Integrating drivers influencing the detection of plant pests carried in the international cut flower trade.
This paper analyses the cut flower market as an example of an invasion pathway along which species of non-indigenous plant pests can travel to reach new areas. The paper examines the probability of pest detection by assessing information on pest detection and detection effort associated with the import of cut flowers. We test the link between the probability of plant pest arrivals, as a precursor to potential invasion, and volume of traded flowers using count data regression models. The analysis is applied to the UK import of specific genera of cut flowers from Kenya between 1996 and 2004. There is a link between pest detection and the Genus of cut flower imported. Hence, pest detection efforts should focus on identifying and targeting those imported plants with a high risk of carrying pest species. For most of the plants studied, efforts allocated to inspection have a significant influence on the probability of pest detection. However, by better targeting inspection efforts, it is shown that plant inspection effort could be reduced without increasing the risk of pest entry. Similarly, for most of the plants analysed, an increase in volume traded will not necessarily lead to an increase in the number of pests entering the UK. For some species, such as Carthamus and Veronica, the volume of flowers traded has a significant and positive impact on the likelihood of pest detection. We conclude that analysis at the rank of plant Genus is important both to understand the effectiveness of plant pest detection efforts and consequently to manage the risk of introduction of non-indigenous species.


Prevalence and factors associated with anemia among children under five years of age in Rombo district, Kilimanjaro region, Northern Tanzania.
Background: Anemia is a severe public health problem affecting more than half of children under five years of age in low-, middle- and high-income countries. We aimed to determine the prevalence and factors associated with anemia among children under five years of age in northern Tanzania. Methods: This was a community-based cross-sectional study conducted in Rombo district, Kilimanjaro region, northern Tanzania in April 2016. Multistage sampling technique was used to select a total of 602 consenting mothers and their children aged 6-59 months and interviewed using a questionnaire. Data were analyzed using Stata version 15.1. We used generalized linear models (binomial family and logit link function) with robust variance estimator to determine factors associated with anemia. Results: Prevalence of anemia was 37.9%, and it was significantly higher among children aged 6-23 months (48.3%) compared to those aged 24-59 months (28.5%). There were no significant differences in anemia prevalence by sex of the child. Adjusted for other factors, children aged 6-23 months had over two times higher odds of being anemic (OR=2.44, 95% CI 1.71, 3.49, p<0.001) compared to those aged 24-59 months. No significant association was found between maternal and nutritional characteristics with anemia among children in this study. Conclusion: Prevalence of anemia was lower than the national and regional prevalence but it still constitutes a significant public health problem, especially among children aged 6-23 months. Interventions such as iron supplementation, food fortification and dietary diversification and management of childhood illnesses in this setting should be targeted towards mothers and children less than two years.


Gastric acid secretion rate and buffer content of the stomach after eating. Results in normal subjects and in patients with duodenal ulcer.
New methods are described by which the buffer content and the rate and pattern of net gastric acid secretion in human subjects fed normal meals can be measured by use of sodium bicarbonate infusion to control intragastric pH. With these techniques, it was shown that the rate of acid secretion in response to a steak meal in seven duodenal ulcer patients was twice the rate achieved in six control subjects and that the amount of acid secreted after eating exceeded the peak histamine response in the ulcer patients but not in the controls. Meal-stimulated acid secretion, expressed as a function of the peak histamine response, was roughly correlated with the serum gastrin concentration (r = 0.45), but it was concluded that other factors must also contribute to the higher than normal secretory responses to a meal found in duodenal ulcer patients. Measurement of buffer content of the stomach revealed that the duodenal ulcer patients emptied the meal buffer at a much more rapid rate than the normal subjects. By 2 h after eating, the ulcer subjects had less than half as much buffer in their stomachs as the controls. The combination of acid hypersecretion and rapid buffer emptying leads to abnormally high gastric acidity after a meal in duodenal ulcer patients. These results suggest that, in addition to a large parietal cell mass, parietal cell responsiveness to a meal and the rate of buffer emptying may be important in the pathogenesis of duodenal ulcer.


[Electrophysiological studies of insulin secretion, physiology and pathophysiology].
Recent progress in experimental diabetes research is reviewed in this article. The application of the patch-clamp technique to the insulin-secreting pancreatic beta-cell has revolutionised our understanding of how an increase in the blood glucose concentration is linked to stimulation of insulin secretion. A major advance was the identification of an ATP-regulated K-channel (KATP-channel) as the glucose-sensitive membrane conductance of the beta-cell. Closure of these channels underlies the glucose-induced depolarisation of the beta-cell, which then triggers the opening of voltage-gated Ca(2+)-channels and the onset of Ca(2+)-dependent exocytosis. With the patch-clamp technique, it was also possible to demonstrate that the KATP-channel represents the molecular target of the hypoglycaemic sulphonylureas, compounds which are used clinically in the treatment of type 2 diabetes.


Multicenter, double-blind comparison of sertraline and placebo in the treatment of posttraumatic stress disorder.
Posttraumatic stress disorder (PTSD) is a common illness associated with significant disability. Few large, placebo-controlled trials have been reported. Outpatients with a DSM-III-R diagnosis of moderate-to-severe PTSD were randomized to 12 weeks of double-blind treatment with either sertraline (N = 100) in flexible daily doses in the range of 50 to 200 mg or placebo (N = 108). Primary outcome measures consisted of the Clinician-Administered PTSD Scale (CAPS-2) total severity score, the patient-rated Impact of Event Scale (IES), and the Clinical Global Impression-Severity (CGI-S) and -Improvement (CGI-I) ratings. Mixed-effects analyses found significantly steeper improvement slopes for sertraline compared with placebo on the CAPS-2 (t = 2.96, P =.003), the IES (t = 2.26, P =.02), the CGI-I score (t = 3.62, P<.001), and the CGI-S score (t = 4.40, P<.001). An intent-to-treat end-point analysis found a 60% responder rate for sertraline and a 38% responder rate for placebo (chi(2)(1) = 8.48, P =.004). Sertraline treatment was well tolerated, with a 9% discontinuation rate because of adverse events, compared with 5% for placebo. Adverse events that were significantly more common in subjects given sertraline compared with placebo consisted of insomnia (35% vs 22%), diarrhea (28% vs 11%), nausea (23% vs 11%), fatigue (13% vs 5%), and decreased appetite (12% vs 1%). The results of the current study suggest that sertraline is a safe, well-tolerated, and significantly effective treatment for PTSD.


Data standards in clinical research: gaps, overlaps, challenges and future directions.
Current efforts to define and implement health data standards are driven by issues related to the quality, cost and continuity of care, patient safety concerns, and desires to speed clinical research findings to the bedside. The President's goal for national adoption of electronic medical records in the next decade, coupled with the current emphasis on translational research, underscore the urgent need for data standards in clinical research. This paper reviews the motivations and requirements for standardized clinical research data, and the current state of standards development and adoption--including gaps and overlaps--in relevant areas. Unresolved issues and informatics challenges related to the adoption of clinical research data and terminology standards are mentioned, as are the collaborations and activities the authors perceive as most likely to address them.


Ray-transfer-matrix model for accurate pulsed cavity ring-down measurement in the mismatching case.
A theoretical model based on the ray-transfer matrix is developed for the pulsed cavity ring-down (CRD) technique to numerically investigate the influence of the geometric parameters of the pulsed-CRD arrangement on the CRD signal. By fitting the spatial distribution of the pulsed laser beam to that of the TEM(00) cavity mode, the geometric parameters are optimized to obtain perfect matching between the laser beam and the ring-down cavity. It is indicated by the numerical simulations that as long as the laser power exiting the ring-down cavity is fully collected, a single exponential-decay signal, identical to the perfectly-matched CRD signal, is obtained in the mismatching case to determine accurately the cavity decay time. Intensity fluctuations appear in the mismatched CRD signal if the laser power exiting the ring-down cavity is not fully collected. Both the conventional exponential decay fitting approach and a linear fitting procedure are employed to analyze these mismatched CRD signals and the latter is recommended to make an accurate pulsed-CRD measurement.


Therapeutic effect of meliacine, an antiviral derived from Melia azedarach L., in mice genital herpetic infection.
Since natural products are considered powerful sources of novel drug discovery, a partially purified extract (meliacine) from the leaves of Melia azedarach L., a plant used in traditional medicine in India for the treatment of several diseases, has been studied. Meliacine exhibits a potent antiviral effect against several viruses without displaying cytotoxicity. The purpose of the present study was to evaluate the therapeutic effect of intravaginal administration of meliacine in a mouse model of genital herpetic infection. BALB/c female mice were infected with MS or G strains of Herpes Simplex Virus type 2 and then treated with meliacine topically. An overall protective effect was observed. Animal survival increased, the severity of the disease was reduced, life span was extended and virus shedding in vagina fluids was diminished. In addition, meliacine reduced the amount of virus that migrated to the brain and vaginal fluids presented higher levels of IFN-gamma and TNF-alpha than untreated infected mice. These results indicate that meliacine could be an alternative therapeutic compound against HSV-2 genital infection.


Bacillus subtilis as a platform for molecular characterisation of regulatory mechanisms of Enterococcus faecalis resistance against cell wall antibiotics.
To combat antibiotic resistance of Enterococcus faecalis, a better understanding of the molecular mechanisms, particularly of antibiotic detection, signal transduction and gene regulation is needed. Because molecular studies in this bacterium can be challenging, we aimed at exploiting the genetically highly tractable Gram-positive model organism Bacillus subtilis as a heterologous host. Two fundamentally different regulators of E. faecalis resistance against cell wall antibiotics, the bacitracin sensor BcrR and the vancomycin-sensing two-component system VanSB-VanRB, were produced in B. subtilis and their functions were monitored using target promoters fused to reporter genes (lacZ and luxABCDE). The bacitracin resistance system BcrR-BcrAB of E. faecalis was fully functional in B. subtilis, both regarding regulation of bcrAB expression and resistance mediated by the transporter BcrAB. Removal of intrinsic bacitracin resistance of B. subtilis increased the sensitivity of the system. The lacZ and luxABCDE reporters were found to both offer sensitive detection of promoter induction on solid media, which is useful for screening of large mutant libraries. The VanSB-VanRB system displayed a gradual dose-response behaviour to vancomycin, but only when produced at low levels in the cell. Taken together, our data show that B. subtilis is a well-suited host for the molecular characterization of regulatory systems controlling resistance against cell wall active compounds in E. faecalis. Importantly, B. subtilis facilitates the careful adjustment of expression levels and genetic background required for full functionality of the introduced regulators.


