Underexpression of the 43 kDa inositol polyphosphate 5-phosphatase is associated with spontaneous calcium oscillations and enhanced calcium responses following endothelin-1 stimulation

The 43 kDa inositol polyphosphate 5-phosphatase (5-phosphatase) hydrolyses the signalling molecules inositol 1,4,5-trisphosphate (Ins(1,4,5)P) and inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P) and thereby regulates cellular transformation. To investigate the role Ins(1,4,5)P-mediated Ca oscillations play in cellular transformation, we studied Ins(1,4,5)P-mediated Ca responses in cells underexpressing the 43 kDa 5-phosphatase. Chronic reduction in 43 kDa 5-phosphatase enzyme activity resulted in a 2.6-fold increase in the resting Ins(1,4,5)P concentration and a 4.1-fold increase in basal intracellular Ca. The increased Ins(1,4,5)P levels resulted in partial emptying (40%) of the Ins(1,4,5)P-sensitive Ca store, however, store-operated Ca influx remained unchanged. In addition, Ins(1,4,5)P receptors were chronically downregulated in unstimulated cells, as shown by a 53% reduction in [H]Ins(1,4,5)P binding to microsomal receptor sites. Agonist stimulation with endothelin-1 resulted in the rapid rise and fall of Ins(1,4,5)P and Ins(1,3,4,5)P levels, with no significant differences in the rates of hydrolysis of these second messengers in antisenseor vector-transfected cells. These studies indicate, in contrast to its predicted action, the 43 kDa 5-phosphatase does not metabolise Ins(1,4,5)P and Ins(1,3,4,5)P post agonist stimulation. Cells with decreased 43 kDa 5-phosphatase activity exhibited spontaneous Ca oscillations in the absence of any agonist stimulation, and increased sensitivity and amplitude of intracellular Ca responses to both high and low dose endothelin-l stimulation. We conclude the 43 kDa 5-phosphatase exerts a profound influence on Ins(1,4,5)P-induced Ca spiking, both in the unstimulated cell and following agonist stimulation. We propose the enhanced Ca oscillations may mediate cellular transformation in cells underexpressing the 43 kDa 5-phosphatase

Survey of ultrasound practice amongst podiatrists in the UK

Background: Ultrasound in podiatry practice encompasses musculoskeletal ultrasound imaging, vascular hand-held Doppler ultrasound and therapeutic ultrasound. Sonography practice is not regulated by the Health and Care Professions Council (HCPC), with no requirement to hold a formal qualification. The College of Podiatry does not currently define ultrasound training and competencies. This study aimed to determine the current use of ultrasound, training received and mentorship received and/or provided by podiatrists using ultrasound. Methods: A quantitative study utilising a cross-sectional, on-line, single-event survey was undertaken within the UK. Results: Completed surveys were received from 284 podiatrists; 173 (70%) use ultrasound as part of their general practice, 139 (49%) for musculoskeletal problems, 131 (46%) for vascular assessment and 39 (14%) to support their surgical practice. Almost a quarter (n=62) worked for more than one organisation; 202 (71%) were employed by the NHS and/or private sector (n=118, 41%). Nearly all (93%) respondents report using a hand-held vascular Doppler in their daily practice; 216 (82%) to support decisions regarding treatment options, 102 (39%) to provide diagnostic reports for other health professionals, and 34 (13%) to guide nerve blocks. Ultrasound imaging was used by 104 (37%) respondents primarily to aid clinical decision making (n=81) and guide interventions (steroid injections n=67; nerve blocks n=39). Ninety-three percent stated they use ultrasound imaging to treat their own patients, while others scan at the request of other podiatrists (n=28) or health professionals (n=18). Few use ultrasound imaging for research (n=7) or education (n=2). Only 32 (11%) respondents (n=20 private sector) use therapeutic ultrasound to treat patients presenting with musculoskeletal complaints, namely tendon pathologies. Few respondents (18%) had completed formal post-graduate CASE (Consortium for the Accreditation of Sonographic Education) accredited ultrasound courses. Forty (14%) respondents receive ultrasound mentorship; the majority from fellow podiatrists (n=17) or medical colleagues (n=15). Over half (n=127) who do not have ultrasound mentorship indicated they would like a mentor predominantly for ultrasound imaging. Fifty-five (19%) report they currently provide ultrasound mentorship for others. Conclusions: Understanding the scope of ultrasound practice, the training undertaken and the requirements for mentorship will underpin the development of competencies and recommendations defined by the College of Podiatry to support professional development and ensure safe practice.</p

HERMES: Towards an Integrated Toolbox to Characterize Functional and Effective Brain Connectivity

