Pulmonary function in patients with acute coronary syndrome treated with ticagrelor or clopidogrel (from the Platelet Inhibition and Patient Outcomes [PLATO] pulmonary function substudy).
The Platelet Inhibition and Patient Outcomes (PLATO) trial showed that ticagrelor reduced the risk for cardiovascular events in patients with acute coronary syndromes compared to clopidogrel but was associated with increased incidence of dyspnea. This substudy assessed whether ticagrelor affects pulmonary function in patients with acute coronary syndromes: 199 patients enrolled in the PLATO trial and receiving randomized treatment with ticagrelor 90 mg twice daily (n = 101) or clopidogrel 75 mg/day (n = 98) took part in the pulmonary function substudy. Patients with advanced lung disease, congestive heart failure, or coronary artery bypass graft surgery after the index event were excluded. Pulse oximetry (blood oxygen saturation), spirometry (forced expiratory volume in 1 second, forced vital capacity, and forced expiratory flow between 25% and 75% of forced vital capacity before and 20 minutes after inhalation of a β(2) agonist), lung volumes (total lung capacity, functional residual capacity, residual volume), and diffusion capacity were performed after patients received study medication for 30 to 40 days. Tests were then repeated <10 days before and approximately 30 days after the discontinuation of study medication. After a mean treatment duration of 31 days, there were no differences between the groups for any of the pulmonary function parameters. At the end of treatment (mean 211 days) and after the discontinuation of study medication (mean 32 days after the last dose), there was also no evidence of a change in pulmonary function in either group. For example, forced expiratory volume in 1 second values before β(2) agonist inhalation in the ticagrelor and clopidogrel groups were 2.81 ± 0.73 and 2.70 ± 0.84 L, respectively, at the first visit and did not change significantly at subsequent visits. In conclusion, no effect of ticagrelor on pulmonary function was seen in this cohort of patients with acute coronary syndromes compared to clopidogrel.


IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells.
Murine IL-10 (cytokine synthesis inhibitory factor) inhibits cytokine production by Th1 cell clones when they are activated under conditions requiring the presence of APC. By preincubating APC with IL-10, we demonstrate that IL-10 acts principally on APC to inhibit IFN-gamma production by Th1 clones. Moreover, IL-10 is not active when Th1 cells are stimulated with glutaraldehyde-fixed APC, which also indicates that its action involves regulation of APC function. Furthermore, IL-10 inhibits cytokine synthesis by Th1 cells stimulated with the super-antigen Staphylococcus enterotoxin B, which does not appear to require processing. Flow microfluorimetry purified splenic or peritoneal B cells and macrophages, and B cell and macrophage cell lines can present Ag to Th1 clones. However, IL-10 acts only on sorted macrophages and the macrophage cell line to suppress IFN-gamma production by Th1 clones. IL-10 does not show this effect when B cells are used as APC. In contrast, IL-10 does not impair the ability of APC to stimulate cytokine production by Th2 cells. IL-10 does not decrease IFN-gamma-induced I-Ad levels on a macrophage cell line. Inasmuch as IL-10 also inhibits IL-2-induced IFN-gamma production by Th1 cells in an Ag-free system requiring only the presence of accessory cells, these data suggest that IL-10 may inhibit macrophage accessory cell function which is independent of TCR-class II MHC interactions.


Surveillance of airborne adenovirus and Mycoplasma pneumoniae in a hospital pediatric department.
This investigation evaluated the distributions of airborne adenovirus and Mycoplasma pneumoniae in public areas in the pediatric department of Children's Hospital in northern Taiwan. The airborne viral and bacterial concentrations were evaluated twice a week for a year using filter sampling with an airflow rate of 12 liters per minute for eight hours in the pediatric outpatient department and 24 hours in the pediatric emergency room. Real-time polymerase chain reaction assays were conducted for analysis. Approximately 18% of the air samples from the pediatric emergency room were found to contain adenovirus. Approximately forty-six percent of the air samples from the pediatric outpatient department contained Mycoplasma pneumoniae DNA products. High detection rates of airborne adenovirus DNA were obtained in July and August in the pediatric public areas. Airborne Mycoplasma pneumoniae was detected only in July in the pediatric emergency room and the peak levels were found from August to January in the pediatric outpatient department. Airborne particles that contained adenovirus and Mycoplasma pneumoniae were the most prevalent in the pediatric public areas. The potential relationship between these airborne viral/bacterial particles and human infection should be examined further.


Health services utilization and cost of retinitis pigmentosa.
To estimate annual per-patient health services utilization and costs of retinitis pigmentosa (RP) in the United States. A retrospective claims analysis of patients with RP (N = 2990) and a 1:1 exactly matched cohort of non-RP patients was conducted using the MarketScan Commercial and Medicare Supplemental Databases. Individuals were continuously enrolled in a commercial health plan or employer-sponsored health insurance for at least 1 year. The following annual outcomes were analyzed using nonlinear multivariate models: inpatient hospital admissions, inpatient hospital days, emergency department visits, outpatient physician visits, and prescription drug refills and inpatient and outpatient medical, pharmacy, and total health care costs. Patients with RP had 0.04 more hospital admissions (P < .001), 0.19 more inpatient hospital days (P < .02), 0.05 more emergency department visits (P < .01), 2.74 more outpatient visits (P < .001), and 2.18 additional prescription drug fills (P < .001) annually compared with their non-RP counterparts. Health care expenditures were significantly higher for patients with RP, who cost $894, $4855, and $452 more for inpatient, outpatient, and pharmacy services, respectively (P < .001). Overall health care costs were $7317 more per patient per year in the RP cohort, with expenditures varying considerably by age. Patients with RP consume substantially greater amounts of health services with significantly higher health care costs. Treatments that slow, halt, or possibly restore RP-related vision loss may prove cost-effective for payers and society.


QA for helical tomotherapy: report of the AAPM Task Group 148.
Helical tomotherapy is a relatively new modality with integrated treatment planning and delivery hardware for radiation therapy treatments. In view of the uniqueness of the hardware design of the helical tomotherapy unit and its implications in routine quality assurance, the Therapy Physics Committee of the American Association of Physicists in Medicine commissioned Task Group 148 to review this modality and make recommendations for quality assurance related methodologies. The specific objectives of this Task Group are: (a) To discuss quality assurance techniques, frequencies, and tolerances and (b) discuss dosimetric verification techniques applicable to this unit. This report summarizes the findings of the Task Group and aims to provide the practicing clinical medical physicist with the insight into the technology that is necessary to establish an independent and comprehensive quality assurance program for a helical tomotherapy unit. The emphasis of the report is to describe the rationale for the proposed QA program and to provide example tests that can be performed, drawing from the collective experience of the task group members and the published literature. It is expected that as technology continues to evolve, so will the test procedures that may be used in the future to perform comprehensive quality assurance for helical tomotherapy units.


Particle shape tunes fragility in hard polyhedron glass-formers.
We demonstrate that fragility, a technologically relevant characteristic of glass formation, depends on particle shape for glass-formers comprised of hard polyhedral particles. We find that hard polyhedron glass-formers become stronger (less fragile) as particle shape becomes increasingly tetrahedral. We correlate fragility with local structure, and show that stronger systems display a stronger preference for a pairwise face-to-face motif that frustrates global periodic ordering and gives rise in most systems studied to bond angle distributions that are peaked around the ideal tetrahedral bond angle. We demonstrate through mean-field-like simulations of explicit particle pairs and surrounding baths of "ghost" particles that the prevalence of this pairwise configuration can be explained via free volume exchange and emergent entropic force arguments. Our study provides a clear and direct link between the local geometry of fluid structure and the properties of glass formation, independent of interaction potential or other non-geometric tuning parameters. We ultimately demonstrate that the engineering of fragility in colloidal systems via slight changes to particle shape is possible.


Pulmonary artery sling: current results with cardiopulmonary bypass.
We have used cardiopulmonary bypass with left pulmonary artery reimplantation for pulmonary artery sling repair since 1985. This review presents our current results with this technique, emphasizing the importance of diagnosis and treatment of frequently associated tracheal stenosis. Since 1985, 34 patients have undergone pulmonary artery sling repair using a median sternotomy and cardiopulmonary bypass. Age ranged from 9 days to 43 years (mean 2.1 ± 7.5 years, median 0.2 years). Twenty-seven patients (79%) had tracheal stenosis secondary to complete cartilage tracheal rings. All patients had preoperative airway imaging with rigid bronchoscopy, and since 2000 all patients have had computed tomography imaging of the chest with 3-dimensional reconstruction (n = 14). Tracheal repair has included pericardial patch tracheoplasty (n = 7), tracheal autograft (n = 10), tracheal resection (n = 4), and slide tracheoplasty (n = 5). All patients had an echocardiogram, and cardiac lesions repaired simultaneously included atrial septal defect (4), tetralogy of Fallot (2), and ventricular septal defect (1). One patient had a severely hypoplastic right lung, and 3 patients had an absent right lung. In these patients, the left pulmonary artery was translocated anterior to the trachea. In all other patients, the left pulmonary artery was reimplanted into the main pulmonary artery. There have been no early deaths or complications related to the use of cardiopulmonary bypass. Median hospital stay was 24 days. There have been 4 late deaths. Two late deaths were the result of complications of tracheal surgery (1 pericardial patch [6 months postoperatively] and 1 autograft [1.7 years postoperatively]). One child died of biliary atresia (0.2 years postoperatively), and 1 child died of pneumonia (5.8 years postoperatively). All recent tracheal stenosis repairs have been with slide tracheoplasty. All left pulmonary arteries are patent with a mean percent flow by perfusion scan of 41% ± 13%. Older patients (n = 2) have noted a significant improvement in exercise tolerance. Pulmonary artery sling is best repaired with median sternotomy, cardiopulmonary bypass, and left pulmonary artery reimplantation. This resulted in uniformly patent left pulmonary arteries in all patients. Preoperative computed tomography imaging, echocardiography, and bronchoscopy are essential for precise operative planning. The frequently associated tracheal stenosis is best repaired with slide tracheoplasty.