Radiological versus histological diagnosis in UIP and NSIP: survival implications.
High resolution computed tomography (HRCT) has an important diagnostic role in idiopathic interstitial pneumonia (IIP). We hypothesised that the HRCT appearance would have an impact on survival in patients with IIP. HRCT scans from patients with histological usual interstitial pneumonia (UIP; n=73) or histological non-specific interstitial pneumonia (NSIP; n=23) were characterised as definite UIP, probable UIP, indeterminate, probable NSIP, or definite NSIP. Cox regression analysis examined the relationships between histopathological and radiological diagnoses and mortality, controlling for patient age, sex, and smoking status. All 27 patients with definite or probable UIP on HRCT had histological UIP; 18 of 44 patients with probable or definite NSIP on HRCT had histological NSIP. Patients with HRCT diagnosed definite or probable UIP had a shorter survival than those with indeterminate CT (hazards ratio (HR) 2.43, 95% CI 1.06 to 5.58; median survival 2.08 v 5.76 years) or HRCT diagnosed definite or probable NSIP (HR 3.47, 95% CI 1.58 to 7.63; median survival 2.08 v 5.81 years). Patients with histological UIP with no HRCT diagnosis of probable or definite UIP fared better than patients with histological UIP and an HRCT diagnosis of definite or probable UIP (HR 0.49, 95% CI 0.25 to 0.98; median survival 5.76 v 2.08 years) and worse than those with a histological diagnosis of NSIP (HR 5.42, 95% CI 1.25 to 23.5; median survival 5.76 v >9 years). Patients with a typical HRCT appearance of UIP experience the highest mortality. A surgical lung biopsy is indicated for patients without an HRCT appearance of UIP to differentiate between histological UIP and NSIP.


Gap junction processing and redistribution revealed by quantitative optical measurements of connexin46 epitopes in the lens.
To map changes in the structure and function of fiber cell gap junctions that occur with lens differentiation. Equatorial lens sections were fluorescently labeled with antibodies to the gap junction protein connexin (Cx)46, the membrane marker wheat germ agglutinin, and the nuclear stain propidium iodide. Two-photon microscopy and digital image analysis were used to quantify label and cell morphology as a function of radial distance (r/a) across the lens. Loop- and tail-specific Cx46 antibodies were used to identify regions of posttranslational modification. Local fiber cell coupling was imaged in situ using two-photon flash photolysis of caged fluorescein. Antibody labeling showed that the cytoplasmic tail of Cx46 was removed in two zones (r/a approximately 0.9 and r/a approximately 0.7). In addition, with increasing depth, the large radially aligned plaques of peripheral fiber cells became fragmented and dispersed around the cell membrane, and cells became more circular in cross section. Fluorescein transfer between peripheral fiber cells was highly anisotropic and occurred predominantly within a column of fiber cells, resulting in radially directed transport. In regions beyond the zone of nuclear loss, transport was more isotropic and occurred across columns of fiber cells. The cleavage of Cx46 is associated with a spatial redistribution of gap junction plaques. The distribution of gap junction plaques around the cell membrane can explain the observed directionality of intercellular solute transfer. The findings suggest that the processing and redistribution of gap junction proteins is central to controlling radial and circumferential solute gradients in different regions within the lens.


Theoretical investigation of aerobic and anaerobic oxidative inactivation of the [NiFe]-hydrogenase active site.
The extraordinary capability of [NiFe]-hydrogenases to catalyse the reversible interconversion of protons and electrons into dihydrogen (H2) has stimulated numerous experimental and theoretical studies addressing the direct utilization of these enzymes in H2 production processes. Unfortunately, the introduction of these natural H2-catalysts in biotechnological applications is limited by their inhibition under oxidising (aerobic and anaerobic) conditions. With the aim of contributing to overcome this limitation, we studied the oxidative inactivation mechanism of [NiFe]-hydrogenases by performing Density Functional Theory (DFT) calculations on a very large model of their active site in which all the amino acids forming the first and second coordination spheres of the NiFe cluster have been explicitly included. We identified an O2 molecule and two H2O molecules as sources of the two oxygen atoms that are inserted at the active site of the inactive forms of the enzyme (Ni-A and Ni-B) under aerobic and anaerobic conditions, respectively. Furthermore, our results support the experimental evidence that the Ni-A-to-Ni-B ratio strongly depends on the number of reducing equivalents available for the process and on the oxidizing conditions under which the reaction takes place.


Engineering yeast transcription machinery for improved ethanol tolerance and production.
Global transcription machinery engineering (gTME) is an approach for reprogramming gene transcription to elicit cellular phenotypes important for technological applications. Here we show the application of gTME to Saccharomyces cerevisiae for improved glucose/ethanol tolerance, a key trait for many biofuels programs. Mutagenesis of the transcription factor Spt15p and selection led to dominant mutations that conferred increased tolerance and more efficient glucose conversion to ethanol. The desired phenotype results from the combined effect of three separate mutations in the SPT15 gene [serine substituted for phenylalanine (Phe(177)Ser) and, similarly, Tyr(195)His, and Lys(218)Arg]. Thus, gTME can provide a route to complex phenotypes that are not readily accessible by traditional methods.


Arginine starvation impairs mitochondrial respiratory function in ASS1-deficient breast cancer cells.
Autophagy is the principal catabolic response to nutrient starvation and is necessary to clear dysfunctional or damaged organelles, but excessive autophagy can be cytotoxic or cytostatic and contributes to cell death. Depending on the abundance of enzymes involved in molecule biosynthesis, cells can be dependent on uptake of exogenous nutrients to provide these molecules. Argininosuccinate synthetase 1 (ASS1) is a key enzyme in arginine biosynthesis, and its abundance is reduced in many solid tumors, making them sensitive to external arginine depletion. We demonstrated that prolonged arginine starvation by exposure to ADI-PEG20 (pegylated arginine deiminase) induced autophagy-dependent death of ASS1-deficient breast cancer cells, because these cells are arginine auxotrophs (dependent on uptake of extracellular arginine). Indeed, these breast cancer cells died in culture when exposed to ADI-PEG20 or cultured in the absence of arginine. Arginine starvation induced mitochondrial oxidative stress, which impaired mitochondrial bioenergetics and integrity. Furthermore, arginine starvation killed breast cancer cells in vivo and in vitro only if they were autophagy-competent. Thus, a key mechanism underlying the lethality induced by prolonged arginine starvation was the cytotoxic autophagy that occurred in response to mitochondrial damage. Last, ASS1 was either low in abundance or absent in more than 60% of 149 random breast cancer biosamples, suggesting that patients with such tumors could be candidates for arginine starvation therapy.


The effect of ingesting a saltbush and barley ration on the carcass and eating quality of sheepmeat.
Forage halophytes such as saltbush (Atriplex spp.) are widely used to revegetate Australian saline land and can provide a medium-quality fodder source. An animal house experiment was conducted to investigate differences in the carcass and eating quality of sheep ingesting saltbush from saline land in combination with a barley supplement. Twenty-six merino hoggets (two groups of 13) were fed either a 60 : 40 dried saltbush (Atriplex nummularia): barley (S + B) ration or a 33 : 25 : 42 lupins : barley : oaten hay ration (C) for 10 weeks prior to commercial slaughter. After 10 weeks, all sheep were commercially slaughtered and a single loin (from 12th rib to chump) collected from each animal for taste-panel analysis. Carcass weight, total tissue depth over the 12th rib 110 mm from the midline (GR fat depth), ultimate pH and colour were determined and X-ray bone densitometry used to estimate the fat content of the carcass. Blood samples were taken to assess the hormonal response to ingesting these diets and fatty acid profiles of the subcutaneous and intramuscular fat were determined. Both groups grew at the same rate (62 g/day) and had similar hot carcass weights (P > 0.01) (17.2 ± 0.3 kg for S + B and 17.9 ± 0.3 kg for C). However, these live weights may not be high enough to be commercially viable such that saltbush and barley may only be suitable as a maintenance feed. The S + B-fed sheep had a significantly (P = 0.055) lower fat and higher lean content (P < 0.05) than the C group. This is a positive finding as fat denudation is a significant cost to processors and farmers can produce sheep that are depositing less fat or more lean per unit of live-weight gain. The decreased fat and increased lean content were attributed to the higher protein : energy ratio available for production and lower circulating insulin and higher growth hormone of the S + B-fed sheep. The lower body-fat content and lower metabolisable energy and digestible organic matter intake did correlate with the sheep fed the S + B diet, having a significantly lower percentage of unsaturated fat and equal levels of saturated fat than the C treatment. Diet had no effect on the ultimate pH or colour of the meat. Treatment had no significant effect on any of the eating-quality attributes (P > 0.1). The drying of the saltbush, the shorter length of the experimental period and the low carcass fat content were believed to have contributed to this result. Further field experiments are needed to clarify the benefits to carcass and eating quality of ingesting saltbush.


Inhibition of the sodium/potassium ATPase impairs N-glycan expression and function.
Aberrant N-linked glycans promote the malignant potential of cells by enhancing the epithelial-to-mesenchymal transition and the invasive phenotype. To identify small molecule inhibitors of N-glycan biosynthesis, we developed a chemical screen based on the ability of the tetravalent plant lectin L-phytohemagglutinin (L-PHA) to bind and crosslink surface glycoproteins with beta1,6GlcNAc-branched complex type N-glycans and thereby induce agglutination and cell death. In this screen, Jurkat cells were treated with a library of off-patent chemicals (n = 1,280) to identify molecules that blocked L-PHA-induced death. The most potent hit from this screen was the cardiac glycoside (CG) dihydroouabain. In secondary assays, a panel of CGs was tested for their effects on L-PHA-induced agglutination and cell death. All of the CGs tested inhibited L-PHA-induced death in Jurkat cells, and the most potent CG tested was digoxin with an EC(50) of 60 +/- 20 nmol/L. Digoxin also increased the fraction of some concanavalin A-binding N-glycans. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, digoxin specifically increased GlcNAc(1)Man(3)GlcNAc(2)Fuc(1) and GlcNAc(2)Man(3)GlcNAc(2)Fuc(1) oligosaccharides demonstrating an impairment of the N-glycan pathway. Consistent with this effect on the N-glycan pathway, digoxin inhibited N-glycosylation-mediated processes of tumor cell migration and invasion. Furthermore, digoxin prevented distant tumor formation in two mouse models of metastatic prostate cancer. Thus, taken together, our high throughput screen identified CGs as modifiers of the N-glycan pathway. These molecules can be used as tools to better understand the role of N-glycans in normal and malignant cells. Moreover, these results may partly explain the anticancer effect of CGs in cardiovascular patients.


