Straining effects in MoS2 monolayer on nanostructured substrates: temperature-dependent photoluminescence and exciton dynamics.
Strain-engineering of two-dimensional (2D) transition metal dichalcogenides (TMDs) has great potential to alter their electronic and optical properties. Thus far, experimental studies of the straining effects in 2D TMDs primarily focused on the static property measurements at room temperature. However, low-temperature and temperature-dependence studies are essential in understanding the underlying mechanisms of the unique properties of monolayer TMDs. Herein, the temperature-dependent dynamic properties of laser shock strain-engineered monolayer MoS2 were studied using temperature-dependent photoluminescence (PL) and pump-probe spectroscopy. Both the photoluminescence spectra and exciton dynamics exhibit the differences between the MoS2 monolayers transferred on the flat and nanostructured surfaces by laser shock strain engineering and display a strong temperature dependence. The laser-induced straining effect and temperature-dependent dynamic behavior of MoS2 were studied through molecular dynamics simulation. The observed behaviors can be explained by the thermally induced strain in the monolayer MoS2 due to the mismatching thermal expansion coefficients of the monolayer and the substrate, which are coupled by the van der Waals forces. The ultrafast pump-probe experiments were performed to investigate the effect of strain on the exciton dynamics upon optical excitation. The results from the pump-probe measurements indicate that the effects of strain extend beyond that of the static properties and profoundly influence the valley carrier dynamics. This report extends the understanding of the substrate-induced straining effect to temperature-dependent luminescence behaviors and dynamic behaviors of the TMD materials.


The effect of Maillard reaction products and yeast strain on the synthesis of key higher alcohols and esters in beer fermentations.
The effect of Maillard reaction products (MRPs), formed during the production of dark malts, on the synthesis of higher alcohols and esters in beer fermentations was investigated by headspace solid-phase microextraction GC-MS. Higher alcohol levels were significantly (p<0.05) higher in dark malt fermentations, while the synthesis of esters was inhibited, due to possible suppression of enzyme activity and/or gene expression linked to ester synthesis. Yeast strain also affected flavour synthesis with Saccharomyces cerevisiae strain A01 producing considerably lower levels of higher alcohols and esters than S288c and L04. S288c produced approximately double the higher alcohol levels and around twenty times more esters compared to L04. Further investigations into malt type-yeast strain interactions in relation to flavour development are required to gain better understanding of flavour synthesis that could assist in the development of new products and reduce R&D costs for the industry.


Boty, a long-terminal-repeat retroelement in the phytopathogenic fungus Botrytis cinerea.
The phytopathogenic fungus Botrytis cinerea can infect an extremely wide range of host plants (tomato, grapevine, strawberry, and flax) without apparent specialization. While studying genetic diversity in this fungus, we found an element which is present in multiple copies and dispersed throughout the genome of some of its isolates. DNA sequence analysis revealed that the element contained direct, long-terminal repeats (LTRs) of 596 bp whose features were characteristic of retroviral and retrotransposon LTRs. Within the element, we identified an open reading frame with sequences homologous to the reverse transcriptase and RNase H domains of retroelement pol genes. We concluded that the element we had identified was a retroelement and named it Boty. By comparing its open reading frame with sequences from other retroelements, we found that Boty is related to the gypsy family of retrotransposons. Boty was present in numerous strains isolated from grapes and tomatoes but not in isolates from lentils. We propose that Boty-containing and Boty-deficient groups represent two lineages in the population of B. cinerea.


Pulse oximetry at high altitude.
Pulse oximetry is a valuable, noninvasive, diagnostic tool for the evaluation of ill individuals at high altitude and is also being increasingly used to monitor the well-being of individuals traveling on high altitude expeditions. Although the devices are simple to use, data output may be inaccurate or hard to interpret in certain situations, which could lead to inappropriate clinical decisions. The purpose of this review is to consider such issues in greater detail. After examining the operating principles of pulse oximetry, we describe the available devices and the potential uses of oximetry at high altitude. We then consider the pitfalls of pulse oximetry in this environment and provide recommendations about how to deal with these issues. Device users should recognize that oxygen saturation changes rapidly in response to small changes in oxygen tensions at high altitude and that device accuracy declines with arterial oxygen saturations of less than 80%. The normal oxygen saturation at a given elevation may not be known with certainty and should be viewed as a range of values, rather than a specific number. For these reasons, clinical decisions should not be based on small differences in saturation over time or among individuals. Effort should also be made to minimize factors that cause measurement errors, including cold extremities, excess ambient light, and ill-fitting oximeter probes. Attention to these and other issues will help the users of these devices to apply them in appropriate situations and to minimize erroneous clinical decisions.


Interaction with ectopic cochlear crista sensory epithelium disrupts basal cochlear sensory epithelium development in Lmx1a mutant mice.
The LIM homeodomain transcription factor Lmx1a shows a dynamic expression in the developing mouse ear that stabilizes in the non-sensory epithelium. Previous work showed that Lmx1a functional null mutants have an additional sensory hair cell patch in the posterior wall of a cochlear duct and have a mix of vestibular and cochlear hair cells in the basal cochlear sensory epithelium. In E13.5 mutants, Sox2-expressing posterior canal crista is continuous with an ectopic "crista sensory epithelium" located in the outer spiral sulcus of the basal cochlear duct. The medial margin of cochlear crista is in contact with the adjacent Sox2-expressing basal cochlear sensory epithelium. By E17.5, this contact has been interrupted by the formation of an intervening non-sensory epithelium, and Atoh1 is expressed in the hair cells of both the cochlear crista and the basal cochlear sensory epithelium. Where cochlear crista was formerly associated with the basal cochlear sensory epithelium, the basal cochlear sensory epithelium lacks an outer hair cell band, and gaps are present in its associated Bmp4 expression. Further apically, where cochlear crista was never present, the cochlear sensory epithelium forms a poorly ordered but complete organ of Corti. We propose that the core prosensory posterior crista is enlarged in the mutant when the absence of Lmx1a expression allows JAG1-NOTCH signaling to propagate into the adjacent epithelium and down the posterior wall of the cochlear duct. We suggest that the cochlear crista propagates in the mutant outer spiral sulcus because it expresses Lmo4 in the absence of Lmx1a.


Relationship Satisfaction and Depression After Traumatic Brain Injury: An Actor-Partner Interdependence Model of Patients and Caregivers in Mexico and Colombia.
Traumatic brain injury represents a major public health concern, particularly in low- and middle-income countries like in Latin America. Family members are often caregivers for individuals with traumatic brain injury, which can result in significant stress. Research is needed to examine depression and quality of the caregiving relationship in these dyads. This study examined relationship quality and depression longitudinally after traumatic brain injury within the caregiving relationship. Dyads (N = 109) composed of individuals with traumatic brain injury and their caregivers were recruited from three hospitals in Mexico and Colombia. They self-reported depression and relationship satisfaction during hospitalization and at 2 and 4 mos after hospitalization. A 2-lag Actor Partner Interdependence Model demonstrated that patients and caregivers reporting high relationship satisfaction at baseline experienced lower depression 2 mos later, which then predicted higher caregiver relationship satisfaction at 4 mos. Moreover, patients with high relationship satisfaction at baseline had caregivers with lower depression at 2 mos, which was then associated with patients' higher satisfaction at 4 mos. Within individuals with traumatic brain injury and caregivers, depression and relationship satisfaction seem to be inversely related. Furthermore, patients' and caregivers' depression and relationship satisfaction impact each other over time, demonstrating interdependence within the caregiving relationship.


Degradation of microRNAs by a family of exoribonucleases in Arabidopsis.
microRNAs (miRNAs) play crucial roles in numerous developmental and metabolic processes in plants and animals. The steady-state levels of miRNAs need to be properly controlled to ensure normal development. Whereas the framework of miRNA biogenesis is established, factors involved in miRNA degradation remain unknown. Here, we show that a family of exoribonucleases encoded by the SMALL RNA DEGRADING NUCLEASE (SDN) genes degrades mature miRNAs in Arabidopsis. SDN1 acts specifically on single-stranded miRNAs in vitro and is sensitive to the 2'-O-methyl modification on the 3' terminal ribose of miRNAs. Simultaneous knockdown of three SDN genes in vivo results in elevated miRNA levels and pleiotropic developmental defects. Therefore, we have uncovered the enzymes that degrade miRNAs and demonstrated that miRNA turnover is crucial for plant development.


Regulation of cell substrate adhesion: effects of small galactosaminoglycan-containing proteoglycans.
Cell adhesion is a process which is initiated by the attachment of cells to specific sites in adhesive matrix proteins via cell surface receptors of the integrin family. This is followed by a reorganization of cytoskeletal elements which results in cell spreading and the formation of focal adhesion plaques. We have examined the effects of a class of small galactosaminoglycan-containing proteoglycans on the various stages of cell adhesion to fibronectin-coated substrates. Our results indicate that dermatan sulfate proteoglycans (DSPGs) derived from cartilage, as well as other related small proteoglycans, inhibit the initial attachment of CHO cells and rat embryo fibroblasts to substrates composed of the 105-kD cell-binding fibronectin fragment, but do not affect cell attachment to intact fibronectin. Although this effect involves binding of DSPGs to the substrate via the protein core, the intact proteoglycan is necessary for the observed activity. Isolated core proteins are inactive. The structural composition of the galactosaminoglycan chain does not appear to be functionally significant since both chondroitin sulfate and various dermatan sulfate proteoglycans of this family inhibit cell attachment to the fibronectin fragment. Neither the percentage of cells spread nor the mean area of spread cells adhering to substrates of intact fibronectin was significantly affected by the DSPGs. However, significantly fewer cells formed focal adhesions in the presence of DSPGs as compared with untreated control cells. These results suggest that the binding of small galactosaminoglycan-containing proteoglycans to a fibronectin substrate may affect several stages in the cell adhesion process.