Activating and silencing histone modifications form independent allelic switch regions in the imprinted Gnas gene.
Activation and suppression of gene transcription is tightly controlled by epigenetic modifications. The imprinted Gnas1 gene region contains closely juxtaposed maternally expressed (Nesp) and paternally expressed (Nespas, Gnasxl, Exon 1A) transcripts, providing a unique opportunity to study how epigenetic modifications change in nucleosomes from active to silenced promoters. Using 30 polymorphic sites across the Gnas1 gene region in (C57BL/6JxMus spretus) F(1) mice and chromatin immunoprecipitation (ChIP) assays we identified two allelic switch regions (ASRs) that mark boundaries of epigenetic information. We show that activating signals (histone acetylation and methylation of H3 Lys4) and silencing signals (histone methylation of H3 Lys9 and DNA methylation) segregate independently across the ASRs and suggest that these ASRs allow the transcriptional elongation to proceed through the silenced domain of nearby imprinted promoters. We discuss these findings in light of recent progress in the conceptualization of nucleosome remodeling during transcriptional elongation and in the development of histone code.


Grassland futures in Great Britain - Productivity assessment and scenarios for land use change opportunities.
To optimise trade-offs provided by future changes in grassland use intensity, spatially and temporally explicit estimates of respective grassland productivities are required at the systems level. Here, we benchmark the potential national availability of grassland biomass, identify optimal strategies for its management, and investigate the relative importance of intensification over reversion (prioritising productivity versus environmental ecosystem services). Process-conservative meta-models for different grasslands were used to calculate the baseline dry matter yields (DMY; 1961-1990) at 1km2 resolution for the whole UK. The effects of climate change, rising atmospheric [CO2] and technological progress on baseline DMYs were used to estimate future grassland productivities (up to 2050) for low and medium CO2 emission scenarios of UKCP09. UK benchmark productivities of 12.5, 8.7 and 2.8t/ha on temporary, permanent and rough-grazing grassland, respectively, accounted for productivity gains by 2010. By 2050, productivities under medium emission scenario are predicted to increase to 15.5 and 9.8t/ha on temporary and permanent grassland, respectively, but not on rough grassland. Based on surveyed grassland distributions for Great Britain in 2010 the annual availability of grassland biomass is likely to rise from 64 to 72milliontonnes by 2050. Assuming optimal N application could close existing productivity gaps of ca. 40% a range of management options could deliver additional 21∗106tonnes of biomass available for bioenergy. Scenarios of changes in grassland use intensity demonstrated considerable scope for maintaining or further increasing grassland production and sparing some grassland for the provision of environmental ecosystem services.


Forensic analysis of Turkish elections in 2017-2018.
With a majority of 'Yes' votes in the Constitutional Referendum of 2017, Turkey continued its drift towards an autocracy. By the will of the Turkish people, this referendum transferred practically all executive power to president Erdoğan. However, the referendum was confronted with a substantial number of allegations of electoral misconducts and irregularities, ranging from state coercion of 'No' supporters to the controversial validity of unstamped ballots. Here we report the results of an election forensic analysis of recent Turkish elections to clarify to what extent it is plausible that these voting irregularities were present and able to influence the outcome of the referendum. We apply statistical forensics tests to identify the specific nature of the alleged electoral malpractices. In particular, we test whether the data contains fingerprints for ballot stuffing (submission of multiple ballots per person during the vote) and voter rigging (coercion and intimidation of voters). Additionally, we perform tests to identify numerical anomalies in the election results. For the 2017 Constitutional Referendum we find systematic and highly significant statistical support for the presence of both ballot stuffing and voter rigging. In 11% of stations we find signs for ballot stuffing with a standard deviation (uncertainty of ballot stuffing probability) of 2.7% (4 sigma event). Removing such ballot-stuffing-characteristic anomalies from the data would tip the overall balance from 'No' to a majority of 'Yes' votes. The 2017 election was followed by early elections in 2018 to directly vote for a new president who would now be head of state and government. We find statistical irregularities in the 2018 presidential and parliamentary elections similar in size and direction to those in 2017. These findings validate that our results unveil systematic and potentially even fraudulent biases that require further attention in order to combat electoral malpractices.


Synthesis of vinyl-terminated Au nanoprisms and nanooctahedra mediated by 3-butenoic acid: direct Au@pNIPAM fabrication with improved SERS capabilities.
Here we describe the first seedless synthesis of vinyl-terminated Au nanotriangular prisms (AuNTPs) and nanooctahedra (AuNOC) in aqueous media. This synthesis is performed by chemical reduction of chloroauric acid (HAuCl4) with 3-butenoic acid (3BA) in the presence of benzyldimethylammonium chloride (BDAC). The principal novelties of the presented method are the use of a mixture of 3BA and BDAC, the synthesis of gold prisms and octahedra with controllable size, and the presence of terminal double bonds on the metal surface. Initially this method produces a mixture of triangular gold nanoprisms and octahedra; however, both morphologies are successfully separated by surfactant micelle induced depletion interaction, reaching percentages up to ∼90%. Moreover, the alkene moieties present on the gold surface are exploited for the fabrication of hybrid core@shell particles. Gold octahedra and triangular prisms are easily encapsulated by free radical polymerization of N-isopropylacrylamide (NIPAM). Finally, in order to obtain a gold core with the most number of tips, AuNTP@pNIPAM microgels were subjected to gold core overgrowth, thus resulting in star-shaped nanoparticles (AuSTs@pNIPAM). We use 4-amino-benzenethiol as the model analyte for SERS investigations. As expected, gold cores with tips and high curvature sites produced the highest plasmonic responses.


Neighborhood socioeconomic circumstances and the co-occurrence of unhealthy lifestyles: evidence from 206,457 Australians in the 45 and up study.
Research on the co-occurrence of unhealthy lifestyles has tended to focus mainly upon the demographic and socioeconomic characteristics of individuals. This study investigated the relevance of neighborhood socioeconomic circumstance for multiple unhealthy lifestyles. An unhealthy lifestyle index was constructed for 206,457 participants in the 45 and Up Study (2006-2009) by summing binary responses on smoking, alcohol, physical activity and five diet-related variables. Higher scores indicated the co-occurrence of unhealthy lifestyles. Association with self-rated health, quality of life; and risk of psychological distress was investigated using multilevel logistic regression. Association between the unhealthy lifestyle index with neighborhood characteristics (local affluence and geographic remoteness) were assessed using multilevel linear regression, adjusting for individual-level characteristics. Nearly 50% of the sample reported 3 or 4 unhealthy lifestyles. Only 1.5% reported zero unhealthy lifestyles and 0.2% had all eight. Compared to people who scored zero, those who scored 8 (the 'unhealthiest' group) were 7 times more likely to rate their health as poor (95%CI 3.6, 13.7), 5 times more likely to report poor quality of life (95%CI 2.6, 10.1), and had a 2.6 times greater risk of psychological distress (95%CI 1.8, 3.7). Higher scores among men decreased with age, whereas a parabolic distribution was observed among women. Neighborhood affluence was independently associated with lower scores on the unhealthy lifestyle index. People on high incomes scored higher on the unhealthy lifestyle index if they were in poorer neighborhoods, while those on low incomes had fewer unhealthy lifestyles if living in more affluent areas. Residents of deprived neighborhoods tend to report more unhealthy lifestyles than their peers in affluent areas, regardless of their individual demographic and socioeconomic characteristics. Future research should investigate the trade-offs of population-level versus geographically targeted multiple lifestyle interventions.


P. falciparum infection and maternofetal antibody transfer in malaria-endemic settings of varying transmission.
During pregnancy, immunoglobulin G (IgG) is transferred from the mother to the fetus, providing protection from disease in early infancy. Plasmodium falciparum infections may reduce maternofetal antibody transfer efficiency, but mechanisms remain unclear. Mother-cord paired serum samples collected at delivery from Papua New Guinea (PNG) and the Thailand-Myanmar Border Area (TMBA) were tested for IgG1 and IgG3 to four P. falciparum antigens and measles antigen, as well as total serum IgG. Multivariable linear regression was conducted to assess the association of peripheral P. falciparum infection during pregnancy or placental P. falciparum infection assessed at delivery with maternofetal antibody transfer efficiency. Path analysis assessed the extent to which associations between P. falciparum infection and antibody transfer were mediated by gestational age at delivery or levels of maternal total serum IgG. Maternofetal antibody transfer efficiency of IgG1 and IgG3 was lower in PNG compared to TMBA (mean difference in cord antibody levels (controlling for maternal antibody levels) ranged from -0.88 to 0.09, median of -0.20 log2 units). Placental P. falciparum infections were associated with substantially lower maternofetal antibody transfer efficiency in PNG primigravid women (mean difference in cord antibody levels (controlling for maternal antibody levels) ranged from -0.62 to -0.10, median of -0.36 log2 units), but not multigravid women. The lower antibody transfer efficiency amongst primigravid women with placental infection was only partially mediated by gestational age at delivery (proportion indirect effect ranged from 0% to 18%), whereas no mediation effects of maternal total serum IgG were observed. Primigravid women may be at risk of impaired maternofetal antibody transport with placental P. falciparum infection. Direct effects of P. falciparum on the placenta, rather than earlier gestational age and elevated serum IgG, are likely responsible for the majority of the reduction in maternofetal antibody transfer efficiency with placental infection.


Highly Strained Heterocycles Constructed from Boron-Boron Multiple Bonds and Heavy Chalcogens.
The reactions of a diborene with elemental selenium or tellurium are shown to afford a diboraselenirane or diboratellurirane, respectively. These reactions are reminiscent of the sequestration of subvalent oxygen and nitrogen in the formation of oxiranes and aziridines; however, such reactivity is not known between alkenes and the heavy chalcogens. Although carbon is too electronegative to affect the reduction of elements with lower relative electronegativity, the highly reducing nature of the B-B double bond enables reactions with Se(0) and Te(0) . The capacity of multiple bonds between boron atoms to donate electron density is highlighted in reactions where diborynes behave as nucleophiles, attacking one of the two Te atoms of diaryltellurides, forming salts consisting of diboratellurenium cations and aryltelluride anions.


