A mutation in EGF repeat-8 of Notch discriminates between Serrate/Jagged and Delta family ligands.
Notch signaling affects many developmental and cellular processes and has been implicated in congenital disorders, stroke, and numerous cancers. The Notch receptor binds its ligands Delta and Serrate and is able to discriminate between them in different contexts. However, the specific domains in Notch responsible for this selectivity are poorly defined. Through genetic screens in Drosophila, we isolated a mutation, Notch(jigsaw), that affects Serrate- but not Delta-dependent signaling. Notch(jigsaw) carries a missense mutation in epidermal growth factor repeat-8 (EGFr-8) and is defective in Serrate binding. A homologous point mutation in mammalian Notch2 also exhibits defects in signaling of a mammalian Serrate homolog, Jagged1. Hence, an evolutionarily conserved valine in EGFr-8 is essential for ligand selectivity and provides a molecular handle to study numerous Notch-dependent signaling events.


Worst case optimization for interfractional motion mitigation in carbon ion therapy of pancreatic cancer.
The efficacy of radiation therapy treatments for pancreatic cancer is compromised by abdominal motion which limits the spatial accuracy for dose delivery - especially for particles. In this work we investigate the potential of worst case optimization for interfractional offline motion mitigation in carbon ion treatments of pancreatic cancer. We implement a worst case optimization algorithm that explicitly models the relative biological effectiveness of carbon ions during inverse planning. We perform a comparative treatment planning study for seven pancreatic cancer patients. Treatment plans that have been generated using worst case optimization are compared against (1) conventional intensity-modulated carbon ion therapy, (2) single field uniform dose carbon ion therapy, and (3) an ideal yet impractical scenario relying on daily re-planning. The dosimetric quality and robustness of the resulting treatment plans is evaluated using reconstructions of the daily delivered dose distributions on fractional control CTs. Idealized daily re-planning consistently gives the best dosimetric results with regard to both target coverage and organ at risk sparing. The absolute reduction of D 95 within the gross tumor volume during fractional dose reconstruction is most pronounced for conventional intensity-modulated carbon ion therapy. Single field uniform dose optimization exhibits no substantial reduction for six of seven patients and values for D 95 for worst case optimization fall in between. The treated volume (D>95 % prescription dose) outside of the gross tumor volume is reduced by a factor of two by worst case optimization compared to conventional optimization and single field uniform dose optimization. Single field uniform dose optimization comes at an increased radiation exposure of normal tissues, e.g. ≈2 Gy (RBE) in the mean dose in the kidneys compared to conventional and worst case optimization and ≈4 Gy (RBE) in D 1 in the spinal cord compared to worst case optimization. Interfractional motion substantially deteriorates dose distributions for carbon ion treatments of pancreatic cancer patients. Single field uniform dose optimization mitigates the negative influence of motion on target coverage at an increased radiation exposure of normal tissue. Worst case optimization enables an exploration of the trade-off between robust target coverage and organ at risk sparing during inverse treatment planning beyond margin concepts.


Non-Rigid Graph Registration Using Active Testing Search.
We present a new approach for matching sets of branching curvilinear structures that form graphs embedded in R2 or R3 and may be subject to deformations. Unlike earlier methods, ours does not rely on local appearance similarity nor does require a good initial alignment. Furthermore, it can cope with non-linear deformations, topological differences, and partial graphs. To handle arbitrary non-linear deformations, we use Gaussian process regressions to represent the geometrical mapping relating the two graphs. In the absence of appearance information, we iteratively establish correspondences between points, update the mapping accordingly, and use it to estimate where to find the most likely correspondences that will be used in the next step. To make the computation tractable for large graphs, the set of new potential matches considered at each iteration is not selected at random as with many RANSAC-based algorithms. Instead, we introduce a so-called Active Testing Search strategy that performs a priority search to favor the most likely matches and speed-up the process. We demonstrate the effectiveness of our approach first on synthetic cases and then on angiography data, retinal fundus images, and microscopy image stacks acquired at very different resolutions.


Pair natural orbital and canonical coupled cluster reaction enthalpies involving light to heavy alkali and alkaline earth metals: the importance of sub-valence correlation.
In this work, we tested canonical and domain based pair natural orbital coupled cluster methods (CCSD(T) and DLPNO-CCSD(T), respectively) for a set of 32 ligand exchange and association/dissociation reaction enthalpies involving ionic complexes of Li, Be, Na, Mg, Ca, Sr, Ba and Pb(ii). Two strategies were investigated: in the former, only valence electrons were included in the correlation treatment, giving rise to the computationally very efficient FC (frozen core) approach; in the latter, all non-ECP electrons were included in the correlation treatment, giving rise to the AE (all electron) approach. Apart from reactions involving Li and Be, the FC approach resulted in non-homogeneous performance. The FC approach leads to very small errors (<2 kcal mol-1) for some reactions of Na, Mg, Ca, Sr, Ba and Pb, while for a few reactions of Ca and Ba deviations up to 40 kcal mol-1 have been obtained. Large errors are both due to artificial mixing of the core (sub-valence) orbitals of metals and the valence orbitals of oxygen and halogens in the molecular orbitals treated as core, and due to neglecting core-core and core-valence correlation effects. These large errors are reduced to a few kcal mol-1 if the AE approach is used or the sub-valence orbitals of metals are included in the correlation treatment. On the technical side, the CCSD(T) and DLPNO-CCSD(T) results differ by a fraction of kcal mol-1, indicating the latter method as the perfect choice when the CPU efficiency is essential. For completely black-box applications, as requested in catalysis or thermochemical calculations, we recommend the DLPNO-CCSD(T) method with all electrons that are not covered by effective core potentials included in the correlation treatment and correlation-consistent polarized core valence basis sets of cc-pwCVQZ(-PP) quality.


Comparison of Nutritional Risk Scores for Predicting Mortality in Japanese Chronic Hemodialysis Patients.
Protein energy wasting (PEW) is consistently associated with poor prognosis in hemodialysis (HD) patients. We compared the predictability of PEW as diagnosed by The International Society of Renal Nutrition and Metabolism criteria (PEWISRNM) and geriatric nutritional risk index (GNRI) for all-cause mortality in Japanese HD patients. As cut-off values for body mass index (BMI) for PEW have not been established in PEWISRNM for Asian populations, these were also investigated. The nutritional status from 409 HD patients was evaluated according to ISRNM and GNRI criteria. To compare the predictability of mortality, C-index, net reclassification improvement (NRI) and integrated discrimination improvement were evaluated. During follow-up (median, 52 months; range, 7 months), 70 patients (17.1%) presented PEW according to ISRNM and 131 patients (32.1%) according to GNRI; in addition, 101 patients (24.7%) died. PEWISRNM and GNRI were identified as independent predictors of death. Addition of PEWISRNM and GNRI to a predictive model based on established risk factors improved NRI and integrated discrimination improvement. However, no differences were found between models including PEWISRNM and GNRI. When lowering the criterion level of BMI per 1 kg/m2 sequentially, PEWISRNM at BMI <20 kg/m2 maximized the hazard ratio for mortality. The model including PEWISRNM at BMI <20 kg/m2 improved NRI compared with the model including GNRI. PEWISRNM and GNRI represent independent predictors of mortality, with comparable predictability. The diagnostic criterion of BMI in the ISRNM for Japanese population might be better at <20 kg/m2 than at <23 kg/m2.


Pharmacokinetics of chloroquine and monodesethylchloroquine in pregnancy.
In order to determine the pharmacokinetic disposition of chloroquine (CQ) and its active metabolite, desethylchloroquine (DECQ), when administered as intermittent presumptive treatment in pregnancy (IPTp) for malaria, 30 Papua New Guinean women in the second or third trimester of pregnancy and 30 age-matched nonpregnant women were administered three daily doses of 450 mg CQ (8.5 mg/kg of body weight/day) in addition to a single dose of sulfadoxine-pyrimethamine. For all women, blood was taken at baseline; at 1, 2, 4, 6, 12, 18, 24, 30, 48, and 72 h posttreatment; and at 7, 10, 14, 28, and 42 days posttreatment. Plasma was subsequently assayed for CQ and DECQ by high-performance liquid chromatography, and population pharmacokinetic modeling was performed. Pregnant subjects had significantly lower area under the plasma concentration-time curve for both CQ (35,750 versus 47,892 microg.h/liter, P < 0.001) and DECQ (23,073 versus 41,584 microg.h/liter, P < 0.001), reflecting significant differences in elimination half-lives and in volumes of distribution and clearances relative to bioavailability. Reduced plasma concentrations of both CQ and DECQ could compromise both curative efficacy and posttreatment prophylactic properties in pregnant patients. Higher IPTp CQ doses may be desirable but could increase the risk of adverse hemodynamic effects.


