Structural basis for the interaction between the Golgi reassembly-stacking protein GRASP65 and the Golgi matrix protein GM130.
GM130 and GRASP65 are Golgi peripheral membrane proteins that play a key role in Golgi stacking and vesicle tethering. However, the molecular details of their interaction and their structural role as a functional unit remain unclear. Here, we present the crystal structure of the PDZ domains of GRASP65 in complex with the GM130 C-terminal peptide at 1.96-Å resolution. In contrast to previous findings proposing that GM130 interacts with GRASP65 at the PDZ2 domain only, our crystal structure of the complex indicates that GM130 binds to GRASP65 at two distinct sites concurrently and that both the PDZ1 and PDZ2 domains of GRASP65 participate in this molecular interaction. Mutagenesis experiments support these structural observations and demonstrate that they are required for GRASP65-GM130 association.


Under the radar or under arrest: How is adolescent boys' first contact with the juvenile justice system related to future offending and arrests?
This study examined the extent to which being arrested during adolescence was associated with subsequent self-reported offending and court-recorded arrests. We also examined whether the way in which the justice system processed adolescents was related to the nature of these associations. The sample included 532 boys who had been arrested ("justice-system-involved") and 99 boys who had never been arrested despite engaging in similar illegal behaviors ("no-justice-system-contact"). Data included official arrest records and youths' self-reported illegal behavior at a baseline interview and a follow-up 6 months later. To reduce group differences at baseline, we calculated matching weights with 2 dozen variables and used these weights in all analyses. Results demonstrated that the groups differed in their rate of change in self-reported offending between the 2 interviews and in their likelihood of being arrested during the study period. The no-justice-system-contact group self-reported the same amount of offending at baseline and the follow up, whereas the justice-system-involved youth who received the most lenient disposition (i.e., sanction and dismiss) decreased their self-reported violent, theft or property, and total offending, and the justice-system-involved youth who received the most punitive disposition (i.e., adjudication) increased their self-reported violent offending. All justice-system-involved youth were more likely to be arrested during the study period than the no-justice-system-contact youth, even after accounting for self-reported offending. Thus, even though some justice system interventions were associated with less subsequent offending, involvement with the juvenile justice system during adolescence, in and of itself, is a significant risk factor for repeated contact with the system. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Double-blindness procedures, rater blindness, and ratings of outcome. Observations from a controlled trial.
We determined whether blindness in a double-blind randomized controlled trial of alprazolam and exposure therapies in patients with panic disorder and agoraphobia was maintained in assessors and patients, what were the factors related to "unblinding," and whether unblinding was associated with clinical outcome. In 129 patients with panic disorder and agoraphobia who were randomized to alprazolam-exposure, placebo-exposure, alprazolam-relaxation, or placebo-relaxation conditions, blindness was tested at the end of treatment by the independent assessors' and patients' classification of the treatment condition. Assessors' classifications were correct in 82% of the alprazolam group and 78% of the placebo group; corresponding figures for patients' classifications were 73% and 70%, respectively. Factors associated with unblinding included drug side effects but not assessors' ratings of treatment outcome. Judgment of the validity of the outcome of a randomized controlled trial is easier if the report notes not only the use of a double-blindness procedure but also details how blind the raters remained and how any unblinding affected their ratings of clinical outcome.


Physiological basis of a steady endogenous current in rat lumbrical muscle.
In an attempt to determine the mechanism by which rat skeletal muscle endplates generate a steady outward current, we measured the effects of several drugs (furosemide, bumetanide, 9-anthracene carboxylic acid [9-AC]) and changes in external ion concentration (Na+, K+, Cl-, Ba++) on resting membrane potential (Vm) and on the steady outward current. Each of the following treatments caused a 10-15-mV hyperpolarization of the membrane: replacement of extracellular Cl- with isethionate, addition of furosemide or bumetanide, and addition of 9-AC. These results suggest that Cl- is actively accumulated by the muscle fibers and that the equilibrium potential of Cl- is more positive than the membrane potential. Removal of external Na+ also caused a large hyperpolarization and is consistent with evidence in other tissues that active Cl- accumulation requires external Na+. The same treatments greatly reduced or abolished the steady outward current, with a time course that paralleled the changes in Vm. These results cannot be explained by a model in which the steady outward current is assumed to arise as a result of a nonuniform distribution of Na+ conductance, but they are consistent with models in which the steady current is produced by a nonuniform distribution of GCl or GK. Other treatments (Na+-free and K+-free solutions, and 50 microM BaCl2) caused a temporary reversal of the steady current. Parallel measurements of Vm suggested that in none of these cases did the electrochemical driving force for K+ change sign, which makes it unlikely that the steady current arises as a result of a nonuniform distribution of GK. All of the results, however, are consistent with a model in which the steady outward current arises as a result of a nonuniform distribution of Cl- conductance, with GCl lower near the endplate than in extrajunctional regions.


Study of a spherical phantom for Gamma knife dosimetry.
Four 16 cm diameter spherical phantoms were modeled in this study: a homogenous water phantom, and three water phantoms with 1 cm thick shell each made of different materials (PMMA, Plastic WaterTM and polystyrene). The PENELOPE Monte Carlo code was utilized to simulate photon beams from the Leksell Gamma Knife (LGK) unit and to determine absorbed dose to water (Dw) from a single 18 mm beam delivered to each phantom. A score spherical volume of 0.007 cm3 was used to simulate the dimensions of the sensitive volume of the Exradin A-16 ionization chamber, in the center of the phantom. In conclusion, the PMMA shell filled with water required a small correction for the determination of the absorbed dose, while remaining within the statistical uncertainty of the calculations (+/- 0.71). Plastic WaterTM and polystyrene shells can be used without correction. There is a potential advantage to measuring the 4 mm helmet output using these spherical water phantoms.


Gadolinium neutron capture brachytherapy (GdNCB), a new treatment method for intravascular brachytherapy.
Restenosis is a major problem after balloon angioplasty and stent implantation. The aim of this study is to introduce gadolinium neutron capture brachytherapy (GdNCB) as a suitable modality for treatment of stenosis. The utility of GdNCB in intravascular brachytherapy (IVBT) of stent stenosis is investigated by using the GEANT4 and MCNP4B Monte Carlo radiation transport codes. To study capture rate, Kerma, absorbed dose and absorbed dose rate around a Gd-containing stent activated with neutrons, a 30 mm long, 5 mm diameter gadolinium foil is chosen. The input data is a neutron spectrum used for clinical neutron capture therapy in Studsvik, Sweden. Thermal neutron capture in gadolinium yields a spectrum of high-energy gamma photons, which due to the build-up effect gives an almost flat dose delivery pattern to the first 4 mm around the stent. The absorbed dose rate is 1.33 Gy/min, 0.25 mm from the stent surface while the dose to normal tissue is in order of 0.22 Gy/min, i.e., a factor of 6 lower. To spare normal tissue further fractionation of the dose is also possible. The capture rate is relatively high at both ends of the foil. The dose distribution from gamma and charge particle radiation at the edges and inside the stent contributes to a nonuniform dose distribution. This will lead to higher doses to the surrounding tissue and may prevent stent edge and in-stent restenosis. The position of the stent can be verified and corrected by the treatment plan prior to activation. Activation of the stent by an external neutron field can be performed days after catherization when the target cells start to proliferate and can be expected to be more radiation sensitive. Another advantage of the nonradioactive gadolinium stent is the possibility to avoid radiation hazard to personnel.


Embryo and endosperm inherit distinct chromatin and transcriptional states from the female gametes in Arabidopsis.
Whether deposited maternal products are important during early seed development in flowering plants remains controversial. Here, we show that RNA interference-mediated downregulation of transcription is deleterious to endosperm development but does not block zygotic divisions. Furthermore, we show that RNA POLYMERASE II is less active in the embryo than in the endosperm. This dimorphic pattern is established late during female gametogenesis and is inherited by the two products of fertilization. This juxtaposition of distinct transcriptional activities correlates with differential patterns of histone H3 lysine 9 dimethylation, LIKE HETEROCHROMATIN PROTEIN1 localization, and Histone H2B turnover in the egg cell versus the central cell. Thus, distinct epigenetic and transcriptional patterns in the embryo and endosperm are already established in their gametic progenitors. We further demonstrate that the non-CG DNA methyltransferase CHROMOMETHYLASE3 (CMT3) and DEMETER-LIKE DNA glycosylases are required for the correct distribution of H3K9 dimethylation in the egg and central cells, respectively, and that plants defective for CMT3 activity show abnormal embryo development. Our results provide evidence that cell-specific mechanisms lead to the differentiation of epigenetically distinct female gametes in Arabidopsis thaliana. They also suggest that the establishment of a quiescent state in the zygote may play a role in the reprogramming of the young plant embryo.


Race-, age-, gender-, and refractive error-related differences in the normal optic disc.
To determine race-, age-, gender-, and refractive error-related differences in the size and topography of the optic disc in healthy Americans. Population-based study. Eastern and southeastern health districts of Baltimore, Md. A population-based sample of 4877 non-institutionalized black and white individuals aged 40 years or older without evidence of optic nerve disease. Race-, age-, gender-, and refractive error-related differences in optic disc measurements: disc area, neural rim area, cup area, cup-to-disc ratio, and neural rim area-to-disc area ratio. We analyzed simultaneous stereoscopic optic disc photographs from 3387 (1534 black and 1853 white) of the 4877 healthy individuals using an image analyzer (Topcon Image Analyzer, Topcon Instrument Corporation, Paramus, NJ). A total of 1490 individuals were excluded owing to the absence of good-quality images from either eye. The image analyzer defined the cup margin 150 microns below the surface of the disc margin. On average, blacks had significantly larger disc areas (blacks, 2.94 mm2; whites, 2.63 mm2), larger cup areas (blacks, 1.04 mm2; whites, 0.71 mm2), larger cup-to-disc ratios (blacks, 0.56; whites, 0.49), similar neural rim areas (blacks, 1.90 mm2; whites, 1.92 mm2), and smaller neural rim area-to-disc area ratios (blacks, 0.66; whites, 0.74) compared with whites. There were no age-related differences in any of the disc measurements. Male subjects had 2% to 3% larger optic discs compared with female subjects. No association between refractive error and any of the optic disc measurements studied was detected. Racial differences in the normal optic disc are present among urban Americans, and these differences must be considered in evaluation of the optic disc for glaucoma and other optic neuropathies. Among the individuals in our study, all of whom were 40 years of age or older, no progressive age-related decline in neural rim area was detectable. Neither gender nor refractive error were associated with any significant differences in the size and topography of the normal optic disc.