Stress, health complaints and self-confidence: a comparison between young adult women in Sweden and USA.
Transition to adulthood is a period in life when women encounter conflicts, ambiguities and rapidly expanding roles that may be stressful and difficult to manage. The aim of this study was to compare stress in daily life, health complaints and self-confidence in 26-year old women in two different cultures. A health survey study was performed among Swedish women (n = 386) and American women (n = 201) living in urban areas at the West coast of Sweden and in Minnesota. Both Swedish and American women reported stress in their everyday life, with higher figures for the Americans. Overall health was rated lower by the Swedish women and they reported more health complaints such as headache, general tiredness, irritability, depression and sleeping disorders. There was a difference between groups in self-confidence with higher figures for excellent self-confidence among American women. However, low self-confidence was reported by more American than Swedish women. A good work situation predicted self-confidence in Swedish women and financial confidence in American women. Physical fitness was associated with self-confidence in both groups. Young women in both cultures experienced high level of stress but health related complaints were more common among Swedish women. High stress and health complaints must be taken seriously and interventions to support young women in the midst of transition to adulthood should contain stress reduction as well as empowerment performed in a more effective way than today in different health care settings and at place of work.


In vivo behavior of murine epidermal cell lines derived from initiated and noninitiated skin.
The in vivo behavior of cell cultures derived from normal and carcinogen-treated mouse epidermis was studied by implanting the cultures in a s.c. vascularized bed protected by a silicone chamber. Cells derived from normal adult mouse epidermis as well as cells derived from tumor-promoter-treated skin were unable to grow in these systems. Conversely, cell lines derived from skin initiated with single doses of N-methyl-N'-nitro-N-nitrosoguanidine or 9,10-dimethyl-1,2-benzanthracene proliferated in these chambers, reforming an epithelial structure. The type of structure in the chambers varied, ranging from formation of almost normal epithelia to atypical invasive behavior. The variable in vivo behavior among the different cell lines may be attributed to the initiation agent, the number of passages of the cultures, random genetic events, the strain of mouse, or a combination of these factors. Most of the cell types used in this study and all the cell lines that were able to grow in these chambers were selected for resistance to Ca-induced terminal differentiation. However, resistance to terminal differentiation according to the Ca2+ switch does not always correlate with the ability to grow in the chambers, since cell lines derived from spontaneous foci of resistance failed to grow in this system. These studies showed some of the possibilities of the SC silicone chambers to study the histogenic potential of cell lines derived from carcinogen-treated epidermis. This system also appears suitable to study the complex relationship between epidermal cells and specialized (dermal) stroma.


Empiric antimicrobial therapy in critical illness: results of a surgical infection society survey.
Antibiotics are prescribed commonly in the intensive care unit (ICU). Often, therapy is initiated empirically; practice patterns are not well characterized. We documented approaches to empiric antibiotic therapy among members of the Surgical Infection Society (SIS). We sent a scenario-based questionnaire to all SIS members. The hypothetical cases addressed empiric broad-spectrum therapy for a patient with pyrexia and leukocytosis and the use of vancomycin for central venous catheter infection. The 113 respondents were primarily surgeons (96%) with a university-based practice (92%). Most attended in the ICU (72%), and they had practiced for 14 +/- 8 years. Whereas 63% of the respondents identified overuse of antibiotics as a problem in their ICU, only 19% said inadequate treatment of infection was a concern. For a febrile patient with negative cultures who was receiving antibiotics, estimates of the likelihood of infection increased across the three scenarios as the degree of organ failure increased (p < 0.0001; chi-square test). Deteriorating organ function was associated with a decision to broaden empiric therapy (58% vs. 33%; p < 0.0001) and to initiate anti-fungal therapy (27% vs. 9%; p < 0.0001) rather than to stop antibiotics and re-culture (15% vs. 51%; p < 0.0001). There was considerable variability in management strategy across the scenarios: Even in the face of organ dysfunction, 58% of physicians would add or change empiric therapy, whereas 30% would not. For each scenario, 23 to 25 antibiotic regimens were designated as optimal therapy. Only 45% of the respondents would initiate empiric vancomycin for suspected central line infection. Variability in approach was not explained by critical care practice, academic position, or country. Clinical deterioration is a strong determinant of a decision to initiate or broaden empiric antibiotic therapy during critical illness. The substantial variability in approach suggests a state of clinical equipoise that calls for more rigorous evaluation through a randomized controlled trial.


Insect herbivory on seedlings of rainforest trees: Effects of density and distance of conspecific and heterospecific neighbors.
Natural enemies of plants such as insect herbivores can contribute to structuring and maintaining plant diversity in tropical forests. Most research in this area has focused on the role of specialized enemies and the extent to which herbivory on individual plant species is density-dependent. Relatively few insect herbivores specialize on a single host plant species. Insect herbivores that feed on more than one plant species may link the regeneration dynamics of their host species through "apparent competition" or "apparent mutualism." We investigated herbivory and survival of seedlings of two tropical tree species (Cordia alliodora and Cordia bicolor) in the forests of Barro Colorado Island (Panama). We used experiments and observations to assess seedling fate in relation to the presence of conspecifics and heterospecifics across a range of spatial scales. Herbivory significantly increased seedling mortality and was highest at high local densities of C. alliodora seedlings. There was also evidence that high local densities of C. alliodora increased herbivory on co-occurring C. bicolor seedlings. Synthesis. The elevated rates of seedling herbivory at high densities of conspecifics documented in our study are consistent with the predictions of the Janzen-Connell hypothesis, which explains how so many plant species can coexist in tropical forests. Our data also highlight the possibility that herbivore-mediated density-dependence, facilitated by herbivores that feed on multiple plant species, can also occur across plant species. Enemy-mediated indirect effects of this sort have the potential to structure plant communities.


The use of femoral stems with exchangeable necks in primary total hip arthroplasty increases the rate of revision.
Femoral stems with exchangeable (modular) necks were introduced to offer surgeons an increased choice when determining the version, offset and length of the femoral neck during total hip arthroplasty (THA). It was hoped that this would improve outcomes and reduce complications, particularly dislocation. In 2010, the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) first reported an increased rate of revision after primary THA using femoral stems with an exchangeable neck. The aim of this study was to provide a more comprehensive up-to-date analysis of primary THA using femoral stems with exchangeable and fixed necks. The data included all primary THA procedures performed for osteoarthritis (OA), reported to the AOANJRR between 01 September 1999 and 31 December 2014. There were 9289 femoral stems with an exchangeable neck and 253 165 femoral stems with a fixed neck. The characteristics of the patients and prostheses including the bearing surface and stem/neck metal combinations were examined using Cox proportional hazard ratios (HRs) and Kaplan-Meier estimates of survivorship. It was found that prostheses with an exchangeable neck had a higher rate of revision and this was evident regardless of the bearing surface or the size of the femoral head. Exchangeable neck prostheses with a titanium stem and a cobalt-chromium neck had a significantly higher rate of revision compared with titanium stem/titanium neck combinations (HR 1.83, 95% confidence interval 1.49 to 2.23, p < 0.001). Revisions were higher for these combinations compared with femoral stems with a fixed neck. There appears to be little evidence to support the continued use of prostheses with an exchangeable neck in primary THA undertaken for OA. Cite this article: Bone Joint J 2017;99-B:766-73.


Physical activity, dietary habits and overall health in overweight and obese children and youth with intellectual disability or autism.
In children and youth with disability, the risk of obesity is higher and is associated with lower levels of physical activity, inappropriate eating behaviors, and chronic health conditions. We determined the effectiveness of a program in managing weight, through changes in physical activity and nutrition behaviors in overweight and obese New Zealand children and youth with intellectual disability or autism. Twenty-two children and youth 14±4 y (mean±SD) and their families participated in a 10-week school-based program. The program consisted of 18 sessions focusing on physical activity and nutrition. Changes were measured immediately after completion of the program (post 1) and at 24 weeks (follow up). Fitness was assessed with the six-minute walk-test (6MWT) and body fatness via waist circumference and BMI. Physical activity and nutrition changes were measured by means of proxy reporting and interviews with parents. Individual interviews were conducted with school teachers and program leaders at 24 weeks to gain feedback regarding the program. Most quantitative outcomes were either unclear or trivial. The only possible change was observed in the six-minute walk-test where 24 weeks post program where participants walked 51 m further. There was however, a substantial reduction in the consumption of confectionery and chocolate at the two measurement points. Parents commented that during the program there were less hospital visits and absences from school related to illness. The program assisted in the development of a supportive community network and participants' abilities to partake in family and community activities. This the first study to report on the results of a physical activity and nutrition program targeted in children and youth with intellectual disability and autism. The results of this study may support and inform future developments of an integrated weight management and prevention program to enhance the health and well being in children and youth with disabilities.


Myc antagonizes Ras-mediated growth arrest in leukemia cells through the inhibition of the Ras-ERK-p21Cip1 pathway.
Even though RAS usually acts as a dominant transforming oncogene, in primary fibroblasts and some established cell lines Ras inhibits proliferation. This can explain the virtual absence of RAS mutations in some types of tumors, such as chronic myeloid leukemia (CML). We report that in the CML cell line K562 Ras induces p21Cip1 expression through the Raf-MEK-ERK pathway. Because K562 cells are deficient for p15INK4b, p16INK4a, p14ARF, and p53, this would be the main mechanism whereby Ras up-regulates p21 expression in these cells. Accordingly, we also found that Ras suppresses K562 growth by signaling through the Raf-ERK pathway. Because c-Myc and Ras cooperate in cell transformation and c-Myc is up-regulated in CML, we investigated the effect of c-Myc on Ras activity in K562 cells. c-Myc antagonized the induction of p21Cip1 mediated by oncogenic H-, K-, and N-Ras and by constitutively activated Raf and ERK2. Activation of the p21Cip1 promoter by Ras was dependent on Sp1/3 binding sites in K562. However, mutational analysis of the p21 promoter and the use of a Gal4-Sp1 chimeric protein strongly suggest that c-Myc affects Sp1 transcriptional activity but not the binding of Sp1 to the p21 promoter. c-Myc-mediated impairment of Ras activity on p21 expression required a transactivation domain, a DNA binding region, and a Max binding region. Moreover, the effect was independent of Miz1 binding to c-Myc. Consistent with its effect on p21Cip1 expression, c-Myc rescued cell growth inhibition induced by Ras. The data suggest that in particular tumor types, such as those associated with CML, c-Myc contributes to tumorigenesis by inhibiting Ras antiproliferative activity.