The analysis of the interdependence between time series has become an important field of research in the last years, mainly as a result of advances in the characterization of dynamical systems from the signals they produce, the introduction of concepts such as generalized and phase synchronization and the application of information theory to time series analysis. In neurophysiology, different analytical tools stemming from these concepts have added to the ‘traditional’ set of linear methods, which includes the cross-correlation and the coherency function in the time and frequency domain, respectively, or more elaborated tools such as Granger Causality. This increase in the number of approaches to tackle the existence of functional (FC) or effective connectivity (EC) between two (or among many) neural networks, along with the mathematical complexity of the corresponding time series analysis tools, makes it desirable to arrange them into a unified-easy-to-use software package. The goal is to allow neuroscientists, neurophysiologists and researchers from related fields to easily access and make use of these analysis methods from a single integrated toolbox. Here we present HERMES (http://hermes.ctb.upm.es), a toolbox for the Matlab® environment (The Mathworks, Inc), which is designed to study functional and effective brain connectivity from neurophysiological data such as multivariate EEG and/or MEG records. It includes also visualization tools and statistical methods to address the problem of multiple comparisons. We believe that this toolbox will be very helpful to all the researchers working in the emerging field of brain connectivity analysis

A genome-wide association study identifies multiple loci for variation in human ear morphology

Here we report a genome-wide association study for non-pathological pinna morphology in over 5,000 Latin Americans. We find genome-wide significant association at seven genomic regions affecting: lobe size and attachment, folding of antihelix, helix rolling, ear protrusion and antitragus size (linear regression P values 2 × 10−8 to 3 × 10−14). Four traits are associated with a functional variant in the Ectodysplasin A receptor (EDAR) gene, a key regulator of embryonic skin appendage development. We confirm expression of Edar in the developing mouse ear and that Edar-deficient mice have an abnormally shaped pinna. Two traits are associated with SNPs in a region overlapping the T-Box Protein 15 (TBX15) gene, a major determinant of mouse skeletal development. Strongest association in this region is observed for SNP rs17023457 located in an evolutionarily conserved binding site for the transcription factor Cartilage paired-class homeoprotein 1 (CART1), and we confirm that rs17023457 alters in vitro binding of CART1

Deletion of the Pluripotency-Associated Tex19.1 Gene Causes Activation of Endogenous Retroviruses and Defective Spermatogenesis in Mice

As genetic information is transmitted through successive generations, it passes between pluripotent cells in the early embryo and germ cells in the developing foetus and adult animal. Tex19.1 encodes a protein of unknown function, whose expression is restricted to germ cells and pluripotent cells. During male spermatogenesis, Tex19.1 expression is highest in mitotic spermatogonia and diminishes as these cells differentiate and progress through meiosis. In pluripotent stem cells, Tex19.1 expression is also downregulated upon differentiation. However, it is not clear whether Tex19.1 has an essential function in germ cells or pluripotent stem cells, or what that function might be. To analyse the potential role of Tex19.1 in pluripotency or germ cell function we have generated Tex19.1−/− knockout mice and analysed the Tex19.1−/− mutant phenotype. Adult Tex19.1−/− knockout males exhibit impaired spermatogenesis. Immunostaining and histological analysis revealed defects in meiotic chromosome synapsis, the persistence of DNA double-strand breaks during meiosis, and a loss of post-meiotic germ cells in the testis. Furthermore, expression of a class of endogenous retroviruses is upregulated during meiosis in the Tex19.1−/− testes. Increased transposition of endogenous retroviruses in the germline of Tex19.1−/− mutant mice, and the concomitant increase in DNA damage, may be sufficient to disrupt the normal processes of recombination and chromosome synapsis during meiosis and cause defects in spermatogenesis. Our results suggest that Tex19.1 is part of a specialised mechanism that operates in the germline to repress transposable genetic elements and maintain genomic stability through successive generations

A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features

We report a genome-wide association scan in over 6,000 Latin Americans for features of scalp hair (shape, colour, greying, balding) and facial hair (beard thickness, monobrow, eyebrow thickness). We found 18 signals of association reaching genome-wide significance (P values 5 × 10−8 to 3 × 10−119), including 10 novel associations. These include novel loci for scalp hair shape and balding, and the first reported loci for hair greying, monobrow, eyebrow and beard thickness. A newly identified locus influencing hair shape includes a Q30R substitution in the Protease Serine S1 family member 53 (PRSS53). We demonstrate that this enzyme is highly expressed in the hair follicle, especially the inner root sheath, and that the Q30R substitution affects enzyme processing and secretion. The genome regions associated with hair features are enriched for signals of selection, consistent with proposals regarding the evolution of human hair

