Nutrients and bioactives in green leafy vegetables and cognitive decline: Prospective study.
To increase understanding of the biological mechanisms underlying the association, we investigated the individual relations to cognitive decline of the primary nutrients and bioactives in green leafy vegetables, including vitamin K (phylloquinone), lutein, β-carotene, nitrate, folate, kaempferol, and α-tocopherol. This was a prospective study of 960 participants of the Memory and Aging Project, ages 58-99 years, who completed a food frequency questionnaire and had ≥2 cognitive assessments over a mean 4.7 years. In a linear mixed model adjusted for age, sex, education, participation in cognitive activities, physical activities, smoking, and seafood and alcohol consumption, consumption of green leafy vegetables was associated with slower cognitive decline; the decline rate for those in the highest quintile of intake (median 1.3 servings/d) was slower by β = 0.05 standardized units (p = 0.0001) or the equivalent of being 11 years younger in age. Higher intakes of each of the nutrients and bioactives except β-carotene were individually associated with slower cognitive decline. In the adjusted models, the rates for the highest vs the lowest quintiles of intake were β = 0.02, p = 0.002 for phylloquinone; β = 0.04, p = 0.002 for lutein; β = 0.05, p < 0.001 for folate; β = 0.03, p = 0.02 for α-tocopherol; β = 0.04, p = 0.002 for nitrate; β = 0.04, p = 0.003 for kaempferol; and β = 0.02, p = 0.08 for β-carotene. Consumption of approximately 1 serving per day of green leafy vegetables and foods rich in phylloquinone, lutein, nitrate, folate, α-tocopherol, and kaempferol may help to slow cognitive decline with aging.


Broadband 2D electronic spectrometer using white light and pulse shaping: noise and signal evaluation at 1 and 100 kHz.
We have developed a broad bandwidth two-dimensional electronic spectrometer that operates shot-to-shot at repetition rates up to 100 kHz using an acousto-optic pulse shaper. It is called a two-dimensional white-light (2D-WL) spectrometer because the input is white-light supercontinuum. Methods for 100 kHz data collection are studied to understand how laser noise is incorporated into 2D spectra during measurement. At 100 kHz, shot-to-shot scanning of the delays and phases of the pulses in the pulse sequence produces a 2D spectrum 13-times faster and with the same signal-to-noise as using mechanical stages and a chopper. Comparing 100 to 1 kHz repetition rates, data acquisition time is decreased by a factor of 200, which is beyond the improvement expected by the repetition rates alone due to reduction in 1/f noise. These improvements arise because shot-to-shot readout and modulation of the pulse train at 100 kHz enables the electronic coherences to be measured faster than the decay in correlation between laser intensities. Using white light supercontinuum for the pump and probe pulses produces high signal-to-noise spectra on samples with optical densities <0.1 within a few minutes of averaging and an instrument response time of <46 fs thereby demonstrating that that simple broadband continuum sources, although weak, are sufficient to create high quality 2D spectra with >200 nm bandwidth.


Human health in relation to exposure to solar ultraviolet radiation under changing stratospheric ozone and climate.
The Montreal Protocol has limited increases in the UV-B (280-315 nm) radiation reaching the Earth's surface as a result of depletion of stratospheric ozone. Nevertheless, the incidence of skin cancers continues to increase in most light-skinned populations, probably due mainly to risky sun exposure behaviour. In locations with strong sun protection programs of long duration, incidence is now reducing in younger age groups. Changes in the epidemiology of UV-induced eye diseases are less clear, due to a lack of data. Exposure to UV radiation plays a role in the development of cataracts, pterygium and possibly age-related macular degeneration; these are major causes of visual impairment world-wide. Photodermatoses and phototoxic reactions to drugs are not uncommon; management of the latter includes recognition of the risks by the prescribing physician. Exposure to UV radiation has benefits for health through the production of vitamin D in the skin and modulation of immune function. The latter has benefits for skin diseases such as psoriasis and possibly for systemic autoimmune diseases such as multiple sclerosis. The health risks of sun exposure can be mitigated through appropriate sun protection, such as clothing with both good UV-blocking characteristics and adequate skin coverage, sunglasses, shade, and sunscreen. New sunscreen preparations provide protection against a broader spectrum of solar radiation, but it is not clear that this has benefits for health. Gaps in knowledge make it difficult to derive evidence-based sun protection advice that balances the risks and benefits of sun exposure.


Characterization of a preclinical model of simultaneous breast and ovarian cancer progression.
Women at increased risk for breast cancer are often also at increased risk for ovarian cancer, reflecting common risk factors and intertwined etiologies for both diseases. Unlike breast cancer prevention, primary ovarian cancer prevention has been impractical due to the low incidence, lack of risk and response biomarkers and difficulties in sampling ovarian tissue. Challenges in the development of ovarian cancer prevention drugs, however, may be circumvented through the development of breast cancer prevention strategies that simultaneously decrease ovarian cancer. In the present study, three commonly used mammary cancer carcinogen models [7,12-dimethylbenz[alpha]anthracene (DMBA), N-methyl-N-nitrosourea (MNU) and estradiol (E2)] were combined with local ovarian DMBA administration to induce progression to mammary and ovarian cancer concurrently in the rat. Animals were treated for 3 or 6 months, and tissue histology as well as proliferation, hormonal and inflammation biomarkers were assessed. Mammary and ovarian morphologies (measured as descriptive histology and dysplasia scores) were normal in vehicle controls. Mammary hyperplasia was observed in DMBA/DMBA (mammary carcinogen/ovarian carcinogen) and MNU/DMBA-treated rats; however, ovarian preneoplastic changes were seldom observed after these treatments. All E2/DMBA-treated rats had mammary hyperplasia, atypia, ductal carcinoma in situ and/or invasive adenocarcinoma, while 50% also developed preneoplastic changes in the ovary (ovarian epithelial and stromal hyperplasia and inclusion cyst formation). In both the mammary gland and ovary, decreased estrogen receptor alpha expression was detected, and in the mammary gland elevated Ki-67 and cyclooxygenase-2 expressions were observed. This combined breast and ovarian cancer rat model (systemic E2 treatment and local ovarian DMBA) may be useful for future dual target breast and ovarian cancer prevention studies.


Serum thrombopoietin and erythropoietin levels in patients with acute promyelocytic leukaemia during all-trans retinoic acid treatment.
Endogenous serum thrombopoietin (TPO) and various cytokines including erythropoietin (EPO), interleukin (IL)-3, IL-6, IL-11, granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage-colony stimulating factor (GM-CSF) and stem cell factor (SCF) levels were measured in five patients with acute promyelocytic leukaemia (APL) during all-trans retinoic acid (RA) treatment. During differentiation-inducing therapy, platelet counts slowly increased and reached a peak between days 29 and 46 (median day 35). Serum TPO levels increased parallel to the increasing platelet counts and reached a maximum level during the first 10-20 d of all-trans RA treatment. The circulating TPO levels then decreased in inverse correlation to the platelet counts. These unique changes in serum TPO levels revealed that TPO levels were not regulated by platelet or megakaryocyte mass in patients with APL during differentiation-inducing therapy, and it would appear that TPO levels are directly regulated by all-trans RA during the first 10-20 d of treatment. In addition, the change in circulating EPO levels and reticulocyte counts were similar to that of the TPO levels and platelet counts during all-trans RA treatment, suggesting a close relationship between TPO and EPO signalling.


Structural and functional divergence within the Dim1/KsgA family of rRNA methyltransferases.
The enzymes of the KsgA/Dim1 family are universally distributed throughout all phylogeny; however, structural and functional differences are known to exist. The well-characterized function of these enzymes is to dimethylate two adjacent adenosines of the small ribosomal subunit in the normal course of ribosome maturation, and the structures of KsgA from Escherichia coli and Dim1 from Homo sapiens and Plasmodium falciparum have been determined. To this point, no examples of archaeal structures have been reported. Here, we report the structure of Dim1 from the thermophilic archaeon Methanocaldococcus jannaschii. While it shares obvious similarities with the bacterial and eukaryotic orthologs, notable structural differences exist among the three members, particularly in the C-terminal domain. Previous work showed that eukaryotic and archaeal Dim1 were able to robustly complement for KsgA in E. coli. Here, we repeated similar experiments to test for complementarity of archaeal Dim1 and bacterial KsgA in Saccharomyces cerevisiae. However, neither the bacterial nor the archaeal ortholog could complement for the eukaryotic Dim1. This might be related to the secondary, non-methyltransferase function that Dim1 is known to play in eukaryotic ribosomal maturation. To further delineate regions of the eukaryotic Dim1 critical to its function, we created and tested KsgA/Dim1 chimeras. Of the chimeras, only one constructed with the N-terminal domain from eukaryotic Dim1 and the C-terminal domain from archaeal Dim1 was able to complement, suggesting that eukaryotic-specific Dim1 function resides in the N-terminal domain also, where few structural differences are observed between members of the KsgA/Dim1 family. Future work is required to identify those determinants directly responsible for Dim1 function in ribosome biogenesis. Finally, we have conclusively established that none of the methyl groups are critically important to growth in yeast under standard conditions at a variety of temperatures.


Exploring folds, evolution and host interactions: understanding effector structure/function in disease and immunity.
Over the past decade, tremendous progress has been made in plant pathology, broadening our understanding of how pathogens colonize their hosts. To manipulate host cell physiology and subvert plant immune responses, pathogens secrete an array of effector proteins. A co-evolutionary arms-race drives the pathogen to constantly reinvent its effector repertoire to undermine plant immunity. In turn, hosts develop novel immune receptors to maintain effector recognition and mount defences. Understanding how effectors promote disease and how they are perceived by the plant's defence network persist as major subjects in the study of plant-pathogen interactions. Here, we focus on recent advances (over roughly the last two years) in understanding structure/function relationships in effectors from bacteria and filamentous plant pathogens. Structure/function studies of bacterial effectors frequently uncover diverse catalytic activities, while structure-informed similarity searches have enabled cataloguing of filamentous pathogen effectors. We also suggest how such advances have informed the study of plant-pathogen interactions.


