A simple role for BDNF in learning and memory?
Since its discovery almost three decades ago, the secreted neurotrophin brain-derived neurotrophic factor (BDNF) has been firmly implicated in the differentiation and survival of neurons of the CNS. More recently, BDNF has also emerged as an important regulator of synaptogenesis and synaptic plasticity mechanisms underlying learning and memory in the adult CNS. In this review we will discuss our knowledge about the multiple intracellular signalling pathways activated by BDNF, and the role of this neurotrophin in long-term synaptic plasticity and memory formation as well as in synaptogenesis. We will show that maturation of BDNF, its cellular localization and its ability to regulate both excitatory and inhibitory synapses in the CNS may result in conflicting alterations in synaptic plasticity and memory formation. Lack of a precise knowledge about the mechanisms by which BDNF influences higher cognitive functions and complex behaviours may constitute a severe limitation in the possibility to devise BDNF-based therapeutics for human disorders of the CNS.


Does eptifibatide confer a greater benefit to patients with unstable angina than with non-ST segment elevation myocardial infarction? Insights from the PURSUIT Trial.
To evaluate the differential effects of eptifibatide therapy on unstable angina vs non-ST elevation myocardial infarction at enrollment, since the separate impact on these two major diagnostic subsets of acute coronary syndrome patients has not been fully investigated. We examined the 9461 patients in the PURSUIT trial (conducted between 1995 and 1997) to compare the effects of eptifibatide on unstable angina and myocardial infarction. The study showed greater and more consistent effects of eptifibatide therapy on unstable angina than non-ST elevation myocardial infarction in reducing 30-day death/(re)infarction (from the unadjusted rate of 13.0% to 11.2%, P=0.059 for unstable angina; and 18.9% to 17.9%, P=0.387 for myocardial infarction), especially among patients who underwent early percutaneous coronary intervention (odds ratios=0.49 and 0.86, 95% confidence intervals=0.30-0.80 and 0.53-1.42, respectively, for unstable angina and myocardial infarction). The only subgroup for whom the benefit of eptifibatide was not evident was female myocardial infarction patients who did not undergo early percutaneous coronary intervention. These data suggest that eptifibatide benefited unstable angina patients more than myocardial infarction patients, especially among those who underwent early percutaneous coronary intervention, and support its use as concomitant therapy with early percutaneous coronary intervention especially in female myocardial infarction patients.


Effect of simvastatin treatment on cardiovascular resource utilization in impaired fasting glucose and diabetes. Findings from the Scandinavian Simvastatin Survival Study.
The Scandinavian Simvastatin Survival Study showed that simvastatin treatment reduced cardiovascular events in hypercholesterolemic subjects with coronary heart disease. The clinical benefits of therapy were similar in all three subgroups: normal fasting glucose (NFG, n = 3,237), impaired fasting glucose (IFG, n = 678), and diabetes (n = 483). This analysis compared the costs of simvastatin treatment with the costs of cardiovascular disease-related hospitalizations in the three subgroups. The cost of simvastatin treatment was defined as the average retail price and the cost of drug safety monitoring and adverse experiences. The costs of cardiovascular disease-related hospitalizations were determined by actual rates of hospitalization and 1995 MEDSTAT diagnosis-related group costs. Within trial, simvastatin treatment cost approximately $6,000 per patient. Simvastatin treatment reduced cardiovascular disease-related hospitalizations by 23% in NFG (P = 0.001), 30% in IFG (P = 0.015), and 40% in diabetic subjects (P = 0.007) within trial (median follow-up of 5.4 years). Average length of stay was reduced by 2.4 days in diabetic subjects (P = 0.021). Total cardiovascular disease-related hospital days were reduced by 28% (P < 0.001) in NFG, 38% (P = 0.005) in IFG, and 55% (P < 0.001) in diabetic subjects. For NFG subjects, simvastatin reduced the average cost of cardiovascular disease-related hospitalizations by $3,585, which offset 60% of the cost of simvastatin therapy. For IFG subjects, average cardiovascular disease-related hospitalization costs were reduced by $4,478, which offset 74% of the drug cost. For diabetic subjects, there was a net cost savings of $1,801 per subject within trial. Simvastatin significantly reduced cardiovascular disease-related hospitalizations and total hospital days for all three groups and significantly reduced length of stay for the diabetic group in addition to providing significant clinical benefits. The benefits were greatest in the diabetic group, with estimated cost savings within trial from simvastatin treatment.


Reducing the global burden of blood pressure-related cardiovascular disease.
To assist in prioritisation for strategies for the control of cardiovascular disease (CVD) worldwide, by estimating the size of the contribution of elevated blood pressure and, more importantly, the likely effects of its modification. We estimated the size of the disease burden attributable to increased blood pressure in Eastern Asia and describe a method for estimating the likely effects of blood pressure lowering strategies. Attributable risk estimates were calculated to assess the likely contribution of increased blood pressure to death from CVD in Asia. Estimates were also made of the possible effects of population-wide (2% lower diastolic blood pressure [DBP] for all) and targeted (7% lower DBP for those with DBP > or =95 mm Hg) blood pressure lowering interventions. These estimates were based on data from several sources, including surveys of blood pressure values in Asian populations, estimates of the incidence of cardiovascular disease in Asia, studies of the associations of blood pressure with cardiovascular disease risks in Asia and elsewhere, and randomized trials of blood pressure lowering treatments. The results suggest that DBP values of 80 mm Hg or more account for about 57% of all stroke deaths and about 24% of all coronary heart disease deaths in Eastern Asian populations. The two intervention strategies proposed would each be expected to avert about 1 in 6 stroke deaths and about 1 in 20 coronary heart disease deaths. This would amount to about 1 million deaths per year throughout Asia by 2020, with about half of those deaths averted in the People's Republic of China. The benefits of the two different approaches would be approximately additive. Increased blood pressure levels are directly responsible for the majority of stroke deaths (more than 50%) and a substantial minority of deaths from coronary heart disease (about 25%) in Eastern Asia. Both modest population-wide blood pressure reductions and more moderate targeted reductions in those with hypertension could be expected to produce large reductions in the burden of cardiovascular disease in these and other Asian regions.


Characterizing the protective component of the alphabeta T cell response to transplantable squamous cell carcinoma.
There is increasing promise that cellular immune response may be manipulated to combat cancer; however, it is also clear that the immune response to cutaneous malignancy comprises different T cell activities that variably inhibit or promote tumor development. Thus, a better understanding of each of these activities is crucial to more effective clinical manipulation. To better characterize the protective anti-tumor effects of alphabeta T cells, we examined the growth of the transplantable squamous cell carcinoma (SCC) line, PDV, which is markedly inhibited in immunocompetent versusalphabeta T cell-deficient mice. We show that the protective response is composed of CD8(+) and interferon-gamma (IFNgamma)-producing CD4(+) cells, and that the most overt effects of these components on tumor growth in situ are to provoke overt focal necroses and to decrease the stromal bed. Tumors growing in the presence of any of these components also show reduced expression of Rae-1, a ligand for the activating NK receptor, NKG2D. Collectively, these data illustrate which components of the alphabeta T cell response against SCC have protective potential, and indicate which aspects of tumor physiology may be most susceptible to their activities.


A novel multimodal platform for assessing surgical technical skills.
Established methods for assessing surgical performance face limitations. Global rating scales and procedure-specific checklists are resource intensive and rely on expert opinions. Alternatives that use technology to track hand movements, such as magnetic and optical tracking systems, are generally expensive and ill suited to the surgical environment. The authors present a new platform that integrates a novel, low-cost optical tracking system, magnetic tracking technology and a videographic recording system to quantify surgical performance synchronously across all modalities. The validity of this platform was tested by examining its ability to differentiate between the performance of expert and novice participants on a basic surgical task. Each modality was able to differentiate between expert and novice participants, and metrics were well correlated across modalities. The authors have developed a platform for assessing surgical performance. It can operate in the absence of expert raters and has the potential to provide immediate feedback to trainees.


The role of blood flow and microRNAs in blood vessel development.
The circulatory system is the first organ system that develops during embryogenesis, and is essential for embryo viability and survival. Crucial for developing a functional vasculature are the specification of arterial-venous identity in vessels and the formation of a hierarchical branched vascular network. Sprouting angiogenesis, intussusception, and flow driven remodeling events collectively contribute to establishing the vascular architecture. At the molecular level, arterial-venous identity and branching are regulated by genetically hardwired mechanisms involving Notch, vascular endothelial growth factor and neural guidance molecule signaling pathways, modulated by hemodynamic factors. MicroRNAs are small, non-coding RNAs that act as silencers to fine-tune the gene expression profile. MicroRNAs are known to influence cell fate decisions, and microRNA expression can be controlled by blood flow, thus placing microRNAs potentially at the center of the genetic cascades regulating vascular differentiation. In the present review, we summarize current progress regarding microRNA functions in blood vessel development with an emphasis on studies performed in zebrafish and mouse models.


Return to Play After Osteochondral Autograft Transplantation of the Capitellum: A Systematic Review.
To determine the rate of return to play and to identify lesion or osteochondral graft characteristics that may influence the return to competitive athletics after osteochondral autograft transplantation (OAT) for symptomatic osteochondritis dissecans (OCD) lesions. A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A duplicate search of PubMed, Embase, Scopus, Web of Science, and CENTRAL databases was performed, beginning from the database inception dates through July 2016, for all articles evaluating the return to play after OAT for OCD lesions of the capitellum. A methodological quality assessment was completed for all included studies. Patient demographics, osteochondral lesion and graft characteristics, the number of patients, and timing of return to competitive activity were collected and evaluated. Association between graft size/number, the time to osseous healing, and return to sport was evaluated. Seven articles met the inclusion criteria. All included studies were case series of moderate quality with a mean Methodological Index for Non-Randomized Studies score of 12/16. Overall, 94% (119/126) of patients undergoing OAT for OCD lesions of the capitellum successfully returned to competitive sports. The mean reported time for unrestricted return to athletic competition after OAT was 5.6 months (range, 3-14 months). Current best evidence suggests that OAT is successful in treating advanced OCD lesions of the capitellum and returning athletes to high-level competition. Evidence supporting the association between the size and number of grafts used and the time to osseous healing and return to sport is currently limited. Our assessment of the time to return to athletic competition was limited because of variable surgical technique, postoperative rehabilitation protocols, and outcome assessment. Level IV, systematic review of Level IV studies.