Evolution of communication protocols using an artificial regulatory network.
I describe the Utrecht Machine (UM), a discrete artificial regulatory network designed for studying how evolution discovers biochemical computation mechanisms. The corresponding binary genome format is compatible with gene deletion, duplication, and recombination. In the simulation presented here, an agent consisting of two UMs, a sender and a receiver, must encode, transmit, and decode a binary word over time using the narrow communication channel between them. This communication problem has chicken-and-egg structure in that a sending mechanism is useless without a corresponding receiving mechanism. An in-depth case study reveals that a coincidence creates a minimal partial solution, from which a sequence of partial sending and receiving mechanisms evolve. Gene duplications contribute by enlarging the regulatory network. Analysis of 60,000 sample runs under a variety of parameter settings confirms that crossover accelerates evolution, that stronger selection tends to find clumsier solutions and finds them more slowly, and that there is implicit selection for robust mechanisms and genomes at the codon level. Typical solutions associate each input bit with an activation speed and combine them almost additively. The parents of breakthrough organisms sometimes have lower fitness scores than others in the population, indicating that populations can cross valleys in the fitness landscape via outlying members. The simulation exhibits back mutations and population-level memory effects not accounted for in traditional population genetics models. All together, these phenomena suggest that new evolutionary models are needed that incorporate regulatory network structure.


Transport of a fluorescent macromolecule via endosomes to the vacuole in Saccharomyces cerevisiae.
Fluorescein isothiocyanate-conjugated dextran (FITC-dextran) is internalized by endocytosis into the lysosome-like vacuoles of Saccharomyces cerevisiae (Makarow, M., 1985, EMBO (Eur. Mol. Biol. Organ.) J. 4:1861-1866). Here we show that under energy depletion conditions FITC-dextran accumulated in a cytoplasmic compartment, from which it could be chased to the vacuole when the energy block was removed. The internal pH of the intermediate compartment under energy depletion was determined by fluorometry to be 5.8. The pH could be raised by the lysosomotropic agent ammonium chloride, the protonophore carbonyl cyanide p-trifluoromethoxyphenyl-hydrazone (CCCP) and the ATPase inhibitors dicyclohexylcarbodiimide (DCCD) and sodium vanadate. The pH of the vacuole was found to be 6.5. It was raised by ammonium chloride, CCCP, and DCCD, but not with sodium vanadate. Efrapeptin had no effect on the internal pH of either compartment. By dissecting the endocytic pathway, two portions of the route leading to the vacuole could be studied separately. The internalization of FITC-dextran from the extracellular fluid to the intermediate compartment followed linear kinetics, was independent of energy, and occurred at temperatures of between 15 degrees and 37 degrees C. Transfer of the marker from the intermediate compartment to the vacuole required energy, took place at temperatures between 19 degrees and 37 degrees C, and had a half-time of 7 min at 37 degrees C. Transport of the marker from the exterior of the cell to the vacuole did not require acidic pH values in the intermediate compartment or the vacuole. We suggest that the cytoplasmic compartment revealed by FITC-dextran, under energy depletion, represents the equivalent of the endosomes of mammalian cells.


Epigenomic regulation of oncogenesis by chromatin remodeling.
Disruption of the intricate gene expression program represents one of major driving factors for the development, progression and maintenance of human cancer, and is often associated with acquired therapeutic resistance. At the molecular level, cancerous phenotypes are the outcome of cellular functions of critical genes, regulatory interactions of histones and chromatin remodeling complexes in response to dynamic and persistent upstream signals. A large body of genetic and biochemical evidence suggests that the chromatin remodelers integrate the extracellular and cytoplasmic signals to control gene activity. Consequently, widespread dysregulation of chromatin remodelers and the resulting inappropriate expression of regulatory genes, together, lead to oncogenesis. We summarize the recent developments and current state of the dysregulation of the chromatin remodeling components as the driving mechanism underlying the growth and progression of human tumors. Because chromatin remodelers, modifying enzymes and protein-protein interactions participate in interpreting the epigenetic code, selective chromatin remodelers and bromodomains have emerged as new frontiers for pharmacological intervention to develop future anti-cancer strategies to be used either as single-agent or in combination therapies with chemotherapeutics or radiotherapy.


Validation of image analysis techniques to measure skin aging features from facial photographs.
Accurate measurement of the extent skin has aged is crucial for skin aging research. Image analysis offers a quick and consistent approach for quantifying skin aging features from photographs, but is prone to technical bias and requires proper validation. Facial photographs of 75 male and 75 female North-European participants, randomly selected from the Rotterdam Study, were graded by two physicians using photonumeric scales for wrinkles (full face, forehead, crow's feet, nasolabial fold and upper lip), pigmented spots and telangiectasia. Image analysis measurements of the same features were optimized using photonumeric grades from 50 participants, then compared to photonumeric grading in the 100 remaining participants stratified by sex. The inter-rater reliability of the photonumeric grades was good to excellent (intraclass correlation coefficients 0.65-0.93). Correlations between the digital measures and the photonumeric grading were moderate to excellent for all the wrinkle comparisons (Spearman's rho ρ = 0.52-0.89) bar the upper lip wrinkles in the men (fair, ρ = 0.30). Correlations were moderate to good for pigmented spots and telangiectasia (ρ = 0.60-0.75). These comparisons demonstrate that all the image analysis measures, bar the upper lip measure in the men, are suitable for use in skin aging research and highlight areas of improvement for future refinements of the techniques.


Refractory duodenal ulcer.
Refractory or intractable ulcer is defined as an ulcer that fails to heal completely after eight to twelve weeks, despite appropriate treatment with a modern antiulcer therapy in a compliant patient. Refractory ulcer should be suspected in individuals diagnosed to have peptic ulcer if their symptoms persist longer than usual: occurrence of complications or simply their ulcers fail to heal, since up to 25% of such patients remain asymptomatic. Conditions associated with refractory ulcer include noncompliance, continuous consumption of nonsteroidal anti-inflammatory drugs, acid hypersecretion, smoking. male gender and other factors with questionable role like advanced age, large ulcer size, prolonged duration of symptoms and the presence of complication like bleeding. Nonpeptic ulcers like tuberculosis, malignancy, Crohn's disease and primary intestinal lymphoma should always be considered in the differential diagnosis. Colonization with H. pylori which is well-known as a cause of frequent recurrences, has not been linked with refractoriness. Patients with refractory ulcers must undergo thorough re-evaluation including repeated endoscopies, obtaining biopsies for microbiology and histology and determination of serum-gastrin level. Once diseases with identifiable etiologies have been ruled out, aggressive medical management with single or multiple antiulcer drugs should be instituted. Such treatments will virtually heal all refractory ulcers. Surgery should be reserved for patients whose ulcers fail to respond to optimal medical therapy or those who develop complications necessitating surgical intervention.


Enhancer-driven chromatin interactions during development promote escape from silencing by a long non-coding RNA.
Gene regulation in eukaryotes is a complex process entailing the establishment of transcriptionally silent chromatin domains interspersed with regions of active transcription. Imprinted domains consist of clusters of genes, some of which exhibit parent-of-origin dependent monoallelic expression, while others are biallelic. The Kcnq1 imprinted domain illustrates the complexities of long-range regulation that coexists with local exceptions. A paternally expressed repressive non-coding RNA, Kcnq1ot1, regulates a domain of up to 750 kb, encompassing 14 genes. We study how the Kcnq1 gene, initially silenced by Kcnq1ot1, undergoes tissue-specific escape from imprinting during development. Specifically, we uncover the role of chromosome conformation during these events. We show that Kcnq1 transitions from monoallelic to biallelic expression during mid gestation in the developing heart. This transition is not associated with the loss of methylation on the Kcnq1 promoter. However, by exploiting chromosome conformation capture (3C) technology, we find tissue-specific and stage-specific chromatin loops between the Kcnq1 promoter and newly identified DNA regulatory elements. These regulatory elements showed in vitro activity in a luciferase assay and in vivo activity in transgenic embryos. By exploring the spatial organization of the Kcnq1 locus, our results reveal a novel mechanism by which local activation of genes can override the regional silencing effects of non-coding RNAs.


Maternal cigarette, alcohol, and coffee consumption in relation to risk of clubfoot.
Clubfoot is associated with maternal cigarette smoking in several studies, but it is not clear if this association is confined to women who smoke throughout the at-risk period. Maternal alcohol and coffee drinking have not been well studied in relation to clubfoot. The present study used data from a population-based case-control study of clubfoot conducted in Massachusetts, New York, and North Carolina from 2007 to 2011. Mothers of 646 isolated clubfoot cases and 2037 controls were interviewed about pregnancy events and exposures, including the timing and frequency of cigarette smoking, alcohol intake, and coffee drinking. More mothers of cases than controls reported smoking during early pregnancy (28.9% vs. 19.1%). Of women who smoked when they became pregnant, those who quit in the month after a first missed period had a 40% increase in clubfoot risk and those who continued to smoke during the next 3 months had more than a doubling in risk, after controlling for demographic factors, parity, obesity, and specific medication exposures. Adjusted odds ratios for women who drank >3 servings of alcohol or coffee per day throughout early pregnancy were 2.38 and 1.77, respectively, but the numbers of exposed women were small and odds ratios were unstable. Clubfoot risk appears to be increased for offspring of women who smoke cigarettes, particularly those who continue smoking after pregnancy is recognisable, regardless of amount. For alcohol and coffee drinkers, suggested increased risks were only observed in higher levels of intake.


Adhesive ligand tether length affects the size and length of focal adhesions and influences cell spreading and attachment.
Cells are known to respond to physical cues from their microenvironment such as matrix rigidity. Discrete adhesive ligands within flexible strands of fibronectin connect cell surface integrins to the broader extracellular matrix and are thought to mediate mechanosensing through the cytoskeleton-integrin-ECM linkage. We set out to determine if adhesive ligand tether length is another physical cue that cells can sense. Substrates were covalently modified with adhesive arginylglycylaspartic acid (RGD) ligands coupled with short (9.5 nm), medium (38.2 nm) and long (318 nm) length inert polyethylene glycol tethers. The size and length of focal adhesions of human foreskin fibroblasts gradually decreased from short to long tethers. Furthermore, we found cell adhesion varies in a linker length dependent manner with a remarkable 75% reduction in the density of cells on the surface and a 50% reduction in cell area between the shortest and longest linkers. We also report the interplay between RGD ligand concentration and tether length in determining cellular spread area. Our findings show that without varying substrate rigidity or ligand density, tether length alone can modulate cellular behaviour.