Nicotine binding to brain receptors requires a strong cation-pi interaction.
Nicotine addiction begins with high-affinity binding of nicotine to acetylcholine (ACh) receptors in the brain. The end result is over 4,000,000 smoking-related deaths annually worldwide and the largest source of preventable mortality in developed countries. Stress reduction, pleasure, improved cognition and other central nervous system effects are strongly associated with smoking. However, if nicotine activated ACh receptors found in muscle as potently as it does brain ACh receptors, smoking would cause intolerable and perhaps fatal muscle contractions. Despite extensive pharmacological, functional and structural studies of ACh receptors, the basis for the differential action of nicotine on brain compared with muscle ACh receptors has not been determined. Here we show that at the alpha4beta2 brain receptors thought to underlie nicotine addiction, the high affinity for nicotine is the result of a strong cation-pi interaction to a specific aromatic amino acid of the receptor, TrpB. In contrast, the low affinity for nicotine at the muscle-type ACh receptor is largely due to the fact that this key interaction is absent, even though the immediate binding site residues, including the key amino acid TrpB, are identical in the brain and muscle receptors. At the same time a hydrogen bond from nicotine to the backbone carbonyl of TrpB is enhanced in the neuronal receptor relative to the muscle type. A point mutation near TrpB that differentiates alpha4beta2 and muscle-type receptors seems to influence the shape of the binding site, allowing nicotine to interact more strongly with TrpB in the neuronal receptor. ACh receptors are established therapeutic targets for Alzheimer's disease, schizophrenia, Parkinson's disease, smoking cessation, pain, attention-deficit hyperactivity disorder, epilepsy, autism and depression. Along with solving a chemical mystery in nicotine addiction, our results provide guidance for efforts to develop drugs that target specific types of nicotinic receptors.


The effect of intraoperative fluid administration on outcomes of patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.
Determine the effect of intraoperative fluids (IOFs) administered during cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) on postoperative patient outcomes. Retrospective cohort study of patients that underwent CRS/HIPEC from February 2010 to June 2017. A total of 335 patients formed the cohort study. Patients who received higher IOFs had longer hospital length of stay (LOS) (34 vs. 22.5 days; P<0.001), extended intensive care unit (ICU) admission (5.3 vs. 3.2 days; P<0.001) and a 12% increase in grade 3/4 complications (P<0.001). Greater amounts of blood product transfusion were associated with longer hospital LOS (33.7 vs. 23 days; P<0.001), and ICU admission (5 vs. 3.4 days; P<0.001) and 12% increase in grade 3/4 complications (P<0.001). When corrected for weight and peritoneal cancer index (PCI), increased transfusion of blood products still resulted in longer hospital LOS (31.2 vs. 25.2 days; P=0.04) and longer ICU admission (4.7 vs. 3.6 days; P=0.03). On multivariable analysis, less blood product transfusions demonstrated a decreased LOS in hospital by 4.8 days (P=0.01) and fewer grade 3/4 complications (OR 0.59; 95% CI, 0.35-0.99; P=0.05). Greater IOF administration is associated with an increase in postoperative morbidity, including hospital LOS, ICU admission and grade 3/4 complications, in patients undergoing CRS/HIPEC.


Core data set on safety, efficacy, and durability of hemophilia gene therapy for a global registry: Communication from the SSC of the ISTH.
Gene therapy for people with hemophilia (PWH) will soon become available outside current clinical trials. The World Federation of Hemophilia (WFH), in collaboration with International Society of Thrombosis and Hemostasis Scientific and Standardization Committee (ISTH SSC), the European Haemophilia Consortium (EHC), the US National Hemophilia Foundation (NHF), the American Thrombosis and Hemostasis Network (ATHN), industry gene therapy development partners and Regulatory liaisons have developed the Gene Therapy Registry (GTR), designed to collect long-term data on all PWH who receive hemophilia gene therapy. The objectives of the GTR are to record the long-term safety and efficacy data post gene therapy infusion and to assess the changes in quality of life and burden of disease post-gene-therapy infusion. The GTR is a prospective, observational, and longitudinal registry developed under the guidance of a multi-stakeholder GTR Steering Committee (GTR SC), composed of health care professionals, patient advocates, industry representatives, and regulatory agency liaisons. All PWH who receive gene therapy by clinical trial or commercial product will be invited to enrol in the registry through their hemophilia treatment centers (HTCs). The registry aims to recruit 100% of eligible post gene therapy PWH globally. Through an iterative process, and following the guidance of the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), the GTR SC has developed a core set of data to be collected on all patients post gene therapy. The core data set includes demographic information, vector infusion details, safety, efficacy, quality of life and burden of disease. The GTR is a global effort to ensure that long term safety and efficacy outcomes are recorded and analysed and rare adverse events, in a small patient population, are identified. Many unknowns on the long-term safety and efficacy of gene therapy for hemophilia may also be addressed.


Access, equity and the role of rights in health care.
Modern health care rhetoric promotes choice and individual patient rights as dominant values. Yet we also accept that in any regime constrained by finite resources, difficult choices between patients are inevitable. How can we balance rights to liberty, on the one hand, with equity in the allocation of scarce resources on the other? For example, the duty of health authorities to allocate resources is a duty owed to the community as a whole, rather than to specific individuals. Macro-duties of this nature are founded on the notion of equity and fairness amongst individuals rather than personal liberty. They presume that if hard choices have to be made, they will be resolved according to fair and consistent principles which treat equal cases equally, and unequal cases unequally. In this paper, we argue for greater clarity and candour in the health care rights debate. With this in mind, we discuss (1) private and public rights, (2) negative and positive rights, (3) procedural and substantive rights, (4) sustainable health care rights and (5) the New Zealand booking system for prioritising access to elective services. This system aims to consider: individual need and ability to benefit alongside the resources made available to elective health services in an attempt to give the principles of equity practical effect. We describe a continuum on which the merits of those, sometimes competing, values--liberty and equity--can be evaluated and assessed.


Self-limiting population genetic control with sex-linked genome editors.
In male heterogametic species the Y chromosome is transmitted solely from fathers to sons, and is selected for based only on its impacts on male fitness. This fact can be exploited to develop efficient pest control strategies that use Y-linked editors to disrupt the fitness of female descendants. With simple population genetic and dynamic models we show that Y-linked editors can be substantially more efficient than other self-limiting strategies and, while not as efficient as gene drive approaches, are expected to have less impact on non-target populations with which there is some gene flow. Efficiency can be further augmented by simultaneously releasing an autosomal X-shredder construct, in either the same or different males. Y-linked editors may be an attractive option to consider when efficient control of a species is desired in some locales but not others.


A peptide derived from the highly conserved protein GAPDH is involved in tissue protection by different antifungal strategies and epithelial immunomodulation.
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has an important role not only in glycolysis but also in nonmetabolic processes, including transcription activation and apoptosis. We report the isolation of a human GAPDH (hGAPDH) (2-32) fragment peptide from human placental tissue exhibiting antimicrobial activity. The peptide was internalized by cells of the pathogenic yeast Candida albicans and initiated a rapid apoptotic mechanism, leading to killing of the fungus. Killing was dose-dependent, with 10 μg ml (3.1 μM) and 100 μg ml hGAPDH (2-32) depolarizing 45% and 90% of the fungal cells in a population, respectively. Experimental C. albicans infection induced epithelial hGAPDH (2-32) expression. Addition of the peptide significantly reduced the tissue damage as compared with untreated experimental infection. Secreted aspartic proteinase (Sap) activity of C. albicans was inhibited by the fragment at higher concentrations, with a median effective dose of 160 mg l(-1) (50 μM) for Sap1p and 200 mg l(-1) (63 μM) for Sap2p, whereas Sap3 was not inhibited at all. Interestingly, hGAPDH (2-32) induced significant epithelial IL-8 and GM-CSF secretion and stimulated Toll-like receptor 4 expression at low concentrations independently of the presence of C. albicans, without any toxic mucosal effects. In the future, the combination of different antifungal strategies, e.g., a conventional fungicidal with immunomodulatory effects and the inhibition of fungal virulence factors, might be a promising treatment option.


Efficacy of low-dose bepridil for prevention of ventricular fibrillation in patients with Brugada syndrome with and without SCN5A mutation.
It has been reported that bepridil prevents ventricular fibrillation (VF) in patients with Brugada syndrome, but the comparative efficacy with and without mutation in the SCN5A gene has not been elucidated. The purpose of this study was to assess the efficacy of low-dose bepridil (100 mg/day) for VF prevention in patients with Brugada syndrome with and without SCN5A mutation. Among 130 patients with Brugada-type electrocardiogram (ECG), low-dose bepridil was administered to seven patients because of repetitive VF episodes, including three with and four without SCN5A mutation. Preventive effect for VF recurrence and changes of the ECG and the signal-averaged ECG were evaluated. Frequencies of VF episodes were reduced after treatment with low-dose bepridil in all three patients with the SCN5A mutation (before: 0.33 versus after: 0.02 episodes/month, P < 0.01), but not in all four patients without the SCN5A mutation (before: 0.43 versus after: 2.94 episodes/month, P = nonsignificant). Levels of ST-segment elevation at J points and duration of low-amplitude signals less than 40 µV in the terminal filtered QRS complex (LAS40) in signal-averaged ECG were improved exclusively in patients with the SCN5A mutation. Treatment with bepridil prevented recurrence of VF along with improvement of ST elevation and LAS40 in patients with Brugada syndrome with the SCN5A mutation.