Formation of Large Intracellular Actin Networks Following Plasmonic Cell Fusion.
Following fusion between two or more individual cells, the resulting cellular entity must undergo extensive restructuring of its plasma membrane and cytoskeleton in order to maintain its mechanical and physiological function. In artificial cell fusion that is executed by external triggering, such restructuring could be problematic due to the absence of preconditioning biological signals. In this work we study the reorganization of the actin filaments in adenocarcinoma cells that were fused using plasmonic triggering, i.e. the irradiation by resonant femtosecond laser pulses of cells specifically targeted by gold nanoparticles. Time-lapse confocal microscopy of the fusing cells has revealed the formation of large-scale actin networks that preserve the local orientations of the original actin cytoskeletons. The results confirm the local nature of the plasmonic interactions that were confined to the cells' plasma membranes and would help studying the development and dynamics of actin networks by offering a relatively stable, living cellular environment that supports large-scale actin growth.


Looking for related posts on GitHub discussions.
Software teams increasingly adopt different tools and communication channels to aid the software collaborative development model and coordinate tasks. Among such resources, software development forums have become widely used by developers. Such environments enable developers to get and share technical information quickly. In line with this trend, GitHub announced GitHub Discussions-a native forum to facilitate collaborative discussions between users and members of communities hosted on the platform. Since GitHub Discussions is a software development forum, it faces challenges similar to those faced by systems used for asynchronous communication, including the problems caused by related posts (duplicated and near-duplicated posts). These related posts can add noise to the platform and compromise project knowledge sharing. Hence, this article addresses the problem of detecting related posts on GitHub Discussions. To achieve this, we propose an approach based on a Sentence-BERT pre-trained general-purpose model: the RD-Detector. We evaluated RD-Detector using data from three communities hosted in GitHub. Our dataset comprises 16,048 discussion posts. Three maintainers and three Software Engineering (SE) researchers manually evaluated the RD-Detector results, achieving 77-100% of precision and 66% of recall. In addition, maintainers pointed out practical applications of the approach, such as providing knowledge to support merging the discussion posts and converting the posts to comments on other related posts. Maintainers can benefit from RD-Detector to address the labor-intensive task of manually detecting related posts.


Development of energy plants and their potential to withstand various extreme environments.
Biomass utilization is increasingly considered as a practical way for sustainable energy supply and long-term environment care around the world. In concerns with food security, starch or sugar-based bioethanol and edible-oilderived biodiesel are severely restricted for large scale production. Alternatively, conversion of lignocellulosic residues from food crops could be considered, but due to its recalcitrance, the current biomass process is unacceptably expensive. In this context, genetic breeding of energy crops appears as a promising solution. To fulfil the global world need as both food and biofuel sources, energy crops are expected to be produced with higher yields and especially in marginal lands. This review focus on recent progress and patents dealing with energy plants and the challenges associated with bioenergy development. We also discuss the potential use of molecular approaches including genome sequencing, molecular markers, and genetic transformation for improving specific traits or generating new cultivars of energy plants.


Clinical experience with butyl-2-cyanoacrylate adhesive in the management of canine and feline corneal disease.
To examine and evaluate clinical indications and postoperative outcome in a series of small animal patients in which corneal disease was managed by the application of butyl 2-cyanoacrylate adhesive. In this retrospective study all small animal patients were identified that presented to the Royal Veterinary College, University of London over a 2-year period, in which corneal disease was managed by the application of butyl 2-cyanoacrylate. Indications for application, complicating factors prior to gluing, glue retention time, postoperative comfort, and extent of subsequent corneal reaction and scarring were noted for each case. Long-term follow-up data concerning visual and cosmetic outcome were obtained from owners and referring veterinarians. Thirty-seven patients (28 dogs and 9 cats), in which 39 eyes were treated, were identified. Indications for corneal gluing in this series included stromal ulceration (26/39 eyes); descemetocele (4/39 eyes); corneal laceration/foreign body (5/39 eyes); lamellar keratectomy (3/39 eyes) and superficial ulceration (1/39 eyes). At least one factor responsible for initiation, persistence or progression of the ulcer was identified in 66.7% of eyes prior to corneal gluing. These included keratomalacia; confirmed bacterial keratitis; corneal edema related to endothelial disease and keratoconjunctivitis sicca. Cyanoacrylate was generally well tolerated by patients with only 8/34 eyes demonstrating transient blepharospasm and increased lacrimation postoperatively. Retention time of cyanoacrylate varied widely from < 1 week to approximately 6 months, but was < 2 months in the majority (89%) of eyes. Exaggerated corneal vascularization was an infrequent postoperative complication, noted in only six canine eyes, and did not appear to be related to initial corneal disease, glue retention time or breed. Butyl 2-cyanoacrylate offers a convenient, economical and effective alternative to other treatment modalities, such as conjunctival grafts, in the management of corneal defects in canine and feline patients.


Ischemic cell death: dynamics of delayed secondary energy failure during reperfusion following focal ischemia.
Reperfusion injury is believed to contribute to the pathophysiology of ischemic cell death, but the precipitating factors have yet to be completely elucidated. The goal of this study was to examine if reflow-induced secondary energy failure is a component in the events that lead to cell death following increasing periods of middle cerebral artery (MCA) occlusion in Wistar rats. Discrete sections within the MCA distribution were dissected and analyzed for high-energy phosphates and glucose. Regional cerebral blood flow was determined by [14C]-iodoantipyrine technique in representative groups. The levels of ATP + P-creatine were initially depressed at the end of the focal ischemia and the concentrations in the penumbra were unchanged for up to 8 h after 2 h of ischemia which contrasts with response in the ischemic core, striatum, and penumbra where the HEP generally recovered to values near those of control only to decrease with increasing periods of reflow. The possibility of a rebound ischemia in secondary energy failure (SEF) was precluded by regional CBF values and concentrations of glucose that were significantly higher than the threshold for an ischemic effect. The depletion of cellular energy stores following SEF strongly indicates that the evolution of infarct during reflow results from loss of ATP and its synthesis.


Robust Decision Analysis under Severe Uncertainty and Ambiguous Tradeoffs: An Invasive Species Case Study.
Bayesian decision analysis is a useful method for risk management decisions, but is limited in its ability to consider severe uncertainty in knowledge, and value ambiguity in management objectives. We study the use of robust Bayesian decision analysis to handle problems where one or both of these issues arise. The robust Bayesian approach models severe uncertainty through bounds on probability distributions, and value ambiguity through bounds on utility functions. To incorporate data, standard Bayesian updating is applied on the entire set of distributions. To elicit our expert's utility representing the value of different management objectives, we use a modified version of the swing weighting procedure that can cope with severe value ambiguity. We demonstrate these methods on an environmental management problem to eradicate an alien invasive marmorkrebs recently discovered in Sweden, which needed a rapid response despite substantial knowledge gaps if the species was still present (i.e., severe uncertainty) and the need for difficult tradeoffs and competing interests (i.e., value ambiguity). We identify that the decision alternatives to drain the system and remove individuals in combination with dredging and sieving with or without a degradable biocide, or increasing pH, are consistently bad under the entire range of probability and utility bounds. This case study shows how robust Bayesian decision analysis provides a transparent methodology for integrating information in risk management problems where little data are available and/or where the tradeoffs are ambiguous.


Access to social capital and risk of HIV infection in Bukoba urban district, Kagera region, Tanzania.
Kagera is one of the 22 regions of Tanzania mainland, which has witnessed a decline in HIV prevalence during the past two decades; decreasing from 24% in 1987 to 4.7 in 2009 in the urban district of Bukoba. Access to social capital, both structural and cognitive, might have played a role in this development. The aim was to examine the association between individual structural and cognitive social capital and socio-economic characteristics and the likelihood of being HIV infected. We conducted a population-based cross-sectional study of 3586 participants, of which 3423 (95%) agreed to test for HIV following pre-test counseling. The HIV testing was performed using enzyme-linked immunosorbent assay (ELISA) antibody detection tests. Multiple logistic regression analysis was applied to estimate the impact of socio-economic factors, individual structural and cognitive social capital and HIV sero-status. Individuals who had access to low levels of both structural and cognitive individual social capital were four and three times more likely to be HIV positive compared to individuals who had access to high levels. The associations remained statistically significant for both individual structural and cognitive social capital after adjusting for potential confounding factors such as age, sex, marital status, occupation, level of education and wealth index (OR =8.6, CI: 5.7-13.0 and OR =2.4, CI: 1.6-3.5 for individual structural and cognitive social capital respectively). For both women and men access to high levels of individual structural and cognitive social capital decreased the risk of being HIV infected. This study confirms previous qualitative studies indicating that access to structural and cognitive social capital is protective to HIV infection. We suggest that policy makers and programme managers of HIV interventions may consider strengthening and facilitating access to social capital as a way of promoting HIV preventive information and interventions in order to reduce new HIV infections in Tanzania.


Multilevel anterior cervical corpectomy and fibular allograft fusion for cervical myelopathy.
This study was conducted to determine the safety and efficacy of multilevel anterior cervical corpectomy and stabilization using fibular allograft in patients with cervical myelopathy. Thirty-six patients underwent this procedure for cervical myelopathy caused by spondylosis (20 patients), ossified posterior longitudinal ligament (four patients), trauma (one patient), or a combination of lesions (11 patients). The mean age (+/- standard deviation) of the patients was 58 +/- 10 years and 30 of the patients were men. The mean duration of symptoms before surgery was 30 +/- 6 months and 11 patients had undergone previous surgery. Prior to surgery, the mean Nurick grade of the myelopathy was 3.1 +/- 1.4. Seventeen patients also had cervicobrachial pain. Four vertebrae were removed in six patients, three in 19, and two in 11 patients. Instrumentation was used in 15 cases. The operative mortality rate was 3% (one patient) and two patients died 2 months postoperatively. Postoperative complications included early graft displacement requiring reoperation (three patients), transient dysphagia (two patients), cerebrospinal fluid leak treated by lumbar drainage (three patients), myocardial infarction (two patients), and late graft fracture (one patient). One patient developed transient worsening of myelopathy and three developed new, temporary radiculopathies. All patients achieved stable bone union and the mean Nurick grade at an average of 31 +/- 20 months (range 0-79 months) postoperatively was 2.4 +/- 1.6 (p < 0.05, t-test). Cervicobrachial pain improved in 10 (59%) of the 17 patients who had preoperative pain and myelopathy improved at least one grade in 17 patients (47%; p < 0.05). Twenty-six surviving patients (72%) were followed for more than 24 months and stable, osseous union occurred in 97%. These results show that extensive, multilevel anterior decompression and stabilization using fibular allograft can be achieved with a perioperative mortality and major morbidity rate of 22% and with significant improvement in pain and myelopathy.