Characterization of a Neochlamydia-like bacterium associated with epitheliocystis in cultured Arctic charr Salvelinus alpinus.
Infections of branchial epithelium by intracellular gram-negative bacteria, termed epitheliocystis, have limited culture of Arctic charr Salvelinus alpinus. To characterize a bacterium associated with epitheliocystis in cultured charr, gills were sampled for histopathologic examination, conventional and immunoelectron microscopy, in situ hybridization, 16S ribosomal DNA (rDNA) amplification, sequence analysis and phylogenetic inference. Sampling was conducted at the Freshwater Institute (Shepherdstown, West Virginia, USA) during outbreaks of epitheliocystis in April and May 2002. Granular, basophilic, cytoplasmic inclusions in charr gill were shown to stain with Macchiavello, Lendrum's phloxine-tartrazine and Gimenez histochemical techniques. Ultrastructurally, inclusions were membrane-bound and contained round to elongate reticulate bodies that were immunoreactive to an antibody against chlamydial lipopolysaccharide, suggesting the presence of similar epitopes. DNA extracted from gills supported amplification of the most polymorphic and phylogenetically relevant region of the 16S rRNA gene, which had 97 to 100% identity with several uncultured clinical Neochlamydia spp. (order Chlamydiales) Clones WB13 (AY225593.1) and WB258 (AY225594.1). Sequence-specific riboprobes localized to inclusions during in situ hybridization experiments. Taxonomic affiliation was inferred by distance- and parsimony-based phylogenetic analyses of the 16S sequence, which branched with Neochlamydia hartmannellae in the order Chlamydiales with high confidence. This is the first molecular characterization of a chlamydia associated with epitheliocystis in Arctic charr and the fourth Neochlamydia spp. sequence to be associated with epitheliocystis. Presence of a clinical neochlamydial sequence, first identified from a cat, in Arctic charr suggests a possible mammalian and piscine host range for some environmental chlamydiae.


p75(NTR) mediates ephrin-A reverse signaling required for axon repulsion and mapping.
Reverse signaling by ephrin-As upon binding EphAs controls axon guidance and mapping. Ephrin-As are GPI-anchored to the membrane, requiring that they complex with transmembrane proteins that transduce their signals. We show that the p75 neurotrophin receptor (NTR) serves this role in retinal axons. p75(NTR) and ephrin-A colocalize within caveolae along retinal axons and form a complex required for Fyn phosphorylation upon binding EphAs, activating a signaling pathway leading to cytoskeletal changes. In vitro, retinal axon repulsion to EphAs by ephrin-A reverse signaling requires p75(NTR), but repulsion to ephrin-As by EphA forward signaling does not. Constitutive and retina-specific p75(NTR) knockout mice have aberrant anterior shifts in retinal axon terminations in superior colliculus, consistent with diminished repellent activity mediated by graded ephrin-A reverse signaling induced by graded collicular EphAs. We conclude that p75(NTR) is a signaling partner for ephrin-As and the ephrin-A- p75(NTR) complex reverse signals to mediate axon repulsion required for guidance and mapping.


Genetic regulation of the ompX porin of Salmonella Typhimurium in response to hydrogen peroxide stress.
Salmonella Typhimurium is a Gram-negative pathogen that causes a systemic disease in mice resembling typhoid fever. During its infective cycle, S. Typhimurium is phagocytized by macrophages and proliferates inside a Salmonella-containing vacuole where Salmonella is exposed and survives oxidative stress induced by H2O2 through modulation of gene expression. After exposure of Salmonella to H2O2, the expression of the porin-encoding gene ompX increases, as previously shown by microarray analysis. Expression of ompX mRNA is regulated at a post-transcriptional level by MicA and CyaR sRNAs in aerobiosis. In addition, sequence analysis predicts a site for OxyS sRNA in ompX mRNA. In this work we sought to evaluate the transcriptional and post-transcriptional regulation of ompX under H2O2 stress. We demonstrate that ompX expression is induced at the transcriptional level in S. Typhimurium under such conditions. Unexpectedly, an increase in ompX gene transcript and promoter activity after challenges with H2O2 does not translate into increased protein levels in the wild-type strain, suggesting that ompX mRNA is also regulated at a post-transcriptional level, at least under oxidative stress. In silico gene sequence analysis predicted that sRNAs CyaR, MicA, and OxyS could regulate ompX mRNA levels. Using rifampicin to inhibit mRNA expression, we show that the sRNAs (MicA, CyaR and OxyS) and the sRNA:mRNA chaperone Hfq positively modulate ompX mRNA levels under H2O2-induced stress in Salmonella during the exponential growth phase in Lennox broth. Our results demonstrate that ompX mRNA is regulated in response to H2O2 by the sRNAs CyaR, MicA and OxyS is Salmonella Typhimurium.


Effects of pupillary light and darkness reflex on the generation of pro- And anti-saccades.
Saccades are often directed toward a stimulus that provides useful information for observers to navigate the visual world. The quality of visual signals of a stimulus is influenced by global luminance, and the pupil constricts or dilates after a luminance increase or decrease, respectively, to optimize visual signals for further information processing. Although luminance level changes regularly in the real environment, saccades are mostly studied in the luminance-unchanged setup. Whether pupillary responses triggered by global luminance changes modulate saccadic behavior are yet to be explored. Through varying background luminance level in an interleaved pro- and anti-saccade paradigm, we investigated the modulation of pupillary luminance responses on the generation of reflexive and voluntary saccades. Subjects were instructed to either automatically look at the peripheral stimulus (pro-saccade) or to suppress the automatic response and voluntarily look in the opposite direction from the stimulus (anti-saccade). Level of background luminance was increased (light), decreased (dark), or unchanged (control) during the instructed fixation period. Saccade reaction time distributions of correct pro- and anti-saccades in the light and dark conditions were differed significantly from those in the control condition. Moreover, the luminance condition modulated saccade kinematics, showing reduced performances in the light condition than in the control condition, particularly in pro-saccades. Modeling results further suggested that both pupil diameter and pupil size derivative significantly modulated saccade behavior, though effect sizes were small and mainly mediated by intersubject differences. Together, our results demonstrated the influence of pupillary luminance responses on the generation of pro- and anti-saccades.


Fluorescent light-up probe with aggregation-induced emission characteristics for in vivo imaging of cell apoptosis.
In this paper, a new live-cell permeable, fluorescent light-up probe comprised of a hydrophilic caspase-specific Asp-Glu-Val-Asp (DEVD) peptide and a hydrophobic tetraphenylethene pyridinium unit has been developed for in vivo cell apoptosis imaging and drug screening. The probe shows a specific light-up response to activated caspase-3/7 with a high signal-to-background ratio. The significant fluorescence turn-on response of the probe is due to the aggregation of cleaved hydrophobic residues that populate the radiative decay channels. With good water solubility and biocompatibility, the probe is demonstrated to be a promising candidate for in vivo real time monitoring of caspase activation and in situ screening of apoptosis-inducing drugs.


Dental students' peer assessment: a prospective pilot study.
Peer assessment is increasingly used in health education. The aims of this study were to evaluate the reliability, accuracy, educational impact and student's perceptions of undergraduate pre-clinical and clinical dental students' structured and prospective Peer assessment and peer feedback protocol. Two Direct Observation of Procedural Skills (DOPS) forms were modified for use in pre-clinical and clinical peer assessment. Ten year two dental students working in a phantom-heads skills laboratory and 16-year five dental students attending a comprehensive care clinic piloted both peer DOPS forms. After training, pairs of students observed, assessed and provided immediate feedback to each other using their respective peer DOPS forms as frameworks. At the end of the 3-month study period, students anonymously provided their perceptions of the protocol. Year 2 and year 5 students completed 57 and 104 peer DOPS forms, respectively. The generalizability coefficient was 0.62 for year 2 (six encounters) and 0.67 for year 5 (seven encounters). Both groups were able to differentiate amongst peer-assessed domains and so detect improvement in peers' performance over time. Peer DOPS scores of both groups showed a positive correlation with their mean end-of-year examination marks (r ≥ 0.505, P ≥ 0.051) although this was not statistically significant. There was no difference (P ≥ 0.094) between the end-of-year examination marks of the participating students and the rest of their respective classes. The vast majority of both groups expressed positive perceptions of the piloted protocol. There are no data in the literature on the prospective use of peer assessment in the dental undergraduate setting. In the current study, both pre-clinical and clinical students demonstrated the ability to identify those domains where peers performed better, as well as those which needed improvement. Despite no observable educational impact, most students reported positive perceptions of the peer DOPS protocol. The results of this pilot study support the need for and the potential benefit of a larger- and longer-term follow-up study utilising the protocol.


Exercise Response Variations in Skeletal Muscle PCr Recovery Rate and Insulin Sensitivity Relate to Muscle Epigenomic Profiles in Individuals With Type 2 Diabetes.
Some individuals with type 2 diabetes do not reap metabolic benefits from exercise training, yet the underlying mechanisms of training response variation are largely unexplored. We classified individuals with type 2 diabetes (n = 17) as nonresponders (n = 6) or responders (n = 11) based on changes in phosphocreatine (PCr) recovery rate after 10 weeks of aerobic training. We aimed to determine whether the training response variation in PCr recovery rate was marked by distinct epigenomic profiles in muscle prior to training. PCr recovery rate as an indicator of in vivo muscle mitochondrial function in vastus lateralis (31P-magnetic resonance spectroscopy), insulin sensitivity (M-value; hyperinsulinemic-euglycemic clamp), aerobic capacity (Vo2peak), and blood profiles were determined pretraining and post-training. Muscle biopsies were performed pretraining in vastus lateralis for the isolation of primary skeletal muscle cells (HSkMCs) and assessments of global DNA methylation and RNA sequencing in muscle tissue and HSkMCs. By design, nonresponders decreased and responders increased PCr recovery rate with training. In nonresponders, insulin sensitivity did not improve and glycemic control (HbA1c) worsened. In responders, insulin sensitivity improved. Vo2peak improved by ∼12% in both groups. Nonresponders and responders were distinguished by distinct pretraining molecular (DNA methylation, RNA expression) patterns in muscle tissue, as well as in HSkMCs. Enrichment analyses identified elevations in glutathione regulation, insulin signaling, and mitochondrial metabolism in nonresponders pretraining, which was reflected in vivo by higher pretraining PCr recovery rate and insulin sensitivity in these same individuals. A training response variation for clinical risk factors in individuals with type 2 diabetes is reflected by distinct basal myocellular epigenomic profiles in muscle tissue, some of which are maintained in HSkMCs, suggesting a cell-autonomous underpinning. Our data provide new evidence to potentially shift the diabetes treatment paradigm for individuals who do not benefit from training, such that supplemental treatment can be designed.


