First-line therapy and methylation status of CHFR in serum influence outcome to chemotherapy versus EGFR tyrosine kinase inhibitors as second-line therapy in stage IV non-small-cell lung cancer patients.
The potential differential effect of first-line treatment and molecular mechanisms on survival to second-line chemotherapy or EGFR tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) has not been fully investigated. In particular, CHFR is frequently methylated in NSCLC and may influence outcome. We analyzed the outcome of second-line chemotherapy or EGFR TKIs in 179 of 366 patients who had been treated in an ERCC1 mRNA-based customized cisplatin trial and correlated the results with CHFR methylation status. CHFR methylation in circulating DNA was examined by methylation-specific assay. A panel of seven human EGFR wild-type NSCLC cell lines was characterized for their sensitivity to sequential treatment with cisplatin and erlotinib, and the results were correlated with CHFR. Patients who had received first-line docetaxel/cisplatin attained an overall survival of 19.2 months when treated with second-line EGFR TKIs, in comparison with 10.7 months when treated with second-line chemotherapy (P = 0.0002). However, for patients who had received first-line docetaxel/gemcitabine, overall survival was 14.8 months with EGFR TKIs and 10.8 months with chemotherapy (P = 0.29). For patients with unmethylated CHFR overall survival to EGFR TKIs was 21.4 months, and 11.2 months for those with treated with chemotherapy (P = 0.0001). In the only lung tumor cell line not expressing CHFR, pretreatment with cisplatin was antagonistic to erlotinib, while it was synergistic in the other six lines. Second-line EGFR TKIs improved survival in patients receiving first-line cisplatin-based treatment. Unmethylated CHFR predicts increased survival to EGFR TKIs.


Acceptorless dehydrogenation of small molecules through cooperative base metal catalysis.
The dehydrogenation of unactivated alkanes is an important transformation both in industrial and biological systems. Recent efforts towards this reaction have revolved around high temperature, organometallic C-H activation by noble metal catalysts that produce alkenes and hydrogen gas as the sole products. Conversely, natural desaturase systems proceed through stepwise hydrogen atom transfer at physiological temperature; however, these transformations require a terminal oxidant. Here we show combining tetra-n-butylammonium decatungstate (TBADT) and cobaloxime pyridine chloride (COPC) can catalytically dehydrogenate unactivated alkanes and alcohols under near-UV irradiation at room temperature with hydrogen as the sole by-product. This noble metal-free process follows a nature-inspired pathway of high- and low-energy hydrogen atom abstractions. The hydrogen evolution ability of cobaloximes is leveraged to render the system catalytic, with cooperative turnover numbers up to 48 and yields up to 83%. Our results demonstrate how cooperative base metal catalysis can achieve transformations previously restricted to precious metal catalysts.


One-pot fabrication of noble-metal nanoparticles that are encapsulated in hollow silica nanospheres: dual roles of poly(acrylic acid).
An efficient and facile one-pot method was developed to fabricate noble-metal nanoparticles (NMNs; Au, Pt, PdO and Ag) that were encapsulated within hollow silica nanospheres (HSNs; NMNs@HSNs) with a size of about 100 nm. NMNs@HSNs were afforded in very high yields between 85-95 %. Poly(acrylic acid) (PAA) polyelectrolyte played a dual role in the fabrication process, both as a core template of the HSNs and as a captor of the NMNs through coordination interactions between the COO(-) groups on the ammonium polyacrylate (APA) polyanionic chains and the empty orbital of the Au atom. The amount of Au loading in Au@HSNs was easily regulated by varying the volume of the HAuCl(4) solution added. In addition, these rattle-type particles were successfully applied in the catalytic reduction of 2-nitroaniline (2-NA) as a model reaction, thus indicating that the micropores in the silica shell could achieve the transport of small species--with a size smaller than that of the micropores--into the cavity. Thus, these fabricated NMNs@HSNs have promising applications in catalysis.


Herpes Simplex Virus Type 2 Prevalence and Association with Inflammatory Cytokines Among Sexual and Gender Minorities Living With and Without HIV-1 from Lagos, Nigeria.
Herpes simplex virus type 2 (HSV-2) is common globally and contributes significantly to the risk of acquiring HIV-1, yet these two sexually transmitted infections have not been sufficiently characterized for sexual and gender minorities (SGM) across Sub-Saharan Africa. To help fill this gap, we performed a retrospective study using plasma and serum samples from 183 SGM enrolled at the Lagos site of the TRUST/RV368 cohort in Nigeria, assayed them for HSV-2 antibodies with the Kalon ELISA and plasma cytokines and chemokines with Luminex, and correlated the findings with HIV-1 viral loads (VLs) and CD4 counts. We found an overall HSV-2 prevalence of 36.6% (49.5% and 23.9% among SGM with and without HIV-1, respectively, p < .001). Moreover, HSV-2-positive status was associated with high circulating concentrations of CCL11 among antiretroviral therapy-treated (p = .031) and untreated (p = .015) participants, and with high concentrations of CCL2 in the untreated group (p = .004), independent of VL. Principal component analysis revealed a strong association of cytokines with HIV-1 VL independent of HSV-2 status. In conclusion, our study finds that HSV-2 prevalence among SGM with HIV-1 is twice as high than HSV-2 prevalence among SGM without HIV-1 in Lagos and suggests that this is associated with higher levels of certain systemic cytokines. Additional work is needed to further characterize the relationship between HSV-2 and HIV-1 in SGM and help develop targeted therapies for coinfected individuals.


Very long-term prognosis in patients with right ventricular apical pacing for sick sinus syndrome.
The impact of right ventricular (RV) apical pacing on very long-term cardiac prognosis is little known. In this study, we retrospectively evaluated the relationship between RV apical pacing and cardiovascular events (CEs) in patients with sick sinus syndrome (SSS) and left ventricular ejection fraction (LVEF) >35%. Total of 532 consecutive pacemaker recipients with SSS and LVEF >35% were divided into two groups according to the mean cumulative per cent RV apical ventricular pacing (mean %VP) (<50%; non-VP group vs ≥50%; VP group) and occurrence of CE was compared using Kaplan-Meier analysis between two groups. Cox hazard model was used to assess predictors of CE after adjusting explanatory variables such as age, atrial fibrillation (AF) and structural heart disease (SHD). Mean %VP was 86.0% and 8.2% in VP and non-VP groups, respectively (p<0.001). During mean follow-up of 13.4±7.0 years, CE occurred in 131 patients and more frequently in VP than non-VP group (p<0.001). However, the VP group was no longer associated with CE after taking into account other variables in multivariate analysis, which revealed AF (HR (HR)=2.08), SHD (HR=4.97), low LVEF (HR=0.98 for every 1% increase) and high age (HR=1.03 for every year of age) were independent predictors for CE. Regarding patients with SHD and/or AF and those aged ≥75 years, Kaplan-Meier curves showed both groups had similar prognosis. Cardiac prognosis of patients with RV apical pacing was poor, but after adjusting for other predictors of CE, RV apical pacing was not a prognostic factor in patients with SSS with LVEF >35%.


The biology and synthesis of α-hydroxytropolones.
α-Hydroxytropolones are a subclass of the troponoid family of natural products that are of high interest due to their broad biological activity and potential as treatment options for several diseases. Despite this promise, there have been scarce synthetic chemistry-driven optimization studies on the molecules. The following review highlights key developments in the biological studies conducted on α-hydroxytropolones to date, including the few synthetic chemistry-driven optimization studies. In addition, we provide an overview of the methods currently available to access these molecules. This review is intended to serve as a resource for those interested in biological activity of α-hydroxytropolones, and inspire the development of new synthetic methods and strategies that could aid in this pursuit.


A Comparative Safety Profile Assessment of Oncolytic Virus Therapy Based on Clinical Trials.
Oncolytic virus therapy (OVT) represents a new class of therapeutic agents in cancer treatment. The molecular and cellular mechanisms of action of OVTs have been evaluated in nonclinical/clinical phase trials. Various genetically modified viruses have been developed as oncolytic agents, and the first approval of an OVT for clinical use was issued by the US Food and Drug Administration in 2015. In this context, more and more clinical development of OVTs is anticipated in the future. This article provides a risk assessment of OVT based on the safety data obtained from all clinical trials to date using a publicly available database. The most common adverse events (AEs) observed in clinical trials have been infection-related symptoms such as fatigue, chills, fever, and nausea; few serious AEs have been observed, regardless of the kind of virus or transfected genes. In vivo systemic infusion of OVTs demonstrated a high percentage of AEs, but most AEs were manageable using common drugs. This paper describes OVTs' specific safety/toxicity profiles and encourages the performance of further clinical trials of OVTs to address the most serious challenges anticipated in the development of OVTs as a new class of drugs for the treatment of cancer.


Ambulatory system for human motion analysis using a kinematic sensor: monitoring of daily physical activity in the elderly.
A new method of physical activity monitoring is presented, which is able to detect body postures (sitting, standing, and lying) and periods of walking in elderly persons using only one kinematic sensor attached to the chest. The wavelet transform, in conjunction with a simple kinematics model, was used to detect different postural transitions (PTs) and walking periods during daily physical activity. To evaluate the system, three studies were performed. The method was first tested on 11 community-dwelling elderly subjects in a gait laboratory where an optical motion system (Vicon) was used as a reference system. In the second study, the system was tested for classifying PTs (i.e., lying-to-sitting, sitting-to-lying, and turning the body in bed) in 24 hospitalized elderly persons. Finally, in a third study monitoring was performed on nine elderly persons for 45-60 min during their daily physical activity. Moreover, the possibility-to-perform long-term monitoring over 12 h has been shown. The first study revealed a close concordance between the ambulatory and reference systems. Overall, subjects performed 349 PTs during this study. Compared with the reference system, the ambulatory system had an overall sensitivity of 99% for detection of the different PTs. Sensitivities and specificities were 93% and 82% in sit-to-stand, and 82% and 94% in stand-to-sit, respectively. In both first and second studies, the ambulatory system also showed a very high accuracy (> 99%) in identifying the 62 transfers or rolling out of bed, as well as 144 different posture changes to the back, ventral, right and left sides. Relatively high sensitivity (> 90%) was obtained for the classification of usual physical activities in the third study in comparison with visual observation. Sensitivities and specificities were, respectively, 90.2% and 93.4% in sitting, 92.2% and 92.1% in "standing + walking," and, finally, 98.4% and 99.7% in lying. Overall detection errors (as percent of range) were 3.9% for "standing + walking," 4.1% for sitting, and 0.3% for lying. Finally, overall symmetric mean average errors were 12% for "standing + walking," 8.2% for sitting, and 1.3% for lying.