Localized outbreaks in an S-I-R model with diffusion.
We investigate an SIRS epidemic model with spatial diffusion and nonlinear incidence rates. We show that for small diffusion rate of the infected class [Formula: see text], the infected population tends to be highly localized at certain points inside the domain, forming K spikes. We then study three distinct destabilization mechanisms, as well as a transition from localized spikes to plateau solutions. Two of the instabilities are due to coarsening (spike death) and self-replication (spike birth), and have well-known analogues in other reaction-diffusion systems such as the Schnakenberg model. The third transition is when a single spike becomes unstable and moves to the boundary. This happens when the diffusion of the recovered class, [Formula: see text] becomes sufficiently small. In all cases, the stability thresholds are computed asymptotically and are verified by numerical experiments. We also show that the spike solution can transit into an plateau-type solution when the diffusion rates of recovered and susceptible class are sufficiently small. Implications for disease spread and control through quarantine are discussed.


In vivo Modeling Implicates APOL1 in Nephropathy: Evidence for Dominant Negative Effects and Epistasis under Anemic Stress.
African Americans have a disproportionate risk for developing nephropathy. This disparity has been attributed to coding variants (G1 and G2) in apolipoprotein L1 (APOL1); however, there is little functional evidence supporting the role of this protein in renal function. Here, we combined genetics and in vivo modeling to examine the role of apol1 in glomerular development and pronephric filtration and to test the pathogenic potential of APOL1 G1 and G2. Translational suppression or CRISPR/Cas9 genome editing of apol1 in zebrafish embryos results in podocyte loss and glomerular filtration defects. Complementation of apol1 morphants with wild-type human APOL1 mRNA rescues these defects. However, the APOL1 G1 risk allele does not ameliorate defects caused by apol1 suppression and the pathogenicity is conferred by the cis effect of both individual variants of the G1 risk haplotype (I384M/S342G). In vivo complementation studies of the G2 risk allele also indicate that the variant is deleterious to protein function. Moreover, APOL1 G2, but not G1, expression alone promotes developmental kidney defects, suggesting a possible dominant-negative effect of the altered protein. In sickle cell disease (SCD) patients, we reported previously a genetic interaction between APOL1 and MYH9. Testing this interaction in vivo by co-suppressing both transcripts yielded no additive effects. However, upon genetic or chemical induction of anemia, we observed a significantly exacerbated nephropathy phenotype. Furthermore, concordant with the genetic interaction observed in SCD patients, APOL1 G2 reduces myh9 expression in vivo, suggesting a possible interaction between the altered APOL1 and myh9. Our data indicate a critical role for APOL1 in renal function that is compromised by nephropathy-risk encoding variants. Moreover, our interaction studies indicate that the MYH9 locus is also relevant to the phenotype in a stressed microenvironment and suggest that consideration of the context-dependent functions of both proteins will be required to develop therapeutic paradigms.


Sarcomatous tumor of the chest wall with osteochondroid differentiation. Evidence of mesothelial origin.
We describe a case of sarcomatous tumor of the chest wall with differentiation toward bone and cartilage that was observed in an asbestos-exposed worker. Although the mesothelial nature of the tumor was at first considered, it was not proven. Later, the tumor was shown to be a mesothelioma using a panel of pertinent antibodies that included a recently described anti-mesothelial cell marker. In addition, asbestos bodies were found in association with the sarcoma cells. Our findings indicate that whenever physicians encounter any type of primary sarcomatoid tumor involving serous membranes, the possibility of malignant mesothelioma should be regarded a priori.


Images of flight nursing in Australia: A study using institutional ethnography.
Pictures speak a thousand words. The traditional romantic image of an Australian aeromedical service is a male doctor and male pilot, out to rescue the male stockman from the red dust of the Australian outback. However, the reality is considerably different, particularly in the current context of the Australian healthcare system. This paper examines the images of flight nursing using a critical lens. The images are derived from popular literature sources from the early 1940s through to the present. A textual analysis of the images of flight nursing using the methodology of institutional ethnography reveals a number of themes including the glamorous, the romantic, and the heroic nurse. This study illustrates that the way these nurses are portrayed within popular literature mirrors the Australian cultural ethic of heroic bush pioneer, yet at the same time the work these nurses do is undervalued by various omissions and misrepresentations. The results from this study have the potential to significantly improve recognition of the work performed by flight nurses and to challenge incorrect cultural myths.


Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study.
Therapeutic options for advanced neuroendocrine tumours (NETs) are limited. We investigated the efficacy and safety of surufatinib (HMPL-012, sulfatinib) in patients with extrapancreatic NETs. SANET-ep was a randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 24 hospitals across China. Patients (aged 18 years or older) with unresectable or metastatic, well differentiated, extrapancreatic NETs, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression on no more than two types of previous systemic regimens were enrolled. Patients were centrally randomly assigned (2:1) using stratified block randomisation (block size 3) via an interactive web response system to receive oral surufatinib at 300 mg per day or matching placebo. Randomisation was stratified by tumour origin, pathological grade, and previous treatment. Patients, investigators, research staff and the sponsor study team were masked to treatment allocation. Crossover to the surufatinib group was allowed for patients in the placebo group at disease progression. The primary endpoint was investigator-assessed progression-free survival, which was analysed in the intention-to-treat population. A preplanned interim analysis was done at 70% of predicted progression-free survival events. This study was registered with ClinicalTrials.gov, NCT02588170. Follow-up is ongoing. Between Dec 9, 2015, and March 31, 2019, 198 patients were randomly assigned to surufatinib (n=129) or placebo (n=69). Median follow-up was 13·8 months (95% CI 11·1-16·7) in the surufatinib group and 16·6 months (9·2-not calculable) in the placebo group. Investigator-assessed median progression-free survival was 9·2 months (95% CI 7·4-11·1) in the surufatinib group versus 3·8 months (3·7-5·7) in the placebo group (hazard ratio 0·33; 95% CI 0·22-0·50; p<0·0001). As the trial met the predefined criteria for early discontinuation of the study at the interim analysis, the study was terminated early, as recommended by the independent data monitoring committee. The most common treatment-related adverse events of grade 3 or worse were hypertension (47 [36%] of 129 patients in the surufatinib group vs nine [13%] of 68 patients in the placebo group) and proteinuria (25 [19%] vs zero). Treatment-related serious adverse events were reported in 32 (25%) of 129 patients in the surufatinib group and nine (13%) of 68 patients in the placebo group. Treatment-related deaths occurred in three patients in the surufatinib group (disseminated intravascular coagulation and hepatic encephalopathy, liver injury, and death with unknown reason) and one patient in the placebo group (cachexia and respiratory failure). Progression-free survival was significantly longer in patients given surufatinib compared with patients given placebo, and surufatinib has a favourable benefit-to-risk profile in patients with progressive, advanced, well differentiated extrapancreatic NETs. Our results suggest that surufatinib might be a new treatment option for this population. Hutchison MediPharma.


Effect of Structured Physical Activity and Nutritional Supplementation on Physical Function in Mobility-Limited Older Adults: Results from the VIVE2 Randomized Trial.
The interactions between nutritional supplementation and physical activity on changes in physical function among older adults remain unclear. The primary objective of this study was to examine the impact of nutritional supplementation plus structured physical activity on 400M walk capacity in mobility-limited older adults across two sites (Boston, USA and Stockholm, Sweden). All subjects participated in a physical activity program (3x/week for 24 weeks), involving walking, strength, balance, and flexibility exercises. Subjects were randomized to a daily nutritional supplement (150kcal, 20g whey protein, 800 IU vitamin D) or placebo (30kcal, non-nutritive). Participants were recruited from urban communities at 2 field centers in Boston MA USA and Stockholm SWE. Mobility-limited (Short Physical Performance Battery (SPPB) ≤9) and vitamin D insufficient (serum 25(OH) D 9 - 24 ng/ml) older adults were recruited for this study. Primary outcome was gait speed assessed by the 400M walk. 149 subjects were randomized into the study (mean age=77.5±5.4; female=46.3%; mean SPPB= 7.9±1.2; mean 25(OH)D=18.7±6.4 ng/ml). Adherence across supplement and placebo groups was similar (86% and 88%, respectively), and was also similar across groups for the physical activity intervention (75% and 72%, respectively). Both groups demonstrated an improvement in gait speed with no significant difference between those who received the nutritional supplement compared to the placebo (0.071 and 0.108 m/s, respectively (p=0.06)). Similar effects in physical function were observed using the SPPB. Serum 25(OH)D increased in supplemented group compared to placebo 7.4 ng/ml versus 1.3 ng/ml respectively. Results suggest improved gait speed following physical activity program with no further improvement with added nutritional supplementation.


Incidences and Risk Factors of Organ Manifestations in the Early Course of Systemic Sclerosis: A Longitudinal EUSTAR Study.
Systemic sclerosis (SSc) is a rare and clinically heterogeneous autoimmune disorder characterised by fibrosis and microvascular obliteration of the skin and internal organs. Organ involvement mostly manifests after a variable period of the onset of Raynaud's phenomenon (RP). We aimed to map the incidence and predictors of pulmonary, cardiac, gastrointestinal (GI) and renal involvement in the early course of SSc. In the EUSTAR cohort, patients with early SSc were identified as those who had a visit within the first year after RP onset. Incident SSc organ manifestations and their risk factors were assessed using Kaplan-Meier methods and Cox regression analysis. Of the 695 SSc patients who had a baseline visit within 1 year after RP onset, the incident non-RP manifestations (in order of frequency) were: skin sclerosis (75%) GI symptoms (71%), impaired diffusing capacity for monoxide<80% predicted (65%), DU (34%), cardiac involvement (32%), FVC<80% predicted (31%), increased PAPsys>40mmHg (14%), and renal crisis (3%). In the heart, incidence rates were highest for diastolic dysfunction, followed by conduction blocks and pericardial effusion. While the main baseline risk factor for a short timespan to develop FVC impairment was diffuse skin involvement, for PAPsys>40mmHg it was higher patient age. The main risk factors for incident cardiac manifestations were anti-topoisomerase autoantibody positivity and older age. Male sex, anti-RNA-polymerase-III positivity, and older age were risk factors associated with incident renal crisis. In SSc patients presenting early after RP onset, approximately half of all incident organ manifestations occur within 2 years and have a simultaneous rather than a sequential onset. These findings have implications for the design of new diagnostic and therapeutic strategies aimed to 'widen' the still very narrow 'window of opportunity'. They may also enable physicians to counsel and manage patients presenting early in the course of SSc more accurately.