The role of oxidoreductases in determining the function of the neisserial lipid A phosphoethanolamine transferase required for resistance to polymyxin.
The decoration of the lipid A headgroups of the lipooligosaccharide (LOS) by the LOS phosphoethanolamine (PEA) transferase (LptA) in Neisseria spp. is central for resistance to polymyxin. The structure of the globular domain of LptA shows that the protein has five disulphide bonds, indicating that it is a potential substrate of the protein oxidation pathway in the bacterial periplasm. When neisserial LptA was expressed in Escherichia coli in the presence of the oxidoreductase, EcDsbA, polymyxin resistance increased 30-fold. LptA decorated one position of the E. coli lipid A headgroups with PEA. In the absence of the EcDsbA, LptA was degraded in E. coli. Neisseria spp. express three oxidoreductases, DsbA1, DsbA2 and DsbA3, each of which appear to donate disulphide bonds to different targets. Inactivation of each oxidoreductase in N. meningitidis enhanced sensitivity to polymyxin with combinatorial mutants displaying an additive increase in sensitivity to polymyxin, indicating that the oxidoreductases were required for multiple pathways leading to polymyxin resistance. Correlates were sought between polymyxin sensitivity, LptA stability or activity and the presence of each of the neisserial oxidoreductases. Only meningococcal mutants lacking DsbA3 had a measurable decrease in the amount of PEA decoration on lipid A headgroups implying that LptA stability was supported by the presence of DsbA3 but did not require DsbA1/2 even though these oxidoreductases could oxidise the protein. This is the first indication that DsbA3 acts as an oxidoreductase in vivo and that multiple oxidoreductases may be involved in oxidising the one target in N. meningitidis. In conclusion, LptA is stabilised by disulphide bonds within the protein. This effect was more pronounced when neisserial LptA was expressed in E. coli than in N. meningitidis and may reflect that other factors in the neisserial periplasm have a role in LptA stability.


Circulating spatial solitons.
A class of optical spatial solitons exhibiting propagation in a closed-loop orbit in a two-dimensional plane is presented. A closed-form particlelike model is derived, indicating that the quasi-centrifugal force acting on these solitons can be balanced by an inhomogeneity in the nonlinear index of refraction. Specifically, a circular-shaped nonlinear interface is shown to facilitate stable orbital propagation of solitons that carve their own circular cavity for a wide range of nonlinearity parameters.


Deletion of ENTPD3 does not impair nucleotide hydrolysis in primary somatosensory neurons or spinal cord.
Ectonucleotidases are membrane-bound or secreted proteins that hydrolyze extracellular nucleotides. Recently, we identified three ectonucleotidases that hydrolyze extracellular adenosine 5'-monophosphate (AMP) to adenosine in primary somatosensory neurons. Currently, it is unclear which ectonucleotidases hydrolyze ATP and ADP in these neurons. Ectonucleoside triphosphate diphosphohydrolases (ENTPDs) comprise a class of enzymes that dephosphorylate extracellular ATP and ADP. Here, we found that ENTPD3 (also known as NTPDase3 or CD39L3) was located in nociceptive and non-nociceptive neurons of the dorsal root ganglion (DRG), in the dorsal horn of the spinal cord, and in free nerve endings in the skin. To determine if ENTPD3 contributes directly to ATP and ADP hydrolysis in these tissues, we generated and characterized an Entpd3 knockout mouse. This mouse lacks ENTPD3 protein in all tissues examined, including the DRG, spinal cord, skin, and bladder. However, DRG and spinal cord tissues from Entpd3 (-/-) mice showed no reduction in histochemical staining when ATP, ADP, AMP, or UTP were used as substrates. Additionally, using fast-scan cyclic voltammetry (FSCV), adenosine production was not impaired in the dorsal spinal cord of Entpd3 (-/-) mice when the substrate ADP was applied. Further, Entpd3 (-/-) mice did not differ in nociceptive behaviors when compared to wild-type mice, although Entpd3 (-/-) mice showed a modest reduction in β-alanine-mediated itch. Taken together, our data indicate that deletion of Entpd3 does not impair ATP or ADP hydrolysis in primary somatosensory neurons or in dorsal spinal cord. Moreover, our data suggest there could be multiple ectonucleotidases that act redundantly to hydrolyze nucleotides in these regions of the nervous system.


Essential but Not Vulnerable: Indazole Sulfonamides Targeting Inosine Monophosphate Dehydrogenase as Potential Leads against Mycobacterium tuberculosis.
A potent, noncytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This noncytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning from Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH). Subsequent biochemical validation confirmed direct inhibition of IMPDH by an uncompetitive mode of inhibition, and growth inhibition could be rescued by supplementation with guanine, a bypass mechanism for the IMPDH pathway. Beads containing immobilized indazole sulfonamides specifically interacted with IMPDH in cell lysates. X-ray crystallography of the IMPDH-IMP-inhibitor complex revealed that the primary interactions of these compounds with IMPDH were direct pi-pi interactions with the IMP substrate. Advanced lead compounds in this series with acceptable pharmacokinetic properties failed to show efficacy in acute or chronic murine models of tuberculosis (TB). Time-kill experiments in vitro suggest that sustained exposure to drug concentrations above the minimum inhibitory concentration (MIC) for 24 h were required for a cidal effect, levels that have been difficult to achieve in vivo. Direct measurement of guanine levels in resected lung tissue from tuberculosis-infected animals and patients revealed 0.5-2 mM concentrations in caseum and normal lung tissue. The high lesional levels of guanine and the slow lytic, growth-rate-dependent effect of IMPDH inhibition pose challenges to developing drugs against this target for use in treating TB.


Positional Isomers of Biphenyl Antimicrobial Peptidomimetic Amphiphiles.
Small-molecule antimicrobial peptidomimetic amphiphiles represent a promising class of novel antimicrobials with the potential for widespread therapeutic application. To investigate the role of spatial positioning for key hydrophobic and hydrophilic groups on the antimicrobial efficacy and selectivity, positional isomers of the lead biphenyl antimicrobial peptidomimetic compound 1 were synthesized and subjected to microbial growth inhibition and mammalian toxicity assays. Positional isomer 4 exhibited 4-8× increased efficacy against the pathogenic Gram-negative bacteria Pseudomonas aeruginosa and Escherichia coli (MIC = 2 μg/mL), while isomers 2, 3, and 7 exhibited a 4× increase in activity against Acinetobacter baumannii (MIC = 4 μg/mL). Changes in molecular shape had a significant impact on Gram-negative antibacterial efficacy and the resultant spectrum of activity, whereas all structural isomers exhibited significant efficacy (MIC = 0.25-8 μg/mL) against Gram-positive bacterial pathogens (e.g., methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecalis).


Integrated plan to augment surge capacity.
Surge capacity is defined as a healthcare system's ability to rapidly expand beyond normal services to meet the increased demand for appropriate space, qualified personnel, medical care, and public health in the event ofbioterrorism, disaster, or other large-scale, public health emergencies. There are many individuals and agencies, including policy makers, planners, administrators, and staff at the federal, state, and local level, involved in the process of planning for and executing policy in respect to a surge in the medical requirements of a population. They are responsible to ensure there is sufficient surge capacity within their own jurisdiction. The [US] federal government has required New York State to create a system of hospital bed surge capacity that provides for 500 adult and pediatric patients per 1 million population, which has been estimated to be an increase of 15-20% in bed availability. In response, the New York City Department of Health and Mental Hygiene (NYC DOH) has requested that area hospitals take an inventory of available beds and set a goal to provide for a 20% surge capacity to be available during a mass-casualty event or other conditions calling for increased inpatient bed availability. In 2003, under the auspices of the NYC DOH, the New York Institute of All Hazard Preparedness (NYIHP) was formed from four unaffiliated, healthcare facilities in Central Brooklyn to address this and other goals. The NYIHP hospitals have developed a surge capacity plan to provide necessary space and utilities. As these plans have been applied, a bed surge capacity of approximately 25% was identified and created for Central Brooklyn to provide for the increased demand on the medical care system that may accompany a disaster. Through the process of developing an integrated plan that would engage a public health incident, the facilities of NYIHP demonstrate that a model of cooperation may be applied to an inherently fractioned medical system.


Dynamics of a type 2 secretion system pseudopilus unraveled by complementary approaches.
Secretion pili, bacterial fibers responsible for transporting proteins to the extracellular milieu in some secretion systems, are very strong structures but at the same time highly flexible. Their flexibility and helical symmetry make structure determination at atomic resolution a challenging task. We have previously used an integrative structural biology approach including liquid-state NMR, cryo-electron microscopy (cryo-EM), and modeling to determine the pseudo-atomic resolution structure of the type 2 secretion system pseudopilus in a mutant form, where we employed NMR to determine the high resolution structure of the pilin (the monomer building block of the pilus). In this work, we determine the pseudo-atomic structure of the wild type pilus, and compare the dynamics of wild type and mutant pili by normal mode analysis. We present a detailed NMR analysis of the dynamics of the pilin in isolation, and compare dynamics and solvent accessibility of isolated and assembled pilins by Hydrogen/Deuterium eXchange Mass Spectrometry (HDX-MS). These complementary approaches provide a comprehensive view of internal and overall dynamics of pili, crucial for their function.


Normal perfusion pressure breakthrough syndrome in giant arteriovenous malformations.
The treatment of large, high-flow cerebral arteriovenous malformations is one of the most difficult operations which neurosurgeons encounter because of the complex surgery and the post-operative effects on the brain. We have evaluated 10 patients with large, high-flow AVMs who underwent surgical resection. Patients were investigated with contrast-enhanced computed tomography and magnetic resonance imaging, 1231-IMP single photon emission computed tomography (SPECT) studies of cerebral flow and cerebral vasodilatory function, intraoperative Laser Doppler flowmetry (4 or 10 patients), and conventional angiography. The volume of the arteriovenous malformation nidi ranged from 32.8 to 210.5 cc. SPECT imaging performed on the first post-operative day showed marked hyperperfusion in the brain tissue surrounding the resected nidus, and these regions were normal on images on the 7th post-operative day. Laser Doppler flowmetry showed sudden, and marked increase in CBF immediately following placement of temporary clips on the main feeding artery. Angiograms done on 7-14 days following surgery showed a stagnating artery, fragile vessel, and a prolonged circulation time. Our results indicate that pre- and post-operative SPECT study, especially a dynamic SPECT study done on the first post-operative day, was the most useful examination for ascertaining the post-operative normal perfusion pressure breakthrough.