Different temperature thresholds for antipyretic intervention in critically ill children with fever due to infection: the FEVER feasibility RCT.
Fever accelerates host immune system control of pathogens but at a high metabolic cost. The optimal approach to fever management and the optimal temperature thresholds used for treatment in critically ill children are unknown. To determine the feasibility of conducting a definitive randomised controlled trial (RCT) to evaluate the clinical effectiveness and cost-effectiveness of different temperature thresholds for antipyretic management. A mixed-methods feasibility study comprising three linked studies - (1) a qualitative study exploring parent and clinician views, (2) an observational study of the epidemiology of fever in children with infection in paediatric intensive care units (PICUs) and (3) a pilot RCT with an integrated-perspectives study. Participants were recruited from (1) four hospitals in England via social media (for the FEVER qualitative study), (2) 22 PICUs in the UK (for the FEVER observational study) and (3) four PICUs in England (for the FEVER pilot RCT). (1) Parents of children with relevant experience were recruited to the FEVER qualitative study, (2) patients who were unplanned admissions to PICUs were recruited to the FEVER observational study and (3) children admitted with infection requiring mechanical ventilation were recruited to the FEVER pilot RCT. Parents of children and clinicians involved in the pilot RCT. The FEVER qualitative study and the FEVER observational study had no interventions. In the FEVER pilot RCT, children were randomly allocated (1 : 1) using research without prior consent (RWPC) to permissive (39.5 °C) or restrictive (37.5 °C) temperature thresholds for antipyretics during their PICU stay while mechanically ventilated. (1) The acceptability of FEVER, RWPC and potential outcomes (in the FEVER qualitative study), (2) the size of the potentially eligible population and the temperature thresholds used (in the FEVER observational study) and (3) recruitment and retention rates, protocol adherence and separation between groups and distribution of potential outcomes (in the FEVER pilot RCT). In the FEVER qualitative study, 25 parents were interviewed and 56 clinicians took part in focus groups. Both the parents and the clinicians found the study acceptable. Clinicians raised concerns regarding temperature thresholds and not using paracetamol for pain/discomfort. In the FEVER observational study, 1853 children with unplanned admissions and infection were admitted to 22 PICUs between March and August 2017. The recruitment rate was 10.9 per site per month. The majority of critically ill children with a maximum temperature of > 37.5 °C received antipyretics. In the FEVER pilot RCT, 100 eligible patients were randomised between September and December 2017 at a recruitment rate of 11.1 per site per month. Consent was provided for 49 out of 51 participants in the restrictive temperature group, but only for 38 out of 49 participants in the permissive temperature group. A separation of 0.5 °C (95% confidence interval 0.2 °C to 0.8 °C) between groups was achieved. A high completeness of outcome measures was achieved. Sixty parents of 57 children took part in interviews and/or completed questionnaires and 98 clinicians took part in focus groups or completed a survey. Parents and clinicians found the pilot RCT and RWPC acceptable. Concerns about children being in pain/discomfort were cited as reasons for withdrawal and non-consent by parents and non-adherence to the protocol by clinicians. Different recruitment periods for observational and pilot studies may not fully reflect the population that is eligible for a definitive RCT. The results identified barriers to delivering the definitive FEVER RCT, including acceptability of the permissive temperature threshold. The findings also provided insight into how these barriers may be overcome, such as by limiting the patient inclusion criteria to invasive ventilation only and by improved site training. A definitive FEVER RCT using a modified protocol should be conducted, but further work is required to agree important outcome measures for clinical trials among critically ill children. The FEVER observational study is registered as NCT03028818 and the FEVER pilot RCT is registered as Current Controlled Trials ISRCTN16022198. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 5. See the NIHR Journals Library website for further project information.


MeDALL (Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine.
The origin of the epidemic of IgE-associated (allergic) diseases is unclear. MeDALL (Mechanisms of the Development of ALLergy), an FP7 European Union project (No. 264357), aims to generate novel knowledge on the mechanisms of initiation of allergy and to propose early diagnosis, prevention, and targets for therapy. A novel phenotype definition and an integrative translational approach are needed to understand how a network of molecular and environmental factors can lead to complex allergic diseases. A novel, stepwise, large-scale, and integrative approach will be led by a network of complementary experts in allergy, epidemiology, allergen biochemistry, immunology, molecular biology, epigenetics, functional genomics, bioinformatics, computational and systems biology. The following steps are proposed: (i) Identification of 'classical' and 'novel' phenotypes in existing birth cohorts; (ii) Building discovery of the relevant mechanisms in IgE-associated allergic diseases in existing longitudinal birth cohorts and Karelian children; (iii) Validation and redefinition of classical and novel phenotypes of IgE-associated allergic diseases; and (iv) Translational integration of systems biology outcomes into health care, including societal aspects. MeDALL will lead to: (i) A better understanding of allergic phenotypes, thus expanding current knowledge of the genomic and environmental determinants of allergic diseases in an integrative way; (ii) Novel diagnostic tools for the early diagnosis of allergy, targets for the development of novel treatment modalities, and prevention of allergic diseases; (iii) Improving the health of European citizens as well as increasing the competitiveness and boosting the innovative capacity of Europe, while addressing global health issues and ethical issues.


Association of brief health literacy screening and blood pressure in primary care.
Health literacy impacts health outcomes. However, the relationship to blood pressure is inconsistent. This study aimed to determine whether health literacy, assessed by clinic staff, is associated with blood pressure among patients with hypertension. The design was a cross-sectional study of a large sample of primary care patient encounters in 3 academic medical center clinics in Nashville, Tennessee. Health literacy was assessed using the Brief Health Literacy Screen, with higher scores indicating higher health literacy. Blood pressure was extracted from the electronic health record. Using 23,483 encounters in 10,644 patients, the authors examined the association of health literacy with blood pressure in multivariable analyses, adjusting for age, gender, race, education, and clinic location. Independent of educational attainment, 3-point increases in health literacy scores were associated with 0.74 mmHg higher systolic blood pressure (95% CI [0.38, 1.09]) and 0.30 mmHg higher diastolic blood pressure (95% CI [0.08, 0.51]). No interaction between education and health literacy was observed (p = .91). In this large primary care population of patients with hypertension, higher health literacy, as screened in clinical practice, was associated with a small increase in blood pressures. Future research is needed to explore this unexpected finding.


The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D).
Given the manifold ways that depression impairs Darwinian fitness, the persistence in the human genome of risk alleles for the disorder remains a much debated mystery. Evolutionary theories that view depressive symptoms as adaptive fail to provide parsimonious explanations for why even mild depressive symptoms impair fitness-relevant social functioning, whereas theories that suggest that depression is maladaptive fail to account for the high prevalence of depression risk alleles in human populations. These limitations warrant novel explanations for the origin and persistence of depression risk alleles. Accordingly, studies on risk alleles for depression were identified using PubMed and Ovid MEDLINE to examine data supporting the hypothesis that risk alleles for depression originated and have been retained in the human genome because these alleles promote pathogen host defense, which includes an integrated suite of immunological and behavioral responses to infection. Depression risk alleles identified by both candidate gene and genome-wide association study (GWAS) methodologies were found to be regularly associated with immune responses to infection that were likely to enhance survival in the ancestral environment. Moreover, data support the role of specific depressive symptoms in pathogen host defense including hyperthermia, reduced bodily iron stores, conservation/withdrawal behavior, hypervigilance and anorexia. By shifting the adaptive context of depression risk alleles from relations with conspecifics to relations with the microbial world, the Pathogen Host Defense (PATHOS-D) hypothesis provides a novel explanation for how depression can be nonadaptive in the social realm, whereas its risk alleles are nonetheless represented at prevalence rates that bespeak an adaptive function.


Topological energy storage of work generated by nanomotors.
Most macroscopic machines rely on wheels and gears. Yet, rigid gears are entirely impractical on the nano-scale. Here we propose a more useful method to couple any rotary engine to any other mechanical elements on the nano- and micro-scale. We argue that a rotary molecular motor attached to an entangled polymer energy storage unit, which together form what we call the "tanglotron" device, is a viable concept that can be experimentally implemented. We derive the torque-entanglement relationship for a tanglotron (its "equation of state") and show that it can be understood by simple statistical mechanics arguments. We find that a typical entanglement at low packing density costs around 6kT. In the high entanglement regime, the free energy diverges logarithmically close to a maximal geometric packing density. We outline several promising applications of the tanglotron idea and conclude that the transmission, storage and back-conversion of topological entanglement energy are not only physically feasible but also practical for a number of reasons.


Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways.
Aggregated alpha-synuclein is the main component of Lewy bodies, intraneuronal inclusions found in brains with Parkinson's disease and dementia with Lewy bodies. A body of evidence implicates oxidative stress in the pathogenesis of these diseases. For example, a large excess (30:1, aldehyde:protein) of the lipid peroxidation end products 4-oxo-2-nonenal (ONE) or 4-hydroxy-2-nonenal (HNE) can induce alpha-synuclein oligomer formation. The objective of the study was to investigate the effect of these reactive aldehydes on alpha-synuclein at a lower molar excess (3:1) at both physiological (7.4) and acidic (5.4) pH. As observed by size-exclusion chromatography, ONE rapidly induced the formation of alpha-synuclein oligomers at both pH values, but the effect was less pronounced under the acidic condition. In contrast, only a small proportion of alpha-synuclein oligomers were formed with low excess HNE-treatment at physiological pH and no oligomers at all under the acidic condition. With prolonged incubation times (up to 96h), more alpha-synuclein was oligomerized at physiological pH for both ONE and HNE. As determined by Western blot, ONE-oligomers were more SDS-stable and to a higher-degree cross-linked as compared to the HNE-induced oligomers. However, as shown by their greater sensitivity to proteinase K treatment, ONE-oligomers, exhibited a less compact structure than HNE-oligomers. As indicated by mass spectrometry, ONE modified most Lys residues, whereas HNE primarily modified the His50 residue and fewer Lys residues, albeit to a higher degree than ONE. Taken together, our data show that the aldehydes ONE and HNE can modify alpha-synuclein and induce oligomerization, even at low molar excess, but to a higher degree at physiological pH and seemingly through different pathways.


Delayed primary excision with subsequent modification of radiotherapy dose for intermediate-risk rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee.
The majority of intermediate-risk rhabdomyosarcoma (RMS) patients have gross residual disease (Group III) after their first operative procedure. It is currently not known if local control rates can be maintained when, following induction chemotherapy, the radiation therapy (RT) dose is decreased after a delayed primary excision (DPE). To answer this question we evaluated patients enrolled on COG D9803 (1999-2005) who had Group III tumors of the bladder dome, extremity or trunk (thorax, abdomen and pelvis) were candidates for DPE at Week 12 if the primary tumor appeared resectable. RT dose was then adjusted by the completeness of DPE: no evidence of disease 36 Gy, microscopic residual 41.4 Gy and gross residual disease (GRD) 50.4 Gy. A total of 161 Group III patients were evaluated (24 bladder dome, 63 extremity and 74 trunk). Seventy-three patients (45%) underwent DPE which achieved removal of all gross disease in 61 (84%) who were then eligible for reduced RT dose (43/73 received 36 Gy, 19/73 received 41.4 Gy). The local 5-year failure rate (0% for bladder dome, 7% for extremity and 20% for trunk) was similar to IRS-IV, which did not encourage DPE and did not allow for DPE adapted RT dose reduction. In conclusion, DPE was performed in 45% of Group III RMS patients with tumors at select anatomic sites (bladder dome, extremity and trunk) and 84% of those who had DPE were eligible for RT dose reduction. Local control outcomes were similar to historic results with RT alone.