Relation of immediate postnatal growth with obesity and related metabolic risk factors in adulthood: the northern Finland birth cohort 1966 study.
The authors examined associations between postnatal growth velocity through age 2 years and metabolic outcomes at age 31 years in a population-based birth-cohort study of 3,778 Finns (1966-1998). Approximately 8 height measurements and 9 weight measurements were obtained from birth to age 2 years. Peak height velocity (PHV) and peak weight velocity (PWV) in infancy were derived from parametric growth curves fitted to longitudinal height and weight growth data. Body mass index (BMI), waist circumference (WC), high density lipoprotein (HDL) cholesterol, triglycerides, glucose, systolic and diastolic blood pressure (BP), and the metabolic syndrome were measured at age 31 years. PHV was significantly positively associated with systolic and diastolic BP and WC in adulthood. For each 8-cm/year (2-standard-deviation) increase in PHV, WC increased by 1.60 cm (95% confidence interval: 0.73, 2.46), after adjustment for potential confounders, including birth weight. PWV was significantly associated with adulthood systolic BP, WC, and BMI. A 4-kg/year higher PWV was associated with a 1.87-cm (95% confidence interval: 1.08, 2.65) larger WC in adulthood, after adjustment for potential confounders. HDL cholesterol (direct), triglycerides (inverse), and metabolic syndrome (inverse) displayed associations with PWV only after BMI was accounted for. These results showed that growth during the immediate postnatal period is associated with adulthood obesity and BP. Lifestyle changes from early life might be important in reducing adulthood obesity and high-BP risk.


Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation.
Chemotherapy without radiation has not controlled most intraocular retinoblastoma, perhaps because of the common high expression of multidrug resistance P-glycoprotein that we found in retinoblastoma. Cyclosporin blocks P-glycoprotein-induced efflux of vincristine and teniposide in vitro, and possibly modulates responses to carboplatin. To avoid eye irradiation in bilateral retinoblastoma patients with RB1 germline mutations, which incurs a high second malignancy rate, we added cyclosporin A to a vincristine-teniposide-carboplatin protocol and consolidated chemotherapy responses with focal therapy. We scored patients requiring irradiation, enucleation, or focal ablation of central vision as failures. In 21 study patients, the overall relapse-free rate at a median follow-up of 3.3 years was 76%, with a rate of 92% for newly diagnosed and 50% for previously treated, relapsed retinoblastoma. Our results for the most unfavorable tumors with vitreous seeds (86% at 3.5 years) are better than published success rates of irradiation for similar tumors, or irradiation with the same chemotherapy without cyclosporin (45% at 2. 6 years). These results also exceeded our historic success rate with similar chemotherapy without cyclosporin, focal therapy, and/or radiation in 19 equivalently poor-risk patients (relapse-free rate 37% at a median follow-up of 5.6 years, P = 0.032), 16 of whom were previously untreated (relapse-free rate also 37%, P = 0.012). A better outcome occurred with higher cyclosporin blood levels and projected tissue exposure. Cyclosporin did not enhance the usual chemotoxicity. This clinical study suggests that cyclosporin improves the long-term response of retinoblastoma to chemotherapy, possibly by more than one mechanism.


Time-domain optical reflectometry measurements using a frequency comb interferometer.
We characterize the temporal response of fiber-optic components using a fiber-based frequency comb interferometer; measurements are compared and validated against a commercial instrument. The main advantage of the instrument lies in the absence of moving parts or a tunable laser, leading to very fast scanning. A measurement of a mechanical distortion, cycled at 130 Hz, on a fiber Bragg grating (FBG) is presented. A complete profile of the mechanical distortion is taken every 2.5 ms (400 Hz scanning speed) and each "snapshot" is taken in 200 micros. This scanning speed was arbitrarily chosen, and the instrument could be set to scan much faster, up to hundreds of kilohertz. With high-reflectivity FBGs, the same instrument could scan simultaneously the profile of 140 wavelength-multiplexed FBGs at 2 kHz.


Inference of population splits and mixtures from genome-wide allele frequency data.
Many aspects of the historical relationships between populations in a species are reflected in genetic data. Inferring these relationships from genetic data, however, remains a challenging task. In this paper, we present a statistical model for inferring the patterns of population splits and mixtures in multiple populations. In our model, the sampled populations in a species are related to their common ancestor through a graph of ancestral populations. Using genome-wide allele frequency data and a Gaussian approximation to genetic drift, we infer the structure of this graph. We applied this method to a set of 55 human populations and a set of 82 dog breeds and wild canids. In both species, we show that a simple bifurcating tree does not fully describe the data; in contrast, we infer many migration events. While some of the migration events that we find have been detected previously, many have not. For example, in the human data, we infer that Cambodians trace approximately 16% of their ancestry to a population ancestral to other extant East Asian populations. In the dog data, we infer that both the boxer and basenji trace a considerable fraction of their ancestry (9% and 25%, respectively) to wolves subsequent to domestication and that East Asian toy breeds (the Shih Tzu and the Pekingese) result from admixture between modern toy breeds and "ancient" Asian breeds. Software implementing the model described here, called TreeMix, is available at http://treemix.googlecode.com.


Systematic review of the status of pfhrp2 and pfhrp3 gene deletion, approaches and methods used for its estimation and reporting in Plasmodium falciparum populations in Africa: review of published studies 2010-2019.
Malaria rapid diagnostic tests based on histidine-rich protein-2 have played a vital role in improving malaria case management and surveillance particularly in Africa, where Plasmodium falciparum is predominant. However, their usefulness has been threatened by the emergence of gene deletion on P. falciparum histidine rich protein 2 (pfhrp2) and P. falciparum histidine rich protein 3 (pfhrp3). Use of standard and recommended methods is key for accurate investigation, confirmation and reporting of pfhrp2 and pfhrp3 gene deletion. A systematic review was conducted to assess the status, methods and approaches that have been used for investigation, confirmation and reporting of pfhrp2 and pfhrp3 gene deletion in Africa. An online search was done using PubMed and MEDLINE Google Scholar for all articles published in English on pfhrp2/3 gene deletion in Africa. Relevant articles that met the inclusion criteria were summarized and assessed based on the protocol recommended by the World Health Organization for confirmation and reporting of pfhrp2/3 gene deletion. The search identified a total of 18 articles out of which 14 (77.7%) fulfilled the criteria for inclusion and were retained for review. The articles were distributed across 12 countries where the pfhrp2 and pfhrp3 gene deletion studies were conducted and reported. The level of pfhrp2/3 gene deletion across selected studies in Africa ranged from the highest 62% to the lowest 0.4%. There was wide variation in methods and approaches including study designs, size and sampling and whether both pfhrp2 and pfhrp3 double deletions or pfhrp2 single deletion were investigated, with a wide variation in laboratory methods. Based on the review, there is evidence of the presence of pfhrp2/3 gene-deleted P. falciparum parasites in Africa. The approaches and methods used for investigation, confirmation and reporting of pfhrp2/3 deleted parasites have varied between studies and across countries. Countries that are considering plans to investigate, confirm and report pfhrp2/3 deletion should use recommended standard and harmonized methods to prevent unnecessary recommendations for costly switch of RDTs in Africa.


Trends in avoidable mortality over the life course in Mexico, 1990-2015: a cross-sectional demographic analysis.
To analyse average lifespan and quantify the effect of avoidable/amenable mortality on the difference between state-specific mortality and a low-mortality benchmark in Mexico during 1990-2015. Retrospective cross-sectional demographic analysis using aggregated data. Vital statistics from the Mexican civil registration system. Aggregated national data (from 91.2 million people in 1995 to 119.9 in 2015) grouped in 64 populations (32 Mexican states (including Mexico City) by sex) with cause-of-death data. Cause-specific contributions to the gap in life expectancy with a low-mortality benchmark in three age groups (0-14, 15-49 and 50-84 years). Infants and children under the age of 15 years show improvements towards maximal survival in all states. However, adult males aged 15 to 49 years show deterioration after 2006 in almost every state due to increasing homicides, and a slow recovery thereafter. Out of 35 potential years, females and males live on average 34.57 (34.48 to 34.67) and 33.80 (33.34 to 34.27), respectively. Adults aged 50 to 84 years show an unexpected decrease in the low mortality benchmark, indicating nationwide deterioration among older adults. Females and males in this age group show an average survival of 28.59 (27.43 to 29.75) and 26.52 (25.33 to 27.73) out of 35 potential years, respectively. State gaps from the benchmark were mainly caused by ischaemic heart diseases, diabetes, cirrhosis and homicides. We find large health disparities between states, particularly for the adult population after 2005. Mexico has succeeded in reducing mortality and between-state inequalities in children. However, adults are becoming vulnerable as they have not been able to reduce the burden of violence and conditions amenable to health services and behaviours, such as diabetes, ischaemic heart diseases and cirrhosis. These trends have led to large health disparities between Mexican states in the last 25 years.


Identification of higher brain centres that may encode the cardiorespiratory response to exercise in humans.
1. Positron emission tomography (PET) was used to identify the neuroanatomical correlates underlying 'central command' during imagination of exercise under hypnosis, in order to uncouple central command from peripheral feedback. 2. Three cognitive conditions were used: condition I, imagination of freewheeling downhill on a bicycle (no change in heart rate, HR, or ventilation, V(I)): condition II, imagination of exercise, cycling uphill (increased HR by 12 % and V(I) by 30 % of the actual exercise response): condition III, volitionally driven hyperventilation to match that achieved in condition II (no change in HR). 3. Subtraction methodology created contrast A (II minus I) highlighting cerebral areas involved in the imagination of exercise and contrast B (III minus I) highlighting areas activated in the direct volitional control of breathing (n = 4 for both; 8 scans per subject). End-tidal P(CO(2)) (P(ET,CO(2))) was held constant throughout PET scanning. 4. In contrast A, significant activations were seen in the right dorso-lateral prefrontal cortex, supplementary motor areas (SMA), the right premotor area (PMA), superolateral sensorimotor areas, thalamus, and bilaterally in the cerebellum. In contrast B, significant activations were present in the SMA and in lateral sensorimotor cortical areas. The SMA/PMA, dorso-lateral prefrontal cortex and the cerebellum are concerned with volitional/motor control, including that of the respiratory muscles. 5. The neuroanatomical areas activated suggest that a significant component of the respiratory response to 'exercise', in the absence of both movement feedback and an increase in CO(2) production, can be generated by what appears to be a behavioural response.