Support vector channel selection in BCI.
Designing a brain computer interface (BCI) system one can choose from a variety of features that may be useful for classifying brain activity during a mental task. For the special case of classifying electroencephalogram (EEG) signals we propose the usage of the state of the art feature selection algorithms Recursive Feature Elimination and Zero-Norm Optimization which are based on the training of support vector machines (SVM). These algorithms can provide more accurate solutions than standard filter methods for feature selection. We adapt the methods for the purpose of selecting EEG channels. For a motor imagery paradigm we show that the number of used channels can be reduced significantly without increasing the classification error. The resulting best channels agree well with the expected underlying cortical activity patterns during the mental tasks. Furthermore we show how time dependent task specific information can be visualized.


Immortalization of human T lymphocytes after transfection of Epstein-Barr virus DNA.
Epstein-Barr virus (EBV), a ubiquitous human herpesvirus, has the ability to transform human B lymphocytes. No other cell type has been experimentally transformed by EBV, either by intact virions or naked viral DNA and subgenomic fragments. Two immortalized human T-lymphoblastoid cell lines have now been established by transfecting cord blood lymphocytes with purified B95-8 viral DNA enclosed in fusogenic Sendai virus envelopes (RSVE) and then exposing the cells to EBV from a P3HR-1 cell subclone. One of these lines, which has been fully characterized, is termed HBD-1. This line is positive for EBV DNA and expresses surface OKT11, OKT4, and Tac receptors, but not M-1, mu immunoglobulin chains, EBV receptors, or B-1 surface markers. The cells contain fully rearranged T-cell receptor genes and germline immunoglobulin genes. The karyotype of the cells is normal, they do not require interleukin-2 for growth, and do not contain human T-lymphotropic virus type I. However, the HBD-1 cells contain incomplete EBV genomes and express several EBV-determined antigens, including the early antigen type D, membrane antigens, but not EBV-determined nuclear antigen (EBNA). This association of the EBV genome with permanently growing hematopoietic cells of non B-cell lineage should prove useful in studies on the mechanism of EBV-mediated cell transformation.


Evolution of changes in upper airway collapsibility during slow induction of anesthesia with propofol.
Upper airway collapsibility is known to increase under anesthesia. This study assessed how this increase in collapsibility evolves during slow Propofol induction and how it relates to anesthesia-induced changes in upper airway muscle activity and conscious state. Nine healthy volunteers were studied. Anesthesia was induced with Propofol in a step-wise manner (effect-site concentration steps of 0.5 microg x ml(-1) from 0 to 3 microg x ml(-1) and thereafter to 4 microg x ml(-1) and 6 microg x ml(-1) [target-controlled infusion]). Airway patency was maintained with continuous positive airway pressure. Pharyngeal collapsibility was assessed at each concentration by measuring critical pressure. Intramuscular genioglossus electromyogram and anesthetic depth (bispectral index score) were monitored throughout. Loss of consciousness was defined as failure to respond to loud verbal command. Loss of consciousness occurred at varying Propofol effect-site concentrations between 1.5 and 4.0 microg x ml(-1). Initially genioglossus electromyographic activity was sustained with increases in Propofol concentration, increasing in some individuals. At or approaching loss of consciousness, it decreased, often abruptly, to minimal values with an accompanying increase in critical pressure. In most subjects, bispectral index score decreased alinearly with increasing Propofol concentration with greatest rate of change coinciding with loss of consciousness. Slow stepwise induction of Propofol anesthesia is associated with an alinear increase in upper airway collapsibility. Disproportionate decreases in genioglossus electromyogram activity and increases in pharyngeal critical closing pressure were observed proximate to loss of consciousness, suggesting that particular vulnerability exists after transition from conscious to unconscious sedation. Such changes may have parallels with upper airway behavior at sleep onset.


Fabrication and characterization of chalcogenide glass photonic crystal waveguides.
We report on the fabrication of chalcogenide glass (Ag-As(2)Se(3)) photonic crystal waveguides and the first detailed characterization of the linear and nonlinear optical properties. The waveguides, fabricated by e-beam lithography and ICP etching exhibit typical transmission spectra of photonic crystal waveguides, and exhibit high optical nonlinearity. Nonlinear phase shift of 1.5pi through self-phase modulation is observed at 0.78 W input peak power in a 400 microm long device. The effective nonlinear parameter gamma(eff) estimated from this result reaches 2.6 x 10(4) W(-1)m(-1). Four-wave mixing is also observed in the waveguide, while two-photon absorption at optical communication wavelengths is sufficiently small and the corresponding figure of merit is larger than 11.


Noradrenaline in preterm infants with cardiovascular compromise.
Noradrenaline (NA) is beneficial in the treatment of term newborns with cardiovascular compromise due to sepsis or pulmonary hypertension, but experiences with NA in preterm infants are limited. The aim of this study is to describe the efficacy and safety of NA in preterm infants. Patient records of preterm infants ≤32 weeks' gestation admitted to two hospitals between 2004 and 2015 and who received NA were reviewed for perinatal morbidities and mortality. Clinical details were collected at the time of NA use, and response on blood pressure, perfusion and oxygenation was documented as well as possible side effects. Forty-eight infants with primary diagnoses of sepsis (63 %) and pulmonary hypertension (23 %) received NA. Normotension was achieved at a median of 1 h in all but one infant at a median dose of 0.5 mcg/kg/min. Infants who died (46 %) were of younger gestational age and had worse cardiovascular function at start of NA compared to infants who survived. Tachycardia was common (31 %), but no additional effects were found on kidney or liver function. NA appears to be tolerated safely by preterm infants with no major side effects. However, effectiveness needs to be studies further in structured trials. What is Known: • Noradrenaline is beneficial in the treatment of term newborns and infants with cardiovascular compromise. • Noradrenaline is known for its potent vasoconstrictive effects and, therefore, infrequently used in preterm infants. What is New: • Noradrenaline used in relative low dose and as first or second line support increases blood pressure in preterm infants with cardiovascular compromise. • Tachycardia was common, but no additional side effects were found.


Determination of potential selective inhibitors for ROCKI and ROCKII isoforms with molecular modeling techniques: structure based docking, ADMET and molecular dynamics simulation.
Rho-associated protein kinases (ROCKs) are a member of the serine/threonine protein kinase family and potential therapeutic target for various diseases. This enzyme has two isoforms, Rho-associated protein kinase I (ROCKI) and Rho-associated protein kinase II (ROCKII). They share an overall 65% homology in all amino acid sequence and 92% homology in kinase domains. Since, the kinase domains of ROCKI and ROCKII are highly conserved and similar, the discovery and design of isoform-selective inhibitors are more challenging. Thus, most currently available agents that is against ROCKs exhibit low selectivity and severe side effects. Therefore, this study aimed to elucidate the interaction of compounds that indicated high potential in experimental studies against ROCKI and ROCKII enzymes in the molecular level with molecular modeling techniques. Firstly, we determined the interaction property of catalytic sites of the ROCKs by analyzing with molecular docking. Based on these results, the best ligands (50 compounds) corresponding to experimental studies were selected, and then absorption, distribution, metabolism and excretion - toxicity (ADMET) analysis of these compounds were implemented. According to these study results, the compound 40 for ROCKI and the compound 50 for ROCKII were identified as selective and highly potent inhibitors. And finally, molecular dynamics (MD) simulations were performed for the stability of ROCKs with identified compounds. In the light of this study, it will be possible to treat diseases that ROCKs have a role by developing more effective and specific ROCK inhibitors. Communicated by Ramaswamy H. Sarma.


Sharing programming resources between Bio* projects through remote procedure call and native call stack strategies.
Open-source software (OSS) encourages computer programmers to reuse software components written by others. In evolutionary bioinformatics, OSS comes in a broad range of programming languages, including C/C++, Perl, Python, Ruby, Java, and R. To avoid writing the same functionality multiple times for different languages, it is possible to share components by bridging computer languages and Bio* projects, such as BioPerl, Biopython, BioRuby, BioJava, and R/Bioconductor. In this chapter, we compare the two principal approaches for sharing software between different programming languages: either by remote procedure call (RPC) or by sharing a local call stack. RPC provides a language-independent protocol over a network interface; examples are RSOAP and Rserve. The local call stack provides a between-language mapping not over the network interface, but directly in computer memory; examples are R bindings, RPy, and languages sharing the Java Virtual Machine stack. This functionality provides strategies for sharing of software between Bio* projects, which can be exploited more often. Here, we present cross-language examples for sequence translation, and measure throughput of the different options. We compare calling into R through native R, RSOAP, Rserve, and RPy interfaces, with the performance of native BioPerl, Biopython, BioJava, and BioRuby implementations, and with call stack bindings to BioJava and the European Molecular Biology Open Software Suite. In general, call stack approaches outperform native Bio* implementations and these, in turn, outperform RPC-based approaches. To test and compare strategies, we provide a downloadable BioNode image with all examples, tools, and libraries included. The BioNode image can be run on VirtualBox-supported operating systems, including Windows, OSX, and Linux.


