling and GAL4-directed expression of marker proteins, we analyzed the projections and compartmentalization of neurons expressing 12 different peptide genes, encoding approximately 75% of the neuropeptides chemically identified within the Drosophila CNS. Results are assembled into standardized plates which provide a guide to identify candidate afferent or target neurons with overlapping projections. In general, we found that putative dendritic compartments of peptidergic neurons are concentrated around the median Fas2 tracts and the terminal plexus. Putative peptide release sites in the ventral nerve cord were also more laterally situated. Our results suggest that i) peptidergic neurons in the Drosophila ventral nerve cord have separated in- and output compartments in specific areas, and ii) volume transmission is a prevailing way of peptidergic communication within the CNS. The data can further be useful to identify colocalized transmitters and receptors, and develop peptidergic neurons as new landmarks

Transcriptome Analysis of the Desert Locust Central Nervous System: Production and Annotation of a Schistocerca gregaria EST Database

) displays a fascinating type of phenotypic plasticity, designated as ‘phase polyphenism’. Depending on environmental conditions, one genome can be translated into two highly divergent phenotypes, termed the solitarious and gregarious (swarming) phase. Although many of the underlying molecular events remain elusive, the central nervous system (CNS) is expected to play a crucial role in the phase transition process. Locusts have also proven to be interesting model organisms in a physiological and neurobiological research context. However, molecular studies in locusts are hampered by the fact that genome/transcriptome sequence information available for this branch of insects is still limited. EST information is highly complementary to the existing orthopteran transcriptomic data. Since many novel transcripts encode neuronal signaling and signal transduction components, this paper includes an overview of these sequences. Furthermore, several transcripts being differentially represented in solitarious and gregarious locusts were retrieved from this EST database. The findings highlight the involvement of the CNS in the phase transition process and indicate that this novel annotated database may also add to the emerging knowledge of concomitant neuronal signaling and neuroplasticity events. EST data constitute an important new source of information that will be instrumental in further unraveling the molecular principles of phase polyphenism, in further establishing locusts as valuable research model organisms and in molecular evolutionary and comparative entomology