A Reasoned Action Model of Male Client Involvement in Commercial Sex Work in Kibera, A Large Informal Settlement in Nairobi, Kenya.
Male clients of female sex workers (FSWs) are epidemiologically important because they can form bridge groups linking high- and low-risk subpopulations. However, because male clients are hard to locate, they are not frequently studied. Recent research emphasizes searching for high-risk behavior groups in locales where new sexual partnerships form and the threat of HIV transmission is high. Sub-Saharan Africa public drinking venues satisfy these criteria. Accordingly, this study developed and implemented a rapid assessment methodology to survey men in bars throughout the large informal settlement of Kibera, Nairobi, Kenya, with the goal of delineating cultural and economic rationales associated with male participation in commercial sex. The study sample consisted of 220 male patrons of 110 bars located throughout Kibera's 11 communities. Logistic regression analysis incorporating a modified Reasoned Action Model indicated that a social norm condoning commercial sex among male peers and the cultural belief that men should practice sex before marriage support commercial sex involvement. Conversely, lacking money to drink and/or pay for sexual services were barriers to male commercial sex involvement. Results are interpreted in light of possible harm reduction programs focusing on FSWs' male clients.


Structure-Function Modeling of Optical Coherence Tomography and Standard Automated Perimetry in the Retina of Patients with Autosomal Dominant Retinitis Pigmentosa.
To assess relationships between structural and functional biomarkers, including new topographic measures of visual field sensitivity, in patients with autosomal dominant retinitis pigmentosa. Spectral domain optical coherence tomography line scans and hill of vision (HOV) sensitivity surfaces from full-field standard automated perimetry were semi-automatically aligned for 60 eyes of 35 patients. Structural biomarkers were extracted from outer retina b-scans along horizontal and vertical midlines. Functional biomarkers were extracted from local sensitivity profiles along the b-scans and from the full visual field. These included topographic measures of functional transition such as the contour of most rapid sensitivity decline around the HOV, herein called HOV slope for convenience. Biomarker relationships were assessed pairwise by coefficients of determination (R2) from mixed-effects analysis with automatic model selection. Structure-function relationships were accurately modeled (conditional R(2)>0.8 in most cases). The best-fit relationship models and correlation patterns for horizontally oriented biomarkers were different than vertically oriented ones. The structural biomarker with the largest number of significant functional correlates was the ellipsoid zone (EZ) width, followed by the total photoreceptor layer thickness. The strongest correlation observed was between EZ width and HOV slope distance (marginal R(2) = 0.85, p<10(-10)). The mean sensitivity defect at the EZ edge was 7.6 dB. Among all functional biomarkers, the HOV slope mean value, HOV slope mean distance, and maximum sensitivity along the b-scan had the largest number of significant structural correlates. Topographic slope metrics show promise as functional biomarkers relevant to the transition zone. EZ width is strongly associated with the location of most rapid HOV decline.


The latent membrane protein 1 of Epstein-Barr virus establishes an antiviral state via induction of interferon-stimulated genes.
Epstein-Barr virus (EBV) infection is associated with several human cancers. Latent membrane protein 1 (LMP-1) is one of the key viral proteins required for transformation of primary B cells in vitro and establishment of EBV latency. In this report, we show that LMP-1 is able to induce the expression of several interferon (IFN)-stimulated genes (ISGs) with antiviral properties such as 2'-5' oligoadenylate synthetase (OAS), stimulated trans-acting factor of 50 kDa (STAF-50), and ISG-15. LMP-1 inhibits vesicular stomatitis virus (VSV) replication at low multiplicity of infection (0.1 pfu/cell). The antiviral effect of LMP-1 is associated with the ability of LMP-1 to induce ISGs; an LMP-1 mutant that cannot induce ISGs fails to induce an antiviral state. High levels of ISGs are expressed in EBV latency cells in which LMP-1 is expressed. EBV latency cells have antiviral activity that inhibits replication of superinfecting VSV. The antiviral activity of LMP-1 is apparently not related to IFN production in our experimental systems. In addition, EBV latency is responsive to viral superinfection: LMP-1 is induced and EBV latency is disrupted by EBV lytic replication during VSV superinfection of EBV latency cells. These data suggest that LMP-1 has antiviral effect, which may be an intrinsic part of EBV latency program to assist the establishment and/or maintenance of EBV latency.


Epigenetic basis for fetal origins of age-related disease.
The current concept of fetal origins of adult diseases describes in utero programming, or adaptation to a spectrum of adverse environmental conditions that ultimately leads to increased susceptibility to age-related diseases (e.g., type 2 diabetes and cardiovascular disease) later in life. Although the precise mechanism of this biological memory remains unclear, mounting evidence suggests an epigenetic basis. The increased susceptibility to chronic disease and involvement of multiple organ systems that is observed is analogous to the decline in resistance to disease that is typical of normal aging. Although the cumulative environment over the course of a lifetime can induce increasing epigenetic dysregulation, we propose that adverse events that occur during early development can induce significant additional dysregulation of the epigenome. Here, we describe the current evidence for fetal origins of adult disease and the associated role of epigenetic dysregulation. In addition, we present a new perspective on the induction of epigenetic alterations in utero, which subsequently lead to an aging phenotype marked by increased susceptibility to age-related diseases.


Norwegian nursing and medical students' perception of interprofessional teamwork: a qualitative study.
Little is known about the ways in which nursing and medical students perceive and understand their roles in interprofessional teamwork. A 2010 report by the World Health Organization highlights the importance of students' understanding of teamwork in healthcare, and their ability to be effective team players. This study aims at describing nursing and medical students' perceptions of interprofessional teamwork, focusing on experiences and recommendations that can be used to guide future educational efforts. The study uses a qualitative research design. Data were collected from four focus group interviews: two homogenous groups (one with medical students, one with nursing students) and two mixed groups (medical and nursing students). The results show that traditional patterns of professional role perception still prevail and strongly influence students' professional attitudes about taking responsibility and sharing responsibility across disciplinary and professional boundaries. It was found that many students had experienced group cultures detrimental to team work. Focusing on clinical training, the study found a substantial variation in perception with regard to the different arenas for interprofessional teamwork, ranging from arenas with collaborative learning to arenas characterized by distrust, confrontation, disrespect and hierarchical structure. This study underlines the importance of a stronger focus on interprofessional teamwork in health care education, particularly in clinical training. The study results suggest that the daily rounds and pre-visit "huddles," or alternatively psychiatric wards, offer arenas suitable for interprofessional training, in keeping with the students' assessments and criteria proposed in previous studies.


Alzheimer's Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection.
Amyloid-β peptide (Aβ) fibrilization and deposition as β-amyloid are hallmarks of Alzheimer's disease (AD) pathology. We recently reported Aβ is an innate immune protein that protects against fungal and bacterial infections. Fibrilization pathways mediate Aβ antimicrobial activities. Thus, infection can seed and dramatically accelerate β-amyloid deposition. Here, we show Aβ oligomers bind herpesvirus surface glycoproteins, accelerating β-amyloid deposition and leading to protective viral entrapment activity in 5XFAD mouse and 3D human neural cell culture infection models against neurotropic herpes simplex virus 1 (HSV1) and human herpesvirus 6A and B. Herpesviridae are linked to AD, but it has been unclear how viruses may induce β-amyloidosis in brain. These data support the notion that Aβ might play a protective role in CNS innate immunity, and suggest an AD etiological mechanism in which herpesviridae infection may directly promote Aβ amyloidosis.


Analysis of the CONRAD computational problems expressing only stochastic uncertainties: neutrons and protons.
Within the scope of CONRAD (A Coordinated Action for Radiation Dosimetry) Work Package 4 on Computational Dosimetry jointly collaborated with the other research actions on internal dosimetry, complex mixed radiation fields at workplaces and medical staff dosimetry. Besides these collaborative actions, WP4 promoted an international comparison on eight problems with their associated experimental data. A first set of three problems, the results of which are herewith summarised, dealt only with the expression of the stochastic uncertainties of the results: the analysis of the response function of a proton recoil telescope detector, the study of a Bonner sphere neutron spectrometer and the analysis of the neutron spectrum and dosimetric quantity H(p)(10) in a thermal neutron facility operated by IRSN Cadarache (the SIGMA facility). A second paper will summarise the results of the other five problems which dealt with the full uncertainty budget estimate. A third paper will present the results of a comparison on in vivo measurements of the (241)Am bone-seeker nuclide distributed in the knee. All the detailed papers will be presented in the WP4 Final Workshop Proceedings.


A pilot study of tumor necrosis factor inhibition in erosive/inflammatory osteoarthritis of the hands.
To determine if anti-tumor necrosis factor (TNF) therapy (adalimumab) can safely improve symptoms of erosive/inflammatory osteoarthritis (EOA). This was an open-label pilot trial in 12 patients with EOA. Patients > 45 years old with EOA of the hands defined by > or = 2 tender and > or = 2 swollen joints (distal interphalangeal, proximal interphalangeal, first carpometacarpal) despite nonsteroidal antiinflammatory drug therapy were eligible. Patients were excluded for autoimmune arthritis, recent disease modifying antirheumatic drug use, prior use of anti-TNF therapy, infection, malignancy, or poorly controlled medical conditions. All patients received adalimumab 40 mg every other week for 12 weeks. Safety was assessed 4 weeks after the final dose. Primary endpoints included safety and American College of Rheumatology (ACR) response. Patients were predominantly female with a mean age of 60 years and 12 years of arthritis. All patients completed the study and safety followup. Adverse events were mild without necessitating discontinuation of study drug. After 12 weeks, there was a statistically significant improvement in the number of swollen joints compared to baseline (p < 0.01). One patient achieved an ACR20 response and 42% achieved an OMERACT-OARSI response. Although we detected no statistically significant improvement in the number of tender joints, grip strength, disability, pain, or global disease assessments, trends suggested modest improvement in all efficacy measures. This small open-label study of patients with EOA demonstrated that adalimumab was well tolerated. Treatment with adalimumab for 3 months did not significantly improve the signs and symptoms of EOA and most patients did not achieve an ACR20. Trends suggested improvement and individual patients had some benefit. Factors limiting interpretation of this study include the lack of a control group, outcomes chosen, number of patients treated, and the duration of treatment.