Neural systems mediating recognition of changes in statistical regularities.
Neuroimaging research has identified several brain systems sensitive to statistical regularities within environmental input. However, the continuous input impinging on sensory organs is rarely stationary and its degree of regularity may itself change over time. The goals of the current fMRI study were to identify systems sensitive to changes in statistical regularities within an ongoing stimulus, and determine to what extent sensitivity to such changes depends on intentional monitoring of order. We predicted that changes in regularity would be coded for in systems previously associated with statistical coding (hippocampus and middle frontal regions) or event segmentation (posterior medial regions). Participants listened to a rapid train of four different tones whose order levels fluctuated over time. In an active task, participants monitored the tones and indicated when they perceived a change in regularity; in a passive task, they performed a concurrent visuo-motor task and could ignore the auditory input. Behavioral responses in the active task were used to define points of consensus between participants regarding changes in regularity. Activity in 7.5s epochs that preceded these order-change points was contrasted with activity during matched-length epochs where no participant indicated a change in order. We found that brain regions differentiating these two types of epochs matched those identified in prior research as mediating event segmentation in narratives and movies. These consisted mainly of medial posterior parietal and occipital regions, with limited involvement of temporal and lateral frontal cortices and no hippocampal involvement. In both tasks, order-change epochs were associated with a higher BOLD response than stable-order epochs, but the specific regions showing this pattern varied across tasks. We suggest that partitioning an input stream on the basis of statistical shifts constitutes a basic neural function underlying the ability to segment both semantic and non-semantic inputs. We further discuss the implications of these findings for neurobiological theories of statistical coding and event segmentation.


Ethical preparedness in health research and care: the role of behavioural approaches.
Public health scholars have long called for preparedness to help better negotiate ethical issues that emerge during public health emergencies. In this paper we argue that the concept of ethical preparedness has much to offer other areas of health beyond pandemic emergencies, particularly in areas where rapid technological developments have the potential to transform aspects of health research and care, as well as the relationship between them. We do this by viewing the ethical decision-making process as a behaviour, and conceptualising ethical preparedness as providing a health research/care setting that can facilitate the promotion of this behaviour. We draw on an implementation science and behaviour change model, COM-B, to demonstrate that to be ethically prepared requires having the capability (ability), opportunity, and motivation (willingness) to work in an ethically prepared way. We use two case examples from our empirical research-one pandemic and one non-pandemic related-to illustrate how our conceptualisation of ethical preparedness can be applied in practice. The first case study was of the UK NHSX COVID-19 contact tracing application case study involved eight in-depth interviews with people involved with the development/governance of this application. The second case involved a complex case regarding familial communication discussed at the UK Genethics Forum. We used deductive qualitative analysis based on the COM-B model categories to analyse the transcripbed data from each case study. Our analysis highlighted that being ethically prepared needs to go beyond merely equipping health professionals with skills and knowledge, or providing research governance actors with ethical principles and/or frameworks. To allow or support these different actors to utilise their skills and knowledge (or principles and frameworks), a focus on the physical and social opportunity is important, as is a better understanding the role of motivation. To understand ethical preparedness, we need to view the process of ethical decision-making as a behaviour. We have provided insight into the specific factors that are needed to promote this behaviour-using examples from both in the pandemic context as well as in areas of health research and medicine where there have been rapid technological developments. This offers a useful starting point for further conceptual work around the notion of being ethically prepared.


Tropane and nicotine alkaloid biosynthesis-novel approaches towards biotechnological production of plant-derived pharmaceuticals.
Many plants belonging to the Solanaceae family have been used as a source of pharmaceuticals for centuries because of their active principles, tropane and nicotine alkaloids. Tropane alkaloids, atropine, hyoscyamine and scopolamine, are among the oldest drugs in medicine. On the other hand nicotine, the addictive agent in tobacco, has only recently gained attention as a backbone for novel potential alkaloids to be used for certain neurological diseases. The biotechnological production of alkaloids utilizing plant cells as hosts would be an attractive option. However, to date very little success in this field has been gained because of the lack of understanding how these compounds are synthesized in a plant cell. Metabolic engineering attempts have already shown that when the rate-limiting steps of the biosynthetic pathway are completely known and the respective genes cloned, the exact regulation towards desired medicinal products will be possible in the near future. The new functional genomics tools, which combine transcriptome and metabolome data, will create a platform to better understand a whole system and to engineer the complex plant biosynthetic pathways. With the help of this technology, it is not only possible to produce known plant metabolites more effectively but also to make arrays of new compounds in plants and cell cultures.


Space exploration, Mars, and the nervous system.
When human beings venture back to the moon and then on to Mars in the coming decade or so, we will be riding on the accumulated data and experience from approximately 50 years of manned space exploration. Virtually every organ system functions differently in the absence of gravity, and some of these changes are maladaptive. From a biologic perspective, long duration spaceflight beyond low Earth orbit presents many unique challenges. Astronauts traveling to Mars will live in the absence of gravity for more than 1 year en route and will have to transition between weightlessness and planetary gravitational forces at the beginning, middle, and end of the mission. We discuss some of what is known about the effects of spaceflight on nervous system function, with emphasis on the neuromuscular and vestibular systems because success of a Mars mission will depend on their proper functioning.


Cyberinfrastructure: empowering a "third way" in biomedical research.
Biomedicine has experienced explosive growth, fueled in parts by the substantial increase of government support, continued development of the biotechnology industry, and the increasing adoption of molecular-based medicine. At its core, it is composed of fiercely independent, innovative, entrepreneurial individuals, organizations, and institutions. The field has developed unprecedented capacity to characterize biologic systems at their most fundamental levels with the use of tools and technologies almost unimaginable a generation ago. Biomedicine is at the precipice of unlocking the very essence of biologic life and enabling a new generation of medicine. Development and deployment of cyberinfrastructure may prove to be on the critical path to obtaining these goals.


Predictors of long-term adverse outcomes in elderly patients over 80 years hospitalized with heart failure. - A report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD)-.
Aging is associated with adverse outcomes in patients with cardiac diseases. Whether elderly patients hospitalized with heart failure (HF) had increased risks for mortality and rehospitalization compared with younger patients during the long-term follow-up was examined. The predictors of these adverse outcomes were also identified. The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) studied prospectively the characteristics and treatments in a broad sample of 2,675 patients hospitalized with worsening HF and the outcomes were followed up. The majority of elderly patients were female, had lower body mass index (BMI), a higher rate of ischemic, valvular, and hypertensive heart disease as etiologies of HF, a lower estimated glomerular filtration rate (eGFR), lower hemoglobin, and higher left ventricular ejection fraction values. Even after adjustment for covariates, the elderly patients were associated with higher risks of adverse outcomes. The predictors for all-cause death were: lower eGFR, lower BMI, male sex, sustained ventricular tachycardia or fibrillation (VT/VF), and the use of diuretics at discharge. Among patients hospitalized with HF, elderly patients had a worse prognosis than younger patients. Lower eGFR, lower BMI, male sex, sustained VT/VF, and diuretic use were independent predictors for all-cause death in these patients with higher risk.


A path of perpetual resilience: exploring the experience of a diabetes-related amputation through grounded theory.
Little research has been done on the experience of diabetes-related amputation. The aim of this study was to allow amputees to describe their experiences of amputation and to generate grounded theory that will lead health professionals towards a more comprehensive understanding of the realities of post-amputation life. Unstructured interviews were conducted with five participants with a diabetes-related amputation living in a rural setting, and their respective carers. The interviews were analysed using Grounded Theory methods. Data analysis revealed three categories: 'imposed powerlessness', 'adaptive functionality' and 'endurance'. The impact of participant's amputations were influenced by continuing limb problems post-amputation and co-existing complications affecting their physical function. Medical errors and lack of awareness of the risks for diabetic amputations resulted in uncertainty and fear. The participants' sense of grief, loss and shock post operatively continued later as they came to terms with their awkwardness of movement, yet they moved forward developing their own sense of hope through a coping process that revealed remarkable ability to endure and exert control over lives that seemed to be at the whim of an ongoing disease process. The substantive theory resulting from this grounded theory study was conceptualised as 'A Path of Perpetual Resilience'. It is important that psychosocial and not just physical adjustment is considered an indicator for determining outcomes for these people, and that future care involves strategies to promote this. A greater sample size is required to determine if these findings are transferable to the general diabetes-related amputation population.