Similarity to peroxisomal-membrane protein family reveals that Sinorhizobium and Brucella BacA affect lipid-A fatty acids.
Sinorhizobium meliloti, a legume symbiont, and Brucella abortus, a phylogenetically related mammalian pathogen, both require the bacterial-encoded BacA protein to establish chronic intracellular infections in their respective hosts. We found that the bacterial BacA proteins share sequence similarity with a family of eukaryotic peroxisomal-membrane proteins, including the human adrenoleukodystrophy protein, required for the efficient transport of very-long-chain fatty acids out of the cytoplasm. This insight, along with the increased sensitivity of BacA-deficient mutants to detergents and cell envelope-disrupting agents, led us to discover that BacA affects the very-long-chain fatty acid (27-OHC28:0 and 29-OHC30:0) content of both Sinorhizobium and Brucella lipid A. We discuss models for how BacA function affects the lipid-A fatty-acid content and why this activity could be important for the establishment of chronic intracellular infections.


Evolution of parasitism in nematode-trapping fungi.
We are studying the evolution of parasitism in a group of soil-living ascomycetes that can grow as saprophytes as well as parasites by forming special morphological structures called traps. Analyses of 18S ribosomal DNA sequences have shown that these fungi form a monophyletic and isolated clade among the ascomycetes. The phylogenetic patterns within this clade are concordant with the morphology of the traps and separate species having adhesive traps (nets, knobs, and branches) from those having constricting rings. This suggests that these nematode-trapping fungi have a common ancestor, and that the ability to capture nematodes has been an important trait for further speciation and diversification within the clade. To obtain information on the genomic basis for this pattern, we recently started a large-scale sequencing project of the nematode-trapping fungus Monacrosporium haptotylum. This will allow the identification of genes uniquely expressed during the development of traps, and elucidate the molecular evolution of such genes within the nematode-trapping fungi clade.


A public health response to the methamphetamine epidemic: the implementation of contingency management to treat methamphetamine dependence.
In response to increases in methamphatemine-associated sexually transmitted diseases, the San Francisco Department of Public Health implemented a contingency management (CM) field program called the Positive Reinforcement Opportunity Project (PROP). Methamphetamine-using men who have sex with men (MSM) in San Francisco qualified for PROP following expressed interest in the program, provision of an observed urine sample that tested positive for methamphetamine metabolites and self-report of recent methamphetamine use. For 12 weeks, PROP participants provided observed urine samples on Mondays, Wednesdays and Fridays and received vouchers of increasing value for each consecutive sample that tested negative to metabolites of methamphetamine. Vouchers were exchanged for goods and services that promoted a healthy lifestyle. No cash was provided. Primary outcomes included acceptability (number of enrollments/time), impact (clinical response to treatment and cost-effectiveness as cost per patient treated). Enrollment in PROP was brisk indicating its acceptability. During the first 10 months of operation, 143 men sought treatment and of these 77.6% were HIV-infected. Of those screened, 111 began CM treatment and averaged 15 (42%) methamphetamine-free urine samples out of a possible 36 samples during the 12-week treatment period; 60% completed 4 weeks of treatment; 48% 8 weeks and 30% 12 weeks. Across all participants, an average of $159 (SD = $165) in vouchers or 35.1% of the maximum possible ($453) was provided for these participants. The average cost per participant of the 143 treated was $800. Clinical responses to CM in PROP were similar to CM delivered in drug treatment programs, supporting the adaptability and effectiveness of CM to non-traditional drug treatment settings. Costs were reasonable and less than or comparable to other methamphetamine outpatient treatment programs. Further expansion of programs like PROP could address the increasing need for acceptable, feasible and cost-effective methamphetamine treatment in this group with exceptionally high rates of HIV-infection.


Mechanism of action of paracetamol.
Paracetamol (acetaminophen) is generally considered to be a weak inhibitor of the synthesis of prostaglandins (PGs). However, the in vivo effects of paracetamol are similar to those of the selective cyclooxygenase-2 (COX-2) inhibitors. Paracetamol also decreases PG concentrations in vivo, but, unlike the selective COX-2 inhibitors, paracetamol does not suppress the inflammation of rheumatoid arthritis. It does, however, decrease swelling after oral surgery in humans and suppresses inflammation in rats and mice. Paracetamol is a weak inhibitor of PG synthesis of COX-1 and COX-2 in broken cell systems, but, by contrast, therapeutic concentrations of paracetamol inhibit PG synthesis in intact cells in vitro when the levels of the substrate arachidonic acid are low (less than about 5 mumol/L). When the levels of arachidonic acid are low, PGs are synthesized largely by COX-2 in cells that contain both COX-1 and COX-2. Thus, the apparent selectivity of paracetamol may be due to inhibition of COX-2-dependent pathways that are proceeding at low rates. This hypothesis is consistent with the similar pharmacological effects of paracetamol and the selective COX-2 inhibitors. COX-3, a splice variant of COX-1, has been suggested to be the site of action of paracetamol, but genomic and kinetic analysis indicates that this selective interaction is unlikely to be clinically relevant. There is considerable evidence that the analgesic effect of paracetamol is central and is due to activation of descending serotonergic pathways, but its primary site of action may still be inhibition of PG synthesis. The action of paracetamol at a molecular level is unclear but could be related to the production of reactive metabolites by the peroxidase function of COX-2, which could deplete glutathione, a cofactor of enzymes such as PGE synthase.


A combined approach for comparative exoproteome analysis of Corynebacterium pseudotuberculosis.
Bacterial exported proteins represent key components of the host-pathogen interplay. Hence, we sought to implement a combined approach for characterizing the entire exoproteome of the pathogenic bacterium Corynebacterium pseudotuberculosis, the etiological agent of caseous lymphadenitis (CLA) in sheep and goats. An optimized protocol of three-phase partitioning (TPP) was used to obtain the C. pseudotuberculosis exoproteins, and a newly introduced method of data-independent MS acquisition (LC-MSE) was employed for protein identification and label-free quantification. Additionally, the recently developed tool SurfG+ was used for in silico prediction of sub-cellular localization of the identified proteins. In total, 93 different extracellular proteins of C. pseudotuberculosis were identified with high confidence by this strategy; 44 proteins were commonly identified in two different strains, isolated from distinct hosts, then composing a core C. pseudotuberculosis exoproteome. Analysis with the SurfG+ tool showed that more than 75% (70/93) of the identified proteins could be predicted as containing signals for active exportation. Moreover, evidence could be found for probable non-classical export of most of the remaining proteins. Comparative analyses of the exoproteomes of two C. pseudotuberculosis strains, in addition to comparison with other experimentally determined corynebacterial exoproteomes, were helpful to gain novel insights into the contribution of the exported proteins in the virulence of this bacterium. The results presented here compose the most comprehensive coverage of the exoproteome of a corynebacterial species so far.


Noggin null allele mice exhibit a microform of holoprosencephaly.
Holoprosencephaly (HPE) is a heterogeneous craniofacial and neural developmental anomaly characterized in its most severe form by the failure of the forebrain to divide. In humans, HPE is associated with disruption of Sonic hedgehog and Nodal signaling pathways, but the role of other signaling pathways has not yet been determined. In this study, we analyzed mice which, due to the lack of the Bmp antagonist Noggin, exhibit elevated Bmp signaling. Noggin(-/-) mice exhibited a solitary median maxillary incisor that developed from a single dental placode, early midfacial narrowing as well as abnormalities in the developing hyoid bone, pituitary gland and vomeronasal organ. In Noggin(-/-) mice, the expression domains of Shh, as well as the Shh target genes Ptch1 and Gli1, were reduced in the frontonasal region at key stages of early facial development. Using E10.5 facial cultures, we show that excessive BMP4 results in reduced Fgf8 and Ptch1 expression. These data suggest that increased Bmp signaling in Noggin(-/-) mice results in downregulation of the hedgehog pathway at a critical stage when the midline craniofacial structures are developing, which leads to a phenotype consistent with a microform of HPE.


Cryptic speciation on the high seas; global phylogenetics of the copepod family Eucalanidae.
Few genetic data are currently available to assess patterns of population differentiation and speciation in planktonic taxa that inhabit the open ocean. A phylogenetic study of the oceanic copepod family Eucalanidae was undertaken to develop a model zooplankton taxon in which speciation events can be confidently identified. A global survey of 20 described species (526 individuals) sampled from 88 locations worldwide found high levels of cryptic diversity at the species level. Mitochondrial (16S rRNA, CO1) and nuclear (ITS2) DNA sequence data support 12 new genetic lineages as highly distinct from other populations with which they are currently considered conspecific. Out of these 12, at least four are new species. The circumglobal, boundary current species Rhincalanus nasutus was found to be a cryptic species complex, with genetic divergence between populations unrelated to geographic distance. 'Conspecific' populations of seven species exhibited varying levels of genetic differentiation between Atlantic and Pacific basins, suggesting that continental landmasses form barriers to dispersal for a subset of circumglobal species. A molecular phylogeny of the family based on both mitochondrial (16S rRNA) and nuclear (ITS2, 18S rRNA) gene loci supports monophyly of the family Eucalanidae, all four eucalanid genera and the 'pileatus' and 'subtenuis' species groups.