Improved detection of DNA motifs using a self-organized clustering of familial binding profiles.
One of the limiting factors in deciphering transcriptional regulatory networks is the effectiveness of motif-finding software. An emerging avenue for improving motif-finding accuracy aims to incorporate generalized binding constraints of related transcription factors (TFs), named familial binding profiles (FBPs), as priors in motif identification methods. A motif-finder can thus be 'biased' towards finding motifs from a particular TF family. However, current motif-finders allow only a single FBP to be used as a prior in a given motif-finding run. In addition, current FBP construction methods are based on manual clustering of position specific scoring matrices (PSSMs) according to the known structural properties of the TF proteins. Manual clustering assumes that the binding preferences of structurally similar TFs will also be similar. This assumption is not true, at least not for some TF families. Automatic PSSM clustering methods are thus required for augmenting the usefulness of FBPs. A novel method is developed for automatic clustering of PSSM models. The resulting FBPs are incorporated into the SOMBRERO motif-finder, significantly improving its performance when finding motifs related to those that have been incorporated. SOMBRERO is thus the only existing de novo motif-finder that can incorporate knowledge of all known PSSMs in a given motif-finding run. The methods outlined will be incorporated into the next release of SOMBRERO, which is available from http://bioinf.nuigalway.ie/sombrero


Cytohesin binder and regulator (cybr) is not essential for T- and dendritic-cell activation and differentiation.
Cybr (also known as Cytip, CASP, and PSCDBP) is an interleukin-12-induced gene expressed exclusively in hematopoietic cells and tissues that associates with Arf guanine nucleotide exchange factors known as cytohesins. Cybr levels are dynamically regulated during T-cell development in the thymus and upon activation of peripheral T cells. In addition, Cybr is induced in activated dendritic cells and has been reported to regulate dendritic cell (DC)-T-cell adhesion. Here we report the generation and characterization of Cybr-deficient mice. Despite the selective expression in hematopoietic cells, there was no intrinsic defect in T- or B-cell development or function in Cybr-deficient mice. The adoptive transfer of Cybr-deficient DCs showed that they migrated efficiently and stimulated proliferation and cytokine production by T cells in vivo. However, competitive stem cell repopulation experiments showed a defect in the abilities of Cybr-deficient T cells to develop in the presence of wild-type precursors. These data suggest that Cybr is not absolutely required for hematopoietic cell development or function, but stem cells lacking Cybr are at a developmental disadvantage compared to wild-type cells. Collectively, these data demonstrate that despite its selective expression in hematopoietic cells, the role of Cybr is limited or largely redundant. Previous in vitro studies using overexpression or short interfering RNA inhibition of the levels of Cybr protein appear to have overestimated its immunological role.


Hybrid de novo transcriptome assembly of poinsettia (Euphorbia pulcherrima Willd. Ex Klotsch) bracts.
Poinsettia is a popular and important ornamental crop, mostly during the Christmas season. Its bract coloration ranges from pink/red to creamy/white shades. Despite its ornamental value, there is a lack of knowledge about the genetics and molecular biology of poinsettia, especially on the mechanisms of color formation. We performed an RNA-Seq analysis in order to shed light on the transcriptome of poinsettia bracts. Moreover, we analyzed the transcriptome differences of red- and white-bracted poinsettia varieties during bract development and coloration. For the assembly of a bract transcriptome, two paired-end cDNA libraries from a red and white poinsettia pair were sequenced with the Illumina technology, and one library from a red-bracted variety was used for PacBio sequencing. Both short and long reads were assembled using a hybrid de novo strategy. Samples of red- and white-bracted poinsettias were sequenced and comparatively analyzed in three color developmental stages in order to understand the mechanisms of color formation and accumulation in the species. The final transcriptome contains 288,524 contigs, with 33% showing confident protein annotation against the TAIR10 database. The BUSCO pipeline, which is based on near-universal orthologous gene groups, was applied to assess the transcriptome completeness. From a total of 1440 BUSCO groups searched, 77% were categorized as complete (41% as single-copy and 36% as duplicated), 10% as fragmented and 13% as missing BUSCOs. The gene expression comparison between red and white varieties of poinsettia showed a differential regulation of the flavonoid biosynthesis pathway only at particular stages of bract development. An initial impairment of the flavonoid pathway early in the color accumulation process for the white poinsettia variety was observed, but these differences were no longer present in the subsequent stages of bract development. Nonetheless, GSTF11 and UGT79B10 showed a lower expression in the last stage of bract development for the white variety and, therefore, are potential candidates for further studies on poinsettia coloration. In summary, this transcriptome analysis provides a valuable foundation for further studies on poinsettia, such as plant breeding and genetics, and highlights crucial information on the molecular mechanism of color formation.


Physicians' Perceptions of Psychological Safety and Peer Performance Feedback.
For continuous professional development, it is imperative that physicians regularly receive performance feedback from their peers. Research shows that professionals are more proactive in learning and knowledge sharing with peers in teams with more psychological safety. Psychological safety has however not been studied in relation to peers' performance feedback. This study investigated the association between physicians' perceptions of psychological safety and performance feedback received from their peers. We invited physicians of cardiology, gastroenterology, obstetrics and gynecology, otorhinolaryngology, pulmonology, neurology, and neurosurgery departments of an academic medical center to participate. Physicians evaluated psychological safety using Edmondson's seven-item validated scale and performance feedback using the adapted four-item feedback subscale of the validated System for Evaluation of Teaching Qualities, including corrective and positive feedback, explanations of feedback, and suggestions for improvement from peers. We analyzed the data using multilevel linear regression analyses adjusted for physicians' sex, years since being certified a medical specialist, and months working in the clinic under the study. This study included 105 physicians (86.8% participated). Psychological safety was positively associated with physicians' perceptions of performance feedback from peers (B = 0.54, 95% confidence interval = 0.34-0.73, P-value <.001). Physicians who experienced more psychological safety were more likely to receive corrective and positive performance feedback from peers, explanations of feedback, and suggestions for improvement. Medical teams should consider investing in psychological safety to encourage performance feedback from peers, and thus support physicians' continuous professional development and their efforts to provide high-quality patient care.


Distribution and expression of microbial rhodopsins in the Baltic Sea and adjacent waters.
Rhodopsins are light-driven ion-pumping membrane proteins found in many organisms and are proposed to be of global importance for oceanic microbial energy generation. Several studies have focused on marine environments, with less exploration of rhodopsins in brackish waters. We investigated microbial rhodopsins in the Baltic Sea using size-fractionated metagenomic and metatranscriptomic datasets collected along a salinity gradient spanning from ∼0 to 35 PSU. The normalised genomic abundance of rhodopsins in Bacteria, as well as rhodopsin gene expression, was highest in the smallest size fraction (0.1-0.8 μm), relative to the medium (0.8-3.0 μm) and large (>3.0 μm) size fractions. The abundance of rhodopsins in the two smaller size fractions displayed a positive correlation with salinity. Proteobacteria and Bacteroidetes rhodopsins were the most abundant while Actinobacteria rhodopsins, or actinorhodopsins, were common at lower salinities. Phylogenetic analysis indicated that rhodopsins have adapted independently to the marine-brackish transition on multiple occasions, giving rise to green light-adapted variants from ancestral blue light-adapted ones. A notable diversity of viral-like rhodopsins was also detected in the dataset and potentially linked with eukaryotic phytoplankton blooms. Finally, a new clade of likely proton-pumping rhodopsin with non-canonical amino acids in the spectral tuning and proton accepting site was identified.


Targeted measles virus vector displaying echistatin infects endothelial cells via alpha(v)beta3 and leads to tumor regression.
Targeting tumor-associated vascular endothelium by replication-competent viral vectors is a promising strategy for cancer gene therapy. Here we describe the development of a viral vector based on the Edmonston vaccine strain of measles virus targeted to integrin alpha(v)beta3, which is expressed abundantly on activated but not quiescent vascular endothelium. We displayed a disintegrin, M28L echistatin that binds with a high affinity to integrin alpha(v)beta3 on the COOH terminus of the viral attachment (H) protein and rescued the replication-competent recombinant virus by reverse genetics. The new targeted virus was named measles virus echistatin vector (MV-ERV). Its native binding to CD46 was purposefully retained to allow virus infection of tumor cells expressing this receptor. MV-ERV correctly displayed echistatin on the outer surface of its envelope and produced interesting ring formation phenomena due to cell detachment upon infection of susceptible Vero cells in vitro. MV-ERV grew to 10(6) plaque-forming units/mL, slightly lower than the parental Edmonston strain of measles virus (MV-Edm), but it selectively infected Chinese hamster ovary cells expressing integrin alpha(v)beta3. It also selectively infected both bovine and human endothelial cells on matrigels and unlike MV-Edm, MV-ERV infected newly formed blood vessels in chorioallantoic membrane assays. In animal models, MV-ERV but not the control MV-Edm caused the regression of s.c. xenografts of resistant multiple myeloma tumors (MM1) in severe combined immunodeficient mice. The tumors were either completely eradicated or their growth was significantly retarded. The specificity, potency, and feasibility of MV-ERV infection clearly show the potential use of MV-ERV in gene therapy for targeting tumor-associated vasculature for the treatment of solid tumors.


Septopreoptic holoprosencephaly: a mild subtype associated with midline craniofacial anomalies.
HPE is a congenital brain malformation characterized by failure of the prosencephalon to divide into 2 hemispheres. We have identified 7 patients who have a mild subtype of HPE in which the midline fusion was restricted to the septal region or preoptic region of the telencephalon. This subtype, which we call septopreoptic HPE, falls in the spectrum of lobar HPE, but lacks significant frontal neocortical fusion seen in lobar HPE. Other imaging characteristics include thickened or dysplastic fornix, absent or hypoplastic anterior CC, and single unpaired ACA. The SP was fully formed in 4, partially formed in 2, and absent in 1. Mild midline craniofacial malformation, such as SMMCI and CNPAS were found in 86% and 71%, respectively. Patients outside of infancy often manifested language delay, learning disabilities, or behavioral disturbances, while motor function was relatively spared.


