Influence of saline media on the fluorescence emission of Bacillus spores.
Single-particle levitation in conjunction with 264.3-nm laser excitation is used to measure the fluorescence emission of individual particles of Bacillus globigii spores. With precise humidity control, the fluorescence emission of wetted and desiccated Bacillus spore particles is measured from 300 to 450 nm. Comparison of spectra for Bacillus spores suspended in a standard buffer aqueous solution and for a desiccated 10-mum-diameter aggregate Bacillus spore particle shows that the spectra is virtually indistinguishable. However, at 85% relative humidity, corresponding to a 4.5M sodium chloride solution, the spore spectra redshifts by approximately 25 nm. It is postulated that the spectra redshifting is a result of specific interactions between the tyrosine fluorophore of the Bacillus spore and the phosphate moieties in the buffer solution.


Recycling Nutrients and Reducing Carbon Emissions in the Baltic Sea Region-Sustainable or Economically Infeasible?
Ecotechnologies have the potential to reduce the use of finite resources while providing a variety of co-benefits to society, though they often lack in market competitiveness. In this study, we investigate the sustainability of ecotechnologies for recovering carbon and nutrients, and demonstrate how a so-called "bottom-up" approach can serve as a decision-making instrument. Based on three case study catchments with a focus on domestic wastewater in Sweden and Poland, and on manure, grass and blackwater substrates in Finland, we apply a cost-benefit analysis (CBA) on system alternatives derived from a participatory process. After drawing on an initial systematic mapping of relevant ecotechnologies, the scope of the CBA is determined by stakeholder suggestions, namely in terms of the considered assessment criteria, the physical impacts and the utilised data. Thus, this CBA is rooted in a localised consideration of ecotechnologies rather than a centralised governmental approach to systems boundaries. The key advantage of applying such a bottom-up approach is that it has gone through a robust participatory selection process by local stakeholders, which provides more legitimacy to the decisions reached compared with traditional feasibility studies. Despite considering the revenues of the recovered products as well as the provision of the non-market goods CO2 mitigation and reduced eutrophication, findings from this study indicate that the benefits of the considered ecotechnologies are often outweighed by their costs. Only anaerobic digestion of agricultural wastes appears to be economically feasible under the current conditions, highlighting that further efforts and incentives may be required to mainstream ecotechnologies.


Developmentally Regulated Production of meso-Zeaxanthin in Chicken Retinal Pigment Epithelium/Choroid and Retina.
meso-Zeaxanthin is a carotenoid that is rarely encountered in nature outside of the vertebrate eye. It is not a constituent of a normal human diet, yet this carotenoid comprises one-third of the primate macular pigment. In the current study, we undertook a systematic approach to biochemically characterize the production of meso-zeaxanthin in the vertebrate eye. Fertilized White Leghorn chicken eggs were analyzed for the presence of carotenoids during development. Yolk, liver, brain, serum, retina, and RPE/choroid were isolated, and carotenoids were extracted. The samples were analyzed on C-30 or chiral HPLC columns to determine the carotenoid composition. Lutein and zeaxanthin were found in all studied nonocular tissues, but no meso-zeaxanthin was ever detected. Among the ocular tissues, the presence of meso-zeaxanthin was consistently observed starting at embryonic day 17 (E17) in the RPE/choroid, several days before its consistent detection in the retina. If RPE/choroid of an embryo was devoid of meso-zeaxanthin, the corresponding retina was always negative as well. This is the first report of developmentally regulated synthesis of meso-zeaxanthin in a vertebrate system. Our observations suggest that the RPE/choroid is the primary site of meso-zeaxanthin synthesis. Identification of meso-zeaxanthin isomerase enzyme in the developing chicken embryo will facilitate our ability to determine the biochemical mechanisms responsible for production of this unique carotenoid in other higher vertebrates, such as humans.


Transsarcolemmal calcium movements in arterially perfused rabbit right ventricle measured with extracellular calcium-sensitive dyes.
Activation-dependent changes of mean extracellular calcium concentrations were monitored spectrophotometrically in arterially perfused right ventricle of rabbit via extracellular application of the calcium-sensitive absorption dyes, antipyrylazo III and tetramethylmurexide. After rest periods of 3 minutes or longer, 10% of total dye-accessible calcium (300-500 microM) is depleted cumulatively from the extracellular space by four to eight beats at 2 Hz stimulation. During continued stimulation, or during quiescence following a depletion response, mean extracellular calcium concentrations return toward the prestimulatory level in the course of 2-4 minutes. A single stimulation placed 2-30 seconds subsequent to rapid pacing results in a potentiated beat with an accompanying net increment of mean extracellular calcium. Total dye-accessible calcium can increase by at least 4% at such a beat, and depletion responses can be repeated immediately thereafter. During a sequence of such responses, extracellular calcium lost cumulatively during three to five rapid beats is replenished, for the most part, by a single post-stimulatory beat. These results demonstrate that most of the "activator pool" of cellular calcium can turn over to the extracellular space during a single contraction cycle in rabbit myocardium, and suggest that, in mammalian myocardium, diastolic calcium efflux may be quantitatively negligible in relation to efflux during excitation-contraction coupling.


Psyllium supplementation in adolescents improves fat distribution & lipid profile: a randomized, participant-blinded, placebo-controlled, crossover trial.
We aimed to assess the effects of psyllium supplementation on insulin sensitivity and other parameters of the metabolic syndrome in an at risk adolescent population. This study encompassed a participant-blinded, randomized, placebo-controlled, crossover trial. Subjects were 47 healthy adolescent males aged 15-16 years, recruited from secondary schools in lower socio-economic areas with high rates of obesity. Participants received 6 g/day of psyllium or placebo for 6 weeks, with a two-week washout before crossing over. Fasting lipid profiles, ambulatory blood pressure, auxological data, body composition, activity levels, and three-day food records were collected at baseline and after each 6-week intervention. Insulin sensitivity was measured by the Matsuda method using glucose and insulin values from an oral glucose tolerance test. 45 subjects completed the study, and compliance was very high: 87% of participants took >80% of prescribed capsules. At baseline, 44% of subjects were overweight or obese. 28% had decreased insulin sensitivity, but none had impaired glucose tolerance. Fibre supplementation led to a 4% reduction in android fat to gynoid fat ratio (p = 0.019), as well as a 0.12 mmol/l (6%) reduction in LDL cholesterol (p = 0.042). No associated adverse events were recorded. Dietary supplementation with 6 g/day of psyllium over 6 weeks improves fat distribution and lipid profile (parameters of the metabolic syndrome) in an at risk population of adolescent males. Australian New Zealand Clinical Trials Registry ACTRN12609000888268.


Design and fabrication of a fingerprint imager with compact LED illumination and compact imaging optics.
In this study, we presented a light-emitting diode-based (LED) miniaturized optical pattern imager for slim mobile phone application. To meet volume constraints, we designed a miniaturized compact illuminating and imaging optical component. The objective was to minimize optical loss using several nano- and micro-fabrication methods. After integration into a single optical body, the prototype imager-with dimensions of 6.8 × 2.2 × 2.5 mm and a weight of 0.4 g-demonstrated clear feasibility in measuring 2D micropatterns with widths of 50 and 10 μm.


Expression and function of the bile acid receptor GpBAR1 (TGR5) in the murine enteric nervous system.
Bile acids (BAs) regulate cells by activating nuclear and membrane-bound receptors. G protein coupled bile acid receptor 1 (GpBAR1) is a membrane-bound G-protein-coupled receptor that can mediate the rapid, transcription-independent actions of BAs. Although BAs have well-known actions on motility and secretion, nothing is known about the localization and function of GpBAR1 in the gastrointestinal tract. We generated an antibody to the C-terminus of human GpBAR1, and characterized the antibody by immunofluorescence and Western blotting of HEK293-GpBAR1-GFP cells. We localized GpBAR1 immunoreactivity (IR) and mRNA in the mouse intestine, and determined the mechanism by which BAs activate GpBAR1 to regulate intestinal motility. The GpBAR1 antibody specifically detected GpBAR1-GFP at the plasma membrane of HEK293 cells, and interacted with proteins corresponding in mass to the GpBAR1-GFP fusion protein. GpBAR1-IR and mRNA were detected in enteric ganglia of the mouse stomach and small and large intestine, and in the muscularis externa and mucosa of the small intestine. Within the myenteric plexus of the intestine, GpBAR1-IR was localized to approximately 50% of all neurons and to >80% of inhibitory motor neurons and descending interneurons expressing nitric oxide synthase. Deoxycholic acid, a GpBAR1 agonist, caused a rapid and sustained inhibition of spontaneous phasic activity of isolated segments of ileum and colon by a neurogenic, cholinergic and nitrergic mechanism, and delayed gastrointestinal transit. G protein coupled bile acid receptor 1 is unexpectedly expressed in enteric neurons. Bile acids activate GpBAR1 on inhibitory motor neurons to release nitric oxide and suppress motility, revealing a novel mechanism for the actions of BAs on intestinal motility.


XcisClique: analysis of regulatory bicliques.
Modeling of cis-elements or regulatory motifs in promoter (upstream) regions of genes is a challenging computational problem. In this work, set of regulatory motifs simultaneously present in the promoters of a set of genes is modeled as a biclique in a suitably defined bipartite graph. A biologically meaningful co-occurrence of multiple cis-elements in a gene promoter is assessed by the combined analysis of genomic and gene expression data. Greater statistical significance is associated with a set of genes that shares a common set of regulatory motifs, while simultaneously exhibiting highly correlated gene expression under given experimental conditions. XcisClique, the system developed in this work, is a comprehensive infrastructure that associates annotated genome and gene expression data, models known cis-elements as regular expressions, identifies maximal bicliques in a bipartite gene-motif graph; and ranks bicliques based on their computed statistical significance. Significance is a function of the probability of occurrence of those motifs in a biclique (a hypergeometric distribution), and on the new sum of absolute values statistic (SAV) that uses Spearman correlations of gene expression vectors. SAV is a statistic well-suited for this purpose as described in the discussion. XcisClique identifies new motif and gene combinations that might indicate as yet unidentified involvement of sets of genes in biological functions and processes. It currently supports Arabidopsis thaliana and can be adapted to other organisms, assuming the existence of annotated genomic sequences, suitable gene expression data, and identified regulatory motifs. A subset of Xcis Clique functionalities, including the motif visualization component MotifSee, source code, and supplementary material are available at https://bioinformatics.cs.vt.edu/xcisclique/.


