Creating solitons with controllable and near-zero velocity in Bose-Einstein condensates.
Established techniques for deterministically creating dark solitons in repulsively interacting atomic Bose-Einstein condensates (BECs) can only access a narrow range of soliton velocities. Because velocity affects the stability of individual solitons and the properties of soliton-soliton interactions, this technical limitation has hindered experimental progress. Here we create dark solitons in highly anisotropic cigar-shaped BECs with arbitrary position and velocity by simultaneously engineering the amplitude and phase of the condensate wave function, improving upon previous techniques which explicitly manipulated only the condensate phase. The single dark soliton solution present in true one-dimensional (1D) systems corresponds to the kink soliton in anisotropic three-dimensional systems and is joined by a host of additional dark solitons, including vortex ring and solitonic vortex solutions. We readily create dark solitons with speeds from zero to half the sound speed. The observed soliton oscillation frequency suggests that we imprinted solitonic vortices, which for our cigar-shaped system are the only stable solitons expected for these velocities. Our numerical simulations of 1D BECs show this technique to be equally effective for creating kink solitons when they are stable. We demonstrate the utility of this technique by deterministically colliding dark solitons with domain walls in two-component spinor BECs.


The efficacy of self-monitoring of blood glucose in NIDDM subjects. A criteria-based literature review.
To determine the efficacy of self-monitoring of blood glucose (SMBG) in NIDDM patients from studies published during the years 1976-1996. A systematic literature search was conducted. The selected studies were assessed for their methodological quality and reviewed on the reported efficacy and on the following topics: characteristics of the study population, follow-up duration, nature of the efficacy measures, use of a therapy decision scheme, nature of the intervention, nature of the SMBG device, patient instruction, type of SMBG regime, assessment of the frequency of self-measurement, and whether feedback was given on the measured glucose levels. Studies with positive conclusions on the efficacy of SMBG were compared with studies with negative conclusions on the basis of the these characteristics to determine which factors could have contributed to the results. Of the 11 studies identified, only 4 met all quality criteria. Six of the studies were randomized controlled trials, of which only one showed positive conclusions regarding the efficacy of SMBG. Although the studies differed on most topics, no factor could be identified as responsible for the results of the studies. The efficacy of SMBG in NIDDM patients is still questionable and should be tested in a rigorous high-quality randomized controlled trial, for which some recommendations are given.


A coupled microscopy approach to assess the nano-landscape of weathering.
Mineral weathering is a balanced interplay among physical, chemical, and biological processes. Fundamental knowledge gaps exist in characterizing the biogeochemical mechanisms that transform microbe-mineral interfaces at submicron scales, particularly in complex field systems. Our objective was to develop methods targeting the nanoscale by using high-resolution microscopy to assess biological and geochemical drivers of weathering in natural settings. Basalt, granite, and quartz (53-250 µm) were deployed in surface soils (10 cm) of three ecosystems (semiarid, subhumid, humid) for one year. We successfully developed a reference grid method to analyze individual grains using: (1) helium ion microscopy to capture micron to sub-nanometer imagery of mineral-organic interactions; and (2) scanning electron microscopy to quantify elemental distribution on the same surfaces via element mapping and point analyses. We detected locations of biomechanical weathering, secondary mineral precipitation, biofilm formation, and grain coatings across the three contrasting climates. To our knowledge, this is the first time these coupled microscopy techniques were applied in the earth and ecosystem sciences to assess microbe-mineral interfaces and in situ biological contributors to incipient weathering.


Rest-activity circadian rhythm in breast cancer survivors at 5 years after the primary diagnosis.
Rest-activity circadian rhythm (RAR) is a marker of the circadian timing system. Particular attention has been given to RAR characteristics in cancer diseases. Specifically, alterations of RAR parameters have been found, at different stages of clinical pathway, in breast cancer (BC) patients. No studies to date have analyzed RAR alterations in breast cancer survivors several years after the diagnosis. The aim of this study was to determine RAR by actigraphy in a population of BC survivors at 5 years after the primary diagnosis, and to compare their RAR characteristics with healthy controls. The study sample was 28 women: 15 BC survivors at 5 years from the primary diagnosis (BC-group) and 13 healthy controls (Ctrl-group), matched for age and body mass index. All participants have been monitored for 7 days by actigraphy to evaluate RAR. A statistically significant circadian rhythm (T = 24) was found in all 28 subjects (p < .001). The group analysis revealed a significant RAR both in BC- and Ctrl-group (p < .001). The acrophase was not different between the BC- and Ctrl-group (15:09 vs. 15:01 hr:min in BC- and Ctrl-group, respectively). In contrast, the MESOR (Midline Estimating Statistic of Rhythm) and the amplitude were lower in the BC-group with respect to the Ctrl-group. Indeed, the MESOR was 192.0 vs. 276.4 activity counts in BC- and Ctrl-group, respectively (p < .001), while the amplitude was 167.0 vs. 222.6 activity counts in BC- and Ctrl-group, respectively (p < .001). These results provide the first experimental evidence of alterations in RAR parameters in BC survivors at 5 years after the primary diagnosis. Larger studies with a prospective design are needed to assess the role of RAR in the quality of life and prognosis in BC survivors.


Studies on tridecaptin B(1), a lipopeptide with activity against multidrug resistant Gram-negative bacteria.
Previously other groups had reported that Paenibacillus polymyxa NRRL B-30507 produces SRCAM 37, a type IIA bacteriocin with antimicrobial activity against Campylobacter jejuni. Genome sequencing and isolation of antimicrobial compounds from this P. polymyxa strain show that the antimicrobial activity is due to polymyxins and tridecaptin B1. The complete structural assignment, synthesis, and antimicrobial profile of tridecaptin B1 is reported, as well as the putative gene cluster responsible for its biosynthesis. This peptide displays strong activity against multidrug resistant Gram-negative bacteria, a finding that is timely to the current problem of antibiotic resistance.


An algorithm to compare two-dimensional footwear outsole images using maximum cliques and speeded-up robust feature.
Footwear examiners are tasked with comparing an outsole impression (Q) left at a crime scene with an impression (K) from a database or from the suspect's shoe. We propose a method for comparing two shoe outsole impressions that relies on robust features (speeded-up robust feature; SURF) on each impression and aligns them using a maximum clique (MC). After alignment, an algorithm we denote MC-COMP is used to extract additional features that are then combined into a univariate similarity score using a random forest (RF). We use a database of shoe outsole impressions that includes images from two models of athletic shoes that were purchased new and then worn by study participants for about 6 months. The shoes share class characteristics such as outsole pattern and size, and thus the comparison is challenging. We find that the RF implemented on SURF outperforms other methods recently proposed in the literature in terms of classification precision. In more realistic scenarios where crime scene impressions may be degraded and smudged, the algorithm we propose-denoted MC-COMP-SURF-shows the best classification performance by detecting unique features better than other methods. The algorithm can be implemented with the R-package shoeprintr.


[Combination of single-port thoracoscopy and laparoscopy for the treatment of esophageal carcinoma: report of 6 cases].
To study the feasibility and early results of radical resection of esophageal carcinoma using single-port thoracoscopy combined with laparoscopy. From March 2010 to December 2010, 6 patients with esophageal carcinoma underwent radical resection by single-port thoracoscopy combined with laparoscopy in the General Hospital of People's Liberation Army. With the patients at a supine position, laparoscopy was performed to complete stomach mobilization and abdominal lymph node dissection. Thoracoscopy was then carried out with the patients lying on the left to mobilize the esophagus and dissect thoracic lymph nodes. Finally, the stomach was pulled into the thoracic cavity via the hiatus of the diaphragm to construct a tube-like stomach, which was then anastomosed to the esophagus using the OrVil system. No patient was converted to open surgery during the operation. The total operative time ranged from 200 to 320 min. The mean laparoscopic time was 75(range, 45-90) min, and the mean thoracoscopic time 160(120-240) min. The mean intraoperative blood loss was 220(160-300) ml. The mean lymph node retrieval was 12(9-18). No anastomotic fistula, chylothorax, lung infection were found postoperatively. After esophageal resection using single-port thoracoscopic and laparoscopy, reconstruction using OrVil system is safe and feasible.


Community Identity and User Engagement in a Multi-Community Landscape.
A community's identity defines and shapes its internal dynamics. Our current understanding of this interplay is mostly limited to glimpses gathered from isolated studies of individual communities. In this work we provide a systematic exploration of the nature of this relation across a wide variety of online communities. To this end we introduce a quantitative, language-based typology reflecting two key aspects of a community's identity: how distinctive, and how temporally dynamic it is. By mapping almost 300 Reddit communities into the landscape induced by this typology, we reveal regularities in how patterns of user engagement vary with the characteristics of a community. Our results suggest that the way new and existing users engage with a community depends strongly and systematically on the nature of the collective identity it fosters, in ways that are highly consequential to community maintainers. For example, communities with distinctive and highly dynamic identities are more likely to retain their users. However, such niche communities also exhibit much larger acculturation gaps between existing users and newcomers, which potentially hinder the integration of the latter. More generally, our methodology reveals differences in how various social phenomena manifest across communities, and shows that structuring the multi-community landscape can lead to a better understanding of the systematic nature of this diversity.


Polymorphism of the 5-HT transporter and response to antidepressants: randomised controlled trial.
Antidepressants exhibit a variety of pharmacological actions including inhibition of the serotonin and noradrenaline transporters. We wished to investigate whether genetic variation could be used to target or personalise treatment, in a comparison of selective serotonin reuptake inhibitors (SSRIs) with noradrenaline reuptake inhibitors (NARIs). To test the hypothesis that patients homozygous for the long (insertion) polymorphism of the serotonin transporter (5-HTTLPR) have an increased response to SSRI antidepressants but not to NARI antidepressants. In an individually randomised, parallel-group controlled trial, people meeting criteria for a depressive episode who were referred by their general practitioner were randomised to receive either citalopram (an SSRI) or reboxetine (an NARI). Randomisation was by means of a remote automated system accessed by telephone. The main outcome was depressive symptoms, measured by Beck Depression Inventory (BDI) total score 6 weeks after randomisation. The trial was registered with the International Standard Randomised Controlled Trials Number registry (ISRCTN31345163). Altogether 298 participants were randomised to receive citalopram and 303 were randomised to reboxetine. At 6 weeks follow-up, complete data were available for 258 participants taking citalopram and 262 taking reboxetine. We found no evidence to support an influence of 5-HTTLPR on outcome following antidepressant treatment. The interaction term for BDI score at 6 weeks was 0.50 (95% CI -2.04 to 3.03, P = 0.70), which indicated that responses to the SSRI and NARI were similar irrespective of 5-HTTLPR genotype. It is unlikely that the 5-HTTLPR polymorphism alone will be clinically useful in predicting response to antidepressants in people with depression.


