Sharp Global Bounds for the Hessian on Pseudo-Hermitian Manifolds

We find sharp bounds for the norm inequality on a Pseudo-hermitian manifold, where the L^2 norm of all second derivatives of the function involving horizontal derivatives is controlled by the L^2 norm of the sub-Laplacian. Perturbation allows us to get a-priori bounds for solutions to sub-elliptic PDE in non-divergence form with bounded measurable coefficients. The method of proof is through a Bochner technique. The Heisenberg group is seen to be en extremal manifold for our inequality in the class of manifolds whose Ricci curvature is non-negative.Comment: 13 page

Activation of SGK1 in endometrial epithelial cells in response to PI3K/AKT inhibition impairs embryo implantation

Background: Serum & Glucocorticoid Regulated Kinase 1 (SGK1) plays a fundamental role in ion and solute transport processes in epithelia. In the endometrium, down-regulation of SGK1 during the window of receptivity facilitates embryo implantation whereas expression of a constitutively active mutant in the murine uterus blocks implantation. Methods/Results: Here, we report that treatment of endometrial epithelial cells with specific inhibitors of the phosphoinositide 3-kinase (PI3K)/AKT activity pathway results in reciprocal activation of SGK1. Flushing of the uterine lumen of mice with a cell permeable, substrate competitive phosphatidylinositol analogue that inhibits AKT activation (AKT inhibitor III) resulted in Sgk1 phosphorylation, down-regulation of the E3 ubiquitin-protein ligase Nedd4-2, and increased expression of epithelial Na+ channels (ENaC). Furthermore, exposure of the uterine lumen to AKT inhibitor III prior to embryo transfer induced a spectrum of early pregnancy defects, ranging from implantation failure to aberrant spacing of implantation sites. Conclusion: Taken together, our data indicate that the balanced activities of two related serine/threonine kinases, AKT and SGK1, critically govern the implantation process

Multi-parallel qPCR provides increased sensitivity and diagnostic breadth for gastrointestinal parasites of humans: field-based inferences on the impact of mass deworming

BACKGROUND: Although chronic morbidity in humans from soil transmitted helminth (STH) infections can be reduced by anthelmintic treatment, inconsistent diagnostic tools make it difficult to reliably measure the impact of deworming programs and often miss light helminth infections. METHODS: Cryopreserved stool samples from 796 people (aged 2-81 years) in four villages in Bungoma County, western Kenya, were assessed using multi-parallel qPCR for 8 parasites and compared to point-of-contact assessments of the same stools by the 2-stool 2-slide Kato-Katz (KK) method. All subjects were treated with albendazole and all Ascaris lumbricoides expelled post-treatment were collected. Three months later, samples from 633 of these people were re-assessed by both qPCR and KK, re-treated with albendazole and the expelled worms collected. RESULTS: Baseline prevalence by qPCR (n = 796) was 17 % for A. lumbricoides, 18 % for Necator americanus, 41 % for Giardia lamblia and 15% for Entamoeba histolytica. The prevalence was <1% for Trichuris trichiura, Ancylostoma duodenale, Strongyloides stercoralis and Cryptosporidium parvum. The sensitivity of qPCR was 98% for A. lumbricoides and N. americanus, whereas KK sensitivity was 70% and 32%, respectively. Furthermore, qPCR detected infections with T. trichiura and S. stercoralis that were missed by KK, and infections with G. lamblia and E. histolytica that cannot be detected by KK. Infection intensities measured by qPCR and by KK were correlated for A. lumbricoides (r = 0.83, p < 0.0001) and N. americanus (r = 0.55, p < 0.0001). The number of A. lumbricoides worms expelled was correlated (p < 0.0001) with both the KK (r = 0.63) and qPCR intensity measurements (r = 0.60). CONCLUSIONS: KK may be an inadequate tool for stool-based surveillance in areas where hookworm or Strongyloides are common or where intensity of helminth infection is low after repeated rounds of chemotherapy. Because deworming programs need to distinguish between populations where parasitic infection is controlled and those where further treatment is required, multi-parallel qPCR (or similar high throughput molecular diagnostics) may provide new and important diagnostic information