[Smoking associated with alcoholism: introduction to the major human dependencies].
To establish the existence of an association between smoking and alcoholism in a general population sample and to compare two samples of alcoholics and non alcoholics matched by age and sex. Health Teaching Unit Murialdo-State Health Department-RS-Brazil in a limited area of 65,000 predicted population a cross-sectional study was undertaken in which adults of 35 y.o. or more were sampled. Of this sample, the alcoholics were selected by applying the CAGE Scale. A non alcoholic random sample was compared with the alcoholic one. It was identified 129 alcoholics among 1,387 adults of 35 y.o. or more. From the general list of adults a random sample of 129 non alcoholics were selected and matched to the alcoholics by age and sex. Both groups were compared. Data were obtained from a 19 item questionnaire. Answers to generic questions were obtained from all family members, such as: income and smoking habit. Specific data were obtained from the interviewed person of 35 y.o. or more, such as: schooling grade, occupation, diseases and respiratory symptoms, smoking habit, Peak Expiratory Flow and alcoholism. Of 129 alcoholics, 109 (84.5%) were male and 20 (15.5%) were female. The smoking prevalence among alcoholics (67%) was greater than among non alcoholics (43%) (p < .002). The kind of occupation distinguished both groups. Among alcoholics unemployment and elementary levels of occupation are more usual while among the abstemious intermediate and superior levels are more frequent (p < .003). The family as well as the personal income are higher among the abstemious (p < .001). There is an increased non significant number of non whites, illiterate people and family smokers among the alcoholics (p < .06). The tendency to start smoking earlier in life and to smoke more cigarettes for a longer period of time was noticed among alcoholics. There is a statistical association between smoking and alcoholism in the sample studied. Alcoholism in this sample is more prevalent among people who fulfil the following conditions: smokers, low income, rudimentary cultural and professional levels.


Common trust and personal safety issues: A systematic review on the acceptability of health and social interventions for persons with lived experience of homelessness.
Persons experiencing homelessness and vulnerable housing or those with lived experience of homelessness have worse health outcomes than individuals who are stably housed. Structural violence can dramatically affect their acceptance of interventions. We carried out a systematic review to understand the factors that influence the acceptability of social and health interventions among persons with lived experience of homelessness. We searched through eight bibliographic databases and selected grey literature sources for articles that were published between 1994 and 2019. We selected primary studies that reported on the experiences of homeless populations interacting with practitioners and service providers working in permanent supportive housing, case management, interventions for substance use, income assistance, and women- and youth-specific interventions. Each study was independently assessed for its methodological quality. We used a framework analysis to identify key findings and used the GRADE-CERQual approach to assess confidence in the key findings. Our search identified 11,017 citations of which 35 primary studies met our inclusion criteria. Our synthesis highlighted that individuals were marginalized, dehumanized and excluded by their lived homelessness experience. As a result, trust and personal safety were highly valued within human interactions. Lived experience of homelessness influenced attitudes toward health and social service professionals and sometimes led to reluctance to accept interventions. Physical and structural violence intersected with low self-esteem, depression and homeless-related stigma. Positive self-identity facilitated links to long-term and integrated services, peer support, and patient-centred engagement. Individuals with lived experience of homelessness face considerable marginalization, dehumanization and structural violence. Practitioners and social service providers should consider anti-oppressive approaches and provide, refer to, or advocate for health and structural interventions using the principles of trauma-informed care. Accepting and respecting others as they are, without judgment, may help practitioners navigate barriers to inclusiveness, equitability, and effectiveness for primary care that targets this marginalized population.


Increased humoral immunity in the jejunum of diarrhoea-predominant irritable bowel syndrome associated with clinical manifestations.
Altered intestinal barrier is associated with immune activation and clinical symptoms in diarrhoea-predominant IBS (IBS-D). Increased mucosal antigen load may induce specific responses; however, local antibody production and its contribution to IBS aetiopathogenesis remain undefined. This study evaluated the role of humoral activity in IBS-D. A single mucosal jejunal biopsy, luminal content and blood were obtained from healthy volunteers (H; n=30) and IBS-D (n=49; Rome III criteria) participants. Intraepithelial lymphocytes, mast cells, B lymphocytes and plasma cells were studied by imaging techniques. Differential gene expression and pathway analysis were assessed by microarray and PCR techniques. Blood and luminal immunoglobulins (Igs) were quantified. Gastrointestinal symptoms, respiratory atopy and stress and depression were also recorded. Patients with IBS-D showed a higher number and activation of mucosal B lymphocytes and plasma cells (p<0.05). Mast cell density was increased in patients with IBS-D (non-atopic) and in close proximity to plasma cells (p<0.05). Microarray profiling identified differential humoral activity in IBS-D, involving proliferation and activation of B lymphocytes and Igs production (p<0.001). Mucosal humoral activity was higher in IBS-D, with upregulation of germline transcripts and Ig genes (1.3-fold-1.7-fold increase; p<0.05), and increased IgG(+) cells and luminal IgG compared with H (p<0.05), with no differences in blood. Biological markers of humoral activity correlated positively with bowel movements, stool form and depression. Enhanced small bowel humoral immunity is a distinctive feature of IBS-D. Mucosal Ig production contributes to local inflammation and clinical manifestations in IBS-D.


Contemporary and emerging magnetic resonance imaging methods for evaluation of moyamoya disease.
Numerous recent technological advances offer the potential to substantially enhance the MRI evaluation of moyamoya disease (MMD). These include high-resolution volumetric imaging, high-resolution vessel wall characterization, improved cerebral angiographic and perfusion techniques, high-field imaging, fast scanning methods, and artificial intelligence. This review discusses the current state-of-the-art MRI applications in these realms, emphasizing key imaging findings, clinical utility, and areas that will benefit from further investigation. Although these techniques may apply to imaging of a wide array of neurovascular or other neurological conditions, consideration of their application to MMD is useful given the comprehensive multidimensional MRI assessment used to evaluate MMD. These MRI techniques span from basic cross-sectional to advanced functional sequences, both qualitative and quantitative.The aim of this review was to provide a comprehensive summary and analysis of current key relevant literature of advanced MRI techniques for the evaluation of MMD with image-rich case examples. These imaging methods can aid clinical characterization, help direct treatment, assist in the evaluation of treatment response, and potentially improve the understanding of the pathophysiology of MMD.


Women's Football: An Examination of Factors That Influence Movement Patterns.
Griffin, J, Larsen, B, Horan, S, Keogh, J, Dodd, K, Andretta, M, and Minahan, C. Title: Women's football: An examination of factors that influence movement patterns. J Strength Cond Res 34(8): 2384-2393, 2020-The popularity and professionalism of women's football has increased in conjunction with participation rates over the last 10 years, with projected female participation rates to double worldwide by 2026. Scientific interest has also increased, in part due to Fédération Internationale de Football Association now allowing global positioning system (GPS) units to be worn during all competitive matches, resulting in investigations into the match demands of women's football. Therefore, the purpose of the present review is to provide a summary of the literature specific to the movement patterns of women's football matches. Contemporary scientific investigation using GPS match data has led to a greater understanding of the movement patterns of football. Greater emphasis has been placed on high-speed running and sprinting during matches because of the strong link to scoring opportunities and being a distinguishing factor between international and national along with elite and subelite competition levels. Further research, however, is warranted in regard to accelerations and decelerations, given the high metabolic and mechanical loads and contribution to high-speed running and sprinting. With an influx of research into the movement patterns of match-play, investigators have begun to examine factors affecting match performance such as positional demands, age, level of competition, opponent, scoreline, and phase of the game. An understanding of the factors that influence match demands is vital to ultimately be able to understand the effects on performance and how manipulating these factors may improve football performance and reduce the risk of injury.


Predictors of large volume paracantesis induced circulatory dysfunction in patients with massive hepatic ascites.
In patients with massive ascites, large volume paracentesis may be associated with complications as circulatory dysfunction. Selection of appropriate patients might reduce such side effects. Forty-five patients known to have liver cirrhosis and presenting with massive ascites were included. There were 27 males and 18 females, with age (mean 51.2+10.64). All patients were subjected to full history, clinical examination, complete blood picture, prothrombin time, serum albumin, total plasma protein, serum bilirubin, serum creatinine, serum electrolytes and plasma renin activity measured by radioimmunoassay. Echocardiographic evaluation for cardiac output, pulmonary artery pressure, diastolic and systolic function before and after paracentesis. Large-volume paracentesis (LVP) ranging 8-18 liters with a mean 9.9 L was performed to all patients. Paracentesis induced circulatory dysfunction (PICD) was defined as increase in plasma renin activity (PRA) of more than 50% of pretreatment value to a level greater than 7.5ng /ml/ hour on the 6th day after paracentesis. The incidence of PICD in patients with massive hepatic ascites was 73.3% (87.5% with Dextran and 38.5% with albumin). There were no serious systemic or local side effects one week following LVP. Type of plasma expander and younger ages were the only independent predictors (odd ratio OR with 95% confidence interval CI, 3.01<21.79<157.58 and 0.80<.88<.97 respectively) Gender and other clinical and laboratory parameters had no influence. Neither electrolytes levels nor hematocrite value had an influence. Ascitic patients showed higher heart rate and cardiac output and lower arterial pressure that was accentuated after LVP (P < 0.01). Echocardiographic diastolic function, A wave velocity and deceleration time of the E wave were markedly increased in cirrhotic patients with tense ascites and the E/A ratio was markedly reduced (0.9 ± 0.3) but was not significantly affected by LVP. Ejection fraction had similar values of the normal patients with a tendency to increase after paracentesis. There were no changes in the left ventricular wall thickness. LVP is a safe and effective procedure for treatment of tense/refractory ascites. PICD is a frequently occurring silent complication following LVP. Salt free human albumin should be the plasma expander of choice especially if at least 8 liters are evacuated. Left ventricular diastolic function is altered in cirrhosis with tense ascites. This may represent an early stage of hepatic cardiomyopathy but was not affected by LVP and this was not reflected on the occurrence of PICD.