The pathway of cell dismantling during programmed cell death in lace plant (Aponogeton madagascariensis) leaves.
Developmentally regulated programmed cell death (PCD) is the controlled death of cells that occurs throughout the life cycle of both plants and animals. The lace plant (Aponogeton madagascariensis) forms perforations between longitudinal and transverse veins in spaces known as areoles, via developmental PCD; cell death begins in the center of these areoles and develops towards the margin, creating a gradient of PCD. This gradient was examined using both long- and short-term live cell imaging, in addition to histochemical staining, in order to establish the order of cellular events that occur during PCD. The first visible change observed was the reduction in anthocyanin pigmentation, followed by initial chloroplast changes and the bundling of actin microfilaments. At this stage, an increased number of transvacuolar strands (TVS) was evident. Perhaps concurrently with this, increased numbers of vesicles, small mitochondrial aggregates, and perinuclear accumulation of both chloroplasts and mitochondria were observed. The invagination of the tonoplast membrane and the presence of vesicles, both containing organelle materials, suggested evidence for both micro- and macro-autophagy, respectively. Mitochondrial aggregates, as well as individual chloroplasts were subsequently seen undergoing Brownian motion in the vacuole. Following these changes, fragmentation of nuclear DNA, breakdown of actin microfilaments and early cell wall changes were detected. The vacuole then swelled, causing nuclear displacement towards the plasma membrane (PM) and tonoplast rupture followed closely, indicating mega-autophagy. Subsequent to tonoplast rupture, cessation of Brownian motion occurred, as well as the loss of mitochondrial membrane potential (ΔΨm), nuclear shrinkage and PM collapse. Timing from tonoplast rupture to PM collapse was approximately 20 minutes. The entire process from initial chlorophyll reduction to PM collapse took approximately 48 hours. Approximately six hours following PM collapse, cell wall disappearance began and was nearly complete within 24 hours. Results showed that a consistent sequence of events occurred during the remodelling of lace plant leaves, which provides an excellent system to study developmental PCD in vivo. These findings can be used to compare and contrast with other developmental PCD examples in plants.


Co-morbidity of Diabetes Mellitus and Orodental Diseases in Nigeria.
Although several epidemiological studies have reported an association between diabetes mellitus (DM) and orodental health. However, the occurrence of the co-morbidity of both diseases has been more of suspicion than evidence-based. DM is a serious public health concern globally, and in Nigeria. Studies have separately documented the prevalence of DM and orodental diseases, but data lack to adequately rationalise co-morbidity of both diseases. The study aimed to report evidence of co-morbidity of DM and orodental diseases in Nigeria. Data published between December, 1970 and June, 2015 were used in writing the review. These data were collated from electronic literature archives and databases. This review suggests evidence of the association of DM and orodental diseases. It revealed that both diseases are densely distributed in South-East, South-South and South-West geopolitical zones of Nigeria, and sparsely spread across other regions of the country. Co-morbidity of both diseases holds promise that will favour public health practice, especially in Nigeria. It is hoped that the association may lead to the establishment of a cost-effective DM screening protocol in Nigeria. Again, screening of DM in dentistries and vice versa may be possible through the relationship of both diseases. It is recommended that the driving force of the co-morbidity be investigated.


Pseudoarthrosis of the ilium after periacetabular osteotomy that was treated by cemented total hip arthroplasty: a case report.
Preserving the hip joint to delay arthroplasty for patients with acetabular dysplasia-associated early-stage osteoarthritis has become more common, and several surgical procedures have demonstrated pain relief and improved hip joint function. Periacetabular osteotomy, one of the joint-preserving surgical procedures of the hip, provides favorable outcomes, although there are no reports of total hip arthroplasty being used to treat pseudoarthrosis of the periacetabular osteotomy segment. Therefore, we report a case of pseudoarthrosis in the osteotomy segment after periacetabular osteotomy. The patient was treated using modified total hip arthroplasty and achieved a favorable short-term outcome. A 62-year-old Japanese woman was diagnosed with bilateral acetabular dysplasia at the age of 50 years, and underwent right and left periacetabular osteotomy at the ages of 52 and 55 years, respectively. When she was 61-years old, she experienced repeated episodes of left coxalgia during walking, with increasing pain at rest, and subsequently visited our department. Plain radiography and computed tomography of her left hip joint confirmed pseudoarthrosis of the periacetabular osteotomy segment. In addition, narrowing of her left hip joint space was observed, which indicated advanced osteoarthritis of the hip. Therefore, she underwent left total hip arthroplasty when she was 62-years old. During the surgery, fibrous fusion of the periacetabular osteotomy segment was confirmed via fluoroscopy, although no abnormal mobility was observed. Thus, the osteotomy segment was fixed with one absorbable screw and two bone pegs (which were prepared using allogeneic bone), and the acetabular cup was fixed using cement. Her postoperative course was generally favorable and bone fusion of the periacetabular osteotomy segment was confirmed at 3 years and 6 months after surgery. Her modified Harris hip score was 43 before the surgery and had improved to 90 at the final follow-up. Modified total hip arthroplasty was successfully used to treat osteoarthritis of the hip and pseudoarthrosis of the periacetabular osteotomy segment. This procedure achieved pseudoarthrosis region bone fusion and a favorable postoperative outcome.


Natural History of Epstein-Barr Virus Replication and Viral Load Dynamics after Alemtuzumab-Based Allogeneic Stem Cell Transplantation.
Epstein-Barr virus (EBV) load monitoring after allogeneic hematopoietic stem cell transplantation (HSCT) enables earlier detection of EBV replication and often serves as a trigger for preemptive therapies aimed at reducing EBV-related diseases. Our institutional strategy is to treat patients with clinical signs of EBV-related disease accompanied by a rising viral load, rather than to intervene based solely on viral load. This affords an opportunity to study the natural history of EBV replication and to assess whether our strategy reduces overtreatment without compromising outcomes. The objectives of the present study were to assess the natural history of untreated EBV replication in patients who underwent an alemtuzumab-based allogeneic HSCT and to examine whether our clinical strategy reduced overtreatment without compromising patient outcomes. In this retrospective single-center observational study of 515 consecutive patients (age ≥18 years) undergoing T cell-depleted allogeneic HSCT incorporating alemtuzumab, patients underwent surveillance monitoring for EBV by quantitative PCR in the peripheral blood at least weekly up to 100 days post-transplantation and longer if they remained on immunosuppressive therapy. The cumulative incidence of EBV detection and EBV-related disease were assessed. Among the 515 patients, 192 had EBV DNA detectable on ≥1 occasion, with a cumulative incidence of 35.8% (31.8% to 40.4%), although this remained below the limit of quantification in 93 patients. The median time to first detection was 89.5 days (range, 0 to 2254 days). The incidence was higher in recipients of sibling donor transplants (45.4% versus 30%; P = .00021) compared with recipients of unrelated donor transplants. Twenty patients developed EBV-related disease (cumulative incidence, 3.9%). Two patients had immunosuppression reduction alone, 18 received rituximab, and 5 required additional therapies. Five patients died from post-transplantation lymphoproliferative disorder, all of whom had received rituximab. The positive predictive value of EBV load for disease was higher in the unrelated donor cohort but remained <75% regardless of EBV threshold (57.1% to 72.7%). The cumulative incidence of EBV-related disease in our study (3.9%) is comparable to that reported in other studies incorporating alemtuzumab, and our clinical strategy reduced overtreatment in this patient population. PCR-based surveillance strategies have limitations, as reflected in the relatively low sensitivity of the assay coupled with the low positive predictive value, which may influence the potential choice of a threshold for preemptive intervention. We conclude that it remains unclear whether treatment based on a rising EBV viral load alone provides superior overall results to treatment based on the development of clinical signs of EBV-related disease in the context of a rising viral load.


Excretion of ouabain by Malpighian tubules of Oncopeltus fasciatus.
An in vitro preparation of Malpighian tubules was used to investigate the excretion of the polar cardiac glycoside, ouabain, in Oncopeltus fasciatus. Tubules were found to consist of at least two morphologically and physiologically distinct segments, both of which metabolized ouabain. The distal segment (segment II) secreted primary urine and ouabain. Secretion of ouabain by segment II was not observed to occur against a concentration gradient and increased with increasing fluid secretion. The proximal segment (segment I) reabsorbed fluid and ouabain but not metabolites. Ouabain was reabsorbed against a strong concentration gradient (23-fold), was independent of fluid reabsorption, and increased with increasing fluid secretion by segment II. In rapidly secreting Malpighian tubules (a situation of high cardiac glycoside secretion by segment II), the presence of segment I reduced the excretion of ouabain by 84-93%, mainly by reducing ouabain concentration. It appears excretory loss of cardiac glycosides can be reduced in O fasciatus and thus may be a factor in the sequestration of cardiac glycosides in this insect.


How lizards turn into snakes: a phylogenetic analysis of body-form evolution in anguid lizards.
One of the most striking morphological transformations in vertebrate evolution is the transition from a lizardlike body form to an elongate, limbless (snakelike) body form. Despite its dramatic nature, this transition has occurred repeatedly among closely related species (especially in squamate reptiles), making it an excellent system for studying macroevolutionary transformations in body plan. In this paper, we examine the evolution of body form in the lizard family Anguidae, a clade in which multiple independent losses of limbs have occurred. We combine a molecular phylogeny for 27 species, our morphometric data, and phylogenetic comparative methods to provide the first statistical phylogenetic tests of several long-standing hypotheses for the evolution of snakelike body form. Our results confirm the hypothesized relationships between body elongation and limb reduction and between limb reduction and digit reduction. However, we find no support for the hypothesized sequence going from body elongation to limb reduction to digit loss, and we show that a burrowing lifestyle is not a necessary correlate of limb loss. We also show that similar degrees of overall body elongation are achieved in two different ways in anguids, that these different modes of elongation are associated with different habitat preferences, and that this dichotomy in body plan and ecology is widespread in limb-reduced squamates. Finally, a recent developmental study has proposed that the transition from lizardlike to snakelike body form involves changes in the expression domains of midbody Hox genes, changes that would link elongation and limb loss and might cause sudden transformations in body form. Our results reject this developmental model and suggest that this transition involves gradual changes occurring over relatively long time scales.