Genetic diversity in the plasticity zone and the presence of the chlamydial plasmid differentiates Chlamydia pecorum strains from pigs, sheep, cattle, and koalas.
Chlamydia pecorum is a globally recognised pathogen of livestock and koalas. To date, comparative genomics of C. pecorum strains from sheep, cattle and koalas has revealed that only single nucleotide polymorphisms (SNPs) and a limited number of pseudogenes appear to contribute to the genetic diversity of this pathogen. No chlamydial plasmid has been detected in these strains despite its ubiquitous presence in almost all other chlamydial species. Genomic analyses have not previously included C. pecorum from porcine hosts. We sequenced the genome of three C. pecorum isolates from pigs with differing pathologies in order to re-evaluate the genetic differences and to update the phylogenetic relationships between C. pecorum from each of the hosts. Whole genome sequences for the three porcine C. pecorum isolates (L1, L17 and L71) were acquired using C. pecorum-specific sequence capture probes with culture-independent methods, and assembled in CLC Genomics Workbench. The pairwise comparative genomic analyses of 16 pig, sheep, cattle and koala C. pecorum genomes were performed using several bioinformatics platforms, while the phylogenetic analyses of the core C. pecorum genomes were performed with predicted recombination regions removed. Following the detection of a C. pecorum plasmid, a newly developed C. pecorum-specific plasmid PCR screening assay was used to evaluate the plasmid distribution in 227 C. pecorum samples from pig, sheep, cattle and koala hosts. Three porcine C. pecorum genomes were sequenced using C. pecorum-specific sequence capture probes with culture-independent methods. Comparative genomics of the newly sequenced porcine C. pecorum genomes revealed an increased average number of SNP differences (~11 500) between porcine and sheep, cattle, and koala C. pecorum strains, compared to previous C. pecorum genome analyses. We also identified a third copy of the chlamydial cytotoxin gene, found only in porcine C. pecorum isolates. Phylogenetic analyses clustered porcine isolates into a distinct clade, highlighting the polyphyletic origin of C. pecorum in livestock. Most surprising, we also discovered a plasmid in the porcine C. pecorum genome. Using this novel C. pecorum plasmid (pCpec) sequence, a) we developed a pCpec screening assay to evaluate the plasmid distribution in C. pecorum from different hosts; and b) to characterise the pCpec sequences from available previously sequenced C. pecorum genome data. pCpec screening showed that the pCpec is common in all hosts of C. pecorum, however not all C. pecorum strains carry pCpec. This study provides further insight into the complexity of C. pecorum epidemiology and novel genomic regions that may be linked to host specificity. C. pecorum plasmid characterisation may aid in improving our understanding of C. pecorum pathogenesis across the variety of host species this animal pathogen infects.


Prescribing activities that engage passive residents. An innovative method.
Individuals with dementia are often passive, which places them at risk for further cognitive and functional decline. Recreational activities have been used in research to reduce passive behaviors, but systematic reviews of these studies have found modest effect sizes for many activities. In this article, we describe the further theoretical development of an innovative method for prescribing activities that have a high likelihood of engaging nursing home residents who are passive and present examples for research application and clinical practice. This method may increase the effect size of activity interventions and encourage more widespread adoption of nonpharmacological interventions in practice.


Suicide and civil commitment.
The contemporary approach to suicide prevention relies primarily on involuntary commitment of the suicidal individual. While there is generally widespread acceptance of the principle of society's right, even its moral obligation, to intervene to prevent a suicide, there is much less agreement concerning the conditions under which such an action should proceed. Most of the debate centers on the widely applied commitment criteria of mental illness and dangerousness to self and others. Questions have also been raised regarding the efficacy of commitment as a preventive measure. In this paper, these controversies are placed in a broader historical context. We examine empirical evidence concerning prevailing commitment criteria and the prophylactic value of involuntary hospitalization, and discuss the appropriateness of our current approach to civil commitment in light of existing data.


Parahydrogen discriminated PHIP at low magnetic fields.
Parahydrogen induced polarization (PHIP) is a powerful hyperpolarization technique. However, as the signal created has an anti-phase characteristic, it is subject to signal cancellation when the experiment is carried out in inhomogeneous magnetic fields or in low fields that lack the necessary spectral resolution. The use of benchtop spectrometers and time domain (TD) analyzers has continuously grown in the last years and many applications are found in the food industry, for non-invasive compound detection or as a test bench for new contrast agents among others. In this type of NMR devices the combination of low and inhomogeneous magnetic fields renders the application of PHIP quite challenging. We have recently shown that the acquisition of J-spectra in high magnetic fields not only removes the anti-phase peak cancellation but also produces a separation of thermal from hyperpolarized signals, providing Parahydrogen Discriminated (PhD-PHIP) spectra. In this work we extend the use of PhD-PHIP to low and inhomogeneous fields. In this case the strong coupling found for the protons of the sample renders spin-echo spectra that have a great complexity, however, a central region in the spectrum with only hyperpolarized signal is clearly identified. This experimental approach is ideal for monitoring real time chemical reaction of pure PHIP signals.


Plasma complement components and activation fragments: associations with age-related macular degeneration genotypes and phenotypes.
Several genes encoding complement system components and fragments are associated with age-related macular degeneration (AMD). This study was conducted to determine whether alterations in circulating levels of these markers of complement activation and regulation are also independently associated with advanced AMD and whether they are related to AMD genotypes. Plasma and DNA samples were selected from individuals in our AMD registry who had progressed to or developed the advanced stages of AMD, including 58 with geographic atrophy and 62 with neovascular disease. Subjects of similar age and sex, but without AMD, and who did not progress were included as controls (n = 60). Plasma complement components (C3, CFB, CFI, CFH, and factor D) and activation fragments (Bb, C3a, C5a, iC3b, and SC5b-9) were analyzed. DNA samples were genotyped for seven single-nucleotide polymorphisms in six genes previously shown to be associated with AMD: CFB, CFH, C2, C3, and CFI and the LOC387715/ARMS2 gene region. The association between AMD and each complement biomarker was assessed by using logistic regression, controlling for age, sex, and proinflammatory risk factors: smoking and body mass index (BMI). Functional genomic analyses were performed to assess the relationship between the complement markers and genotypes. Concordance, or C, statistics were calculated to assess the effect of complement components and activation fragments in an AMD gene-environment prediction model. The highest quartiles of Bb and C5a were significantly associated with advanced AMD, when compared with the lowest quartiles. In multivariate models without genetic variants, the odds ratio (OR) for Bb was 3.3 (95% confidence interval [CI] = 1.3-8.6), and the OR for C5a was 3.6 (95% CI = 1.2-10.3). With adjustment for genetic variants, these ORs were substantially higher. The alternative pathway regulator CFH was inversely associated with AMD in the model without genotypes (OR = 0.3; P = 0.01). Positive associations were found between BMI and plasma C3, CFB, CFH, iC3b, and C3a. There were also significant associations between C5a fragment and LOC387715/ARMS2 and C3 genotypes (P for trend = 0.02, 0.04), respectively. C statistics for models with behavioral and genetic factors increased to 0.94 +/- 0.20 with the addition of C3a, Bb, and C5a. Increased levels of activation fragments Bb and C5a are independently associated with AMD. Higher BMI is related to increased levels of complement components. C5a is associated with AMD genotypes. C statistics are stronger with the addition of C3a, Bb, and C5a in predictive models. Results implicate ongoing activation of the alternative complement pathway in AMD pathogenesis.


Dairy Product Consumption and Prostate Cancer Risk in the United States.
An ongoing controversy exists regarding the effect of dairy products on prostate cancer risk in observational studies. We prospectively investigated the associations between dairy product consumption and prostate cancer risk among men in the United States. After calculating pre-diagnostic intake of individual or subgroups of dairy products using a validated food frequency questionnaire, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for pathologically-verified cases of incident prostate cancer among men, overall, or stratified by severity. Among 49,472 men, 4134 were diagnosed with prostate cancer during an average follow-up period of 11.2 years. The median total dairy intake was 101 g/1000 kcal. Consumption of total, individual, or subgroups of dairy products was not statistically significantly associated with prostate cancer risk overall (HR = 1.05, 95% CI = 0.96-1.15 comparing the highest with lowest quartile) or stratified by severity, except for regular-fat dairy product intake with late-stage prostate cancer risk (HR = 1.37, 95% CI = 1.04-1.82 comparing the highest with lowest quartile) and 2%-fat milk intake with advanced prostate cancer risk (HR = 1.14, 95% CI = 1.02-1.28 comparing the higher than median intake with no intake group). Our findings do not support the previously reported harmful impact of dairy consumption on overall prostate cancer risk among men in the United States.


Selective modification of nanoparticle arrays by laser-induced self assembly (MONA-LISA): putting control into bottom-up plasmonic nanostructuring.
Nano-structuring of metals is one of the greatest challenges for the future of plasmonic and photonic devices. Such a technological challenge calls for the development of ultra-fast, high-throughput and low-cost fabrication techniques. Laser processing, accounts for the aforementioned properties, representing an unrivalled tool towards the anticipated arrival of modules based in metallic nanostructures, with an extra advantage: the ease of scalability. In the present work we take advantage of the ability to tune the laser wavelength to either match the absorption spectral profile of the metal or to be resonant with the plasma oscillation frequency, and demonstrate the utilization of different optical absorption mechanisms that are size-selective and enable the fabrication of pre-determined patterns of metal nanostructures. Thus, we overcome the greatest challenge of Laser Induced Self Assembly by combining simultaneously large-scale character with atomic-scale precision. The proposed process can serve as a platform that will stimulate further progress towards the engineering of plasmonic devices.