Vitamin E inhibits experimental carcinogenesis and tumour angiogenesis.
In an experiment in which vitamin E inhibited carcinogenesis, it was found that tumour angiogenesis and tumour growth-factor alpha (TGF alpha) expression were also inhibited. Forty male golden hamsters were divided into four equal groups. Group 1 animals had the left buccal pouches painted three times weekly with 7,12-dimethylbenz(a)anthracene (DMBA) for 14 weeks. Group 2 animals had the same procedure of DMBA applications but also received alpha tocopherol. Groups 3 and 4 were vitamin E and untreated controls. Angiogenesis was studied with factor 8-related antigen (F8-RA) which identifies endothelial cells. TGF alpha was studied with the appropriate antibody. Staining was effected by the standard avidin-biotin horseradish peroxidase system. Mean tumour volume was significantly lower in the DMBA-vitamin E group compared to the tumour control group. Angiogenesis was significantly inhibited in the DMBA-vitamin E group and TGF alpha expression was also inhibited. It is suggested that inhibition of tumour angiogenesis by vitamin E may be an additional mechanism for the anticancer action of vitamin E.


Complications following nasotracheal intubation using cuffed polyvinyl chloride tube: a prospective cross sectional study.
To examine the complications following nasotracheal intubation by documenting the nasal traumas observed with the use of untreated cuffed polyvinyl chloride tube in unprepared nostrils. Patients who had maxillofacial surgeries under general anesthesia, muscle relaxation and nasotracheal intubation were included in the study. Nasotracheal intubation was carried out after induction of anesthesia was effected with intravenous propofol and suxamethonium by an Anesthetist using well lubricated cuffed polyvinyl chloride tube. Sizes 6.0, 6.5 and 7.0mm were inserted in females while sizes 7.0 and 7.5mm were inserted in males. Occasionally, the natural curve of the tube guides it through the cords without the aid of Magill forceps. Anterior rhinoscopy was performed by otolaryngologist 24 hours after surgery. Results were subjected to statistical analysis. Sixty four patients were included in the study. They were between the ages of 21 and 63 years (mean 33.2 ± 14.1 years); they were 39 males and 25 females. The most frequently used nasotracheal tube (NT) was size 7.0mm internal diameter. Epistaxis was noticed in 52 (81.2%) patients. There were no statistically significant differences in the incidence of epistaxis observed in males and females, and also between right and left nostrils. A total of 46.8% of nasal trauma were inferior turbinate trauma involving the inferior medial aspect. The use of untreated cuffed polyvinyl chloride tube for nasotracheal intubation in unprepared nostrils is associated with a high incidence of epistaxis and nasal trauma.


Seminiferous tubule molecular imaging for evaluation of male fertility: Seeing is believing.
The proper assessment of male fertility is essential for diagnosing and treating male infertility. Currently, spermiogram and Johnsen testicular biopsy score counts are used to assess male fertility. However, spermiogram is not a suitable option for non-obstructive azoospermia patients, and Johnsen testicular biopsy scores only represent localized and not the overall spermatogenesis. Whole-mount staining was a novel method for evaluating protein expression in the tissue. Thus, we explored its application in human seminiferous tubules. Testicular biopsies from 57 azoospermia patients were categorized as obstructive azoospermia (OA), maturation arrest (MA) and Sertoli-cells only syndrome (SCOS). We performed whole-mount staining of their seminiferous tubules and evaluated the spermatogonial stem cells (SSCs), differentiated spermatogonia (SG), spermatocytes (SPC) and spermatids (SD) with their respective markers (GFRA1, CD117, SYCP3, and PNA) to assess fertility. GFRA1, CD117, SYCP3, and PNA were not expressed in SCOS patients, whereas all of them were detected in OA patients. In MA patients with arrested spermatogenesis at the SPC stage, GFRA1, CD117, and SYCP3, but not PNA were expressed in the seminiferous tubules. In MA patients with arrested spermatogenesis at the spermatogonia stage, only GFRA1 was expressed in the seminiferous tubules. These results were consistent with the Johnsen testicular biopsy score counts except for one patient, where although only Sertoli cells were indicated by the score, SSCs were also detected in the whole-mounts. Collectively, whole-mount staining could be used to analyze the inherent spermatogenesis of seminiferous tubules through staining of germ cells at different stages. It offers a more accurate and promising faster method for assessing male fertility compared with traditional biopsy screening. And it could have potential value for the clinical purpose for male fertility management.


[The fate of the old Jejoong Won following the establishment of the new Jejoong Won (Severance Hospital)].
Dr. Allen, the first Protestant missionary in Korea, had an opportunity of saving the life of the queen's nephew shortly after his arrival in Korea in 1884. In gratitude the King established the Royal Korean Hospital (Jejoong Won), the first hospital in Korea, and appointed Dr. Allen in charge of the medical affairs of the hospital. After Dr. Allen's resignation from the mission, the work was successively carried on by Drs. JW Heron, RA Hardie, CC Vinton and OR Avison, the last of whom arrived in 1893. In 1894 the connection of the Hospital with the Korean Government was severed and the work taken over by the Northern Presbyterian Mission. Since then, it has been a distinctly mission institute. In 1900, while attending the Ecumenical Conference of Foreign Missions in Carnegie Hall, New York, Dr. Avison made the acquaintance of a philanthropist LH Severance, who made a gift of $10,000 for a new hospital. This building, the first modern hospital in Korea, was opened and dedicated in 1904. It was named the Severance Hospital. As the new hospital was built, the old hospital building was to be returned to the Korean Government according to the agreement made in 1894. On retaking the old hospital, the Korean Government paid $30,289.99 won for the renovation of the original building and new buildings established in the site during the period of Avison's entire charge of Jejoong Won. The old hospital building was used as an official residence for a diplomatic adviser Stevens, who was assassinated for his pro-Japan activities, and as a social club for Japanese officials.


Improved carbon dioxide absorption in double-charged ionic liquids.
Four divalent ionic liquids based on imidazolium cations with alkyl or ether functionalized side-chains were synthesised and characterized: 3,3'-(tetraethyleneglycol-1,11-diyl)bis(1-methyl-1H-imidazolium)bromide, [tetraEG(mim)2][Br]2, 3,3'-(tetraethyleneglycol-1,11-diyl)bis(1-methyl-1H-imidazolium)acetate, [tetraEG(mim)2][OAc]2, 1-butyl-3-methylimidazolium malonate, [C4mim]2[Mal], and 3-butyl-1-methylimidazolium glutarate, [C4mim]2[Glut]. Their densities vary between 1.1 and 1.5 g cm-3 and their viscosities between 0.2 and 4 Pa s at 353 K. We found that the molar volumes are not additive, especially in the case of the divalent ionic liquids based on the double-charged imidazolium cations, meaning that they cannot be predicted using common group contribution methods. The reason for this behaviour could be explained by the structure of the cations, which is dominated by intramolecular hydrogen bonding. The carboxylate-based divalent ionic liquids absorb reversibly large quantities of carbon dioxide following a chemical mechanism described before. An improved 1 : 1 stoichiometry is achieved both in a double-charged imidazolium acetate ionic liquid and in imidazolium carboxylate salts with double charged anions. This behaviour places these ionic liquids amongst the best performing for carbon dioxide absorption.


Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement.
Colorectal cancer is the second leading cause of cancer death in the United States. In 2016, an estimated 134,000 persons will be diagnosed with the disease, and about 49,000 will die from it. Colorectal cancer is most frequently diagnosed among adults aged 65 to 74 years; the median age at death from colorectal cancer is 68 years. To update the 2008 US Preventive Services Task Force (USPSTF) recommendation on screening for colorectal cancer. The USPSTF reviewed the evidence on the effectiveness of screening with colonoscopy, flexible sigmoidoscopy, computed tomography colonography, the guaiac-based fecal occult blood test, the fecal immunochemical test, the multitargeted stool DNA test, and the methylated SEPT9 DNA test in reducing the incidence of and mortality from colorectal cancer or all-cause mortality; the harms of these screening tests; and the test performance characteristics of these tests for detecting adenomatous polyps, advanced adenomas based on size, or both, as well as colorectal cancer. The USPSTF also commissioned a comparative modeling study to provide information on optimal starting and stopping ages and screening intervals across the different available screening methods. The USPSTF concludes with high certainty that screening for colorectal cancer in average-risk, asymptomatic adults aged 50 to 75 years is of substantial net benefit. Multiple screening strategies are available to choose from, with different levels of evidence to support their effectiveness, as well as unique advantages and limitations, although there are no empirical data to demonstrate that any of the reviewed strategies provide a greater net benefit. Screening for colorectal cancer is a substantially underused preventive health strategy in the United States. The USPSTF recommends screening for colorectal cancer starting at age 50 years and continuing until age 75 years (A recommendation). The decision to screen for colorectal cancer in adults aged 76 to 85 years should be an individual one, taking into account the patient's overall health and prior screening history (C recommendation).


Transcriptional and post-transcriptional regulation of cGMP-dependent protein kinase (PKG-I): pathophysiological significance.
The ability of the endothelium to produce nitric oxide, which induces generation of cyclic guanosine monophosphate (cGMP) that activates cGMP-dependent protein kinase (PKG-I), in vascular smooth muscle cells (VSMCs), is essential for the maintenance of vascular homeostasis. Yet, disturbance of this nitric oxide/cGMP/PKG-I pathway has been shown to play an important role in many cardiovascular diseases. In the last two decades, in vitro and in vivo models of vascular injury have shown that PKG-I is suppressed following nitric oxide, cGMP, cytokine, and growth factor stimulation. The molecular basis for these changes in PKG-I expression is still poorly understood, and they are likely to be mediated by a number of processes, including changes in gene transcription, mRNA stability, protein synthesis, or protein degradation. Emerging studies have begun to define mechanisms responsible for changes in PKG-I expression and have identified cis- and trans-acting regulatory elements, with a plausible role being attributed to post-translational control of PKG-I protein levels. This review will focus mainly on recent advances in understanding of the regulation of PKG-I expression in VSMCs, with an emphasis on the physiological and pathological significance of PKG-I down-regulation in VSMCs in certain circumstances.