Site-specific mapping and quantification of protein S-sulphenylation in cells.
Cysteine S-sulphenylation provides redox regulation of protein functions, but the global cellular impact of this transient post-translational modification remains unexplored. We describe a chemoproteomic workflow to map and quantify over 1,000 S-sulphenylation sites on more than 700 proteins in intact cells. Quantitative analysis of human cells stimulated with hydrogen peroxide or epidermal growth factor measured hundreds of site selective redox changes. Different cysteines in the same proteins displayed dramatic differences in susceptibility to S-sulphenylation. Newly discovered S-sulphenylations provided mechanistic support for proposed cysteine redox reactions and suggested novel redox mechanisms, including S-sulphenyl-mediated redox regulation of the transcription factor HIF1A by SIRT6. S-sulphenylation is favored at solvent-exposed protein surfaces and is associated with sequence motifs that are distinct from those for other thiol modifications. S-sulphenylations affect regulators of phosphorylation, acetylation and ubiquitylation, which suggest regulatory crosstalk between redox control and signalling pathways.


Misoprostol for miscarriage management in a woman with previous five cesarean deliveries: a case report and literature review.
Misoprostol is an effective medical method for the management of pregnancy loss. However, data on its efficacy and safety in women with previous cesarean deliveries are limited. We report a 36-year-old patient, gravida 11 para 6, with a diagnosis of missed miscarriage at 15 weeks of gestation. The patient had a significant obstetric history of previous five cesarean deliveries and uterine rupture. Following patient counseling about the medical and surgical options of managing her miscarriage, the patient opted for medical method. Low-dose misoprostol of 100 µg was inserted vaginally and repeated again after 6 hours. The patient had an uneventful complete miscarriage following the second dose of misoprostol. No uterine rupture, no extra vaginal bleeding, and no blood transfusion were observed. We conclude that adopting a low-dose misoprostol protocol could be potentially safe and effective in managing second trimester missed miscarriage in women with repeated cesarean deliveries and/or uterine rupture history. Further studies are needed to confirm these results.


The effect of hemorrhagic shock in a caprine tibial fracture model.
The purpose of this study was to assess effects of hemorrhagic shock on fracture healing in a large animal closed fracture model. Prospective randomized trial. University Medical Center. Eight skeletally mature neutered male goats. Standardized bilateral closed midshaft tibia fractures were created in all the goats. The goats were randomized to a hemorrhage, shock and resuscitation group (shock group), or a control group. Hemorrhagic shock was induced in the four goats in the shock group. The shock state was maintained for thirty minutes. The remaining four goats were used as a control group. All fractures were stabilized with a standardized external fixator. Swan-Ganz catheters were used to record cardiac output (CO). Arterial blood was sampled to determine base deficit values for the goats after hemorrhage. Radiographs were obtained weekly. After four weeks the tibias were harvested and nondestructively tested in torsion. Immediately after mechanical testing, the tibias were processed for histologic analysis. Standard histomorphologic indices, including total bone volume (TV/BV%), osteoblast surfaces (Ob/BS%), and osteoid surface (OS/BS%), were measured. One goat in the shock group became agitated upon emergence from anesthesia and dislodged two of his external fixator pins. This animal was killed and was not included in the analysis of results. One goat that would have been entered into the control group was then switched to the shock group, leaving four goats in the shock group and three in the control group. One goat in the shock group developed a nonunion of his left tibia fracture. This nonunion occurred because of loosening of pin fixation in the distal tibia. The nonunited bone was not included in the analysis of results. The animal's right tibia healed uneventfully. Hemorrhage uniformly resulted in shock. In the shock group goats, average CO on induction of anesthesia was 3.7 l/min. Average CO dropped to 0.7 after hemorrhage and rose to 6.6 after fluid resuscitation. The average base deficit for the shock group animals was -9.9. The control group animals had minor drops in average CO, from 4.5 on induction of anesthesia to 4.3 on emergence from anesthesia. Radiographic analysis showed no apparent differences in healing between groups when comparing callus area and density. With the exception of the nonunion, all tibiae were considered to be healing normally radiographically. Biomechanical testing showed no statistical difference between the shock and control groups in maximum torque (p = 0.95), stiffness (p = 0.64), and energy absorbed at failure (p = 0.91). Histomorphologic results indicated there were no differences between groups. Shock did not appear to influence bone formation rate or callus remodeling compared with controls (p = 0.6). No evidence of osteocyte necrosis was observed. In this study no significant difference was found between the shock and control groups in any of the parameters measured. Transient hemorrhagic shock does not appear to adversely affect closed tibia fracture healing in a goat model.


Electromyographic Assessment of the Efficacy of Deep Dry Needling versus the Ischemic Compression Technique in Gastrocnemius of Medium-Distance Triathletes.
Several studies have shown that gastrocnemius is frequently injured in triathletes. The causes of these injuries are similar to those that cause the appearance of the myofascial pain syndrome (MPS). The ischemic compression technique (ICT) and deep dry needling (DDN) are considered two of the main MPS treatment methods in latent myofascial trigger points (MTrPs). In this study superficial electromyographic (EMG) activity in lateral and medial gastrocnemius of triathletes with latent MTrPs was measured before and immediately after either DDN or ICT treatment. Taking into account superficial EMG activity of lateral and medial gastrocnemius, the immediate effectiveness in latent MTrPs of both DDN and ICT was compared. A total of 34 triathletes was randomly divided in two groups. The first and second groups (n = 17 in each group) underwent only one session of DDN and ICT, respectively. EMG measurement of gastrocnemius was assessed before and immediately after treatment. Statistically significant differences (p = 0.037) were shown for a reduction of superficial EMG measurements differences (%) of the experimental group (DDN) with respect to the intervention group (ICT) at a speed of 1 m/s immediately after both interventions, although not at speeds of 1.5 m/s or 2.5 m/s. A statistically significant linear regression prediction model was shown for EMG outcome measurement differences at V1 (speed of 1 m/s) which was only predicted for the treatment group (R2 = 0.129; β = 8.054; F = 4.734; p = 0.037) showing a reduction of this difference under DDN treatment. DDN administration requires experience and excellent anatomical knowledge. According to our findings immediately after treatment of latent MTrPs, DDN could be advisable for triathletes who train at a speed lower than 1 m/s, while ICT could be a more advisable technique than DDN for training or competitions at speeds greater than 1.5 m/s.


Are seasonal and income variations accountable for bowel and bladder dysfunction symptoms in children?
Certain illnesses tend to occur more commonly at certain times of the year. It is also known that individuals of different socioeconomic groups have a predilection for physical ailments that in some cases may be related to poor access to healthcare or may be related to environmental or work related causes. We hypothesized that there may be a difference between patients from season to season and from different socioeconomic groups and their presenting lower urinary tract symptoms (LUTS). We reviewed our electronic medical record going back for 5 years, selecting out all patients who presented to all 10 of our offices in a wide geographic area that covers 22 million people of all races and income levels in the Tristate area of New York. We identified 13,346 patients, 6,010 males and 6,957 females, and 379 were excluded for not meeting age inclusion criteria. The descriptive statistics based on age, median income for both males and females can be found in Tables I, II, III, and IV, respectively. Of note, males were older than females at presentation (8.1 vs. 6.9 years) with no difference in median incomes between families. There were more UTIs in females and more dysuria complaints in males. Urinary incontinence also appeared to be more prevalent in females than males, while males had more issues with fecal soiling than the females. What was obvious was that urgency and frequency was positively correlated with high income groups. On the other hand urinary incontinence represented either by itself or combined with UUI was more prevalent in the high school group. Fecal soiling was also more prevalent in the high school group. UTIs were more prevalent in the high school group but surprisingly there was no difference in patients that were not able to empty their bladders. Conversely we found that constipation was more prevalent in the professional group than in the other groups which is the opposite of the FS findings. Lastly dysuria appeared to be more prevalent in the P group. It is clear that there are marked differences in the results between high school income and professional income groups in particular with the U and F, along with C which correlate with high income professionals' children. UUI, UI, UTI, along with FS are associated with high school income parents. Neurourol. Urodynam. 36:148-154, 2017. © 2015 Wiley Periodicals, Inc.


First-line pharmacotherapy approaches for generalized anxiety disorder.
Many patients with generalized anxiety disorder (GAD) do not receive adequate treatment. Several classes of drugs, including benzodiazepines, azapirones, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, antihistamines, alpha(2)delta Ca++ channel modulators, and atypical antipsychotics are consistently beneficial in patients with GAD. Cognitive therapy is also effective as a first-line treatment. When individualizing treatment, drug dose ranges and side effect profiles need to be considered, as well as the patient's comorbid conditions. Doses may need to be reduced for elderly or medically ill patients or those taking other medications. Doses may need to be increased for refractory cases. Common comorbid conditions with GAD include depression, alcohol or drug abuse, social anxiety disorder, and panic disorder. In patients with significant depression, an antidepressant is more likely to succeed than a benzodiazepine. Generalized anxiety disorder is a chronic illness that requires long-term treatment. Remission is attainable but can take several months, and stopping medication increases the risk of relapse within the first year of initiating treatment.


Detection of rare antigen-presenting cells through T cell-intrinsic meandering motility, mediated by Myo1g.
To mount an immune response, T lymphocytes must successfully search for foreign material bound to the surface of antigen-presenting cells. How T cells optimize their chances of encountering and responding to these antigens is unknown. T cell motility in tissues resembles a random or Levy walk and is regulated in part by external factors including chemokines and lymph-node topology, but motility parameters such as speed and propensity to turn may also be cell intrinsic. Here we found that the unconventional myosin 1g (Myo1g) motor generates membrane tension, enforces cell-intrinsic meandering search, and enhances T-DC interactions during lymph-node surveillance. Increased turning and meandering motility, as opposed to ballistic motility, is enhanced by Myo1g. Myo1g acts as a "turning motor" and generates a form of cellular "flânerie." Modeling and antigen challenges show that these intrinsically programmed elements of motility search are critical for the detection of rare cognate antigen-presenting cells.