Serum paraoxonase activity, total thiols levels, and oxidative status in patients with acute brucellosis.
It is well known that paraoxonase-1 (PON1) activity may decrease during the course of infection and inflammation. The aim of this study was to investigate serum PON1 activity, oxidative status, and thiols levels in patients with acute brucellosis. In addition, we investigated the PON1 phenotype in patients with acute brucellosis. Thirty patients with acute brucellosis and 35 healthy controls were enrolled. Serum paraoxonase and arylesterase activities, thiols levels, lipid hydroperoxide levels, total antioxidant capacity (TAC), total oxidant status (TOS) and oxidative stress index (OSI) were determined. Serum basal and salt-stimulated paraoxonase-arylesterase activities, TAC levels and thiols levels were significantly lower in patients with acute brucellosis than controls (for all, p < 0.05), while LOOH levels, TOS levels, and OSI values were significantly higher (for all, p < 0.05). We concluded that oxidative stress is increased, while serum PON1 activity is decreased in patients with acute brucellosis. These results indicate that lower PON1 activity is associated with oxidant-antioxidant imbalance.


Impairment of CCR6+ and CXCR3+ Th Cell Migration in HIV-1 Infection Is Rescued by Modulating Actin Polymerization.
CD4+ T cell repopulation of the gut is rarely achieved in HIV-1-infected individuals who are receiving clinically effective antiretroviral therapy. Alterations in the integrity of the mucosal barrier have been indicated as a cause for chronic immune activation and disease progression. In this study, we present evidence that persistent immune activation causes impairment of lymphocytes to respond to chemotactic stimuli, thus preventing their trafficking from the blood stream to peripheral organs. CCR6+ and CXCR3+ Th cells accumulate in the blood of aviremic HIV-1-infected patients on long-term antiretroviral therapy, and their frequency in the circulation positively correlates to levels of soluble CD14 in plasma, a marker of chronic immune activation. Th cells show an impaired response to chemotactic stimuli both in humans and in the pathogenic model of SIV infection, and this defect is due to hyperactivation of cofilin and inefficient actin polymerization. Taking advantage of a murine model of chronic immune activation, we demonstrate that cytoskeleton remodeling, induced by okadaic acid, restores lymphocyte migration in response to chemokines, both in vitro and in vivo. This study calls for novel pharmacological approaches in those pathological conditions characterized by persistent immune activation and loss of trafficking of T cell subsets to niches that sustain their maturation and activities.


Effect of semi-rigid or flexible mitral ring annuloplasty on anterior leaflet three-dimensional geometry.
A saddle-shaped mitral annulus may optimize anterior leaflet shape and, in theory, reduce leaflet and chordal stress. Although annuloplasty rings alter native annular height and immobilize the posterior mitral leaflet, their effects on anterior leaflet geometry are unknown. Four radiopaque markers were placed on the central meridian of the anterior mitral leaflet (AML), and eight on the mitral annulus, of 20 sheep. Six animals were then implanted with a Carpentier-Edwards Physio ring, and six a Medtronic Duran flexible ring. Eight animals served as controls. All animals were then studied with biplane 60 Hz videofluoroscopy at 7-10 days after surgery. The angle Theta was calculated as the angle between each AML leaflet marker and the annular septal-lateral diameter, while AML marker excursion was expressed as the difference between maximum and minimum angle Theta during the cardiac cycle. The intrinsic AML shape was described by three angles, each between three consecutive leaflet markers from the mid-septal annular marker to the leaflet edge (Phi1-3, from annulus to leaflet edge). Hemodynamic parameters differed only in left ventricular pressure, which was higher in control animals. Anterior leaflet excursion during the cardiac cycle for all four leaflet markers did not change with ring annuloplasty. The intrinsic leaflet angles (Phi1-3) were also unaffected by annular fixation, and thus leaflet shape remained unaltered. Neither semi-rigid nor flexible annuloplasty rings affected anterior leaflet excursion or the intrinsic geometry of the AML at end-systole or end-diastole. These data suggest that, in normal sheep hearts, annuloplasty rings do not alter anterior leaflet shape and hence do not perturb leaflet stress distribution.


Characteristics and Safety of Cardiopulmonary Exercise Testing in Elderly Patients with Cardiovascular Diseases in Korea.
Clinical use of cardiopulmonary exercise tests (CPETs) is increasing in elderly patients with cardiovascular (CV) diseases. However, data on Korean populations are limited. In this study, we aimed to examine the characteristics and safety of CPET in an elderly Korean population with CV disease. We retrospectively analyzed records of 1485 patients (older than 65 years in age, with various underlying CV diseases) who underwent CPET. All CPET was performed using the modified Bruce ramp protocol. The mean age of patients was 71.6±4.7 years with 63.9% being men, 567 patients aged 60-65 years, 818 patients aged 70-79 years, and 100 patients aged 80-89 years. The mean respiratory exchange ratio was 1.09±0.14. During CPET, three adverse cardiovascular events occurred (total 0.20%), all ventricular tachycardia. All subjects showed an average exercise capacity of 21.3±5.5 mL/kg/min at peak VO₂ and 6.1±1.6 metabolic equivalents of task, and men showed better exercise capacity than women on most CEPT parameters. A significant difference was seen in peak oxygen uptake according to age group (65-69 years, 22.9±5.8; 70-79 years, 20.7±5.1; 80-89 years, 17.0±4.5 mL/kg/min, p<0.001). The most common causes for CPET termination were dyspnea (64.8%) and leg pain (24.3%), with higher incidence of leg pain in octogenarians compared to other age groups (65-69 years, 22.4%; 70-79 years, 24.6%; 80-89 years, 32.0%, p<0.001). CPET was relatively a safe and useful modality to assess exercise capacity, even in an elderly Korean population with underlying CV diseases.


New challenge of developing combined radio-drug therapy.
Combined modality treatment can be used to improve control of the local disease at the expense of increased toxicity. Several randomized trials have demonstrated that this combined modality therapy is better than radiotherapy alone or chemotherapy alone in the treatment of locally advanced diseases. Several new targets as well as potential new radio-sensitizers have been identified. To speed-up the process of developing new combined modality treatments, good preclinical models for optimization of the ratio between efficacy and toxicity and a well established methodology within a network of advanced high-tech laboratories and clinical departments devoted to early phase trials, are mandatory. The Synergy of Targeted Agents and Radiation Therapy (STAR) platform of the European Organisation for Research and Treatment of Cancer (EORTC) is gathering these tools.


Lab on a single microbead: an ultrasensitive detection strategy enabling microRNA analysis at the single-molecule level.
Detection of a single nucleic acid molecule is of great significance for both fundamental biochemistry studies and clinical diagnostics. By using microRNA (miRNA) as a model target, herein, we have developed a single-microbead-based sensing (SMBS) platform, which simply enables the detection of miRNA at the single-molecule level. In this strategy, an isothermal exponential amplification reaction (EXPAR) is rationally designed towards specific miRNAs and all products of the EXPAR are integrated onto a single microbead for signal amplification and fluorescence enrichment. This pushes the detection of miRNAs down to 1 aM in a 5 μL sample, corresponding to 3 copies of the miRNA molecule. This new strategy also affords high selectivity and it is capable of distinguishing among homologous miRNA family members even with a single-base difference. Due to its ultrahigh sensitivity and selectivity, the proposed SMBS platform has been successfully applied to the detection of miRNA extracted from a single cell.


The cytochrome b gene as a phylogenetic marker: the limits of resolution for analyzing relationships among cichlid fishes.
The mitochondrial cytochrome b (cyt-b) gene is widely used in systematic studies to resolve divergences at many taxonomic levels. The present study focuses mainly on the utility of cyt-b as a molecular marker for inferring phylogenetic relationship at various levels within the fish family Cichlidae. A total of 78 taxa were used in the present analysis, representing all the major groups in the family Cichlidae (72 taxa) and other families from the suborders Labroidei and Percoidei. Gene trees obtained from cyt-b are compared to a published total evidence tree derived from previous studies. Minimum evolution trees based on cyt-b data resulted in topologies congruent with all previous analyses. Parsimony analyses downweighting transitions relative to transversions (ts1:tv4) or excluding transitions at third codon positions resulted in more robust bootstrap support for recognized clades than unweighted parsimony. Relative rate tests detected significantly long branches for some taxa (LB taxa) which were composed mainly by dwarf Neotropical cichlids. An improvement of the phylogenetic signal, as shown by the four-cluster likelihood mapping analysis, and higher bootstrap values were obtained by excluding LB taxa. Despite some limitations of cyt-b as a phylogenetic marker, this gene either alone or in combination with other data sets yields a tree that is in agreement with the well-established phylogeny of cichlid fish.


Revitalising Evidence-based Policy for the Sendai Framework for Disaster Risk Reduction 2015-2030: Lessons from Existing International Science Partnerships.
The convergence of agreements on disaster risk reduction (DRR), development finance, sustainable development and climate change in 2015 presents a unique opportunity for coherence across these inter-related policy areas. At the same time, demand is growing for a more prominent and effective role for science and technology in providing evidence for policy, with the international community recognising that successful disaster risk reduction (DRR) depends on it. Reflecting this ambition, science is included as a core aspect of the Sendai Framework for Disaster Risk Reduction 2015-2030, although the ways in which this will be implemented in practice is still unclear. This paper aims to inform the implementation of international science coordination for DRR by examining a number of existing international science partnerships used across other relevant areas of policy to understand best practice, options for coordination and lessons identified. In the field of DRR, the science-policy interface needs to be strengthened in line with the best practice described in this review. An enhanced UNISDR Scientific and Technical Advisory Group will be given the mandate for to enhance the evidence base for DRR and mobilise science and technical work in coordination with a broad range of stakeholders. The structure and function of an enhanced STAG must be as open, as inclusive and as participatory as possible in order to build trust in new and existing institutions at local, national, regional and global levels. The challenge for the international community is to facilitate evidence-based policy making by formally recognising the links between DRR, development finance, sustainable development and climate change in the upcoming post-2015 agreements.