Hericium erinaceus polysaccharide-protein HEG-5 inhibits SGC-7901 cell growth via cell cycle arrest and apoptosis.
HEG-5 is a novel polysaccharide-protein purified from the fermented mycelia of Hericium erinaceus CZ-2. The present study aims to investigate the effects of HEG-5 on proliferation, cell cycle and apoptosis of human gastric cancer cells SGC-7901. Here, we first uncover that HEG-5 significantly inhibited the proliferation and colony formation of SGC-7901 cells by promoting apoptosis and cell cycle arrest at S phase. RT-PCR and Western blot analysis suggested that HEG-5 could decrease the expressions of Bcl2, PI3K and AKT1, while increase the expressions of Caspase-8, Caspase-3, p53, CDK4, Bax and Bad. These findings indicated that the Caspase-8/-3-dependent, p53-dependent mitochondrial-mediated and PI3k/Akt signaling pathways involved in the molecular events of HEG-5 induced apoptosis and cell cycle arrest. Thus, our study provides in vitro evidence that HEG-5 may be taken as a potential candidate for treating gastric cancer.


Modulation frequency features for phoneme recognition in noisy speech.
In this letter, a new feature extraction technique based on modulation spectrum derived from syllable-length segments of subband temporal envelopes is proposed. These subband envelopes are derived from autoregressive modeling of Hilbert envelopes of the signal in critical bands, processed by both a static (logarithmic) and a dynamic (adaptive loops) compression. These features are then used for machine recognition of phonemes in telephone speech. Without degrading the performance in clean conditions, the proposed features show significant improvements compared to other state-of-the-art speech analysis techniques. In addition to the overall phoneme recognition rates, the performance with broad phonetic classes is reported.


A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects.
Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis. Structural studies have identified phospholipids as potential LRH-1 ligands, but their functional relevance is unclear. Here we show that an unusual phosphatidylcholine species with two saturated 12 carbon fatty acid acyl side chains (dilauroyl phosphatidylcholine (DLPC)) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and lowers hepatic triglycerides and serum glucose. DLPC treatment also decreases hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Both the antidiabetic and lipotropic effects are lost in liver-specific Lrh-1 knockouts. These findings identify an LRH-1 dependent phosphatidylcholine signalling pathway that regulates bile acid metabolism and glucose homeostasis.


Deterministic tropical tree community turnover: evidence from patterns of functional beta diversity along an elevational gradient.
Explaining the mechanisms that produce the enormous diversity within and between tropical tree communities is a pressing challenge for plant community ecologists. Mechanistic hypotheses range from niche-based deterministic to dispersal-based stochastic models. Strong tests of these hypotheses require detailed information regarding the functional strategies of species. A few tropical studies to date have examined trait dispersion within individual forest plots using species trait means in order to ask whether coexisting species tend to be more or less functionally similar than expected given a null model. The present work takes an alternative approach by: (i) explicitly incorporating population-level trait variability; and (ii) quantifying the functional beta diversity in a series of 15 tropical forest plots arrayed along an elevational gradient. The results show a strong pattern of decay in community functional similarity with elevation. These observed patterns of functional beta diversity are shown to be highly non-random and support a deterministic model of tropical tree community assembly and turnover.


Prenatal Ethanol Exposure Persistently Alters Endocannabinoid Signaling and Endocannabinoid-Mediated Excitatory Synaptic Plasticity in Ventral Tegmental Area Dopamine Neurons.
Prenatal ethanol exposure (PE) leads to increased addiction risk which could be mediated by enhanced excitatory synaptic strength in ventral tegmental area (VTA) dopamine (DA) neurons. Previous studies have shown that PE enhances excitatory synaptic strength by facilitating an anti-Hebbian form of long-term potentiation (LTP). In this study, we investigated the effect of PE on endocannabinoid-mediated long-term depression (eCB-LTD) in VTA DA neurons. Rats were exposed to moderate (3 g/kg/d) or high (6 g/kg/d) levels of ethanol during gestation. Whole-cell recordings were conducted in male offspring between 4 and 10 weeks old.We found that PE led to increased amphetamine self-administration. Both moderate and high levels of PE persistently reduced low-frequency stimulation-induced eCB-LTD. Furthermore, action potential-independent glutamate release was regulated by tonic eCB signaling in PE animals. Mechanistic studies for impaired eCB-LTD revealed that PE downregulated CB1 receptor function. Interestingly, eCB-LTD in PE animals was rescued by metabotropic glutamate receptor I activation, suggesting that PE did not impair the synthesis/release of eCBs. In contrast, eCB-LTD in PE animals was not rescued by increasing presynaptic activity, which actually led to LTP in PE animals, whereas LTD was still observed in controls. This result shows that the regulation of excitatory synaptic plasticity is fundamentally altered in PE animals. Together, PE leads to impaired eCB-LTD at the excitatory synapses of VTA DA neurons primarily due to CB1 receptor downregulation. This effect could contribute to enhanced LTP and the maintenance of augmented excitatory synaptic strength in VTA DA neurons and increased addiction risk after PE.SIGNIFICANCE STATEMENT Prenatal ethanol exposure (PE) is among many adverse developmental factors known to increase drug addiction risk. Increased excitatory synaptic strength in VTA DA neurons is a critical cellular mechanism for addiction risk. Our results show that PE persistently alters eCB signaling and impairs eCB-LTD at the excitatory synapses, an important synaptic plasticity that weakens synaptic strength. These effects combined with PE-induced anti-Hebbian long-term potentiation reported in a previous study could result in the maintenance of enhanced excitatory synaptic strength in VTA DA neurons, which in turn contributes to PE-induced increase in addiction risk. Our findings also suggest that restoring normal eCB signaling in VTA DA neurons could be a useful strategy for treating behavioral symptoms caused by PE.


Hemodynamic Impairment Measured by Positron-Emission Tomography Is Regionally Associated with Decreased Cortical Thickness in Moyamoya Phenomenon.
Impaired cerebrovascular reactivity has been associated with decreased cortical thickness in patients with arterial occlusive diseases. This study tests the hypothesis that severe hemodynamic impairment, indicated by increased oxygen extraction fraction ratios on positron-emission tomography with 15O tracers, is associated with decreased cortical thickness in patients with Moyamoya phenomenon. Patients with unilateral or bilateral idiopathic Moyamoya phenomenon were recruited. Oxygen extraction fraction ratio maps were generated from cerebral images of O[15O] counts divided by H2[15O] counts with normalization by corresponding cerebellar counts. The normal range of the oxygen extraction fraction ratio was estimated from historically available healthy control subjects. Cortical thickness was estimated from T1-weighted MR imaging and FreeSurfer. Regional samples of oxygen extraction fraction ratios and cortical thicknesses were drawn using FreeSurfer parcellations, retaining only parcellations from the vascular territory of the middle cerebral artery. Complete MR imaging and PET datasets were available in 35 subjects, including 23 women; the mean age at scanning was 44 years. Patients with Moyamoya phenomenon had a significantly increased regional oxygen extraction fraction ratio compared with 15 healthy control subjects (P < .001). Regional oxygen extraction fraction ratio and age were significant predictors of cortical thickness (P < .001 for each) in a generalized linear mixed-effects model. Using hemisphere averages and patient averages, we found that only age was a significant predictor of cortical thickness (P < .001). Chronic hemodynamic impairment, as indicated by a higher regional oxygen extraction fraction ratio, was significantly predictive of reduced cortical thickness in mixed-effects analysis of FreeSurfer regions. This phenomenon may be related to reversible metabolic down-regulation.


Objectively Measured Sitting and Standing in Workers: Cross-Sectional Relationship with Autonomic Cardiac Modulation.
Excessive sitting and standing are proposed risk factors for cardiovascular diseases (CVDs), possibly due to autonomic imbalance. This study examines the association of objectively measured sitting and standing with nocturnal autonomic cardiac modulation. The cross-sectional study examined 490 blue-collar workers in three Danish occupational sectors. Sitting and standing during work and leisure were assessed during 1⁻5 days using accelerometers. Heart rate (HR) and heart rate variability (HRV) were obtained during nocturnal sleep as markers of resting autonomic modulation. The associations of sitting and standing still (h/day) with HR and HRV were assessed with linear regression models, adjusted for age, gender, body mass index, smoking, and physical activity. More sitting time during leisure was associated with elevated HR (p = 0.02), and showed a trend towards reduced HRV. More standing time at work was associated with lower HR (p = 0.02), and with increased parasympathetic indices of HRV (root mean squared successive differences of R-R intervals p = 0.05; high-frequency power p = 0.07). These findings, while cross-sectional and restricted to blue-collar workers, suggest that sitting at leisure is detrimental to autonomic cardiac modulation, but standing at work is beneficial. However, the small effect size is likely insufficient to mitigate the previously shown detrimental effects of prolonged standing on CVD.


Propensity of Hydrated Excess Protons and Hydroxide Anions for the Air-Water Interface.
Significant effort has been undertaken to better understand the molecular details governing the propensity of ions for the air-water interface. Facilitated by computationally efficient reactive molecular dynamics simulations, new and statistically conclusive molecular-scale results on the affinity of the hydrated excess proton and hydroxide anion for the air-water interface are presented. These simulations capture the dynamic bond breaking and formation processes (charge defect delocalization) that are important for correctly describing the solvation and transport of these complex species. The excess proton is found to be attracted to the interface, which is correlated with a favorable enthalpic contribution and consistent with reducing the disruption in the hydrogen bond network caused by the ion complex. However, a recent refinement of the underlying reactive potential energy function for the hydrated excess proton shows the interfacial attraction to be weaker, albeit nonzero, a result that is consistent with the experimental surface tension measurements. The influence of a weak hydrogen bond donated from water to the protonated oxygen, recently found to play an important role in excess hydrated proton transport in bulk water, is seen to also be important for this study. In contrast, the hydroxide ion is found to be repelled from the air-water interface. This repulsion is characterized by a reduction of the energetically favorable ion-water interactions, which creates an enthalpic penalty as the ion approaches the interface. Finally, we find that the fluctuation in the coordination number around water sheds new light on the observed entropic trends for both ions.