Leukemias resembling acute promyelocytic leukemia, microgranular variant.
Acute promyelocytic leukemia (APL) should be distinguished from other subtypes of acute myeloid leukemia (AML) because of the increased risk of disseminated intravascular coagulation (DIC) and its response to arsenic compounds and retinoids. Some cases of AML seem morphologically similar to the microgranular variant of APL (French-American-British [FAB] AML-M3v) but lack the t(15;17). We evaluated 8 cases of APL-like leukemias for subtle morphologic, cytochemical, immunophenotypic, and cytogenetic differences compared with 5 cases of promyelocytic leukemia/retinoic receptor alpha (PML/RARalpha)-positive APL (FAB AML-M3v). We also evaluated both groups for the presence of DIC. No differences among the groups were noted in blast size, chromatin pattern, nuclear morphologic features, intensity of myeloperoxidase staining, or presence of Auer rods. Immunophenotypes were similar; both types of cases lacked CD34 and HLA-DR and were CD13+ and CD33+. Two cases of APL-like leukemias also were CD56+. DIC was present in 2 patients with M3v. Our study shows that there are no definitive morphologic, cytochemical, or immunophenotypic findings that can distinguish these cases from PML/RARalpha-positive APL.


Promoting healthful family meals to prevent obesity: HOME Plus, a randomized controlled trial.
Family meal frequency has been shown to be strongly associated with better dietary intake; however, associations with weight status have been mixed. Family meals-focused randomized controlled trials with weight outcomes have not been previously conducted. Therefore, this study purpose was to describe weight-related outcomes of the HOME Plus study, the first family meals-focused randomized controlled trial to prevent excess weight gain among youth. Families (n = 160 8-12-year-old children and their parents/guardians) were randomized to intervention (n = 81) or control (n = 79) groups. Data were collected at baseline (2011-2012), post-intervention (12-months post-baseline) and follow-up (21-months post-baseline). The intervention included ten monthly group sessions (nutrition education; hands-on meal and snack planning, preparation, and skill development; screen time reductions) and five motivational, goal-setting phone calls. The main outcome was child body mass index (BMI) z-score. General linear models, adjusted for baseline values and demographics, showed no significant treatment group differences in BMI z-scores at post-intervention or follow-up; however, a promising reduction in excess weight gain was observed. Post-hoc stratification by pubertal onset indicated prepubescent children in the intervention group had significantly lower BMI z-scores than their control group counterparts. The study used a strong theoretical framework, rigorous design, quality measurement and a program with high fidelity to test a family meals-focused obesity prevention intervention. It showed a modest decrease in excess weight gain. The significant intervention effect among prepubescent children suggests the intervention may be more efficacious among relatively young children, although more research with appropriately powered samples are needed to replicate this finding. This study is registered at www.clinicaltrials.gov NCT01538615. Registered 01/17/2012.


Model system for irreversible inhibition of Nek2: thiol addition to ethynylpurines and related substituted heterocycles.
Recent studies have shown that irreversible inhibition of Nek2 kinase [(Never in mitosis gene a)-related kinase 2], overexpression of which is observed in several cancers, can be achieved using Michael acceptors containing an ethynyl group, which target the enzyme's cysteine 22 residue lying near the catalytic site. The model studies described herein demonstrate an analogous capture of the ethynyl moiety in a series of ethynyl-heterocycles (e.g. 6-ethynyl-N-phenyl-9H-purin-2-amine) by N-acetylcysteine methyl ester in the presence of 1,4-diazabicyclo[2.2.2]octane in either dimethyl sulfoxide or N,N-dimethylformamide. Kinetic studies showed a 50-fold range in reactivity with 7-ethynyl-N-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine being the most reactive compound, whereas 4-ethynyl-N-phenyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine was the least reactive. Studies of the isomeric compounds, 2-(3-((6-ethynyl-7-methyl-7H-purin-2-yl)amino)phenyl)acetamide and 2-(3-((6-ethynyl-9-methyl-9H-purin-2-yl)amino)phenyl)acetamide, revealed the N(7)-methyl isomer to be 5-fold more reactive than the 9-methyl isomer, which is ascribed to a buttressing effect in the N(7)-methyl compound. Comparison of the crystal structures of these isomers showed that the ethynyl group is significantly displaced away from the methyl group exclusively in the N(7)-methyl isomer with an sp(2) bond angle of 124°, whereas the corresponding angle in the N(9)-methyl isomer was the expected 120°. The results of this study indicate heterocyclic scaffolds that are likely to be more promising for inhibition of Nek2 and other kinases containing a reactive cysteine.


Vitamin C may have similar beneficial effects to Gemfibrozil on serum high-density lipoprotein-cholesterol in type 2 diabetic patients.
Type 2 diabetes mellitus (DM-T2) is commonly associated with increased triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and low high-density lipoprotein cholesterol (HDL-C) levels. Fibrates like gemfibrozil are frequently used in diabetic patients to decrease TG and increase HDL-C levels. We compared the efficacy of Vitamin C, an antioxidant vitamin, with gemfibrozil on serum HDL-C in diabetic patients. Type 2 diabetic patients, referred to our out-patient clinic were randomly divided into three groups. After 1 month of lifestyle and diet modifications, groups A, B, and C were prescribed 1000 mg Vitamin C, 600 mg gemfibrozil and combination of both, respectively. Before the study initiation and after 6(th) week of drug prescription, the blood samples were taken and analyzed for total cholesterol (Total-C), HDL-C, TG, fasting blood sugar (FBS), and hemoglobin A1c (HbA1c) levels. Sixty-seven patients entered, and 50 patients (18 male, 32 female) finished the study. Overall, serum HDL-C increased significantly from 39.8 to 45.2 mg/dL in the participants (P = 0.001). HDL-C increased 6.3, 4.4 and 5.0 mg/dL in groups A, B and C, respectively (related significances were 0.017, 0.022 and 0.033, respectively). Significant decrease of serum TG and Total-C occurred in gemfibrozil and combination groups, but not in Vitamin C group. Changes in serum HDL-C between three groups were not significant (P = 0.963). We found a significant decrease in TG and Total-C in the groups B and C (P < 0.05), but no significant changes of TG, Total-C, LDL-C, FBS and HbA1c in group A (P > 0.05). The results demonstrated that Vitamin C may have beneficial effects on HDL-C in diabetic patients without significant effects on plasma glucose or other lipid parameters; however, its role for the treatment of low HDL-C patients should be evaluated in larger studies.


The pancreatic beta-cell as a fuel sensor: an electrophysiologist's viewpoint.
The pancreatic beta cell serves as the fuel sensor of the entire body and controls, via secretion of the hypoglycaemic hormone insulin, the blood glucose concentrations within narrow limits by regulation of glucose uptake and release. During the last 30 years, a combination of biochemical and ultrastructural approaches has resulted in dramatic progress in the understanding of the processes by which glucose and other nutrients modulate the release of insulin. The beta cells have also been investigated using electrophysiological techniques and were thus found to be electrically excitable and to undergo complex changes in their membrane potential when exposed to glucose and other stimulators of secretion. The application of the patch-clamp technique to the pancreatic islet preparations has revolutionized the understanding of how bioelectrical processes participate in the fuel-sensing of the beta cell. An important achievement was the identification of an ATP-sensitive K(+)-channel as the resting and glucose-sensitive membrane conductance of the beta cell. This channel also constitutes the target of the hypoglycaemic sulphonylureas: a group of compounds which have been used successfully in the treatment of insulin-dependent diabetes mellitus for several decades.


The role of the proteasomal ATPases and activator monoubiquitylation in regulating Gal4 binding to promoters.
Recent studies have shown that the intersection between transcription and proteins involved in the ubiquitin-proteasome pathway encompasses both proteolytic and nonproteolytic functions. Examples of the latter type include evidence that monoubiquitylation of some transcriptional activators stimulates their activity. In addition, the proteasomal ATPases are recruited to many active promoters through binding to activators and play an important, nonproteolytic role in promoter escape and elongation. In this study, we report the discovery of a new nonproteolytic activity of the proteasome (specifically the proteasomal ATPases): the active destabilization of activator-promoter complexes. This reaction depends on the presence of an activation domain and ATP. Destabilization is inhibited in vitro and in vivo if the protein is monoubiquitylated or if ubiquitin is genetically fused to the activator. The fact that monoubiquitylated activator is resistant to the "stripping" activity of the proteasomal ATPases may explain, in part, why some activators require this modification in order to function efficiently.


n-ZnO nanorods/p+-Si (111) heterojunction light emitting diodes.
In this study, we report the effects of thermal annealing in nitrogen ambient on the optical and electrical properties of zinc oxide (ZnO) nanorod (NR) arrays for the application in light emission diodes (LED). The single-crystalline ZnO NR array was synthesized on p+-Si (111) substrate without seed layer using simple, low-cost, and low-temperature hydrothermal method. The substrate surface was functionalized by hydrofluoric acid and self-assembled monolayer of octadecyltrimethoxysilane ((CH3 (CH2)17Si(OCH3)3). ZnO NRs were characterized by field emission scanning electron microscopy (FESEM), X-ray diffraction (XRD), and micro-photoluminescence (micro-PL). The results of FESEM and XRD indicate that single crystalline ZnO NRs with (002) preferred orientation along the substrate surface is successfully grown on functionalized p+-Si (111) substrate. The current-voltage and electroluminescence (EL) characteristics of the LED show that the most suitable annealing temperature ranges from 400°C to 600°C. Both PL and EL spectra show broadband emissions, ultraviolet and visible (green-yellow) light. The white-like light emission is able to be observed by naked eyes.


Blood Plasma Self-Separation Technologies during the Self-Driven Flow in Microfluidic Platforms.
Blood plasma is the most commonly used biofluid in disease diagnostic and biomedical analysis due to it contains various biomarkers. The majority of the blood plasma separation is still handled with centrifugation, which is off-chip and time-consuming. Therefore, in the Lab-on-a-chip (LOC) field, an effective microfluidic blood plasma separation platform attracts researchers' attention globally. Blood plasma self-separation technologies are usually divided into two categories: active self-separation and passive self-separation. Passive self-separation technologies, in contrast with active self-separation, only rely on microchannel geometry, microfluidic phenomena and hydrodynamic forces. Passive self-separation devices are driven by the capillary flow, which is generated due to the characteristics of the surface of the channel and its interaction with the fluid. Comparing to the active plasma separation techniques, passive plasma separation methods are more considered in the microfluidic platform, owing to their ease of fabrication, portable, user-friendly features. We propose an extensive review of mechanisms of passive self-separation technologies and enumerate some experimental details and devices to exploit these effects. The performances, limitations and challenges of these technologies and devices are also compared and discussed.