The effect of coach and player injury knowledge, attitudes and beliefs on adherence to the FIFA 11+ programme in female youth soccer.
Injury knowledge and beliefs influence uptake of prevention programmes, but the relationship between knowledge, beliefs and adherence remains unclear. To describe injury knowledge and beliefs among youth female soccer coaches and players, and to identify the relationship between these factors, different delivery strategies of the FIFA 11+ programme and adherence. A subcohort analysis from a cluster-randomised controlled trial of 31 female soccer teams (coaches n=29, players (ages 13-18) n=258). Preseason and postseason questionnaires were used to assess knowledge and beliefs. Teams recorded FIFA 11+ adherence during the season. At baseline, 62.8% (95% CI 48.4% to 77.3%) of coaches and 75.8% (95% CI 71.5% to 80.1%) of players considered 'inadequate warm-up' a risk factor for injury. There was no effect of delivery method (OR=1.1; 95% CI 0.8 to 1.5) or adherence (OR=1.0; 95% CI 0.9 to 1.1) on this belief. At baseline, 13.8% (95% CI 1.3% to 26.4%) of coaches believed a warm-up could prevent muscle injuries, but none believed it could prevent knee and ankle injuries. For players, 9.7% (95% CI 6.1% to 13.3%), 4.7% (95% CI 2.1% to 7.3%) and 4.7% (95% CI 2.1% to 7.3%) believed a warm-up would prevent muscle, knee and ankle injuries, respectively. Years of playing experience were negatively associated with high adherence for coaches (OR=0.93; 0.88 to 0.99) and players (OR=0.92; 0.85 to 0.98). There were gaps in injury knowledge and beliefs, which differed for coaches and players. Beliefs did not significantly affect adherence to the FIFA 11+, suggesting additional motivational factors should be considered.


Resonance energy transfer measurements between substrate binding sites within the large (Klenow) fragment of Escherichia coli DNA polymerase I.
Resonance energy transfer was used to determine separation distances between fluorescent derivatives of substrates for Klenow fragment and a unique sulfhydryl, cysteine 907, on the enzyme. Fluorescent derivatives of duplex DNA, deoxynucleotide triphosphates (dNTP), and deoxynucleotide monophosphates (dNMP), modified with aminonaphthalenesulfonates (ANS), served as energy-transfer donors to the fluorophore used to modify cysteine 907, 4-[N-[(iodoacetoxy)ethyl]-N-methylamino]-7-nitrobenz-2-oxa-1,3-diazole (IANBD). The labeling of cysteine 907 with NBD caused no decrease in the enzyme's polymerase activity, suggesting that the probe did not significantly alter the conformation of the enzyme. The efficiency of singlet-singlet resonance energy transfer was determined from the quantum yield of the donor in the presence and absence of acceptor. By Förster's theory, the measured distances between cysteine 907 and binding sites for duplex DNA, dNTP, and dNMP were 25-39, 19-28, and 17-26 A, respectively. As the fluorophores, attached to the substrates via a tether arm, are separated from the substrates by approximately 12 A, the distances measured between binding sites are subject to this uncertainty. To measure the separation between binding sites for duplex DNA and dNMP, and to reduce the uncertainty introduced by the tether arm, two experiments were carried out. In the first, duplex DNA was labeled with the acceptor fluorophore NBD and used with the donor ANS-modified dNMP to yield a measured distance separating these two sites of 19-28 A.(ABSTRACT TRUNCATED AT 250 WORDS)


The Node and beyond-using social media in cell and developmental biology.
Traditionally, strong scientific communities have been at least partly built around physical proximity - either by members of the same department or institute, or through regular meetings and conferences. The online environment and the rise of social media platforms now make it easier to build virtual communities of geographically dispersed people with a common interest. In this article, we explore how such networks can be nurtured, focussing on the Node - a community blog for and by developmental biologists. We also discuss the value of social media outlets like Twitter in building and maintaining scientific communities online.


Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia.
Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms. This can potentially generate correlated copy-number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukaemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21). We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL. Here we show that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have approximately 2,700-fold increased risk of developing iAMP21 ALL compared to the general population. In such cases, amplification is initiated by a chromothripsis event involving both sister chromatids of the Robertsonian chromosome, a novel mechanism for cancer predisposition. In sporadic iAMP21, breakage-fusion-bridge cycles are typically the initiating event, often followed by chromothripsis. In both sporadic and rob(15;21)c-associated iAMP21, the final stages frequently involve duplications of the entire abnormal chromosome. The end-product is a derivative of chromosome 21 or the rob(15;21)c chromosome with gene dosage optimized for leukaemic potential, showing constrained copy-number levels over multiple linked genes. Thus, dicentric chromosomes may be an important precipitant of chromothripsis, as we show rob(15;21)c to be constitutionally dicentric and breakage-fusion-bridge cycles generate dicentric chromosomes somatically. Furthermore, our data illustrate that several cancer-specific mutational processes, applied sequentially, can coordinate to fashion copy-number profiles over large genomic scales, incrementally refining the fitness benefits of aggregated gene dosage changes.


Activity modulation and allosteric control of a scaffolded DNAzyme using a dynamic DNA nanostructure.
Recognition of the fundamental importance of allosteric regulation in biology dates back to not long after its discovery in the 1960s. Our ability to rationally engineer this potentially useful property into normally non-allosteric catalysts, however, remains limited. In response we report a DNA nanotechnology-enabled approach for introducing allostery into catalytic nucleic acids. Specifically, we have grafted one or two copies of a peroxidase-like DNAzyme, hemin-bound G-quadruplex (hemin-G), onto a DNA tetrahedral nanostructure in such a manner as to cause them to interact, modulating their catalytic activity. We achieve allosteric regulation of these catalysts by incorporating dynamically responsive oligonucleotides that respond to specific "effector" molecules (complementary oligonucleotides or small molecules), altering the spacing between the catalytic sites and thus regulating their activity. This designable approach thus enables subtle allosteric modulation in DNAzymes that is potentially of use for nanomedicine and nanomachines.


Self-mixing interference measurement system of a fiber ring laser with ultra-narrow linewidth.
A novel device for self-mixing interference measurement based on the fiber ring laser with ultra-narrow linewidth was investigated for the first time. In order to achieve requirement of our measurement system, a saturable-absorber which consists of a segment un-pumped erbium-doped fiber and a fiber Bragg grating is employed to provide a fine mode selection and guarantee the ultra-narrow linewidth operation. Results demonstrate that the signal-to-noise ratio of the self-mixing interference signal could be enhanced from 18.01 dB to 38.35 dB by inserting a saturable-absorber in the laser cavity. It is in good agreement with the theoretical analysis and proved potential using in self-mixing interference measurement system for high sensitivity and remote measurement.


The calcium-sensing receptor directly regulates proximal tubular functions.
Capasso et al. show a role of the calcium-sensing receptor (CaSR) in enhancing proximal tubular fluid absorption and urinary acidification by stimulation of luminal Na(+)/H(+) exchanger (NHE) activity. NHE3 is required for sodium and fluid absorption, and its activity is coupled to passive reabsorption of a major fraction of calcium through the paracellular route. These data shed new light on the regulation of the kidney by the CaSR and whether it directly affects proximal tubular functions.


Preference for attractive faces is species-specific.
Studies on facial attractiveness in human adults, infants, and newborns have consistently reported a visual preference for faces rated as attractive compared with faces rated as unattractive. Biological accounts of facial attractiveness have typically presented such preferences as arising from adaptations for mate choice or as by-products of general sensory bias. In this cross-species study, we examined whether explicit ratings of attractiveness made by human judges would predict implicit visual preferences in other humans and also in rhesus macaques and, if they do, whether such preferences would extend beyond conspecific faces. Results showed that human ratings of attractiveness can predict implicit preferences in nonhuman primates (macaque monkeys; Macaca mulatta). However, we also found a species-specific effect of face attractiveness in which humans showed a visual preference for human faces (but not macaque faces) rated as attractive, and macaques displayed a visual preference for macaque faces (but not human faces) rated as attractive. Overall, the findings suggest that attentional bias toward attractive faces arises neither from an exclusive operation of mate choice adaptation mechanisms nor from the sole influence of a general sensory bias, but rather reflects their interaction. The influence of a general sensory bias may be modulated by the categorization of a face as conspecific or heterospecific, leading to species-specific preference for attractive faces. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Multiparameter precursor analysis of T-cell responses to antigen.
Triggering of the T-cell receptor by cognate antigen induces a variety of cellular events leading to cell proliferation and differentiation. While the plasticity and diversity of T-cell responses have been recognized for a long time, few quantitative studies have been conducted to measure what proportion of specific T cells will enter a given differentiation program after antigen stimulation. In the present study, we analyzed human T cells cultured with influenza-peptide-loaded dendritic cells. We compared three individual methods for assaying the frequency of antigen-specific T cells: ELISPOT, tetramer-binding, and proliferation. The three methods yielded similar but not identical results. In order to study these differences at the single cell level, we developed a multiparameter flow cytometric method, which allows simultaneous analysis of antigen-specific tetramer binding, T-cell proliferation, and cytokine production. Based on these data, we used flow precursor frequency analysis to calculate the proportion of eight different precursor subsets in the original, resting population. We conclude that approximately half of the cells that bound specific tetramers actually proliferated and synthesized IFNgamma in response to antigen. In addition, similar numbers of cells that did not bind tetramer proliferated (but did not synthesize IFNgamma). The method allows for an estimate of the precursor frequency of each functional subset within the initial population. It could be applied to additional markers of function and differentiation, combining all parameters into a description of the complex response potential of a T-cell pool.