First-principles calculations of phonon behaviors in graphether: a comparative study with graphene.
Recently, a two-dimensional (2D) oxocarbon monolayer, graphether, has been arousing extensive attention owing to its excellent electrical properties. In this work, we calculate the lattice thermal conductivity (k) of graphether and graphene using first-principles calculations and the phonon Boltzmann transport equation. At 300 K, the lattice thermal conductivities of graphether and graphene along the armchair direction are 600.91 W m-1 K-1 and 3544.41 W m-1 K-1, respectively. Moreover, the electron localization function is employed to reveal the origin of the anisotropic k of graphether. Furthermore, the harmonic and anharmonic properties of graphether and graphene are analyzed. We attribute the lower k of graphether to the smaller phonon group velocity and shorter phonon lifetime. Finally, the size effects of phonon transport in graphether and graphene are studied, and the results show that the lattice thermal conductivities are significantly dependent on the system length. The analysis of phonon behaviors in our study contributes to an in-depth understanding of the thermal transport in graphether for the first time, which provides valuable guidelines for graphether-based phonon engineering applications and 2D nanoelectronic devices.


The catalytic copper of peptidylglycine alpha-hydroxylating monooxygenase also plays a critical structural role.
Many bioactive peptides require amidation of their carboxy terminus to exhibit full biological activity. Peptidylglycine alpha-hydroxylating monooxygenase (PHM; EC 22.214.171.124), the enzyme that catalyzes the first of the two steps of this reaction, is composed of two domains, each of which binds one copper atom (CuH and CuM). The CuM site includes Met(314) and two His residues as ligands. Mutation of Met(314) to Ile inactivates PHM, but has only a minimal effect on the EXAFS spectrum of the oxidized enzyme, implying that it contributes only marginally to stabilization of the CuM site. To characterize the role of Met(314) as a CuM ligand, we determined the structure of the Met(314)Ile-PHM mutant. Since the mutant protein failed to crystallize in the conditions of the original wild-type protein, this structure determination required finding a new crystal form. The Met(314)Ile-PHM mutant structure confirms that the mutation does not abolish CuM binding to the enzyme, but causes other structural perturbations that affect the overall stability of the enzyme and the integrity of the CuH site. To eliminate possible effects of crystal contacts, we redetermined the structure of wt-PHM in the Met(314)Ile-PHM crystal form and showed that it does not differ from the structure of wild-type (wt)-PHM in the original crystals. Met(314)Ile-PHM was also shown to be less stable than wt-PHM by differential scanning calorimetry. Both structural and calorimetric studies point to a structural role for the CuM site, in addition to its established catalytic role.


Perceptions of sex education for young people in Lesotho.
This study aimed to identify the views of young people, parents and teachers concerning sex education in Lesotho. It was conducted at a time when the national government was considering the introduction of Population and Family Life Education, which includes sex education, into the national school curriculum. Forty-six focus group discussions were held with young people (10), parents (30) and teachers (6) to identify current sources of sex education and views of the proposed introduction of school-based sex education in Lesotho. Findings show the limited and problematic sources of sex education for adolescents in Lesotho. They also highlight broad support for the introduction of sex education in the national school curriculum among young people, parents and teachers. Of key importance for the development of a sex education curriculum is the balance between providing young people with information and developing their skills in sexual empowerment and negotiating sexual pressure. The use of pupil-centred interactive pedagogies was seen as essential. Teachers, however, highlighted the need for training in the delivery of sex education, which includes instruction on course materials, teaching methodologies and developing sensitivity to teaching sexual issues to young people.


Risk behaviours of an interrelated syphilis-infected sexual network of men who have sex with men.
We examined the risk behaviours in an interrelated sexual network of 33 syphilis-infected men who have sex with men on the use of condoms, substances and websites to meet sexual partners. Our study used a descriptive exploratory design to investigate co-occurring high-risk behaviours in this interrelated sexual network to inform future health interventions and research directions. Although the risk behaviours for human immunodeficiency virus transmission in men who have sex with men have been studied, few have studied the high-risk population of men who already have syphilis, and even fewer have studied the risk behaviours in sexual networks of syphilis-infected men who have sex with men who were identified using contact tracing. The data were collected from semi-structured, individual interviews at a not-for-profit lesbian, gay, bisexual and transgender health centre in a large city in the Midwestern USA. Inconsistent condom use was substantial during both insertive (92%) and receptive (88%) anal intercourse. Most participants (97%) reported using one or more substances prior to or during anal intercourse, and Internet websites were the most common place to meet sexual partners (88%). High-risk behaviours were significant within this syphilis-infected sexual network of men who have sex with men. The majority of our 33 participants were non-Hispanic Whites (n = 27, 82%), possessed a baccalaureate degree or higher (n = 23, 70%), and actively sought out unprotected anal intercourse [21 participants (64%) used BareBackRT.com, a website to seek out unprotected anal intercourse]. Nurses should be more informed about the risk factors of a high-risk sexual network of syphilis-infected men who have sex with men. Interrelated sexual networks have high levels of similarity among participants' high-risk behaviours; contact tracing may be used to identify individual participants for relevant risk-reduction interventions.


Brain protection during ascending aortic repair for Stanford type A acute aortic dissection surgery. Nationwide analysis in Japan.
The optimal brain protection strategy for use during acute type A aortic dissection surgery is controversial. We reviewed the results for 2 different methods: antegrade cerebral perfusion (ACP) and retrograde cerebral perfusion (RCP), during ascending aortic repair for acute type A aortic dissection for the period between 2008 and 2012 nationwide. Cases involving root repair, arch vessel reconstruction and/or concomitant procedures were excluded. Using the Japan Adult Cardiovascular Surgery Database, a total of 4,128 patients (ACP, n=2,769; RCP, n=1,359; mean age, 69.1±11.8 years; male 41.9%) were identified. The overall operative mortality was 8.6%. Following propensity score matching, among 1,320 matched pairs, differences in baseline characteristics between the 2 patient groups diminished. Cardiac arrest time (ACP 116±36 vs. RCP102±38 min, P<0.001), perfusion time (192±54 vs. 174±53 min, P<0.001) and operative time (378±117 vs. 340±108 min, P<0.001) were significantly shorter in the RCP group. There were no significant differences between the 2 groups regarding the incidence of operative mortality or neurological complications, including stroke (ACP 11.2% vs. RCP 9.7%). Postoperative ventilation time was significantly longer in the ACP group (ACP 128.9±355.7 vs. RCP 98.5±301.7 h, P=0.018). There were no differences in other early postoperative complications, such as re-exploration, renal failure, and mediastinitis. Among patients undergoing dissection repair without arch vessel reconstruction, RCP had similar mortality and neurological outcome to ACP.


Quantifying HIV transmission flow between high-prevalence hotspots and surrounding communities: a population-based study in Rakai, Uganda.
International and global organisations advocate targeting interventions to areas of high HIV prevalence (ie, hotspots). To better understand the potential benefits of geo-targeted control, we assessed the extent to which HIV hotspots along Lake Victoria sustain transmission in neighbouring populations in south-central Uganda. We did a population-based survey in Rakai, Uganda, using data from the Rakai Community Cohort Study. The study surveyed all individuals aged 15-49 years in four high-prevalence Lake Victoria fishing communities and 36 neighbouring inland communities. Viral RNA was deep sequenced from participants infected with HIV who were antiretroviral therapy-naive during the observation period. Phylogenetic analysis was used to infer partial HIV transmission networks, including direction of transmission. Reconstructed networks were interpreted through data for current residence and migration history. HIV transmission flows within and between high-prevalence and low-prevalence areas were quantified adjusting for incomplete sampling of the population. Between Aug 10, 2011, and Jan 30, 2015, data were collected for the Rakai Community Cohort Study. 25 882 individuals participated, including an estimated 75·7% of the lakeside population and 16·2% of the inland population in the Rakai region of Uganda. 5142 participants were HIV-positive (2703 [13·7%] in inland and 2439 [40·1%] in fishing communities). 3878 (75·4%) people who were HIV-positive did not report antiretroviral therapy use, of whom 2652 (68·4%) had virus deep-sequenced at sufficient quality for phylogenetic analysis. 446 transmission networks were reconstructed, including 293 linked pairs with inferred direction of transmission. Adjusting for incomplete sampling, an estimated 5·7% (95% credibility interval 4·4-7·3) of transmissions occurred within lakeside areas, 89·2% (86·0-91·8) within inland areas, 1·3% (0·6-2·6) from lakeside to inland areas, and 3·7% (2·3-5·8) from inland to lakeside areas. Cross-community HIV transmissions between Lake Victoria hotspots and surrounding inland populations are infrequent and when they occur, virus more commonly flows into rather than out of hotspots. This result suggests that targeted interventions to these hotspots will not alone control the epidemic in inland populations, where most transmissions occur. Thus, geographical targeting of high prevalence areas might not be effective for broader epidemic control depending on underlying epidemic dynamics. The Bill & Melinda Gates Foundation, the National Institute of Allergy and Infectious Diseases, the National Institute of Mental Health, the National Institute of Child Health and Development, the Division of Intramural Research of the National Institute for Allergy and Infectious Diseases, the World Bank, the Doris Duke Charitable Foundation, the Johns Hopkins University Center for AIDS Research, and the President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention.


Investigation of Gelatinase Gene Expression and Growth of Enterococcus faecalis Clinical Isolates in Biofilm Models.
Enterococcus faecalis is the major reason for biofilm-related infections and it also interacts with Staphylococcus aureus in biofilms. Gelatinase (gelE) enzyme is an important virulence factor of E. faecalis for biofilm formation. This study aimed to compare the biofilm producing E. faecalis isolates from urine and urinary catheters. The influence of S. aureus on the growth of E. faecalis biofilm cells was also investigated in a dual biofilm model in vitro. Another aim was to evaluate E. faecalis gelE gene expression during biofilm formation. Firstly, crystal violet staining was used to measure the total biofilm biomass of the isolates. Secondly, plate counting was performed to determine the biofilm formation ability of E. faecalis isolates and the effect of S. aureus on E. faecalis biofilm formation. Finally, the gelE expression profile of the isolates was assessed by quantitative real time-polymerase chain reaction. According to crystal violet staining and plate counting, all E. faecalis isolates were biofilm producers and the number of E. faecalis sessile cells increased in the presence of S. aureus. Among the 21 E. faecalis isolates, ten expressed high levels of the gelE gene, while eight of them had low expression profiles (p<0.05). When they grow together, S. aureus may give some advantages to E. faecalis such as increasing sessile cell growth. The expression of the gelE gene was not affected by E. faecalis biofilm formation of the isolates collected from the patients with urinary tract infections.