Quantitative MRI in patients with idiopathic generalized epilepsy. Evidence of widespread cerebral structural changes.
In patients with idiopathic generalized epilepsy (IGE), visual inspection of routine MRI is normal. However, pathological studies have shown microdysgenesis in grey and white matter in a large percentage of autopsies from cases of IGE. Recently, widespread structural changes not evident on visual inspection of high resolution MRI have been shown using quantitative MRI in patients with apparently focal cerebral dysgenesis. We sought to determine whether similar quantitative changes might be present in patients with IGE, reflecting possible underlying structural abnormalities. Twenty patients with juvenile myoclonic epilepsy, 10 patients each with childhood absence epilepsy and juvenile absence epilepsy, five patients with tonic-clonic seizures on awakening and 30 control subjects had T1-weighted volume acquisition MRI scans on a 1.5T GE scanner. The cerebral hemispheres were segmented semi-automatically, allowing the comparison of normalized cortical and subcortical matter volumes between groups, and investigation of the regional distribution of cortical and subcortical matter in individual subjects. Patients with IGE had significantly larger cortical grey matter volumes than control subjects. Significant abnormalities of the regional distribution of cerebral grey and subcortical matter were found in eight out of 20 patients with juvenile myoclonic epilepsy, one out of 10 patients with childhood absence epilepsy, four out of 10 patients with juvenile absence epilepsy and two out of five patients with tonic-clonic seizures on awakening, but in none of the 30 control subjects. Using MRI-segmentation, we identified widespread cerebral structural changes in patients with various IGE syndromes. Quantitative MRI supports the existence of structural abnormalities in patients with IGE.


A significant decrease in diagnosis of primary progressive multiple sclerosis: A cohort study.
Several reports indicate changes to prevalence, incidence, female-to-male ratio in multiple sclerosis. Diagnostic criteria, course definitions and clinical management of the disease have also undergone change during the recent decades. To investigate temporal trends in the diagnosis of primary progressive multiple sclerosis (PPMS) in Sweden. Through the Swedish MS registry we investigated the proportion of PPMS diagnosis in birth, diagnosis and age period cohorts using Poisson regression. A total of 16,915 patients were categorised into six birth-cohorts from 1946 to 1975 and seven date-of-diagnosis-cohorts from 1980 to 2014. We observed a decrease in the uncorrected analysis of diagnosis of PPMS from 19.2% to 2.2% and an average decrease of 23% (p < 0.001) per 5-year birth-cohort in the adjusted analysis. An average 21% (p < 0.001) decrease per diagnosis-cohort was seen. In the age-specific diagnosis period cohorts the same decreasing trend of PPMS diagnosis was observed in almost all groups. The diagnosis of PPMS has significantly decreased in Sweden specifically after introduction of disease-modifying treatments. Such decrease can have severe impacts on the future research on PPMS. Our data also suggest that the current trend to emphasise presence or absence of inflammatory activity is already reflected in clinical practice.


Use of Oral Cholera Vaccine and Knowledge, Attitudes, and Practices Regarding Safe Water, Sanitation and Hygiene in a Long-Standing Refugee Camp, Thailand, 2012-2014.
Oral cholera vaccines (OCVs) are relatively new public health interventions, and limited data exist on the potential impact of OCV use on traditional cholera prevention and control measures-safe water, sanitation and hygiene (WaSH). To assess OCV acceptability and knowledge, attitudes, and practices (KAPs) regarding cholera and WaSH, we conducted cross-sectional surveys, 1 month before (baseline) and 3 and 12 months after (first and second follow-up) a preemptive OCV campaign in Maela, a long-standing refugee camp on the Thailand-Burma border. We randomly selected households for the surveys, and administered questionnaires to female heads of households. In total, 271 (77%), 187 (81%), and 199 (85%) households were included in the baseline, first and second follow-up surveys, respectively. Anticipated OCV acceptability was 97% at baseline, and 91% and 85% of household members were reported to have received 1 and 2 OCV doses at first follow-up. Compared with baseline, statistically significant differences (95% Wald confidence interval not overlapping zero) were noted at first and second follow-up among the proportions of respondents who correctly identified two or more means of cholera prevention (62% versus 78% and 80%), reported boiling or treating drinking water (19% versus 44% and 69%), and washing hands with soap (66% versus 77% and 85%); a significant difference was also observed in the proportion of households with soap available at handwashing areas (84% versus 90% and 95%), consistent with reported behaviors. No significant difference was noted in the proportion of households testing positive for Escherichia coli in stored household drinking water at second follow-up (39% versus 49% and 34%). Overall, we observed some positive, and no negative changes in cholera- and WaSH-related KAPs after an OCV campaign in Maela refugee camp. OCV campaigns may provide opportunities to reinforce beneficial WaSH-related KAPs for comprehensive cholera prevention and control.


Interleukin-15-Stimulated Natural Killer Cells Clear HIV-1-Infected Cells following Latency Reversal Ex Vivo.
Current efforts toward human immunodeficiency virus (HIV) eradication include approaches to augment immune recognition and elimination of persistently infected cells following latency reversal. Natural killer (NK) cells, the main effectors of the innate immune system, recognize and clear targets using different mechanisms than CD8+ T cells, offering an alternative or complementary approach for HIV clearance strategies. We assessed the impact of interleukin 15 (IL-15) treatment on NK cell function and the potential for stimulated NK cells to clear the HIV reservoir. We measured NK cell receptor expression, antibody-dependent cell-mediated cytotoxicity (ADCC), cytotoxicity, interferon gamma (IFN-γ) production, and antiviral activity in autologous HIV replication systems. All NK cell functions were uniformly improved by IL-15, and, more importantly, IL-15-treated NK cells were able to clear latently HIV-infected cells after exposure to vorinostat, a clinically relevant latency-reversing agent. We also demonstrate that NK cells from HIV-infected individuals aviremic on antiretroviral therapy can be efficiently stimulated with IL-15. Our work opens a promising line of investigation leading to future immunotherapies to clear persistent HIV infection using NK cells.IMPORTANCE In the search for an HIV cure, strategies to enhance immune function to allow recognition and clearance of HIV-infected cells following latency reversal are being evaluated. Natural killer (NK) cells possess characteristics that can be exploited for immunotherapy against persistent HIV infection. We demonstrate that NK cells from HIV-positive donors can be strongly stimulated with IL-15, improving their antiviral and cytotoxic potential and, more importantly, clearing HIV-infected cells after latency reversal with a clinically relevant drug. Our results encourage further investigation to design NK cell-based immunotherapies to achieve HIV eradication.


Calcisponges have a ParaHox gene and dynamic expression of dispersed NK homeobox genes.
Sponges are simple animals with few cell types, but their genomes paradoxically contain a wide variety of developmental transcription factors, including homeobox genes belonging to the Antennapedia (ANTP) class, which in bilaterians encompass Hox, ParaHox and NK genes. In the genome of the demosponge Amphimedon queenslandica, no Hox or ParaHox genes are present, but NK genes are linked in a tight cluster similar to the NK clusters of bilaterians. It has been proposed that Hox and ParaHox genes originated from NK cluster genes after divergence of sponges from the lineage leading to cnidarians and bilaterians. On the other hand, synteny analysis lends support to the notion that the absence of Hox and ParaHox genes in Amphimedon is a result of secondary loss (the ghost locus hypothesis). Here we analysed complete suites of ANTP-class homeoboxes in two calcareous sponges, Sycon ciliatum and Leucosolenia complicata. Our phylogenetic analyses demonstrate that these calcisponges possess orthologues of bilaterian NK genes (Hex, Hmx and Msx), a varying number of additional NK genes and one ParaHox gene, Cdx. Despite the generation of scaffolds spanning multiple genes, we find no evidence of clustering of Sycon NK genes. All Sycon ANTP-class genes are developmentally expressed, with patterns suggesting their involvement in cell type specification in embryos and adults, metamorphosis and body plan patterning. These results demonstrate that ParaHox genes predate the origin of sponges, thus confirming the ghost locus hypothesis, and highlight the need to analyse the genomes of multiple sponge lineages to obtain a complete picture of the ancestral composition of the first animal genome.


Global 3D imaging of Yersinia ruckeri bacterin uptake in rainbow trout fry.
Yersinia ruckeri is the causative agent of enteric redmouth disease (ERM) in rainbow trout, and the first commercially available fish vaccine was an immersion vaccine against ERM consisting of Y. ruckeri bacterin. The ERM immersion vaccine has been successfully used in aquaculture farming of salmonids for more than 35 years. The gills and the gastrointestinal (GI) tract are believed to be the portals of antigen uptake during waterborne vaccination against ERM; however, the actual sites of bacterin uptake are only partly understood. In order to obtain insight into bacterin uptake during waterborne vaccination, optical projection tomography (OPT) together with immunohistochemistry (IHC) was applied to visualize bacterin uptake and processing in whole rainbow trout fry. Visualization by OPT revealed that the bacterin was initially taken up via gill lamellae from within 30 seconds post vaccination. Later, bacterin uptake was detected on other mucosal surfaces such as skin and olfactory bulb from 5 to 30 minutes post vaccination. The GI tract was found to be filled with a complex of bacterin and mucus at 3 hours post vaccination and the bacterin remained in the GI tract for at least 24 hours. Large amounts of bacterin were present in the blood, and an accumulation of bacterin was found in filtering lymphoid organs such as spleen and trunk kidney where the bacterin accumulates 24 hours post vaccination as demonstrated by OPT and IHC. These results suggest that bacterin is taken up via the gill epithelium in the earliest phases of the bath exposure and from the GI tract in the later phase. The bacterin then enters the blood circulatory system, after which it is filtered by spleen and trunk kidney, before finally accumulating in lymphoid organs where adaptive immunity against ERM is likely to develop.


Identification of mast cells in the cellular response to myocardial infarction.
Myocardial infarction is associated with an acute inflammatory response, leading to replacement of injured cardiomyocytes with granulation tissue. Mast cells are actively involved in postinfarction inflammation by releasing histamine and tumor necrosis factor-alpha, triggering a cytokine cascade. During the proliferative phase of healing, mast cells accumulate in the infarct and may regulate fibrous tissue deposition and angiogenesis by releasing growth factors, angiogenic mediators, and proteases. This chapter describes simple and reliable methods used to identify mast cells in control and infarcted canine hearts. Toluidine blue staining, labeling with conjugated avidin, and tryptase histochemistry are useful in the detection of mast cells in canine tissues. In the healing infarct, mast cells are associated with other cell types that are important for granulation tissue formation. We present immunohistochemical methods identifying monocytes, neutrophils, macrophages, endothelial cells, myofibroblasts, and smooth muscle cells in dog infarcts. These techniques are useful tools for pathological studies in canine models.