Electron scattering cross sections from nitrobenzene in the energy range 0.4-1000 eV: the role of dipole interactions in measurements and calculations.
Absolute total electron scattering cross sections (TCS) for nitrobenzene molecules with impact energies from 0.4 to 1000 eV have been measured by means of two different electron-transmission experimental arrangements. For the lower energies (0.4-250 eV) a magnetically confined electron beam system has been used, while for energies above 100 eV a linear beam transmission technique with high angular resolution allowed accurate measurements up to 1000 eV impact energy. In both cases random uncertainties were maintained below 5-8%. Systematic errors arising from the angular and energy resolution limits of each apparatus are analysed in detail and quantified with the help of our theoretical calculations. Differential elastic and integral elastic, excitation and ionisation as well as momentum transfer cross sections have been calculated, for the whole energy range considered here, by using an independent atom model in combination with the screening corrected additivity rule method including interference effects (IAM-SCARI). Due to the significant permanent dipole moment of nitrobenzene, additional differential and integral rotational excitation cross sections have been calculated in the framework of the Born approximation. If we ignore the rotational excitations, our calculated total cross section agrees well with our experimental results for impact energies above 15 eV. Additionally, they overlap at 10 eV with the low energy Schwinger Multichannel method with Pseudo Potentials (SMCPP) calculation available in the literature (L. S. Maioli and M. H. F. Bettega, J. Chem. Phys., 2017, 147, 164305). We find a broad feature in the experimental TCS at around 1.0 eV, which has been related to the formation of the NO2- anion and assigned to the π*(b1) resonance, according to previous mass spectra available in the literature. Other local maxima in the TCSs are found at 4.0 ± 0.2 and 5.0 ± 0.2 eV and are assigned to core excited resonances leading to the formation of the NO2- and O2- anions, respectively. Finally, for energies below 10 eV, differences found between the present measurements, the SMCPP calculation and our previous data for non-polar benzene have revealed the importance of accurately calculating the rotational excitation contribution to the TCS before comparing theoretical and experimental data. This comparison suggests that our dipole-Born calculation for nitrobenzene overestimates the magnitude of the rotational excitation cross sections below 10 eV.


Persantine aspirin trial in cerebral ischemia--Part III: Risk factors for stroke. The American-Canadian Co-Operative Study Group.
This third paper from the Persantine Aspirin Trial examines the data to identify risk factors for stroke in persons with a history of carotid territory transient ischemic attacks (TIAs) Fifteen centers in the United States and Canada participated, and 890 subjects were admitted and randomly allocated to either aspirin plus placebo or aspirin plus dipyridamole (Persantine). Persons with the following characteristics were in greater jeopardy for stroke, retinal infarction, or death: older age, history of heart disease, history of peripheral vascular disease, and persisting neurologic deficit from a recent event. Elevated diastolic blood pressure, diabetes, use of estrogen, and smoking were not found to be risk factors. Elevated systolic blood pressure was a risk factor primarily in subjects with a history of heart disease. Estrogen use may actually have had a protective effect for women. This cannot be considered as a report of the natural history of TIA patients; it does identify risk factors in a specific cohort of subjects under treatment.


Identity profiles in lesbian, gay, and bisexual youth: the role of family influences.
Sexual identity development is a central task of adolescence and young adulthood and can be especially challenging for sexual minority youth. Recent research has moved from a stage model of identity development in lesbian, gay, and bisexual (LGB) youth to examining identity in a non-linear, multidimensional manner. In addition, although families have been identified as important to youth's identity development, limited research has examined the influence of parental responses to youth's disclosure of their LGB sexual orientation on LGB identity. The current study examined a multidimensional model of LGB identity and its links with parental support and rejection. One hundred and sixty-nine LGB adolescents and young adults (ages 14-24, 56 % male, 48 % gay, 31 % lesbian, 21 % bisexual) described themselves on dimensions of LGB identity and reported on parental rejection, sexuality-specific social support, and non-sexuality-specific social support. Using latent profile analysis (LPA), two profiles were identified, indicating that youth experience both affirmed and struggling identities. Results indicated that parental rejection and sexuality-specific social support from families were salient links to LGB identity profile classification, while non-sexuality specific social support was unrelated. Parental rejection and sexuality-specific social support may be important to target in interventions for families to foster affirmed LGB identity development in youth.


Glycemic control is related to the electrophysiologic severity of diabetic peripheral sensorimotor polyneuropathy.
The aim of the present study was to examine risk factors for the electrophysiologic severity of diabetic peripheral sensorimotor polyneuropathy (DSP). A total of 97 patients with type 1 diabetes (25 patients) or type 2 diabetes (72 patients) were included in this cross-sectional study. Nerve conduction studies (NCS) were performed on median motor and sensory nerves, peroneal motor nerve, and both sural nerves. The severity of DSP was expressed as the sum of nerve conduction velocities (SNCV) and the score of distal amplitudes (SAMP) of the above-mentioned nerves. General linear models were used to assess the relationship between overall severity of DSP as well as the severity of lower extremity, upper extremity, motor nerve, or sensory nerve involvement and various risk factors. GHb was significantly related to both SNCV and SAMP in univariate and multivariate regression analyses. This relationship was present in models where GHb was handled either as a continuous variable or as a categorical variable with highest significance level, with a GHb cutoff level of 9%. The difference in NCV for individual nerves in patients with good-to-moderate glycemic control (GHb < or =9%) and those with poor glycemic control (GHb > or =9%) ranged from 1.8 to 3.6 m/s. SAMP was also significantly lower in patients with poor control. SNCV was also significantly related in multivariate analysis to duration of diabetes and height, while SAMP was related to duration of diabetes, age, and male sex. The severity of DSP expressed by electrophysiologic criteria was significantly related to glycemic control in a study including patients with type 1 or type 2 diabetes. Based on the results of the present study, it might be predicted that better diabetic control would decrease the severity of DSP.


A Multiscale Agent-Based in silico Model of Liver Fibrosis Progression.
Chronic hepatic inflammation involves a complex interplay of inflammatory and mechanical influences, ultimately manifesting in a characteristic histopathology of liver fibrosis. We created an agent-based model (ABM) of liver tissue in order to computationally examine the consequence of liver inflammation. Our liver fibrosis ABM (LFABM) is comprised of literature-derived rules describing molecular and histopathological aspects of inflammation and fibrosis in a section of chemically injured liver. Hepatocytes are modeled as agents within hexagonal lobules. Injury triggers an inflammatory reaction, which leads to activation of local Kupffer cells and recruitment of monocytes from circulation. Portal fibroblasts and hepatic stellate cells are activated locally by the products of inflammation. The various agents in the simulation are regulated by above-threshold concentrations of pro- and anti-inflammatory cytokines and damage-associated molecular pattern molecules. The simulation progresses from chronic inflammation to collagen deposition, exhibiting periportal fibrosis followed by bridging fibrosis, and culminating in disruption of the regular lobular structure. The ABM exhibited key histopathological features observed in liver sections from rats treated with carbon tetrachloride (CCl4). An in silico "tension test" for the hepatic lobules predicted an overall increase in tissue stiffness, in line with clinical elastography literature and published studies in CCl4-treated rats. Therapy simulations suggested differential anti-fibrotic effects of neutralizing tumor necrosis factor alpha vs. enhancing M2 Kupffer cells. We conclude that a computational model of liver inflammation on a structural skeleton of physical forces can recapitulate key histopathological and macroscopic properties of CCl4-injured liver. This multiscale approach linking molecular and chemomechanical stimuli enables a model that could be used to gain translationally relevant insights into liver fibrosis.


Couple perceptions of fibromyalgia symptoms: the role of communication.
The objectives of the current study were to describe fibromyalgia patient-spouse incongruence regarding patient pain, fatigue, and physical function; and to examine the associations of individual and interpersonal factors with patient-spouse incongruence. Two hundred four fibromyalgia patients and their coresiding partners rated the patient's symptoms and function. Multilevel modeling revealed that spouses, on average, rated patient fatigue significantly lower than patients. Couple incongruence was not significantly different from zero, on average, for pain severity, interference, or physical function. However, there was significant variability across couples in how they rated the severity of symptoms and function, and how much incongruence existed within couples. Controlling for individual factors, patient and spouse reports of communication problems were significantly associated with levels of couple incongruence regarding patient fatigue and physical function, albeit in opposing directions. Across couples, incongruence was high when patients rated communication problems as high; incongruence was low when spouses rated communication problems as high. An important within-couple interaction was found for pain interference, suggesting that couples who are similar on level of communication problems experience low incongruence; those with disparate ratings of communication problems experience high incongruence. Findings suggest the important roles of spouse response and the patient's perception of how well the couple is communicating. Couple-level interventions targeting communication or other interpersonal factors may help to decrease incongruence and lead to better patient outcomes.


Downregulation of protein disulfide isomerase in sepsis and its role in tumor necrosis factor-alpha release.
Protein disulfide isomerase (PDI) is an important factor for the protein modification step in the post-translational event. PDI plays an essential role in cell survival under various stress conditions. It has been reported that PDI can serve as a negative regulator of nuclear factor-kappa-B (NF-kappaB) and that it can inhibit lipopolysaccharide (LPS)-induced proinflammatory cytokine production in macrophages. Thus, PDI may be an intracellular anti-inflammatory molecule. Although we have previously shown that Kupffer cell-derived proinflammatory cytokines cause liver injury in sepsis, the effect of sepsis on PDI expression as well as the effect of PDI inhibition on cytokine production have not been investigated. We therefore hypothesized that sepsis downregulates PDI expression and that the inhibition of PDI promotes proinflammatory cytokine production. Adult male rats were subjected to sepsis by cecal ligation and puncture (CLP) or endotoxemia (continuous infusion of 1 microg/kg body weight LPS by an osmotic pump) for 20 hours. Hepatic tissues were collected and PDI gene expression was determined. In additional experiments, cells from a macrophage-like cell line, RAW 264.7, were treated with 100 ng/mL LPS for 4 hours and protein expressions were measured. RAW 264.7 cells were also treated with bacitracin, a specific PDI inhibitor, for 24 hours, and tumor necrosis factor-alpha (TNF-alpha) gene and protein expression as well as its release in the cell supernatant were determined. To further confirm the beneficial effect of PDI in sepsis, RAW 264.7 cells were transfected with PDI short interfering RNA (siRNA) and PDI gene expression and TNF-alpha release were measured by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. PDI gene expression was significantly decreased by 28% and 69% at 20 hours after CLP or LPS infusion, respectively. LPS also decreased PDI protein expression by 33% in RAW 264.7 cells. Incubation of RAW 264.7 cells with bacitracin significantly increased TNF-alpha gene expression and TNF-alpha release as well as its cellular levels in a dose-dependent manner. Transfection of RAW 264.7 cells with PDI siRNA produced an average 36.8% inhibition of the PDI gene expression. This downregulation was correlated with a 3.19-fold increase in TNF-alpha release into the cell supernatant. Taken together, these results suggest that downregulation of PDI by sepsis significantly increases proinflammatory cytokine production. Thus, prevention of PDI downregulation in sepsis may be a novel approach to attenuate hyperinflammation and to reduce tissue injury under such conditions.