Health benefits of Moringa oleifera.
Phytomedicines are believed to have benefits over conventional drugs and are regaining interest in current research. Moringa oleifera is a multi-purpose herbal plant used as human food and an alternative for medicinal purposes worldwide. It has been identified by researchers as a plant with numerous health benefits including nutritional and medicinal advantages. Moringa oleifera contains essential amino acids, carotenoids in leaves, and components with nutraceutical properties, supporting the idea of using this plant as a nutritional supplement or constituent in food preparation. Some nutritional evaluation has been carried out in leaves and stem. An important factor that accounts for the medicinal uses of Moringa oleifera is its very wide range of vital antioxidants, antibiotics and nutrients including vitamins and minerals. Almost all parts from Moringa can be used as a source for nutrition with other useful values. This mini-review elaborate on details its health benefits.


The 5-hydroxytryptamine2 agonist, (+-)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane stimulates the hypothalamic-pituitary-adrenal (HPA) axis. I. Acute effects on HPA axis activity and corticotropin-releasing factor-containing neurons in the rat brain.
Corticotropin-releasing factor (CRF) is the major physiological regulator of adrenocorticotrophic hormone (ACTH) secretion from the anterior pituitary. In vivo and in vitro studies have suggested that hypothalamic CRF secretion is under stimulatory serotonergic control, although the receptor subtype(s) responsible have not been definitely determined. The acute effects of the 5-hydroxytryptamine2 agonist, (+-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB), were examined on a number of biochemical indices of hypothalamic-pituitary-adrenal axis activity in vivo. DOB increased plasma ACTH and corticosterone concentrations at doses greater than 0.1 mg/kg. This effect is dose-dependent. Peak effects occurred 30 min postinjection and returned to basal levels by 4 hr after DOB injection. These effects of DOB are hypothesized to be mediated by the release of hypothalamic CRF because pretreatment with the CRF receptor antagonist (alpha-helical CRF9-41) significantly attenuated the ACTH response to DOB. Median eminence CRF content was also decreased following DOB administration in the presence of the protein synthesis inhibitor, cycloheximide (200 mg/kg i.p.), suggestive of release of CRF from median eminence terminals as a result of DOB activation of CRF neurons. DOB administration was without effect on brain CRF concentrations in all of the 12 extrahypothalamic brain regions studied 60 min after injection. These results, taken together, support a stimulatory role for 5-hydroxytryptamine2 receptors on hypothalamic CRF secretion.


Variations of Histone Modification Patterns: Contributions of Inter-plant Variability and Technical Factors.
Inter-individual variability of conspecific plants is governed by differences in their genetically determined growth and development traits, environmental conditions, and adaptive responses under epigenetic control involving histone post-translational modifications. The apparent variability in histone modifications among plants might be increased by technical variation introduced in sample processing during epigenetic analyses. Thus, to detect true variations in epigenetic histone patterns associated with given factors, the basal variability among samples that is not associated with them must be estimated. To improve knowledge of relative contribution of biological and technical variation, mass spectrometry was used to examine histone modification patterns (acetylation and methylation) among Arabidopsis thaliana plants of ecotypes Columbia 0 (Col-0) and Wassilewskija (Ws) homogenized by two techniques (grinding in a cryomill or with a mortar and pestle). We found little difference in histone modification profiles between the ecotypes. However, in comparison of the biological and technical components of variability, we found consistently higher inter-individual variability in histone mark levels among Ws plants than among Col-0 plants (grown from seeds collected either from single plants or sets of plants). Thus, more replicates of Ws would be needed for rigorous analysis of epigenetic marks. Regarding technical variability, the cryomill introduced detectably more heterogeneity in the data than the mortar and pestle treatment, but mass spectrometric analyses had minor apparent effects. Our study shows that it is essential to consider inter-sample variance and estimate suitable numbers of biological replicates for statistical analysis for each studied organism when investigating changes in epigenetic histone profiles.


One-Pot Polyol Synthesis of Pt/CeO2 and Au/CeO2 Nanopowders as Catalysts for CO Oxidation.
The facile one-pot synthesis of CeO2-based catalysts has been developed to prepare a relatively large amount of nanopowders with relevant catalytic activity towards CO oxidation. The method consists of a two-steps process carried out in ethylene glycol: in the first step, 5 nm well-crystallized pure CeO2 is prepared. In a subsequent second step, a salt of a noble metal is added to the CeO2 suspension and the deposition of the noble metal on the nanocrystalline CeO2 is induced by heating. Two catalysts were prepared: Pt/CeO2 and Au/CeO2. The as-prepared catalysts, the thermally treated catalysts, as well as the pure CeO2, are characterized by XRD, TGA, XPS, FTIR, HR-TEM, STEM, particle size distribution, and N2-physisorption. In spite of the identical preparation protocol, Au and Pt behave in a completely different way: Au forms rather large particles, most of them with triangular shape, easily identifiable and dispersed in the CeO2 matrix. In contrast, Pt was not identified as isolated particles. The high resolution X-ray diffraction carried out on the Pt/CeO2 thermally treated sample (500 degrees C for 1 h) shows a significant CeO2 lattice shrinkage, which can be interpreted as an at least partial incorporation of Pt into the CeO2 crystal lattice. Moreover, only Pt2+ and Pt4+ species were identified by XPS. In literature, the incorporation of Pt into the CeO2 lattice is supported by first-principle calculations and experimentally demonstrated only by combustion synthesis methods. To the best of our knowledge this is the first report where ionically dispersed Pt into the CeO2 lattice is obtained via a liquid synthesis method. The thermally treated Pt/CeO2 sample revealed good activity with 50% CO conversion at almost room temperature.


Mapping complementary features of cross-species structural connectivity to construct realistic "Virtual Brains".
Modern systems neuroscience increasingly leans on large-scale multi-lab neuroinformatics initiatives to provide necessary capacity for biologically realistic modeling of primate whole-brain activity. Here, we present a framework to assemble primate brain's biologically plausible anatomical backbone for such modeling initiatives. In this framework, structural connectivity is determined by adding complementary information from invasive macaque axonal tract tracing and non-invasive human diffusion tensor imaging. Both modalities are combined by means of available interspecies registration tools and a newly developed Bayesian probabilistic modeling approach to extract common connectivity evidence. We demonstrate how this novel framework is embedded in the whole-brain simulation platform called The Virtual Brain (TVB). Hum Brain Mapp 38:2080-2093, 2017. © 2017 Wiley Periodicals, Inc.


Smartphone, Smart Surgeon, what about a 'Smart Logbook'?
Mobile phone applications (Apps) have become a vital assistant to medical personnel in today's technologically advanced era. The utility of Apps with case logbook capabilities has not yet been explored. To assess and evaluate all currently available surgical and procedural case logbook Apps. A comprehensive search was conducted in April 2015 on the Android Play Store, iTunes (Apple App Store, iOS), and BlackBerry World for surgical and/or procedural logbooks. The search terms'surgical logbook', 'logbook', 'procedure logbook' and 'surgical log' were used. Apps which could not be utilized as a surgical/procedural logbook were excluded. Each App was individually assessed and rated using preset criteria, by the unit consultant, registrars, and medical officer. In total, 2 740 Apps were assessed. After applying our exclusion criteria, only 16 Apps were relevant, and 11 suitable for critical review. Data sizes ranged from 510Kb to 12.2Mb. Costing of the Apps ranged from ZAR 0.00 to ZAR 105.32. The overall study scores revealed the following top five rated Apps: Surgical Logbook by Surgilog; Surgeon Logbook Pro; Surgery Notebook, Surgical Logbook, and Universal Logbook. The current mobile Apps available are efficient in replacing traditional case logbooks. The use of the 'Smart Logbook' may become common practice in the life of the modern-day surgeon.


Non-fluorescent quantification of single mRNA with transient absorption microscopy.
Single molecule detection is confounded by the background signals from the biological environment, such as autofluorescence, Rayleigh scattering, or turbidity in cells and tissues. In this article, we report on the utilization of gold nanoparticles (AuNPs) as an orthogonal probe for non-fluorescence detection of single molecules with a transient absorption microscopy (TAM). The developed system and concepts were validated by quantitative evaluation of human epidermal receptor 2 (Her2) mRNA in cancer cells and tissues at single copy sensitivity. Results from TAM suggest that the average number of Her2 copies in SK-BR-3 and MCF-7 breast cancer cells is 203.19 ± 80.48, and 11.29 ± 4.47, respectively. Furthermore, TAM offers excellent signal-to-noise ratio in detecting mRNA in clinical tissues, indicating a significantly higher expression of Her2 genes in breast cancer tissues than that of normal tissues. Our single cell quantification TAM strategy was validated with a fluorescence in situ hybridization approach. Our demonstration shows that TAM has the potential to provide a new dimension in biomarker quantification at single molecule sensitivity in turbid biological environments providing a strong basis for clinical monitoring.