Meditation lowers stress and supports forgiveness among college students: a randomized controlled trial.
The authors evaluated the effects on stress, rumination, forgiveness, and hope of two 8-week, 90-min/wk training programs for college undergraduates in meditation-based stress-management tools. After a pretest, the authors randomly allocated college undergraduates to training in mindfulness-based stress reduction (MBSR; n = 15), Easwaran's Eight-Point Program (EPP; n = 14), or wait-list control (n = 15). The authors gathered pretest, posttest, and 8-week follow-up data on self-report outcome measures. The authors observed no post-treatment differences between MBSR and EPP or between posttest and 8-week follow-up (p > .10). Compared with controls, treated participants (n = 29) demonstrated significant benefits for stress (p < .05, Cohen's d = -.45) and forgiveness (p < .05, d = .34) and marginal benefits for rumination (p < .10, d = -.34). Evidence suggests that meditation-based stress-management practices reduce stress and enhance forgiveness among college undergraduates. Such programs merit further study as potential health-promotion tools for college populations.


IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation.
Activating mutations in the KRAS oncogene are prevalent in pancreatic ductal adenocarcinoma (PDAC). We previously demonstrated that pancreatic intraepithelial neoplasia (PanIN) formation, which precedes malignant transformation, associates with the expression of immediate early response 3 (Ier3) as part of a prooncogenic transcriptional pathway. Here, we evaluated the role of IER3 in PanIN formation and PDAC development. In human pancreatic cancer cells, IER3 expression efficiently sustained ERK1/2 phosphorylation by inhibiting phosphatase PP2A activity. Moreover, IER3 enhanced KrasG12D-dependent oncogenesis in the pancreas, as both PanIN and PDAC development were delayed in IER3-deficient KrasG12D mice. IER3 expression was discrete in healthy acinar cells, becoming highly prominent in peritumoral acini, and particularly high in acinar ductal metaplasia (ADM) and PanIN lesions, where IER3 colocalized with phosphorylated ERK1/2. However, IER3 was absent in undifferentiated PDAC, which suggests that the IER3-dependent pathway is an early event in pancreatic tumorigenesis. IER3 expression was induced by both mild and severe pancreatitis, which promoted PanIN formation and progression to PDAC in KrasG12D mice. In IER3-deficient mice, pancreatitis abolished KrasG12D-induced proliferation, which suggests that pancreatitis enhances the oncogenic effect of KRAS through induction of IER3 expression. Together, our data indicate that IER3 supports KRASG12D-associated oncogenesis in the pancreas by sustaining ERK1/2 phosphorylation via phosphatase PP2A inhibition.


Early graft failure of xenogeneic islets in NOD mice is accompanied by high levels of interleukin-1 and low levels of transforming growth factor-beta mRNA in the grafts.
Early graft failure, graft rejection, and autoimmune recurrence remain unresolved issues in islet xenotransplantation in type 1 diabetes. The first aim of this study was to examine the existence of early graft failure in spontaneously diabetic autoimmune NOD mice after rat islet transplantation under technically controlled circumstances. The second aim was to examine the mediators of this early xenograft dysfunction. First, we demonstrated a higher percentage of early xenograft failure (48%) in spontaneously diabetic NOD mice as compared with chemically diabetic old NOD (13%, P < 0.05) and C57Bl/6 (7%, P < 0.01) mice. In addition, in spontaneously diabetic NOD mice, xenogeneic islets displayed early graft failure more frequently than allogeneic (23%, P < or = 0.05) or isogeneic islets (7%, P < 0.01). No early graft failure was observed in allotransplantation or isotransplantation in chemically diabetic mice. Reverse transcriptase-polymerase chain reaction analysis of cytokine mRNA in islet xenografts 8 h after transplantation showed higher levels of interleukin (IL)-1 mRNA in autoimmune diabetic mice compared with chemically diabetic old NOD mice (1.40 +/- 0.32 vs. 0.90 +/- 0.14 IL-1 copies/beta-actin copies, P < 0.05). In contrast, mRNA levels of transforming growth factor (TGF)-beta were lower in spontaneously diabetic NOD mice than in chemically diabetic old NOD mice (0.67 +/- 0.16 vs. 1.36 +/- 0.50 TGF-beta copies/beta-actin copies, P < 0.05). No differences in tumor necrosis factor-alpha, IL-6, and inducible nitric oxide synthase were seen between autoimmune and nonautoimmune diabetic mice. T-cell cytokines (IL-2, IL-4, IL-10, and gamma-interferon) were absent in all mice until 48 h after transplantation. These data suggest that early islet xenograft failure is more common in spontaneously diabetic NOD mice and could be due to a nonspecific inflammatory reaction locally in the grafts.


Visual search and selection of natural stimuli in the pigeon: the attention threshold hypothesis.
During visual search for samples of varying proportions of familiar, natural food grains displayed against a complex gravel background, pigeons exhibited "matching selection," a tendency to overselect the more common grain. The matching-selection effect was decreased at low levels of stimulus/background contrast and reversed when the grains were highly conspicuous. The results were consistent with the hypothesis that stimulus detectability should be enhanced by recent experience with a particular grain type, but they showed no convincing indications of a corresponding effect on the response criterion. An explanatory model, termed the attention threshold hypothesis, argues that the mean latency of discovery can be minimized by selectively attending to one stimulus type at a time and switching to a more generally receptive state when the rate of discovery falls below a threshold value. The model appears to account for the fact that the response rate was highest toward samples containing a single grain type and decreased as the relative proportions approached equality. Additional consequences of the adoption of this theoretical perspective were explored in some detail. Among other results, the evidence suggests that the switching threshold might be chosen so as to optimize the rate of food discovery.


Therapeutic use of self: a nationwide survey of practitioners' attitudes and experiences.
Practitioners' preparation for, attitudes toward, and experience of the therapeutic relationship and use of self were explored using a survey study with a random sample of 1,000 American Occupational Therapy Association members. Participants reported a high value for the therapeutic relationship and use of self; most felt that they were inadequately trained and that the field lacks sufficient knowledge in these areas. Regardless of practitioners' age, gender, experience level, setting, treatment intensity, and client impairment, those who placed higher value on the use of self and had more training related to the therapeutic use of self were more likely to report interpersonal difficulties and feelings of positive regard for clients and were more likely to report concerns about clients. The findings suggest that more attention needs to be paid to the therapeutic relationship and to the therapeutic use of self in education and in research.


Exendin-4 and glucagon-like-peptide-1: NMR structural comparisons in the solution and micelle-associated states.
Exendin-4, a 39 amino acid peptide originally isolated from the oral secretions of the lizard Heloderma suspectum, has been shown to share certain activities with glucagon-like-peptide-1 (GLP-1), a 30 amino acid peptide. We have determined the structuring preferences of exendin-4 and GLP-1 by NMR in both the solution and dodecylphosphocholine (DPC) micelle-associated states. Based on both chemical shift deviations and the pattern of intermediate range NOEs, both peptides display significant helicity from residue 7 to residue 28 with greater fraying at the N-terminus. Thornton and Gorenstein [(1994) Biochemistry 33, 3532-3539] reported that the presence of a flexible, helix-destabilizing, glycine at residue 16 in GLP-1 was an important feature for membrane and receptor binding. Exendin-4 has a helix-favoring glutamate as residue 16. In the micelle-associated state, NMR data indicate that GLP-1 is less helical than exendin-4 due to the presence of Gly16; chemical shift deviations along the peptide sequence suggest that Gly16 serves as an N-cap for a second, more persistent, helix. In 30 vol-% trifluoroethanol (TFE), a single continuous helix is evident in a significant fraction of the GLP-1 conformers present. Exendin-4 has a more regular and less fluxional helix in both media and displays stable tertiary structure in the solution state. In the micelle-bound state of exendin-4, a single helix (residues 11-27) is observed with residues 31-39 completely disordered and undergoing rapid segmental motion. In aqueous fluoroalcohol or aqueous glycol, the Leu21-Pro38 span of exendin-4 forms a compact tertiary fold (the Trp-cage) which shields the side chain of Trp25 from solvent exposure and produces ring current shifts as large as 3 ppm. This tertiary structure is partially populated in water and fully populated in aqueous TFE. The Leu21-Pro38 segment of exendin-4 may be the smallest protein-like folding unit observed to date. When the Trp-cage forms, fraying of the exendin-4 helix occurs exclusively from the N-terminus; backbone NHs for the C-terminal residues of the helix display H/D exchange protection factors as large as 10(5) at 9 degrees C. In contrast, no tertiary structure is evident when exendin-4 binds to DPC micelles. An energetically favorable insertion of the tryptophan ring into the DPC micelle is suggested as the basis for this change. With the exception of exendin-4 in media containing fluoro alcohol cosolvents, NMR structure ensembles generated from the NOE data do not fully reflect the conformational averaging present in these systems. Secondary structure definition from chemical shift deviations may be the most appropriate treatment for peptides that lack tertiary structure.