AVSS: Airborne Video Surveillance System.
Most surveillance systems only contain CCTVs. CCTVs, however, provide only limited maneuverability against dynamic targets and are inefficient for short term surveillance. Such limitations do not raise much concern in some cases, but for the scenario in which traditional surveillance systems do not suffice, adopting a fleet of UAVs can help overcoming the limitations. In this paper, we present a surveillance system implemented with a fleet of unmanned aerial vehicles (UAVs). A surveillance system implemented with a fleet of UAVs is easy to deploy and maintain. A UAV fleet requires little time to deploy and set up, and removing the surveillance is also virtually instant. The system we propose deploys UAVs to the target area for installation and perform surveillance operations. The camera mounted UAVs act as surveillance probes, the server provides overall control of the surveillance system, and the fleet platform provides fleet-wise control of the UAVs. In the proposed system, the UAVs establish a network and enable multi-hop communication, which allows the system to widen its coverage area. The operator of the system can control the fleet of UAVs via the fleet platform and receive surveillance information gathered by the UAVs. The proposed system is described in detail along with the algorithm for effective placement of the UAVs. The prototype of the system is presented, and the experiment carried out shows that the system can successfully perform surveillance over an area set by the system.


Solvation of hydrophobes in water and simple liquids.
The solvation of nonpolar molecules in water and that in simple liquids are compared and contrasted. First, solvation thermodynamics is reviewed in a way that focuses on how the enthalpy and entropy of solvation depend on the choice of microscopic volume change v in the solvation process--including special choices v being zero (fixed-volume condition) and v being the partial molecular volume of a solute molecule (fixed-pressure condition)--and how the solvation quantities are related with temperature derivatives of the solvation free energy. Second, the solvation free energy and the solvation enthalpy of a Lennard-Jones (LJ) atom in model water are calculated in the parameter space representing the solute size and the strength of the solute-solvent interaction, and the results are compared with those for an LJ atom in the LJ solvent. The solvation diagrams showing domains of different types of solvation in the parameter space are obtained both for the constant-volume condition and for the constant-pressure condition. Similarities between water and the simple liquid are found when the constant-volume solvation is considered while a significant difference manifests itself in the fixed-pressure solvation. The domain of solvation of hydrophobic character in the parameter space is large in the constant-volume solvation both for water and for the simple liquid. When switched to the constant-pressure condition accompanying a microscopic volume change, the hydrophobic domain remains large in water but it becomes significantly small in the simple liquid. The contrasting results are due to the smallness of the thermal pressure coefficient of water at low temperatures.


Dynamics of gas phase Ne(*) + NH3 and Ne(*) + ND3 Penning ionisation at low temperatures.
Two isotopic chemical reactions, Ne(*) + NH3, and Ne(*) + ND3, have been studied at low collision energies by means of a merged beams technique. Partial cross sections have been recorded for the two reactive channels, namely, Ne(*) + NH3 → Ne + NH3(+) + e(-), and Ne(*) + NH3 → Ne + NH2(+) + H + e(-), by detecting the NH3(+) and NH2(+) product ions, respectively. The cross sections for both reactions were found to increase with decreasing collision energy, Ecoll, in the range 8 μeV < Ecoll < 20 meV. The measured rate constant exhibits a curvature in a log(k)-log(Ecoll) plot from which it is concluded that the Langevin capture model does not properly describe the Ne(*) + NH3 reaction in the entire range of collision energies covered here. Calculations based on multichannel quantum defect theory were performed to reproduce and interpret the experimental results. Good agreement was obtained by including long range van der Waals interactions combined with a 6-12 Lennard-Jones potential. The branching ratio between the two reactive channels, Γ = [NH2(+)]/[NH2(+)] + [NH3(+)], is relatively constant, Γ ≈ 0.3, in the entire collision energy range studied here. Possible reasons for this observation are discussed and rationalized in terms of relative time scales of the reactant approach and the molecular rotation. Isotopic differences between the Ne(*) + NH3 and Ne(*) + ND3 reactions are small, as suggested by nearly equal branching ratios and cross sections for the two reactions.


Starting where I am: a grounded theory exploration of mindfulness as a facilitator of transition in living with a long-term condition.
To explore how practising mindfulness affects people's experiences of living with a long-term condition. Increasing evidence suggest that mindfulness meditation-based interventions benefit people with long-term conditions, particularly in terms of psychological well-being. Most evidence, however, relates to short-term outcomes and limited information exists about how people use mindfulness in the longer term and how this affects their experience of living with their condition. A qualitative study using constructivist-informed grounded theory. Using interviews, diaries and focus groups, data were collected between 2011 - 2012 from participants and/or trainers of Breathworks' mindfulness intervention. Phased recruitment enabled theoretical sampling, with data analysed concurrently using Charmaz's two-stage coding strategy. The final sample comprised 41 adults with diverse physical and/or mental health conditions. Participants reported predominantly positive experiences, almost all identifying significant changes in thinking and behaviour. A core process of 'Starting where I am' was formulated, highlighting how people became more aware and accepting of their condition and thus able to self-care more effectively. The process was encapsulated in five themes: Getting a new perspective; Feeling equipped to cope; Doing life differently; Seeing a change; and Finding mindfulness difficult. Strong resonances were identified between participants' experiences and the process of transition through which people come to terms with challenging life events. Mindfulness can be conceptualized as a facilitator of transition, enabling people to adapt to living with a long-term condition. Transition is associated with improved, self-directed self-management, which is significant to both people with long-term conditions and healthcare providers.


On Writing and Reading Artistic Computational Ecosystems.
We study the use of the generative systems known as computational ecosystems to convey artistic and narrative aims. These are virtual worlds running on computers, composed of agents that trade units of energy and emulate cycles of life and behaviors adapted from biological life forms. In this article we propose a conceptual framework in order to understand these systems, which are involved in processes of authorship and interpretation that this investigation analyzes in order to identify critical instruments for artistic exploration. We formulate a model of narrative that we call system stories (after Mitchell Whitelaw), characterized by the dynamic network of material and conceptual processes that define these artefacts. They account for narrative constellations with multiple agencies from which meaning and messages emerge. Finally, we present three case studies to explore the potential of this model within an artistic and generative domain, arguing that this understanding expands and enriches the palette of the language of these systems.


In vivo antitumoral effect of Plantago major L. extract on Balb/C mouse with Ehrlich ascites tumor.
The aim of this study is to investigate the antitumor activity of Plantago major L. extract in Ehrlich ascites tumor (EAT) bearing Balb/C mice in vivo. Thirty male Balb/C mice were divided into 5 groups: 3 treatment groups and 2 control groups (6 per group). Treatment groups and the negative control group were injected with EAT (1 x 10(6) cells) intraperitoneally to develop ascites tumor. P. major L. extract (1%, 2% and 3% concentration extracts, 0.1 ml/day/mouse) were given p.o. for 10 alternate days. The control group was treated with 0.9% NaCl solution (0.1 ml/day/mouse). The changes of body weight in animals were recorded. On the 11th day, all of the mice were sacrified and their tissues were stained with haematoxylen and eosin for pathological studies. Body weights of in 3 treatment groups and the negative control group were elevated because of tumor burden. The maximal weight gain was recorded in the negative control group and the minimal weight gain was recorded in Group I. Pathological studies showed that P. major L. extract (especially 1% concentration) has inhibitive effect on EAT. P. major has an inhibitory effect on EAT in a dose dependent manner.


Active targeting of cancer cells using folic acid-conjugated platinum nanoparticles.
Interaction of nanoparticles with human cells is an interesting topic for understanding toxicity and developing potential drug candidates. Water soluble platinum nanoparticles were synthesized via reduction of hexachloroplatinic acid using sodium borohydride in the presence of capping agents. The bioactivity of folic acid and poly(vinyl pyrrolidone) capped platinum nanoparticles (Pt-nps) has been investigated using commercially available cell lines. In the cell viability experiments, PVP-capped nanoparticles were found to be less toxic (>80% viability), whereas, folic acid-capped platinum nanoparticles showed a reduced viability down to 24% after 72 h of exposure at a concentration of 100 μg ml(-1) for MCF7 breast cancer cells. Such toxicity, combined with the possibility to incorporate functional organic molecules as capping agents, can be used for developing new drug candidates.


Linked Sensitivity Analysis, Calibration, and Uncertainty Analysis Using a System Dynamics Model for Stroke Comparative Effectiveness Research.
As health services researchers and decision makers tackle more difficult problems using simulation models, the number of parameters and the corresponding degree of uncertainty have increased. This often results in reduced confidence in such complex models to guide decision making. To demonstrate a systematic approach of linked sensitivity analysis, calibration, and uncertainty analysis to improve confidence in complex models. Four techniques were integrated and applied to a System Dynamics stroke model of US veterans, which was developed to inform systemwide intervention and research planning: Morris method (sensitivity analysis), multistart Powell hill-climbing algorithm and generalized likelihood uncertainty estimation (calibration), and Monte Carlo simulation (uncertainty analysis). Of 60 uncertain parameters, sensitivity analysis identified 29 needing calibration, 7 that did not need calibration but significantly influenced key stroke outcomes, and 24 not influential to calibration or stroke outcomes that were fixed at their best guess values. One thousand alternative well-calibrated baselines were obtained to reflect calibration uncertainty and brought into uncertainty analysis. The initial stroke incidence rate among veterans was identified as the most influential uncertain parameter, for which further data should be collected. That said, accounting for current uncertainty, the analysis of 15 distinct prevention and treatment interventions provided a robust conclusion that hypertension control for all veterans would yield the largest gain in quality-adjusted life years. For complex health care models, a mixed approach was applied to examine the uncertainty surrounding key stroke outcomes and the robustness of conclusions. We demonstrate that this rigorous approach can be practical and advocate for such analysis to promote understanding of the limits of certainty in applying models to current decisions and to guide future data collection.