Older patients with chronic myeloid leukemia (≥65 years) profit more from higher imatinib doses than younger patients: a subanalysis of the randomized CML-Study IV.
The impact of imatinib dose on response rates and survival in older patients with chronic myeloid leukemia in chronic phase has not been studied well. We analyzed data from the German CML-Study IV, a randomized five-arm treatment optimization study in newly diagnosed BCR-ABL-positive chronic myeloid leukemia in chronic phase. Patients randomized to imatinib 400 mg/day (IM400) or imatinib 800 mg/day (IM800) and stratified according to age (≥65 years vs. <65 years) were compared regarding dose, response, adverse events, rates of progression, and survival. The full 800 mg dose was given after a 6-week run-in period with imatinib 400 mg/day. The dose could then be reduced according to tolerability. A total of 828 patients were randomized to IM400 or IM800. Seven hundred eighty-four patients were evaluable (IM400, 382; IM800, 402). One hundred ten patients (29 %) on IM400 and 83 (21 %) on IM800 were ≥65 years. The median dose per day was lower for patients ≥65 years on IM800, with the highest median dose in the first year (466 mg/day for patients ≥65 years vs. 630 mg/day for patients <65 years). Older patients on IM800 achieved major molecular remission and deep molecular remission as fast as younger patients, in contrast to standard dose imatinib with which older patients achieved remissions much later than younger patients. Grades 3 and 4 adverse events were similar in both age groups. Five-year relative survival for older patients was comparable to that of younger patients. We suggest that the optimal dose for older patients is higher than 400 mg/day. ClinicalTrials.gov identifier: NCT00055874


A "give" in tension and sarcomere dynamics in cardiac muscle relaxation.
Isometric relaxation in cardiac sarcomeres is characterised by an early, very slow phase of tension fall which is terminated by a 'give' in tension. A 'give' which occurs during relaxation in cardiac muscle can not be attributed to decrease in myofilament overlap. After the 'give' asynchronous motion occurs between sarcomeres, but the duration and extent of their displacement is limited. Intriguingly, the effect of isotonic displacements on the early fall in the velocity of sarcomere shortening indicates that an internal resistance increases near the peak of contraction. The complex shape of the sarcomere's complete force-velocity relation, with lengthening motions in particular, was consistent with an idealized model of cross-bridge cycling. The sarcomere's resistance to stretch is high at low velocity, but it diminishes to reveal yielding at larger velocities. Relative to tension, the resistance to yielding does not decrease during relaxation, and it may actually increase. The decay of isometric tension after a controlled stretch also slows during relaxation. Consequently, cycling slows in those cross-bridges which form (or persist but produce less force) later in contraction. Changes in cross-bridge properties may restrict sarcomere shortening, prolong activation, but promote a disequilibrium which favors rapid relaxation in cardiac muscle.


An in vitro system to evaluate the effects of ischemia on survival of cells used for cell therapy.
Maintaining cell viability is a major challenge associated with transplanting cells into ischemic myocardium to restore function. A likely contributor to significant cell death during cardiac cell therapy is hypoxia/anoxia. We developed a system that enabled quantification and association of cell survival with oxygen and nutrient values within in vitro constructs. Myoblasts were suspended in 2% collagen gels in 1 cm diameter x 1 cm deep constructs. At 48 +/- 3 h post-seeding, oxygen levels were measured using microelectrodes and gels were snap-frozen. Bioluminescence metabolite imaging and TUNEL staining were performed on cryosections. Oxygen and glucose consumption and lactate production rates were calculated by fitting data to Fick's second law of diffusion with Michaelis-Menten kinetics. Oxygen levels dropped to 0 mmHg and glucose levels dropped from 4.28 to 3.18 mM within the first 2000 mum of construct depth. Cell viability dropped to approximately 40% over that same distance and continued to drop further into the construct. We believe this system provides a reproducible and controllable test bed to compare survival, proliferation, and phenotype of various cell inputs (e.g., myoblasts, mesenchymal stem cells, and cardiac stem cells) and the impact of different treatment regimens on the likelihood of survival of transplanted cells.


Overweight and obese adolescent girls: the importance of promoting sensible eating and activity behaviors from the start of the adolescent period.
The adolescent period is associated with changes in eating and activity behaviors in girls. Less reliance on parental provision and choice of food, coupled with a decrease in participation in physical activity and sport, can create an energy imbalance, predisposing to weight gain. Physiological alterations to body composition, reduction in insulin sensitivity, and psychological adjustments may further amplify the risk of becoming overweight and maintaining an unhealthy level of body fat into childbearing years. During pregnancy excess body fat is a risk factor for poor pregnancy outcomes and may predispose an infant to a lifelong heightened risk of being overweight and developing chronic disease. Interventions aimed at preventing the accumulation of body fat in adolescent girls and young women may have far reaching impact and be critically important in reducing intergenerational weight gain. Lifestyle interventions in adolescence have the potential to modify adult obesity risk by switching at-risk individuals from a high to lower obesity risk trajectory. This paper discusses multiple approaches to assist at-risk individuals reduce obesity risk. A key focus is placed on engagement in food preparation and choice, and opportunities for physical activity and sport. Support, education, and opportunity at home and at school, are often associated with the success of lifestyle interventions, and may enable adolescents to make positive choices, and engage in health promoting behaviors during adolescence and childbearing years.


EEG characteristics prior to and following the evoked K-Complex.
This study was designed to determine if the K-Complex reflects an arousal from sleep or a sleep protection mechanism. Ten participants were presented auditory stimuli every 20 s while asleep. Trials were sorted according to the presence or absence of a K-Complex. A fast Fourier Transformation of the data was computed on EEG segments prior to and following stimulus onset. The log power of activity in delta, theta, alpha, sigma, and beta bandwidths was computed. When a K-Complex was elicited, there were no differences in EEG activity prior to and following the stimulus. However, during slow wave sleep, when a K-Complex was not elicited, there was a significant overall increase in theta, alpha, sigma, and beta activity following stimulus. These results tend to support the notion that the K-Complex appears to prevent arousal.


Effect of neonatal test environment on recording transient-evoked otoacoustic emissions.
To examine the effect of test environment on recording transient-evoked otoacoustic emissions (TEOAE) in neonates. Thirty-two infants from the newborn nursery (NBN) who passed a screening auditory brainstem response (SABR) test and were at least 34 weeks' postconceptional age were studied. One ear of each newborn was tested using TEOAE in 5 different test environments: open bassinet in the NBN (E1), working isolet located in the NBN (E2), nonfunctioning isolet in the NBN (E3), nonfunctioning isolet in a quiet room off the NBN (E4), and open bassinet in a quiet room (E5). The number of high noise samples (HNS), the test duration (in seconds), the signal-to-noise ratio (SNR; in dB) measured at bandwidths centered at 1.6, 2.4, 3.2, and 4.0 kHz, and the percentage of neonates with a fail screening outcome based on a common pass-fail screening criteria were compared in the 5 test environments. There were statistically significant differences in the number of HNS accumulated in the 5 test environments (F = 6.79). The use of a nonfunctioning isolet in both the NBN and within a room off the NBN (E3 and E4, respectively) resulted in significantly fewer HNS than when TEOAEs were recorded in the other 3 test environments (E1, E2, and E5). Mean test duration was significantly different among the 5 locations (F = 6. 53). Posthoc analyses revealed that test time in E3 and E4 was significantly shorter than in E1 and E2. The percentage of newborns with a fail (</=3 dB SNR at 2.4, 3.2, and 4.0 kHz) outcome was lowest in E3 (6.3%) and the same in E1 and E4 (12.5%). A high percentage of infants received a fail outcome when tested in both the working isolet and in the open bassinet in a room off the nursery (21.8% and 25%, respectively). SNR (in dB) for bandwidths centered at 1.6, 2.4, and 3.2 kHz was negatively correlated with the HNS in the working isolet. SNR (in dB) at 4.0 kHz was negatively correlated with the HNS when TEOAEs were recorded in the open bassinet in a room adjacent to the NBN. The number of HNS was correlated with overall test time in each environment. Test environments typically used for newborn hearing screening can influence the recording of TEOAEs. Performing the TEOAE test with the neonate placed in a nonfunctioning isolet located in either the NBN or in a room off of the NBN resulted in the most desirable outcomes (shortest test times, fewest HNS, highest SNR (in dB), and fewest fail outcomes).


Theory-based communication skills training for medicine counter assistants to improve consultations for non-prescription medicines.
Medicine counter assistants (MCAs) supply the majority of non-prescription medicines (NPMs) to consumers. Suboptimal communication during consultations between consumers and MCAs has been identified as a major cause of inappropriate supply. Evidence from medical consultations suggests that training in specified communication skills can change professional behaviour. A feasibility study was conducted to evaluate the effect of theory-based communication skills training for MCAs. Thirty MCAs were recruited from 21 community pharmacies in Grampian, Scotland. The intervention comprised 2 4-hour training sessions, held 1 month apart. The sessions were informed by results from previous studies and the Calgary-Cambridge evidence-based model of communication skills training. Strategies for guiding individuals through change were adopted from cognitive behavioural therapy techniques. The theory of planned behaviour was used to assess potential pathways to behaviour change. Recorded data were collected during covert visits to the pharmacies by simulated patients at baseline and 1 month after each training session. Communication performance was measured as the number and type of questions asked. Compared with baseline measures, the total number of questions asked increased in the intervention group at both time-points. No change was shown in the control group between baseline and follow-up 1, and a decrease was shown in the total number of questions from follow-up 1 to 2. The intervention appeared to have greater effect on consultations involving advice, compared with those concerning product requests. Communication performance improved following training. Increased information exchange is associated with guideline-compliant supply of NPMs. A substantive randomised, controlled trial is now planned to assess the intervention.


Molecular Study of Dirofilaria immitis and Dirofilaria repens in Dogs from Tunisia.
Dirofilaria immitis and Dirofilaria repens are mosquito-borne nematodes which infect primarily dogs as their main definitive hosts. They cause cardiopulmonary (D. immitis) or cutaneous (D. repens) dirofilariasis in canids and other carnivores and can accidentally be transmitted to humans where they can induce a variety of clinical outcomes depending on organ localization. Dirofilaria spp. infection in dogs was assessed using molecular methods (PCR and sequencing) to identify the different Dirofilaria species occurring in 200 dogs from Northern and Central Tunisia. The overall molecular prevalence of Dirofilaria spp. was 17.5% (35/200). The prevalence of D. immitis (14.5%) was significantly higher than for D. repens (3%). Molecular prevalence of D. immitis was significantly higher in suburban compared to urban and rural regions. There was no difference in molecular prevalence of D. immitis or D. repens according to the dogs' (sex or use). Dirofilaria immitis amplicons (accession numbers KR676386) fall into the same clade with D. immitis from China, India and Taiwan. Comparison of the partial sequences of D. repensITS2 rDNA gene (KR676387) revealed 99.6% similarity with D. repens reported in dogs from USA. It had also 97.6% similarity with D. repens from mosquitoes in Czech Republic. High dog parasite burdens should motivate both medical doctors and veterinarians to consider these frequent infections.