Short-term plasticity of kainate receptor-mediated EPSCs induced by NMDA receptors at hippocampal mossy fiber synapses.
Kainate receptors (KARs) are heteromeric ionotropic glutamate receptors that play a variety of functions in the regulation of the activity of synaptic networks. Little is known about the regulation of the function of synaptic KARs in the brain. In the present study, we found that a conditioning activation of synaptic NMDA receptors (NMDARs) induces short-term depression of KAR-EPSCs but not of AMPA receptor-EPSCs at synapses between mossy fibers and CA3 pyramidal cells. Short-term depression of KAR-EPSCs by synaptic NMDARs peaked at 1 s and reversed within 20 s, was likely induced and expressed postsynaptically, and was homosynaptic. It depended on a rise of Ca2+ in the postsynaptic cell and on the activation of the phosphatase calcineurin that likely binds to the GluR6b (glutamate receptor subunit 6b) subunit splice variant allowing the dephosphorylation of KARs and inhibition of activity. Finally, we show in the current-clamp mode that short-term depression of KAR-EPSPs is induced by the coincident discharge of action potentials in the postsynaptic cell together with synaptic stimulation. Hence, this study describes a form of short-term synaptic plasticity that is postsynaptic, depends on the temporal order of presynaptic and postsynaptic spiking, and likely affects the summation properties of mossy fiber EPSPs.


Is group singing special? Health, well-being and social bonds in community-based adult education classes.
Evidence demonstrates that group singing improves health and well-being, but the precise mechanisms remain unknown. Given that cohesive social networks also positively influence health, we focus on the social aspects of singing, exploring whether improvements in health and well-being are mediated by stronger social bonds, both to the group as a whole (collective-bonding) and to individual classmates (relational-bonding). To do so, seven newly-formed community-based adult education classes (four singing, N=84, and three comparison classes studying creative writing or crafts, N=51) were followed over seven months. Self-report questionnaire data on mental and physical health, well-being, and social bonding were collected at Months 1, 3 and 7. We demonstrate that physical and mental health and satisfaction with life significantly improved over time in both conditions. Path analysis did not show any indirect effects via social bonding of Condition on health and well-being. However, higher collective-bonding at timepoint 3 significantly predicted increased flourishing, reduced anxiety and improved physical health independently of baseline levels. In contrast, relational-bonding showed no such effects, suggesting that it is feeling part of a group that particularly yields health and well-being benefits. Moreover, these results indicate that singing may not improve health and well-being more than other types of activities. Nonetheless, these findings encourage further work to refine our understanding of the social aspects of community-based adult education classes in promoting health, well-being and community cohesion.


Smoking behaviors among people with disabilities in Korea.
Most reports concerning smoking behaviors in people with disabilities have been from Western societies; knowledge of smoking behaviors in Asian countries, including Korea, is insufficient. This study investigates the smoking behaviors of people with a disability compared to the general population in Korea. We compared the smoking behaviors of people with a disability with the general population by using datasets from the 2011 National Survey of Disabled People and an age- and sex-matched random sample from the 5th Korean National Health and Nutrition Examination Survey. Random samples of people 18 years of age and older with disabilities (n = 5636) and of the general population were used (n = 5636). The main outcome measures include smoking behaviors by type, severity, and age at disability onset. People with a mental or physical impairment have higher current smoking rates (38.1% and 26.3%, respectively) than the general population (23.3%). In particular, current smokers with psychiatric impairment were more likely to smoke more than 20 cigarettes a day (61.2%). People with a disability, regardless of severity or age at onset, were less likely than the general population to have attempted to quit smoking. Smoking behaviors differed according to the type of disability. These results suggest that interventions for smoking prevention and cessation need to be tailored according to disability characteristics.


Censoring of autoreactive B cell development by the pre-B cell receptor.
Antibody diversity occurs randomly as B cells recombine their immunoglobulin (Ig) heavy- and light-chain genes during development. This process inevitably generates reactivity against self structures, and several mechanisms prevent the development of autoreactive B cells. We report here a role for the pre-B cell receptor, composed of Ig heavy and surrogate light chains, in the negative selection of cells expressing Ig heavy chains with the potential to generate autoantibodies. Surrogate light-chain-deficient (SLC-/-) mice harbored elevated levels of antinuclear antibodies (ANAs) in their serum and showed evidence of escape of pre-B cells expressing prototypic autoantibody heavy chains from negative selection, leading to mature autoantibody secreting CD21-CD23- B cells in the periphery. Thus, the pre-B cell receptor appears to censor the development of certain autoantibody-secreting cells and may represent an important factor in multifactorial autoimmune diseases.


Double-blind, placebo-controlled trial of topiramate augmentation in treatment-resistant obsessive-compulsive disorder.
From 40% to 60% of obsessive-compulsive disorder (OCD) patients fail to tolerate or respond to selective serotonin reuptake inhibitors (SSRIs). Preclinical and neuroimaging studies have shown abnormally high glutamatergic concentrations in OCD patients and an association between decreased caudate glutamatergic concentrations and reduced OCD symptom severity after SSRI treatment. Topiramate inhibits glutamatergic conduction. Thirty-six adult patients with DSM-IV-defined OCD were randomly assigned to topiramate (n = 18) and placebo (n = 18) groups in this 12-week, double-blind, placebo-controlled, parallel-groups trial. Subjects were taking the maximum SSRI dose they could tolerate for at least 12 weeks and their current dose for at least 6 weeks, which was maintained throughout the study. Primary outcome measures were changes in the Yale-Brown Obsessive Compulsive Scale (YBOCS) total score and compulsions and obsessions subscores. Patients were recruited and followed up between April 1, 2003, and April 13, 2006. Using mixed regression models (time [weeks] × treatment), we found a significant treatment effect on the YBOCS compulsions (P = .014) subscale, but not the obsessions (P = .99) subscale or the total score (P = .11). Over the 12-week trial, the topiramate group (mean endpoint dose = 177.8 ± 134.2 mg/d; range, 50-400 mg/d) showed an average linear decrease of 5.38 points on the compulsions subscale compared to 0.6 points in the placebo group. Thirteen topiramate and 14 placebo subjects completed the study. Topiramate was not well tolerated in this trial: 28% (5/18) of the subjects discontinued the drug for adverse effects, and 39% (7/18) had a dose reduction for this reason. The results of this first double-blind, placebo-controlled trial of topiramate augmentation for treatment-resistant OCD suggest that topiramate may be beneficial for compulsions, but not obsessions. Modifications in glutamatergic function may be responsible, at least in part, for the improved response in compulsions seen with topiramate. clinicaltrials.gov Identifier: NCT00211744.


Genome-Wide Analysis Identifies an Essential Human TBX3 Pacemaker Enhancer.
The development and function of the pacemaker cardiomyocytes of the sinoatrial node (SAN), the leading pacemaker of the heart, are tightly controlled by a conserved network of transcription factors, including TBX3 (T-box transcription factor 3), ISL1 (ISL LIM homeobox 1), and SHOX2 (short stature homeobox 2). Yet, the regulatory DNA elements (REs) controlling target gene expression in the SAN pacemaker cells have remained undefined. Identification of the regulatory landscape of human SAN-like pacemaker cells and functional assessment of SAN-specific REs potentially involved in pacemaker cell gene regulation. We performed Assay for Transposase-Accessible Chromatin using sequencing on human pluripotent stem cell-derived SAN-like pacemaker cells and ventricle-like cells and identified thousands of putative REs specific for either human cell type. We validated pacemaker cell-specific elements in the SHOX2 and TBX3 loci. CRISPR-mediated homozygous deletion of the mouse ortholog of a noncoding region with candidate pacemaker-specific REs in the SHOX2 locus resulted in selective loss of Shox2 expression from the developing SAN and embryonic lethality. Putative pacemaker-specific REs were identified up to 1 Mbp upstream of TBX3 in a region close to MED13L harboring variants associated with heart rate recovery after exercise. The orthologous region was deleted in mice, which resulted in selective loss of expression of Tbx3 from the SAN and (cardiac) ganglia and in neonatal lethality. Expression of Tbx3 was maintained in other tissues including the atrioventricular conduction system, lungs, and liver. Heterozygous adult mice showed increased SAN recovery times after pacing. The human REs harboring the associated variants robustly drove expression in the SAN of transgenic mouse embryos. We provided a genome-wide collection of candidate human pacemaker-specific REs, including the loci of SHOX2, TBX3, and ISL1, and identified a link between human genetic variants influencing heart rate recovery after exercise and a variant RE with highly conserved function, driving SAN expression of TBX3.


A genetically engineered thermally responsive sustained release curcumin depot to treat neuroinflammation.
Radiculopathy, a painful neuroinflammation that can accompany intervertebral disc herniation, is associated with locally increased levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα). Systemic administration of TNF antagonists for radiculopathy in the clinic has shown mixed results, and there is growing interest in the local delivery of anti-inflammatory drugs to treat this pathology as well as similar inflammatory events of peripheral nerve injury. Curcumin, a known antagonist of TNFα in multiple cell types and tissues, was chemically modified and conjugated to a thermally responsive elastin-like polypeptide (ELP) to create an injectable depot for sustained, local delivery of curcumin to treat neuroinflammation. ELPs are biopolymers capable of thermally-triggered in situ depot formation that have been successfully employed as drug carriers and biomaterials in several applications. ELP-curcumin conjugates were shown to display high drug loading, rapidly release curcumin in vitro via degradable carbamate bonds, and retain in vitro bioactivity against TNFα-induced cytotoxicity and monocyte activation with IC50 only two-fold higher than curcumin. When injected proximal to the sciatic nerve in mice via intramuscular (i.m.) injection, ELP-curcumin conjugates underwent a thermally triggered soluble-insoluble phase transition, leading to in situ formation of a depot that released curcumin over 4days post-injection and decreased plasma AUC 7-fold.