Manganese superoxide dismutase protects nNOS neurons from NMDA and nitric oxide-mediated neurotoxicity.
Neuronal nitric oxide synthase (nNOS) neurons kill adjacent neurons through the action of NMDA-glutamate receptor activation, although they remain relatively resistant to the toxic effects of NMDA and NO. The molecular basis of the resistance of nNOS neurons to toxic insults is unknown. To begin to understand the molecular mechanisms of the resistance of nNOS neurons, we developed a pheochromacytoma-derived cell line (PC12) that is resistant to the toxic effects of NO. We found through serial analysis of gene expression (SAGE) that manganese superoxide dismutase (MnSOD) is enriched in the NO-resistant PC12 cell-derived line (PC12-R). Antisense MnSOD renders PC12-R cells sensitive to NO toxicity and increases the sensitivity to NO in the parental, NO-sensitive PC12 line (PC12-S). Adenoviral transfer of MnSOD protects PC12-S cells against NO toxicity. We extended these studies to cortical cultures and showed that MnSOD is enriched in nNOS neurons and that antisense MnSOD renders nNOS neurons susceptible to NMDA neurotoxicity, although it has little effect on the overall susceptibility of cortical neurons to NMDA toxicity. Overexpression of MnSOD provides dramatic protection against NMDA and NO toxicity in cortical cultures, but not against kainate or AMPA neurotoxicity. Furthermore, nNOS neurons from MnSOD -/- mice are markedly sensitive to NMDA toxicity. Adenoviral transfer of MnSOD to MnSOD-/- cultures restores resistance of nNOS neurons to NMDA toxicity. Thus, MnSOD is a major protective protein that appears to be essential for the resistance of nNOS neurons in cortical cultures to NMDA mediated neurotoxicity.


Structural characterization of NrnC identifies unifying features of dinucleotidases.
RNA degradation is fundamental for cellular homeostasis. The process is carried out by various classes of endolytic and exolytic enzymes that together degrade an RNA polymer to mono-ribonucleotides. Within the exoribonucleases, nano-RNases play a unique role as they act on the smallest breakdown products and hence catalyze the final steps in the process. We recently showed that oligoribonuclease (Orn) acts as a dedicated diribonucleotidase, defining the ultimate step in RNA degradation that is crucial for cellular fitness (Kim et al., 2019). Whether such a specific activity exists in organisms that lack Orn-type exoribonucleases remained unclear. Through quantitative structure-function analyses, we show here that NrnC-type RNases share this narrow substrate length preference with Orn. Although NrnC and Orn employ similar structural features that distinguish these two classes of dinucleotidases from other exonucleases, the key determinants for dinucleotidase activity are realized through distinct structural scaffolds. The structures, together with comparative genomic analyses of the phylogeny of DEDD-type exoribonucleases, indicate convergent evolution as the mechanism of how dinucleotidase activity emerged repeatedly in various organisms. The evolutionary pressure to maintain dinucleotidase activity further underlines the important role these analogous proteins play for cell growth.


Tissue macrophage heterogeneity: issues and prospects.
The vast majority of macrophages in the body are present in tissues outside the circulation, yet their remarkable phenotypic heterogeneity within different anatomical compartments in the steady state and disease remains essentially unexplored. The development of immunocytochemical and fluorescent histological methods has revealed the presence and morphological diversity of macrophages within tissues, especially in the mouse, but functional specialisation in situ is difficult to establish and their mechanistic basis remains unknown, particularly in humans, in spite of the rich material available. In this review, we consider some of the technical issues that hamper investigation, assess the contribution of cell differentiation and modulation to macrophage heterogeneity within tissues and illustrate variation of macrophages and closely related cells in selected organs in mouse and man.


Patient comfort in the intensive care unit: a multicentre, binational point prevalence study of analgesia, sedation and delirium management.
To measure the prevalence of assessment and management practices for analgesia, sedation and delirium in patients in Australian and New Zealand intensive care units. We developed survey items from a modified Delphi panel and included them in a binational, point prevalence study. We used a standard case report form to capture retrospective patient data on management of analgesia, sedation and delirium at the end of a 4-hour period on the study day. Other data were collected during independent assessment of patient status and medication requirements. Data were collected on 569 patients in 41 ICUs. Pain assessment was documented in the 4 hours before study observation in 46% of patients. Of 319 assessable patients, 16% had moderate pain and 6% had severe pain. Routine sedation assessment using a scale was recorded in 63% of intubated and ventilated patients. When assessed, 38% were alert and calm, or drowsy and rousable, 22% were lightly to moderately sedated, 31% were deeply sedated (66% of these had a documented indication), and 9% were agitated or restless. Sedatives were titrated to a target level in 42% of patients. Routine assessment of delirium occurred in 3%, and at study assessment 9% had delirium. Wrist or arm restraints were used for 7% of patients. Only two-thirds of sedated patients had their sedation levels formally assessed, half had pain assessed and very few had formal assessment of delirium. Our description of current practices, and other observational data, may help in planning further research in this area.


Early Medicaid Expansion In Connecticut Stemmed The Growth In Hospital Uncompensated Care.
As states continue to debate whether or not to expand Medicaid under the Affordable Care Act (ACA), a key consideration is the impact of expansion on the financial position of hospitals, including their burden of uncompensated care. Conclusive evidence from coverage expansions that occurred in 2014 is several years away. In the meantime, we analyzed the experience of hospitals in Connecticut, which expanded Medicaid coverage to a large number of childless adults in April 2010 under the ACA. Using hospital-level panel data from Medicare cost reports, we performed difference-in-differences analyses to compare the change in Medicaid volume and uncompensated care in the period 2007-13 in Connecticut to changes in other Northeastern states. We found that early Medicaid expansion in Connecticut was associated with an increase in Medicaid discharges of 7-9 percentage points, relative to a baseline rate of 11 percent, and an increase of 7-8 percentage points in Medicaid revenue as a share of total revenue, relative to a baseline share of 10 percent. Also, in contrast to the national and regional trends of increasing uncompensated care during this period, hospitals in Connecticut experienced no increase in uncompensated care. We conclude that uncompensated care in Connecticut was roughly one-third lower than what it would have been without early Medicaid expansion. The results suggest that ACA Medicaid expansions could reduce hospitals' uncompensated care burden.


Association between PARP-1 V762A polymorphism and cancer susceptibility: a meta-analysis.
Poly(ADP-ribose) polymerase-1 (PARP-1 catalyzes poly(ADP-ribosyl)ation to various proteins involved in many cellular processes, including DNA damage detection and repair and cell proliferation and death. PARP-1 has been implicated in human carcinogenesis, but the association between the most-studied PARP-1 V762A polymorphism (rs1136410) and risk of various cancers was reported with inconclusive results. The aim of this study was to assess the association between the PARP-1 V762A polymorphism and cancer risk. A meta-analysis of 21 studies with 12,027 cancer patients and 14,106 cancer-free controls was conducted to evaluate the strength of the association using odds ratio (OR) with 95% confidence interval (CI). Overall, no significant association was found between the PARP-1 V762A polymorphism and cancer risk. In the stratified analyses, however, it was found that the variant A allele of the PARP-1 V762A polymorphism was associated with an increased risk of cancer among Asian populations (VA + AA vs. VV: OR = 1.11, 95% CI: 1.01-1.23; P(heterogeneity) = 0.210), but a decreased risk of cancer (VA + AA vs. VV: OR = 0.89, 95% CI: 0.80-1.00; P(heterogeneity) = 0.004) among Caucasian populations, especially for glioma risk (OR = 0.79, 95% CI: 0.69-0.90; P(heterogeneity) = 0.800). This meta-analysis found evidence for an association of the PARP-1 V 762A polymorphism with increased risk of cancer among Asians, but decreased risk of cancer among Caucasians, particularly of glioma. Further well-designed studies with large sample sizes of different ethnic populations and different cancer types are warranted to confirm these findings.


Phase 2 trial of paclitaxel, 13-cis retinoic acid, and interferon alfa-2b in the treatment of advanced stage or recurrent cervical cancer.
Overexpression of bcl-2 is a mechanism of drug resistance in cervical cancer. Agents that down-regulate bcl-2 may decrease tumor cell threshold and sensitize tumor cells to chemotherapy. The objective of this multi-institutional phase 2 trial was to evaluate the efficacy and toxicity of paclitaxel and bcl-2 modulators (13-cis retinoic acid and interferon alfa-2b) in patients with advanced-stage or recurrent cervical cancer. Patients had biopsy-proven metastatic, first relapse, or persistent cervical cancer with no prior chemotherapy except for chemosensitizing agents. The treatment consisted of oral 13-cis retinoic acid, 1 mg/kg, and subcutaneous interferon alfa-2b, 6 mU/m, days 1 to 4, and intravenous paclitaxel, 175 mg/m, day 4 until disease progression or adverse events prohibited treatment. The primary endpoint was overall response rate. Thirty-three patients were enrolled between March 2001 and June 2009. Thirty-one patients were eligible for evaluation of treatment response. Twenty-seven patients (82%) received prior concurrent chemoradiation or radiotherapy alone before study enrollment. The overall response rate was 30% (6 complete responses and 4 partial responses). Furthermore, 7 patients (21%) had stable disease. Grade 3 or 4 adverse events included neutropenia (n =16 [48%]), febrile neutropenia (n = 1 [3%]), and anemia (n = 1 [3%]). There were no treatment-related deaths. The median progression-free survival was 3.4 months (95% confidence interval, 2.0-7.4 months), and overall survival was 11.2 months (95% confidence interval, 7.5-26.2 months). Of 6 patients with complete responses, 5 patients survived more than 2 years. Combination therapy with paclitaxel, 13-cis retinoic acid, and interferon alfa-2b is feasible and safe in treating patients with advanced and recurrent cervical cancer.


Applying 'Patient Blood Management' in the trauma center.
The purpose of this review is to highlight the use of tranexamic acid, point-of-care testing, algorithm-based treatment of trauma-associated coagulopathy with factor concentrates to reduce blood loss and transfusion requirements in order to improve outcome. In addition, the management of patients on new oral anticoagulants, drugs with renewed interest and the tolerance of relatively low hemoglobin levels in the context of trauma will be discussed. Early administration of tranexamic acid reduces mortality without increasing the risk of thromboembolic events. Point-of-care testing is increasingly recommended. Goal-directed individualized coagulation algorithms with the use of factor concentrates allow reducing the amount of allogeneic blood products to be administered. Treatment of trauma patients with one of the new oral anticoagulants is challenging. Furthermore, new mechanisms have been discovered such as deep neuromuscular blockade to better tolerate acute anemia. Applying Patient Blood Management concept to the trauma patient is possible and efficacious. Antihyperfibrinolytics such as tranexamic acid, point-of-care testing and coagulation algorithms with the use of factor concentrates allow a reduction of the number of transfusions, the costs and will likely ameliorate outcome of major trauma patients.