Generation of Ultrastable Microwaves via Optical Frequency Division

There has been increased interest in the use and manipulation of optical fields to address challenging problems that have traditionally been approached with microwave electronics. Some examples that benefit from the low transmission loss, agile modulation and large bandwidths accessible with coherent optical systems include signal distribution, arbitrary waveform generation, and novel imaging. We extend these advantages to demonstrate a microwave generator based on a high-Q optical resonator and a frequency comb functioning as an optical-to-microwave divider. This provides a 10 GHz electrical signal with fractional frequency instability <8e-16 at 1 s, a value comparable to that produced by the best microwave oscillators, but without the need for cryogenic temperatures. Such a low-noise source can benefit radar systems, improve the bandwidth and resolution of communications and digital sampling systems, and be valuable for large baseline interferometry, precision spectroscopy and the realization of atomic time

Family composition and age at menarche: findings from the international Health Behaviour in School-Aged Children Study

This research was funded by The University of St Andrews and NHS Health Scotland.Background Early menarche has been associated with father absence, stepfather presence and adverse health consequences in later life. This article assesses the association of different family compositions with the age at menarche. Pathways are explored which may explain any association between family characteristics and pubertal timing. Methods Cross-sectional, international data on the age at menarche, family structure and covariates (age, psychosomatic complaints, media consumption, physical activity) were collected from the 2009–2010 Health Behaviour in School-aged Children (HBSC) survey. The sample focuses on 15-year old girls comprising 36,175 individuals across 40 countries in Europe and North America (N = 21,075 for age at menarche). The study examined the association of different family characteristics with age at menarche. Regression and path analyses were applied incorporating multilevel techniques to adjust for the nested nature of data within countries. Results Living with mother (Cohen’s d = .12), father (d = .08), brothers (d = .04) and sisters (d = .06) are independently associated with later age at menarche. Living in a foster home (d = −.16), with ‘someone else’ (d = −.11), stepmother (d = −.10) or stepfather (d = −.06) was associated with earlier menarche. Path models show that up to 89% of these effects can be explained through lifestyle and psychological variables. Conclusions Earlier menarche is reported amongst those with living conditions other than a family consisting of two biological parents. This can partly be explained by girls’ higher Body Mass Index in these families which is a biological determinant of early menarche. Lower physical activity and elevated psychosomatic complaints were also more often found in girls in these family environments.Publisher PDFPeer reviewe

From theory to 'measurement' in complex interventions: methodological lessons from the development of an e-health normalisation instrument

&lt;b&gt;Background&lt;/b&gt; Although empirical and theoretical understanding of processes of implementation in health care is advancing, translation of theory into structured measures that capture the complex interplay between interventions, individuals and context remain limited. This paper aimed to (1) describe the process and outcome of a project to develop a theory-based instrument for measuring implementation processes relating to e-health interventions; and (2) identify key issues and methodological challenges for advancing work in this field.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt; A 30-item instrument (Technology Adoption Readiness Scale (TARS)) for measuring normalisation processes in the context of e-health service interventions was developed on the basis on Normalization Process Theory (NPT). NPT focuses on how new practices become routinely embedded within social contexts. The instrument was pre-tested in two health care settings in which e-health (electronic facilitation of healthcare decision-making and practice) was used by health care professionals.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt; The developed instrument was pre-tested in two professional samples (N = 46; N = 231). Ratings of items representing normalisation 'processes' were significantly related to staff members' perceptions of whether or not e-health had become 'routine'. Key methodological challenges are discussed in relation to: translating multi-component theoretical constructs into simple questions; developing and choosing appropriate outcome measures; conducting multiple-stakeholder assessments; instrument and question framing; and more general issues for instrument development in practice contexts.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt; To develop theory-derived measures of implementation process for progressing research in this field, four key recommendations are made relating to (1) greater attention to underlying theoretical assumptions and extent of translation work required; (2) the need for appropriate but flexible approaches to outcomes measurement; (3) representation of multiple perspectives and collaborative nature of work; and (4) emphasis on generic measurement approaches that can be flexibly tailored to particular contexts of study

A single residue substitution in the receptor-binding domain of H5N1 hemagglutinin is critical for packaging into pseudotyped lentiviral particles