Molecular breeding in developing countries: challenges and perspectives.
Molecular breeding (MB) holds great promise for developing countries. However, the developing countries are hardly homogeneous in its implementation. Whilst newly industrialised countries routinely use several MB applications and are exploring the latest approaches, developing countries with mid-level economies are testing marker applications and taking initial steps towards adopting MB in day-to-day breeding. Various bottlenecks still impede adoption in these countries. Limited human resources and inadequate field infrastructure remain major challenges, although through virtual platforms aided by the information and communication technology revolution, breeders now have better access to genomic resources, advanced laboratory services, and robust analytical and data management tools. These developments are bound to have impact crop improvement in developing countries.


Effect of neurotransmitter-selective drugs in mice selected for differential sensitivity to the hypothermic actions of ethanol.
Mice selectively bred for resistance (HOT) and sensitivity (COLD) to the hypothermic effect of EtOH were tested for their hypothermic response to neurotransmitter-specific drugs and for the effect of such drugs on EtOH induced hypothermia (HT). The drugs administered were the opiate drugs morphine, levorphanol and U50488H, the dopamine agonists apomorphine, LY171535 and SKF38393, the dopamine antagonist chlorpromazine, the alpha adrenergic agonist St587, the cholinergic agonist nicotine and amphetamine, which increases the release of catecholamines. All of the drugs tested, with the exception of SKF38393 and amphetamine, induced a hypothermic response in HOT and COLD mice. SKF38393 had no effect on body temperature or HT produced by EtOH. Amphetamine caused HT at low doses and hyperthermia at high doses. COLD mice were more sensitive than HOT mice to the hypothermic effect of morphine and levorphanol, mu-opiate agonists, and U50488H, a relatively specific kappa agonist. All of the other drugs tested were approximately equally potent in HOT and COLD mice. These results suggest that the differential sensitivity of HOT and COLD mice to EtOH-induced HT may be partially mediated through genetic changes in opiate mechanisms.


Preconcentration method of antimony using modified thiol cotton fiber for isotopic analyses of antimony in natural samples.
It is very important to investigate antimony geochemical behavior in order to identify its source, or reveal contamination processes, since antimony and its compounds are considered to be pollutants of high priority by the Environmental Protection Agency of the United States (USEPA). However, the concentration of antimony in most geological samples is very low, and its stable isotope mass difference is only 1.6%. An antimony preconcentration method for isotope analysis using modified Thiol Cotton Fiber has been developed. Using this new method, the recovery of antimony was 99.5 ± 3.6% (n = 3) and blank values were <0.1 ng. The standard error of the ε(123)Sb isotope ratios in the proposed method is only 0.4ε, much smaller than those of the previous method. The proposed method is therefore effective in the preconcentration and separation of antimony for antimony isotope analysis.


A novel benzothiazole-based mononuclear platinum(II) complex displaying potent antiproliferative activity in HepG-2 cells via mitochondrial-mediated apoptosis.
A novel mononuclear platinum(II) complex, [Pt(L-H)Cl] (1, where L= N-(4-(benzo[d]thiazol-2-yl)phenyl)-2-((2-pyridylmethyl)(2-hydroxyethyl)-amino)acetamide), was obtained by covalently tethering a benzothiazole derivative 2-(4-aminophenyl)benzothiazole to the 2-pyridylmethyl-2-hydroxyethylamine chelating PtII center. In vitro tests indicated that complex 1 displayed excellent antiproliferative activity against the tested cancer cell lines, especially liver cancer HepG-2 and SMMC-7221 cells. Importantly, the complex possessed 4.33-fold higher antiproliferative activity as compared with cisplatin against HepG-2 cells, but was less toxic to the normal cell line L02 with the selectivity index (SI = IC50(L02)/IC50(HepG-2)) value of 8.36 compared to cisplatin (SI, 1.40). The results suggested that 1 might have the potential to act as a candidate for the treatment of hepatocellular carcinoma (HCC). Cellular uptake and distribution studies showed that 1 could effectively pass through the membrane of cells, enter the nuclei and mitochondria, induce the platination of cellular DNA. The interaction of 1 with CT-DNA demonstrated that 1 could effectively bind to DNA in a dual binding mode, i.e., the intercalation of the 2-(4-aminophenyl)benzothiazole unit plus monofunctional platination of the platinum(II) moiety. In addition, Hoechst 33342 staining and flow cytometry analysis illustrated that 1 arrested the cell cycle in HepG-2 cancer cells at G2/M phases, induced mitochondrial membrane depolarization, increased ROS generation, and caused obvious cell apoptosis. Further cellular mechanism studies elucidated that 1 triggered HepG-2 cell apoptosis via the mitochondrial-mediated pathway by upregulating the gene and protein expression levels of Bax, downregulating the gene and protein expression levels of Bcl-2, and activating the caspase cascade.


Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms.
Redundant mechanisms mediate colon cancer angiogenesis. Targeting multiple angiogenic factors simultaneously may improve survival of mice with colon cancer metastases. BALB/c mice underwent splenic injection with CT-26 colon cancer cells to generate liver metastases and received administration of either vehicle alone or a tyrosine kinase inhibitor for vascular endothelial growth factor, basic fibroblast growth factor, and platelet-derived growth factor receptors (SU6668). Mice were sacrificed when they became moribund as determined by a blinded observer. In a parallel experiment, groups of mice were sacrificed at earlier time points to better define the kinetics of the effect of SU6668 on angiogenic parameters over time. SU6668 increased median survival by 58% (P < 0.001) and led to a progressive increase in tumor cell and endothelial cell apoptosis that increased over time. In addition, pericyte vessel coverage and tumor vascularity were significantly decreased in mice treated with SU6668. Based on current knowledge of endothelial cell survival, these data suggest that SU6668 may prevent tumor endothelial cell survival directly (vascular endothelial growth factor) and indirectly (pericyte coverage) by affecting endothelial cell survival mechanisms.


Psychosocial Risk Impacts Mortality in Women After Liver Transplantation.
Liver transplant candidates undergo psychosocial assessment as a component of their pretransplant evaluation. Global psychosocial assessment scales, including the Psychosocial Assessment of Candidates for Transplantation (PACT), capture and quantify these psychiatric and social variables. Our primary aim was to assess for an association between global PACT score and survival in liver transplant recipients. This retrospective cohort study examined records of all liver recipients at one U.S. Transplant Center from 2000 to 2012 with outcomes monitoring until 07/01/2016. We investigated for associations between the following variables and mortality: PACT score, age, gender, marital status, race, alcoholic liver disease (ALD), and body mass index (BMI). Statistical methods included Student's t-test, Wilcoxon rank sum test, chi-square, Fisher's exact test, Kaplan-Meier curve, and Cox proportional hazard models. Of 1040 liver recipients, 538 had a documented PACT score. Among these, PACT score was not associated with mortality. In women, a lower PACT score was associated with mortality (p = 0.003) even after adjustments for age, marital status, and BMI. Women with ALD had a 2-fold increased hazard of death (p = 0.012). Increasing age was associated with increased risk of death for the cohort as a whole (p = 0.019) and for men (p = 0.014). In men, being married and BMI were marginally protective (p = 0.10 and p = 0.13, respectively). Transplant psychosocial screening scales, specifically the PACT, identify psychosocial burden and may predict post-transplant outcomes in certain populations. In female liver recipients, lower PACT scores and ALD were associated with a greater risk of post-transplant mortality.


A rare case of left innominate vein aneurysm mimicking thymoma.
Thoracic venous aneurysms are very rare conditions, even more unusual from left innominate vein. We report a case of a 57-year-old male who presented an anterior mediastinal mass suspicious of thymoma by chest computed tomography. Median sternotomy was performed aiming for total thymectomy, but intraoperative findings and final pathology confirmed the diagnosis of left innominate vein aneurysm. The patient underwent aneurysmectomy and reconstruction of the left innominate vein. The patient remains well 2 years after surgery. The new thoughts provoked by this case are that video-assisted thoracic surgery for this condition is dangerous and mediastinal mass should be evaluated further by magnetic resonance imaging, venography or venous phase computed tomography.


Morphological abnormalities of the recto-anal inhibitory reflex reflects symptom pattern in neurogenic bowel.
Bowel dysfunction amongst multiple sclerosis (MS) and spinal cord injury (SCI) patients often manifests as fecal incontinence (FI) or constipation, but the pathophysiology is poorly understood. Anorectal physiology provides an objective assessment of lower bowel functions and is increasingly being used in clinical practice. The purpose of this study was to correlate symptoms of bowel dysfunction in patients with spinal cord disease with findings in anorectal physiology. We hypothesized that specific abnormalities will correlate with symptoms: prolonged recto-anal inhibitory reflex in patients with incontinence and decreased rectal mucosal blood flow in patients with constipation. Forty-nine patients with MS (35 with predominant FI and 14 constipation), 46 supraconal SCI (mixed symptom load), and 21 healthy volunteers matched for age and sex were studied. Subjects completed validated constipation and FI symptom questionnaires. Patients underwent standard anorectal physiology, including assessment of rectal mucosal blood flow and recto-anal inhibitory reflex (RAIR). Severity of constipation correlates significantly with distension sensitivity (urge volume [r = 0.68, p = 0.002] and maximal volume [r = 0.39, p = 0.03]). Severity of constipation also correlated with diminished rectal mucosal blood flow in both patient groups (r = -0.51, p = 0.006). In both groups, constipation correlated with diminished relaxation of the sphincters in the RAIR whilst fecal incontinence correlated with a prolonged duration of RAIR (r = 0.33, p = 0.009) and recovery phase (r = 0.37, p = 0.05). Bowel symptoms in patients with MS and SCI correlate with specific alterations of anorectal physiology. This provides objective assessment of bowel symptoms and may allow tailored treatment to individual patients.