Activity of protein kinase CK2 uncouples Bid cleavage from caspase-8 activation.
In the present study, we quantitatively analysed the interface between apoptosis initiation and execution by determining caspase-8 activation, Bid cleavage and mitochondrial engagement (onset of mitochondrial depolarisation) in individual HeLa cervical cancer cells following exposure to tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL). Employing resonance-energy-transfer probes containing either the caspase-8 recognition site IETD or full-length Bid, we observed a significant delay between the times of caspase-8 activation and Bid cleavage, suggesting the existence of control steps separating these two processes. Subsequent analyses suggested that the divergence of caspase-8 activation and Bid cleavage are critically controlled by kinase signalling: inhibiting protein kinase CK2 by using 5,6-dichloro-l-(beta-D-ribofuranosyl-1)-benzimidazole (DRB) or by overexpression of a dominant-negative CK2alpha catalytic subunit largely eliminated the lag time between caspase-8 activation and Bid cleavage. We conclude that caspase-8 activation and Bid cleavage are temporally uncoupled events, providing transient tolerance to caspase-8 activities.


RNAi in budding yeast.
RNA interference (RNAi), a gene-silencing pathway triggered by double-stranded RNA, is conserved in diverse eukaryotic species but has been lost in the model budding yeast Saccharomyces cerevisiae. Here, we show that RNAi is present in other budding yeast species, including Saccharomyces castellii and Candida albicans. These species use noncanonical Dicer proteins to generate small interfering RNAs, which mostly correspond to transposable elements and Y' subtelomeric repeats. In S. castellii, RNAi mutants are viable but have excess Y' messenger RNA levels. In S. cerevisiae, introducing Dicer and Argonaute of S. castellii restores RNAi, and the reconstituted pathway silences endogenous retrotransposons. These results identify a previously unknown class of Dicer proteins, bring the tool of RNAi to the study of budding yeasts, and bring the tools of budding yeast to the study of RNAi.


Ghrelin-related peptides exert protective effects in the cerebral circulation of male mice through a nonclassical ghrelin receptor(s).
The ghrelin-related peptides, acylated ghrelin, des-acylated ghrelin, and obestatin, are novel gastrointestinal hormones. We firstly investigated whether the ghrelin gene, ghrelin O-acyltransferase, and the ghrelin receptor (GH secretagogue receptor 1a [GHSR1a]) are expressed in mouse cerebral arteries. Secondly, we assessed the cerebrovascular actions of ghrelin-related peptides by examining their effects on vasodilator nitric oxide (NO) and superoxide production. Using RT-PCR, we found the ghrelin gene and ghrelin O-acyltransferase to be expressed at negligible levels in cerebral arteries from male wild-type mice. mRNA expression of GHSR1a was also found to be low in cerebral arteries, and GHSR protein was undetectable in GHSR-enhanced green fluorescent protein mice. We next found that exogenous acylated ghrelin had no effect on the tone of perfused cerebral arteries or superoxide production. By contrast, exogenous des-acylated ghrelin or obestatin elicited powerful vasodilator responses (EC50 < 10 pmol/L) that were abolished by the NO synthase inhibitor N(ω)-nitro-L-arginine methyl ester. Furthermore, exogenous des-acylated ghrelin suppressed superoxide production in cerebral arteries. Consistent with our GHSR expression data, vasodilator effects of des-acylated ghrelin or obestatin were sustained in the presence of YIL-781 (GHSR1a antagonist) and in arteries from Ghsr-deficient mice. Using ghrelin-deficient (Ghrl(-/-)) mice, we also found that endogenous production of ghrelin-related peptides regulates NO bioactivity and superoxide levels in the cerebral circulation. Specifically, we show that NO bioactivity was markedly reduced in Ghrl(-/-) vs wild-type mice, and superoxide levels were elevated. These findings reveal protective actions of exogenous and endogenous ghrelin-related peptides in the cerebral circulation and show the existence of a novel ghrelin receptor(s) in the cerebral endothelium.


A study of benzocaine gel dosing for toothache.
This pilot study evaluated subject compliance with a proposed OTC label with improved dosing directions for self-application of a 20% benzocaine gel for toothache pain, and assessed the methodology for evaluating efficacy in a future pivotal study of benzocaine gel. It was hypothesized that > or = 75% of subjects would apply < or = 400 mg of product (80 mg benzocaine). Exploratory analyses of efficacy were also performed. Thirty patients with spontaneous pain of moderate or severe intensity from a single tooth due to caries, a lost restoration, or a fracture entered this randomized, parallel group, double-blind study. Before self-applying 20% benzocaine gel or placebo, patients read a label containing new dosing directions, including a picture of how much product to apply to their tooth and the surrounding gingival tissues. The amount applied was determined by weighing the tube before and after dosing. Following dosing, pain intensity and relief were recorded every five minutes through 30 minutes, then every ten minutes through 120 minutes. Responders were defined as those subjects who experienced at least a one-unit reduction in pain intensity from baseline at two consecutive time points within the first 20 minutes. Onset of meaningful relief was recorded using a stopwatch. The percentage of responders was compared using the Mantel-Haenszel test. ANOVA was employed to test for differences in Pain Relief Combined with Pain Intensity Difference (PRID), and the areas under the curve at 30, 60, 90, and 120 minutes for this measure (SPRID). Median onset and duration times were compared using the Cox proportional hazards model. Adverse events were recorded if and when they occurred. It was found that 86.7% of the subjects (26/30) applied < or = 375 mg of product (mean +/- SD = 327.7 +/- 276.8 mg). The benzocaine group had a significantly higher (p = 0.022) responder rate (86.7%) than the placebo group (46.7%). Significant differences in favor of the benzocaine group were also recorded for PRID at 10, 15, and 30 minutes (p < 0.05) and SPRID-30 (p = 0.037). Median onset and duration times were 8.3 minutes and > 115 minutes for the benzocaine group, >120 minutes and 5 minutes for the placebo group. There were no adverse events recorded in the study. The improved dosing directions resulted in a high percentage of subjects self-applying an appropriate amount of benzocaine gel or matching placebo. The label and study methodology appear suitable for a pivotal dose-response study in subjects with toothache pain. While the current study was not statistically powered to make firm efficacy conclusions, 20% benzocaine gel appeared more efficacious than placebo, providing a rapid onset of pain relief and a relatively long duration of action.


Demographic history has influenced nucleotide diversity in European Pinus sylvestris populations.
To infer the role of natural selection in shaping standing genetic diversity, it is necessary to assess the genomewide impact of demographic history on nucleotide diversity. In this study we analyzed sequence diversity of 16 nuclear loci in eight Pinus sylvestris populations. Populations were divided into four geographical groups on the basis of their current location and the geographical history of the region: northern Europe, central Europe, Spain, and Turkey. There were no among-group differences in the level of silent nucleotide diversity, which was approximately 0.005/bp in all groups. There was some evidence that linkage disequilibrium extended further in northern Europe than in central Europe: the estimates of the population recombination rate parameter, rho, were 0.0064 and 0.0294, respectively. The summary statistics of nucleotide diversity in central and northern European populations were compatible with an ancient bottleneck rather than the standard neutral model.


Integrating Allyl Electrophiles into Nickel-Catalyzed Conjunctive Cross-Coupling.
Allylation and conjunctive cross-coupling represent two useful, yet largely distinct, reactivity paradigms in catalysis. The union of these two processes would offer exciting possibilities in organic synthesis but remains largely unknown. Herein, we report the use of allyl electrophiles in nickel-catalyzed conjunctive cross-coupling with a non-conjugated alkene and dimethylzinc. The transformation is enabled by weakly coordinating, monodentate aza-heterocycle directing groups that are useful building blocks in synthesis, including saccharin, pyridones, pyrazoles, and triazoles. The reaction occurs under mild conditions and is compatible with a wide range of allyl electrophiles. High chemoselectivity through substrate directivity is demonstrated by the facile reactivity of the β-γ alkene of the starting material, whereas the ϵ-ζ alkene of the product is preserved. The generality of this approach is further illustrated through the development of an analogous method with alkyne substrates. Mechanistic studies reveal the importance of the dissociation of the weakly coordinating directing group to allow the allyl moiety to bind and facilitate C(sp3 )-C(sp3 ) reductive elimination.


Network Architecture and Mutational Sensitivity of the C. elegans Metabolome.
A fundamental issue in evolutionary systems biology is understanding the relationship between the topological architecture of a biological network, such as a metabolic network, and the evolution of the network. The rate at which an element in a metabolic network accumulates genetic variation via new mutations depends on both the size of the mutational target it presents and its robustness to mutational perturbation. Quantifying the relationship between topological properties of network elements and the mutability of those elements will facilitate understanding the variation in and evolution of networks at the level of populations and higher taxa. We report an investigation into the relationship between two topological properties of 29 metabolites in the C. elegans metabolic network and the sensitivity of those metabolites to the cumulative effects of spontaneous mutation. The correlations between measures of network centrality and mutability are not statistically significant, but several trends point toward a weak positive association between network centrality and mutational sensitivity. There is a small but significant negative association between the mutational correlation of a pair of metabolites (rM ) and the shortest path length between those metabolites. Positive association between the centrality of a metabolite and its mutational heritability is consistent with centrally-positioned metabolites presenting a larger mutational target than peripheral ones, and is inconsistent with centrality conferring mutational robustness, at least in toto. The weakness of the correlation between rM and the shortest path length between pairs of metabolites suggests that network locality is an important but not overwhelming factor governing mutational pleiotropy. These findings provide necessary background against which the effects of other evolutionary forces, most importantly natural selection, can be interpreted.