Androgen receptor in Sertoli cells is not required for testosterone-induced suppression of spermatogenesis, but contributes to Sertoli cell organization in Utp14b jsd mice.
Testosterone acting through the androgen receptor (AR) maintains the arrest of spermatogonial differentiation in juvenile spermatogonial depletion (jsd mutation in the Utp14b gene) mutant adult male mice. It is not known which of the somatic cell types expressing AR mediates this inhibition. To determine whether Sertoli cells are responsible, we selectively eliminated AR in Sertoli cells in jsd mice containing a floxed-Ar gene and an anti-Müllerian hormone-Cre transgene. In these Sertoli AR-knockout (SCARKO)-jsd mice, spermatogonial differentiation did not recover. However, the normal organization of Sertoli cell nuclei was drastically disrupted in SCARKO-jsd mice compared with SCARKO or jsd mice. In addition, the extent of ectoplasmic specializations was reduced; tight junctions were not found; vinculin, an anchoring protein found in ectoplasmic specializations, became uniformly distributed in the cytoplasm; and the adult Sertoli cells showed excess heterochromatin subjacent to their nuclear envelope. Despite the abnormalities in Sertoli cells in SCARKO-jsd mice, global suppression of testosterone action and levels was still effective in restoring the differentiated germ cells, and this was accompanied by an improved arrangement of Sertoli cell nuclei. We conclude that Sertoli cells are not targets for the testosterone-mediated inhibition of spermatogonial differentiation in jsd mice, and that both AR in Sertoli cells and the presence of differentiated germ cells contribute to maintaining the organization of Sertoli cells within the seminiferous tubules.


Polyamine-Cladded 18-Ring-Channel Gallium Phosphites with High-Capacity Hydrogen Adsorption and Carbon Dioxide Capture.
In this study, we synthesized a unique inorganic framework bearing the largest 18-membered-ring channels in gallium phosphites, denoted as NTHU-15, which displayed genuine porosity even though large organic templates were present. The idea of using the "template-cladded" strategy succeeded in releasing channel space of up to ∼24% of the unit-cell volume as highly positive-charged organic templates were manipulated to cling to the anionic inorganic walls. NTHU-15 showed both high H2 uptake of 3.8 mmol/g at 77 K and effective CO2 adsorption of ∼2.4 mmol/g at 298 K, which surpassed those of all other known extra-large-channel inorganic framework structures. NTHU-15 has been successful at overcoming the long-standing problem of organic-templated extra-large-channel structures as opposed to a "true open" framework. Moreover, it realized practical gas sorption functionality in innovated metal phosphites. In view of its high stability in hot water and high selectivity for CO2 adsorption, NTHU-15 may be the first novel inorganic framework material to be applied to the field of flue gas cleaning.


Conceptualizing a model: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force--2.
The appropriate development of a model begins with understanding the problem that is being represented. The aim of this article was to provide a series of consensus-based best practices regarding the process of model conceptualization. For the purpose of this series of articles, we consider the development of models whose purpose is to inform medical decisions and health-related resource allocation questions. We specifically divide the conceptualization process into two distinct components: the conceptualization of the problem, which converts knowledge of the health care process or decision into a representation of the problem, followed by the conceptualization of the model itself, which matches the attributes and characteristics of a particular modeling type with the needs of the problem being represented. Recommendations are made regarding the structure of the modeling team, agreement on the statement of the problem, the structure, perspective, and target population of the model, and the interventions and outcomes represented. Best practices relating to the specific characteristics of model structure and which characteristics of the problem might be most easily represented in a specific modeling method are presented. Each section contains a number of recommendations that were iterated among the authors, as well as among the wider modeling taskforce, jointly set up by the International Society for Pharmacoeconomics and Outcomes Research and the Society for Medical Decision Making.


Secretion of IL-4 from human basophils. The relationship between IL-4 mRNA and protein in resting and stimulated basophils.
Purified human basophils have been examined for secretion of IL-4 protein and expression of IL-4 mRNA after stimulation with several secretagogues. In general, these studies used a 15-min preincubation with IL-3, before challenge with secretagogues. Under these conditions, IL-4 release averaged 30 pg/10(6) basophils (range 4-70) after challenge with anti-IgE Ab. FMLP and C5a led to somewhat lower levels of secretion. A direct comparison of basophils at 88 to 99% purity with basophils from the same preparations, but at lower purities, showed that the amount of IL-4 secretion was proportional to the purity of the basophils. The presence of mRNA for IL-4 (as determined by reverse transcriptase-PCR, competitive reverse transcriptase-PCR, or Northern blots) was also strictly related to the purity of the basophils. IL-4 mRNA was also found to be constitutively present and was increased after stimulation. The concentration of polyclonal anti-IgE Ab required for optimal IL-4 release was somewhat less than that required for optimal histamine release. IL-4 secretion was slower (t1/2 of 1.5 h) than histamine release and was inhibited by cycloheximide. In a final series of studies, we found that IL-3 was not required for IL-4 secretion; a short 15-min preincubation with IL-3 resulted in the same or slightly less IL-4 release than no treatment with IL-3. In contrast, an 18-h pretreatment with IL-3 resulted in a nearly tenfold increase in IL-4 secretion. We conclude that human basophils secrete IL-4 in response to several secretagogues and that IL-3 priming is not necessary to observe IL-4 secretion.


Higher overcommitment to work is associated with lower norepinephrine secretion before and after acute psychosocial stress in men.
Overcommitment (OC) is a pattern of excessive striving. In reaction to work stress, OC has been associated with higher sympathetic nervous system activation and cortisol release, but data on neuroendocrine reactivity to standardized stressors are scarce. We investigated whether OC is associated with differential levels of the stress hormones norepinephrine and cortisol in response to acute psychosocial stress. Fifty-eight medication-free non-smoking men aged between 20 and 65 years (mean+/-S.E.M.: 36.3+/-1.8) underwent an acute standardized psychosocial stress task combining public speaking and mental arithmetic in front of an audience. We assessed OC as well as a variety of psychological control variables including vital exhaustion, perfectionism, chronic stress, and cognitive stress appraisal. Moreover, we measured plasma norepinephrine as well as salivary cortisol before and after stress and several times up to 60 min thereafter. Higher OC was associated with lower baseline norepinephrine levels (r = -0.37, p < 0.01). General linear models controlling for age, BMI, and mean arterial blood pressure revealed that higher overcommitment was associated with lower norepinephrine and cortisol levels before and after stress (p's < 0.02) as well as with lower norepinephrine stress reactivity (p = 0.02). Additional controlling for the potential psychological confounders vital exhaustion, perfectionism, chronic stress, and depression confirmed lower norepinephrine levels before and after stress (p < 0.01) as well lower norepinephrine stress reactivity (p = 0.02) with increasing OC. Higher OC independently explained 13% of the total norepinephrine stress response (beta = -0.46, p < 0.01, R(2) change = 0.13). Our findings suggest blunted increases in norepinephrine following stress with increasing OC potentially mirroring blunted stress reactivity of the sympathetic nervous system.


Modal analysis of enhanced absorption in silicon nanowire arrays.
We analyze the absorption of solar radiation by silicon nanowire arrays, which are being considered for photovoltaic applications. These structures have been shown to have enhanced absorption compared with thin films, however the mechanism responsible for this is not understood. Using a new, semi-analytic model, we show that the enhanced absorption can be attributed to a few modes of the array, which couple well to incident light, overlap well with the nanowires, and exhibit strong Fabry-Pérot resonances. For some wavelengths the absorption is further enhanced by slow light effects. We study the evolution of these modes with wavelength to explain the various features of the absorption spectra, focusing first on a dilute array at normal incidence, before generalizing to a dense array and off-normal angles of incidence. The understanding developed will allow for optimization of simple SiNW arrays, as well as the development of more advanced designs.


Magnetically shaped cell aggregates: from granular to contractile materials.
In recent decades, significant advances have been made in the description and modelling of tissue morphogenesis. By contrast, the initial steps leading to the formation of a tissue structure, through cell-cell adhesion, have so far been described only for small numbers of interacting cells. Here, through the use of remote magnetic forces, we succeeded at creating cell aggregates of half million cells, instantaneously and for several cell types, not only those known to form spheroids. This magnetic compaction gives access to the cell elasticity, found in the range of 800 Pa. The magnetic force can be removed at any time, allowing the cell mass to evolve spontaneously thereafter. The dynamics of contraction of these cell aggregates just after their formation (or, in contrast, their spreading for non-interacting monocyte cells) provides direct information on cell-cell interactions and allows retrieving the adhesion energy, in between 0.05 and 2 mJ m(-2), depending on the cell type tested, and in the case of cohesive aggregates. Thus, we show, by probing a large number of cell types, that cell aggregates behave like complex materials, undergoing a transition from a wet granular to contractile network, and that this transition is controlled by cell-cell interactions.


Using flow relaxography to elucidate flow relaxivity.
We have investigated the theoretical and experimental linear dependence of the reciprocal of the apparent longitudinal relaxation time [(T*1)-1] of the NMR signal from spins in a flowing fluid on the volume flow rate, Fv, the so-called inflow effect. We refer to the coefficient of this dependence as the longitudinal flow relaxivity, r1F. A very simple model predicts that, under a range of conditions pertinent to modern flow studies and perfusion imaging experiments, r1F is controlled by the volume of the fluid in which the magnetization is perturbed by pulsed RF inversion or saturation, not the detection volume, and that it can be approximated as the reciprocal of half of the inversion volume. Phantom sample experiments, using a new, quantitative approach that we call flow relaxography, confirm the general predictions of this simple model. There are two intriguing implications of these findings for general NMR flow studies as well as for medical applications. It should be possible to vary the value of r1F by simply (noninvasively) adjusting the inversion slice thickness, and thus measure the value of (blood 1H2O, for example) Fv in a vessel without changing Fv, from the resultant varying T*1 values. Also, it should be possible to extrapolate to the intrinsic T1 value of the fluid signal (as if it were stationary), without altering or stopping the flow. Again, these are quite successful in phantom sample studies. Imaging versions of the flow relaxographic experiments are also possible. The twin goals of flow studies in medical MRI are the quantitative discrimination of the signals from flowing and nonflowing spins, and the accurate measurement of the flow rate of the former.