A cost effective method of identifying and recruiting persons over 80 free of dementia or mild cognitive impairment.
For observational or prevention studies, accurately identifying by mail and telephone cognitively normal elderly volunteers would be cost effective. We describe how to recruit cognitively normal sib-pairs over age 80 using commercially available lists by age and ZIP code. We mailed an Institutional Review Board-approved letter to 24,366 persons over 85 around Jacksonville, FL, and received approximately 3,000 postcard replies with approximately 500 answering 3 screening statements affirmatively. Of these, we recruited 128 persons who underwent both in-person and telephone evaluations, the latter using the Telephone Interview of Cognitive Status-modified (TICS-m) and Clinical Dementia Rating scale (CDR). Blinded to the TICS-m and CDR data, clinicians made a consensus diagnosis for each participant, 120 were normal and 8 had mild cognitive impairment. With CDR, 119 patients (93%) screened as normal, and of these 115 (97%) were confirmed as normal with the consensus diagnosis. A TICS-m score cut-off of <29 resulted in a similar proportion of normals in the screened sample (97% or 103/106); however, 13 normal volunteers would have been excluded because they scored <29 on the TICS-m. Supplementing the sample, we recruited 12 age-matched cases having consensus diagnosis of dementia (n=2) or mild cognitive impairment (n=10). A CDR>0 correctly identified 12/12, whereas the TICS-m <29 correctly identified 7/12. Hearing loss present in 50% did not influence TICS-m or CDR performance. Using stringent entry criteria and the telephone CDR, this method accurately identified normal elderly persons.


Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel.
A major use of the 1000 Genomes Project (1000 GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000 GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants.


Measuring earthquakes from optical satellite images.
Système pour l'Observation de la Terre images are used to map ground displacements induced by earthquakes. Deformations (offsets) induced by stereoscopic effect and roll, pitch, and yaw of satellite and detector artifacts are estimated and compensated. Images are then resampled in a cartographic projection with a low-bias interpolator. A subpixel correlator in the Fourier domain provides two-dimensional offset maps with independent measurements approximately every 160 m. Biases on offsets are compensated from calibration. High-frequency noise (0.125 m(-1)) is approximately 0.01 pixels. Low-frequency noise (lower than 0.001 m(-1)) exceeds 0.2 pixels and is partially compensated from modeling. Applied to the Landers earthquake, measurements show the fault with an accuracy of a few tens of meters and yields displacement on the fault with an accuracy of better than 20 cm. Comparison with a model derived from geodetic data shows that offsets bring new insights into the faulting process.


Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression.
Concurrent activation of RAS/ERK and PI3K/AKT pathways is implicated in prostate cancer progression. The negative regulators of these pathways, including sprouty2 (SPRY2), protein phosphatase 2A (PP2A), and phosphatase and tensin homolog (PTEN), are commonly inactivated in prostate cancer. The molecular basis of cooperation between these genetic alterations is unknown. Here, we show that SPRY2 deficiency alone triggers activation of AKT and ERK, but this is insufficient to drive tumorigenesis. In addition to AKT and ERK activation, SPRY2 loss also activates a PP2A-dependent tumor suppressor checkpoint. Mechanistically, the PP2A-mediated growth arrest depends on GSK3β and is ultimately mediated by nuclear PTEN. In murine prostate cancer models, Pten haploinsufficiency synergized with Spry2 deficiency to drive tumorigenesis, including metastasis. Together, these results show that loss of Pten cooperates with Spry2 deficiency by bypassing a novel tumor suppressor checkpoint. Furthermore, loss of SPRY2 expression correlates strongly with loss of PTEN and/or PP2A subunits in human prostate cancer. This underlines the cooperation between SPRY2 deficiency and PTEN or PP2A inactivation in promoting tumorigenesis. Overall, we propose SPRY2, PTEN, and PP2A status as an important determinant of prostate cancer progression. Characterization of this trio may facilitate patient stratification for targeted therapies and chemopreventive interventions.


A comprehensive literatures update of clinical researches of superparamagnetic resonance iron oxide nanoparticles for magnetic resonance imaging.
This paper aims to update the clinical researches using superparamagnetic iron oxide (SPIO) nanoparticles as magnetic resonance imaging (MRI) contrast agent published during the past five years. PubMed database was used for literature search, and the search terms were (SPIO OR superparamagnetic iron oxide OR Resovist OR Ferumoxytol OR Ferumoxtran-10) AND (MRI OR magnetic resonance imaging). The literature search results show clinical research on SPIO remains robust, particularly fuelled by the approval of ferumoxytol for intravenously administration. SPIOs have been tested on MR angiography, sentinel lymph node detection, lymph node metastasis evaluation; inflammation evaluation; blood volume measurement; as well as liver imaging. Two experimental SPIOs with unique potentials are also discussed in this review. A curcumin-conjugated SPIO can penetrate brain blood barrier (BBB) and bind to amyloid plaques in Alzheime's disease transgenic mice brain, and thereafter detectable by MRI. Another SPIO was fabricated with a core of Fe3O4 nanoparticle and a shell coating of concentrated hydrophilic polymer brushes and are almost not taken by peripheral macrophages as well as by mononuclear phagocytes and reticuloendothelial system (RES) due to the suppression of non-specific protein binding caused by their stealthy ''brush-afforded'' structure. This SPIO may offer potentials for the applications such as drug targeting and tissue or organ imaging other than liver and lymph nodes.


Enhanced recovery programmes for lower limb arthroplasty in the UK.
Enhanced recovery programmes (ERPs) reduce patient morbidity and mortality, and provide significant cost savings by reducing length of stay. Currently, no uniform ERP guidelines exist for lower limb arthroplasty in the UK. The aim of this study was to identify variations in ERPs and determine adherence to local policy. Hospitals offering elective total knee arthroplasty (TKA) and total hip arthroplasty (THA) (23 and 22 centres respectively) contributed details of their ERPs, and performed an audit (15 patients per centre) to assess compliance. Contrasting content and detail of ERPs was noted across centres. Adherence to ERPs varied significantly (40-100% for TKA, 17-94% for THA). Analysis identified perioperative use of dexamethasone, tranexamic acid and early mobilisation for TKA, and procedures performed in teaching hospitals for THA as being associated with a reduced length of stay. This study highlights variation in practice and poor compliance with local ERPs. Given the proven benefits of ERPs, evidence-based guidelines in the context of local skillsets should be established to optimise the patient care pathway.


Tryptophan depletion in normal volunteers produces selective impairments in learning and memory.
The amino-acid L-tryptophan is essential in the synthesis of brain serotonin, and its depletion can lead to a widespread reduction in central serotonergic activity. A placebo-controlled cross-over within-subjects design (n = 12) examined the effects of tryptophan depletion on human cognitive performance. A low-tryptophan (low-TRP) drink successfully reduced the levels of plasma and total free tryptophan. Computerized tests of memory, learning and executive function revealed selective and non-sedative impairments on cognitive performance following the active drink. Specifically, low-TRP impaired learning as seen in tests of visual discrimination and paired associates. Furthermore, low-TRP lengthened thinking times during the Tower of London planning task, but only in subjects already familiar with the task, suggesting a retrieval deficit. No evidence was found for an effect of the low-TRP drink on measures sensitive to frontal lobe dysfunction, supporting instead a specific role for the serotonergic system in the processes of memory and learning not directly implicated in frontal lobe function.


Co-activation of microRNAs by Zelda is essential for early Drosophila development.
Transcription factors and microRNAs (miRNAs) are two important classes of trans-regulators in differential gene expression. Transcription factors occupy cis-regulatory motifs in DNA to activate or repress gene transcription, whereas miRNAs specifically pair with seed sites in target mRNAs to trigger mRNA decay or inhibit translation. Dynamic spatiotemporal expression patterns of transcription factors and miRNAs during development point to their stage- and tissue-specific functions. Recent studies have focused on miRNA functions during development; however, much remains to explore regarding how the expression of miRNAs is initiated and how dynamic miRNA expression patterns are achieved by transcriptional regulatory networks at different developmental stages. Here, we focused on the identification, regulation and function of miRNAs during the earliest stage of Drosophila development, when the maternal-to-zygotic transition (MZT) takes place. Eleven miRNA clusters comprise the first set of miRNAs activated in the blastoderm embryo. The transcriptional activator Zelda is required for their proper activation and regulation, and Zelda binding observed in genome-wide binding profiles is predictive of enhancer activity. In addition, other blastoderm transcription factors, comprising both activators and repressors, the activities of which are potentiated and coordinated by Zelda, contribute to the accurate temporal and spatial expression of these miRNAs, which are known to function in diverse developmental processes. Although previous genetic studies showed no early phenotypes upon loss of individual miRNAs, our analysis of the miR-1; miR-9a double mutant revealed defects in gastrulation, demonstrating the importance of co-activation of miRNAs by Zelda during the MZT.


Blood retention and antigenicity of polycarboxybetaine-modified liposomes.
Zwitterionic polycarboxybetaines (PCBs) have gained attention as alternative stealth polymers whose liposomal formulation and protein conjugates were reported not to elicit anti-polymer antibodies. Here, we studied the blood retention and antigenicity of liposomes modified with PCBs focusing on their chemical structures and doses. We compared PCBs with either 1 or 3 (PCB1 or PCB3) spacer carbons between the carboxylate and ammonium groups. PCB3-modified liposomes had a short blood retention, whereas PCB1-modified liposomes demonstrated extended blood retention that was somewhat superior to PEGylated liposome. This confirmed the excellent non-fouling nature of PCB1 reported previously. Interestingly, PCB1-liposome as well as PCB3-liposome elicited specific IgMs toward each PCB. The dose-dependent production of specific IgMs to PCB-liposomes was similar to that of PEGylated liposome, i.e., high doses of PCB-liposomes reduced the production of specific IgMs, termed immunological tolerance. These results indicate the importance of investigating the effect of dose to clarify the existence of antigenicity of stealth polymers.