Ethnic Related Selection for an ADH Class I Variant within East Asia

The alcohol dehydrogenases (ADH) are widely studied enzymes and the evolution of the mammalian gene cluster encoding these enzymes is also well studied. Previous studies have shown that the ADH1B*47His allele at one of the seven genes in humans is associated with a decrease in the risk of alcoholism and the core molecular region with this allele has been selected for in some East Asian populations. As the frequency of ADH1B*47His is highest in East Asia, and very low in most of the rest of the world, we have undertaken more detailed investigation in this geographic region.Here we report new data on 30 SNPs in the ADH7 and Class I ADH region in samples of 24 populations from China and Laos. These populations cover a wide geographic region and diverse ethnicities. Combined with our previously published East Asian data for these SNPs in 8 populations, we have typed populations from all of the 6 major linguistic phyla (Altaic including Korean-Japanese and inland Altaic, Sino-Tibetan, Hmong-Mien, Austro-Asiatic, Daic, and Austronesian). The ADH1B genotyping data are strongly related to ethnicity. Only some eastern ethnic phyla or subphyla (Korean-Japanese, Han Chinese, Hmong-Mien, Daic, and Austronesian) have a high frequency of ADH1B*47His. ADH1B haplotype data clustered the populations into linguistic subphyla, and divided the subphyla into eastern and western parts. In the Hmong-Mien and Altaic populations, the extended haplotype homozygosity (EHH) and relative EHH (REHH) tests for the ADH1B core were consistent with selection for the haplotype with derived SNP alleles. In the other ethnic phyla, the core showed only a weak signal of selection at best.The selection distribution is more significantly correlated with the frequency of the derived ADH1B regulatory region polymorphism than the derived amino-acid altering allele ADH1B*47His. Thus, the real focus of selection may be the regulatory region. The obvious ethnicity-related distributions of ADH1B diversities suggest the existence of some culture-related selective forces that have acted on the ADH1B region

Estrogenic Plant Extracts Reverse Weight Gain and Fat Accumulation without Causing Mammary Gland or Uterine Proliferation

Long-term estrogen deficiency increases the risk of obesity, diabetes and metabolic syndrome in postmenopausal women. Menopausal hormone therapy containing estrogens might prevent these conditions, but its prolonged use increases the risk of breast cancer, as wells as endometrial cancer if used without progestins. Animal studies indicate that beneficial effects of estrogens in adipose tissue and adverse effects on mammary gland and uterus are mediated by estrogen receptor alpha (ERα). One strategy to improve the safety of estrogens to prevent/treat obesity, diabetes and metabolic syndrome is to develop estrogens that act as agonists in adipose tissue, but not in mammary gland and uterus. We considered plant extracts, which have been the source of many pharmaceuticals, as a source of tissue selective estrogens. Extracts from two plants, Glycyrrhiza uralensis (RG) and Pueraria montana var. lobata (RP) bound to ERα, activated ERα responsive reporters, and reversed weight gain and fat accumulation comparable to estradiol in ovariectomized obese mice maintained on a high fat diet. Unlike estradiol, RG and RP did not induce proliferative effects on mammary gland and uterus. Gene expression profiling demonstrated that RG and RP induced estradiol-like regulation of genes in abdominal fat, but not in mammary gland and uterus. The compounds in extracts from RG and RP might constitute a new class of tissue selective estrogens to reverse weight gain, fat accumulation and metabolic syndrome in postmenopausal women

A genome-wide association scan implicates <i>DCHS2, RUNX2, GLI3, PAX1</i> and <i>EDAR</i> in human facial variation

We report a genome-wide association scan for facial features in ∼6,000 Latin Americans. We evaluated 14 traits on an ordinal scale and found significant association (P values−8) at single-nucleotide polymorphisms (SNPs) in four genomic regions for three nose-related traits: columella inclination (4q31), nose bridge breadth (6p21) and nose wing breadth (7p13 and 20p11). In a subsample of ∼3,000 individuals we obtained quantitative traits related to 9 of the ordinal phenotypes and, also, a measure of nasion position. Quantitative analyses confirmed the ordinal-based associations, identified SNPs in 2q12 associated to chin protrusion, and replicated the reported association of nasion position with SNPs in PAX3. Strongest association in 2q12, 4q31, 6p21 and 7p13 was observed for SNPs in the EDAR, DCHS2, RUNX2 and GLI3 genes, respectively. Associated SNPs in 20p11 extend to PAX1. Consistent with the effect of EDAR on chin protrusion, we documented alterations of mandible length in mice with modified Edar function