Development and Co-design of NeuroOrb: A Novel "Serious Gaming" System Targeting Cognitive Impairment in Parkinson's Disease.
Whilst Parkinson's disease (PD) is typically thought of as a motor disease, a significant number of individuals also experience cognitive impairment (CI), ranging from mild-CI to dementia. One technique that may prove effective in delaying the onset of CI in PD is cognitive training (CT); however, evidence to date is variable. This may be due to the implementation of CT in this population, with the motor impairments of PD potentially hampering the ability to use standard equipment, such as pen-and-paper or a computer mouse. This may, in turn, promote negative attitudes toward the CT paradigm, which may correlate with poorer outcomes. Consequently, optimizing a system for the delivery of CT in the PD population may improve the accessibility of and engagement with the CT paradigm, subsequently leading to better outcomes. To achieve this, the NeuroOrb Gaming System was designed, coupling a novel accessible controller, specifically developed for use with people with motor impairments, with a "Serious Games" software suite, custom-designed to target the cognitive domains typically affected in PD. The aim of the current study was to evaluate the usability of the NeuroOrb through a reiterative co-design process, in order to optimize the system for future use in clinical trials of CT in individuals with PD. Individuals with PD (n = 13; mean age = 68.15 years; mean disease duration = 8 years) were recruited from the community and participated in three co-design loops. After implementation of key stakeholder feedback to make significant modifications to the system, system usability was improved and participant attitudes toward the NeuroOrb were very positive. Taken together, this provides rationale for moving forward with a future clinical trial investigating the utility of the NeuroOrb as a tool to deliver CT in PD.


ICE1 promotes the link between splicing and nonsense-mediated mRNA decay.
The nonsense-mediated mRNA decay (NMD) pathway detects aberrant transcripts containing premature termination codons (PTCs) and regulates expression of 5-10% of non-aberrant human mRNAs. To date, most proteins involved in NMD have been identified by genetic screens in model organisms; however, the increased complexity of gene expression regulation in human cells suggests that additional proteins may participate in the human NMD pathway. To identify proteins required for NMD, we performed a genome-wide RNAi screen against >21,000 genes. Canonical members of the NMD pathway were highly enriched as top hits in the siRNA screen, along with numerous candidate NMD factors, including the conserved ICE1/KIAA0947 protein. RNAseq studies reveal that depletion of ICE1 globally enhances accumulation and stability of NMD-target mRNAs. Further, our data suggest that ICE1 uses a putative MIF4G domain to interact with exon junction complex (EJC) proteins and promotes the association of the NMD protein UPF3B with the EJC.


Inspiratory muscle training using an incremental endurance test alleviates dyspnea and improves functional status in patients with chronic heart failure.
The benefits of inspiratory muscle training (IMT) in patients with chronic heart failure (CHF) have been inadequately studied. Using a prospective, age and sex-matched controlled study, we investigated 35 patients with moderate to severe CHF (NYHA class II-III and left ventricular ejection fraction 24.4+/-1.3% [mean+/-SEM]). An incremental respiratory endurance test using a fixed respiratory workload was provided by software with an electronic mouth pressure manometer interfaced with a computer. The training group (n=20) exercised at 60% of individual sustained maximal inspiratory pressure (SMIP) and the control group (n=15) at 15% of SMIP. All patients exercised three times weekly for 10 weeks. Pulmonary function, exercise capacity, dyspnea and quality of life were assessed, pre- and post-training. The training group significantly increased both maximum inspiratory pressure (Pimax), (111+/-6.8 versus 83+/-5.7 cmH2O, P<0.001), and SMIP (527822+/-51358 versus 367360+/-41111 cmH2O/sec x 10(-1), P<0.001). Peak VO2 increased after training (17.8+/-1.2 versus 15.4+/-0.9 ml/kg/min, P<0.005), as did the six-minute walking distance (433+/-16 versus 367+/-22 meters, P<0.001). Perceived dyspnea assessed using the Borg scale was reduced for both the treadmill (12.7+/-0.57 versus 14.2+/-0.48, P<0.005) and the walking (9+/-0.48 versus 10.5+/-0.67, P<0.005) exercise tests and the quality of life score was also improved (21.1+/-3.5 versus 25.2+/-4, P<0.01). Resting heart rate was significantly reduced with training (77+/-3.3 versus 80+/-3 beats/min, P<0.05). The control group significantly increased Pimax (86.6+/-6.3 versus 78.4+/-6.9 cmH2O, P<0.05), but decreased SMIP (274972+/-32399 versus 204661+/-37184 cmH2O/sec x 10(1), P<0.005). No other significant effect on exercise capacity, heart rate, dyspnea, or quality of life was observed in this group. Inspiratory muscle training using an incremental endurance test, successfully increases both inspiratory strength and endurance, alleviates dyspnea and improves functional status in CHF.


Successful Ultrasound-Guided Percutaneous Drainage of Multiple Splenic Abscesses in a Kidney Transplant Patient With Encapsulated Sclerosing Peritonitis: A Case Report.
Differential diagnosis of post-transplant infections should include rare/uncommon foci and pathogens. We present a rare case of life-threatening infection, a splenic abscess in a 53-year-old woman who was transplanted with a cadaveric kidney 5 months previously. The patient was admitted to our clinic with chills, shivering, and fever. She required a kidney transplant because of end-stage renal disease secondary to systemic lupus erythematosus, which had previously been treated by means of peritoneal dialysis for 7 years, until encapsulated sclerosing peritonitis developed, at which time therapy was changed to hemodialysis for 1 year. On physical examination, the patient was slightly lethargic and had tenderness in the left upper quadrant of the abdomen. Laboratory evaluation revealed leukocytosis and high acute phase reactant. Abdominal ultrasonography (US) revealed multiple abscesses in the spleen, but splenectomy was not recommended because of her history of sclerosing peritonitis. Percutaneous drainage catheters were placed under US guidance. Culture of blood and fluid drained from the abscess revealed imipenem-sensitive Escherichia coli and Klebsiella spp. Imipenem (500 mg IV q6hr) was initiated, and the drainage volume was 40 to 50 mL/day in the first week and gradually decreased through the third week. The abscess was completely drained over a period of 6 weeks, as confirmed by computed tomography; percutaneous catheters were then removed. Although splenic abscesses are life-threatening, especially for immunocompromised patients, this case suggests that percutaneous drainage guided by US or computed tomography is an efficient treatment alternative to splenectomy.


Where should patient safety be installed?
The structure of an organization is important, and structure has a profound influence on the way people work and what gets done. Where work units and individuals in an organization are placed, to whom they report, and with whom they are grouped signals power, prestige, and privilege. It also divides workers into groups with common interests and motivations. The question is, where should patient safety be placed in a health care organization? Such a question can be answered only within a framework of understanding that gives a clear definition to patient safety. We define safety, as do safety professionals from other industries, as the reduction of risk. This definition is also in concert with the risk management model that identifies claims management, risk financing, and loss control as its foundational triad.


Predominant immediate-early transcripts of human cytomegalovirus AD 169.
Transcription of the human cytomegalovirus genome (strain AD 169) was investigated at the immediate-early (IE) time after infection, by using cycloheximide to suppress virus-specific protein synthesis. In total cell RNA, four predominant IE transcripts were found which were encoded by one contiguous region of the long unique segment between map units 0.06 and 0.16 in prototype arrangement of human cytomegalovirus AD 169 DNA. Analysis by Northern blot hybridizations demonstrated that the transcripts possessed a size of 1.9, 2.2, 2.3, and 5.0 kilobases, respectively. Coding sequences and directions of transcriptions were mapped by Northern blots and hybridizations with oligodeoxythymidylic acid-primed and randomly primed cDNA. The 1.9-, 2.2-, and 2.3-kilobase RNAs were found in the polyadenylated fraction of IE RNA exclusively; in contrast, a part of the 5.0-kilobase RNA appeared polyadenylated, although the majority of the same transcript was found in the nonpolyadenylated pool. Also, different from the other IE genes, the DNA coding for the 5.0-kilobase IE RNA was transcribed in high quantities during the late phase of virus replication, suggesting an exemption from the temporal regulation of herpesvirus transcription.


Laparoscopic gastric resection approaches for gastrointestinal stromal tumors of stomach.
To evaluate laparoscopic gastric resection for gastrointestinal stromal tumors (GIST). From June, 2003 to October, 2009, 56 patients with gastric GIST who underwent laparoscopic gastric resection were retrospectively reviewed, and their surgical procedure, perioperative outcomes, pathology, and follow-up outcomes were analyzed. All patients underwent laparoscopic gastric resection successfully, including 33 laparoscopic wedge resections, 19 laparoscopic transgastric tumor-everting resections, 3 laparoscopic-assisted distal gastrectomies, and 1 laparoscopic-assisted endoscopic resection. The operative approaches performed were mostly based on the tumor location. No conversions were observed. The mean operative duration was 90 minutes (30 to 210 min), blood loss was 55 mL (5 to 180 mL), time for passage of flatus was 2 days (1 to 11 d), and the postoperative hospital stay was 7 days (3 to 13 d). The resection margin was microscopic negative. After 21.5 months (6 to 76 mo) of follow-up, there was no operative recurrence and metastasis. Laparoscopic gastric resection for selective cases of gastric GISTs is safe, feasible, and effective. Laparoscopic wedge resection procedure is the first choice for most GISTs located in fundus and anterior wall, laparoscopic transgastric tumor-everting resection procedure can be used in cases with the tumor located in esophagogastric junction area and in posterior wall of the stomach as well. For antral tumors, laparoscopic subtotal gastrectomy with gastrojejunostomy should be performed.


Nanotechnological Strategies as Smart ways for Diagnosis and Treatment of the Atherosclerosis.
Atherosclerosis provokes a continuous worsening of affected vessels causing a blood flow diminution with several complications and with clinical manifestations that generally appear in advanced phases of the illness. Hence, the conventional therapies are not enough because the atherosclerotic injuries are often irrevocable. For this reason, emerges the necessity to implement smart ways of drug supply and develop new therapeutic targets that decrease the advance atherosclerotic lesion. It results due to particular interest to use new tools for prevention, diagnosis, and treatment of this cardiovascular disease, thus concentrating our attention to accomplish better management on the immune system. Finally, this mini-review highlights the most recent knowledge about nanotechnology as a robust, novel and promissory therapeutic option applied to atherosclerotic pathology, nevertheless, we also alert for possible issues associated with their use.


