Antichain cutsets of strongly connected posets

Rival and Zaguia showed that the antichain cutsets of a finite Boolean lattice are exactly the level sets. We show that a similar characterization of antichain cutsets holds for any strongly connected poset of locally finite height. As a corollary, we get such a characterization for semimodular lattices, supersolvable lattices, Bruhat orders, locally shellable lattices, and many more. We also consider a generalization to strongly connected hypergraphs having finite edges.Comment: 12 pages; v2 contains minor fixes for publicatio

Osteoporosis in young adults: pathophysiology, diagnosis, and management

Postmenopausal osteoporosis is mainly caused by increased bone remodeling resulting from estrogen deficiency. Indications for treatment are based on low areal bone mineral density (aBMD, T-score ≤ −2.5), typical fragility fractures (spine or hip), and more recently, an elevated 10-year fracture probability (by FRAX®). In contrast, there is no clear definition of osteoporosis nor intervention thresholds in younger individuals. Low aBMD in a young adult may reflect a physiologically low peak bone mass, such as in lean but otherwise healthy persons, whereas fractures commonly occur with high-impact trauma, i.e., without bone fragility. Furthermore, low aBMD associated with vitamin D deficiency may be highly prevalent in some regions of the world. Nevertheless, true osteoporosis in the young can occur, which we define as a T-score below −2.5 at spine or hip in association with a chronic disease known to affect bone metabolism. In the absence of secondary causes, the presence of fragility fractures, such as in vertebrae, may point towards genetic or idiopathic osteoporosis. In turn, treatment of the underlying condition may improve bone mass as well. In rare cases, a bone-specific treatment may be indicated, although evidence is scarce for a true benefit on fracture risk. The International Osteoporosis Foundation (IOF) convened a working group to review pathophysiology, diagnosis, and management of osteoporosis in the young, excluding children and adolescents, and provide a screening strategy including laboratory exams for a systematic approach of this conditio

Mechanistic study of an immobilized molecular electrocatalyst by in situ gap-plasmon-assisted spectro-electrochemistry

Immobilized first-row transition metal complexes are potential low-cost electrocatalysts for selective CO2 conversion in the production of renewable fuels. Mechanistic understanding of their function is vital for the development of next-generation catalysts, although the poor surface sensitivity of many techniques makes this challenging. Here, a nickel bis(terpyridine) complex is introduced as a CO2 reduction electrocatalyst in a unique electrode geometry, sandwiched by thiol-anchoring moieties between two gold surfaces. Gap-plasmon-assisted surface-enhanced Raman scattering spectroscopy coupled with density functional theory calculations reveals that the nature of the anchoring group plays a pivotal role in the catalytic mechanism. Our in situ spectro-electrochemical measurement enables the detection of as few as eight molecules undergoing redox transformations in individual plasmonic hotspots, together with the calibration of electrical fields via vibrational Stark effects. This advance allows rapid exploration of non-resonant redox reactions at the few-molecule level and provides scope for future mechanistic studies of single molecules

Signaling via PI3K/FOXO1A pathway modulates formation and survival of human embryonic stem cell-derived endothelial cells

Vascular derivatives of human embryonic stem cells (hESC) are being developed as sources of tissue-specific cells for organ regeneration. However, identity of developmental pathways that modulate the specification of endothelial cells is not known yet. We studied phosphatidylinositol 3-kinase (PI3K)-Forkhead box O transcription factor 1A (FOXO1A) pathways during differentiation of hESC toward endothelial lineage and on proliferation, maturation, and cell death of hESC-derived endothelial cells (hESC-EC). During differentiation of hESC, expression of FOXO1A transcription factor was linked to the expression of a cluster of angiogenesis- and vascular remodeling-related genes. PI3K inhibitor LY294002 activated FOXO1A and induced formation of CD31(+) hESC-EC. In contrast, differentiating hESC with silenced FOXO1A by small interfering RNA (siRNA) showed lower mRNA levels of CD31 and angiopoietin2. LY294002 decreased proliferative activity of purified hESC-EC, while FOXO1A siRNA increased their proliferation. LY294002 inhibits migration and tube formation of hESC-EC; in contrast, FOXO1A siRNA increased in vitro tube formation activity of hESC-EC. After in vivo conditioning of cells in athymic nude rats, cells retain their low FOXO1A expression levels. PI3K/FOXO1A pathway is important for function and survival of hESC-EC and in the regulation of endothelial cell fate. Understanding these properties of hESC-EC may help in future applications for treatment of injured organs

A role for an Hsp70 nucleotide exchange factor in the regulation of synaptic vesicle endocytosis

© The Author(s), 2013. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Journal of Neuroscience 33 (2013): 8009-8021, doi:10.1523/JNEUROSCI.4505-12.2013.Neurotransmission requires a continuously available pool of synaptic vesicles (SVs) that can fuse with the plasma membrane and release their neurotransmitter contents upon stimulation. After fusion, SV membranes and membrane proteins are retrieved from the presynaptic plasma membrane by clathrin-mediated endocytosis. After the internalization of a clathrin-coated vesicle, the vesicle must uncoat to replenish the pool of SVs. Clathrin-coated vesicle uncoating requires ATP and is mediated by the ubiquitous molecular chaperone Hsc70. In vitro, depolymerized clathrin forms a stable complex with Hsc70*ADP. This complex can be dissociated by nucleotide exchange factors (NEFs) that release ADP from Hsc70, allowing ATP to bind and induce disruption of the clathrin:Hsc70 association. Whether NEFs generally play similar roles in vesicle trafficking in vivo and whether they play such roles in SV endocytosis in particular is unknown. To address this question, we used information from recent structural and mechanistic studies of Hsp70:NEF and Hsp70:co-chaperone interactions to design a NEF inhibitor. Using acute perturbations at giant reticulospinal synapses of the sea lamprey (Petromyzon marinus), we found that this NEF inhibitor inhibited SV endocytosis. When this inhibitor was mutated so that it could no longer bind and inhibit Hsp110 (a NEF that we find to be highly abundant in brain cytosol), its ability to inhibit SV endocytosis was eliminated. These observations indicate that the action of a NEF, most likely Hsp110, is normally required during SV trafficking to release clathrin from Hsc70 and make it available for additional rounds of endocytosis.This work was supported by the National Institutes of Health (Grant #NS029051 to E.M.L. and Grant #NS078165 to J.R.M.).2013-11-0