Proton pump inhibitors and risk of hip fracture: a meta-analysis of observational studies.
We performed a meta-analysis of relevant studies to quantify the magnitude of the association between proton pump inhibitors (PPIs) and risk of hip fracture. Patients with PPIs had a greater risk of hip fracture than those without PPI therapy (RR 1.20, 95% CI 1.14-1.28, p < 0.0001). These results could be taken into consideration with caution, and patients should also be concerned about the inappropriate use of PPIs. Proton pump inhibitors (PPIs) are generally considered as first-line medicine with great safety profile, commonly prescribed for gastroesophageal reflux disease (GERD) and peptic ulcer disease. However, several epidemiological studies documented that long-term use of PPIs may be associated with an increased risk of hip fracture. Although, the optimal magnitude of the hip fracture risk is still undetermined. We, therefore, performed a meta-analysis of relevant studies to quantify the magnitude of the association between PPIs and risk of hip fracture. We collected relevant articles using MEDLINE, EMBASE, Google Scholar, and Web of Science from January 1, 1990, to March 31, 2018. We included only the large (n ≥ 500) observational studies with a follow-up duration of at least one year in which the hip fracture patients were identified by a standard procedure. Two of the authors extracted data from each included study independently according to a standardized protocol. A total of 24 observational studies with 2,103,800 participants (319,568 hip fracture patients) met all the eligibility criteria. Patients with PPIs had a greater risk of hip fracture than those without PPI therapy (RR 1.20, 95% CI 1.14-1.28, p < 0.0001). An increased association was also observed in both low and medium doses of PPI taken and hip fracture risk (RR 1.17, 95% CI 1.05-1.29, p = 0.002; RR 1.28, 95% CI 1.14-1.44, p < 0.0001), but it appeared to be even greater among the patients with higher dose (RR 1.30, 95% CI 1.20-1.40, p < 0.0001). Moreover, the overall pooled risk ratios were 1.20 (95% CI 1.15-1.25, p < 0.0001) and 1.24 (95% CI 1.10-1.40, p < 0.0001) for the patients with short- and long-term PPI therapy, respectively, compared with PPI non-users. Our results suggest that PPI use is significantly associated with an increased risk of hip fracture development, which is not observed in H2RA exposure. Physicians should, therefore, exercise caution when considering a long-term PPI treatment to their patients who already have an elevated risk of hip fracture. In addition, patients should be concerned about the inappropriate use of PPIs; if necessary, then, they should continue to receive it with a clear indication.


A framework on the emergence and effectiveness of global health networks.
Since 1990 mortality and morbidity decline has been more extensive for some conditions prevalent in low- and middle-income countries than for others. One reason may be differences in the effectiveness of global health networks, which have proliferated in recent years. Some may be more capable than others in attracting attention to a condition, in generating funding, in developing interventions and in convincing national governments to adopt policies. This article introduces a supplement on the emergence and effectiveness of global health networks. The supplement examines networks concerned with six global health problems: tuberculosis (TB), pneumonia, tobacco use, alcohol harm, maternal mortality and newborn deaths. This article presents a conceptual framework delineating factors that may shape why networks crystallize more easily surrounding some issues than others, and once formed, why some are better able than others to shape policy and public health outcomes. All supplement papers draw on this framework. The framework consists of 10 factors in three categories: (1) features of the networks and actors that comprise them, including leadership, governance arrangements, network composition and framing strategies; (2) conditions in the global policy environment, including potential allies and opponents, funding availability and global expectations concerning which issues should be prioritized; (3) and characteristics of the issue, including severity, tractability and affected groups. The article also explains the design of the project, which is grounded in comparison of networks surrounding three matched issues: TB and pneumonia, tobacco use and alcohol harm, and maternal and newborn survival. Despite similar burden and issue characteristics, there has been considerably greater policy traction for the first in each pair. The supplement articles aim to explain the role of networks in shaping these differences, and collectively represent the first comparative effort to understand the emergence and effectiveness of global health networks.


Changes in the basement membrane zone components during skeletal muscle fiber degeneration and regeneration.
The basement membrane of skeletal muscle fibers is believed to persist unchanged during myofiber degeneration and act as a tubular structure within which the regeneration of new myofibers occurs. In the present study we describe macromolecular changes in the basement membrane zone during muscle degeneration and regeneration, as monitored by immunofluorescence using specific antibodies against types IV and V collagen, laminin, and heparan sulfate proteoglycan and by the binding of concanavalin A (Con A). Skeletal muscle regeneration was induced by autotransplantation of the extensor digitorum longus muscle in rats. After this procedure, the myofibers degenerate; this is followed by myosatellite cell activation, proliferation, and fusion, resulting in the formation of new myotubes that mature into myofibers. In normal muscle, the distribution of types IV and V collagen, laminin, heparan sulfate proteoglycan, and Con A binding was seen in the pericellular basement membrane region. In autotransplanted muscle, the various components of the basement membrane zone disappeared, leaving behind some unidentifiable component that still bound Con A. Around the regenerated myotubes a new basement membrane (zone) reappeared, which persisted during maturation of the regenerating muscle. The distribution of various basement membrane components in the regenerated myofibers was similar to that seen in the normal muscle. Based on our present and previous study (Gulati, A.K., A.H. Reddi, and A.A. Zalewski, 1982, Anat. Rec. 204:175-183), it appears that some of the original basement membrane zone components disappear during myofiber degeneration and initial regeneration. As a new basement membrane develops, its components reappear and persist in the mature myofibers. We conclude that skeletal muscle fiber basement membrane (zone) is not a static structure as previously thought, but rather that its components change quite rapidly during myofiber degeneration and regeneration.


In vivo depletion of free thiols does not account for nitroglycerin-induced tolerance: a thiol-nitrate interaction hypothesis as an alternative explanation for nitroglycerin activity and tolerance.
The present study investigates the effects of thiol-depleting/ modifying agents on the activity of and tolerance to nitroglycerin (GTN), sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) in an in vivo rat model. Rats were treated with either vehicle (control), GTN (before and after induction of tolerance), diethyl maleate (a thiol-depleting agent) or N-ethylmaleimide (a thiol-modifying agent). The effects of GTN, SNP and SNAP on vascular cyclic GMP levels were investigated before and after each treatment. In addition, plasma and tissue thiol concentrations were measured in the same tissues as used for the determination of cyclic GMP in aorta and inferior vena cava after single and serial i.v. bolus doses of each drug. Depletion of free thiols (glutathione and cysteine) was not found to accompany tolerance development in GTN-treated tolerant rats or to significantly enhance tolerance development or augment its magnitude in diethyl maleate-treated rats. When rats were pretreated with a low single dose of N-ethylmaleimide, where no significant changes in vascular free thiols were observed, significant reduction in GTN- and SNP-induced, but not SNAP-induced, vascular cyclic GMP production was obtained. Considering the differential effects of diethyl maleate (mainly free thiol depletion) and N-ethylmaleimide (mainly proteinous thiol-alkylation) on vascular thiols, these results indicate that depletion of sulfhydryl groups other than those from free glutathione and cysteine seems to be involved in the mechanisms defining GTN and SNP (but not SNAP) action and tolerance. Here we propose that SNAP may act either directly by nitrosation of the heme moiety of the enzyme or via an S-enzyme-S-drug transnitrosation reaction, whereas GTN and SNP actions are mediated by the formation of S-nitrosothiol on the enzyme itself, rather than by activation of the enzyme by free S-nitrosothiols.


Recombinant Sendai virus as a novel vaccine candidate for respiratory syncytial virus.
Respiratory syncytial virus (RSV) is among the most important and serious pediatric respiratory diseases, and yet after more than four decades of research an effective vaccine is still unavailable. This review examines the role of the immune response in reducing disease severity; considers the history of RSV vaccine development; and advocates the potential utility of Sendai virus (a murine paramyxovirus) as a xenogenic vaccine vector for the delivery of RSV antigens. The immunogenicity and protective efficacy of RSV-recombinant Sendai virus vectors constructed using reverse genetics is examined. RSV-recombinant Sendai virus is easy to grow (i.e., achieves extremely high titers in eggs), is easy to administer (intranasal drops), and elicits both B- and T-cell responses leading to protection from RSV challenge in a small-animal model. Unmodified Sendai virus is currently being studied in clinical trials as a vaccine for its closely related human cognate (human parainfluenza virus type 1). Sendai virus may prove an enormously valuable vaccine platform, permitting the delivery of recombinants targeting important pediatric respiratory pathogens, RSV chief among them.


The Tea Tree Genome Provides Insights into Tea Flavor and Independent Evolution of Caffeine Biosynthesis.
Tea is the world's oldest and most popular caffeine-containing beverage with immense economic, medicinal, and cultural importance. Here, we present the first high-quality nucleotide sequence of the repeat-rich (80.9%), 3.02-Gb genome of the cultivated tea tree Camellia sinensis. We show that an extraordinarily large genome size of tea tree is resulted from the slow, steady, and long-term amplification of a few LTR retrotransposon families. In addition to a recent whole-genome duplication event, lineage-specific expansions of genes associated with flavonoid metabolic biosynthesis were discovered, which enhance catechin production, terpene enzyme activation, and stress tolerance, important features for tea flavor and adaptation. We demonstrate an independent and rapid evolution of the tea caffeine synthesis pathway relative to cacao and coffee. A comparative study among 25 Camellia species revealed that higher expression levels of most flavonoid- and caffeine- but not theanine-related genes contribute to the increased production of catechins and caffeine and thus enhance tea-processing suitability and tea quality. These novel findings pave the way for further metabolomic and functional genomic refinement of characteristic biosynthesis pathways and will help develop a more diversified set of tea flavors that would eventually satisfy and attract more tea drinkers worldwide.


Six new record species of whiteflies (Hemiptera: Aleyrodidae) infesting Morus alba in China.
To determine the species of whiteflies occurring on mulberry, Morus alba L. (Rosales: Moraceae) in China, we collected samples in more than 87 sites in 16 provinces of China from 2008 to 2011. In total, 10 species, representing seven genera of the subfamily Aleyrodinae, were identified. Of these, six species are newly recorded on mulberry in China, namely, Aleuroclava ficicola Takahashi, Aleuroclava gordoniae (Takahashi), Aleurotrachelus camelliae (Kuwana), Bemisia afer (Priesner & Hosny), Bemisia tabaci Gennadius, and Pealius machili Takahashi. Information on the taxonomy, distribution, and host plants of the whitefly species found on mulberry in China, along with a brief description and illustrations of each species are provided.