Localization and characterization of 35S-t-butylbicyclophosphorothionate binding in rat brain: an autoradiographic study.
35S-t-butylbicyclophosphorothionate (TBPS) binding to slide-mounted rat brain sections was characterized for subsequent autoradiographic analysis. Cortical brain mash slices, preincubated with EDTA to remove endogenous GABA, were used for biochemical characterization. Steady state for 35S-TBPS binding was reached by 3 hr of incubation at 22 degrees C. The association rate constant (K1) and dissociation rate constant (K2) were 0.377 min-1 microM-1 and 0.011 min-1, respectively. Dissociation was monophasic and slow (t1/2 = 80 min). The kinetically derived KD was 29.4 nM. Scatchard analysis indicated a single population of binding sites with a KD of 21.0 +/- 2.2 nM and a Bmax of 1.59 +/- 0.13 pmol/mg protein. Both picrotoxin and muscimol inhibited 35S-TBPS binding completely with IC50s of 251 +/- 13 nM and 203 +/- 41 nM and nHs of 0.98 and 1.4, respectively. The distribution of 35S-TBPS binding sites in the rat brain resembles that of other ligands that bind to GABAA receptor complex with some regionally specific differences. Regions with a high degree of 35S-TBPS binding included the inferior colliculus, medial septal nucleus, central and paracentral nuclei of the thalamus, olfactory tubercle, zona incerta, dentate gyrus, and substantia nigra. 35S-TBPS preferentially bound to the molecular vs granular layer of the cerebellum. Omission of the preincubation markedly but variably decreased 35S-TBPS binding. The greatest regional decreases occurred in areas with a high degree of GABA synthesis. In addition, 35S-TBPS binding was inhibited to different degrees in the cell layers of the cerebellum. The addition of 1 microM GABA to the incubation medium of preincubated slices also produced variable decreases in 35S-TBPS binding to cerebellar layers. These findings support previous studies that demonstrate GABAA receptor heterogeneity. Our study confirms the suitability of 35S-TBPS for use as a ligand in autoradiography and demonstrates that the distribution of 35S-TBPS binding sites is significantly influenced by the preincubation-incubation conditions used.


Descriptive and longitudinal observations on the relationship of borderline personality disorder and bipolar disorder.
The purpose of this study was to test whether borderline personality disorder is a variant of bipolar disorder by examining the rates of co-occurrence in both disorders, the effects of co-occurrence on a longitudinal course, and whether the presence of either disorder confers the risk for new onsets of the other. A prospective repeated-measures design with reliable independent diagnostic measures and 4 years of follow-up was used to assess 196 patients with borderline personality disorder and 433 patients with other personality disorders. Patients with borderline personality disorder had a significantly higher co-occurrence of bipolar disorder (19.4%) than did patients with other personality disorders. However, this co-occurrence did not appear to affect the subsequent course of borderline personality disorder. Although only 8.2% of the borderline personality disorder patients developed new onsets of bipolar disorder, this rate was higher than in patients with other personality disorders. Patients with other personality disorders with co-occurring bipolar disorder generally had more new onsets of borderline personality disorder (25%) than did patients with other personality disorders without co-occurring bipolar disorder (10%). A modest association between borderline personality disorder and bipolar disorder is reported.


The Different Dynamic Changes of Nerve Growth Factor in the Dorsal Horn and Dorsal Root Ganglion Leads to Hyperalgesia and Allodynia in Diabetic Neuropathic Pain.
Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes and more than half of the patients with DPN have self-reported symptoms referring to painful diabetic neuropathy (PDN). Nerve growth factor (NGF) is a key factor for the nervous system, but the role of it in the neuropathic pain of diabetic patients is unclear. This study aimed to investigate the relationship between the dynamic expression of NGF in dorsal horn and dorsal root ganglion (DRG) of diabetic rats and hyperalgesia and allodynia in diabetic neuropathic pain. It also aimed to explore the effects of exogenous mouse NGF (mNGF) on NGF expression in dorsal horn, DRG, and mechanical pain threshold. Animal research study. Experimental research laboratory. The model of diabetes was established by a single intraperitoneal injection of streptozocin (STZ 55 mg/kg). Firstly, the rats were randomly divided into 2 groups: control group (n = 10) and diabetes group (n = 40). The diabetes group contained 4 subgroups: diabetes week 1 group (DM1, n = 10), diabetes week 2 group (DM2, n = 10), diabetes week 4 group (DM4, n = 10), and diabetes week 8 group (DM8, n = 10). Then, the other rats were randomly divided into 2 groups: control group (n = 10) and treatment group (n = 30). The treatment group contained 3 subgroups: saline group (n = 10), low dose mNGF group (mNGF1, n = 10), and high dose mNGF group (mNGF2, n = 10). Mechanical pain threshold was assessed using Von Frey hairs, before the establishment of the diabetes model and 1, 2, 4, and 8 weeks after the establishment. The NGF expression in dorsal horn and DRG was measured by western blot. The mechanical pain threshold decreased one week after the establishment of the diabetes model, which continued for 8 weeks. The NGF expression in the dorsal horn was reduced 2 weeks after diabetes induction and the decreased NGF expression continued for 4 weeks. However, the NGF expression in DRG was reduced one week after diabetes induction and remained at a low level for 8 weeks. Hyperalgesia occurred when the NGF expression in the DRG decreased and further reduction in the NGF expression in the dorsal horn caused concomitant allodynia. The mechanical pain threshold was significantly elevated 2 weeks after mNGF treatment. The course of diabetes should be much longer and there is not a precise analysis of the quantitative relation between the NGF expression in the dorsal horn/DRG and hyperalgesia/allodynia. In diabetic neuropathic pain, the dynamic changes of the NGF expression in dorsal horn and DRG is involved in the development of hyperalgesia and allodynia respectively. Exogenous mNGF may relieve diabetic neuropathic pain by increasing the NGF expression in dorsal horn and DRG.


The healer or the druggist: effects of two health care policies in Taiwan on elderly patients' choice between physician and pharmacist services.
When both physicians and pharmacists in Taiwan prescribed and dispensed drugs, many elderly people considered the two types of health care providers more or less synonymous (i.e., close substitutes). Two policies mandated in the 1990 s changed this perception: National Health Insurance (NHI), which provides insurance coverage to all citizens, and a separation policy (SP) that forbid physicians from dispensing and pharmacists from prescribing drugs. The author finds that by providing an economic incentive to the previously uninsured elderly, NHI raised the probability that they would visit physicians, relative to their continuously insured counterparts. In particular, some previously uninsured elderly who once only visited pharmacists were more likely to also visit physicians after NHI was implemented. Following this, the SP made it more likely that all elderly patients would only visit physicians and buy drugs from on-site pharmacists hired by physicians--a result different than its policy goal.


[Trends in frequency of consumption of beans assessed by means of a telephone survey in Brazilian state capitals between 2006 and 2009].
The scope of this paper was to analyze the trends of frequency of consumption of beans between the years 2006 and 2009 in the Brazilian capitals. This is a historical series using the Vigitel database for all Brazilian state capitals. Consumption of beans was described in terms of relative frequency and the trend was assessed using Poisson regression. Between 65.79% (2009) and 71.85% (2006) of participants reported consuming beans five or more days per week. The capitals Goiania, Belo Horizonte, Palmas, Brasilia and Cuiaba were in the highest frequency range of consumption throughout the study period. Individuals with a BMI in the appropriate and low weight category had the highest frequencies of consumption in comparison with the overweight and the obese. A significant reduction trend in the consumption of beans per year of the research, except for the 45 to 54-year-old range, was detected. The conclusion drawn was that there has been a significant reduction in the consumption of beans in the Brazilian population and the adoption of monitoring and incentive policies is necessary due to the benefits of the legume.


On the promotion of human flourishing.
Many empirical studies throughout the social and biomedical sciences focus only on very narrow outcomes such as income, or a single specific disease state, or a measure of positive affect. Human well-being or flourishing, however, consists in a much broader range of states and outcomes, certainly including mental and physical health, but also encompassing happiness and life satisfaction, meaning and purpose, character and virtue, and close social relationships. The empirical literature from longitudinal, experimental, and quasiexperimental studies is reviewed in attempt to identify major determinants of human flourishing, broadly conceived. Measures of human flourishing are proposed. Discussion is given to the implications of a broader conception of human flourishing, and of the research reviewed, for policy, and for future research in the biomedical and social sciences.


Genetic and biochemical analysis of yeast and human cap trimethylguanosine synthase: functional overlap of 2,2,7-trimethylguanosine caps, small nuclear ribonucleoprotein components, pre-mRNA splicing factors, and RNA decay pathways.
Trimethylguanosine synthase (Tgs1) is the enzyme that converts standard m(7)G caps to the 2,2,7-trimethylguanosine (TMG) caps characteristic of spliceosomal small nuclear RNAs. Fungi and mammalian somatic cells are able to grow in the absence of Tgs1 and TMG caps, suggesting that an essential function of the TMG cap might be obscured by functional redundancy. A systematic screen in budding yeast identified nonessential genes that, when deleted, caused synthetic growth defects with tgs1Delta. The Tgs1 interaction network embraced proteins implicated in small nuclear ribonucleoprotein function and spliceosome assembly, including Mud2, Nam8, Brr1, Lea1, Ist3, Isy1, Cwc21, and Bud13. Complementation of the synthetic lethality of mud2Delta tgs1Delta and nam8Delta tgs1Delta strains by wild-type TGS1, but not by catalytically defective mutants, indicated that the TMG cap is essential for mitotic growth when redundant splicing factors are missing. Our genetic analysis also highlighted synthetic interactions of Tgs1 with proteins implicated in RNA end processing and decay (Pat1, Lsm1, and Trf4) and regulation of polymerase II transcription (Rpn4, Spt3, Srb2, Soh1, Swr1, and Htz1). We find that the C-terminal domain of human Tgs1 can function in lieu of the yeast protein in vivo. We present a biochemical characterization of the human Tgs1 guanine-N2 methyltransferase reaction and identify individual amino acids required for methyltransferase activity in vitro and in vivo.