MicroRNA antagonism of the picornaviral life cycle: alternative mechanisms of interference.
In addition to modulating the function and stability of cellular mRNAs, microRNAs can profoundly affect the life cycles of viruses bearing sequence complementary targets, a finding recently exploited to ameliorate toxicities of vaccines and oncolytic viruses. To elucidate the mechanisms underlying microRNA-mediated antiviral activity, we modified the 3' untranslated region (3'UTR) of Coxsackievirus A21 to incorporate targets with varying degrees of homology to endogenous microRNAs. We show that microRNAs can interrupt the picornavirus life-cycle at multiple levels, including catalytic degradation of the viral RNA genome, suppression of cap-independent mRNA translation, and interference with genome encapsidation. In addition, we have examined the extent to which endogenous microRNAs can suppress viral replication in vivo and how viruses can overcome this inhibition by microRNA saturation in mouse cancer models.


Implantation of a closed-loop stimulation in the management of medically refractory focal epilepsy: a technical note.
Open-loop stimulation studies have shown varying control of seizures with stimulation of different anatomical targets. A recent multi-institutional clinical study utilizing an external closed-loop stimulation system had promising results. A novel implantable closed-loop Responsive Neurostimulation System (RNS) (Neuropace, Inc., Mountainview, Calif., USA) consisting of a cranially implanted pulse generator, one or two quadripolar subdural strip or depth leads and a programmer is under testing in a prospective clinical trial. The RNS pulse generator continuously analyzes the patient's electrocortigrams (ECoGs) and automatically triggers electrical stimulation when specific ECoG characteristics programmed by the clinician, as indicative of electrographic seizures or precursor of epileptiform activities, are detected. The pulse generator then stores diagnostic information detailing detections and stimulations, including multichannel stored ECoGs. The RNS programmer communicates transcutaneously with the implanted pulse generator when initiated by a clinician. The RNS programmer can download diagnostics and store ECoGs for review. The RNS programmer can then be used to program detection and stimulation parameters. In our current communication, we describe the selection criteria for implanting this system, the preparation of the surgical candidates as well as the surgical technique. We also present our preliminary results with 8 patients who had an RNS implanted. Seven patients (87.5%) had more than 45% decrease in their seizure frequency. The mean follow-up time in our series was 9.2 months. The implantation of a closed-loop stimulation system, in our experience, represents a safe and relatively simple surgical procedure. However, the efficacy of this new treatment modality remains to be determined in further multi-institutional, prospective clinical studies.


An analysis of disease-gene relationship from Medline abstracts by DigSee.
Diseases are developed by abnormal behavior of genes in biological events such as gene regulation, mutation, phosphorylation, and epigenetics and post-translational modification. Many studies of text mining attempted to identify the relationship between gene and disease by mining the literature, but they did not consider the biological events in which genes show abnormal behaviour in response to diseases. In this study, we propose to identify disease-related genes that are involved in the development of disease through biological events from Medline abstracts. We identified associations between 13,054 genes and 4,494 disease types, which cover more disease-related genes than manually curated databases for all disease types (e.g., Online Mendelian Inheritance in Man) and also than those for specific diseases (e.g., Alzheimer's disease and hypertension). We show that the text mining findings are reliable, as per the PubMed scale, in that the disease-disease relationships inferred from the literature-wide findings are similar to those inferred from manually curated databases in a well-known study. In addition, literature-wide distribution of biological events across disease types reveals different characteristics of disease types.


Cancer Survivors' Experience With Telehealth: A Systematic Review and Thematic Synthesis.
Net survival rates of cancer are increasing worldwide, placing a strain on health service provision. There is a drive to transfer the care of cancer survivors-individuals living with and beyond cancer-to the community and encourage them to play an active role in their own care. Telehealth, the use of technology in remote exchange of data and communication between patients and health care professionals (HCPs), is an important contributor to this evolving model of care. Telehealth interventions are "complex," and understanding patient experiences of them is important in evaluating their impact. However, a wider view of patient experience is lacking as qualitative studies detailing cancer survivor engagement with telehealth are yet to be synthesized. To systematically identify, appraise, and synthesize qualitative research evidence on the experiences of adult cancer survivors participating in telehealth interventions, to characterize the patient experience of telehealth interventions for this group. Medline (PubMed), PsychINFO, Cumulative Index for Nursing and Allied Health Professionals (CINAHL), Embase, and Cochrane Central Register of Controlled Trials were searched on August 14, 2015, and March 8, 2016, for English-language papers published between 2006 and 2016. Inclusion criteria were as follows: adult cancer survivors aged 18 years and over, cancer diagnosis, experience of participating in a telehealth intervention (defined as remote communication or remote monitoring with an HCP delivered by telephone, Internet, or hand-held or mobile technology), and reporting qualitative data including verbatim quotes. An adapted Critical Appraisal Skill Programme (CASP) checklist for qualitative research was used to assess paper quality. The results section of each included article was coded line by line, and all papers underwent inductive analysis, involving comparison, reexamination, and grouping of codes to develop descriptive themes. Analytical themes were developed through an iterative process of reflection on, and interpretation of, the descriptive themes within and across studies. Across the 22 included papers, 3 analytical themes emerged, each with 3 descriptive subthemes: (1) influence of telehealth on the disrupted lives of cancer survivors (convenience, independence, and burden); (2) personalized care across physical distance (time, space, and the human factor); and (3) remote reassurance-a safety net of health care professional connection (active connection, passive connection, and slipping through the net). Telehealth interventions represent a convenient approach, which can potentially minimize treatment burden and disruption to cancer survivors' lives. Telehealth interventions can facilitate an experience of personalized care and reassurance for those living with and beyond cancer; however, it is important to consider individual factors when tailoring interventions to ensure engagement promotes benefit rather than burden. Telehealth interventions can provide cancer survivors with independence and reassurance. Future telehealth interventions need to be developed iteratively in collaboration with a broad range of cancer survivors to maximize engagement and benefit.


Antioxidant and antimicrobial properties of Casteanea sativa Miller chestnut honey produced on Mount Etna (Sicily).
The aim of this study was the evaluation of antibacterial and antioxidant properties of Monofloral Etna Castanea sativa Miller honeys. Escherichia coli ATCC 25,922, Pseudomonas aeruginosa ATCC 27,853, Enterococcus faecalis ATCC 29,211 and Staphylococcus aureus ATCC 29,213 were investigated for their susceptibilities to two different honeys. Antioxidant activity was evaluated by ORAC, NO scavenger assays, FRAP and DPPH. Antioxidant activity and antibacterial properties were compared with chestnut honeys from different geographical areas and with Manuka honey. UPLC-MS/MS was used for major components characteri sation.


Magnetic remanence in single atoms.
A permanent magnet retains a substantial fraction of its saturation magnetization in the absence of an external magnetic field. Realizing magnetic remanence in a single atom allows for storing and processing information in the smallest unit of matter. We show that individual holmium (Ho) atoms adsorbed on ultrathin MgO(100) layers on Ag(100) exhibit magnetic remanence up to a temperature of 30 kelvin and a relaxation time of 1500 seconds at 10 kelvin. This extraordinary stability is achieved by the realization of a symmetry-protected magnetic ground state and by decoupling the Ho spin from the underlying metal by a tunnel barrier.


Chronic social stress leads to altered sleep homeostasis in mice.
Disturbed sleep and altered sleep homeostasis are core features of many psychiatric disorders such as depression. Chronic uncontrollable stress is considered an important factor in the development of depression, but little is known on how chronic stress affects sleep regulation and sleep homeostasis. We therefore examined the effects of chronic social stress (CSS) on sleep regulation in mice. Adult male C57BL/6 mice were implanted for electrocortical recordings (ECoG) and underwent either a 10-day CSS protocol or control handling (CON). Subsequently, ECoG was assessed across a 24-h post-stress baseline, followed by a 4-h sleep deprivation, and then a 20-h recovery period. After sleep deprivation, CSS mice showed a blunted increase in sleep pressure compared to CON mice, as measured using slow wave activity (SWA, electroencephalographic power between 1-4Hz) during non-rapid eye movement (NREM) sleep. Vigilance states did not differ between CSS and CON mice during post-stress baseline, sleep deprivation or recovery, with the exception of CSS mice exhibiting increased REM sleep during recovery sleep. Behavior during sleep deprivation was not affected by CSS. Our data provide evidence that CSS alters the homeostatic regulation of sleep SWA in mice. In contrast to acute social stress, which results in a faster SWA build-up, CSS decelerates the homeostatic build up. These findings are discussed in relation to the causal contribution of stress-induced sleep disturbance to depression.


Diagnostic diversity - an indicator of institutional and regional healthcare quality.
Our aim was to estimate the diagnostic performance of institutions and healthcare regions from a nationwide hospitalisation database. The Shannon diversity index was used as an indicator of diagnostic performance based on the International Classification of Disease, 10th revision, German Modification (ICD-10-GM codes). The dataset included a total of 9,325,326 hospitalisation cases from 2009 to 2015 and was provided by the Swiss Federal Office for Statistics. A total of 16,435 diagnostic items from the ICD-10-GM codes were taken as the basis for the calculation of the diagnostic diversity index (DDI). Numerical simulations were performed to evaluate the effect of misdiagnoses in the DDI. We arbitrarily defined the minimum clinically important difference (MCID) as 10% misdiagnoses. The R statistical software was used for all analyses. Diagnostic performance of institutions and healthcare regions as measured by the DDI were strongly associated with caseload and number of inhabitants, respectively. A caseload of >7217 hospitalisations per year for institutions and a population size >363,522 for healthcare regions were indicators of an acceptable diagnostic performance. Among hospitals, there was notable heterogeneity of diagnostic diversity, which was strongly associated with caseload. Application of misdiagnosis-thresholds within each ICD-10-GM category allowed classification of hospitals in four distinct groups: high-volume hospitals with an all-over comprehensive diagnostic performance; high- to mid-volume hospitals with extensive to relevant basic diagnostic performance in most categories; low-volume specialised hospitals with a high diagnostic performance in a single category; and low-volume hospitals with inadequate diagnostic performance in all categories. The diagnostic diversity observed in the 26 Swiss healthcare regions showed relevant heterogeneity, an association with ICD-10-GM code utilisation, and was strongly associated with the size of the healthcare region. The limited diagnostic performance in small healthcare regions was partially, but not fully, compensated for by consumption of health services outside of their own healthcare region. Calculation of the DDI from ICD-10 codes is easy and complements the information derived from other quality indicators as it sheds a light on the fitness of the institutionalised interplay between primary and specialised medical inpatient care. &nbsp.