Sodium salicylate promotes neutrophil apoptosis by stimulating caspase-dependent turnover of Mcl-1.
Mcl-1 is an antiapoptotic member of the Bcl-2 family of proteins that plays a central role in cell survival of neutrophils and other cells. The protein is unusual among family members in that it has a very short half-life of 2-3 h. In this report, we show that sodium salicylate (at 10 mM) greatly enhances the rate at which neutrophils undergo apoptosis and, in parallel, greatly accelerates the turnover rate of Mcl-1, decreasing its half-life to only 90 min. Whereas constitutive and GM-CSF-modified Mcl-1 turnover is regulated by the proteasome, the accelerated sodium salicylate-induced Mcl-1 turnover is mediated largely via caspases. Sodium salicylate resulted in rapid activation of caspase-3, -8, -9, and -10, and salicylate-accelerated Mcl-1 turnover was partly blocked by caspase inhibitors. Sodium salicylate also induced dramatic changes in the activities of members of the MAPK family implicated in Mcl-1 turnover and apoptosis. For example, sodium salicylate blocked GM-CSF-stimulated Erk and Akt activation, but resulted in rapid and sustained activation of p38-MAPK, an event mimicked by okadaic acid that also accelerates Mcl-1 turnover and neutrophil apoptosis. These data thus shed important new insights into the dynamic and highly regulated control of neutrophil apoptosis that is effected by modification in the rate of Mcl-1 turnover.


7-Deaza cyclic adenosine 5'-diphosphate ribose: first example of a Ca(2+)-mobilizing partial agonist related to cyclic adenosine 5'-diphosphate ribose.
Cyclic adenosine 5'-diphosphate ribose (cADPR), a naturally occurring metabolite of nicotinamide adenine dinucleotide (NAD+), mobilizes Ca2+ from non-mitochondrial stores in a variety of mammalian and invertebrate tissues. It has been shown that cADPR activates ryanodine-sensitive Ca(2+)-release channels, working independently of inositol 1,4,5-trisphosphate (IP3) to mobilize intracellular Ca2+ stores. In some systems, cADPR has been shown to be more potent than IP3. The chemo-enzymatic synthesis of structurally modified analogues of cADPR can provide pharmacological tools for probing this new Ca(2+)-signaling pathway. In this work, we describe the synthesis and evaluation of a structural mimic of cADPR with different Ca(2+)-releasing properties. 7-Deaza cyclic adenosine 5'-diphosphate ribose (7-deaza cADPR), a novel cADPR analogue modified in the purine ring, was synthesized and its ability to release Ca2+ from non-mitochondrial pools in homogenates made from sea urchin eggs was investigated. 7-Deaza cADPR was more effective in releasing Ca2+ than cADPR, but it only released approximately 66% of the Ca2+ released by a maximal concentration of cADPR. It was also more resistant to hydrolysis than cADPR. If we administered increasing concentrations of 7-deaza cADPR at the same time as a maximal concentration of cADPR, the induction of Ca2+ release by cADPR was antagonized. 7-Deaza cADPR has a Ca(2+)-release profile consistent with that of a partial agonist, and it is the first reported example of such a compound to act at the cADPR receptor. The imidazole ring of cADPR is clearly important in stimulating the Ca(2+)-release machinery, and the present results demonstrate that structural modification of a site other than position 8 of the purine ring can affect the efficacy of Ca2+ release. 7-Deaza cADPR represents a significant step forwards in designing modulators of the cADPR signaling pathway.


Impairment of the ubiquitin-proteasome system by protein aggregation.
Intracellular deposition of aggregated and ubiquitylated proteins is a prominent cytopathological feature of most neurodegenerative disorders. Whether protein aggregates themselves are pathogenic or are the consequence of an underlying molecular lesion is unclear. Here, we report that protein aggregation directly impaired the function of the ubiquitin-proteasome system. Transient expression of two unrelated aggregation-prone proteins, a huntingtin fragment containing a pathogenic polyglutamine repeat and a folding mutant of cystic fibrosis transmembrane conductance regulator, caused nearly complete inhibition of the ubiquitin-proteasome system. Because of the central role of ubiquitin-dependent proteolysis in regulating fundamental cellular events such as cell division and apoptosis, our data suggest a potential mechanism linking protein aggregation to cellular disregulation and cell death.


Investigating walnut consumption and cognitive trajectories in a representative sample of older US adults.
Existing research suggests walnut intake may be associated with better cognitive function in older adults, yet few studies utilise longitudinal data from observational studies of ageing populations. Our objective was to estimate the association between whole walnut intake and cognitive change in a representative sample of older Americans. Secondary analysis of the Health and Retirement Study and Health Care and Nutrition Study. Walnut consumption was defined as a categorical measure (none, low intake (0·01-0·08 1 oz. servings per day) and moderate intake (>0·08 1 oz. servings per day)) and cognitive function was measured using the Telephone Interview for Cognitive Status. Latent growth modelling estimated the association between walnut consumption and trajectories of cognitive status over a 4-year observational period. Sensitivity analyses assessing non-random dropout and Monte Carlo power analyses were conducted to contextualise results. The USA. A sample of 3632 US adults aged 65 years and older. Those reporting any walnut consumption had greater cognitive scores at baseline than those not consuming walnuts (low walnut consumption, b = 1·53, se = 0·21, P < 0·001; moderate walnut consumption, b = 2·22, se = 0·27, P < 0·001), but walnut consumption was not associated with cognitive change. Walnut consumption was positively associated with socioeconomic status and health behaviours as well as intake of nutrients identified to have neuroprotective benefits. We identified an association between walnut consumption and cognitive function in older adults, although we did not find that walnut consumption was protective against age-related cognitive decline.


Evidence-based policymaking: a critique.
The idea that policy should be based on best research evidence might appear to be self-evident. But a closer analysis reveals a number of problems and paradoxes inherent in the concept of "evidence-based policymaking." The current conflict over evidence-based policymaking parallels a long-standing "paradigm war" in social research between positivist, interpretivist, and critical approaches. This article draws from this debate in order to inform the discussions over the appropriateness of evidence- based policymaking and the related question of what is the nature of policymaking. The positivist, empiricist worldview that underpins the theory and practice of evidence-based medicine (EBM) fails to address key elements of the policymaking process. In particular, a narrowly "evidence-based" framing of policymaking is inherently unable to explore the complex, context-dependent, and value-laden way in which competing options are negotiated by individuals and interest groups. Sociolinguistic tools such as argumentation theory offer opportunities for developing richer theories about how policymaking happens. Such tools also have potential practical application in the policymaking process: by enhancing participants' awareness of their own values and those of others, the quality of the collective deliberation that lies at the heart of policymaking may itself improve.


Apigenin Ameliorates Dyslipidemia, Hepatic Steatosis and Insulin Resistance by Modulating Metabolic and Transcriptional Profiles in the Liver of High-Fat Diet-Induced Obese Mice.
Several in vitro and in vivo studies have reported the anti-inflammatory, anti-diabetic and anti-obesity effects of the flavonoid apigenin. However, the long-term supplementary effects of low-dose apigenin on obesity are unclear. Therefore, we investigated the protective effects of apigenin against obesity and related metabolic disturbances by exploring the metabolic and transcriptional responses in high-fat diet (HFD)-induced obese mice. C57BL/6J mice were fed an HFD or apigenin (0.005%, w/w)-supplemented HFD for 16 weeks. In HFD-fed mice, apigenin lowered plasma levels of free fatty acid, total cholesterol, apolipoprotein B and hepatic dysfunction markers and ameliorated hepatic steatosis and hepatomegaly, without altering food intake and adiposity. These effects were partly attributed to upregulated expression of genes regulating fatty acid oxidation, tricarboxylic acid cycle, oxidative phosphorylation, electron transport chain and cholesterol homeostasis, downregulated expression of lipolytic and lipogenic genes and decreased activities of enzymes responsible for triglyceride and cholesterol ester synthesis in the liver. Moreover, apigenin lowered plasma levels of pro-inflammatory mediators and fasting blood glucose. The anti-hyperglycemic effect of apigenin appeared to be related to decreased insulin resistance, hyperinsulinemia and hepatic gluconeogenic enzymes activities. Thus, apigenin can ameliorate HFD-induced comorbidities via metabolic and transcriptional modulations in the liver.


Conserved but flexible modularity in the zebrafish skull: implications for craniofacial evolvability.
Morphological variation is the outward manifestation of development and provides fodder for adaptive evolution. Because of this contingency, evolution is often thought to be biased by developmental processes and functional interactions among structures, which are statistically detectable through forms of covariance among traits. This can take the form of substructures of integrated traits, termed modules, which together comprise patterns of variational modularity. While modularity is essential to an understanding of evolutionary potential, biologists currently have little understanding of its genetic basis and its temporal dynamics over generations. To address these open questions, we compared patterns of craniofacial modularity among laboratory strains, defined mutant lines and a wild population of zebrafish (Danio rerio). Our findings suggest that relatively simple genetic changes can have profound effects on covariance, without greatly affecting craniofacial shape. Moreover, we show that instead of completely deconstructing the covariance structure among sets of traits, mutations cause shifts among seemingly latent patterns of modularity suggesting that the skull may be predisposed towards a limited number of phenotypes. This new insight may serve to greatly increase the evolvability of a population by providing a range of 'preset' patterns of modularity that can appear readily and allow for rapid evolution.


Adipogenic and anti-adipogenic factors in the pituitary and other organs.
Adipose conversion of cultured 3T3 cells is known to depend on an adipogenic factor present in serum. In the presence of this factor, extracts of different organs were found to inhibit the adipose conversion. The most active extracts were derived from brain, uterus, and pituitary, but other organs also possessed appreciable activity. Fibroblast growth factor partially purified from both brain and pituitary was much more active in suppressing adipose conversion than were crude extracts of the corresponding organs. Purified platelet-derived growth factor was also an effective inhibitor. Of all the tissue extracts tested, only pituitary possessed, in addition to the inhibitory activity, an adipogenic factor similar to that demonstrated previously in serum. This was revealed at concentrations of extract too low for the inhibitory factor to be effective. Under these conditions the pituitary extract had a specific adipogenic activity orders of magnitude higher than that of serum. We suggest that the adipogenic factor of serum may originate in the pituitary.