A Rapid Method for Directed Gene Knockout for Screening in G0 Zebrafish.
Zebrafish is a powerful model for forward genetics. Reverse genetic approaches are limited by the time required to generate stable mutant lines. We describe a system for gene knockout that consistently produces null phenotypes in G0 zebrafish. Yolk injection of sets of four CRISPR/Cas9 ribonucleoprotein complexes redundantly targeting a single gene recapitulated germline-transmitted knockout phenotypes in >90% of G0 embryos for each of 8 test genes. Early embryonic (6 hpf) and stable adult phenotypes were produced. Simultaneous multi-gene knockout was feasible but associated with toxicity in some cases. To facilitate use, we generated a lookup table of four-guide sets for 21,386 zebrafish genes and validated several. Using this resource, we targeted 50 cardiomyocyte transcriptional regulators and uncovered a role of zbtb16a in cardiac development. This system provides a platform for rapid screening of genes of interest in development, physiology, and disease models in zebrafish.


Complex hair cycle domain patterns and regenerative hair waves in living rodents.
Single hair follicles go through regeneration and involution cycles. In a population, hair follicles may affect each other during anagen re-entry, thus forming propagating regenerative hair waves. We review these regenerative hair waves and complex hair cycle domains, which were recently reported in transgenic mice. Two non-invasive methods to track the propagating hair wave in large populations of hair follicles in vivo are described. We also reviewed early accounts of "hair growth patterns" from classical literature. We decipher the "behavior rules" that dictate how dynamic hair waves lead to complex hair cycle domains. In general, a single domain expands when a regenerative hair wave reaches a responsive region and boundaries form when the wave reaches a non-responsive region. As mice age, multiple hair cycle domains form, each with its own regeneration rhythm. Domain patterns can be reset by physiological events such as pregnancy and lactation. Longitudinal sections across domains show arrays of follicles in a continuum of hair cycle stages. Hair cycle domains are different from regional specificity domains. Regenerative hair waves are different from the developmental wave of newly forming hair follicles. The study provides insights into the dynamic states of adult skin and physiological regulation of organ regeneration.


A comparison of anchored conjunctival rotation flap and conjunctival autograft techniques in pterygium surgery.
To compare conjunctival autograft and anchored conjunctival rotation flap techniques, in terms of recurrence and complication rates, after performing a primary pterygium surgery. Sixty patients who underwent pterygium surgery, which was performed on 1 eye (M:F = 25:35), either using conjunctival autograft (25 eyes) or anchored conjunctival rotation flap (35 eyes) techniques, were followed up postoperatively for a minimum period of 18 months. The anchored conjunctival rotation flap surgery was conducted by designing a conjunctival flap with a similar shape as that of the autograft, but with the preservation of the inferior limbal anchoring point (1 mm) by the incomplete cutting of the limbal area. After rotation of the flap around the anchoring point, the flap was tightened with sutures to cover the bare scleral area. Early postoperative complications, such as flap or graft edema and granuloma formation, were assessed. The recurrence rate of pterygium was evaluated, and a comparison was made between the 2 surgical techniques. The recurrence rate was 8.0% in the conjunctival autograft group and 8.6% in the anchored conjunctival rotational flap group (P = 0.659). However, the occurrence of flap or graft edema was lower for anchored conjunctival rotational flap surgery (14.3% vs. 72.0%, P < 0.001). No granuloma formation was observed in either group. The anchored conjunctival rotational flap surgery showed similar pterygium recurrence rates and a lower incidence of flap edema, while enabling simple recognition of flap orientation, compared with the conjunctival autograft technique.


Clinical outcomes of intraoperative radiation therapy for extremity sarcomas.
Purpose. Radiation of extremity lesions, a key component of limb-sparing therapy, presents particular challenges, with significant risks of toxicities. We sought to explore the efficacy of intraoperative radiation therapy (IORT) in the treatment of soft tissue sarcomas of the extremities. Patients. Between 1995 and 2001, 17 patients received IORT for soft tissue sarcomas of the extremities. Indications for IORT included recurrent tumors in a previously radiated field or tumors adjacent to critical structures. Results. Gross total resections were achieved in all 17 patients. Two patients experienced locoregional relapses, six patients recurred at metastatic sites, and one patient died without recurrence. Thirty-six month estimates for locoregional control, disease free survival, and overall survival were 86%, 50%, and 78%, respectively. IORT was extremely well tolerated, with no toxicities referable to IORT. Conclusions. For patients with soft tissue sarcomas of the extremities, IORT used as a boost to EBRT provides excellent local control, with limited acute toxicities.


Primary visual cortex activity along the apparent-motion trace reflects illusory perception.
The illusion of apparent motion can be induced when visual stimuli are successively presented at different locations. It has been shown in previous studies that motion-sensitive regions in extrastriate cortex are relevant for the processing of apparent motion, but it is unclear whether primary visual cortex (V1) is also involved in the representation of the illusory motion path. We investigated, in human subjects, apparent-motion-related activity in patches of V1 representing locations along the path of illusory stimulus motion using functional magnetic resonance imaging. Here we show that apparent motion caused a blood-oxygenation-level-dependent response along the V1 representations of the apparent-motion path, including regions that were not directly activated by the apparent-motion-inducing stimuli. This response was unaltered when participants had to perform an attention-demanding task that diverted their attention away from the stimulus. With a bistable motion quartet, we confirmed that the activity was related to the conscious perception of movement. Our data suggest that V1 is part of the network that represents the illusory path of apparent motion. The activation in V1 can be explained either by lateral interactions within V1 or by feedback mechanisms from higher visual areas, especially the motion-sensitive human MT/V5 complex.


DART-MS Facilitated Quantification of Cannabinoids in Complex Edible Matrices-Focus on Chocolates and Gelatin-Based Fruit Candies.
Traditional methods for detecting and quantifying cannabinoids in Cannabis sativa materials are most often chromatography-based, and they generally require extensive sample preparation protocols to render materials into a form that can be injected into the systems without the risk of contaminating or damaging the equipment. This challenge is amplified when interrogating the increasingly broad range of matrix types that cannabinoids are infused within, such as edibles that also contain sugars, fats, lipids, and carbohydrates. The requisite application of highly nuanced methods that must be developed for each matrix type is, in addition to being resource-intensive and time-consuming, highly impractical and unsustainable for crime laboratories endeavoring to perform such analyses in a routine manner, since they are often under-resourced while typically also confronting sample testing backlogs. A key to resolving this issue is to identify an analysis approach that avoids the requirement for nuanced method development by being applicable to a broader range of matrix types. Ambient ionization mass spectrometry (AIMS) methods have shown great promise in their ability to rapidly interrogate samples. Therefore, this study focused on developing validated protocols using AIMS (specifically, direct analysis in real time-high-resolution mass spectrometry, or DART-HRMS) to detect and quantify Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in edible matrices. Calibration curves were developed using deuterated counterparts of THC and CBD as internal standards. Following the use of high cannabinoid recovery rate extraction protocols for chocolates and gelatin-based fruit candies or "gummies", the DART-HRMS approach was applied to quantify cannabinoid levels in commercially available cannabinoid-infused candies, yielding results similar to those reported on the product labels. Importantly, the developed method circumvented challenges encountered using traditional approaches. As the Cannabis field continues to evolve and new matrix types emerge on the market, the DART-HRMS detection and quantification protocols can be readily applied without the need for major procedural adaptations.


Girls' Empowerment and Adolescent Pregnancy: A Systematic Review.
Background: 21 million girls get pregnant every year. Many initiatives are empowering girls. Various studies have looked at girl empowerment, however, there is contradicting evidence, and even less literature from developing countries. Methods: We searched articles published between January 2000 to January 2019. We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered our protocol on the International Prospective Register of Systematic Reviews PROSPERO (CRD42019117414). Nine articles were selected for review. Quality appraisal was done using separate tools for qualitative studies, cohort and cross-sectional studies and randomized control trials. Results: Eight studies included educational empowerment, four studies included community empowerment, three studies included economic empowerment, while two studies discussed policy empowerment. Three studies were of fair quality; two qualitative and one cross-sectional study were of high quality, while three studies had low quality. Discussion. Studies showed a favorable impact of girl empowerment on adolescent pregnancies and risky sexual behaviors. Education empowerment came through formal education or health systems such as in family planning clinics. Community empowerment was seen as crucial in girls' development, from interactions with parents to cultural practices. Economic empowerment was direct like cash transfer programs or indirect through benefits of economic growth. Policies such as contraceptive availability or compulsory school helped reduce pregnancies.


Expanding the Host Range of Hepatitis C Virus through Viral Adaptation.
Hepatitis C virus (HCV) species tropism is incompletely understood. We have previously shown that at the level of entry, human CD81 and occludin (OCLN) comprise the minimal set of human factors needed for viral uptake into murine cells. As an alternative approach to genetic humanization, species barriers can be overcome by adapting HCV to use the murine orthologues of these entry factors. We previously generated a murine tropic HCV (mtHCV or Jc1/mCD81) strain harboring three mutations within the viral envelope proteins that allowed productive entry into mouse cell lines. In this study, we aimed to characterize the ability of mtHCV to enter and infect mouse hepatocytes in vivo and in vitro Using a highly sensitive, Cre-activatable reporter, we demonstrate that mtHCV can enter mouse hepatocytes in vivo in the absence of any human cofactors. Viral entry still relied on expression of mouse CD81 and SCARB1 and was more efficient when mouse CD81 and OCLN were overexpressed. HCV entry could be significantly reduced in the presence of anti-HCV E2 specific antibodies, suggesting that uptake of mtHCV is dependent on viral glycoproteins. Despite mtHCV's ability to enter murine hepatocytes in vivo, we did not observe persistent infection, even in animals with severely blunted type I and III interferon signaling and impaired adaptive immune responses. Altogether, these results establish proof of concept that the barriers limiting HCV species tropism can be overcome by viral adaptation. However, additional viral adaptations will likely be needed to increase the robustness of a murine model system for hepatitis C. At least 150 million individuals are chronically infected with HCV and are at risk of developing serious liver disease. Despite the advent of effective antiviral therapy, the frequency of chronic carriers has only marginally decreased. A major roadblock in developing a vaccine that would prevent transmission is the scarcity of animal models that are susceptible to HCV infection. It is poorly understood why HCV infects only humans and chimpanzees. To develop an animal model for hepatitis C, previous efforts focused on modifying the host environment of mice, for example, to render them more susceptible to HCV infection. Here, we attempted a complementary approach in which a laboratory-derived HCV variant was tested for its ability to infect mice. We demonstrate that this engineered HCV strain can enter mouse liver cells but does not replicate efficiently. Thus, additional adaptations are likely needed to construct a robust animal model for HCV.