An evaluation of the choices for well-being project.
The relationship between mental health, self-esteem and unemployment is well established. Emerging research suggests that interventions such as Cognitive Behavioural Therapy (CBT) can counter the negative effects of unemployment and may improve re-employment. This study evaluated the effectiveness of a manual-based programme, which combines CBT with job skills training, in improving the psychological health and job- seeking skills of unemployed individuals within the UK. One hundred and nine unemployed individuals, suffering mild to moderate mental health problems, were referred to the programme. Of these, 47 completed the programme and 32 attended follow-up. The impact of the manualised course was evaluated using a randomised control trial with a waiting list control. On completion of the programme, participants showed improvements in mental health, self- esteem and job-search self-efficacy as well as a reduction in the occurrence of negative automatic thoughts. Twenty participants gained employment and improvements persisted at follow-up. Considering the initial levels of psychological distress and mental health problems among the unemployed sample, the need for adequate service provision for the unemployed is recommended.


CD36 gene transfer confers capacity for phagocytosis of cells undergoing apoptosis.
Phagocyte recognition and ingestion of intact cells undergoing apoptosis are key events in this generally important program of cell death. Insufficient phagocyte capacity for apoptotic cells can result in failure to clear dying cells before membrane integrity is lost, resulting in leakage of noxious cell contents and severe tissue damage. However, no means has been available to increase phagocytic clearance of apoptotic cells. We now report that transfection of the macrophage adhesion molecule CD36 into human Bowes melanoma cells specifically conferred greatly increased capacity to ingest apoptotic neutrophils, lymphocytes, and fibroblasts, comparable to that exhibited by macrophages. Furthermore, when CD36 was transfected into another cell type with limited capacity to take up apoptotic bodies, the monkey COS-7 cell, similar effects were observed. Therefore, CD36 gene transfer can confer "professional" capacity to ingest apoptotic cells upon "amateur" phagocytes.


Angiotensinogen is cleaved to angiotensin in isolated rat blood vessels.
The cleavage of synthetic tetradecapeptide renin substrate has been used to infer the presence of renin in the walls of isolated blood vessels; however, the conversion of natural angiotensinogen to angiotensin in isolated blood vessels has not been reported. We studied the release of angiotensinogen and the formation of angiotensins in a bloodless, perfused, isolated hind limb preparation of the rat. Perfusion with a modified Tyrode's solution resulted in spontaneous release of 4.7 +/- 1.5 pmol per 30 minutes of angiotensinogen as measured directly by radioimmunoassay. Western blot further identified the released material as angiotensinogen. Spontaneous release of angiotensins I and II was demonstrated by high performance liquid chromatography and radioimmunoassay. When highly purified rat angiotensinogen was added to the perfusate, release of angiotensin II was increased 14-fold compared with saline infusion. Captopril (10 mumol/L) inhibited angiotensinogen-induced angiotensin II release by 67% and led to an increase in angiotensin I release by 301%. Bilateral nephrectomy 24 hours before the experiments reduced basal angiotensin release below the detection limit and blunted angiotensinogen-induced angiotensin II formation by 95%. We conclude that active renin is present in the vessel wall and interacts with its natural substrate to form angiotensin peptides. Our data support the notion that the bulk of vascular renin is taken up from the circulation.


Changes in memory before and after stroke differ by age and sex, but not by race.
Post-stroke memory impairment is more common among older adults, women and blacks. It is unclear whether post-stroke differences reflect differential effects of stroke per se or differences in prestroke functioning. We compare memory trajectories before and after stroke by age, sex and race. Health and Retirement Study participants aged ≥50 years (n = 17,341), with no stroke history at baseline, were interviewed biennially up to 10 years for first self- or proxy-reported stroke (n = 1,574). Segmented linear regression models were used to compare annual rates of memory change before and after stroke among 1,169 stroke survivors, 405 stroke decedents and 15,767 stroke-free participants. Effect modification was evaluated with analyses stratified by baseline age (≤70 vs. >70), sex and race (white vs. nonwhite), and using interaction terms between age/sex/race indicators and annual memory change. Older (>70 years) adults experienced a faster memory decline before stroke (-0.19 vs. -0.10 points/year for survivors, -0.24 vs. -0.13 points/year for decedents, p < 0.001 for both interactions), and among stroke survivors, larger memory decrements (-0.64 vs. -0.26 points, p < 0.001) at stroke and faster memory decline (-0.15 vs. -0.07 points/year, p = 0.003) after stroke onset, compared to younger adults. Female stroke survivors experienced a faster prestroke memory decline than male stroke survivors (-0.14 vs. -0.10 points/year, p < 0.001). However, no sex differences were seen for other contrasts. Although whites had higher post-stroke memory scores than nonwhites, race was not associated with rate of memory decline during any period of time; i.e. race did not significantly modify the rate of decline before or after stroke or the immediate effect of stroke on memory. Older age predicted worse memory change before, at and after stroke onset. Sex and race differences in post-stroke memory outcomes might be attributable to prestroke disparities, which may be unrelated to cerebrovascular disease.


Specifying the effects of religion on medical helpseeking: the case of infertility.
Several recent studies have examined the connection between religion and medical service utilization. This relationship is complicated because religiosity may be associated with beliefs that either promote or hinder medical helpseeking. The current study uses structural equation modeling to examine the relationship between religion and fertility-related helpseeking using a probability sample of 2183 infertile women in the United States. We found that, although religiosity is not directly associated with helpseeking for infertility, it is indirectly associated through mediating variables that operate in opposing directions. More specifically, religiosity is associated with greater belief in the importance of motherhood, which in turn is associated with increased likelihood of helpseeking. Religiosity is also associated with greater ethical concerns about infertility treatment, which are associated with decreased likelihood of helpseeking. Additionally, the relationships are not linear throughout the helpseeking process. Thus, the influence of religiosity on infertility helpseeking is indirect and complex. These findings support the growing consensus that religiously-based behaviours and beliefs are associated with levels of health service utilization.


Origin, domain, and dynamics of rate-induced variations of functional refractory period in rabbit atrioventricular node.
Different aspects of the intrinsic regulation of rate-induced variations of functional refractory period of atrioventricular node (FRPN) were studied in isolated rabbit heart preparations. First, the hypothesis that these variations originate from the net interaction between facilitation and fatigue was tested. For a constant fast rate, selective effects of faciliation and of steady-stage fatigue were independently shown to shorten and prolong, respectively, FRPN while their combined effects were shown to result in intermediate changes corresponding to the sum of their individual effects. Second, selective and combined effects on FRPN were shown to start for rates corresponding to the upper half of the 1:1 nodal conduction range and to reach their maximums at the fastest rate tested. Third, the time-courses of fatigue-induced prolongations in nodal conduction time and FRPN were shown to be closely linked. Facilitation effects on conduction time and FRPN were confirmed, as previously shown for in situ dog hearts, to be linked, but time-independent. Fourth, FRPN was shown not to correspond to particular limits in its subintervals, but to be, nevertheless, related to nodal refractoriness. Fifth, it was demonstrated that, in conditions of combined facilitation and transient fatigue such as those prevailing in current endocavitary investigations of nodal function, FRPN could be shortened, left unchanged or prolonged by a constant fast rate depending on its duration. In conclusion, the present study demonstrates the dual origin of rate-induced FRPN variations, their rate and time dependence, their relation to changes in nodal refractoriness, and their involvements in various nodal responses.


Suture repair of umbilical hernia during caesarean section: a case-control study.
The objective of this study was to investigate the additional burdens in terms of pain, prolongation of surgery and morbidity which is added to elective caesarean section if umbilical hernia suture repair is performed simultaneously. Secondly, patient's satisfaction and hernia recurrence rate were assessed. Consecutive women with symptomatic umbilical hernia undergoing internal or external suture repair during elective caesarean were included in this retrospective cohort-control study. Data on post-operative pain, duration of surgery and morbidity of a combined procedure were collected. These patients were matched 1:10 to women undergoing caesarean section only. Additionally, two subgroups were assessed separately: external and internal suture hernia repair. These subgroups were compared for patient's satisfaction, cosmesis, body image and recurrence rate. Fourteen patients with a mean age of 37 years were analysed. Internal suture repair (n = 7) prolonged caesarean section by 20 min (p = 0.001) and external suture repair (n = 7) by 34 min (p < 0.0001). Suture repair did not increase morphine use (0.38 ± 0.2 vs. 0.4 ± 02 mg/kg body weight), had no procedure-related morbidity and prolonged hospitalization by 0.5 days (p = 0.01). At a median follow-up of 37 (5-125) months, two recurrences in each surgical technique, internal and external suture repair, occurred (28 %). Body image and cosmesis score showed a higher level of functioning in internal suture repair (p = 0.02; p = 0.04). Despite a high recurrence rate, internal suture repair of a symptomatic umbilical hernia during elective caesarean section should be offered to women if requested. No additional morbidity or scar is added to caesarean section. Internal repair is faster, and cosmetic results are better, additional skin or fascia dissection is avoided, and it seems to be as effective as an external approach. Yet, women must be informed on the high recurrence rate.


Factors associated with adherence to chemotherapy guidelines in patients with non-small cell lung cancer.
Evidence-based guidelines recommend chemotherapy for medically fit patients with stages II-IV non-small cell lung cancer (NSCLC). Adherence to chemotherapy guidelines has rarely been studied among large populations, mainly because performance status (PS), a key component in assessing chemotherapy appropriateness, is missing from claims-based datasets. Among a large cohort of patients with known PS, we describe first line chemotherapy use relative to guideline recommendations and identify patient factors associated with guideline concordant use. Insured patients, ages 50+, with stages II-IV NSCLC between 2000 and 2007 were identified via tumor registry (n=406). Chart abstracted PS, automated medical claims, Census tract information, and travel distance were linked to tumor registry data. Chemotherapy was considered appropriate for patients with PS 0-2. Multivariate logit models were fit to evaluate patient characteristics associated with chemotherapy over- and under-use per guideline recommendations. Tests of statistical significance were two sided. Overall compliance with first line chemotherapy guidelines was 71%. Significant (p<0.05) predictors of chemotherapy underuse (19%) included increasing age (odds ratio [OR], 1.09), higher income (OR, 1.02), diagnosed before 2003 (OR, 2.05), and vehicle access (OR, 6.96) in the patient's neighborhood. Significant predictors of chemotherapy overuse (10%) included decreasing age (OR, 0.92), diagnosed after 2003 (OR, 3.24), and higher income (OR, 1.05) in the patient's neighborhood. Among NSCLC patients 29% do not receive guideline recommended chemotherapy treatment missing opportunities for cure or beneficial palliation, or receiving chemotherapy with more risk of harm than benefit. Care concordant with guidelines is influenced by age, economic considerations such as income and transportation barriers.