Posthospitalization Follow-Up of Patients With Heart Failure Using eHealth Solutions: Restricted Systematic Review.
Heart failure (HF) is a clinical syndrome with high incidence rates, a substantial symptom and treatment burden, and a significant risk of readmission within 30 days after hospitalization. The COVID-19 pandemic has revealed the significance of using eHealth interventions to follow up on the care needs of patients with HF to support self-care, increase quality of life (QoL), and reduce readmission rates during the transition between hospital and home. The aims of this review are to summarize research on the content and delivery modes of HF posthospitalization eHealth interventions, explore patient adherence to the interventions, and examine the effects on the patient outcomes of self-care, QoL, and readmissions. A restricted systematic review study design was used. Literature searches and reviews followed the (PRISMA-S) Preferred Reporting Items for Systematic Reviews and Meta-Analyses literature search extension checklist, and the CINAHL, MEDLINE, Embase, and Cochrane Library databases were searched for studies published between 2015 and 2020. The review process involved 3 groups of researchers working in pairs. The Mixed Methods Appraisal Tool was used to assess the included studies' methodological quality. A thematic analysis method was used to analyze data extracted from the studies. A total of 18 studies were examined in this review. The studies were published between 2015 and 2019, with 56% (10/18) of them published in the United States. Of the 18 studies, 16 (89%) were randomized controlled trials, and 14 (78%) recruited patients upon hospital discharge to eHealth interventions lasting from 14 days to 12 months. The studies involved structured telephone calls, interactive voice response, and telemonitoring and included elements of patient education, counseling, social and emotional support, and self-monitoring of symptoms and vital signs. Of the 18 studies, 11 (61%) provided information on patient adherence, and the adherence levels were 72%-99%. When used for posthospitalization follow-up of patients with HF, eHealth interventions can positively affect QoL, whereas its impact is less evident for self-care and readmissions. This review suggests that patients with HF should receive prompt follow-up after hospitalization and eHealth interventions have the potential to improve these patients' QoL. Patient adherence in eHealth follow-up trials shows promise for successful future interventions and adherence research. Further studies are warranted to examine the effects of eHealth interventions on self-care and readmissions among patients with HF.


Analysis of membrane proteins from human chronic myelogenous leukemia cells: comparison of extraction methods for multidimensional LC-MS/MS.
An important strategy for "shotgun proteomics" profiling involves solution proteolysis of proteins, followed by peptide separation using multidimensional liquid chromatography and automated sequencing by mass spectrometry (LC-MS/MS). Several protocols for extracting and handling membrane proteins for shotgun proteomics experiments have been reported, but few direct comparisons of different protocols have been reported. We compare four methods for preparing membrane proteins from human cells, using acid labile surfactants (ALS), urea, and mixed organic-aqueous solvents. These methods were compared with respect to their efficiency of protein solubilization and proteolysis, peptide and protein recovery, membrane protein enrichment, and peptide coverage of transmembrane proteins. Overall, approximately 50-60% of proteins recovered were membrane-associated, identified from Gene Ontology annotations and transmembrane prediction software. Samples extracted with ALS, extracted with urea followed by dilution, or extracted with urea followed by desalting yielded comparable peptide recoveries and sequence coverage of transmembrane proteins. In contrast, suboptimal proteolysis was observed with organic solvent. Urea extraction followed by desalting may be a particularly useful approach, as it is less costly than ALS and yields satisfactory protein denaturation and proteolysis under conditions that minimize reactivity with urea-derived cyanate. Spectral counting was used to compare datasets of proteins from membrane samples with those of soluble proteins from K562 cells, and to estimate fold differences in protein abundances. Proteins most highly abundant in the membrane samples showed enrichment of integral membrane protein identifications, consistent with their isolation by differential centrifugation.


A combined epidemiologic and metabolomic approach improves CKD prediction.
Metabolomic approaches have begun to catalog the metabolic disturbances that accompany CKD, but whether metabolite alterations can predict future CKD is unknown. We performed liquid chromatography/mass spectrometry-based metabolite profiling on plasma from 1434 participants in the Framingham Heart Study (FHS) who did not have CKD at baseline. During the following 8 years, 123 individuals developed CKD, defined by an estimated GFR of <60 ml/min per 1.73 m(2). Numerous metabolites were associated with incident CKD, including 16 that achieved the Bonferroni-adjusted significance threshold of P≤0.00023. To explore how the human kidney modulates these metabolites, we profiled arterial and renal venous plasma from nine individuals. Nine metabolites that predicted CKD in the FHS cohort decreased more than creatinine across the renal circulation, suggesting that they may reflect non-GFR-dependent functions, such as renal metabolism and secretion. Urine isotope dilution studies identified citrulline and choline as markers of renal metabolism and kynurenic acid as a marker of renal secretion. In turn, these analytes remained associated with incident CKD in the FHS cohort, even after adjustment for eGFR, age, sex, diabetes, hypertension, and proteinuria at baseline. Addition of a multimarker metabolite panel to clinical variables significantly increased the c-statistic (0.77-0.83, P<0.0001); net reclassification improvement was 0.78 (95% confidence interval, 0.60 to 0.95; P<0.0001). Thus, the addition of metabolite profiling to clinical data may significantly improve the ability to predict whether an individual will develop CKD by identifying predictors of renal risk that are independent of estimated GFR.


Limitations of Conventional Magnetic Resonance Imaging as a Predictor of Death or Disability Following Neonatal Hypoxic-Ischemic Encephalopathy in the Late Hypothermia Trial.
To investigate if magnetic resonance imaging (MRI) is an accurate predictor for death or moderate-severe disability at 18-22 months of age among infants with neonatal encephalopathy in a trial of cooling initiated at 6-24 hours. Subgroup analysis of infants ≥36 weeks of gestation with moderate-severe neonatal encephalopathy randomized at 6-24 postnatal hours to hypothermia or usual care in a multicenter trial of late hypothermia. MRI scans were performed per each center's practice and interpreted by 2 central readers using the Eunice Kennedy Shriver National Institute of Child Health and Human Development injury score (6 levels, normal to hemispheric devastation). Neurodevelopmental outcomes were assessed at 18-22 months of age. Of 168 enrollees, 128 had an interpretable MRI and were seen in follow-up (n = 119) or died (n = 9). MRI findings were predominantly acute injury and did not differ by cooling treatment. At 18-22 months, death or severe disability occurred in 20.3%. No infant had moderate disability. Agreement between central readers was moderate (weighted kappa 0.56, 95% CI 0.45-0.67). The adjusted odds of death or severe disability increased 3.7-fold (95% CI 1.8-7.9) for each increment of injury score. The area under the curve for severe MRI patterns to predict death or severe disability was 0.77 and the positive and negative predictive values were 36% and 100%, respectively. MRI injury scores were associated with neurodevelopmental outcome at 18-22 months among infants in the Late Hypothermia Trial. However, the results suggest caution when using qualitative interpretations of MRI images to provide prognostic information to families following perinatal hypoxia-ischemia. Clinicaltrials.gov: NCT00614744.


Tetrahydrobiopterin (BH4), a cofactor for nNOS, restores gastric emptying and nNOS expression in female diabetic rats.
Gastroparesis is a debilitating disease predominantly affecting young women. Recently, dysregulation of neuronal nitric oxide synthase (nNOS) in myenteric plexus neurons has been implicated for delayed solid gastric emptying/gastroparesis in diabetic patients. In this study, we have explored the role of tetrahydrobiopterin (BH4), a major cofactor for nNOS activity and NO synthesis in diabetic gastroparesis. Diabetes was induced with single injection of streptozotocin (55 mg/kg body wt, ip) in female rats, with experiments performed on week 3 or 9 following induction, with or without 3-wk BH4 supplementation. Gastric pyloric BH4 levels were significantly decreased in diabetic female rats compared with control (18.6 +/- 1.45 vs. 31.0 +/- 2.31 pmol/mg protein). In vitro studies showed that 2,4-diamino-6-hydroxypyrimidine (DAHP), an inhibitor of BH4 synthesis, significantly decreased gastric NO release and nitrergic relaxation. Three-week dietary supplementation of BH4 either from day 1 or week 6 significantly attenuated diabetes-induced delayed gastric emptying for solids (3 wk: BH4, 67 +/- 6.7 vs. diabetic, 36.05 +/- 7.09; 9 wk: BH4, 57 +/- 8.45 vs. diabetic, 33 +/- 9.91) and diabetes-induced reduction in pyloric nNOS-alpha protein expression in female rats. Supplementation of BH4 significantly restored gastric nNOS-alpha dimerization in 9-wk-old diabetic female rats. In addition, BH4 treatment reversed (17.23 +/- 5.81 vs. 42.0 +/- 2.70 mmHg x s) the diabetes-induced changes in intragastric pressures (IGP) and gastric pyloric nitrergic relaxation (-0.62 +/- 0.01 vs. -0.22 +/- 0.07). BH4 deficiency plays a critical role in diabetes-induced alterations including delayed solid gastric emptying, increased IGP, reduced pyloric nitrergic relaxation, and nNOS-alpha expression in female rats. Supplementation of BH4 accelerates gastric emptying by restoring nitrergic system in diabetic female rats. Therefore, BH4 supplementation is a potential therapeutic option for female patients of diabetic gastroparesis.


Fasting and cancer: molecular mechanisms and clinical application.
The vulnerability of cancer cells to nutrient deprivation and their dependency on specific metabolites are emerging hallmarks of cancer. Fasting or fasting-mimicking diets (FMDs) lead to wide alterations in growth factors and in metabolite levels, generating environments that can reduce the capability of cancer cells to adapt and survive and thus improving the effects of cancer therapies. In addition, fasting or FMDs increase resistance to chemotherapy in normal but not cancer cells and promote regeneration in normal tissues, which could help prevent detrimental and potentially life-threatening side effects of treatments. While fasting is hardly tolerated by patients, both animal and clinical studies show that cycles of low-calorie FMDs are feasible and overall safe. Several clinical trials evaluating the effect of fasting or FMDs on treatment-emergent adverse events and on efficacy outcomes are ongoing. We propose that the combination of FMDs with chemotherapy, immunotherapy or other treatments represents a potentially promising strategy to increase treatment efficacy, prevent resistance acquisition and reduce side effects.