Controlled thermoreversible transfer of poly(oxazoline) micelles between an ionic liquid and water.
Poly(2-nonyl-2-oxazoline-block-2-ethyl-2-oxazoline) block copolymer micelles were investigated as an alternative system to the approach proposed by He and Lodge (Y. He and T. P. Lodge, J. Am. Chem. Soc., 2006, 128, 12666) for the thermoreversible transfer of micelles between a hydrophobic ionic liquid phase and an aqueous phase; this work describes the possibility of thermally triggering and controlling this process.


"I'll never forget this": evaluating a pilot workshop in effective communication for dental students.
This study evaluated a pilot workshop for teaching communication skills to dental students. The methodology is based on an experiential learning approach, the use of realistic clinical scenarios, simulated patients, and an integrated teaching team of both educational researchers and dentists. Furthermore, the methodology was adapted for short workshops, which is thought to offer better possibilities for frequent and effective training of communication skills throughout the curriculum. The work-shop was piloted with groups of six to ten students from the sixth and tenth semesters (n=94). Results show that the majority of students found the tasks meaningful and well aligned with how they perceived their future profession as dentists. Most students also thought that they learned from the task. An interesting finding is that students not only found it instructive to practice how to communicate in authentic situations, but that they generally found the workshop to be thought-provoking while at the same time providing structure and intellectual tools for the future. A possible explanation for this finding is the sharing of explicit criteria for high-quality communication.


Transient thermal effect, nonlinear refraction and nonlinear absorption properties of graphene oxide sheets in dispersion.
The nonlinear refraction (NLR) properties of graphene oxide (GO) in N, N-Dimethylformamide (DMF) was studied in nanosecond, picosecond and femtosecond time regimes by Z-scan technique. Results show that the dispersion of GO in DMF exhibits negative NLR properties in nanosecond time regime, which is mainly attributed to transient thermal effect in the dispersion. The dispersion also exhibits negative NLR in picosecond and femtosecond time regimes, which are arising from sp(2)- hybridized carbon domains and sp(3)- hybridized matrix in GO sheets. To illustrate the relations between NLR and nonlinear absorption (NLA), NLA properties of the dispersion were also studied in nanosecond, picosecond and femtosecond time regimes.


catena-Poly[[bis-(nitrato-κO)copper(II)]-μ-1,4-bis-(4,5-dihydro-1,3-oxazol-2-yl)-benzene-κN:N'].
In the title coordination polymer, [Cu(NO(3))(2)(C(12)H(12)N(2)O(2))](n), the Cu(II) ion, situated on an inversion center, is coordinated by two O atoms from two nitrate anions and two N atoms from two 1,4-bis-(4,5-dihydro-1,3-oxazol-2-yl)benzene (L) ligands in a distorted square-planar geometry. Each L ligand also lies across an inversion center and bridges two Cu(II) ions, forming a polymeric chain running along the [101] direction. The three O atoms of the nitrate group are disordered over two positions in a 3:2 ratio.


Focal adhesion kinase promotes phospholipase C-gamma1 activity.
The nonreceptor tyrosine kinase FAK ("focal adhesion kinase") is a key mediator of integrin signaling events controlling cellular responses to the extracellular matrix, including spreading, migration, proliferation, and survival. Integrin-ligand interactions stimulate FAK tyrosine phosphorylation and activation of FAK signaling functions. Here evidence is presented that the FAK autophosphorylation site Tyr-397 mediates a direct interaction with the C-terminal Src homology 2 domain of phospholipase C (PLC)-gamma1 and that this is required for both adhesion-dependent association of the two molecules and increased inositol phosphate production in mouse embryo fibroblasts. Overexpression of FAK and PLC-gamma1 in COS-7 cells increases PLC-gamma1 enzymatic activity and tyrosine phosphorylation, also dependent on FAK Tyr-397. However, FAK appears incapable of directly phosphorylating PLC-gamma1. These observations suggest a role for FAK in recruiting PLC-gamma1 to the plasma membrane at sites of cell-matrix adhesion and there promoting its enzymatic activity, possibly by releasing the repression caused by intramolecular interactions of the PLC-gamma1 Src homology domains and/or by positioning it for phosphorylation by associated Src-family kinases. These findings expand the known signaling functions of FAK and provide mechanistic insight into integrin-stimulation of PLC-gamma1.


Prevalence and Major Causes of Visual Impairment in Iranian Adults: A Systematic Review.
The purpose of this study is to provide a pooled estimate of moderate-to-severe visual impairment (MSVI) and blindness in Iran for people 50 years and over and to identify the major causes through systematic review. International (PubMed, ISI Web of Science, and Scopus) and national databases (Scientific Information Database, Barakat Knowledge Network System, Iran Databank of Ophthalmology Research, and Magiran) databases were searched. Following relevance assessment and critical appraisal, eight studies were included. A funnel plot was drawn to explore the stability for estimation. Single-variable meta-regression analysis was applied for heterogeneity assessment, and a random effect model was used (but no significant source for the observed heterogeneity was found). Age-standardized pooled estimate of MSVI was 4.24% (95% confidence interval [CI]: 2.92-5.56); 3.98% (95% CI: 2.37-5.59) for men, and 4.08% (95% CI: 2.95-5.21) for women. Blindness (visual acuity <3/60) prevalence was 1.31% (95% CI: 1.23-1.39); 0.96% (95% CI: 0.89-1.03) for men, and 1.13% (95% CI: 1.06-1.20) for women. Causes of visual impairment (VI) were cataract (40.23%), amblyopia (12.03%), corneal opacity (9.63%), age-related macular degeneration (9.31%), diabetic retinopathy (4.94%), and glaucoma (3.67%). VI prevalence in the 50 years and older population in Iran seems significantly better than the corresponding global estimates. A rough 60% rate of treatable VI was estimated, mostly attributable to unoperated cataract.


Genetic distance sampling: a novel sampling method for obtaining core collections using genetic distances with an application to cultivated lettuce.
This paper introduces a novel sampling method for obtaining core collections, entitled genetic distance sampling. The method incorporates information about distances between individual accessions into a random sampling procedure. A basic feature of the method is that automatically larger samples are obtained if accessions are further apart and smaller samples if accessions are closer together. Genetic distance sampling can be used in conjunction with predefined stratifications of the accessions. Sample sizes are determined automatically; they depend on the distances between accessions within strata. The method is applied to the collection of cultivated lettuce of the Centre for Genetic Resources, the Netherlands. In this paper, genetic distances between accessions are obtained using AFLP marker data. However, genetic distance sampling can be applied using any measure of genetic distance between accessions. Some properties of genetic distance sampling are discussed.


A grounded theory study to identify caregiving phases and support needs across the Alzheimer's disease trajectory.
Caregivers of individuals with Alzheimer's disease require support across the full disease trajectory. The aim of this study was to develop a conceptual framework of caregiving phases across the Alzheimer's disease and caregiving trajectories and the corresponding caregiver support needs. Constructivist grounded theory informed data collection and analysis. 40 spousal (n = 20) and adult children (n = 20) caregivers were interviewed. Recruitment was completed when theoretical saturation was achieved. Member-checking interviews occurred with 10 participants. Participants described five phases of caregiving related to their responsibilities to support people with Alzheimer's disease including monitoring initial symptoms, navigating their diagnosis, assisting with instrumental activities of daily living, assisting with basic activities of daily living, and preparing for the future. Support (i.e., informational, emotional, instrumental, and appraisal) needs were often specific to the phase of care. For example, during the initial symptoms phase, caregivers reported needing information to assist them to distinguish normal aging from cognitive impairment. In contrast, during the preparing for the future phase, caregivers emphasized support for accessing institutional long term-care placement. Findings highlight caregiver-identified phases of caregiving and corresponding support needs across the Alzheimer's disease trajectory. Findings can inform the development, evaluation and implementation of programs and services to meet caregivers' changing needs across the disease trajectory.IMPLICATIONS FOR REHABILITATIONCaregivers for individuals with Alzheimer's disease can experience distinct caregiving phases across the disease trajectory with corresponding support needs.Rehabilitation clinicians can use these findings to help caregivers navigate available supports at appropriate times to ensure that their needs are addressed across the disease trajectory.Occupational therapists and other rehabilitation professionals can enable caregivers with timely education and support as they progress across the disease trajectory.


Yeast adapts to a changing stressful environment by evolving cross-protection and anticipatory gene regulation.
Organisms can protect themselves against future environmental change. An example is cross-protection, where physiological adaptation against a present environmental stressor can protect an organism against a future stressor. Another is anticipation, where an organism uses information about its present environment to trigger gene expression and other physiological changes adaptive in future environments. "Predictive" abilities like this exist in organisms that have been exposed to periodic changes in environments. It is unknown how readily they can evolve. To answer this question, we carried out laboratory evolution experiments in the yeast Saccharomyces cerevisiae. Specifically, we exposed three replicate populations of yeast to environments that varied cyclically between two stressors, salt stress and oxidative stress, every 10 generations, for a total of 300 generations. We evolved six replicate control populations in only one of these stressors for the same amount of time. We analyzed fitness changes and genome-scale expression changes in all these evolved populations. Our populations evolved asymmetric cross protection, where oxidative stress protects against salt stress but not vice versa. Gene expression data also suggest the evolution of anticipation and basal gene expression changes that occur uniquely in cyclic environments. Our study shows that highly complex physiological states that are adaptive in future environments can evolve on very short evolutionary time scales.


Universality of Plasmon Excitations in Dirac Semimetals.
We investigate the properties of the collective plasmon excitations in Dirac semimetals by using the methods of relativistic field theory. We find a strong and narrow plasmon excitation whose frequency is in the terahertz (THz) range which may be important for practical applications. The properties of the plasmon appear universal for all Dirac semimetals, due to the large degeneracy of the quasiparticles and the small Fermi velocity, v_{F}≪c. This universality is closely analogous to the phenomenon of "dimensional transmutation" that is responsible for the emergence of dimensionful scales in relativistic field theories such as quantum chromodynamics.