Identification and Validation of Evolutionarily Conserved Unusually Short Pre-mRNA Introns in the Human Genome.
According to the length distribution of human introns, there is a large population of short introns with a threshold of 65 nucleotides (nt) and a peak at 85 nt. Using human genome and transcriptome databases, we investigated the introns shorter than 66 nt, termed ultra-short introns, the identities of which are scarcely known. Here, we provide for the first time a list of bona fide human ultra-short introns, which have never been characterized elsewhere. By conducting BLAST searches of the databases, we screened 22 introns (37-65 nt) with conserved lengths and sequences among closely related species. We then provide experimental and bioinformatic evidence for the splicing of 15 introns, of which 12 introns were remarkably G-rich and 9 introns contained completely inefficient splice sites and/or branch sites. These unorthodox characteristics of ultra-short introns suggest that there are unknown splicing mechanisms that differ from the well-established mechanism.


Short- and long-term individual variation in cardiac troponin in patients with stable coronary artery disease.
A rise or fall of cardiac troponin is a prerequisite for the diagnosis of acute myocardial infarction. Defining significant changes requires knowledge of both biological and analytical variation. The short-term biological variation of cardiac troponin in healthy individuals is 3%-48%. However, healthy individuals may not be representative for patients in whom cardiac troponin measurement is often of clinical importance. Therefore, we studied the individual variation of cardiac troponin in patients with symptoms of stable coronary artery disease. Twenty-four patients scheduled for elective coronary angiography were included. Blood samples were drawn once at enrollment and serially at six 4-h intervals on the day before coronary angiography. Cardiac troponin was measured with hs-cTn assays from Abbott Laboratories (premarket cTnI assay) and Roche Diagnostics (Elecsys(®) cTnT assay with two different lots). The short-term individual variation in cardiac troponin I (cTnI) was 14%, the reference change value (RCV) 49%, and RCV-log-normal (rise/fall) 54%/-35%. The corresponding values for cTnT were 7%, 23%, and 26%/-21%. The long-term variation for cTnI was 24%, RCV 69%, and RCV-log-normal (rise/fall) 97%/-49%. The corresponding values for cTnT were 11%, 32%, and 37%/-27%. The short-term individual variation of cardiac troponin in patients with symptoms of stable coronary artery disease is similar to the biological variation previously demonstrated in healthy individuals. Our results suggest that a change in cardiac troponin concentrations of >50% can be used in attempting to diagnose acute myocardial injury. To detect significant long-term changes in cardiac troponin concentrations, larger changes will be required.


An increase in the burden of neonatal admissions to a rural district hospital in Kenya over 19 years.
Most of the global neonatal deaths occur in developing nations, mostly in rural homes. Many of the newborns who receive formal medical care are treated in rural district hospitals and other peripheral health centres. However there are no published studies demonstrating trends in neonatal admissions and outcome in rural health care facilities in resource poor regions. Such information is critical in planning public health interventions. In this study we therefore aimed at describing the pattern of neonatal admissions to a Kenyan rural district hospital and their outcome over a 19 year period, examining clinical indicators of inpatient neonatal mortality and also trends in utilization of a rural hospital for deliveries. Prospectively collected data on neonates is compared to non-neonatal paediatric (≤ 5 years old) admissions and deliveries' in the maternity unit at Kilifi District Hospital from January 1(st) 1990 up to December 31(st) 2008, to document the pattern of neonatal admissions, deliveries and changes in inpatient deaths. Trends were examined using time series models with likelihood ratios utilised to identify indicators of inpatient neonatal death. The proportion of neonatal admissions of the total paediatric ≤ 5 years admissions significantly increased from 11% in 1990 to 20% by 2008 (trend 0.83 (95% confidence interval 0.45-1.21). Most of the increase in burden was from neonates born in hospital and very young neonates aged < 7 days. Hospital deliveries also increased significantly. Clinical diagnoses of neonatal sepsis, prematurity, neonatal jaundice, neonatal encephalopathy, tetanus and neonatal meningitis accounted for over 75% of the inpatient neonatal admissions. Inpatient case fatality for all ≤ 5 years declined significantly over the 19 years. However, neonatal deaths comprised 33% of all inpatient death among children aged ≤ 5 years in 1990, this increased to 55% by 2008. Tetanus 256/390 (67%), prematurity 554/1,280(43%) and neonatal encephalopathy 253/778(33%) had the highest case fatality. A combination of six indicators: irregular respiration, oxygen saturation of <90%, pallor, neck stiffness, weight < 1.5 kg, and abnormally elevated blood glucose > 7 mmol/l predicted inpatient neonatal death with a sensitivity of 81% and a specificity of 68%. There is clear evidence of increasing burden in neonatal admissions at a rural district hospital in contrast to reducing numbers of non-neonatal paediatrics' admissions aged ≤ 5 years. Though the inpatient case fatality for all admissions aged ≤ 5 years declined significantly, neonates now comprise close to 60% of all inpatient deaths. Simple indicators may identify neonates at risk of death.


Somatostatin triggers rhythmic electrical firing in hypothalamic GHRH neurons.
Hypothalamic growth hormone-releasing hormone (GHRH) neurons orchestrate body growth/maturation and have been implicated in feeding responses and ageing. However, the electrical patterns that dictate GHRH neuron functions have remained elusive. Since the inhibitory neuropeptide somatostatin (SST) is considered to be a primary oscillator of the GH axis, we examined its acute effects on GHRH neurons in brain slices from male and female GHRH-GFP mice. At the cellular level, SST irregularly suppressed GHRH neuron electrical activity, leading to slow oscillations at the population level. This resulted from an initial inhibitory action at the GHRH neuron level via K(+) channel activation, followed by a delayed, sst1/sst2 receptor-dependent unbalancing of glutamatergic and GABAergic synaptic inputs. The oscillation patterns induced by SST were sexually dimorphic, and could be explained by differential actions of SST on both GABAergic and glutamatergic currents. Thus, a tripartite neuronal circuit involving a fast hyperpolarization and a dual regulation of synaptic inputs appeared sufficient in pacing the activity of the GHRH neuronal population. These "feed-forward loops" may represent basic building blocks involved in the regulation of GHRH release and its downstream sexual specific functions.


Targeting of calcineurin to an NFAT-like docking site is required for the calcium-dependent activation of the background K+ channel, TRESK.
The two-pore domain K(+) channel, TRESK (TWIK-related spinal cord K(+) channel) is activated in response to the calcium signal by the calcium/calmodulin-dependent protein phosphatase, calcineurin. In the present study we report that calcineurin also interacts with TRESK via an NFAT-like docking site, in addition to its enzymatic action. In its intracellular loop, mouse TRESK possesses the amino acid sequence, PQIVID, which is similar to the calcineurin binding consensus motif, PXIXIT (where X denotes any amino acids), necessary for NFAT (nuclear factor of activated T cells) activation and nuclear translocation. Mutations of the PQIVID sequence of TRESK to PQIVIA, PQIVAD, or PQAVAD increasingly deteriorated the calcium-dependent activation in the listed order and correspondingly reduced the benzocaine sensitivity (a property discriminating activated channels from resting ones), when it was measured after the calcium signal in Xenopus oocytes. Microinjection of VIVIT peptide, designed to inhibit the NFAT-calcineurin interaction specifically, also eliminated TRESK activation. The intracellular loop of TRESK, expressed as a GST fusion protein, bound constitutively active calcineurin in vitro. PQAVAD mutation as well as addition of VIVIT peptide to the reaction abrogated this calcineurin binding. Wild type calcineurin was recruited to GST-TRESK-loop in the presence of calcium and calmodulin. These results indicate that the PQIVID sequence is a docking site for calcineurin, and its occupancy is required for the calcium-dependent regulation of TRESK. Immunosuppressive compounds, developed to target the NFAT binding site of calcineurin, are also expected to interfere with TRESK regulation, in addition to their desired effect on NFAT.


Assessment of adaptive behaviour in children with intellectual disability in Oman: an examination of ABAS-3 factor structure and validation in the Arab context.
In Oman and elsewhere in Arab countries school professionals rely on measures that were developed in Western countries. Measures that assess adaptive behaviour (AB) that have been developed in Western cultures are argued to be culturally bound. Nevertheless, these measures are used elsewhere despite a paucity of data that examine their cross-national transportability. The theme of test adaptation and transportability of psychological measures is an important issue for school/educational psychologists, clinicians and educational professionals. The present study describes the adaptation process of the U.S.-developed Adaptive Behaviour Assessment System, Third Edition Teacher Form (ABAS-3-TF) for ages 5 to 14 in the Sultanate of Oman, one of the Gulf Cooperation Council (GCC) countries. Procedures implemented to help ensure a valid translation and cultural adaptation process are described. Data on 410 children with intellectual disability are examined using the Arabic version of ABAS-3-TF, focusing on testing its factor structure and gender invariance. Data from the Arabic version of ABAS-3-TF provide evidence for the adequacy of a one general factor model. Scale reliability is high for the Arabic version. The finding of invariance across males and females indicate that the scale's factor structure is similar for the two groups. The Arabic version of ABAS-3-TF is adequate for use by clinicians, school psychologists and educational professionals in Oman.


Stimulation of fibroblast chemotaxis by human recombinant tumor necrosis factor alpha (TNF-alpha) and a synthetic TNF-alpha 31-68 peptide.
Macrophages are a major source of fibrogenic factors that promote healing of injured tissue. The recruitment of fibroblasts to sites of tissue injury is a prerequisite for optimal repair of tissue damage. In the present study, human recombinant tumor necrosis factor alpha (hrTNF-alpha), a major macrophage-derived cytokine, was demonstrated to be a potent fibroblast chemoattractant, inducing migration at picomolar concentrations. Anti-hrTNF-alpha monoclonal antibody neutralized most of the fibroblast chemotactic activity generated during short-term culture of human peripheral blood monocytes stimulated with bacterial lipopolysaccharide, suggesting that TNF-alpha is a major monocyte-derived fibroblast chemoattractant. The portion of the human TNF-alpha molecule responsible for its chemotactic stimulation of fibroblasts appears to reside in residues 31-68. This region is highly conserved between TNF-alpha and lymphotoxin. This peptide is not only itself chemotactic but is also able to block the chemotactic response of fibroblasts to hrTNF-alpha and vice versa, suggesting that they each mediate fibroblast migration through similar mechanisms. These data further underscore the potential importance of TNF-alpha in modulating a variety of fibroblast functions, including chemotaxis and synthesis of collagen, glycosaminoglycans, interleukin 1 alpha (IL-1 alpha) and -beta, human histocompatibility leukocyte antigen A and B antigens, collagenase, prostaglandin E2, and IL-6.