The role of disclosure in relation to assent to participate in HIV-related research among HIV-infected youth: a formative study.
The objective of this study was to develop a culturally appropriate approach for obtaining assent from children aged eight to 17 years to participate in paediatric HIV-related operational research in Kinshasa, Democratic Republic of Congo (DRC). Included within this objective was to determine whether or not HIV disclosure should be included as part of the assent process prior to research participation, a component of research participation, or not incorporated in any aspect of the child's involvement in the research. Factors that influence parents' and caregivers' decisions to disclose HIV status to children in non-research contexts were also explored. A qualitative formative study was conducted. Semi-structured interviews were conducted with 19 youth living with HIV, 36 parents and caregivers of youth living with HIV, and 17 health professionals who provide care and support to youth living with HIV and their families. Participants were purposefully selected from three HIV care, treatment and/or psychosocial support programmes in Kinshasa, DRC. Most youth interviewed believed minors participating in HIV-related research should be informed of their HIV-positive status. Parents and caregivers and health professionals had varied perspectives on if and when HIV status should be disclosed to minors during research participation. The age of the youth influenced parents and caregivers' responses, and disclosure to adolescents was more frequently supported than disclosure to children.Several parents and caregivers, as well as some health professionals, suggested that minors should never be told their HIV-positive status when participating in HIV-related research, regardless of their age. Within the context of treatment programmes, disclosure of HIV status to minors was supported by youth, parents and caregivers, and health professionals as a means to improve adherence to medication. In settings where most minors are unaware of their HIV infection, researchers should consider excluding the term, "HIV", when explaining HIV-related research to minors, and omitting it from assent forms or informational sheets related to research participation. However, an individualized disclosure plan should be initiated with parents and caregivers at the time of enrolment in HIV-related research, particularly in research that involves treatment.


Biomarker expression and druggable gene alterations for development of an appropriate therapeutic protocol for pulmonary adenosquamous carcinoma.
Pulmonary adenosquamous carcinoma (ASC) is more aggressive than adenocarcinoma (AC) and squamous cell carcinoma (SCC). The genetic features and biomarkers of ASC are not well known. Here, we attempted to identify potential therapeutic markers for ASC. Surgically resected ASC samples from 65 patients were analysed. We examined the expression of β III-tubulin, thymidylate synthase, breast cancer susceptibility gene 1 and ribonucleotide reductase M1 (RRM1); identified mutations in epidermal growth factor receptor (EGFR), KRAS, BRAF and HER2; and detected ALK, ROS1 and RET rearrangements. Gene amplification and expression of EGFR, human epidermal growth factor receptor 2 (HER2), fibroblast growth factor receptor-1 and MET were also examined. β III-Tubulin showed the highest expression (P = 0.002), and its expression was more frequent in the AC than in the SCC component (P = 0.013). RRM1 expression was more frequent in the SCC component (P = 0.046). EGFR and KRAS mutations were detected in both components (21.5 and 10.9%, respectively). ALK and ROS1 rearrangements and MET amplification were detected in both components in one (1.5%) case. In ASC, drug response-specific gene alterations could occur in both AC and SCC components, suggesting that patients with confirmed or suspected ASC should undergo further testing for driver gene analyses.


Characterization of BAY 1905254, an Immune Checkpoint Inhibitor Targeting the Immunoglobulin-Like Domain Containing Receptor 2 (ILDR2).
The immunoglobulin-like domain containing receptor 2 (ILDR2), a type I transmembrane protein belonging to the B7 family of immunomodulatory receptors, has been described to induce an immunosuppressive effect on T-cell responses. Besides its expression in several nonlymphoid tissue types, we found that ILDR2 was also expressed in fibroblastic reticular cells (FRC) in the stromal part of the lymph node. These immunoregulatory cells were located in the T-cell zone and were essential for the recruitment of naïve T cells and activated dendritic cells to the lymph nodes. Previously, it has been shown that an ILDR2-Fc fusion protein exhibits immunomodulatory effects in several models of autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and type I diabetes. Herein, we report the generation and characterization of a human/mouse/monkey cross-reactive anti-ILDR2 hIgG2 antibody, BAY 1905254, developed to block the immunosuppressive activity of ILDR2 for cancer immunotherapy. BAY 1905254 was shown to promote T-cell activation in vitro and enhance antigen-specific T-cell proliferation and cytotoxicity in vivo in mice. BAY 1905254 also showed potent efficacy in various syngeneic mouse cancer models, and the efficacy was found to correlate with increasing mutational load in the cancer models used. Additive or even synergistic antitumor effects were observed when BAY 1905254 was administered in combination with anti-PD-L1, an immunogenic cell death-inducing chemotherapeutic, or with tumor antigen immunization. Taken together, our data showed that BAY 1905254 is a potential drug candidate for cancer immunotherapy, supporting its further evaluation.


Achieving enhanced cell penetration of short conformationally constrained peptides through amphiphilicity tuning.
Due to their enhanced stability and cell permeability, cyclic cell-penetrating peptides have been widely used as delivery vectors for transporting cell-impermeable cargos into cells. In this study, we synthesized a panel of conformationally constrained peptides with either α-helix or β-hairpin conformations. We tuned the amphiphilicity of these constrained peptides with different distributions of charged or hydrophobic residues and compared their cellular uptake efficiencies in different cell lines. We found that the amphipathicity of these conformationally constrained peptides correlates well with their cellular uptake efficiency. We proposed that peptides with larger hydrophobic moments (HMs) have stronger binding affinities with the cell membrane which further accelerates the endocytosis process. This finding should provide an approach towards the design of more potent conformationally constrained cell-penetrating peptides for biomedical applications.


Development of Health Research Structures Over the Last 25 Years: Main Achievements and Challenges.
In 1990, one of the most important strategies of supporting and managing reproductive research focused on development of research structures. This targeted vision, at the first step, mainly followed through creating research units. The present paper aims to explore the policies and strategies of medical research centers (MRCs)development, and its achievements and challenges over the last 25 years. Based on expected outcomes of better directions of research activities aligned with the priorities and policies of research, the Deputy of Research and Technology of Ministry of Health and Medical Education (MOHME), initiated the set up and development of research units. During the last 24 years, the number of MRCs has increased from 1 in 1992 to 736 in 2016. The progressive trends of expansion of the research centers are affected by a complex set of influencing factors. At first steps of program, the process of establishment and development of research structures followed slow trends in few unstructured primary centers. From 2008 to 2012, a rapid investment in development of research structures in biomedicine fields led to numerous complex challenges in supervision and management of MRCs (MRCs). Participatory approach in research centers management, benefiting from all available capacities of research stakeholders, could be considered as a practical strategy for better management of limitations and achieving targeted goals.


The INTEROCC case-control study: risk of meningioma and occupational exposure to selected combustion products, dusts and other chemical agents.
Little is known about occupational risk factors for meningioma. To study whether risk of meningioma is associated with several occupational exposures, including selected combustion products, dusts and other chemical agents. The INTEROCC study was an international case-control study of brain cancer conducted in seven countries. Data collection by interview included lifetime occupational histories. A job exposure matrix was used to derive estimates of exposure for the 12 agents. ORs for ever versus never exposed and for exposure-response using duration of exposure and cumulative exposure were derived using conditional logistic regression stratified by sex, age group, country/region, adjusted for education. These analyses included 1906 cases and 5565 controls. For 11 of the 12 agents, no excess risk was found for ever exposed. For ever exposure to oil mists, an elevated OR of 1.57 (95% CI 1.10 to 2.22, 51 exposed cases) was found. Statistically significant exposure-response relationships were observed with cumulative exposure (p=0.01) and duration of exposure (p=0.04). Among women, there were also significant trends for cumulative and duration of exposure to asbestos and excesses in the highest exposure categories for formaldehyde. Most agents examined did not provoke excess risks of meningioma. The main finding from this study is that it is the first study to identify a statistical association between exposure to oil mists and meningioma. This may be a chance finding or could be due to confounding with iron exposure and further research is required to understand whether the relationship is causal.


Cortical plasticity in patients with Parkinson's disease a window for therapeutic non-invasive neuromodulation.
Several evidences in animal models have consistently an alteration of cortico-striatal plasticity, which is related to the degeneration of the substantia nigra. An alteration of plasticity have also been reported in humans by recording evoked field potentials in the substantia nigra pars reticulata of PD patients undergoing subthalamic nucleus (STN) stimulation where high-frequency (HF) in the OFF state did not induce a lasting change in field potential amplitude in the substantia nigra. In addition protocols of non-invasive brain stimulation, such as paired associative stimulation (PAS) and theta-burst stimulation (TBS), can be used to investigate cortical plasticity of the human primary motor cortex. Despite data reported in literature are apparently controversial with some studies showing a reduced or increased or even normal LTP and LTD like plasticity, recent evidences suggest the hypothesis that these different pat- terns of cortical plasticity likely depend on the stage of the disease and on the concomitant administration of L-DOPA. The current review will provide an up-to-date of these issues on cortical plasticity in PD discussing the clinical implications in rehabilitation. In addition in the last section we will review the state of art of non invasive neuro- modulation as adjuvant treatment in the advanced stage of the disease.


Evaluation of the mental health benefits of yoga in a secondary school: a preliminary randomized controlled trial.
The goal of this study was to evaluate potential mental health benefits of yoga for adolescents in secondary school. Students were randomly assigned to either regular physical education classes or to 11 weeks of yoga sessions based upon the Yoga Ed program over a single semester. Students completed baseline and end-program self-report measures of mood, anxiety, perceived stress, resilience, and other mental health variables. Independent evaluation of individual outcome measures revealed that yoga participants showed statistically significant differences over time relative to controls on measures of anger control and fatigue/inertia. Most outcome measures exhibited a pattern of worsening in the control group over time, whereas changes in the yoga group over time were either minimal or showed slight improvements. These preliminary results suggest that implementation of yoga is acceptable and feasible in a secondary school setting and has the potential of playing a protective or preventive role in maintaining mental health.