Genes encoded in the major histocompatibility complex affecting the generation of peptides for TAP transport.
The B cell line 721.174 has lost the ability to present intracellular antigens to major histocompatibility complex (MHC) class I-restricted cytotoxic T lymphocytes (CTL). This phenotype results from a homozygous deletion in the MHC that includes the peptide transporter genes TAP1 and TAP2, and the proteasome subunits LMP2 and LMP7. Recent work has shown that such cells transfected with TAP genes load their class I molecules with endogenous peptides, and present several viral epitopes to class I-restricted CTL. These data implied that the LMP2 and LMP7 genes were not required for the presentation of most epitopes through class I molecules. By contrast, while confirming the previous reports, we have identified several epitopes that appear to require genes in the MHC in addition to the TAP for their presentation. Further analysis localizes the defect to proteolysis in the cytosol. In one case, presentation could be partially restored by re-expression of full-length LMP7. Control experiments with LMP7, from which the putative pro-region had been removed, failed to restore presentation, and this lack of effect correlated with failure of the shortened LMP7 to incorporate into the proteasome. These results suggest a role for LMP7 in the generation of a viral epitope, but leave open the possibility that additional genes within the .174 deletion are required for full restoration of antigen presentation.


Sensitive ultrashort pulse chirp measurement.
The chirp of an ultrashort laser pulse can be extracted with high accuracy from a modified spectrum auto-interferometric correlation waveform by using a new time domain algorithm that allows signal averaging. We display results revealing high sensitivity to chirp even with signal-to-noise levels approaching unity. Correction algorithms have been developed to accommodate signal distortion arising from bandwidth limitations, interferometer misalignment, and nonquadratic detector response.


Comparison of multiexcitation fluorescence and diffuse reflectance spectroscopy for the diagnosis of breast cancer (March 2003).
Nonmalignant (n = 36) and malignant (n = 20) tissue samples were obtained from breast cancer and breast reduction surgeries. These tissues were characterized using multiple excitation wavelength fluorescence spectroscopy and diffuse reflectance spectroscopy in the ultraviolet-visible wavelength range, immediately after excision. Spectra were then analyzed using principal component analysis (PCA) as a data reduction technique. PCA was performed on each fluorescence spectrum, as well as on the diffuse reflectance spectrum individually, to establish a set of principal components for each spectrum. A Wilcoxon rank-sum test was used to determine which principal components show statistically significant differences between malignant and nonmalignant tissues. Finally, a support vector machine (SVM) algorithm was utilized to classify the samples based on the diagnostically useful principal components. Cross-validation of this nonparametric algorithm was carried out to determine its classification accuracy in an unbiased manner. Multiexcitation fluorescence spectroscopy was successful in discriminating malignant and nonmalignant tissues, with a sensitivity and specificity of 70% and 92%, respectively. The sensitivity (30%) and specificity (78%) of diffuse reflectance spectroscopy alone was significantly lower. Combining fluorescence and diffuse reflectance spectra did not improve the classification accuracy of an algorithm based on fluorescence spectra alone. The fluorescence excitation-emission wavelengths identified as being diagnostic from the PCA-SVM algorithm suggest that the important fluorophores for breast cancer diagnosis are most likely tryptophan, NAD(P)H and flavoproteins.


Management of in-sent restenosis after carotid artery stenting in high-risk patients.
Carotid artery stenting (CAS) has emerged as an acceptable treatment alternative in patients with carotid bifurcation disease. Although early results of CAS have been promising, long-term clinical outcomes remain less certain. We report herein the frequency, management, and clinical outcome of in-stent restenosis (ISR) after CAS at a single academic institution. Clinical records of 208 CAS procedures in 188 patients with carotid stenosis of 80% or greater, including 48 (26.5%) asymptomatic patients, during a 42-month period were analyzed. Follow-up serial carotid duplex ultrasound scans were performed. Selective angiography and repeat intervention were performed when duplex ultrasound scans showed 80% or greater ISR. Treatment outcomes of ISR interventions were analyzed. Over a median 17-month follow-up, 33 (15.9%) ISRs of 60% or greater were found, according to the Doppler criteria. Among them, seven patients (3.4%) with a mean age of 68 years (range, 65-87 years) developed high-grade ISR (> or =80%), and they all underwent further endovascular interventions. Six patients with high-grade ISR were asymptomatic, whereas one remaining patient presented with a transient ischemic attack. Five of seven ISRs occurred within 12 months of CAS, and two occurred at 18 months' follow-up. Treatment indications for initial CAS in these seven patients included recurrent stenosis after CEA (n = 4), radiation-induced stenosis (n = 1), and high-cardiac-risk criteria (n = 2). Treatment modalities for ISR included balloon angioplasty alone (n = 1), cutting balloon angioplasty alone (n = 4), cutting balloon angioplasty with stent placement (n = 1), and balloon angioplasty with stent placement (n = 1). Technical success was achieved in all patients, and no periprocedural complications occurred. Two patients with post-CEA restenosis developed restenosis after ISR interventions, both of whom were successfully treated with cutting balloon angioplasty at 6 and 8 months. The remaining five patients showed an absence of recurrent stenosis or symptoms during a mean follow-up of 12 months (range, 3-37 months). By using the Kaplan-Meier analysis, the freedom from 80% or greater ISR after CAS procedures at 12, 24, 36, and 42 months was 97%, 97%, 96%, and 94%, respectively. Our study showed that ISR after CAS remains uncommon. Successful treatment of ISR can be achieved by endovascular interventions, which incurred no instance of periprocedural complications in our series. Patients who developed ISR after CEA were likely to develop restenosis after IRS intervention. Diligent ultrasound follow-up scans are important after CAS, particularly in patients with post-CEA restenosis.


Autologous stem cell therapy for peripheral arterial disease meta-analysis and systematic review of the literature.
Peripheral arterial disease (PAD) is a common cause of disability and mortality. Up to one third of patients are not susceptible to traditional revascularization and may benefit from stem cell therapies. In this meta-analysis, we sought to determine whether autologous cell therapy is effective in the treatment of PAD. We searched the English literature in Medline, Excerpta Medica and the Cochrane database for trials of autologous cell therapy in patients with PAD published before 31 January 2009. We included controlled and non-controlled, randomized and non-randomized trials using autologous bone marrow or granulocyte colony stimulating factor (G-CSF) mobilized peripheral blood cells to treat PAD. We also collected data from trials of G-CSF monotherapy, as a control treatment. In a meta-analysis of 37 trials, autologous cell therapy was effective in improving surrogate indexes of ischemia, subjective symptoms and hard endpoints (ulcer healing and amputation). On the contrary, G-CSF monotherapy was not associated with significant improvement in the same endpoints. Patients with thromboangiitis obliterans showed some larger benefits than patients with atherosclerotic PAD. The intramuscular route of administration and the use of bone marrow cells seemed somehow more effective than intrarterial administration and the use of mobilized peripheral blood cells. The procedures were well tolerated and generally safe. This meta-analysis indicates that intramuscular autologous bone marrow cell therapy is a feasible, relatively safe and potentially effective therapeutic strategy for PAD patients, who are not candidate for traditional revascularization. Larger, placebo-controlled, randomized multicenter trials need to be planned and conducted to confirm these findings.


Talin is required for integrin-mediated platelet function in hemostasis and thrombosis.
Integrins are critical for hemostasis and thrombosis because they mediate both platelet adhesion and aggregation. Talin is an integrin-binding cytoplasmic adaptor that is a central organizer of focal adhesions, and loss of talin phenocopies integrin deletion in Drosophila. Here, we have examined the role of talin in mammalian integrin function in vivo by selectively disrupting the talin1 gene in mouse platelet precursor megakaryocytes. Talin null megakaryocytes produced circulating platelets that exhibited normal morphology yet manifested profoundly impaired hemostatic function. Specifically, platelet-specific deletion of talin1 led to spontaneous hemorrhage and pathological bleeding. Ex vivo and in vitro studies revealed that loss of talin1 resulted in dramatically impaired integrin alphaIIbbeta3-mediated platelet aggregation and beta1 integrin-mediated platelet adhesion. Furthermore, loss of talin1 strongly inhibited the activation of platelet beta1 and beta3 integrins in response to platelet agonists. These data establish that platelet talin plays a crucial role in hemostasis and provide the first proof that talin is required for the activation and function of mammalian alpha2beta1 and alphaIIbbeta3 integrins in vivo.


The isotopic nature of the Earth's accreting material through time.
The Earth formed by accretion of Moon- to Mars-size embryos coming from various heliocentric distances. The isotopic nature of these bodies is unknown. However, taking meteorites as a guide, most models assume that the Earth must have formed from a heterogeneous assortment of embryos with distinct isotopic compositions. High-precision measurements, however, show that the Earth, the Moon and enstatite meteorites have almost indistinguishable isotopic compositions. Models have been proposed that reconcile the Earth-Moon similarity with the inferred heterogeneous nature of Earth-forming material, but these models either require specific geometries for the Moon-forming impact or can explain only one aspect of the Earth-Moon similarity (that is, 17O). Here I show that elements with distinct affinities for metal can be used to decipher the isotopic nature of the Earth's accreting material through time. I find that the mantle signatures of lithophile O, Ca, Ti and Nd, moderately siderophile Cr, Ni and Mo, and highly siderophile Ru record different stages of the Earth's accretion; yet all those elements point to material that was isotopically most similar to enstatite meteorites. This isotopic similarity indicates that the material accreted by the Earth always comprised a large fraction of enstatite-type impactors (about half were E-type in the first 60 per cent of the accretion and all of the impactors were E-type after that). Accordingly, the giant impactor that formed the Moon probably had an isotopic composition similar to that of the Earth, hence relaxing the constraints on models of lunar formation. Enstatite meteorites and the Earth were formed from the same isotopic reservoir but they diverged in their chemical evolution owing to subsequent fractionation by nebular and planetary processes.