Social network-based recruitment successfully reveals HIV-1 transmission networks among high-risk individuals in El Salvador.
HIV in Central America is concentrated among certain groups such as men who have sex with men (MSM) and female sex workers (FSWs). We compared social recruitment chains and HIV transmission clusters from 699 MSM and 787 FSWs to better understand factors contributing to ongoing HIV transmission in El Salvador. Phylogenies were reconstructed using pol sequences from 119 HIV-positive individuals recruited by respondent-driven sampling (RDS) and compared with RDS chains in 3 cities in El Salvador. Transmission clusters with a mean pairwise genetic distance ≤ 0.015 and Bayesian posterior probabilities =1 were identified. Factors associated with cluster membership were evaluated among MSM. Sequences from 34 (43%) MSM and 4 (10%) FSW grouped in 14 transmission clusters. Clusters were defined by risk group (12 MSM clusters) and geographic residence (only 1 spanned separate cities). In 4 MSM clusters (all n = 2), individuals were also members of the same RDS chain, but only 2 had members directly linked through recruitment. All large clusters (n ≥ 3) spanned >1 RDS chain. Among MSM, factors independently associated with cluster membership included recent infection by BED assay (P = 0.02), sex with stable male partners (P = 0.02), and sex with ≥ 3 male partners in the past year (P = 0.04). We found few HIV transmissions corresponding directly with the social recruitment. However, we identified clustering in nearly one-half of MSM suggesting that RDS recruitment was indirectly but successfully uncovering transmission networks, particularly among recent infections. Interrogating RDS chains with phylogenetic analyses may help refine methods for identifying transmission clusters.


Reporting results of human biomonitoring of environmental chemicals to study participants: a comparison of approaches followed in two Canadian studies.
Biomonitoring is used increasingly as an indicator and quantitative measure of exposure; however, there is a large gap in interpreting and communicating biomonitoring results to study participants. Two separate, national biomonitoring initiatives are under way in Canada; the household recruitment-based Canadian Health Measures Survey (CHMS) and the clinic recruitment-based Maternal-Infant Research on Environmental Chemicals (MIREC) Study. The CHMS provides participants with the option to receive all their results, but this option is not provided to MIREC participants. The approach to reporting results to participants depends on the availability of reference ranges and guidelines for which tissue concentrations may be interpreted as being elevated or associated with increased health risks, how participants are recruited, unique vulnerabilities of the population, legislation governing access to personal information, and decisions of research ethics committees. It is the researchers' responsibility to present the best case for their approach and, once the decision has been made, to inform participants about access to their results through the consent process.


Identification and distribution of New World Leishmania species characterized by serodeme analysis using monoclonal antibodies.
Five hundred thirty stocks of Leishmania isolated from human and domestic and wild reservoir hosts, representing a wide geographic distribution of endemic foci of American cutaneous (ACL) and visceral leishmaniases (AVL) were characterized and identified at species and/or subspecies levels based on their reactivity to a cross-panel of specific monoclonal antibodies using a radioimmune binding assay. This study confirms and extends our preliminary results on the high specificity of some of these monoclonals for the L. braziliensis, L. mexicana, and L. donovani complexes. This study also demonstrates the relative stability of these molecular markers and the general usefulness of the method for parasite identification. Two hundred ninety-two of 420 isolates of ACL were classified as members of the L. braziliensis complex. Two hundred twenty-seven were L. b. braziliensis; these showed the widest geographical distribution (Brazil: Amazonas, Bahia, Ceara, Espirito Santo, Goias, Minas Gerais, Para, Paraiba, Rio de Janeiro, and Sao Paulo; Honduras: Santa Barbara and Yoko; Peru: Ancash, Piura, and Ucayali; and Venezuela: Cojedes, Distrito Federal, Lara, Portuguesa, Vale Hondo, Yaracuy, and Zulia). Forty-one stocks were identified as L. b. guyanensis (from North Brazil: Amazonas, Amapa, Para, and Rondonia). Twenty-one stocks were identified as L. b. panamensis (from Costa Rica: Alajuela, Guanacasten, Limon, Puntarenas, and San Jose; and Honduras: El Paraiso, and Olancho). Out of 128 isolates classified as members of the L. mexicana complex, 74 were differentiated as L. m. amazonensis (from Bolivia; Brazil: Amazonas, Bahia, Ceara, Goias, Maranhao, Mato Grosso do Norte, and Para; Peru: Pasco Forest and Van Humboldt; and Venezuela: Carabobo, Guarico, and Merida). Forty-four stocks were identified as L. m. venezuelensis (from Venezuela: Lara). Six stocks were L. m. mexicana (from Belize; and Mexico: Campeche [corrected] and Quintana Roo, Yucatan). One hundred ten isolates from AVL were identified as L. donovani chagasi (from Brazil: Bahia, Ceara, Maranhao, Minas Gerais, Mato Grosso do Sul, Piaui, Rio de Janeiro, and Sergipe; and Honduras: Valle). The implications of these results with respect to both the clinical and epidemiological data (including the detection of seven unusual characterized stocks) are discussed.


Towards Evidence-based Control of Opisthorchis viverrini.
Transmission of the carcinogenic liver fluke Opisthorchis viverrini is ongoing across Southeast Asia. Endemic countries within the region are in different stages of achieving control. However, evidence on which interventions are the most effective for reducing parasite transmission, and the resulting liver cancer, is currently lacking. Quantitative modelling can be used to evaluate different control measures against O. viverrini and assist the design of clinical trials. In this article we evaluate the epidemiological parameters that underpin models of O. viverrini and the data necessary for their estimation, with the aim of developing evidence-based strategies for parasite control at a national or regional level.


Fragmentation-free LC-MS can identify hundreds of proteins.
One of the most common approaches for large-scale protein identification is LC, followed by MS. If more than a few proteins are to be identified, the additional fragmentation of individual peptides has so far been considered as indispensable, and thus, the associated costs, in terms of instrument time and infrastructure, as unavoidable. Here, we present evidence to the contrary. Using a combination of (i) highly accurate and precise mass measurements, (ii) modern retention time prediction, and (iii) a robust scoring algorithm, we were able to identify 257 proteins of Francisella tularensis from a single LC-MS experiment in a fragmentation-free approach (i.e. without experimental fragmentation spectra). This number amounts to 59% of the number of proteins identified in a standard fragmentation-based approach, when executed with the same false discovery rate. Independent evidence supports at least 27 of a set of 31 proteins that were identified only in the fragmentation-free approach. Our results suggest that additional developments in retention time prediction, measurement technology, and scoring algorithms may render fragmentation-free approaches an interesting complement or an alternative to fragmentation-based approaches.


High-temporal-resolution view of transcription and chromatin states across distinct metabolic states in budding yeast.
Under continuous, glucose-limited conditions, budding yeast exhibit robust metabolic cycles associated with major oscillations of gene expression. How such fluctuations are linked to changes in chromatin status is not well understood. Here we examine the correlated genome-wide transcription and chromatin states across the yeast metabolic cycle at unprecedented temporal resolution, revealing a 'just-in-time supply chain' by which components from specific cellular processes such as ribosome biogenesis become available in a highly coordinated manner. We identify distinct chromatin and splicing patterns associated with different gene categories and determine the relative timing of chromatin modifications relative to maximal transcription. There is unexpected variation in the chromatin modification and expression relationship, with histone acetylation peaks occurring with varying timing and 'sharpness' relative to RNA expression both within and between cycle phases. Chromatin-modifier occupancy reveals subtly distinct spatial and temporal patterns compared to those of the modifications themselves.


The impact of thioredoxin reduction of allosteric disulfide bonds on the therapeutic potential of monoclonal antibodies.
Therapeutic mAbs are used to manage a wide range of cancers and autoimmune disorders. However, mAb-based treatments are not always successful, highlighting the need for a better understanding of the factors influencing mAb efficacy. Increased levels of oxidative stress associated with several diseases are counteracted by the activities of various oxidoreductase enzymes, such as thioredoxin (Trx), which also reduces allosteric disulfide bonds in proteins, including mAbs. Here, using an array of in vitro assays, we explored the functional effects of Trx-mediated reduction on the mechanisms of action of six therapeutic mAbs. We found that Trx reduces the interchain disulfide bonds of the mAbs, after which they remain intact but have altered function. In general, this reduction increased antigen-binding capacity, resulting in, for example, enhanced tumor necrosis factor (TNF) neutralization by two anti-TNF mAbs. Conversely, Trx reduction decreased the antiproliferative activity of an anti-tyrosine kinase-type cell-surface receptor HER2 mAb. In all of the mAbs, Fc receptor binding was abrogated by Trx activity, with significant loss in both complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) activity of the mAbs tested. We also confirmed that without alkylation, Trx-reduced interchain disulfide bonds reoxidize, and ADCC activity is restored. In summary, Trx-mediated reduction has a substantial impact on the functional effects of an mAb, including variable effects on antigen binding and Fc function, with the potential to significantly impact mAb efficacy in vivo.


Detection of gene communities in multi-networks reveals cancer drivers.
We propose a new multi-network-based strategy to integrate different layers of genomic information and use them in a coordinate way to identify driving cancer genes. The multi-networks that we consider combine transcription factor co-targeting, microRNA co-targeting, protein-protein interaction and gene co-expression networks. The rationale behind this choice is that gene co-expression and protein-protein interactions require a tight coregulation of the partners and that such a fine tuned regulation can be obtained only combining both the transcriptional and post-transcriptional layers of regulation. To extract the relevant biological information from the multi-network we studied its partition into communities. To this end we applied a consensus clustering algorithm based on state of art community detection methods. Even if our procedure is valid in principle for any pathology in this work we concentrate on gastric, lung, pancreas and colorectal cancer and identified from the enrichment analysis of the multi-network communities a set of candidate driver cancer genes. Some of them were already known oncogenes while a few are new. The combination of the different layers of information allowed us to extract from the multi-network indications on the regulatory pattern and functional role of both the already known and the new candidate driver genes.