Distribution and biomarkers of carbon-14-labeled fullerene C60 ([(14) C(U)]C60 ) in female rats and mice for up to 30 days after intravenous exposure.
A comprehensive distribution study was conducted in female rats and mice exposed to a suspension of uniformly carbon-14-labeled C60 ([(14) C(U)]C60 ). Rodents were administered [(14) C(U)]C60 (~0.9 mg kg(-1) body weight) or 5% polyvinylpyrrolidone-saline vehicle alone via a single tail vein injection. Tissues were collected at 1 h and 1, 7, 14 and 30 days after administration. A separate group of rodents received five daily injections of suspensions of either [(14) C(U)]C60 or vehicle with tissue collection 14 days post exposure. Radioactivity was detected in over 20 tissues at all time points. The highest concentration of radioactivity in rodents at each time point was in liver, lungs and spleen. Elimination of [(14) C(U)]C60 was < 2% in urine and feces at any 24 h time points. [(14) C(U)]C60 and [(14) C(U)]C60 -retinol were detected in liver of rats and together accounted for ~99% and ~56% of the total recovered at 1 and 30 days postexposure, respectively. The blood radioactivity at 1 h after [(14) C(U)]C60 exposure was fourfold higher in rats than in mice; blood radioactivity was still in circulation at 30 days post [(14) C(U)]C60 exposure in both species (<1%). Levels of oxidative stress markers increased by 5 days after exposure and remained elevated, while levels of inflammation markers initially increased and then returned to control values. The level of cardiovascular marker von Willebrand factor, increased in rats, but remained at control levels in mice. This study demonstrates that [(14) C(U)]C60 is retained in female rodents with little elimination by 30 days after i.v. exposure, and leads to systemic oxidative stress.


Antimicrobial peptide-inspired NH125 analogues: bacterial and fungal biofilm-eradicating agents and rapid killers of MRSA persisters.
During microbial infection, antimicrobial peptides are utilized by the immune response to rapidly eradicate microbial pathogens through the destruction of cellular membranes. Inspired by antimicrobial peptides, quaternary ammonium cationic (QAC) compounds have emerged as agents capable of destroying bacterial membranes leading to rapid bacterial death, including the eradication of persistent, surface-attached bacterial biofilms. NH125, an imidazolium cation with a sixteen membered fatty tail, was recently reported to eradicate persister cells and was our starting point for the development of novel antimicrobial agents. Here, we describe the design, chemical synthesis and biological investigations of a collection of 30 diverse NH125 analogues which provided critical insights into structural features that are important for antimicrobial activities in this class. From these studies, multiple NH125 analogues were identified to possess potent antibacterial and antifungal activities, eradicate both bacterial and fungal biofilms and rapidly eradicate MRSA persister cells in stationary phase. NH125 analogues also demonstrated more rapid persister cell killing activities against MRSA when tested alongside a panel of diverse membrane-active agents, including BAC-16 and daptomycin. NH125 analogues could have a significant impact on persister- and biofilm-related problems in numerous biomedical applications.


A physiological role for connective tissue growth factor in early wound healing.
Mesenchymal stem cells (MSCs) that overexpress secreted frizzled-related protein 2 (sFRP2) exhibit an enhanced reparative phenotype. The secretomes of sFRP2-overexpressing MSCs and vector control-MSCs were compared through liquid chromatography tandem mass spectrometry. Proteomic profiling revealed that connective tissue growth factor (CTGF; CCN2) was overrepresented in the conditioned media of sFRP2-overexpressing MSCs and MSC-derived CTGF could thus be an important paracrine effector. Subcutaneously implanted, MSC-loaded polyvinyl alcohol (PVA) sponges and stented excisional wounds were used as wound models to study the dynamics of CTGF expression. Granulation tissue generated within the sponges and full-thickness skin wounds showed transient upregulation of CTGF expression by MSCs and fibroblasts, implying a role for this molecule in early tissue repair. Although collagen and COL1A2 mRNA were not increased when recombinant CTGF was administered to sponges during the early phase (day 1-6) of tissue repair, prolonged administration (>15 days) of exogenous CTGF into PVA sponges resulted in fibroblast proliferation and increased deposition of collagen within the experimental granulation tissue. In support of its physiological role, CTGF immunoinhibition during early repair (days 0-7) reduced the quantity, organizational quality and vascularity of experimental granulation tissue in the sponge model. However, CTGF haploinsufficiency was not enough to reduce collagen deposition in excisional wounds. Similar to acute murine wound models, CTGF was transiently present in the early phase of human acute burn wound healing. Together, these results further support a physiological role for CTGF in wound repair and demonstrate that when CTGF expression is confined to early tissue repair, it serves a pro-reparative role. These data also further illustrate the potential of MSC-derived paracrine modulators to enhance tissue repair.


Positive response to trastuzumab in a case of HER2-overexpressing metastatic gastric cancer that presented as severe thrombocytopenia.
Trastuzumab, a humanized monoclonal antibody directed against human epidermal growth factor receptor 2 (HER2), has been shown to be active against metastatic gastric cancers that overexpress HER2. A 47-year-old man presented with a headache and visual disturbance. He was subsequently found to have an intracranial hemorrhage. Laboratory testing showed severe thrombocytopenia, and a bone marrow biopsy revealed aggregates of malignant tumor cells. Endoscopic biopsy of an ulcerative lesion of the gastric antrum confirmed signet ring cell carcinoma based on the results of H&E staining. Immunohistochemistry of the tumor cells revealed HER2 overexpression with an intensity of 3+, and silver in situ hybridization showed HER2 gene amplification. The patient was treated with trastuzumab because of the presence of severe thrombocytopenia. After 2 months of trastuzumab therapy, gastric wall thickening and ascites were diminished and thrombocytopenia was markedly improved. Trastuzumab was continued for an additional 3 months. This is the first report of a positive response to trastuzumab in a patient with HER2-overexpressing metastatic gastric cancer that was accompanied by bone marrow involvement and severe thrombocytopenia. This finding is of considerable relevance for difficult cases of metastatic gastric cancer that preclude the administration of aggressive antineoplastic regimens.


Identifying the Misshapen Head: Craniosynostosis and Related Disorders.
Pediatric care providers, pediatricians, pediatric subspecialty physicians, and other health care providers should be able to recognize children with abnormal head shapes that occur as a result of both synostotic and deformational processes. The purpose of this clinical report is to review the characteristic head shape changes, as well as secondary craniofacial characteristics, that occur in the setting of the various primary craniosynostoses and deformations. As an introduction, the physiology and genetics of skull growth as well as the pathophysiology underlying craniosynostosis are reviewed. This is followed by a description of each type of primary craniosynostosis (metopic, unicoronal, bicoronal, sagittal, lambdoid, and frontosphenoidal) and their resultant head shape changes, with an emphasis on differentiating conditions that require surgical correction from those (bathrocephaly, deformational plagiocephaly/brachycephaly, and neonatal intensive care unit-associated skill deformation, known as NICUcephaly) that do not. The report ends with a brief discussion of microcephaly as it relates to craniosynostosis as well as fontanelle closure. The intent is to improve pediatric care providers' recognition and timely referral for craniosynostosis and their differentiation of synostotic from deformational and other nonoperative head shape changes.


Design of a Transcriptional Biosensor for the Portable, On-Demand Detection of Cyanuric Acid.
Rapid molecular biosensing is an emerging application area for synthetic biology. Here, we engineer a portable biosensor for cyanuric acid (CYA), an analyte of interest for human and environmental health, using a LysR-type transcription regulator (LTTR) from Pseudomonas within the context of Escherichia coli gene expression machinery. To overcome cross-host portability challenges of LTTRs, we rationally engineered hybrid Pseudomonas-E. coli promoters by integrating DNA elements required for transcriptional activity and ligand-dependent regulation from both hosts, which enabled E. coli to function as a whole-cell biosensor for CYA. To alleviate challenges of whole-cell biosensing, we adapted these promoter designs to function within a freeze-dried E. coli cell-free system to sense CYA. This portable, on-demand system robustly detects CYA within an hour from laboratory and real-world samples and works with both fluorescent and colorimetric reporters. This work elucidates general principles to facilitate the engineering of a wider array of LTTR-based environmental sensors.


Health timeline: an insight-based study of a timeline visualization of clinical data.
The increasing complexity and volume of clinical data poses a challenge in the decision-making process. Data visualizations can assist in this process by speeding up the time required to analyze and understand clinical data. Even though empirical experiments show that visualizations facilitate clinical data understanding, a consistent method to assess their effectiveness is still missing. The insight-based methodology determines the quality of insights a user acquires from the visualization. Insights receive a value from one to five points based on a domain-specific criteria. Five professional psychiatrists took part in the study using real de-identified clinical data spanning 4 years of medical history. A total of 50 assessments were transcribed and analyzed. Comparing a total of 558 insights using Health Timeline and 576 without, the mean value using the Timeline (1.7) was higher than without (1.26; p<0.01), similarly the cumulative value with the Timeline (11.87) was higher than without (10.96: p<0.01). The average time required to formulate the first insight with the Timeline was higher (13.16 s) than without (7 s; p<0.01). Seven insights achieved the highest possible value using Health Timeline while none were obtained without it. The Health Timeline effectively improved understanding of clinical data and helped participants recognize complex patterns from the data. By applying the insight-based methodology, the effectiveness of the Health Timeline was quantified, documented and demonstrated. As an outcome of this exercise, we propose the use of such methodologies to measure the effectiveness of visualizations that assist the clinical decision-making process.