Repurposing of the antihistamine chlorcyclizine and related compounds for treatment of hepatitis C virus infection.
Hepatitis C virus (HCV) infection affects an estimated 185 million people worldwide, with chronic infection often leading to liver cirrhosis and hepatocellular carcinoma. Although HCV is curable, there is an unmet need for the development of effective and affordable treatment options. Through a cell-based high-throughput screen, we identified chlorcyclizine HCl (CCZ), an over-the-counter drug for allergy symptoms, as a potent inhibitor of HCV infection. CCZ inhibited HCV infection in human hepatoma cells and primary human hepatocytes. The mode of action of CCZ is mediated by inhibiting an early stage of HCV infection, probably targeting viral entry into host cells. The in vitro antiviral effect of CCZ was synergistic with other anti-HCV drugs, including ribavirin, interferon-α, telaprevir, boceprevir, sofosbuvir, daclatasvir, and cyclosporin A, without significant cytotoxicity, suggesting its potential in combination therapy of hepatitis C. In the mouse pharmacokinetic model, CCZ showed preferential liver distribution. In chimeric mice engrafted with primary human hepatocytes, CCZ significantly inhibited infection of HCV genotypes 1b and 2a, without evidence of emergence of drug resistance, during 4 and 6 weeks of treatment, respectively. With its established clinical safety profile as an allergy medication, affordability, and a simple chemical structure for optimization, CCZ represents a promising candidate for drug repurposing and further development as an effective and accessible agent for treatment of HCV infection.


Comparative genomic mapping of uncharacterized canine retinal ESTs to identify novel candidate genes for hereditary retinal disorders.
To identify the genomic location of previously uncharacterized canine retina-expressed expressed sequence tags (ESTs), and thus identify potential candidate genes for heritable retinal disorders. A set of over 500 retinal canine ESTs were mapped onto the canine genome using the RHDF(5000-2) radiation hybrid (RH) panel, and the resulting map positions were compared to their respective localization in the CanFam2 assembly of the canine genome sequence. Unique map positions could be assigned for 99% of the mapped clones, of which only 29% showed significant homology to known RefSeq sequences. A comparison between RH map and sequence assembly indicated some areas of discrepancy. Retinal expressed genes were not concentrated in particular areas of the canine genome, and also were located on the canine Y chromosome (CFAY). Several of the EST clones were located within areas of conserved synteny to human retinal disease loci. RH mapping of canine retinal ESTs provides insight into the location of potential candidate genes for hereditary retinal disorders, and, by comparison with the assembled canine genome sequence, highlights inconsistencies with the current assembly. Regions of conserved synteny between the canine and the human genomes allow this information to be extrapolated to identify potential positional candidate genes for mapped human retinal disorders. Furthermore, these ESTs can help identify novel or uncharacterized genes of significance for better understanding of retinal morphology, physiology, and pathology.


Racial and Ethnic Differences in Breastfeeding.
Breastfeeding rates differ among racial/ethnic groups in the United States. Our aim was to test whether racial/ethnic disparities in demographic characteristics, hospital use of infant formula, and family history of breastfeeding mediated racial/ethnic gaps in breastfeeding outcomes. We analyzed data from the Community and Child Health Network study (N = 1636). Breastfeeding initiation, postnatal intent to breastfeed, and breastfeeding duration were assessed postpartum. Hierarchical linear modeling was used to estimate relative odds of breastfeeding initiation, postnatal intent, and duration among racial/ethnic groups and to test the candidate mediators of maternal age, income, household composition, employment, marital status, postpartum depression, preterm birth, smoking, belief that "breast is best," family history of breastfeeding, in-hospital formula introduction, and WIC participation. Spanish-speaking Hispanic mothers were most likely to initiate (91%), intend (92%), and maintain (mean duration, 17.1 weeks) breastfeeding, followed by English-speaking Hispanic mothers (initiation 90%, intent 88%; mean duration, 10.4 weeks) and white mothers (initiation 78%, intent 77%; mean duration, 16.5 weeks); black mothers were least likely to initiate (61%), intend (57%), and maintain breastfeeding (mean duration, 6.4 weeks). Demographic variables fully mediated disparities between black and white mothers in intent and initiation, whereas demographic characteristics and in-hospital formula feeding fully mediated breastfeeding duration. Family breastfeeding history and demographic characteristics helped explain the higher breastfeeding rates of Hispanic mothers relative to white and black mothers. Hospitals and policy makers should limit in-hospital formula feeding and consider family history of breastfeeding and demographic characteristics to reduce racial/ethnic breastfeeding disparities.


Antagonism between EGFR and Wingless signalling in the larval cuticle of Drosophila.
Signalling by the epidermal growth factor receptor (EGFR) plays a critical role in the segmental patterning of the ventral larval cuticle in Drosophila: by expressing a dominant-negative EGFR molecule or Spitz, an activating ligand of EGFR, we show that EGFR signalling specifies the anterior denticles in each segment of the larval abdomen. We provide evidence that these denticles derive from a segmental zone of embryonic cells in which EGFR signalling activity is maximal. Within each segment, there is a competition between the denticle fate specified by EGFR signalling and the naked cuticle fate specified by Wingless signalling. The final pattern of the denticle belts is the product of this antagonism between the two signalling pathways. Finally, we show that the segmental zones of high EGFR signalling activity depend on bithorax gene function and that they account for the main difference in shape between abdominal and thoracic denticle belts.


The relation of red blood cell fatty acids with vascular stiffness, cardiac structure and left ventricular function: the Framingham Heart Study.
Polyunsaturated fatty acids have been associated with beneficial influences on cardiovascular health. However, the underlying mechanisms are not clear, and data on the relations of polyunsaturated fatty acids to subclinical disease measures such as vascular stiffness and cardiac function are sparse and inconclusive. In a large community-based cohort, we examined the relations of omega-3 and other fatty acids to a comprehensive panel of vascular function measures (assessing microvascular function and large artery stiffness), cardiac structure and left ventricular function. Red blood cell (RBC) membrane fatty acid composition, a measure of long-term fatty acid intake, was assessed in participants of the Framingham Offspring Study and Omni cohorts and related to tonometry-derived measures of vascular stiffness and to a panel of echocardiographic traits using partial correlations. Up to n=3055 individuals (56% women, mean age 66 years) were available for analyses. In age- and sex-adjusted models, higher RBC omega-3 content was moderately associated (p≤0.002) with several measures of vascular stiffness and function in a protective direction. However, after multivariable adjustment, only an association of higher RBC omega-3 content with lower carotid-femoral pulse wave velocity (a measure of aortic stiffness) remained significant (r = -0.06, p=0.002). In secondary analyses, higher linoleic acid, the major nutritional omega-6 fatty acid, was associated with smaller left atrial size, even after multivariable adjustment (r = -0.064, p<0.001). In conclusion, in our cross-sectional community-based study, we found several associations consistent with the notion of protective effects of omega-3 and linoleic acid. The clinical significance of these modest associations remains to be elucidated.


Visible Versus Near-Infrared Optical Performance of Diffractive Multifocal Intraocular Lenses.
The purpose of this study was to compare the optical performance of diffractive multifocal intraocular lenses (DMIOLs) with visible (VIS) illumination with that of near infrared (NIR) illumination, the latter being used to test pseudophakic eyes in clinical aberrometers and double-pass systems. Two DMIOLs of different design (Tecnis +2.75 D ZKB00 and AcrySof +2.5 D SV25T0) were tested in vitro in a model eye under both VIS (λ = 530 nm) and NIR (λ = 780 nm) illumination, and variations in the add power of the lenses were determined. Moreover, for the two wavelengths, the energy efficiency and modulation transfer function at the DMIOLs' far and near foci were measured with pupils of 3.0 and 4.5 mm. Two counterpart monofocal IOLs (Tecnis ZA9003 and AcrySof SN60WF) were included as references in the comparison. With VIS light, the two DMIOLs produced relatively well-contrasted images at their near and far foci. Under NIR illumination, the add power increased, whereas the energy efficiency of the near focus decreased and that of far focus increased. Hence, the DMIOLs tended to behave like monofocal lenses because they generated good quality well-contrasted images only at their far foci. In addition to changes in add power, the optical performances of the DMIOLs measured under either VIS or NIR illumination are considerably different. Whereas they show two distinct (near and far) foci under VIS light, their optical performances under NIR illumination are clearly biased in favor of their far focus. These results may help prevent a misleading use of NIR-based clinical instruments for the assessment of eyes implanted with DMIOLs.


Acceleration of discrete stochastic biochemical simulation using GPGPU.
For systems made up of a small number of molecules, such as a biochemical network in a single cell, a simulation requires a stochastic approach, instead of a deterministic approach. The stochastic simulation algorithm (SSA) simulates the stochastic behavior of a spatially homogeneous system. Since stochastic approaches produce different results each time they are used, multiple runs are required in order to obtain statistical results; this results in a large computational cost. We have implemented a parallel method for using SSA to simulate a stochastic model; the method uses a graphics processing unit (GPU), which enables multiple realizations at the same time, and thus reduces the computational time and cost. During the simulation, for the purpose of analysis, each time course is recorded at each time step. A straightforward implementation of this method on a GPU is about 16 times faster than a sequential simulation on a CPU with hybrid parallelization; each of the multiple simulations is run simultaneously, and the computational tasks within each simulation are parallelized. We also implemented an improvement to the memory access and reduced the memory footprint, in order to optimize the computations on the GPU. We also implemented an asynchronous data transfer scheme to accelerate the time course recording function. To analyze the acceleration of our implementation on various sizes of model, we performed SSA simulations on different model sizes and compared these computation times to those for sequential simulations with a CPU. When used with the improved time course recording function, our method was shown to accelerate the SSA simulation by a factor of up to 130.