Controllable co-segregation synthesis of wafer-scale hexagonal boron nitride thin films.
A facile and scalable co-segregation method is used to grow hexagonal boron nitride (h-BN) thin films from B- and N-containing metals. By annealing the sandwiched metal substrates in vacuum, sub-monolayer h-BN flakes, monolayer h-BN films, and multilayer h-BN thin films of varying thickness are successfully prepared. This approach follows an underneath-growth mode and exhibits good thickness- and location-control.


Mind-body therapies for menopausal symptoms: a systematic review.
To systematically review the peer-reviewed literature regarding the effects of self-administered mind-body therapies on menopausal symptoms. To identify qualifying studies, we searched 10 scientific databases and scanned bibliographies of relevant review papers and all identified articles. The methodological quality of all studies was assessed systematically using predefined criteria. Twenty-one papers representing 18 clinical trials from 6 countries met our inclusion criteria, including 12 randomized controlled trials (N=719), 1 non-randomized controlled trial (N=58), and 5 uncontrolled trials (N=105). Interventions included yoga and/or meditation-based programs, tai chi, and other relaxation practices, including muscle relaxation and breath-based techniques, relaxation response training, and low-frequency sound-wave therapy. Eight of the nine studies of yoga, tai chi, and meditation-based programs reported improvement in overall menopausal and vasomotor symptoms; six of seven trials indicated improvement in mood and sleep with yoga-based programs, and four studies reported reduced musculoskeletal pain. Results from the remaining nine trials suggest that breath-based and other relaxation therapies also show promise for alleviating vasomotor and other menopausal symptoms, although intergroup findings were mixed. Most studies reviewed suffered methodological or other limitations, complicating interpretation of findings. Collectively, findings of these studies suggest that yoga-based and certain other mind-body therapies may be beneficial for alleviating specific menopausal symptoms. However, the limitations characterizing most studies hinder interpretation of findings and preclude firm conclusions regarding efficacy. Additional large, methodologically sound trials are needed to determine the effects of specific mind-body therapies on menopausal symptoms, examine long-term outcomes, and investigate underlying mechanisms.


Bringing continuing medical education to the bedside: the University of California, San Francisco Hospitalist Mini-College.
As a relatively new generalist specialty, hospitalists must acquire new competencies that may not have been taught during their training years. Continuing medical education (CME) has traditionally been a mechanism to meet training needs but often fails to apply adult learning principles and fulfill current demands. We developed an innovative 3-day course called the University of California, San Francisco Hospitalist Mini-College (UHMC) that brings adult learners to the bedside for small-group learning focused on content areas relevant to today's hospitalists. The program was built on a structure of 4 clinical domains and 2 clinical skills labs. Sessions about patient safety and immersion into traditional academic learning vehicles, such as morning report and a morbidity and mortality conference, were also included. Participants completed a precourse survey and a postcourse evaluation. Over 5 years, 152 participants enrolled and completed the program; 91% completed the pre-UHMC survey and 89% completed the postcourse evaluation. Overall, participants rated the quality of the UHMC course highly (4.65; 1-5 scale). Ninety-eight percent of UHMC participants (n = 57) in 2011 to 2012 reported a "high" or "definite" likelihood to change practice, higher than the 78% reported by the 11,447 participants in other UCSF CME courses during the same time period. The UHMC successfully brought participants to an academic health center for a participatory, hands-on, and small-group learning experience that was highly rated. A shift of CME from a hotel conference room to the bedside is feasible, valued by participants, and offers a new paradigm for how to maintain and improve hospitalist competencies.


Clinical Feasibility of Ultrafast Contrast-Enhanced T1-Weighted 3D-EPI for Evaluating Intracranial Enhancing Lesions in Oncology Patients: Comparison with Standard 3D MPRAGE Sequence.
Contrast-enhanced 3D T1WI is a preferred sequence for brain tumor imaging despite the long scan time. This study investigated the clinical feasibility of ultrafast contrast-enhanced T1WI by 3D echo-planar imaging compared with a standard contrast-enhanced 3D MPRAGE sequence for evaluating intracranial enhancing lesions in oncology patients. Sixty-one patients in oncology underwent brain MR imaging including both contrast-enhanced T1WI, 3D-EPI and 3D MPRAGE, in a single examination session for evaluating intracranial tumors. Two neuroradiologists evaluated image quality, lesion conspicuity, diagnostic confidence, number and size of the lesions, and contrast-to-noise ratio measurements from the 2 different sequences. Ultrafast 3D-EPI T1WI did not reveal significant differences in diagnostic confidence, contrast-to-noise ratiolesion/parenchyma, and the number of enhancing lesions compared with MPRAGE (P > .05). However, ultrafast 3D-EPI T1WI revealed inferior image quality, inferior anatomic delineation and greater susceptibility artifacts with fewer motion artifacts than images obtained with MPRAGE. The mean contrast-to-noise ratioWM/GM and visual conspicuity of the lesion on ultrafast 3D-EPI T1WI were lower than those of MPRAGE (P < .001). Ultrafast 3D-EPI T1WI showed comparable diagnostic performance with sufficient image quality and a 7-fold reduction in scan time for evaluating intracranial enhancing lesions compared with standard MPRAGE, even though it was limited by an inferior image quality and frequent susceptibility artifacts. Therefore, we believe that ultrafast 3D-EPI T1WI may be a viable option in oncology patients prone to movement during imaging studies.


Fragile X syndrome: a review of associated medical problems.
Fragile X syndrome (FXS) is the most common known genetic cause of inherited intellectual disability and the most common known single-gene cause of autism spectrum disorder. It has been reported that a spectrum of medical problems are commonly experienced by people with FXS, such as otitis media, seizures, and gastrointestinal problems. Previous studies examining the prevalence of medical problems related to FXS have been challenging to interpret because of their marked differences in population, setting, and sampling. Through this comprehensive review, we update the literature by reviewing studies that have reported on prominent medical problems associated with FXS. We then compare prevalence results from those studies with results from a large cross-sectional database consisting of data collected by fragile X clinics that specialize in the care of children with FXS and are part of the Fragile X Clinical and Research Consortium. It is vital for pediatricians and other clinicians to be familiar with the medical problems related to FXS so that affected patients may receive proper diagnosis and treatment; improved care may lead to better quality of life for these patients and their families.


Home food availability, parental dietary intake, and familial eating habits influence the diet quality of urban Hispanic children.
The home food environment influences children's eating behaviors and potentially affects overall diet quality. The aim of the present study was to evaluate the relationship between the home food environment and Hispanic children's diet quality. Hispanic children, 10-14 years of age (n=187), and their parents participated in this cross-sectional study. The Healthy Eating Index (HEI) was used to determine diet quality based on reported dietary intake obtained through a food frequency questionnaire administered to the children. Parents self-reported home food availability, familial eating habits, and their own habitual diet through a home environment survey. The children's HEI total score was 59.4±8.8. Reported diets did not adhere to the dietary recommendations for total vegetables, greens and beans, whole grains, seafood and plant proteins, fatty acids, refined grains, sodium, solid fats, and added sugars. None of the participants had "good" scores (HEI, >80), 86% had scores that "need improvement" (HEI, 51-80), and 14% had "poor" scores (HEI, <50). Children with lower HEI scores had sugar-sweetened beverages available at home and participated in family meals while watching television more frequently, when compared with children with higher HEI scores. Home food availability, parental diet, and familial eating habits seem to play an important role in the diet quality of children. Interventions targeting family education on healthful dietary habits at home could have a positive impact on children's diet quality and overall health.


Autocrine production and action of IL-3 and granulocyte colony-stimulating factor in chronic myeloid leukemia.
Primitive subsets of leukemic cells isolated by using fluorescence-activated cell sorting from patients with newly diagnosed Ph(+)/BCR-ABL(+) chronic myeloid leukemia display an abnormal ability to proliferate in vitro in the absence of added growth factors. We now show from analyses of growth-factor gene expression, protein production, and antibody inhibition studies that this deregulated growth can be explained, at least in part, by a novel differentiation-controlled autocrine mechanism. This mechanism involves the consistent and selective activation of IL-3 and granulocyte colony-stimulating factor (G-CSF) production and a stimulation of STAT5 phosphorylation in CD34(+) leukemic cells. When these cells differentiate into CD34(-) cells in vivo, IL-3 and G-CSF production declines, and the cells concomitantly lose their capacity for autonomous growth in vitro despite their continued expression of BCR-ABL. Based on previous studies of normal cells, excessive exposure of the most primitive chronic myeloid leukemia cells to IL-3 and G-CSF through an autocrine mechanism could explain their paradoxically decreased self-renewal in vitro and slow accumulation in vivo, in spite of an increased cycling activity and selective expansion of later compartments.


High-frequency genetic contents variations in clinical Candida albicans isolates.
Genome plasticity is a hallmark of Candida albicans and is believed to be an adaptation strategy. But the extent of such genomic variability is not well investigated. In this study, genetic contents of clinical C. albicans isolates were investigated at whole-genome level with array-based comparative genomic hybridization (array CGH) technology. It was revealed that C. albicans possessed variations of genetic contents, as well as aneuploidy. The variable genes were scattered across the chromosomes, as well clustered in particular regions, including sub-telomeric regions, retrotransposon-insertion sites and a variable region on chromosome 6.


Large scale isolation of non-uniform shear stress-responsive genes from cultured human endothelial cells through the preparation of a subtracted cDNA library.
To investigate the molecular mechanisms responsible for the regional selectivity of early atherogenesis, we have applied a non-uniform shear stress to cultured human umbilical vein endothelial cells (HUVEC). We used a microcarrier culture system and a combination of subtraction and reverse-subtraction methods to isolate a number of genes upregulated by shear stress. The resultant subtracted library includes several known genes (e.g. MCP-1, TM) whose responsiveness to shear stress has been previously reported, indicating that the library is enriched for genes upregulated by shear stress. Also included are atherosclerosis-related genes (e.g. CTGF, IL-8) whose responsiveness to shear stress had not been demonstrated, other known genes whose relationship to atherosclerosis had not been reported, and novel genes. Some responsive to centrifugal force and shear stress (RECS) genes are also upregulated following stimulation by steady laminar shear stress in a parallel plate chamber. Interestingly, the library includes ET-1 and PAI, which are well known atherogenic factors that are downregulated by laminar shear stress. This implies that turbulent shear stress has effects on HUVEC that are different from those elicited by laminar shear stress. Importantly, analysis of specimens taken from human aorta showed that several RECS genes are transcriptionally upregulated in atherosclerotic lesions, suggesting that the subtracted library includes novel therapeutic targets for the treatment of atherosclerosis.


Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder.
Dominant optic atrophy (DOA) and axonal peripheral neuropathy (Charcot-Marie-Tooth type 2, or CMT2) are hereditary neurodegenerative disorders most commonly caused by mutations in the canonical mitochondrial fusion genes OPA1 and MFN2, respectively. In yeast, homologs of OPA1 (Mgm1) and MFN2 (Fzo1) work in concert with Ugo1, for which no human equivalent has been identified thus far. By whole-exome sequencing of patients with optic atrophy and CMT2, we identified four families with recessive mutations in SLC25A46. We demonstrate that SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein mitofilin (Fcj1). Loss of function in cultured cells and in zebrafish unexpectedly leads to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the fish. The discovery of SLC25A46 strengthens the genetic overlap between optic atrophy and CMT2 while exemplifying a new class of modified solute transporters linked to mitochondrial dynamics.


Comparative protective efficacy of a newly generated live recombinant thermostable highly attenuated vaccine rK148/GVII-F using a single regimen against lethal NDV GVII.1.1.
A thermostable, safe, and effective NDV GVII recombinant vaccine was generated.Fusion gene replacement with GVII did not affect GI K148/08 virus thermostability.Strain rK148/GVII-F provided adequate protection against a lethal NDV challenge.Oropharyngeal shedding was significantly reduced on post-challenge days 5 and 7.


Spatial Attention-Guided Generative Adversarial Network for Synthesizing Contrast-enhanced Computed Tomography Images.
Compared to non-contrast computed tomography (NC-CT) scans, contrast-enhanced (CE) CT scans provide more abundant information about focal liver lesions (FLLs), which play a crucial role in the FLLs diagnosis. However, CE-CT scans require patient to inject contrast agent into the body, which increase the physical and economic burden of the patient. In this paper, we propose a spatial attention-guided generative adversarial network (SAG-GAN), which can directly obtain corresponding CE-CT images from the patient's NC-CT images. In the SAG-GAN, we devise a spatial attention-guided generator, which utilize a lightweight spatial attention module to highlight synthesis task-related areas in NC-CT image and neglect unrelated areas. To assess the performance of our approach, we test it on two tasks: synthesizing CE-CT images in arterial phase and portal venous phase. Both qualitative and quantitative results demonstrate that SAG-GAN is superior to existing GANs-based image synthesis methods.


Loneliness and social isolation as risk factors for mortality: a meta-analytic review.
Actual and perceived social isolation are both associated with increased risk for early mortality. In this meta-analytic review, our objective is to establish the overall and relative magnitude of social isolation and loneliness and to examine possible moderators. We conducted a literature search of studies (January 1980 to February 2014) using MEDLINE, CINAHL, PsycINFO, Social Work Abstracts, and Google Scholar. The included studies provided quantitative data on mortality as affected by loneliness, social isolation, or living alone. Across studies in which several possible confounds were statistically controlled for, the weighted average effect sizes were as follows: social isolation odds ratio (OR) = 1.29, loneliness OR = 1.26, and living alone OR = 1.32, corresponding to an average of 29%, 26%, and 32% increased likelihood of mortality, respectively. We found no differences between measures of objective and subjective social isolation. Results remain consistent across gender, length of follow-up, and world region, but initial health status has an influence on the findings. Results also differ across participant age, with social deficits being more predictive of death in samples with an average age younger than 65 years. Overall, the influence of both objective and subjective social isolation on risk for mortality is comparable with well-established risk factors for mortality.


Abnormal Activations of Super-Enhancers Enhance the Carcinogenicity in Lung Adenocarcinoma.
Lung tumors and normal lung tissues show large differences in epigenetic modification which can affect the chromosome structure and expression of genes. However, the epigenetic reprogramming in lung adenocarcinoma remains unclear. With the bioinformatics analysis, we found that some activated super-enhancers (SEs) only appear in lung adenocarcinoma cells, and 781 abnormal activated super-enhancers (AASEs) were found. Not only are the traditional oncogenes found to be activated by AASEs, such as MET and SLC2A1, but also some new genes were activated by AASEs, which probably contributes to the carcinogenic process in lung cancer. The enrichment analysis of the genes activated by AASEs shows that the glycolysis process and cell proliferation were enhanced and the apoptotic process was negatively regulated. Two AASEs were separately knockout by CRISPR/Cas9 in A549, PC-9, and H1299 cell lines and the expression of target genes decreased. The motif of CTCF, SMARCA1, SOX4, FOXM1, IRF3, IRF7, and STAT2 was enriched in AASEs, supporting that the chromosome structure changed and these transcription factors would be the master regulators on the formation of AASEs. This study provided comprehensive insight into the mechanisms of SEs, as well as a potential therapeutic target for lung cancer.


Genetic and metabolic diversity of Trichoderma: a case study on South-East Asian isolates.
We have used isolates of Trichoderma spp. collected in South-East Asia, including Taiwan and Western Indonesia, to assess the genetic and metabolic diversity of endemic species of Trichoderma. Ninety-six strains were isolated in total, and identified at the species level by analysis of morphological and biochemical characters (Biolog system), and by sequence analysis of their internal transcribed spacer regions 1 and 2 (ITS1 and 2) of the rDNA cluster, using ex-type strains and taxonomically established isolates of Trichoderma as reference. Seventy-eight isolates were positively identified as Trichoderma harzianum/Trichoderma inhamatum (37 strains) Trichoderma virens (16 strains), Trichoderma spirale (8 strains), Trichoderma koningii (3 strains), Trichoderma atroviride (3 strains), Trichoderma asperellum (4 strains), Hypocrea jecorina (anamorph: Trichoderma reesei; 2 strains), Trichoderma viride (2 strains), Trichoderma hamatum (1 strain), and Trichoderma ghanense (1 strain). Analysis of biochemical characters revealed that T. virens, T. spirale, T. asperellum, T. koningii, H. jecorina, and T. ghanense formed clearly defined clusters, thus exhibiting species-specific metabolic properties. In biochemical character analysis T. atroviride and T. viride formed partially overlapping clusters, indicating that these two species may share overlapping metabolic characteristics. This behavior was even more striking with T. harzianum/T. inhamatum where genotypes defined on the basis of ITS1 and 2 sequences overlapped significantly with adjacent genotypes in the biochemical character analysis, and four strains from the same location (Bali, Indonesia) even clustered with species from section Longibrachiatum. The data indicate that the T. harzianum/T. inhamatum group represents species with high metabolic diversity and partially unique metabolic characteristics. Nineteen strains yielded three different ITS1/2 sequence types which were not alignable with any known species. They were also uniquely characterized by morphological and biochemical characters and therefore represent three new taxa of Trichoderma.


Cost-effectiveness of proton pump inhibitors versus laparoscopic Nissen fundoplication for patients with gastroesophageal reflux disease: a systematic review of the literature.
Gastroesophageal reflux disease is a common condition in Western countries. It is unknown whether medical or surgical treatment is more cost-effective. This study was conducted to determine whether laparoscopic Nissen fundoplication or treatment by proton pump inhibitors is the most cost-effective for gastroesophageal reflux disease in the long term. Medline, EMBASE, and Cochrane databases were searched for articles published between January 1990 and 2010. The search results were screened by two independent reviewers for economic evaluations comparing costs and effects of laparoscopic Nissen fundoplication and proton pump inhibitors in adults eligible for both treatments. Cost and effectiveness or utility data were extracted for both treatment modalities. The quality of the economic evaluations was scored using a dedicated checklist, as were the levels of evidence. Four publications were included; all were based on decision analytic models. The economic evaluations were all of similar quality and all based on data with a variety of evidence levels. Surgery was more expensive than medical treatment in three publications. Two papers reported more quality-adjusted life-years for surgery. However, one of these reported more symptom-free months for medical treatment. In two publications surgery was considered to be the most cost-effective treatment, whereas the other two favored medical treatment. The results with regard to cost-effectiveness are inconclusive. All four economic models are based on high- and low-quality data. More reliable estimates of cost-effectiveness based on long-term trial data are needed.


Exotic Compositional Ordering in Manganese-Nickel-Arsenic (Mn-Ni-As) Intermetallics.
In this work we benefited from recent advances in tools for crystal-structure analysis that enabled us to describe an exotic nanoscale phenomenon in structural chemistry. The Mn0.60 Ni0.40 As sample of the Mn1-x Nix As solid solution, exhibits an incommensurate compositional modulation intimately coupled with positional modulations. The average structure is of the simple NiAs type, but in contrast to a normal solid solution, we observe that manganese and nickel segregate periodically at the nano-level into ordered MnAs and NiAs layers with thickness of 2-4 face-shared octahedra. The detailed description was obtained by combination of 3D electron diffraction, scanning transmission electron microscopy, and neutron diffraction. The distribution of the manganese and nickel layers is perfectly described by a modulation vector q=0.360(3) c*. Displacive modulations are observed for all elements as a consequence of the occupational modulation, and as a means to achieve acceptable Ni-As and Mn-As distances. This modulated evolution of magnetic MnAs and non-magnetic NiAs-layers with periodicity at approximately 10 Å level, may provide an avenue for spintronics.


Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c+ cells through TLR4.
Breast milk oligosaccharides shape the intestinal environment by affecting mucosal immunity and bacterial colonization. To clarify the role of milk oligosaccharide sialyl(α2,3)lactose (3SL) in intestinal physiology and disease, we investigated colitis development in Il10(-/-) mice exposed to normal or 3SL-deficient milk during lactation. Onset and progression of intestinal inflammation were delayed in Il10(-/-) mice deficient for the α2,3 sialyltransferase 4 (ST3GAL4) responsible for 3SL biosynthesis. The proinflammatory role of 3SL was confirmed by showing that oral supplementation of newborn Il10(-/-);St3gal4(-/-) mice with 3SL increased colitis severity. Conversely, fostering of newborn Il10(-/-) mice to lactating St3gal4(-/-) mothers reduced colitis severity. 3SL directly stimulated mesenteric lymph node CD11c(+) dendritic cells and induced production of cytokines required for expansion of TH1 and TH17 T cells. The stimulatory effect of 3SL was attenuated in Tlr4-deficient CD11c(+) cells, demonstrating that 3SL induces inflammation through Toll-like receptor 4 (TLR4) signaling. Thus, 3SL directly modulates mucosal immunity, which increases susceptibility to colitis.