The Effect of Optic Flow Speed on Active Participation During Robot-Assisted Treadmill Walking in Healthy Adults.
This study aimed to investigate: 1) the effect of optic flow speed manipulation on active participation during robot-assisted treadmill walking (RATW), 2) the influence of the type of virtual environment, and 3) the level of motion sickness and enjoyment. Twenty-eight healthy older adults were randomized in two groups: "stimulus rich" Park group (50% male, 61± 6 year) and "stimulus poor" Hallway group (43% male, 62± 5 year). Subjects walked in the Lokomat with immersive virtual reality (VR) with a matched, slow and fast optic flow speed, each lasting 7 minutes. Active participation was measured by continuously assessing the human-machine interaction torques at the hip and knee joints and muscle activity of the Vastus Medialis and Biceps Femoris. Motion sickness and enjoyment were assessed with the Simulator Sickness Questionnaire (SSQ) and Physical Activity Enjoyment Scale (PACES) respectively. In both groups optic flow speed manipulation in both directions led to a decrease in bilateral hip interaction torques towards flexion at the end of the stance phase compared to matched speed. In the Hallway group, walking with slow optic flow elicited 32% more muscle activity of the Vastus Medialis. There were no significant differences between both groups for the SSQ and PACES. Optic flow speed manipulation appears to have only a small effect on the active participation of healthy people during RATW. The type of virtual environment did not affect their activity, motion sickness or enjoyment. However, the addition of immersive VR during RATW was well tolerated and enjoyable. Further research with patients is necessary.


Trianthema portulacastrum Linn. (Bishkhapra).
World Health Organization (WHO) has recommended that traditional health and folk medicine systems are proved to be more effective in health problems worldwide. Trianthema portulacastrum Linn. is a herb used in Ayurvedic medicine. The principal constituent of T. portulacastrum Linn. is ecdysterone and the other constituents are trianthenol, 3-acetylaleuritolic acid, 5,2'-dihydroxy-7-methoxy-6,8-dimethylflavone, leptorumol, 3,4-dimethoxy cinnamic acid, 5-hydroxy-2-methoxybenzaldehyde, p-methoxybenzoic acid, and beta cyanin. Different parts of Trianthema portulacastrum Linn. are traditionally used as analgesic, stomachic, laxative, treatment of blood disease, anemia, inflammation, and night blindness. Laboratory investigations on extracts of the plant have demonstrated significant pharmacological activities, such as antioxidant, diuretic, analgesic, hepatoprotective, and anticarcinogenic. This article compiles all updated information related to T. portulacastrum Linn. Scientifically proved activities are co-related with traditional concepts. Scientific evidence exists with respect to their major and minor constituents. The novelty and applicability of T. portulacastrum are hidden. Such things should be overcome through modern scientific concepts.


Failure of hairpin-ended and nicked DNA To activate DNA-dependent protein kinase: implications for V(D)J recombination.
V(D)J recombination is initiated by a coordinated cleavage reaction that nicks DNA at two sites and then forms a hairpin coding end and blunt signal end at each site. Following cleavage, the DNA ends are joined by a process that is incompletely understood but nevertheless depends on DNA-dependent protein kinase (DNA-PK), which consists of Ku and a 460-kDa catalytic subunit (DNA-PKCS or p460). Ku directs DNA-PKCS to DNA ends to efficiently activate the kinase. In vivo, the mouse SCID mutation in DNA-PKCS disrupts joining of the hairpin coding ends but spares joining of the open signal ends. To better understand the mechanism of V(D)J recombination, we measured the activation of DNA-PK by the three DNA structures formed during the cleavage reaction: open ends, DNA nicks, and hairpin ends. Although open DNA ends strongly activated DNA-PK, nicked DNA substrates and hairpin-ended DNA did not. Therefore, even though efficient processing of hairpin coding ends requires DNA-PKCS, this may occur by activation of the kinase bound to the cogenerated open signal end rather than to the hairpin end itself.


Heavier pnictogens - treasures for optical electronic and reactivity tuning.
We highlight recent advances in organopnictogen chemistry contrasting the properties of lighter and heavier pnictogens. Exploring new bonding situations, discovering unprecedented reactivities and producing fascinating opto-electronic materials are some of the most prominent directions of current organopnicogen research. Expanding the chemical toolbox towards the heavier group 15 elements will continue to create new opportunities to tailor molecular properties for small molecule activation/reactivity and materials applications alike. This frontier article illustrates the elemental substitution approach in selected literature examples.


Serological evidence of human infections with highly pathogenic avian influenza A(H5N1) virus: a systematic review and meta-analysis.
Highly pathogenic avian influenza A(H5N1) virus poses a global public health threat given severe and fatal zoonotic infections since 1997 and ongoing A(H5N1) virus circulation among poultry in several countries. A comprehensive assessment of the seroprevalence of A(H5N1) virus antibodies remains a gap and limits understanding of the true risk of A(H5N1) virus infection. We conducted a systematic review and meta-analysis of published serosurveys to assess the risk of subclinical and clinically mild A(H5N1) virus infections. We assessed A(H5N1) virus antibody titers and changes in titers among populations with variable exposures to different A(H5N1) viruses. Across studies using the World Health Organization-recommended seropositive definition, the point estimates of the seroprevalence of A(H5N1) virus-specific antibodies were higher in poultry-exposed populations (range 0-0.6%) and persons exposed to both human A(H5N1) cases and infected birds (range 0.4-1.8%) than in close contacts of A(H5N1) cases or the general population (none to very low frequencies). Seroprevalence was higher in persons exposed to A(H5N1) clade 0 virus (1.9%, range 0.7-3.2%) than in participants exposed to other clades of A(H5N1) virus (range 0-0.5%) (p < 0.05). Seroprevalence was higher in poultry-exposed populations (range 0-1.9%) if such studies utilized antigenically similar A(H5N1) virus antigens in assays to A(H5N1) viruses circulating among poultry. These low seroprevalences suggest that subclinical and clinically mild human A(H5N1) virus infections are uncommon. Standardized serological survey and laboratory methods are needed to fully understand the extent and risk of human A(H5N1) virus infections.


Cranberry and its phytochemicals: a review of in vitro anticancer studies.
This article reviews the existing research on the anticancer properties of cranberry fruit and key phytochemicals that are likely contributors to chemoprevention. Results from in vitro studies using a variety of tumor models show that polyphenolic extracts from Vaccinium macrocarpon inhibit the growth and proliferation of breast, colon, prostate, lung, and other tumors, as do flavonols, proanthocyanidin oligomers, and triterpenoids isolated from the fruit. The unique combination of phytochemicals found in cranberry fruit may produce synergistic health benefits. Possible chemopreventive mechanisms of action by cranberry phytochemicals include induction of apoptosis in tumor cells, reduced ornithine decarboxylase activity, decreased expression of matrix metalloproteinases associated with prostate tumor metastasis, and antiinflammatory activities including inhibition of cyclooxygenases. These findings suggest a potential role for cranberry as a dietary chemopreventive and provide direction for future research.


Predictive validity of risk assessments in juvenile offenders: Comparing the SAVRY, PCL:YV, and YLS/CMI with unstructured clinical assessments.
This study examined the validity and reliability of the Structured Assessment of Violence Risk in Youth (SAVRY), the Youth Level of Service/Case Management Inventory (YLS/CMI), and the Psychopathy Checklist: Youth Version (PCL:YV) in a sample of Spanish adolescents with a community sanction (N = 105). Self-reported delinquency with a follow-up period of 1 year was used as the outcome measure. The predictive validity of the three measures was compared with the unstructured judgment of the juvenile's probation officer and the self-appraisal of the juvenile. The three measures showed moderate effect sizes, ranging from area under the curve (AUC) = .75 (SAVRY) to AUC = .72 (PCL:YV), in predicting juvenile reoffending. The two unstructured judgments had no significant predictive validity whereas the SAVRY had significantly higher predictive validity compared with both unstructured judgments. Finally, SAVRY protective factor total scores and SAVRY summary risk ratings did not add incremental validity over SAVRY risk total scores. The high base rates of both violent (65.4%) and general reoffending (81.9%) underline the need for further risk assessment and management research with this population.


A Comprehensive 6A Framework for Improving Patient Self-Management of Hypertension Using mHealth Services: Qualitative Thematic Analysis.
Hypertension affects over 15% of the world's population and is a significant global public health and socioeconomic challenge. Mobile health (mHealth) services have been increasingly introduced to support hypertensive patients to improve their self-management behaviors, such as adherence to pharmacotherapy and lifestyle modifications. This study aims to explore patients' perceptions of mHealth services and the mechanisms by which the services support them to self-manage their hypertension. A semistructured, in-depth interview study was conducted with 22 outpatients of the General Hospital of Ningxia Medical University from March to May 2019. In 2015, the hospital introduced an mHealth service to support community-dwelling outpatients with self-management of hypertension. Content analysis was conducted by following a grounded theory approach for inductive thematic extraction. Constant comparison and categorization classified the first-level codes with similar meanings into higher-level themes. The patient-perceived mechanisms by which the mHealth service supported their self-management of hypertension were summarized as 6A: access, assessment, assistance, awareness, ability, and activation. With the portability of mobile phones and digitization of information, the mHealth service provided outpatients with easy access to assess their vital signs and self-management behaviors. The assessment results gave the patients real-time awareness of their health conditions and self-management performance, which activated their self-management behaviors. The mHealth service also gave outpatients access to assistance, which included health education and self-management reminders. Both types of assistance could also be activated by abnormal assessment results, that is, uncontrolled or deteriorating blood pressure values, discomfort symptoms, or not using the service for a long period. With its scalable use to handle any possible information and services, the mHealth service provided outpatients with educational materials to learn at their own pace. This led to an improvement in self-management awareness and ability, again activating their self-management behaviors. The patients would like to see further improvements in the service to provide more useful, personalized information and reliable services. The mHealth service extended the traditional hypertension care model beyond the hospital and clinician's office. It provided outpatients with easy access to otherwise inaccessible hypertension management services. This led to process improvement for outpatients to access health assessment and health care assistance and improved their awareness and self-management ability, which activated their hypertension self-management behaviors. Future studies can apply the 6A framework to guide the design, implementation, and evaluation of mHealth services for outpatients to self-manage chronic conditions.