Osteoclastic miR-214 targets TRAF3 to contribute to osteolytic bone metastasis of breast cancer.
The role of osteoclastic miRNAs in regulating osteolytic bone metastasis (OBM) of breast cancer is still underexplored. Here, we examined the expression profiles of osteoclastogenic miRNAs in human bone specimens and identified that miR-214-3p was significantly upregulated in breast cancer patients with OBM. Consistently, we found increased miR-214-3p within osteoclasts, which was associated with the elevated bone resorption, during the development of OBM in human breast cancer xenografted nude mice (BCX). Furthermore, genetic ablation of osteoclastic miR-214-3p in nude mice prevent the development of OBM. Conditioned medium from MDA-MB-231 cells dramatically stimulated miR-214-3p expression to promote osteoclast differentiation. Mechanistically, a series of in vitro study showed that miR-214-3p directly targeted Traf3 to promote osteoclast activity and bone-resorbing activity. In addition, osteoclast-specific miR-214-3p knock-in mice showed remarkably increased bone resorption when compared to the littermate controls, which was attenuated after osteoclast-targeted treatment with Traf3 3'UTR-containing plasmid. In BCX nude mice, osteoclast-targeted antagomir-214-3p delivery could recover the TRAF3 protein expression and attenuate the development of OBM, respectively. Collectively, inhibition of osteoclastic miR-214-3p may be a potential therapeutic strategy for breast cancer patients with OBM. Meanwhile, the intraosseous TRAF3 could be a promising biomarker for evaluation of the treatment response of antagomir-214-3p.


Precuring of self-etching bonding agents and its effect on bond strength of resin composite to dentin and enamel.
To evaluate and compare shear bond strength of 3 self-etching bonding agents to enamel and dentin when the bonding agent is light cured before the application of resin composite or co-cured together with the resin composite. One hundred twenty extracted teeth were wet ground to create a flat bonding area on enamel and dentin. Three bonding agents (Adper Prompt-L-Pop, Clearfil SE Bond, and Xeno III) were applied to either dentin or enamel according to the manufacturers' directions. In half of the specimens, bonding agents were light cured immediately after their application (Group PRC). The other half were not light cured until resin composite application (Group COC). Resin composite was placed into a Teflon tube and light cured over the adhesive. Specimens were stored in deionized water for 24 hours at room temperature before being loaded in shear until failure with an Instron testing machine. Shear bond strength (in megapascals) was analyzed with 2-factor ANOVA, separate single-factor ANOVA models for cure and material, and Tukey's Honestly Significant Differences multiple comparison procedure. All testing was performed at the 5% significance level (n=10). Light-curing the adhesive separately produced significantly higher bond strengths to dentin (P <.001) than did the co-cure method. Group PRC did not produce significantly different bond strengths to enamel (P = .420). Pre-curing of self-etching adhesives before curing of the resin composite produces greater bond strength to dentin. The curing technique has no significant effect on enamel bond strength of self-etching adhesives.


Measurement of DSM-5 section II personality disorder constructs using the MMPI-2-RF in clinical and forensic samples.
In the current study, we evaluated the associations between the Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF; Ben-Porath & Tellegen, 2008) scale scores and the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5; American Psychiatric Association, 2013) Section II personality disorder (PD) criterion counts in inpatient and forensic psychiatric samples from The Netherlands using structured clinical interviews to operationalize PDs. The inpatient psychiatric sample included 190 male and female patients and the forensic sample included 162 male psychiatric patients. We conducted correlation and count regression analyses to evaluate the utility of relevant MMPI-2-RF scales in predicting PD criterion count scores. Generally, results from these analyses emerged as conceptually expected and provided evidence that MMPI-2-RF scales can be useful in assessing PDs. At the zero-order level, most hypothesized associations between Section II disorders and MMPI-2-RF scales were supported. Similarly, in the regression analyses, a unique set of predictors emerged for each PD that was generally in line with conceptual expectations. Additionally, the results provided general evidence that PDs can be captured by dimensional psychopathology constructs, which has implications for both DSM-5 Section III specifically and the personality psychopathology literature more broadly.


Radiation-induced reprogramming of breast cancer cells.
Breast cancers are thought to be organized hierarchically with a small number of breast cancer stem cells (BCSCs) able to regrow a tumor while their progeny lack this ability. Recently, several groups reported enrichment for BCSCs when breast cancers were subjected to classic anticancer treatment. However, the underlying mechanisms leading to this enrichment are incompletely understood. Using non-BCSCs sorted from patient samples, we found that ionizing radiation reprogrammed differentiated breast cancer cells into induced BCSCs (iBCSCs). iBCSCs showed increased mammosphere formation, increased tumorigenicity, and expressed the same stemness-related genes as BCSCs from nonirradiated samples. Reprogramming occurred in a polyploid subpopulation of cells, coincided with re-expression of the transcription factors Oct4, sex determining region Y-box 2, Nanog, and Klf4, and could be partially prevented by Notch inhibition. We conclude that radiation may induce a BCSC phenotype in differentiated breast cancer cells and that this mechanism contributes to increased BCSC numbers seen after classic anticancer treatment.


Caustics in a meridional plane produced by concave conic mirrors.
We study the formation of caustic surfaces produced by a concave conic mirror considering a point source placed at arbitrary position along the optical axis. Using the caustic formula and a paraxial approximation, we derive analytic expressions to evaluate the spherical aberration at the third order. A formula to reduce this aberration at any order is provided, which gives the condition for stigmatic points. Furthermore, we apply the formulas to evaluate the circle of least confusion for a concave conic mirror as a function of all parameters involved in the process of reflection.


Family-based programmes for preventing smoking by children and adolescents.
There is evidence that family and friends influence children's decisions to smoke. To assess the effectiveness of interventions to help families stop children starting smoking. We searched 14 electronic bibliographic databases, including the Cochrane Tobacco Addiction Group specialized register, MEDLINE, EMBASE, PsycINFO, CINAHL unpublished material, and key articles' reference lists. We performed free-text internet searches and targeted searches of appropriate websites, and hand-searched key journals not available electronically. We consulted authors and experts in the field. The most recent search was 3 April 2014. There were no date or language limitations. Randomised controlled trials (RCTs) of interventions with children (aged 5-12) or adolescents (aged 13-18) and families to deter tobacco use. The primary outcome was the effect of the intervention on the smoking status of children who reported no use of tobacco at baseline. Included trials had to report outcomes measured at least six months from the start of the intervention. We reviewed all potentially relevant citations and retrieved the full text to determine whether the study was an RCT and matched our inclusion criteria. Two authors independently extracted study data for each RCT and assessed them for risk of bias. We pooled risk ratios using a Mantel-Haenszel fixed effect model. Twenty-seven RCTs were included. The interventions were very heterogeneous in the components of the family intervention, the other risk behaviours targeted alongside tobacco, the age of children at baseline and the length of follow-up. Two interventions were tested by two RCTs, one was tested by three RCTs and the remaining 20 distinct interventions were tested only by one RCT. Twenty-three interventions were tested in the USA, two in Europe, one in Australia and one in India.The control conditions fell into two main groups: no intervention or usual care; or school-based interventions provided to all participants. These two groups of studies were considered separately.Most studies had a judgement of 'unclear' for at least one risk of bias criteria, so the quality of evidence was downgraded to moderate. Although there was heterogeneity between studies there was little evidence of statistical heterogeneity in the results. We were unable to extract data from all studies in a format that allowed inclusion in a meta-analysis.There was moderate quality evidence family-based interventions had a positive impact on preventing smoking when compared to a no intervention control. Nine studies (4810 participants) reporting smoking uptake amongst baseline non-smokers could be pooled, but eight studies with about 5000 participants could not be pooled because of insufficient data. The pooled estimate detected a significant reduction in smoking behaviour in the intervention arms (risk ratio [RR] 0.76, 95% confidence interval [CI] 0.68 to 0.84). Most of these studies used intensive interventions. Estimates for the medium and low intensity subgroups were similar but confidence intervals were wide. Two studies in which some of the 4487 participants already had smoking experience at baseline did not detect evidence of effect (RR 1.04, 95% CI 0.93 to 1.17).Eight RCTs compared a combined family plus school intervention to a school intervention only. Of the three studies with data, two RCTS with outcomes for 2301 baseline never smokers detected evidence of an effect (RR 0.85, 95% CI 0.75 to 0.96) and one study with data for 1096 participants not restricted to never users at baseline also detected a benefit (RR 0.60, 95% CI 0.38 to 0.94). The other five studies with about 18,500 participants did not report data in a format allowing meta-analysis. One RCT also compared a family intervention to a school 'good behaviour' intervention and did not detect a difference between the two types of programme (RR 1.05, 95% CI 0.80 to 1.38, n = 388).No studies identified any adverse effects of intervention. There is moderate quality evidence to suggest that family-based interventions can have a positive effect on preventing children and adolescents from starting to smoke. There were more studies of high intensity programmes compared to a control group receiving no intervention, than there were for other compairsons. The evidence is therefore strongest for high intensity programmes used independently of school interventions. Programmes typically addressed family functioning, and were introduced when children were between 11 and 14 years old. Based on this moderate quality evidence a family intervention might reduce uptake or experimentation with smoking by between 16 and 32%. However, these findings should be interpreted cautiously because effect estimates could not include data from all studies. Our interpretation is that the common feature of the effective high intensity interventions was encouraging authoritative parenting (which is usually defined as showing strong interest in and care for the adolescent, often with rule setting). This is different from authoritarian parenting (do as I say) or neglectful or unsupervised parenting.


Targeting the Kv1.3 potassium channel for immunosuppression in vascularized composite allotransplantation - a pilot study.
Kv1.3-channels are critically involved in activation and function of effector memory T cells. Blocking Kv1.3-channels was investigated for its effect on skin rejection in a rat limb-transplantation-model. Animals received the Kv1.3-blocker correolide C systemically or locally as intra-graft-treatment in combination with tacrolimus. Systemic (intraperitoneal) administration of correolide C resulted in slight, but significant prolongation of allograft survival compared with untreated and placebo treated controls. In 4/6 correolide C treated animals, histology showed an intact epidermis and a mild infiltrate by day 10. High correolide C plasma trough levels correlated with prolonged allograft survival. A decrease in CD4+ and CD8+ effector memory T cells was observed in allograft skin, peripheral blood and the spleen on day 5. When applied subcutaneously in combination with systemic tacrolimus (30 days+/-anti-lymphocyte serum) detectable, but insignificant prolongation of graft survival was achieved. 2/5 animals showed an intact epidermis and a mild infiltrate until day 45. Tapering systemic tacrolimus and weaning on day 50 resulted in rejection by day 55, regardless of local correolide C treatment. Subcutaneous injection did not lead to systemic plasma levels. The Kv1.3-channel is a potential drug target worth exploring in more detail for immunosuppression in vascularized composite allotransplantation.