Ionic selectivity, saturation, and block in a K+-selective channel from sarcoplasmic reticulum.
The open-channel conductance properties of a voltage-gated channel from sarcoplasmic reticulum were studied in planar phospholipid membranes. The channel is ideally selective for K+ over Cl- and for K+ over Ca++. In symmetrical 1 M solutions, the single-channel conductance (in pmho) falls in the order: K+ (214) > NH4+ (157) > Rb+ (125) > Na+ (72) > La+ (8.1) > Cs+ (< 3). In neutral bilayers, the channel conductance saturates with ion activity according to a rectangular hyperbolic relation, with half-saturation activities of 54 mM for K+ and 34 mM for Na+. Under symmetrical salt conditions, the K+:Na+ channel conductance ratio increases with salt activity, but the permeability ratio, measured by single-channel bi-ionic potentials, is constant between 20 mM and 2.5 M salt; the permeability ratio is equal to the conductance ratio in the limit of low-salt concentration. The channel conductance varies < 5% in the voltage range -100 to +70 mV. The maximum conductance varies K+ and Na+ is only weakly temperature dependent (delta H++ = 4.6 and 5.3 kcal/mol, respectively), but that of Li+ varies strongly with temperature (delta H++ = 13 kcal/mol). The channel's K+ conductance is blocked asymmetrically by Cs+, and this block is competitive with K+. The results are consistent with an Eyring-type barriers as it permeates the channel. The data conform to Lüger's (1973. Biochem. Biophys. Acta. 311:423-441) predictions for a "pure" single-ion channel.


Electron tomography of insect flight muscle in rigor and AMPPNP at 23 degrees C.
Treatment of rigor fibers of insect flight muscle (IFM) with AMPPNP at 23 degrees C causes a 70% drop in tension with little change in stiffness. In order to visualize the changes in crossbridge conformation and distribution that give rise to the mechanical response, we have produced three-dimensional reconstructions by tomography of both rigor and AMPPNP-treated muscle that do not average the repeating motifs of crossbridges, and thereby retain information on variability of crossbridge structure and distribution. Tomograms can be averaged when display of only the regular features is wanted. Tomograms of rigor IFM show double-headed lead and single-headed rear crossbridges. Tomograms of IFM treated with AMPPNP at 23 degrees C reveal many double-headed and some single-headed "lead" bridges but few crossbridges corresponding to the rear bridges of rigor. Instead, new non-rigor forms of variably angled crossbridges are found bound to actin sites not labeled with myosin heads in rigor. This indicates that the rear bridges of rigor have redistributed during the transition from rigor to the AMPPNP state, which could explain the maintenance of rigor stiffness despite the loss of tension. Comparison of in situ crossbridges in tomograms of rigor with atomic model of acto-S1, the complex formed by myosin subfragment 1 and actin, reveals that the regulatory domain of S1 would require significant bending and realignment to fit into both types of rigor crossbridges. The modifications are particularly significant for the rear bridges and suggest that differential strain in the regulatory domain of rear bridges may be the basis for their detachment and redistribution upon binding AMPPNP. Similar comparison using lead-type crossbridges in AMPPNP reveals departures from the rigor acto-S1 atomic model that include azimuthal straightening and a slight M-ward bending in the regulatory domain. Both the motor and regulatory domains of the new non-rigor crossbridges differ from those in the atomic model of acto-S1. A new crossbridge motif identified in AMPPNP-treated muscle consists of paired rigor-like and non-rigor crossbridges and suggests possible transitions in the myosin working stroke.


Expression of Sox family genes in early lamprey development.
Members of the Sox (Sry-related high mobility group box) family of transcription factors play a variety of roles during development of both vertebrates and invertebrates. A marked expansion in gene number occurred during the emergence of vertebrates, apparently via gene duplication events that are thought to have facilitated new functions. By screening a macroarrayed library as well as the lamprey genome, we have isolated genes of the Sox B, D, E and F subfamilies in the basal jawless vertebrate, lamprey. The expression patterns of all identified Sox genes were examined from gastrulation through early organogenesis (embryonic day 4-14), with particular emphasis on the neural crest, a vertebrate innovation. Coupled with phylogenetic analysis of these Sox genes, the results provide insight into gene duplication and di-vergence in paralog deployment occurring during early vertebrate evolution.


Psychometric Evaluation of Kingston Caregiver Stress Scale.
Standardized measurement of caregiver stress is a component of Medicare's new health care benefit supporting care planning for people with dementia. In this article we identify existing measures of caregiver stress, strain and burden and propose specific criteria for choosing tools that may be suitable for wide use in primary care settings. We reviewed 22 measures and identified one, the Kingston Caregiver Stress Scale (KCSS), which met all the proposed criteria but had not been studied in a U.S. We conducted a psychometric evaluation of KCSS to determine its potential usefulness as a care planning tool with a U.S. We examined the internal consistency, test-retest reliability, component structure, and relationship to depression and anxiety in 227 dementia caregivers at two U.S. sites. The KCSS has high internal consistency and test-retest reliability, a strong factor structure, and moderate to high correlations with caregiver depression and anxiety. KCSS is a good candidate for use as part of comprehensive care planning for people with dementia and their caregivers. Routine assessment of caregiver stress in clinical care may facilitate timely intervention and potentially improve both patient and caregiver outcomes.


Characterization of the steric defense of the HIV-1 gp41 N-trimer region.
During viral entry, HIV gp41 adopts a transient conformation called the "prehairpin intermediate" in which a highly conserved therapeutic target, the N-trimer, is exposed. Despite extensive discovery efforts, potent and broadly neutralizing antibodies that target the N-trimer are elusive. We previously demonstrated the N-trimer is protected by a steric block that prevents large proteins, such as antibodies, from accessing it. Here we further characterize the steric block and identify its source. To study the N-trimer steric accessibility, we produced two sets of C-peptide inhibitors (a potent inhibitor targeting the N-trimer) fused to cargo proteins of increasing size facing either the virus or cell side of the prehairpin intermediate. Both bulky inhibitor sets show a steric block, but the effect is more pronounced with virus-side cargo. Additionally, both sets maintain their potencies in a modified entry assay that removes possible sources of target cell steric hindrance. These results implicate a viral source, likely gp120, as the primary component of the steric block. In addition, we studied the steric accessibility of the "pocket" region of the N-trimer, a highly attractive drug and vaccine target. We demonstrated a pocket-specific antibody, D5, is more potent as an scFv than as a full-length IgG, suggesting the N-trimer steric restriction extends to the pocket. This characterization will facilitate the design of sterically restricted antigens that mimic the steric environment of the N-trimer in the prehairpin intermediate and are capable of inducing potent and broadly neutralizing antibodies that circumvent the N-trimer steric block.


[Evaluation of verapamil for hypertension by an isometric exercise test].
Since the resting blood pressure (BP) does not predict round-the-clock values, in order to evaluate the disease and its response to treatment BP should be measured during exertion. Verapamil, either 120 mg or 160 mg, twice daily, was given to 60 hypertensives at rest and during isometric effort, according to our previously reported protocol. There was a significant response (p less than 0.005) to the treatments. Sustained release verapamil, 240 mg once a day, reduced systolic and diastolic BP significantly in 38 of 45 hypertensives at rest and during isometric effort. A simple, inexpensive, cost-effective, hand-grip method is strongly recommended as an integral part of treatment evaluation. The combination of highly effective drugs together with a simple method of BP evaluation may result in improved long-term treatment.


Ethical aspects of the physician surplus: implications for family practice.
Higher costs, increasing technology, and more physicians are the three predominant influences facing medicine today. These three forces in turn present three groups of ethical issues for physicians: competition and changed fiscal incentives, effects of organized practice on autonomy and confidentiality, and the problems of the interface between primary and consultant physicians. Family physicians must learn to adapt their practices in ethical ways to the rapid changes that are occurring. Thoughtful insight is essential to the process.


Novel catalytic photochemical and hydrothermal treatment processes for acid dye wastewater.
The purpose of the present study was to evaluate the catalytic effect of a heteropoly acid, namely H4SiW12O40, on aqueous Acid Orange 7, a well-known, representative textile monoazo dye applied to nylon fabrics, in sub-critical water (T = 160 degrees C-290 degrees C; P = 0.6-3.0 MPa, pH = 2.6) and under near-UV-VIS light irradiation (isopropanol: water ratio = 1:10: pH = 2.8). SiW12O40-catalyzed photochemical Acid Orange 7 bleaching was also explored in the presence of two dye assisting chemicals as well as in simulated acid dye wastewater at its natural, acidic pH under otherwise identical reaction conditions. Though less explored than TiO2-mediated, heterogeneous photocatalytic treatment, heteropolyacid-catalyzed thermal and/or photoatalytic re-mediation could be an attractive alternative for the degradation of refractory, colored compounds using relatively mild wet oxidation operating conditions or even natural solar light.


Stochastic search variable selection for identifying multiple quantitative trait loci.
In this article, we utilize stochastic search variable selection methodology to develop a Bayesian method for identifying multiple quantitative trait loci (QTL) for complex traits in experimental designs. The proposed procedure entails embedding multiple regression in a hierarchical normal mixture model, where latent indicators for all markers are used to identify the multiple markers. The markers with significant effects can be identified as those with higher posterior probability included in the model. A simple and easy-to-use Gibbs sampler is employed to generate samples from the joint posterior distribution of all unknowns including the latent indicators, genetic effects for all markers, and other model parameters. The proposed method was evaluated using simulated data and illustrated using a real data set. The results demonstrate that the proposed method works well under typical situations of most QTL studies in terms of number of markers and marker density.