Pro-BDNF Knockout Causes Abnormal Motor Behaviours and Early Death in Mice.
Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family, best characterized for its survival and differentiative effects in the central nervous system. Pro-BDNF, known as the precursor of BDNF, is believed to have opposite functions to mature BDNF (mBDNF). The opposing effects of Pro-BDNF and mBDNF have led researchers to propose a 'yin' (Pro-BDNF) and 'yang' (mBDNF) model of which, the specific mechanism of its opposing functions is unclear and requires further investigation. In order to elucidate pro-BDNF's explicit role, we established a pro-BDNF knockout (KO) mouse model. This BDNF pro-domain KO mouse model showed significant weight loss, impaired righting reflex, abnormal motor behaviours and short lifespan (less than 22 days), mimicking a Huntington's disease (HD)-like phenotype. ELISA results showed BDNF pro-domain KO not only blocked pro-BDNF, but also significantly affected the level of mBDNF. Abnormal morphologic changes were found in the dentate gyrus (DG) of the hippocampus in pro-BDNF KO mice, and western blot confirmed significant cell apoptosis in pro-BDNF KO mice brains. Furthermore, the expression of glutamic acid decarboxylase 65/67 (GAD65/67) was significantly reduced in pro-BDNF KO mice, indicating impaired inhibitory neurotransmission. Heterozygous (Het) mice showed impaired learning and memory capability and depressive-like behaviours, compared with wild type (WT) mice. Overall, these results support that pro-domain of BDNF is an indispensable part of the BDNF gene; without the proper formation of pro-BDNF, mBDNF cannot be produced successfully and function correctly on its own. Our study also supports the BDNF hypothesis in the pathogenesis of HD.


Effect of chrysin on methotrexate-induced testicular damage in rats.
This study was conducted on 28 male Wistar albino rats to determine the effects of chrysin on methotrexate-induced damage to testicular tissue. Rats were grouped into four groups of seven rats reach: Group 1 (n = 7) was the control group to which no drugs were administered; this group was only provided with food and water. Group 2 (n = 7) was administered 20 mg/kg of methotrexate once intraperitoneally. Group 3 (n = 7) was administered 50 mg/kg of chrysin for 7 days orally. Group 4 (n = 7) was administered 20 mg/kg of methotrexate once intraperitoneally, followed by oral administration of 50 mg/kg of chrysin for 7 days. At the end of the experiment, rats were anaesthetised, rat testes were removed, and spermatozoon was obtained from the cauda epididymis. It was determined that sperm count and motility, glutathione peroxidase, superoxide dismutase and catalase activities decreased in the methotrexate group, whereas malondialdehyde, tumour necrosis factor-α, interleukin-1β and nuclear kappa factor B expression levels increased. Furthermore, damage to tubulus seminiferus structures and affusion in germ cells was identified. In the methotrexate + chrysin administered group, sperm count improved, biochemical enzyme levels increased, and structural improvements were observed in testicular tubules. These findings demonstrated that chrysin plays a protective role in testicular damage in rats.


Calcineurin and CRTC2 mediate FSH and TGFβ1 upregulation of Cyp19a1 and Nr5a in ovary granulosa cells.
Estrogens are essential for female reproduction and overall well-being, and estrogens in the circulation are largely synthesized in ovarian granulosa cells. Using primary cultures of ovarian granulosa cells from gonadotropin-primed immature rats, we have recently discovered that pituitary FSH and ovarian cytokine transforming growth factor beta 1 (TGFβ1) induce calcineurin-mediated dephosphorylation-activation of cAMP-response element-binding protein (CREB)-regulated transcription coactivator (CRTC2) to modulate the expression of Star, Cyp11a1, and Hsd3b leading to increased production of progesterone. This study explored the role of calcineurin and CRTC2 in FSH and TGFβ1 regulation of Cyp19a1 expression in granulosa cells. Ovarian granulosa cells treated with FSH displayed increased aromatase protein at 24 h post-treatment, which subsided by 48 h, while TGFβ1 acting through its type 1 receptor augmented the action of FSH with a greater and longer effects. It is known that the ovary-specific Cyp19a1 PII-promoter contains crucial response elements for CREB and nuclear receptor NR5A subfamily liver receptor homolog 1 (LRH1/NR5A2) and steroidogenic factor 1 (SF1/NR5A1), and that the Nr5a2 promoter also has a potential CREB-binding site. Herein, we demonstrate that FSH+TGFβ1 increased LRH1 and SF1 protein levels, and their binding to the Cyp19a1 PII-promoter evidenced, determined by chromatin immunoprecipitation analysis. Moreover, pretreatment with calcineurin auto-inhibitory peptide (CNI) abolished the FSH+TGFβ1-upregulated but not FSH-upregulated aromatase activity at 48 h, and the corresponding mRNA changes in Cyp19a1, and Nr5a2 and Nr5a1 at 24 h. In addition, FSH and TGFβ1 increased CRTC2 binding to the Cyp19a1 PII-promoter and Nr5a2 promoter at 24 h, with CREB bound constitutively. In summary, the results of this study indicate that calcineurin and CRTC2 have important roles in mediating FSH and TGFβ1 collateral upregulation of Cyp19a1 expression together with its transcription regulators Nr5a2 and Nr5a1 in ovarian granulosa cells.


Predicting treatment time with the Lidcombe Program: replication and meta-analysis.
The benefits of treating stuttering close to onset have become obvious in recent years, and the Lidcombe Program has emerged as an effective and safe treatment method for children in their preschool years. The benefits of implementing the programme with young children, however, need to be weighed against the knowledge that many children recover from stuttering without treatment. In light of this, speech-language therapists need to know how long treatment is likely to take and whether treatment time can be predicted. In particular, they need to know if adopting a 'watchful waiting' approach--to see if natural recovery occurs--jeopardizes responsiveness to treatment. A recent Australian study of 250 preschool-age children found that stuttering rate was the only significant predictor of treatment time with the Lidcombe Program. In other words, children whose stuttering was more severe took longer to pass through the programme. There were other trends in the data but they did not reach significance. The present study, conducted independently in the UK, was designed to replicate the Australian study. Direct replication enabled pooling of the data from the two studies in a meta-analysis. The study included 66 children who began treatment before 6 years of age. They were treated with the Lidcombe Program at a specialist stuttering clinic in Norwich. Logistic regression analyses were conducted on the data. The data from both the British and Australian cohorts were pooled in a meta-analysis. Results indicated that Stage 1 of the Lidcombe Program was completed in a median of 11 clinic visits, which is in line with the findings of the Australian study. Stuttering rate at first clinic visit was again found to be a significant predictor of treatment time. The remaining data trends were similar to those in the Australian data. In the meta-analysis, stuttering rate was once more found to be a predictor of treatment time. Of particular interest, however, was that the increased power provided by the meta-analysis identified an additional predictor, namely onset-to-treatment interval. Contrary to what is known about the responsiveness of children to the Starkweather and Gottwald treatment, and contrary to what might be expected given what we know about natural recovery, children who had been stuttering for more than 12 months took less time to progress through the programme than children who had been stuttering for less than 12 months. These findings indicate that delaying intervention with the Lidcombe Program for 1 year after onset, within the preschool years, is unlikely to jeopardize responsiveness to treatment. The clinical implications of these findings are discussed.


Effect of grape seed proanthocyanidin extract on hard exudates in patients with non-proliferative diabetic retinopathy.
To evaluate the efficacy and safety of orally administered grape seed proanthocyanidin extract (GSPE) in patients with non-proliferative diabetic retinopathy (NPDR). In this randomized (1:2:2), multicentre, double-blind trial, patients (n = 124; age: 40-78 years) were administered placebo, calcium dobesilate (CD; 750 mg/d), or GSPE (150 mg/d) orally for up to 12 months. All patients had retinal thickening with hard exudates (HEs) that met predefined criteria; the median best-corrected visual acuity was 0.8, as assessed using the Snellen visual acuity card. The main outcome measure was an improvement in HEs by at least 1 grade on a 10-grade severity scale. This was evaluated using fundus photography over 1 year. The rate of improvement in the HE severity was higher in the GSPE group than in the CD group. No statistically significant difference existed among the study groups in optical coherence tomography parameters, such as central subfield macular thickness and total macular volume (TMV). However, in the GSPE group, TMV after 9 months of treatment was significantly decreased compared with that at baseline. The GSPE group showed a significantly greater improvement in HE severity than did the placebo or CD group. Four cases in the GSPE group and 2 in the CD group were determined to have developed potential treatment-related adverse reactions, which were all gastrointestinal in nature. Oral GSPE therapy for 1 year improved HEs in patients with NPDR. The efficacy of GSPE for HEs was higher than that of oral CD in the study patients.


Attitudes to water fluoridation in South Africa 1998. Part I. Analysis by age, sex, population and province.
The successful implementation of water fluoridation (WF) depends upon support from the public. A survey was conducted in 1998 by the Human Sciences Research Council to assess attitudes of the South African population towards WF. A representative sample of 2,220 persons over the age of 18 years was interviewed. Questions relating to current knowledge, sources of information, the purpose of water fluoridation and its desirability as a public health measure were put to respondents. Only 25% of the population had heard or read of WF. The major sources of information were the electronic and printed media (40% and 27% respectively), while 2.5% heard about it from dentists. Just over a third of the sample (35.5%) identified the purpose of WF as protecting teeth from decay; 28% said it was to purify water and 28.5% were uncertain of, or did not know its purpose. Nearly two-thirds (61.9%) indicated that fluoride should be added to drinking water if it can reduce tooth decay, while 9% were not in favour and 29% were uncertain. The results suggest that most people do not know what WF is or does, though most were in agreement that it should be implemented to reduce tooth decay.


The Later Stone Age calvaria from Iwo Eleru, Nigeria: morphology and chronology.
In recent years the Later Stone Age has been redated to a much deeper time depth than previously thought. At the same time, human remains from this time period are scarce in Africa, and even rarer in West Africa. The Iwo Eleru burial is one of the few human skeletal remains associated with Later Stone Age artifacts in that region with a proposed Pleistocene date. We undertook a morphometric reanalysis of this cranium in order to better assess its affinities. We also conducted Uranium-series dating to re-evaluate its chronology. A 3-D geometric morphometric analysis of cranial landmarks and semilandmarks was conducted using a large comparative fossil and modern human sample. The measurements were collected in the form of three dimensional coordinates and processed using Generalized Procrustes Analysis. Principal components, canonical variates, Mahalanobis D(2) and Procrustes distance analyses were performed. The results were further visualized by comparing specimen and mean configurations. Results point to a morphological similarity with late archaic African specimens dating to the Late Pleistocene. A long bone cortical fragment was made available for U-series analysis in order to re-date the specimen. The results (∼11.7-16.3 ka) support a terminal Pleistocene chronology for the Iwo Eleru burial as was also suggested by the original radiocarbon dating results and by stratigraphic evidence. Our findings are in accordance with suggestions of deep population substructure in Africa and a complex evolutionary process for the origin of modern humans. They further highlight the dearth of hominin finds from West Africa, and underscore our real lack of knowledge of human evolution in that region.