Protein interactions regulating vesicle transport between the endoplasmic reticulum and Golgi apparatus in mammalian cells.
The proposed cis-Golgi vesicle receptor syntaxin 5 was found in a complex with Golgi-associated SNARE of 28 kDa (GOS-28), rbet1, rsly1, and two novel proteins characterized herein: rat sec22b and membrin, both cytoplasmically oriented integral membrane proteins. The complex appears to recapitulate vesicle docking interactions of proteins originating from distinct compartments, since syntaxin 5, rbet1, and GOS-28 localize to Golgi membranes, whereas mouse sec22b and membrin accumulate in the endoplasmic reticulum. Protein interactions in the complex are dramatically rearranged by N-ethylmaleimide-sensitive factor. The complex consists of two or more subcomplexes with some members (rat sec22b and syntaxin 5) in common and others (rbet1 and GOS-28) mutually exclusively associated. We propose that these protein interactions determine vesicle docking/fusion fidelity between the endoplasmic reticulum and Golgi.


Thr435 phosphorylation regulates RelA (p65) NF-kappaB subunit transactivation.
Phosphorylation of the RelA (p65) NF-kappaB (nuclear factor kappaB) subunit has been previously shown to modulate its ability to induce or repress transcription. In the present study we have investigated the consequences of Thr435 phosphorylation within the C-terminal transactivation domain of RelA. We confirm that Thr435 is phosphorylated in cells and is induced by TNFalpha (tumour necrosis factor alpha) treatment. Mutational analysis of this site revealed gene-specific effects on transcription, with a T435D phosphomimetic mutant significantly enhancing Cxcl2 (CXC chemokine ligand 2) mRNA levels in reconstituted Rela-/- mouse embryonic fibroblasts. Chromatin immunoprecipitation analysis revealed that this mutation results in enhanced levels of histone acetylation associated with decreased recruitment of HDAC1 (histone deacetylase 1). Moreover, mutation of this site disrupted RelA interaction with HDAC1 in vitro. Thr435 phosphorylation of promoter-bound RelA was also detected at NF-kappaB target genes following TNFalpha treatment in wild-type mouse embryonic fibroblasts. Phosphorylation at this site therefore provides an additional mechanism through which the specificity of NF-kappaB transcriptional activity can be modulated in cells.


Melanin chemistry and the ecology of stress.
Knowledge of melanin chemistry has important implications for the study of the evolutionary ecology of animal pigmentation, but the actual chemical diversity of these widely expressed biological pigments has been largely overlooked. Considering all melanin forms and the different conditions of endogenous oxidative stress during their synthesis provides information about physiological costs and benefits of different pigmentation patterns and opens a new perspective to understanding the evolution of color phenotypes in animals.


Alessandro Moretta and Transporter Associated With Antigen Processing (TAP) Deficiency: On Giant's Shoulders.
The laboratory hosting me for my Ph.D. described in 1994 the first human cases of TAP deficiency in two siblings with recurrent bacterial airway infections and a negative Human Leukocyte Antigen class I (HLA) serotyping. At this time, it became clear that natural killer (NK) cells interact with HLA class I molecules which inhibit them. Inhibitory receptors were postulated, and Alessandro Moretta was the first to generate monoclonal anti-human NK cell antibodies that bound to such molecules, which he characterized in detail (Killer Immunoglobulin-like receptors-KIR). Natural killer cells from healthy donors preferentially kill targets with absent HLA class I molecules ("missing self" concept), whereas we observed that the NK cells from the TAP-deficient patients were hypo-responsive and did not lyse the HLA class I-negative leukemia cell line K562. Moreover, they were not very active in antibody-dependent cellular cytotoxicity assays. To address the question if such NK cells would express KIR or not, my thesis supervisor requested the anti-KIR antibodies from Alessandro Moretta, who was kind enough to provide us generously with aliquots. It turned out that the NK cells from the TAP-deficient individuals expressed most of these inhibitory receptors normally. We then had the privilege to receive almost every new antibody generated in the Moretta lab and to complete the phenotypic studies of the NK cells from our patients. I had the great chance to meet Alessandro Moretta at several occasions. He deeply impressed me each time and strongly influenced my way of thinking.


Dual activation of pathways regulated by steroid receptors and peptide growth factors in primary prostate cancer revealed by Factor Analysis of microarray data.
We use an approach based on Factor Analysis to analyze datasets generated for transcriptional profiling. The method groups samples into biologically relevant categories, and enables the identification of genes and pathways most significantly associated to each phenotypic group, while allowing for the participation of a given gene in more than one cluster. Genes assigned to each cluster are used for the detection of pathways predominantly activated in that cluster by finding statistically significant associated GO terms. We tested the approach with a published dataset of microarray experiments in yeast. Upon validation with the yeast dataset, we applied the technique to a prostate cancer dataset. Two major pathways are shown to be activated in organ-confined, non-metastatic prostate cancer: those regulated by the androgen receptor and by receptor tyrosine kinases. A number of gene markers (HER3, IQGAP2 and POR1) highlighted by the software and related to the later pathway have been validated experimentally a posteriori on independent samples. Using a new microarray analysis tool followed by a posteriori experimental validation of the results, we have confirmed several putative markers of malignancy associated with peptide growth factor signalling in prostate cancer and revealed others, most notably ERRB3 (HER3). Our study suggest that, in primary prostate cancer, HER3, together or not with HER4, rather than in receptor complexes involving HER2, could play an important role in the biology of these tumors. These results provide new evidence for the role of receptor tyrosine kinases in the establishment and progression of prostate cancer.


Yoga in Correctional Settings: A Randomized Controlled Study.
The effect of yoga in the reduction of depressive symptoms, anxiety, stress, anger as well as in the increased ability of behavioral control has been shown. These effects of yoga are highly relevant for prison inmates who often have poor mental health and low impulse control. While it has been shown that yoga and meditation can be effective in improving subjective well-being, mental health, and executive functioning within prison populations, only a limited number of studies have proved this, using randomized controlled settings. A total of 152 participants from nine Swedish correctional facilities were randomly assigned to a 10-week yoga group (one class a week; N = 77) or a control group (N = 75). Before and after the intervention period, participants answered questionnaires measuring stress, aggression, affective states, sleep quality, and psychological well-being and completed a computerized test measuring attention and impulsivity. After the intervention period, significant improvements were found on 13 of the 16 variables within the yoga group (e.g., less perceived stress, better sleep quality, an increased psychological and emotional well-being, less aggressive, and antisocial behavior) and on two within the control group. Compared to the control group, yoga class participants reported significantly improved emotional well-being and less antisocial behavior after 10 weeks of yoga. They also showed improved performance on the computerized test that measures attention and impulse control. It can be concluded that the yoga practiced in Swedish correctional facilities has positive effects on inmates' well-being and on considerable risk factors associated with recidivism, such as impulsivity and antisocial behavior. Accordingly, the results show that yoga practice can play an important part in the rehabilitation of prison inmates.


The Usefulness of Muscle Biopsy in Initial Diagnostic Evaluation of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes.
The disease entity mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is characterized by an early onset of stroke-like episodes. MELAS is the most dominant subtype of mitochondrial disease. Molecular genetic testing is important in the diagnosis of MELAS. The mitochondrial DNA (mtDNA) 3243A>G mutation is found in 80% of MELAS patients. Nevertheless, molecular analysis alone may be insufficient to diagnose MELAS because of mtDNA heteroplasmy. This study aimed to evaluate whether muscle biopsy is useful in MELAS patients as an initial diagnostic evaluation method. The medical records of patients who were diagnosed with MELAS at the Department of Pediatrics of Gangnam Severance Hospital between January 2006 and January 2017 were reviewed. The study population included 12 patients. They were divided into two subgroups according to whether the results of muscle pathology were in accordance with mitochondrial diseases. Clinical variables, diagnostic evaluations, and clinical outcomes were compared between the two groups. Of the 12 patients, seven were muscle pathology-positive for mitochondrial disease. No statistically significant difference in clinical data was observed between the groups that were muscle pathology-positive and muscle pathology-negative for mtDNA 3243A>G mutation. Additionally, the patients with weakness as the initial symptom were all muscle pathology-positive. The usefulness of muscle biopsy appears to be limited to an initial confirmative diagnostic evaluation of MELAS. Muscle biopsy can provide some information in MELAS patients with weakness not confirmed by genetic testing.


Probiotic supplement use among young children in Taiwan: a prospective cohort study.
The objective of this study is to provide details on probiotic supplement use among young children in Taiwan. This study is based on the Taiwan Birth Cohort Study database. We used questionnaires to collect information on probiotic supplement use among young children from birth to 18 months of age, while also considering their demographic characteristics and other covariates. Low-birth-weight infants, preterm infants, those with birth defects, and those with caregivers who returned incomplete questionnaires were excluded. The final valid sample comprised 16,991 cases. Approximately half the children received probiotic supplements before the age of 18 months. Only 6.3% of the children received probiotic supplements during the two periods of birth to 6 months and 7 to 18 months. Firstborn children, native mothers, mothers with higher educational levels, higher family income, and parents who lead healthy lifestyles were positively related to probiotic supplement use among children. Young children who were breastfed, with eczema, or with gastrointestinal tract problems were significantly positively associated with probiotic supplement use. The findings show that probiotic supplement usage among young children is associated with a more socially advantaged circumstance and certain child health factors, such as eczema, diarrhea, and constipation. Parents might use probiotic supplements for prevention or treatment of child diseases. The findings of this research could serve as a baseline for future studies, and provide insight into probiotic supplement use behavior for health professionals caring for infants and young children.


Green and efficient three-component synthesis of 4H-pyran catalysed by CuFe2O4@starch as a magnetically recyclable bionanocatalyst.
The development of simple, practical and inexpensive catalysis systems using natural materials is one of the main goals of pharmaceutical chemistry as well as green chemistry. Owing to the ability of easy separation of nanocatalyst, those goals could be approached by applying heterogeneous bionanocatalyst in combination with magnetic nanoparticles. Starch is one of the most abundant natural polymers; therefore, preparing bionanocatalyst from starch is very valuable as starch is largely available and inexpensive. An ecologically benign and efficacious heterogeneous nanocatalyst was prepared based on a biopolymer, and its attributes and morphology were specified by using Fourier transform infrared spectra, scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), thermal analysis and vibrating sample magnetometer measurements; followed by studying catalytic behaviour of bionanocomposite in a multicomponent reaction to synthesize of 4H-pyran derivatives. 4H-pyran is extremely valuable in pharmaceutical chemistry, and the development of methods for synthesis of different derivatives of 4H-pyran is momentous. Revealing environmentally benign nature, mild condition, easy work-up, low cost and non-toxicity are some of the advantages of this protocol. Besides, the bionanocomposite was recovered using an external magnetic bar and could be re-used at least six times with no further decrease in its catalytic activity.