Effects of histone deacetylase inhibitors on amygdaloid histone acetylation and neuropeptide Y expression: a role in anxiety-like and alcohol-drinking behaviours.
Recent studies have demonstrated the involvement of epigenetic mechanisms in psychiatric disorders, including alcoholism. Here, we investigated the effects of histone deacetylase (HDAC) inhibitor, trichostatin A (TSA) on amygdaloid HDAC-induced histone deacetylation and neuropeptide Y (NPY) expression and on anxiety-like and alcohol-drinking behaviours in alcohol-preferring (P) and -non-preferring (NP) rats. It was found that P rats displayed higher anxiety-like and alcohol-drinking behaviours, higher amygdaloid nuclear, but not cytosolic, HDAC activity, which was associated with increased HDAC2 protein levels and deficits in histone acetylation and NPY expression in the central (CeA) and medial nucleus of amygdala (MeA), as compared to NP rats. TSA treatment attenuated the anxiety-like and alcohol-drinking behaviours, with concomitant reductions in amygdaloid nuclear, but not cytosolic HDAC activity, and HDAC2, but not HDAC4, protein levels in the CeA and MeA of P rats, without effect in NP rats. TSA treatment also increased global histone acetylation (H3-K9 and H4-K8) and NPY expression in the CeA and MeA of P, but not in NP rats. Histone H3 acetylation within the NPY promoter was also innately lower in the amygdala of P rats compared with NP rats; which was normalized by TSA treatment. Voluntary ethanol intake in P, but not NP rats, produced anxiolytic effects and decreased the HDAC2 levels and increased histone acetylation in the CeA and MeA. These results suggest that higher HDAC2 expression-related deficits in histone acetylation may be involved in lower NPY expression in the amygdala of P rats, and operative in controlling anxiety-like and alcohol-drinking behaviours.


Metastatic Melanoma With Leptomeningeal Disease.
Leptomeningeal disease in patients with melanoma historically portends a grim prognosis, with median survival measured in weeks to months. The advent of effective immunotherapy and targeted agents may modify the outcome of such patients. This case report describes a 43-year-old patient diagnosed with stage IIIa BRAF-positive cutaneous melanoma in 2012 who subsequently developed leptomeningeal involvement as her sole site of melanotic metastasis. She received multiple systemic therapies and radiotherapy and survived 2.5 years after her diagnosis with central nervous system involvement. This case report highlights the importance of a multidisciplinary team and the advent of effective agents, which offers the potential for significantly improved outcomes for patients with metastatic melanoma involving the central nervous system.


Preliminary identification of hemoglobin q-iran in an Iranian family from central province of Iran by globin chain analysis on HPLC.
Many abnormal α-chain hemoglobins (Hbs) are caused by single nucleotide mutations in α1- or α2-goblin genes. One of these Hbs is Hb Q-Iran which is resulted from a point mutation at codon 75 of the α1-globin gene (Asp→His). The identification of Hb Q-Iran was observed in two members of a family from the Central Province of Iran. In this study, Globin chain analysis on high performance liquid chromatography (HPLC) and DNA sequencing were applied. An unusual Hb variant, like HbS on alkaline pH electrophoresis was identified from samples of a father and his son from Arak city in the Central Province of Iran. The variant was further characterized by globin chain analysis and DNA sequencing methods. Globin chain analysis revealed an unknown globin chain peak after α-globin chain peak with a different retention time from βs-globin chain, as the control in both samples. Genetic analysis led to the identification of an unknown Hb variant, Hb Q-Iran. Globin chain analysis showed the presence of an unknown globin chain, and likewise DNA sequencing revealed HbQ-Iran. In other words, Globin chain analysis procedure could preliminarily detect an unknown globin chain.


OsCOP1 regulates embryo development and flavonoid biosynthesis in rice (Oryza sativa L.).
Novel mutations of OsCOP1 were identified to be responsible for yellowish pericarp and embryo lethal phenotype, which revealed that OsCOP1 plays a crucial role in flavonoid biosynthesis and embryogenesis in rice seed. Successful production of viable seeds is a major component of plant life cycles, and seed development is a complex, highly regulated process that affects characteristics such as seed viability and color. In this study, three yellowish-pericarp embryo lethal (yel) mutants, yel-hc, yel-sk, and yel-cc, were produced from three different japonica cultivars of rice (Oryza sativa L). Mutant seeds had yellowish pericarps and exhibited embryonic lethality, with significantly reduced grain size and weight. Morphological aberrations were apparent by 5 days after pollination, with abnormal embryo development and increased flavonoid accumulation observed in the yel mutants. Genetic analysis and mapping revealed that the phenotype of the three yel mutants was controlled by a single recessive gene, LOC_Os02g53140, an ortholog of Arabidopsis thaliana CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1). The yel-hc, yel-sk, and yel-cc mutants carried mutations in the RING finger, coiled-coil, and WD40 repeat domains, respectively, of OsCOP1. CRISPR/Cas9-targeted mutagenesis was used to knock out OsCOP1 by targeting its functional domains, and transgenic seed displayed the yel mutant phenotype. Overexpression of OsCOP1 in a homozygous yel-hc mutant background restored pericarp color, and the aberrant flavonoid accumulation observed in yel-hc mutant was significantly reduced in the embryo and endosperm. These results demonstrate that OsCOP1 is associated with embryo development and flavonoid biosynthesis in rice grains. This study will facilitate a better understanding of the functional roles of OsCOP1 involved in early embryogenesis and flavonoid biosynthesis in rice seeds.


The ATP-binding cassette transporter-encoding gene CgSNQ2 is contributing to the CgPDR1-dependent azole resistance of Candida glabrata.
Our previous investigation on Candida glabrata azole-resistant isolates identified two isolates with unaltered expression of CgCDR1/CgCDR2, but with upregulation of another ATP-binding cassette transporter, CgSNQ2, which is a gene highly similar to ScSNQ2 from Saccharomyces cerevisiae. One of the two isolates (BPY55) was used here to elucidate this phenomenon. Disruption of CgSNQ2 in BPY55 decreased azole resistance, whereas reintroduction of the gene in a CgSNQ2 deletion mutant fully reversed this effect. Expression of CgSNQ2 in a S. cerevisiae strain lacking PDR5 mediated not only resistance to azoles but also to 4-nitroquinoline N-oxide, which is a ScSNQ2-specific substrate. A putative gain-of-function mutation, P822L, was identified in CgPDR1 from BPY55. Disruption of CgPDR1 in BPY55 conferred enhanced azole susceptibility and eliminated CgSNQ2 expression, whereas introduction of the mutated allele in a susceptible strain where CgPDR1 had been disrupted conferred azole resistance and CgSNQ2 upregulation, indicating that CgSNQ2 was controlled by CgPDR1. Finally, CgSNQ2 was shown to be involved in the in vivo response to fluconazole. Together, our data first demonstrate that CgSNQ2 contributes to the development of CgPDR1-dependent azole resistance in C. glabrata. The overlapping in function and regulation between CgSNQ2 and ScSNQ2 further highlight the relationship between S. cerevisiae and C. glabrata.


Hepatocyte growth factor activators, inhibitors and antagonists and their implication in cancer intervention.
Hepatocyte growth factor (HGF), otherwise known as scatter factor (SF), has been demonstrated over the past decade to elicit a number of functions that may be tumorigenic, and enhance the invasive/metastatic nature of cancer cells. Clinical studies have also demonstrated that HGF/SF, together with its receptor, cMET, is closely related to the disease progression and prognosis of patients with cancer. The past few years have seen the identification of numerous inhibitors and antagonists to the action of HGF/SF. These factors have demonstrated a possible role in minimising the action of HGF/SF on cancer cells, and may be of therapeutic value in the future. This article overviews the activators, inhibitors, and antagonists to HGF/SF and discusses the possible implications in cancer therapy.


Variance estimation for statistics computed from single recurrent event processes.
This article is concerned with variance estimation for statistics that are computed from single recurrent event processes. Such statistics are important in diagnosis for each individual recurrent event process. The proposed method only assumes a semiparametric form for the first-order structure of the processes but not for the second-order (i.e., dependence) structure. The new variance estimator is shown to be consistent for the target parameter under very mild conditions. The estimator can be used in many applications in semiparametric rate regression analysis of recurrent event data such as outlier detection, residual diagnosis, as well as robust regression. A simulation study and application to two real data examples are used to demonstrate the use of the proposed method.


The gastrula transition reorganizes replication-origin selection in Caenorhabditis elegans.
Although some features underlying replication-origin activation in metazoan cells have been determined, little is known about their regulation during metazoan development. Using the nascent-strand purification method, here we identified replication origins throughout Caenorhabditis elegans embryonic development and found that the origin repertoire is thoroughly reorganized after gastrulation onset. During the pluripotent embryonic stages (pregastrula), potential cruciform structures and open chromatin are determining factors that establish replication origins. The observed enrichment of replication origins in transcription factor-binding sites and their presence in promoters of highly transcribed genes, particularly operons, suggest that transcriptional activity contributes to replication initiation before gastrulation. After the gastrula transition, when embryonic differentiation programs are set, new origins are selected at enhancers, close to CpG-island-like sequences, and at noncoding genes. Our findings suggest that origin selection coordinates replication initiation with transcriptional programs during metazoan development.


Artificial selection for food colour preferences.
Colour is an important factor in food detection and acquisition by animals using visually based foraging. Colour can be used to identify the suitability of a food source or improve the efficiency of food detection, and can even be linked to mate choice. Food colour preferences are known to exist, but whether these preferences are heritable and how these preferences evolve is unknown. Using the freshwater fish Poecilia reticulata, we artificially selected for chase behaviour towards two different-coloured moving stimuli: red and blue spots. A response to selection was only seen for chase behaviours towards the red, with realized heritabilities ranging from 0.25 to 0.30. Despite intense selection, no significant chase response was recorded for the blue-selected lines. This lack of response may be due to the motion-detection mechanism in the guppy visual system and may have novel implications for the evolvability of responses to colour-related signals. The behavioural response to several colours after five generations of selection suggests that the colour opponency system of the fish may regulate the response to selection.


Epigastric sensations as an unusual manifestation of adult absence epilepsy.
We report the case of a 39-year-old woman with onset of daily epigastric sensations associated with brief episodes of unresponsive blank stare, which have been interpreted as complex partial seizures with occasional secondary generalisation. Phenytoin as monotherapy and in combination with valproate had not been effective. During video-EEG we recorded typical absences with brief 3 second spike, and slow-wave discharges of up to 5 seconds, which were recognized by the patient herself. All absences were preceded by epigastric sensations. There was no indication of focal epilepsy. Monotherapy with valproate substantially decreased the frequency of the absences. In conclusion, this case is peculiar for several reasons: 1) late onset of absence epilepsy, 2) epigastric sensation at onset of absence seizures, 3) recognition of brief "phantom" absences and 4) presumable adverse effects of phenytoin.