Health services research in Europe and its use for informing policy.
As an applied field of research, health services research (HSR) is undertaken primarily to inform health care policy. However, the relationship between policy and HSR is not straightforward. Many policies are developed without taking account of available evidence. Our objective was to provide an overview of the infrastructure and capacity of HSR in Europe, and to explore the links between HSR and policy in European countries. A survey of health policy experts in 34 European countries undertaken between September 2009 and June 2010, covering: funding and prioritizing HSR; production and producers of HSR; health policy users of HSR; activities to promote the use of HSR; and barriers and facilitators to using HSR in policy-making. Experts were selected based on their professional expertise and reputation in HSR and/or health policy. Information was returned from 30 of the 34 countries. Infrastructure and capacity for HSR varied widely across countries as did the mechanisms likely to promote the use of research for national policy-making. In many cases, HSR was not separately identified from other health-related research. Government funding for HSR varied between zero and over €170 million per year (in 2004). Few countries had mechanisms to match HSR priorities with those of policy-makers. Although most countries provided some relevant training, multidisciplinary training was available in few countries. Few mechanisms supporting the use of research in policy were reported. One exception was coverage decisions for new drugs and technologies where formal accountability for the use of health technology assessments appeared to be most developed. Overall, respondents struggled to locate information on many aspects of HSR, particularly its use in decision-making. HSR is unevenly developed across Europe. There is considerable scope to build the infrastructure and to take steps to improve the use of HSR in policy-making. There is also a need for research, as opposed to expert opinion, on how HSR is undertaken and used.


Automatic online layer separation for vessel enhancement in X-ray angiograms for percutaneous coronary interventions.
Percutaneous coronary intervention is a minimally invasive procedure that is usually performed under image guidance using X-ray angiograms in which coronary arteries are opacified with contrast agent. In X-ray images, 3D objects are projected on a 2D plane, generating semi-transparent layers that overlap each other. The overlapping of structures makes robust automatic information processing of the X-ray images, such as vessel extraction which is highly relevant to support smart image guidance, challenging. In this paper, we propose an automatic online layer separation approach that robustly separates interventional X-ray angiograms into three layers: a breathing layer, a quasi-static layer and a vessel layer that contains information of coronary arteries and medical instruments. The method uses morphological closing and an online robust PCA algorithm to separate the three layers. The proposed layer separation method ran fast and was demonstrated to significantly improve the vessel visibility in clinical X-ray images and showed better performance than other related online or prospective approaches. The potential of the proposed approach was demonstrated by enhancing contrast of vessels in X-ray images with low vessel contrast, which would facilitate the use of reduced amount of contrast agent to prevent contrast-induced side effects.


Insulin and EGF receptors integrate the Ras and Rap signaling pathways.
Ras is a low molecular weight (Mr 21,000) GTP binding protein that plays an essential role in cell proliferation and differentiation. Mutations that result in constitutive activation of Ras are associated with several types of neoplastic tissue in mammals and expression of these alleles into cultured fibroblasts results in cellular transformation. Opposing the Ras activation pathway, the low molecular GTP binding protein Rap was originally observed to revert or suppress the transformed phenotype in Ki-Ras-transformed fibroblasts. This apparent antagonism between Ras and Rap function may reflect the ability of Rap and Ras to interact with the same downstream effectors, since these proteins share identical sequences within their respective effector domains. Although the precise molecular details remained to be established, there is a substantial similarity in the upstream signaling mechanisms that regulate both Ras and Rap activation. Ras GTP binding is stimulated upon the targeting of the Ras guanylnucleotide exchange factor SOS to the plasma membrane location of Ras. The carboxyl terminal domain of SOS contains a proline-rich regions that directs its association with the SH3 domains of the small adapter protein, Grb2. Similarly, the formation of active GTP-bound Rap results from the specific interaction with the Rap guanylnucleotide exchange factor C3G which specifically associates with the central SH3 domain of the small adapter protein, CrkII. Thus, efficient regulation of receptor tyrosine kinase downstream signaling events require the coordinate interplay of these two pathways.


Near field detector for integrated surface plasmon resonance biosensor applications.
Integrated surface plasmon resonance biosensors promise to enable compact and portable biosensing at high sensitivities. To replace the far field detector traditionally used to detect surface plasmons we integrate a near field detector below a functionalized gold film. The evanescent field of a surface plasmon at the aqueous-gold interface is converted into photocurrent by a thin film organic heterojunction diode. We demonstrate that use of the near field detector is equivalent to the traditional far field measurement of reflectivity. The sensor is stable and reversible in an aqueous environment for periods of 6 hrs. For specific binding of neutravidin, the detection limit is 4 microg/cm(2). The sensitivity can be improved by reducing surface roughness of the gold layers and optimization of the device design. From simulations, we predict a maximum sensitivity that is two times lower than a comparable conventional SPR biosensor.


Biallelic and Genome Wide Association Mapping of Germanium Tolerant Loci in Rice (Oryza sativa L.).
Rice plants accumulate high concentrations of silicon. Silicon has been shown to be involved in plant growth, high yield, and mitigating biotic and abiotic stresses. However, it has been demonstrated that inorganic arsenic is taken up by rice through silicon transporters under anaerobic conditions, thus the ability to efficiently take up silicon may be considered either a positive or a negative trait in rice. Germanium is an analogue of silicon that produces brown lesions in shoots and leaves, and germanium toxicity has been used to identify mutants in silicon and arsenic transport. In this study, two different genetic mapping methods were performed to determine the loci involved in germanium sensitivity in rice. Genetic mapping in the biparental cross of Bala × Azucena (an F6 population) and a genome wide association (GWA) study with 350 accessions from the Rice Diversity Panel 1 were conducted using 15 μM of germanic acid. This identified a number of germanium sensitive loci: some co-localised with previously identified quantitative trait loci (QTL) for tissue silicon or arsenic concentration, none co-localised with Lsi1 or Lsi6, while one single nucleotide polymorphism (SNP) was detected within 200 kb of Lsi2 (these are genes known to transport silicon, whose identity was discovered using germanium toxicity). However, examining candidate genes that are within the genomic region of the loci detected above reveals genes homologous to both Lsi1 and Lsi2, as well as a number of other candidate genes, which are discussed.


The unquenched triplet excited state of the fluorescent OFF/ON Bodipy-derived molecular probe based on photo-induced electron transfer.
Fluorescent molecular probes based on photo-induced electron transfer (PET) are well-known for which fluorescence is efficiently tuned OFF/ON by a PET process. Now we demonstrate that the triplet excited state of the probes is unable to be quenched by PET, which is in stark contrast to the singlet excited state (fluorescence). This conclusion was proved by the preparation of a fluorescent molecular probe BDP-DPA, which shows enhanced fluorescence upon addition of a Zn(ii) salt. With fluorescence spectroscopy, nanosecond transient absorption spectroscopy and electrochemical studies, we found that the triplet excited state of BDP-DPA was not quenched by any PET process, although the singlet excited state (fluorescence) of BDP-DPA was quenched. The results are useful for the study of the triplet excited states of organic chromophores and for designing external stimuli-activatable triplet photosensitizers for triplet-triplet annihilation upconversion and photodynamic therapy.


Variability in Resting State Network and Functional Network Connectivity Associated With Schizophrenia Genetic Risk: A Pilot Study.
Imaging genetics posits a valuable strategy for elucidating genetic influences on brain abnormalities in psychiatric disorders. However, association analysis between 2D genetic data (subject × genetic variable) and 3D first-level functional magnetic resonance imaging (fMRI) data (subject × voxel × time) has been challenging given the asymmetry in data dimension. A summary feature needs to be derived for the imaging modality to compute inter-modality association at subject level. In this work, we propose to use variability in resting state networks (RSNs) and functional network connectivity (FNC) as potential features for purpose of association analysis. We conducted a pilot study to investigate the proposed features in a dataset of 171 healthy controls and 134 patients with schizophrenia (SZ). We computed variability in RSN and FNC in a group independent component analysis framework and tested three types of variability metrics, namely Euclidean distance, Pearson correlation and Kullback-Leibler (KL) divergence. Euclidean distance and Pearson correlation metrics more effectively discriminated controls from patients than KL divergence. The group differences observed with variability in RSN and FNC were highly consistent, indicating patients presenting increased deviation from the cohort-common pattern of RSN and FNC than controls. The variability in RSN and FNC showed significant associations with network global efficiency, the more the deviation, the lower the efficiency. Furthermore, the RSN and FNC variability were found to associate with individual SZ risk SNPs as well as cumulative polygenic risk score for SZ. Collectively the current findings provide preliminary evidence for variability in RSN and FNC being promising imaging features that may find applications as biomarkers and in imaging genetic association analysis.