Blueberry proanthocyanidins and anthocyanins improve metabolic health through a gut microbiota-dependent mechanism in diet-induced obese mice.
Blueberry consumption can prevent obesity-linked metabolic diseases, and it has been proposed that the polyphenol content of blueberries may contribute to these effects. Polyphenols have been shown to favorably impact metabolic health, but the role of specific polyphenol classes and whether the gut microbiota is linked to these effects remain unclear. We aimed to evaluate the impact of whole blueberry powder and blueberry polyphenols on the development of obesity and insulin resistance and to determine the potential role of gut microbes in these effects by using fecal microbiota transplantation (FMT). Sixty-eight C57BL/6 male mice were assigned to one of the following diets for 12 wk: balanced diet (Chow); high-fat, high-sucrose diet (HFHS); or HFHS supplemented with whole blueberry powder (BB), anthocyanidin (ANT)-rich extract, or proanthocyanidin (PAC)-rich extract. After 8 wk, mice were housed in metabolic cages, and an oral glucose tolerance test (OGTT) was performed. Sixty germ-free mice fed HFHS diet received FMT from one of the above groups biweekly for 8 wk, followed by an OGTT. PAC-treated mice were leaner than HFHS controls although they had the same energy intake and were more physically active. This observation was reproduced in germ-free mice receiving FMT from PAC-treated mice. PAC- and ANT-treated mice showed improved insulin responses during OGTT, and this finding was also reproduced in germ-free mice following FMT. These results show that blueberry PAC and ANT polyphenols can reduce diet-induced body weight and improve insulin sensitivity and that at least part of these beneficial effects are explained by modulation of the gut microbiota.


What 'outliers' tell us about missed opportunities for tuberculosis control: a cross-sectional study of patients in Mumbai, India.
India's Revised National Tuberculosis Control Programme (RNTCP) is deemed highly successful in terms of detection and cure rates. However, some patients experience delays in accessing diagnosis and treatment. Patients falling between the 96th and 100th percentiles for these access indicators are often ignored as atypical 'outliers' when assessing programme performance. They may, however, provide clues to understanding why some patients never reach the programme. This paper examines the underlying vulnerabilities of patients with extreme values for delays in accessing the RNTCP in Mumbai city, India. We conducted a cross-sectional study with 266 new sputum positive patients registered with the RNTCP in Mumbai. Patients were classified as 'outliers' if patient, provider and system delays were beyond the 95th percentile for the respective variable. Case profiles of 'outliers' for patient, provider and system delays were examined and compared with the rest of the sample to identify key factors responsible for delays. Forty-two patients were 'outliers' on one or more of the delay variables. All 'outliers' had a significantly lower per capita income than the remaining sample. The lack of economic resources was compounded by social, structural and environmental vulnerabilities. Longer patient delays were related to patients' perception of symptoms as non-serious. Provider delays were incurred as a result of private providers' failure to respond to tuberculosis in a timely manner. Diagnostic and treatment delays were minimal, however, analysis of the 'outliers' revealed the importance of social support in enabling access to the programme. A proxy for those who fail to reach the programme, these case profiles highlight unique vulnerabilities that need innovative approaches by the RNTCP. The focus on 'outliers' provides a less resource- and time-intensive alternative to community-based studies for understanding the barriers to reaching public health programmes.


A computational framework for distinguishing direct versus indirect interactions in human functional protein-protein interaction networks.
Recognition of indirect interactions is instrumental to in silico reconstruction of signaling pathways and sheds light on the exploration of unknown physical paths between two indirectly interacting genes. However, very limited computational methods have explicitly exploited the indirect interactions with experimental evidence thus far. In this work, we attempt to distinguish direct versus indirect interactions in human functional protein-protein interaction (PPI) networks via a predictive l2-regularized logistic regression model built on the experimental data. The l2-regularized logistic regression method is adopted to counteract the potential homolog noise and reduce the computational complexity on large training data. Computational results show that the proposed model demonstrates promising performance even though the training data are highly skewed. From the 304 799 PPIs that are curated in several databases, the proposed method detects 23 131 indirect interactions, most of which have been verified by the breadth-first graph search algorithm to find dozens of physical paths between the interacting partners. Pathway enrichment analysis shows that most of the physical paths can be mapped onto more than one human signaling pathway, indicating that there do exist a series of biochemical signals between the two indirectly interacting genes. The interactome-scale computational results promise to provide useful cues to the following applications: (1) exploration of unknown physical PPIs or physical paths between two indirectly interacting genes; (2) amending or extending the existing signaling pathways; (3) recognition of the physical PPIs for druggable target discovery.


A general diastereoselective synthesis of highly functionalized ferrocenyl ambiphiles enabled on a large scale by electrochemical purification.
A general synthesis of highly functionalized ferrocenes, which include (P,B)- and (N,B)-ambiphiles, has been developed at a multigram scale. Diastereoselective stepwise modification of di-tert-butylated ferrocenes included the unprecedented separation of electroactive species. Bulky alkyl groups on ferrocenes ensure planar chirality of ambiphiles and enforce closer proximity of antagonist Lewis functions.


Endothelin-1 induces contraction of female rat internal pudendal and clitoral arteries through ET(A) receptor and rho-kinase activation.
Endothelin-1 (ET-1), a potent vasoconstrictor peptide, acts mainly through the Gprotein-coupled ET(A) receptor (ET(A)R). Increased vascular ET-1 production and constrictor sensitivity have been observed in various cardiovascular diseases, including hypertension, as well as erectile dysfunction. The internal pudendal artery (IPA) supplies blood to the vagina and clitoris. Inadequate blood flow through the IPA may lead to insufficient vaginal engorgement and clitoral tumescence. Characterize the effects of ET-1 on the IPA and clitoral artery (CA). IPA and CA from female Sprague Dawley rats (225-250 g) were mounted in myograph chambers. Arterial segments were submitted to increasing concentrations of ET-1 (10-10-10-6 M). Segments were incubated with the ET(A)R antagonist, atrasentan (10-8 M) or the Rho-kinase inhibitor, Y-27632 (10-6 M) 30 minutes prior to agonist exposure. All E(max) values are expressed as % KCl-induced maximal contraction. ET(A)R, RhoA, and Rho-kinase expression from IPA was evaluated by Western blot. mRNA of preproET-1, ET(A)R, ET(B)R, RhoA, and Rho-kinase were measured by real time PCR. ET-1 constrictor sensitivity in IPA and CA, protein expression and messenger RNA levels of ET-1-mediated constriction components. ET-1 concentration-dependently contracted IPA (% Contraction and pD2, respectively: 156 ± 18, 8.2 ± 0.1) and CA (163 ± 12, 8.8 ± 0.08), while ET(A)R antagonism reduced ET-1-mediated contraction (IPA: 104 ± 23, 6.4 ± 0.2; CA: 112 ± 17, 6.6 ± 0.08). Pretreatment with Y-27632 significantly shifted ET-1 pD2 in IPA (108 ± 24, 7.9 ± 0.1) and CA (147 ± 58 and 8.0 ± 0.25). Protein expression of ET(A)R, ET(B)R, RhoA, and Rho-kinase were detected in IPA. IPA and CA contained preproET-1, ET(A)R, ET(B)R, RhoA, and Rho-kinase message. We observed that the IPA and CA are sensitive to ET-1, signaling through the ET(A)R and Rho-kinase pathway. These data indicate that ET-1 may play a role in vaginal and clitoral blood flow and may be important in pathologies where ET-1 levels are elevated.


Identifying genetic variants that affect viability in large cohorts.
A number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists in testing whether the frequency of an allele varies across ages, accounting for variation in ancestry. We applied it to the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort and to the parents of participants in the UK Biobank. Across the genome, we found only a few common variants with large effects on age-specific mortality: tagging the APOE ε4 allele and near CHRNA3. These results suggest that when large, even late-onset effects are kept at low frequency by purifying selection. Testing viability effects of sets of genetic variants that jointly influence 1 of 42 traits, we detected a number of strong signals. In participants of the UK Biobank of British ancestry, we found that variants that delay puberty timing are associated with a longer parental life span (P~6.2 × 10-6 for fathers and P~2.0 × 10-3 for mothers), consistent with epidemiological studies. Similarly, variants associated with later age at first birth are associated with a longer maternal life span (P~1.4 × 10-3). Signals are also observed for variants influencing cholesterol levels, risk of coronary artery disease (CAD), body mass index, as well as risk of asthma. These signals exhibit consistent effects in the GERA cohort and among participants of the UK Biobank of non-British ancestry. We also found marked differences between males and females, most notably at the CHRNA3 locus, and variants associated with risk of CAD and cholesterol levels. Beyond our findings, the analysis serves as a proof of principle for how upcoming biomedical data sets can be used to learn about selection effects in contemporary humans.


T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation.
TGF-beta1 is a regulatory cytokine with a pleiotropic role in immune responses. TGF-beta1 is widely expressed in leukocytes and stromal cells. However, the functions of TGF-beta1 expressed by specific lineages of cells remain unknown in vivo. Here, we show that mice with a T cell-specific deletion of the Tgfb1 gene developed lethal immunopathology in multiple organs, and this development was associated with enhanced T cell proliferation, activation, and CD4+ T cell differentiation into T helper 1 (Th1) and Th2 cells. TGF-beta1 produced by Foxp3-expressing regulatory T cells was required to inhibit Th1-cell differentiation and inflammatory-bowel disease in a transfer model. In addition, T cell-produced TGF-beta1 promoted Th17-cell differentiation and was indispensable for the induction of experimental autoimmune encephalomyelitis. These findings reveal essential roles for T cell-produced TGF-beta1 in controlling differentiation of T helper cells and controlling inflammatory diseases.


Comparison of two stretching methods and optimization of stretching protocol for the piriformis muscle.
Piriformis syndrome is an uncommon diagnosis for a non-discogenic form of sciatica whose treatment has traditionally focused on stretching the piriformis muscle (PiM). Conventional stretches include hip flexion, adduction, and external rotation. Using three-dimensional modeling, we quantified the amount of (PiM) elongation resulting from two conventional stretches and we investigated by use of a computational model alternate stretching protocols that would optimize PiM stretching. Seven subjects underwent three CT scans: one supine, one with hip flexion, adduction, then external rotation (ADD stretch), and one with hip flexion, external rotation, then adduction (ExR stretch). Three-dimensional bone models were constructed from the CT scans. PiM elongation during these stretches, femoral neck inclination, femoral head anteversion, and trochanteric anteversion were measured. A computer program was developed to map PiM length over a range of hip joint positions and was validated against the measured scans. ExR and ADD stretches elongated the PiM similarly by approximately 12%. Femoral head and greater trochanter anteversion influenced PiM elongation. Placing the hip joints in 115° of hip flexion, 40° of external rotation and 25° of adduction or 120° of hip flexion, 50° of external rotation and 30° of adduction increased PiM elongation by 30-40% compared to conventional stretches (15.1 and 15.3% increases in PiM muscle length, respectively). ExR and ADD stretches elongate the PiM similarly and therefore may have similar clinical effectiveness. The optimized stretches led to larger increases in PiM length and may be more easily performed by some patients due to increased hip flexion.