Mutational analysis of the rolA gene of Agrobacterium rhizogenes in tobacco: function of the rolA pre-mRNA intron and rolA proteins defective in their biological activity.
The rolA gene of Agrobacterium rhizogenes contains in its untranslated leader region a spliceosomal intron, which is spliced in Arabidopsis and in Nicotiana tabacum. Expression under the control of the 35S promoter from cauliflower mosaic virus of a rolA gene derivative defective in splicing still causes alterations of growth in transgenic tobacco plants. Splicing of rolA mRNA is required for efficient expression of the rolA phenotype in vivo. Moreover, splicing is required for efficient in vitro translation of the rolA mRNA. In contrast, expression of a 35S-rolA gene derivative with the ATG initiation codon replaced by ATA does not cause any phenotypical alteration. Mutations leading to amino acid substitutions at positions 37 and 40 of the rolA coding region were isolated as null mutants in Arabidopsis plants transgenic for the rolA gene. However, when expressed in tobacco under the control of the 35S promoter, they cause a rolA phenotype reduced in the expressivity of its traits. The molecular characterization of rolA mutants might be useful for understanding the biochemical function of the rolA protein.


The Schmidt Syndrome.
Addison's disease (AD) is a rare endocrine condition related to adrenal insufficiency. Autoimmune adrenalitis is commonly associated with autoimmune diseases. Autoimmune Addison's Disease (AAD) describes Autoimmune Polyendocrine Syndrome (APS) in 60% of patients with an important immunitary pathogenesis imprinting. We describes a case of Autoimmune Polyendocrine Syndrome charachterize by adrenal insufficiency and thyroid disease (Schmidt Syndrome). In this case report, Addison's disease had a slow onset in absence of the typical weight loss. In our considerations this is due to the concomitant hypothyroidism that masked some typical signs and also limited acute presentation.


Slow wave sleep and 5-HT2 receptor sensitivity during maintenance tricyclic antidepressant treatment.
The 5-HT2 receptor antagonist cyproheptadine significantly increased slow wave sleep in 12 healthy control subjects but not in 12 patients with a history of major depression, maintained on tricyclic antidepressant treatment. Cyproheptadine produced a similar reduction in REM sleep in both groups of subjects. The results are consistent with the hypothesis that tricyclic antidepressant treatment alters brain 5-HT2 receptor sensitivity, but a primary abnormality in slow wave sleep regulation in depressed patients cannot be excluded.


Multiomics analysis couples mRNA turnover and translational control of glutamine metabolism to the differentiation of the activated CD4+ T cell.
The ZFP36 family of RNA-binding proteins acts post-transcriptionally to repress translation and promote RNA decay. Studies of genes and pathways regulated by the ZFP36 family in CD4+ T cells have focussed largely on cytokines, but their impact on metabolic reprogramming and differentiation is unclear. Using CD4+ T cells lacking Zfp36 and Zfp36l1, we combined the quantification of mRNA transcription, stability, abundance and translation with crosslinking immunoprecipitation and metabolic profiling to determine how they regulate T cell metabolism and differentiation. Our results suggest that ZFP36 and ZFP36L1 act directly to limit the expression of genes driving anabolic processes by two distinct routes: by targeting transcription factors and by targeting transcripts encoding rate-limiting enzymes. These enzymes span numerous metabolic pathways including glycolysis, one-carbon metabolism and glutaminolysis. Direct binding and repression of transcripts encoding glutamine transporter SLC38A2 correlated with increased cellular glutamine content in ZFP36/ZFP36L1-deficient T cells. Increased conversion of glutamine to α-ketoglutarate in these cells was consistent with direct binding of ZFP36/ZFP36L1 to Gls (encoding glutaminase) and Glud1 (encoding glutamate dehydrogenase). We propose that ZFP36 and ZFP36L1 as well as glutamine and α-ketoglutarate are limiting factors for the acquisition of the cytotoxic CD4+ T cell fate. Our data implicate ZFP36 and ZFP36L1 in limiting glutamine anaplerosis and differentiation of activated CD4+ T cells, likely mediated by direct binding to transcripts of critical genes that drive these processes.


Expression of the mouse labial-like homeobox-containing genes, Hox 2.9 and Hox 1.6, during segmentation of the hindbrain.
The sequence of a mouse Hox 2.9 cDNA clone is presented. The predicted homeodomain is similar to that of the Drosophila gene labial showing 80% identity. The equivalent gene in the Hox 1 cluster is Hox 1.6 which shows extensive similarity to Hox 2.9 both within and outside the homeodomain. Hox 2.9 and Hox 1.6 are the only two mouse members of the labial-like family of homeobox-containing genes as yet identified. Hox 2.9 has previously been shown to be expressed in a single segmental unit of the developing hindbrain (rhombomere) and has been predicted to be involved in conferring rhombomere identity. To analyse further the function of Hox 2.9 during development and to determine if the other mouse labial-like gene Hox 1.6, displays similar properties, we have investigated the expression patterns of these two genes and an additional rhombomere-specific gene, Krox 20, on consecutive embryonic sections at closely staged intervals. This detailed analysis has enabled us to draw the following conclusions: (1) There are extensive similarities in the temporal and spatial expression of Hox 2.9 and Hox 1.6, throughout the period that both genes are expressed in the embryo (7 1/2 to 10 days). At 8 days the genes occupy identical domains in the neuroectoderm and mesoderm with the same sharp anterior boundary in the presumptive hindbrain. These similarities indicate a functional relationship between the genes and further suggest that the labial-like genes are responding to similar signals in the embryo. (2) By 9 days the neuroectoderm expression of both genes retreats posteriorly along the anteroposterior (AP) axis. The difference at this stage between the expression patterns is the persistence of Hox 2.9 in a specific region of the hindbrain, illustrating the capacity of Hox 2.9 to respond to additional positional regulatory signals and indicating a unique function for this gene in the hindbrain. (3) The restriction of Hox 2.9 expression in the hindbrain occurs at 8 1/2 days, approximately the same time as Krox 20 is first detected in the posterior adjoining domain. The mutually exclusive expression of Hox 2.9 and Krox 20 demarcated by sharp expression boundaries suggest that compartmentalisation of cells within the hindbrain has occurred up to 6 h before rhombomeres (morphological segments) are clearly visible. (4) Hox 2.9 expression is confined to the region of rhombomere 4 that shows cell lineage restriction and, unlike Krox 20, is expressed throughout the period that rhombomeres are visible (to 11 1/2 days).(ABSTRACT TRUNCATED AT 400 WORDS)


The evolution of insect germline specification strategies.
The establishment of the germline is essential for sexually reproducing organisms. In animals, there are two major strategies to specify the germline: maternal provision and zygotic induction. The molecular basis of the maternal provision mode has been well characterized in several model organisms (fly, frog, fish, and nematode), while that of the zygotic induction mode has mainly been studied in mammalian models such as the mouse. Shifts in germline determination modes occur unexpectedly frequently and many such shifts have occurred several times among insects. Given their general tractability and rapidly increasing genomic and genetic tools applicable to many species, the insects present a uniquely powerful model system for understanding major transitions in reproductive strategies, and developmental processes in general.


Regional quantification of cardiac metabolism with hyperpolarized [1-13C]-pyruvate MRI evaluated in an oral glucose challenge.
The heart has metabolic flexibility, which is influenced by fed/fasting states, and pathologies such as myocardial ischemia and hypertrophic cardiomyopathy (HCM). Hyperpolarized (HP) 13C-pyruvate MRI is a promising new tool for non-invasive quantification of myocardial glycolytic and Krebs cycle flux. However, human studies of HP 13C-MRI have yet to demonstrate regional quantification of metabolism, which is important in regional ischemia and HCM patients with asymmetric septal/apical hypertrophy. We developed and applied methods for whole-heart imaging of 13C-pyruvate, 13C-lactate and 13C-bicarbonate, following intravenous administration of [1-13C]-pyruvate. The image acquisition used an autonomous scanning method including bolus tracking, real-time magnetic field calibrations and metabolite-specific imaging. For quantification of metabolism, we evaluated 13C metabolite images, ratio metrics, and pharmacokinetic modeling to provide measurements of myocardial lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) mediated metabolic conversion in 5 healthy volunteers (fasting & 30 min following oral glucose load). We demonstrate whole heart coverage for dynamic measurement of pyruvate-to-lactate conversion via LDH and pyruvate-to-bicarbonate conversion via PDH at a resolution of 6×6×21 mm3 (13C-pyruvate) and 12×12×21 mm3 (13C-lactate, 13C-bicarbonate) . 13C-pyruvate and 13C-lactate were detected simultaneously in the RV blood pool, immediately after intravenous injection, reflecting LDH activity in blood. In healthy volunteers, myocardial 13C-pyruvate-SNR, 13C-lactate-SNR, 13C-bicarbonate-SNR, 13C-lactate/pyruvate ratio, 13C-pyruvate-to-lactate conversion rate, kPL, and 13C-pyruvate-to-bicarbonate conversion rate, kPB, all had statistically significant increases following oral glucose challenge. kPB, reflecting PDH activity and pyruvate entering the Krebs Cycle, had the highest correlation with blood glucose levels and was statistically significant. We demonstrate first-in-human regional quantifications of cardiac metabolism by HP 13C-pyruvate MRI that aims to reflect LDH and PDH activity.