Coexistence and transition between Cassie and Wenzel state on pillared hydrophobic surface.
Water droplets on rugged hydrophobic surfaces typically exhibit one of the following two states: (i) the Wenzel state [Wenzel RN (1936) Ind Eng Chem 28:988-994] in which water droplets are in full contact with the rugged surface (referred as the wetted contact) or (ii) the Cassie state [Cassie, ABD, Baxter S (1944) Trans Faraday Soc 40:546-551] in which water droplets are in contact with peaks of the rugged surface as well as the "air pockets" trapped between surface grooves (the composite contact). Here, we show large-scale molecular dynamics simulation of transition between Wenzel state and Cassie state of water droplets on a periodic nanopillared hydrophobic surface. Physical conditions that can strongly affect the transition include the height of nanopillars, the spacing between pillars, the intrinsic contact angle, and the impinging velocity of water nanodroplet ("raining" simulation). There exists a critical pillar height beyond which water droplets on the pillared surface can be either in the Wenzel state or in the Cassie state, depending on their initial location. The free-energy barrier separating the Wenzel and Cassie state was computed on the basis of a statistical-mechanics method and kinetic raining simulation. The barrier ranges from a few tenths of k(B)T(0) (where k(B) is the Boltzmann constant, and T(0) is the ambient temperature) for a rugged surface at the critical pillar height to approximately 8 k(B)T(0) for the surface with pillar height greater than the length scale of water droplets. For a highly rugged surface, the barrier from the Wenzel-to-Cassie state is much higher than from Cassie-to-Wenzel state. Hence, once a droplet is trapped deeply inside the grooves, it would be much harder to relocate on top of high pillars.


Healthy Heart Africa: a prospective evaluation of programme outcomes on individuals' hypertension awareness, screening, diagnosis and treatment in rural Kenya at 12 months.
To evaluate the impact of Healthy Heart Africa (HHA), a comprehensive hypertension intervention programme, on hypertension awareness, knowledge, screening and diagnosis among rural communities in Kenya. Individuals from rural households near intervention and matched control healthcare facilities were randomly surveyed at baseline and the end point (after 12 months). A difference-in-differences analysis estimated the impact of HHA. This analysis included 838 individuals (intervention, n = 432; control, n = 406) at baseline and 698 (n = 364 and n = 334, respectively) at the end point. At baseline, both groups had high hypertension awareness (> 80%) but poor knowledge. After 12 months, healthcare providers were the primary information source for the intervention group only (p < 0.05). At the end point, respondents' knowledge of hypertension risk factors, consequences and management trended higher among the intervention versus the control group. Hypertension screening/diagnosis and patient recall of provider recommendations remained unchanged in both groups. HHA improved hypertension knowledge but screening and diagnosis remained unchanged after 12 months.


Dysregulation of BRD4 Function Underlies the Functional Abnormalities of MeCP2 Mutant Neurons.
Rett syndrome (RTT), mainly caused by mutations in methyl-CpG binding protein 2 (MeCP2), is one of the most prevalent intellectual disorders without effective therapies. Here, we used 2D and 3D human brain cultures to investigate MeCP2 function. We found that MeCP2 mutations cause severe abnormalities in human interneurons (INs). Surprisingly, treatment with a BET inhibitor, JQ1, rescued the molecular and functional phenotypes of MeCP2 mutant INs. We uncovered that abnormal increases in chromatin binding of BRD4 and enhancer-promoter interactions underlie the abnormal transcription in MeCP2 mutant INs, which were recovered to normal levels by JQ1. We revealed cell-type-specific transcriptome impairment in MeCP2 mutant region-specific human brain organoids that were rescued by JQ1. Finally, JQ1 ameliorated RTT-like phenotypes in mice. These data demonstrate that BRD4 dysregulation is a critical driver for RTT etiology and suggest that targeting BRD4 could be a potential therapeutic opportunity for RTT.


Treatment of thoracic spine pain and pseudovisceral symptoms with dry needling and manual therapy in a 78-year-old female: A case report.
Case Report. Thoracic spine pain and movement dysfunction is a relatively common problem in the general population but has received little attention in research. Dry needling is frequently utilized by physical therapists and has been shown to reduce pain and improve function in areas, such as the cervical and lumbar spine, shoulder, hip, and knee. However, little research has been performed on the use of dry needling in the thoracic area with only two prior case studies being published. This case report documents the use of dry needling and manual therapy to treat a patient with symptoms of thoracic spine pain with concurrent pseudovisceral symptoms of chest pain and difficulty breathing. The patient was a 78-year-old female who was referred to physical therapy with complaints of pain focused in her mid-thoracic spine radiating anteriorly into her chest. The patient underwent medical diagnostic tests prior to her referral to physical therapy to rule out cardiac pathology, pulmonary pathology, and fracture. She was treated with dry needling and manual therapy for a total of four sessions over a two-week period. Fifteen days after her initial evaluation, the patient reported she was pain-free with a pain score of 0/10 on the VAS. She reported she was no longer taking pain medication or NSAIDS. She was able to return to normal daily activities without restriction and normal sleep pattern. Her score on the Oswestry disability index at intake was 42% impairment and 2% impairment after 4 treatments. At follow-up 6 weeks and 12 weeks after her discharge from physical therapy, the patient reported she continued to be pain-free.


A shared genetic propensity underlies experiences of bullying victimization in late childhood and self-rated paranoid thinking in adolescence.
Bullying is a risk factor for developing psychotic experiences (PEs). Whether bullying is associated with particular PEs, and the extent to which genes and environments influence the association, are unknown. This study investigated which specific PEs in adolescence are associated with earlier bullying victimization and the genetic and environmental contributions underlying their association. Participants were 4826 twin pairs from a longitudinal community-based twin study in England and Wales who reported on their bullying victimization at the age of 12 years. Measures of specific PEs (self-rated Paranoia, Hallucinations, Cognitive disorganization, Grandiosity, Anhedonia, and parent-rated Negative Symptoms) were recorded at age of 16 years. Childhood bullying victimization was most strongly associated with Paranoia in adolescence (r = .26; P < .01), with weaker associations with Hallucinations, Cognitive Disorganization, parent-rated Negative Symptoms (r = .12-.20; P < .01), Grandiosity (r = .04; P < .05), and Anhedonia (r = .00, n.s.). Bivariate twin model-fitting demonstrated that bullying victimization and Paranoia were both heritable (35% and 52%, respectively) with unique environmental influences (39% and 48%, respectively), and bullying victimization showed common environmental influences (26%). The association between bullying victimization and Paranoia operated almost entirely via genetic influences (bivariate heritability = 93%), with considerable genetic overlap (genetic correlation = .55). In contrast to the assumed role of bullying victimization as an environmental trigger, these data suggest that bullying victimization in late childhood is particularly linked to self-rated Paranoia in adolescence via a shared genetic propensity. Clinically, individuals with a history of bullying victimization are predicted to be particularly susceptible to paranoid symptoms.


Comparison of the Effectiveness of Ablative and Non-Ablative Fractional Laser Treatments for Early Stage Thyroidectomy Scars.
Open thyroidectomy is conventionally performed at the anterior side of neck, which is a body part with a comparatively great degree of open exposure; due to this, postoperative scarring may cause distress in patients. We aimed to compare the effects of ablative and nonablative fractional laser treatments on thyroidectomy scars. We examined medical records in a retrospective manner and analyzed scars based on their digital images by using the modified Manchester Scar Scale (mMSS). Between February 2012 and May 2013, 55 patients with thyroidectomy scars were treated with ablative (34 patients) or nonablative (21 patients) fractional laser. Each patient underwent 4 laser treatment sessions in 3-4 week intervals, 1-2 months postoperatively. Scar improvement was assessed using patient images and the mMSS scale. The mean decrease in scar score was 3.91 and 3.47 in the ablative and nonablative groups, respectively; the reduction between 2 groups did not exhibit any significant difference (P=0.16). We used the scale once again to individually evaluate scar attributes. The nonablative group accounted for a considerably higher color score value (P=0.03); the ablative group accounted for a considerably higher contour score value (P<0.01). Patient satisfaction was high and no complications occurred. Both types of fractional laser treatments can be used successfully for thyroidectomy scar treatment with minimal complications; however, results indicate that higher effectiveness may be obtained from the use of ablative and nonablative lasers for hypertrophic scars and early erythematous scars, respectively. Therefore, the appropriate laser for scar treatment should be selected according to its specific characteristics.