Two types of afferent terminals innervate cochlear inner hair cells in C57BL/6J mice.
Afferent synapses on inner hair cells (IHC) transfer auditory information to the central nervous system (CNS). Despite the importance of these synapses for normal hearing, their response to cochlear disease and dysfunction is not well understood. The C57BL/6J mouse is a model for presbycusis and noise-induced hearing loss because of its age-related hearing loss and susceptibility to acoustic over-exposure. In this context, we sought to establish normal synaptic structure in order to better evaluate synaptic changes due to presbycusis and noise exposure. Ultrastructural analysis of IHCs and afferent terminals was performed in a normal hearing 3-month-old C57BL/6J mouse at cochlear sites corresponding to 8, 16 and 32 kHz using semi-serial sections. A stereologic survey of random sections was conducted of IHCs in 11 additional mice. Two morphologically distinct groups of afferent terminals were identified at all 3 frequency locations in 11 out of 12 animals. "Simple" endings demonstrated classic features of bouton terminals, whereas "folded" endings were larger in size and exhibited a novel morphologic feature that consisted of a fully internalized double membrane that partially divided the terminal into two compartments. In many cases, the double membrane was continuous with the outer terminal membrane as if produced by an invagination. We still must determine the generality of these observations with respect to other mouse strains.


The Effectiveness of Interventions on Sustained Childhood Physical Activity: A Systematic Review and Meta-Analysis of Controlled Studies.
Increased physical activity (PA) has been associated with a reduction in non-communicable disease risk factors and outcomes. However, interventions to increase childhood PA typically produce small to negligible effects. Recent reviews are limited due to lack of post-intervention follow-up measurement. This review aimed to examine measured effects at least six months post-intervention. We searched PubMed, MEDLINE, EMBASE, PsychINFO, ScienceDirect, SportDiscus and Google Scholar between 1st January 1991 and 1st November 2014 for controlled studies reporting six-month post-intervention measurement for children aged 5 to 18 years. 14 studies met inclusion criteria; 12 reported moderate-to-vigorous PA (MVPA) (n = 5790) and 10 reported total PA (TPA) (n = 4855). We calculated overall effect estimates and 95% CI's using random effects modelling with inverse variance weighting. Mean difference was calculated for MVPA, with standardised mean difference calculated to TPA due to measurement variation. Meta-regression assessed heterogeneity by continuous level variables. Negligible mean difference in MVPA existed in favour of the intervention group, amounting to 1.47 (95% CI -1.88, 4.82) mins/day compared to controls, while no difference was recorded on TPA. Sub-group analyses revealed males (2.65 mins/day: 95% CI 2.03, 3.27) reported higher levels of MVPA than females (-0.42 mins/day: 95% CI -7.77, 6.94), community settings (2.67 mins/day: 95% CI 2.05, 3.28) were more effective than school settings (1.70 mins/day: 95% CI -4.84, 8.25), and that treatment (4.47 mins/day: 95% CI -0.81, 9.76) demonstrated greater effects than population approaches (1.03 mins/day: 95% CI -2.54, 4.60). Meta-regression revealed no significant differences by factor on pooled effects. Significant heterogeneity existed between studies and potential for small study effects was present. Improved PA levels subsequent to intervention were not maintained six month post-intervention. A potentially useful avenue of future research is to specifically explore community treatment of high risk individuals. PROSPERO CRD42014007545.


Heterotypic passive protection induced by synthetic peptides corresponding to VP7 and VP4 of bovine rotavirus.
We have evaluated the potential of two peptides derived from highly conserved regions of rotavirus outer capsid proteins (VP7 and VP4) to act as a rotavirus vaccine. The capacity of peptides coupled to rotavirus VP6 spherical particles to provide passive protection in a murine model was compared with the protection induced by peptide-keyhole limpet hemocyanin (KLH) conjugates. Female mice were immunized a total of three times before and during pregnancy. Suckling mouse pups were challenged at 7 days of age with either homologous or heterologous rotavirus serotypes. The efficacy of vaccination was determined by analyzing the clinical symptoms and measuring xylose adsorption in the intestine. In this model the VP4 peptide-VP6 conjugate provided protection equal to that obtained using bovine rotavirus (BRV) as the immunogen. The VP7 peptide-VP6 conjugate provided slightly less protection than the VP4 peptide-VP6 conjugate. A mixture of the VP4 peptide-VP6 and VP7 peptide-VP6 conjugates provided better heterologous protection than immunization with BRV. In contrast, KLH-conjugated peptides provided only partial protection. The significance of a synthetic-peptide-based rotavirus vaccine in the prevention of rotavirus infections is discussed.


Mobile phone messaging for facilitating self-management of long-term illnesses.
Long-term illnesses affect a significant proportion of the population in developed and developing countries. Mobile phone messaging applications, such as Short Message Service (SMS) and Multimedia Message Service (MMS), may present convenient, cost-effective ways of supporting self-management and improving patients' self-efficacy skills through, for instance, medication reminders, therapy adjustments or supportive messages. To assess the effects of mobile phone messaging applications designed to facilitate self-management of long-term illnesses, in terms of impact on health outcomes and patients' capacity to self-manage their condition. Secondary objectives include assessment of: user evaluation of the intervention; health service utilisation and costs; and possible risks and harms associated with the intervention. We searched the Cochrane Central Register of Controlled Trials (CENTRAL,The Cochrane Library 2009, Issue 2), MEDLINE (OvidSP) (January 1993 to June 2009), EMBASE (OvidSP) (January 1993 to June 2009), PsycINFO (OvidSP) (January 1993 to June 2009), CINAHL (EbscoHOST) (January 1993 to June 2009), LILACS (January 1993 to June 2009) and African Health Anthology (January 1993 to June 2009).We also reviewed grey literature (including trial registers) and reference lists of articles. We included randomised controlled trials (RCTs), quasi-randomised controlled trials (QRCTs), controlled before-after (CBA) studies, or interrupted time series (ITS) studies with at least three time points before and after the intervention. We selected only studies where it was possible to assess the effects of mobile phone messaging independent of other technologies or interventions. Two review authors independently assessed all studies against the inclusion criteria, with any disagreements resolved by a third review author. Study design features, characteristics of target populations, interventions and controls, and results data were extracted by two review authors and confirmed by a third. Primary outcomes of interest were health outcomes as a result of the intervention and capacity to self-manage long-term conditions. We also considered patients' and providers' evaluation of the intervention, perceptions of safety, health service utilisation and costs, and potential harms or adverse effects. The included studies were heterogeneous in type of condition addressed, intervention characteristics and outcome measures. Therefore, a meta-analysis to derive an overall effect size for the main outcome categories was not considered justified and findings are presented narratively. We included four randomised controlled trials involving 182 participants.For the primary outcome of health outcomes, including physiological measures, there is moderate quality evidence from two studies involving people with diabetes showing no statistical difference from text messaging interventions compared with usual care or email reminders for glycaemic control (HbA1c), the frequency of diabetic complications, or body weight. There is moderate quality evidence from one study of hypertensive patients that the mean blood pressure and the proportion of patients who achieved blood pressure control were not significantly different in the intervention and control groups, and that there was no statistically significant difference in mean body weight between the groups. There is moderate quality evidence from one study that asthma patients receiving a text messaging intervention experienced greater improvements on peak expiratory flow variability (mean difference (MD) -11.12, 95% confidence interval (CI) -19.56 to -2.68) and the pooled symptom score comprising four items (cough, night symptoms, sleep quality, and maximum tolerated activity) (MD -0.36, 95% CI -0.56 to -0.17) compared with the control group. However, the study found no significant differences between the groups in impact on forced vital capacity or forced expiratory flow in 1 second.For the primary outcome of capacity to self-manage the condition, there is moderate quality evidence from one study that diabetes patients receiving the text messaging intervention demonstrated improved scores on measures of self-management capacity (Self-Efficacy for Diabetes score (MD 6.10, 95% CI 0.45 to 11.75), Diabetes Social Support Interview pooled score (MD 4.39, 95% CI 2.85 to 5.92)), but did not show improved knowledge of diabetes. There is moderate quality evidence from three studies of the effects on treatment compliance. One study showed an increase in hypertensive patients' rates of medication compliance in the intervention group (MD 8.90, 95% CI 0.18 to 17.62) compared with the control group, but in another study there was no statistically significant effect on rates of compliance with peak expiratory flow measurement in asthma patients. Text message prompts for diabetic patients initially also resulted in a higher number of blood glucose results sent back (46.0) than email prompts did (23.5).For the secondary outcome of participants' evaluation of the intervention, there is very low quality evidence from two studies that patients receiving mobile phone messaging support reported perceived improvement in diabetes self-management, wanted to continue receiving messages, and preferred mobile phone messaging to email as a method to access a computerised reminder system.For the secondary outcome of health service utilisation, there is very low quality evidence from two studies. Diabetes patients receiving text messaging support made a comparable number of clinic visits and calls to an emergency hotline as patients without the support. For asthma patients the total number of office visits was higher in the text messaging group, whereas the number of hospital admissions was higher for the control group.Because of the small number of trials included, and the low overall number of participants, for any of the reviewed outcomes the quality of the evidence can at best be considered moderate. We found some, albeit very limited, indications that in certain cases mobile phone messaging interventions may provide benefit in supporting the self-management of long-term illnesses. However, there are significant information gaps regarding the long-term effects, acceptability, costs, and risks of such interventions. Given the enthusiasm with which so-called mHealth interventions are currently being implemented, further research into these issues is needed.