Unifying Single-Channel Permeability From Rare-Event Sampling and Steady-State Flux.
Various all-atom molecular dynamics (MD) simulation methods have been developed to compute free energies and crossing rates of ions and small molecules through ion channels. However, a systemic comparison across different methods is scarce. Using a carbon nanotube as a model of small conductance ion channel, we computed the single-channel permeability for potassium ion using umbrella sampling, Markovian milestoning, and steady-state flux under applied voltage. We show that a slightly modified inhomogeneous solubility-diffusion equation yields a single-channel permeability consistent with the mean first passage time (MFPT) based method. For milestoning, applying cylindrical and spherical bulk boundary conditions yield consistent MFPT if factoring in the effective bulk concentration. The sensitivity of the MFPT to the output frequency of collective variables is highlighted using the convergence and symmetricity of the inward and outward MFPT profiles. The consistent transport kinetic results from all three methods demonstrated the robustness of MD-based methods in computing ion channel permeation. The advantages and disadvantages of each technique are discussed, focusing on the future applications of milestoning in more complex systems.


Associations Between the Small Hive Beetle and the Yeast Kodamaea ohmeri Throughout the Host Life Cycle.
The small hive beetle, Aethina tumida Murray (Coleoptera: Nitidulidae), is a pest of colonies of social bees, including the honeybee Apis mellifera L. (Hymenoptera: Apidae). We investigated A. tumida oviposition behavior and development and found that it laid eggs in clutches that ranged in size (3-75 eggs per clutch) and that when fed on hive products in laboratory culture (27°C; RH 65%; 12:12 (L:D) h) it completed three larval instars before pupation. The yeast Kodamaea ohmeri (Etchells & Bell) Y. Yamada, T. Suzuki, M. Matsuda & K. Mikata (Ascomycota: Saccharomycotina) is associated with A. tumida, but the exact nature of this relationship is unknown. We examined the association in host eggs, larvae, pupae, and adults to establish its extent and potential specificity and determined the likely mechanism of vertical transmission. K. ohmeri was detected in egg mucilage and on host cuticle and from internal preparations of A. tumida at every stage of development. Based on colony forming unit (CFU) counts, the K. ohmeri densities varied significantly between developmental stages; the highest internal density was recorded in third instar larvae. Presence of K. ohmeri within adult A. tumida was not affected by contamination of the cuticle by the yeast during the larval and pupal stages nor by the mated status of the adult. This deepened understanding of A. tumida ovipositional behavior and larval development along with a better understanding of the relationship between K. ohmeri and its host is important for the development of management strategies for this important pest.


Genetic associations of type 2 diabetes with islet amyloid polypeptide processing and degrading pathways in asian populations.
Type 2 diabetes (T2D) is a complex disease characterized by beta cell dysfunctions. Islet amyloid polypeptide (IAPP) is highly conserved and co-secreted with insulin with over 40% of autopsy cases of T2D showing islet amyloid formation due to IAPP aggregation. Dysregulation in IAPP processing, stabilization and degradation can cause excessive oligomerization with beta cell toxicity. Previous studies examining genetic associations of pathways implicated in IAPP metabolism have yielded conflicting results due to small sample size, insufficient interrogation of gene structure and gene-gene interactions. In this multi-staged study, we screened 89 tag single nucleotide polymorphisms (SNPs) in 6 candidate genes implicated in IAPP metabolism and tested for independent and joint associations with T2D and beta cell dysfunctions. Positive signals in the stage-1 were confirmed by de novo and in silico analysis in a multi-centre unrelated case-control cohort. We examined the association of significant SNPs with quantitative traits in a subset of controls and performed bioinformatics and relevant functional analyses. Amongst the tag SNPs, rs1583645 in carboxypeptidase E (CPE) and rs6583813 in insulin degrading enzyme (IDE) were associated with 1.09 to 1.28 fold increased risk of T2D (P Meta = 9.4×10(-3) and 0.02 respectively) in a meta-analysis of East Asians. Using genetic risk scores (GRS) with each risk variant scoring 1, subjects with GRS≥3 (8.2% of the cohort) had 56% higher risk of T2D than those with GRS = 0 (P = 0.01). In a subcohort of control subjects, plasma IAPP increased and beta cell function index declined with GRS (P = 0.008 and 0.03 respectively). Bioinformatics and functional analyses of CPE rs1583645 predicted regulatory elements for chromatin modification and transcription factors, suggesting differential DNA-protein interactions and gene expression. Taken together, these results support the importance of dysregulation of IAPP metabolism in T2D in East Asians.


Androgenesis-inducing stress treatments change phytohormone levels in anthers of three legume species (Fabaceae).
Legumes are recalcitrant to androgenesis and induction protocols were only recently developed for pea (Pisum sativum L.) and chickpea (Cicer arietinum L.), albeit with low regeneration frequencies. Androgenesis is thought to be mediated through abscisic acid (ABA) but other phytohormones, such as auxins, cytokinins, and gibberellins, have also been implicated. In view of improving induction protocols, the hormone content of pea, chickpea, and lentil anthers was measured after exposure to cold, centrifugation, electroporation, sonication, osmotic shock, or various combinations thereof using an analytical mass spectrometer. Indole-3-acetic acid (IAA) had a key function during the induction process. In pea, high concentrations of IAA-asparagine (IAA-Asp), a putative IAA metabolite, accumulated during the application of the different stresses. In chickpea, the IAA-Asp concentration increased 30-fold compared to pea but only during the osmotic shock treatment and likely as a result of the presence of exogenous IAA in the medium. In contrast, no treatment in lentil (Lens culinaris) invoked such an increase in IAA-Asp content. Of the various cytokinins monitored, only cis zeatin riboside increased after centrifugation and electroporation in pea and possibly chickpea. No bioactive gibberellins were detected in any species investigated, indicating that this hormone group is likely not linked to androgenesis in legumes. In contrast to the other stresses, osmotic shock treatment caused a reduction in the levels of all hormones analyzed, with the exception of IAA-Asp in chickpea. A short period of low hormone content might be a necessary transition phase for androgenesis induction of legumes. Five androgenesis-inducing stress treatments changed content of ABA, auxin and cytokinin in anthers of three legumes. Osmotic shock treatment differed because it reduced hormone content to very low levels.


Aldehyde dehydrogenase as a marker and functional mediator of metastasis in solid tumors.
There is accumulating evidence indicating that aldehyde dehydrogenase (ALDH) activity selects for cancer cells with increased aggressiveness, capacity for sustained proliferation, and plasticity in primary tumors. However, emerging data also suggests an important mechanistic role for the ALDH family of isoenzymes in the metastatic activity of tumor cells. Recent studies indicate that ALDH correlates with either increased or decreased metastatic capacity in a cellular context-dependent manner. Importantly, it appears that different ALDH isoforms support increased metastatic capacity in different tumor types. This review assesses the potential of ALDH as biological marker and mechanistic mediator of metastasis in solid tumors. In many malignancies, most notably in breast cancer, ALDH activity and expression appears to be a promising marker and potential therapeutic target for treating metastasis in the clinical setting.


Effects of angiotensin converting enzyme inhibition or angiotensin receptor blockade in dialysis patients: a nationwide data survey and propensity analysis.
Long-term benefit of using a renin-angiotensin-aldosterone system blocker such as an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB) for patients already receiving dialysis remains undetermined. The aim of this study is to assess the efficacy and safety of ACEI or ARB use in dialysis patients. We performed a population-based cohort study with time-to-event analyses to estimate the relation between the use of ACEI/ARB and their outcomes. We used a nationwide database (Registry for Catastrophic Illnesses) for Taiwan, which has data from 1995 to 2008 nearly of all patients who received dialysis therapy. The records of all dialysis patients aged ≥18 with no evidence of cardiovascular (CV) events in 1997 and 1998 (133,564 patients) were examined. Users (n = 50,961) and nonusers (n = 59,913) of an ACEI/ARB were derived. We then used propensity score matching and Cox proportional hazards regression models to estimate adjusted hazard ratios (HRs) for all-cause mortality and CV events in users and nonusers of an ACRI/ARB. The 15,182 patients, who used an ACEI/ARB, and the 15,182 nonusers had comparable baseline characteristics during the 14 years of follow-up. The mortality was significantly greater in patients who did not use an ACEI/ARB (HR = 0.90, 95% confidence interval = 0.86-0.93). Subgroup analysis of 3 tertiles of patients who used different total amounts of ACEI/ARB during the study period indicated that CV events were more common in patients who used an ACEI/ARB for a short duration (tertile 1: HR = 1.63), but less common in those who used an ACEI/ARB for long durations (tertile 2: HR = 1.05; tertile 3: HR = 0.94; trend for declining HR from tertile 1 to 3: P < 0.001). The mortality benefit provided by use of an ACEI/ARB was consistent across most patient subgroups, as was the benefit of ARB monotherapy rather than ACEI monotherapy. Independent of traditional risk factors, overall mortality was significantly lower in dialysis patients who used an ACEI/ARB. In addition, subjects who used an ACEI/ARB for longer durations were significantly less likely to experience CV events.


Teaching ethics using games: Impact on Iranian nursing students' moral sensitivity.
This study seeks to develop a method of teaching ethics to nursing students using games. We used the one-group pretest-posttest design with 30 undergraduate nursing students as participants. Professional ethics education was provided for 17 weeks in 90-minute sessions. The Lutzen ethical sensitivity questionnaire and a checklist of the satisfaction levels of games used measured the effects of training. Repeated-measures ANOVA and the Greenhouse-Geisser correction were used to measure ethics game satisfaction. After training, total moral sensitivity questionnaire scores increased significantly (p = 0.02). The score on awareness of the relationship with the patient and the application of ethics concepts in ethical decisions from the subdomain of moral sensitivity increased significantly. Card sorting and drawing or art production earned the highest scores of satisfaction. The results show that playing games is a useful approach to developing moral sensitivity among nursing students to make them more sensitive toward ethics issues in their professional environment.