An evaluation of the appropriateness of advice and healthcare contacts made following calls to NHS Direct Wales

Background: An evaluation of NHS Direct Wales (NHSDW), a national telephone-based healthcare advice and information service, was undertaken. A key objective was to describe the actions of callers and assess the appropriateness of advice and healthcare contacts made following calls, results of which are reported here. Methods: Postal questionnaires were sent to consecutive callers to NHSDW in May 2002 and February 2004 to determine 1) callers' actions following calls and 2) their views about the appropriateness of: advice given; and when to seek further care. An independent clinical panel agreed and applied a set of rules about healthcare sites where examinations, investigations, treatments and referrals could be obtained. The rules were then applied to the subsequent contacts to healthcare services reported by respondents and actions were classified in terms of whether they had been necessary and sufficient for the care received. Results: Response rates were similar in each survey: 1033/1897 (54.5%); 606/1204 (50.3%), with 75% reporting contacting NHSDW. In both surveys, nearly half of all callers reported making no further healthcare contact after their call to NHSDW. The most frequent subsequent contacts made were with GPs. More than four fifths of callers rated the advice given - concerning any further care needed and when to seek it - as appropriate (further care needed: survey 1: 673/729, 82.3%; survey 2: 389/421, 92.4%; when to seek further care - survey 1: 462/555, 83.2%; survey 2: n = 295/346, 85.3%). A similar proportion of cases was also rated through the rule set and backed up by the clinical panel as having taken necessary and sufficient actions following their calls to NHSDW (survey 1: 624/729, 80.6%; survey 2: 362/421, 84.4%), with more unnecessary than insufficient actions identified at each survey (survey 1: unnecessary 132/729, 17.1% versus insufficient 11/729, 1.4%; survey 2: unnecessary 47/421, 11.0% versus insufficient 14/421, 3.3%). Conclusion: Based on NHSDW caller surveys responses and applying a transparent rule set to caller actions a large majority of subsequent actions were assessed as appropriate, with insufficient contacts particularly infrequent. The challenge for NHSDW is to reduce the number of unnecessary contacts made following calls to the service, whilst maintaining safety.</p

Next Generation Driver for Attosecond and Laser-plasma Physics

The observation and manipulation of electron dynamics in matter call for attosecond light pulses, routinely available from high-order harmonic generation driven by few-femtosecond lasers. However, the energy limitation of these lasers supports only weak sources and correspondingly linear attosecond studies. Here we report on an optical parametric synthesizer designed for nonlinear attosecond optics and relativistic laser-plasma physics. This synthesizer uniquely combines ultra-relativistic focused intensities of about 10(20)W/cm(2) with a pulse duration of sub-two carrier-wave cycles. The coherent combination of two sequentially amplified and complementary spectral ranges yields sub-5-fs pulses with multi-TW peak power. The application of this source allows the generation of a broad spectral continuum at 100-eV photon energy in gases as well as high-order harmonics in relativistic plasmas. Unprecedented spatio-temporal confinement of light now permits the investigation of electric-field-driven electron phenomena in the relativistic regime and ultimately the rise of next-generation intense isolated attosecond sources

Application of laser-induced double ablation of plasma for enhanced macroparticle acceleration

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Atlas of lesion locations and postsurgical seizure freedom in focal cortical dysplasia: A MELD study

Objective: Drug-resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The distribution of these lesions across the cerebral cortex and the impact of lesion location on clinical presentation and surgical outcome are largely unknown. We created a neuroimaging cohort of patients with individually mapped FCDs to determine factors associated with lesion location and predictors of postsurgical outcome. Methods: The MELD (Multi-centre Epilepsy Lesion Detection) project collated a retrospective cohort of 580 patients with epilepsy attributed to FCD from 20 epilepsy centers worldwide. Magnetic resonance imaging-based maps of individual FCDs with accompanying demographic, clinical, and surgical information were collected. We mapped the distribution of FCDs, examined for associations between clinical factors and lesion location, and developed a predictive model of postsurgical seizure freedom. Results: FCDs were nonuniformly distributed, concentrating in the superior frontal sulcus, frontal pole, and temporal pole. Epilepsy onset was typically before the age of 10 years. Earlier epilepsy onset was associated with lesions in primary sensory areas, whereas later epilepsy onset was associated with lesions in association cortices. Lesions in temporal and occipital lobes tended to be larger than frontal lobe lesions. Seizure freedom rates varied with FCD location, from around 30% in visual, motor, and premotor areas to 75% in superior temporal and frontal gyri. The predictive model of postsurgical seizure freedom had a positive predictive value of 70% and negative predictive value of 61%. Significance: FCD location is an important determinant of its size, the age at epilepsy onset, and the likelihood of seizure freedom postsurgery. Our atlas of lesion locations can be used to guide the radiological search for subtle lesions in individual patients. Our atlas of regional seizure freedom rates and associated predictive model can be used to estimate individual likelihoods of postsurgical seizure freedom. Data-driven atlases and predictive models are essential for evidence-based, precision medicine and risk counseling in epilepsy