Propensity score-weighted analysis of chemotherapy after PD-1 inhibitors versus chemotherapy alone in patients with non-small cell lung cancer (WJOG10217L).
Studies have suggested that chemotherapy after immune checkpoint inhibitors may confer an improved response for non-small cell lung cancer (NSCLC). However, potential selection bias in such studies has not been addressed. We therefore applied propensity score analysis to investigate the efficacy of chemotherapy after PD-1 inhibitor treatment (CAP) compared with chemotherapy alone. We conducted a retrospective observational cohort study for patients treated at 47 institutions across Japan between April 1, 2014 and July 31, 2017. Eligible patients had advanced or recurrent NSCLC who have undergone chemotherapy. Patients subsequently treated with chemotherapy (docetaxel with or without ramucirumab, S-1 or pemetrexed) either after PD-1 inhibitor therapy (CAP cohort) or alone (control cohort) were included. The primary end point was objective response rate (ORR). Inverse probability weighting (IPW) was applied to adjust for potential confounding factors. A total of 1439 patients (243 and 1196 in the CAP and control cohorts, respectively) was available for unadjusted analysis. Several baseline characteristics-including age, histology, EGFR or ALK genetic alterations, and brain metastasis-differed significantly between the two cohorts. After adjustment for patient characteristics with the IPW method, ORR was 18.9% for the CAP cohort and 11.0% for the control cohort (ORR ratio 1.71; 95% CI 1.19 to 2.46; p=0.004). IPW-adjusted Kaplan-Meier curves showed that median progression-free survival (PFS) for the CAP and control cohorts was 2.8 and 2.7 months (IPW-adjusted HR 0.95; 95% CI 0.80 to 1.12; p=0.55), and median overall survival (OS) was 9.2 and 10.4 months (IPW-adjusted HR 1.05; 95% CI 0.86 to 1.28; p=0.63), respectively. After accounting for selection bias by propensity score analysis, CAP showed a significantly higher ORR compared with chemotherapy alone, with the primary end point of ORR being achieved. However, these results did not translate into a PFS or OS advantage, suggesting that prior administration of PD-1 inhibitors may result in a synergistic antitumor effect with subsequent chemotherapy, but that such an effect is transient. CAP therefore does not appear to achieve durable tumor control or confer a lasting survival benefit.


Virtual water maze learning in human increases functional connectivity between posterior hippocampus and dorsal caudate.
Recent work has demonstrated that functional connectivity between remote brain regions can be modulated by task learning or the performance of an already well-learned task. Here, we investigated the extent to which initial learning and stable performance of a spatial navigation task modulates functional connectivity between subregions of hippocampus and striatum. Subjects actively navigated through a virtual water maze environment and used visual cues to learn the position of a fixed spatial location. Resting-state functional magnetic resonance imaging scans were collected before and after virtual water maze navigation in two scan sessions conducted 1 week apart, with a behavior-only training session in between. There was a large significant reduction in the time taken to intercept the target location during scan session 1 and a small significant reduction during the behavior-only training session. No further reduction was observed during scan session 2. This indicates that scan session 1 represented initial learning and scan session 2 represented stable performance. We observed an increase in functional connectivity between left posterior hippocampus and left dorsal caudate that was specific to scan session 1. Importantly, the magnitude of the increase in functional connectivity was correlated with offline gains in task performance. Our findings suggest cooperative interaction occurs between posterior hippocampus and dorsal caudate during awake rest following the initial phase of spatial navigation learning. Furthermore, we speculate that the increase in functional connectivity observed during awake rest after initial learning might reflect consolidation-related processing.


Effect of surgery on pancreatic tumor-dependent lymphocyte asset: modulation of natural killer cell frequency and cytotoxic function.
Tumor burden and invasiveness establish a microenvironment that surgery could alter. This study shows a comprehensive analysis of size, dynamics, and function of peripheral lymphocyte subsets in pancreatic cancer patients before and at different times after duodenopancreatectomy. Lymphocyte frequency and natural cytotoxicity were evaluated by flow cytometry and in vitro assay on peripheral blood from initial and advanced-stage pancreatic cancer patients before (BS), at day 7 (PS7), and at day 30 (PS30) after surgery. An increase in natural killer (NK) cells and the diminution of B-cells occurred at PS30, whereas cytotoxicity decreased at PS7. The positive correlation between NK frequency and cytotoxicity at BS and PS7 revealed an altered NK behavior. The elevation of NK cell frequency at PS30, an initial defect in CD56bright NK, and the aberrant correlation between NK frequency and cytotoxicity remained significant in advanced-stage patients, whereas the diminution of NK cytotoxicity only affected initial stage patients. The NK cell functional ability is altered in presurgery patients; duodenopancreatectomy is associated with short-term impairment of NK function and with a long-term NK cell augmentation and reversion of the aberrant NK behavior, which may impact on immunosurveillance against residual cancer.


Effectiveness of oxide films in reducing mercury release from amalgams.
The release of mercury from four freshly-triturated amalgams into air, argon, and moist air environments was quantitated at three different temperatures. Although a measurable amount of mercury was released from dental amalgam, the evaporation rate was immediately reduced by several phenomena, the most important being the formation of an oxide film on the surface. This hypothesis was supported by the fact that release rates were elevated in an inert argon environment, but declined dramatically once air was introduced and oxidation could occur. The further amalgamation of "free" mercury, as well as the presence of water vapor, also contributed to the reduced release rates observed during aging. Mercury release was reduced to a negligible level within three to four hours after trituration. Only one of the amalgams, Tytin, demonstrated a thermal dependence for mercury release in air. The results of this study suggest that the exposure to mercury vapor from a freshly placed amalgam restoration would be negligible in consideration of the normal estimated daily intake from all other sources.


Recent Advances in Collaborative Scheduling of Computing Tasks in an Edge Computing Paradigm.
In edge computing, edge devices can offload their overloaded computing tasks to an edge server. This can give full play to an edge server's advantages in computing and storage, and efficiently execute computing tasks. However, if they together offload all the overloaded computing tasks to an edge server, it can be overloaded, thereby resulting in the high processing delay of many computing tasks and unexpectedly high energy consumption. On the other hand, the resources in idle edge devices may be wasted and resource-rich cloud centers may be underutilized. Therefore, it is essential to explore a computing task collaborative scheduling mechanism with an edge server, a cloud center and edge devices according to task characteristics, optimization objectives and system status. It can help one realize efficient collaborative scheduling and precise execution of all computing tasks. This work analyzes and summarizes the edge computing scenarios in an edge computing paradigm. It then classifies the computing tasks in edge computing scenarios. Next, it formulates the optimization problem of computation offloading for an edge computing system. According to the problem formulation, the collaborative scheduling methods of computing tasks are then reviewed. Finally, future research issues for advanced collaborative scheduling in the context of edge computing are indicated.


Infant feeding methods and maternal sleep and daytime functioning.
Our purpose was to explore maternal actigraphically measured sleep, subjective sleep reports, and daytime functioning on the basis of current feeding method status during postpartum weeks 2 through 12. Objectively measured total sleep time, sleep efficiency, and fragmentation, subjectively reported numbers of nocturnal awakenings, total nocturnal wake time, and sleep quality, and sleepiness/fatigue measured by using the fatigue visual analog scale, the Stanford Sleepiness Scale, or the Epworth Sleepiness Scale were assessed. We did not find differences between women who were exclusively breastfeeding, exclusively formula feeding, or using a combination of the 2 methods, with respect to the assessed parameters. Efforts to encourage women to breastfeed should include information about sleep. Specifically, women should be told that choosing to formula feed does not equate with improved sleep. The risks of not breastfeeding should be weighed against the cumulative lack of evidence indicating any benefit of formula feeding on maternal sleep.


Protective effects of alpha-ketoglutarate against aluminum toxicity in Drosophila melanogaster.
In recent years, Drosophila melanogaster has emerged as a model for studies on aluminum toxicity. The current study aimed to disclose the mechanisms of aluminum toxicity in D. melanogaster at larval and adult stages and examined the potential protective effects of dietary alpha-ketoglutarate (AKG). Flies were reared on food containing 10 mM AlCl3, 10 mM AKG or both additives. Rearing on an AlCl3-containing diet induced behavioral defects, and decreased fecundity and long-term survival of female flies. The addition of dietary AKG did not ameliorate locomotor and taste behavior defects or the higher sensitivity to oxidative stress, but improved heat stress resistance, egg-laying capability and survival of females treated with AlCl3. Metabolic effects of AlCl3 exposure on flies included an imbalance of metal content, decreased glucose levels, increased free iron and storage triacylglyceride (TAG) levels, mitochondria dysfunction, and the development of oxidative stress. Dietary AKG did not prevent AlCl3 effects on glucose and TAG, but improved metal homeostasis, inhibited the increase in free Fe and restored the functional activity of iron-containing enzymes such as aconitase. In addition, AKG decreased the intensity of oxidative stress seen in AlCl3-reared adult flies, probably due to inhibition of iron mobilization. The results show that AKG is not a full antidote against Al toxicity but is able to relieve multiple metabolic effects of high aluminum. Furthermore, the modulating ability of AKG can clearly be helpful in exploring the molecular mechanisms of Al toxicity.


Microevolution in the pansecondary metabolome of Aspergillus flavus and its potential macroevolutionary implications for filamentous fungi.
Fungi produce a wealth of pharmacologically bioactive secondary metabolites (SMs) from biosynthetic gene clusters (BGCs). It is common practice for drug discovery efforts to treat species' secondary metabolomes as being well represented by a single or a small number of representative genomes. However, this approach misses the possibility that intraspecific population dynamics, such as adaptation to environmental conditions or local microbiomes, may harbor novel BGCs that contribute to the overall niche breadth of species. Using 94 isolates of Aspergillus flavus, a cosmopolitan model fungus, sampled from seven states in the United States, we dereplicate 7,821 BGCs into 92 unique BGCs. We find that more than 25% of pangenomic BGCs show population-specific patterns of presence/absence or protein divergence. Population-specific BGCs make up most of the accessory-genome BGCs, suggesting that different ecological forces that maintain accessory genomes may be partially mediated by population-specific differences in secondary metabolism. We use ultra-high-performance high-resolution mass spectrometry to confirm that these genetic differences in BGCs also result in chemotypic differences in SM production in different populations, which could mediate ecological interactions and be acted on by selection. Thus, our results suggest a paradigm shift that previously unrealized population-level reservoirs of SM diversity may be of significant evolutionary, ecological, and pharmacological importance. Last, we find that several population-specific BGCs from A. flavus are present in Aspergillus parasiticus and Aspergillus minisclerotigenes and discuss how the microevolutionary patterns we uncover inform macroevolutionary inferences and help to align fungal secondary metabolism with existing evolutionary theory.