© 2012 Tang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Serological studies for influenza infection and vaccine response often involve microneutralization and hemagglutination inhibition assays to evaluate neutralizing antibodies against human and avian influenza viruses, including H5N1. We have previously characterized lentiviral particles pseudotyped with H5-HA (H5pp) and validated an H5pp-based assay as a safe alternative for high-throughput serological studies in BSL-2 facilities. Here we show that H5-HAs from different clades do not always give rise to efficient production of H5pp and the underlying mechanisms are addressed. Methodology/Findings: We have carried out mutational analysis to delineate the molecular determinants responsible for efficient packaging of HA from A/Cambodia/40808/2005 (H5Cam) and A/Anhui/1/2005 (H5Anh) into H5pp. Our results demonstrate that a single A134V mutation in the 130-loop of the receptor binding domain is sufficient to render H5Anh the ability to generate H5Anh-pp efficiently, whereas the reverse V134A mutation greatly hampers production of H5Cam-pp. Although protein expression in total cell lysates is similar for H5Anh and H5Cam, cell surface expression of H5Cam is detected at a significantly higher level than that of H5Anh. We further demonstrate by several independent lines of evidence that the behaviour of H5Anh can be explained by a stronger binding to sialic acid receptors implicating residue 134. Conclusions: We have identified a single A134V mutation as the molecular determinant in H5-HA for efficient incorporation into H5pp envelope and delineated the underlying mechanism. The reduced binding to sialic acid receptors as a result of the A134V mutation not only exerts a critical influence in pseudotyping efficiency of H5-HA, but has also an impact at the whole virus level. Because A134V substitution has been reported as a naturally occurring mutation in human host, our results may have implications for the understanding of human host adaptation of avian influenza H5N1 virusesThis work was supported by grants from the Research Fund for the Control of Infectious Diseases of Hong Kong (RFCID#08070972), the Area of Excellence Scheme of the University Grants Committee (grant AoE/M-12/-06 of the Hong Kong Special Administrative Region, China), the French Ministry of Health, and the RESPARI project of the Institut Pasteur International Network

LEFTY2 inhibits endometrial receptivity by downregulating Orai1 expression and store-operated Ca²+ entry

Early embryo development and endometrial differentiation are initially independent processes, and synchronization, imposed by a limited window of implantation, is critical for reproductive success. A putative negative regulator of endometrial receptivity is LEFTY2, a member of the transforming growth factor (TGF)-β family. LEFTY2 is highly expressed in decidualizing human endometrial stromal cells (HESCs) during the late luteal phase of the menstrual cycle, coinciding with the closure of the window of implantation. Here, we show that flushing of the uterine lumen in mice with recombinant LEFTY2 inhibits the expression of key receptivity genes, including Cox2, Bmp2, and Wnt4, and blocks embryo implantation. In Ishikawa cells, a human endometrial epithelial cell line, LEFTY2 downregulated the expression of calcium release-activated calcium channel protein 1, encoded by ORAI1, and inhibited store-operated Ca2+ entry (SOCE). Furthermore, LEFTY2 and the Orai1 blockers 2-APB, MRS-1845, as well as YM-58483, inhibited, whereas the Ca2+ ionophore, ionomycin, strongly upregulated COX2, BMP2 and WNT4 expression in decidualizing HESCs. These findings suggest that LEFTY2 closes the implantation window, at least in part, by downregulating Orai1, which in turn limits SOCE and antagonizes expression of Ca2+-sensitive receptivity genes

Chromatic Illumination Discrimination Ability Reveals that Human Colour Constancy Is Optimised for Blue Daylight Illuminations

The phenomenon of colour constancy in human visual perception keeps surface colours constant, despite changes in their reflected light due to changing illumination. Although colour constancy has evolved under a constrained subset of illuminations, it is unknown whether its underlying mechanisms, thought to involve multiple components from retina to cortex, are optimised for particular environmental variations. Here we demonstrate a new method for investigating colour constancy using illumination matching in real scenes which, unlike previous methods using surface matching and simulated scenes, allows testing of multiple, real illuminations. We use real scenes consisting of solid familiar or unfamiliar objects against uniform or variegated backgrounds and compare discrimination performance for typical illuminations from the daylight chromaticity locus (approximately blue-yellow) and atypical spectra from an orthogonal locus (approximately red-green, at correlated colour temperature 6700 K), all produced in real time by a 10-channel LED illuminator. We find that discrimination of illumination changes is poorer along the daylight locus than the atypical locus, and is poorest particularly for bluer illumination changes, demonstrating conversely that surface colour constancy is best for blue daylight illuminations. Illumination discrimination is also enhanced, and therefore colour constancy diminished, for uniform backgrounds, irrespective of the object type. These results are not explained by statistical properties of the scene signal changes at the retinal level. We conclude that high-level mechanisms of colour constancy are biased for the blue daylight illuminations and variegated backgrounds to which the human visual system has typically been exposed