Asystole immediately following intravenous fat emulsion for overdose.
Use of intravenous fat emulsion (IFE) for the treatment of poisoned patients in extremis is increasing. Little literature exists describing failures and complications of IFE. We describe two cardiac arrests temporally associated with IFE. A 50-year-old woman presented after ingesting 80 total tablets of metoprolol 25 mg and bupropion 150 mg. Bradycardia and hypotension were refractory to calcium salts, catecholamines, and high dose insulin (HDI). With a pulse of 40/min and mean arterial pressure (MAP) of 30 mmHg, 100 mL of 20 % IFE was given; within 30 s, brady-asystolic arrest occurred. Pulses returned after 3 min of CPR. The patient died on hospital day 4 of multisystem organ failure (MSOF). A 53-year-old man presented after ingesting of 3,600 mg of diltiazem and 1,200 mg of propranolol. Bradycardia and hypotension were refractory to calcium salts, catecholamines, HDI, bicarbonate, and atropine. With a pulse of 30/min and a MAP of 40 mmHg, 150 mL of 20 % IFE was given; within 1 min, a brady-asystolic arrest occurred. Pulses returned after 6 min of CPR. The patient died on hospital day 7 of MSOF. Reported cases of IFE failures or potential complications are sparse. This report adds only case experience, not clarity. We report two cardiac arrests that were temporally associated with IFE.


Molecular mechanisms of ribosomal protein gene coregulation.
The 137 ribosomal protein genes (RPGs) of Saccharomyces provide a model for gene coregulation. We examined the positional and functional organization of their regulators (Rap1 [repressor activator protein 1], Fhl1, Ifh1, Sfp1, and Hmo1), the transcription machinery (TFIIB, TFIID, and RNA polymerase II), and chromatin at near-base-pair resolution using ChIP-exo, as RPGs are coordinately reprogrammed. Where Hmo1 is enriched, Fhl1, Ifh1, Sfp1, and Hmo1 cross-linked broadly to promoter DNA in an RPG-specific manner and demarcated by general minor groove widening. Importantly, Hmo1 extended 20-50 base pairs (bp) downstream from Fhl1. Upon RPG repression, Fhl1 remained in place. Hmo1 dissociated, which was coupled to an upstream shift of the +1 nucleosome, as reflected by the Hmo1 extension and core promoter region. Fhl1 and Hmo1 may create two regulatable and positionally distinct barriers, against which chromatin remodelers position the +1 nucleosome into either an activating or a repressive state. Consistent with in vitro studies, we found that specific TFIID subunits, in addition to cross-linking at the core promoter, made precise cross-links at Rap1 sites, which we interpret to reflect native Rap1-TFIID interactions. Our findings suggest how sequence-specific DNA binding regulates nucleosome positioning and transcription complex assembly >300 bp away and how coregulation coevolved with coding sequences.


The relationship between the coherent size, binding energy and dissociation dynamics of charge transfer excitons at organic interfaces.
At organic semiconductor interfaces, an electron and a hole can be bound Coulombically to form an interfacial charge transfer (CT) exciton. It is still under debate how a CT exciton can overcome its strong binding and dissociate into free carriers. Experimentally, capturing the evolution of the CT exciton on time (fs-ps) and length scales (nm) in which the dissociation process occurs is challenging. To overcome this challenge, time-resolved two photon photoemission spectroscopy is used to measure the binding energies and electronic coherent sizes of a series of CT states at organic interfaces, and capture the temporal dynamics of these CT excitons after their excitation. Using zinc phthalocyanine (ZnPc)/fullerene (C60) interface as a model system, it is shown that the interfacial CT process first populates a hot CT state with a coherent size of ~4 nm. Hot and delocalized CT excitons subsequently relax into CT excitons with lower energies and smaller coherent sizes. To correlate the CT exciton properties with the dissociation efficiency, we develop a method that exploits graphene field effect transistors to probe the rate and yield of free carrier generation at the interface. Our results show that exciton dissociation can be more efficient if one can extract electrons from the hot and delocalized CT state. We propose a cascade structure that would serve this purpose.


Treatment compliance and effectiveness of a cognitive behavioural intervention for low back pain: a complier average causal effect approach to the BeST data set.
Group cognitive behavioural intervention (CBI) is effective in reducing low-back pain and disability in comparison to advice in primary care. The aim of this analysis was to investigate the impact of compliance on estimates of treatment effect and to identify factors associated with compliance. In this multicentre trial, 701 adults with troublesome sub-acute or chronic low-back pain were recruited from 56 general practices. Participants were randomised to advice (control n = 233) or advice plus CBI (n = 468). Compliance was specified a priori as attending a minimum of three group sessions and the individual assessment. We estimated the complier average causal effect (CACE) of treatment. Comparison of the CACE estimate of the mean treatment difference to the intention-to-treat (ITT) estimate at 12 months showed a greater benefit of CBI amongst participants compliant with treatment on the Roland Morris Questionnaire (CACE: 1.6 points, 95% CI 0.51 to 2.74; ITT: 1.3 points, 95% CI 0.55 to 2.07), the Modified Von Korff disability score (CACE: 12.1 points, 95% CI 6.07 to 18.17; ITT: 8.6 points, 95% CI 4.58 to 12.64) and the Modified von Korff pain score (CACE: 10.4 points, 95% CI 4.64 to 16.10; ITT: 7.0 points, 95% CI 3.26 to 10.74). People who were non-compliant were younger and had higher pain scores at randomisation. Treatment compliance is important in the effectiveness of group CBI. Younger people and those with more pain are at greater risk of non-compliance. Current Controlled Trials ISRCTN54717854.


Concern about HIV and AIDS among older people in the slums of Nairobi, Kenya.
The article explores the way that social networks and personal experiences affect perceived HIV-related concerns among people aged 50 years or older living in a low resource neighborhood with high HIV prevalence in Nairobi, Kenya. Multiple logistic regression is used to model the association between the reporting of an HIV-related concern and individual-level characteristics, personal experiences, and social interaction. The main concerns regarding HIV reported by older people in the study included caring for orphaned children (65%), caring for people with AIDS (48%), and losing material and social support from adult children (36%). Interestingly, 38% of respondents voiced concerns about HIV infection among older people. Respondents who had been individually affected by HIV and AIDS, who were part of a wide social network, or who participated in community activities were frequently more likely to report a concern. The findings highlight the significance of the role of social interaction and social networks in the diffusion of information and knowledge. These findings have implications for HIV and AIDS policy and programs, highlighting the potential for social networks and community-level interventions to educate and increase awareness about HIV and AIDS among older people. Community leaders can make good peer educators and communication agents for HIV/AIDS campaigns. Additionally, the recognized high level of personal vulnerability to HIV infection among older people suggests the need for targeted sexual behavior change programs among this often neglected group.


Lysophosphatidic acid stimulates neurotransmitter-like conductance changes that precede GABA and L-glutamate in early, presumptive cortical neuroblasts.
During neurogenesis in the embryonic cerebral cortex, the classical neurotransmitters GABA and L-glutamate stimulate ionic conductance changes in ventricular zone (VZ) neuroblasts. Lysophosphatidic acid (LPA) is a bioactive phospholipid producing myriad effects on cells including alterations in membrane conductances (for review, see Moolenaar et al., 1995). Developmental expression patterns of its first cloned receptor gene, lpA1/vzg-1 (Hecht et al., 1996; Fukushima et al., 1998) in the VZ suggested that functional LPA receptors were synthesized at these early times, and thus, LPA could be an earlier stimulus to VZ cells than the neurotransmitters GABA and L-glutamate. To address this possibility, primary cultures of electrically coupled, presumptive cortical neuroblast clusters were identified by age, morphology, electrophysiological profile, BrdU incorporation, and nestin immunostaining. Single cells from cortical neuroblast cell lines were also examined. Whole-cell variation of the patch-clamp technique was used to record from nestin-immunoreactive cells after stimulation by local administration of ligands. After initial plating at embryonic day 11 (E11), cells responded only to LPA but not to GABA or L-glutamate. Continued growth in culture for up to 12 hr produced more LPA-responsive cells, but also a growing population of GABA- or L-glutamate-responsive cells. Cultures from E12 embryos showed LPA as well as GABA and L-glutamate responses, with LPA-responsive cells still representing a majority. Overall, >50% of cells responded to LPA with depolarization mediated by either chloride or nonselective cation conductances. These data implicate LPA as the earliest reported extracellular stimulus of ionic conductance changes for cortical neuroblasts and provide evidence for LPA as a novel, physiological component in CNS development.


Consequences of range contractions and range shifts on molecular diversity.
Due to past and current climatic changes, range contractions and range shifts are essential stages in the history of a species. However, unlike range expansions, the molecular consequences of these processes have been little investigated. In order to fill this gap, we simulated patterns of molecular diversity within and between populations for various types of range contractions and range shifts. We show that range contractions tend to decrease genetic diversity as compared with population with stable ranges but quite counterintuitively fast range contractions preserve higher levels of diversity and induce lower levels of genetic differentiation among refuge areas than slow contractions. Contrastingly, fast range shifts lead to lower levels of diversity than slow range shifts. At odds with our expectations, we find that species actively migrating toward refuge areas can only preserve higher levels of diversity in refugia if the contraction is rapid. Under slow range contraction or slow range shift, active migration toward refugia lead to a larger loss of diversity as compared with scenarios with isotropic migration and may thus not be a good evolutionary strategy. These results suggest that the levels of diversity preserved after a climate change both within and between refuge areas will not only depend on the dispersal abilities of a species but also on the speed of the change. It also implies that a given episode of climatic change will impact differently species with different generation times.