Achievement of high rates of in vitro synthesis of 1,4-beta-D-glucan: activation by cooperative interaction of the Acetobacter xylinum enzyme system with GTP, polyethylene glycol, and a protein factor.
Regulatory properties of a cellulose synthase (UDP-forming)(UDPglucose:1,4-beta-D-glucan 4-beta-D-glucosyltransferase, EC 220.127.116.11) have been demonstrated by using enzyme preparations derived from cells of Acetobacter xylinum. Preparation of a particulate fraction in the presence of 20% (wt/vol) polyethylene glycol-4000 (PEG-4000) yields enzyme with activity 3- to 10-fold higher than that previously reported. The enzyme prepared in this fashion also shows a further marked, specific activation by GTP. The Ka for GTP is 34 microM. Guanosine 5'-[gamma-thio]triphosphate, an analog of GTP, is even more effective than GTP (Ka for guanosine 5'-[gamma-thio]triphosphate = 17 microM). A large number of other nucleotides and nucleotide derivatives were tested with no effect. Enzyme prepared in the absence of PEG-4000 does not respond to GTP because it lacks a protein factor necessary for GTP activation. PEG-4000 promotes the interaction of the protein factor with the enzyme. The factor itself has no synthase activity nor does it stimulate activity of the enzyme in the absence of GTP. In the presence of GTP, protein factor, and PEG-4000, initial rates of enzyme activity 200 times greater than those previously reported can be achieved. Such rates exceed 40% of the in vivo rate of cellulose synthesis from glucose.


Measurement of air-sea exchange of dimethyl sulfide and acetone by PTR-MS coupled with gradient flux technique.
We developed a new method for in situ measurement of air-sea fluxes of multiple volatile organic compounds (VOCs) by combining proton transfer reaction-mass spectrometry (PTR-MS) and gradient flux (GF) technique. The PTR-MS/GF system was first deployed to determine the air-sea flux of VOCs in the open ocean of the western Pacific, in addition to carbon dioxide and water vapor. Each profiling at seven heights from the ocean surface up to 14 m took 7 min. In total, 34 vertical profiles of VOCs in the marine atmosphere just above the ocean surface were obtained. The vertical gradient observed was significant for dimethyl sulfide (DMS) and acetone with the best-fit curves on quasi-logarithmic relationship. The mean fluxes of DMS and acetone were 5.5 ± 1.5 and 2.7 ± 1.3 μmol/m(2)/day, respectively. These fluxes are in general in accordance with those reported by previous expeditions.


Negative autoregulation of Mash1 expression in CNS development.
Mash1, a neural-specific bHLH transcription factor, is essential for the formation of multiple CNS and PNS neural lineages. Transcription from the Mash1 locus is elevated in mice null for Mash1, suggesting that MASH1 normally acts to repress its own transcription. This activity is contrary to the positive autoregulation of other proneural bHLH proteins. To investigate the mechanisms involved in this process, sequences flanking the Mash1 gene were tested for the ability to mediate negative autoregulation. A Mash1/lacZ transgene containing 36 kb of cis-regulatory sequence exhibits an increase in lacZ expression in the Mash1 mutant background, which phenocopies the observation of transcriptional autoregulation at the endogenous Mash1 locus. Using Mash1/lacZ lines with progressively less cis-acting sequence, autoregulatory responsive elements were demonstrated to colocalize with a previously characterized 1.2-kb CNS enhancer. Mutations of E-box sites within this enhancer did not result in an apparent loss of autoregulation, suggesting that MASH1 does not directly repress its own transcription. Interestingly, these mutations did not indicate any underlying positive auto- or cross-regulation of Mash1. Furthermore, the loss of autoregulation in the Mash1 mutant background is reminiscent of a loss of lateral inhibitory signaling. However, mutations in HES consensus sites, the likely purveyors of Notch-mediated lateral inhibition, do not support a role for these sites in negative autoregulation. We hypothesize that MASH1 normally inhibits its own expression indirectly, possibly through a HES-mediated repression of positive regulators or through novel HES binding sites.


A novel pathway of rapid TLR-triggered activation of integrin-dependent leukocyte adhesion that requires Rap1 GTPase.
Rapid β2-integrin activation is indispensable for leukocyte adhesion and recruitment to sites of infection and is mediated by chemokine- or P-selectin glycoprotein ligand-1-induced inside-out signaling. Here we uncovered a novel pathway for rapid activation of integrin-dependent leukocyte adhesion, triggered by toll-like receptor (TLR)-mediated signaling. TLR2 or TLR5 ligation rapidly activated integrin-dependent leukocyte adhesion to immobilized ICAM-1 and fibronectin. Consistently, in vivo administration of the TLR2-ligand Pam3CSK4 increased integrin-dependent slow rolling and adhesion to endothelium within minutes, as identified by intravital microscopy in the cremaster model. TLR2 and TLR5 ligation increased β2-integrin affinity, as assessed by the detection of activation-dependent neoepitopes. TLR2- and TLR5-triggered integrin activation in leukocytes required enhanced Rap1 GTPase activity, which was mediated by Rac1 activation and NADPH oxidase-2-dependent reactive oxygen species production. This novel direct pathway linking initial pathogen recognition by TLRs to rapid β2-integrin activation may critically regulate acute leukocyte infiltration to sites of pathogen invasion.


How do electron localization functions describe π-electron delocalization?
Scalar fields provide an intuitive picture of chemical bonding. In particular, the electron localization function (ELF) has proven to be highly valuable in interpreting a broad range of bonding patterns. The discrimination between enhanced or reduced electron (de)localization within cyclic π-conjugated systems remains, however, challenging for ELF. In order to clearly distinguish between the local properties of ten highly and weakly π-(de)localized prototype systems, we compare the ELFs of both the canonical wave functions and electron-localized states (diabatic) with those of two closely related scalar fields: the electron localizability indicator (ELI-D) and the localized orbital locator (LOL). The simplest LOL function distinguishes enhanced from weak π-(de)localization in an insightful and reliable manner. LOL offers the finest contrast between annulenes with 4n/4n + 2 π electrons and their inorganic analogues as well as between hyperconjugated cyclopentadiene derivatives. LOL(π) also gives an appealing and intuitive picture of the π-bond. In contrast, the most popular ELF fails to capture subtle contrasting local electronic properties and suffers from the arbitrariness of the σ/π dissection. The orbital separation of the most recent ELI-D is clear-cut but the interpretations sometime less straightforward in the present context.


Genomic interplay in bacterial communities: implications for growth promoting practices in animal husbandry.
The discovery of antibiotics heralded the start of a "Golden Age" in the history of medicine. Over the years, the use of antibiotics extended beyond medical practice into animal husbandry, aquaculture and agriculture. Now, however, we face the worldwide threat of diseases caused by pathogenic bacteria that are resistant to all existing major classes of antibiotic, reflecting the possibility of an end to the antibiotic era. The seriousness of the threat is underscored by the severely limited production of new classes of antibiotics. Evolution of bacteria resistant to multiple antibiotics results from the inherent genetic capability that bacteria have to adapt rapidly to changing environmental conditions. Consequently, under antibiotic selection pressures, bacteria have acquired resistance to all classes of antibiotics, sometimes very shortly after their introduction. Arguably, the evolution and rapid dissemination of multiple drug resistant genes en-masse across microbial pathogens is one of the most serious threats to human health. In this context, effective surveillance strategies to track the development of resistance to multiple antibiotics are vital to managing global infection control. These surveillance strategies are necessary for not only human health but also for animal health, aquaculture and plant production. Shortfalls in the present surveillance strategies need to be identified. Raising awareness of the genetic events that promote co-selection of resistance to multiple antimicrobials is an important prerequisite to the design and implementation of molecular surveillance strategies. In this review we will discuss how lateral gene transfer (LGT), driven by the use of low-dose antibiotics in animal husbandry, has likely played a significant role in the evolution of multiple drug resistance (MDR) in Gram-negative bacteria and has complicated molecular surveillance strategies adopted for predicting imminent resistance threats.


Randomised controlled trial of the effectiveness of a respiratory health worker in reducing impairment, disability, and handicap due to chronic airflow limitation.
A randomised controlled trial was undertaken to determine whether a respiratory health worker was effective in reducing the respiratory impairment, disability, and handicap experienced by patients with chronic airflow limitation attending a respiratory outpatient department. The 152 adults (aged 30-75 years) who participated had a prebronchodilator forced expiratory volume in one second (FEV1) below 60% predicted and no other disease. They were randomised to receive the care of a respiratory health worker or the normal services provided by the outpatient department. The respiratory health worker provided health education and symptom and treatment monitoring in liaison with primary care services. After one year there was little difference between the two groups in spirometric values (FEV1 and forced vital capacity before and after salbutamol 200 micrograms), disability (six minute walking distance and paced step test), and handicap (sickness impact profile, hospital anxiety and depression scale). Patients not looked after by the respiratory health worker were more likely to die (relative risk 2.9 (95% confidence limits 0.8, 10.2); when age and FEV1 were controlled for this risk increased to 5.5 (95% confidence limits 1.2, 24.5). Patients looked after by the respiratory health worker attended their general practitioner more frequently and were prescribed a greater range of drugs. This is the third study to have found limited measurable benefit in terms of morbidity from the intervention of a respiratory health worker. This may be due to the ability of such workers to keep frail patients alive.


Identifying Policy Best-Practices to Support the Contribution of Aquatic Foods to Food and Nutrition Security.
The relationship between aquatic foods and food nutrition and security is increasingly recognised in policy and practice, yet many governance instruments do not acknowledge or support this important connection. The most effective policy approaches to support the link between these sectors, or 'best practices' are currently unknown. We reviewed relevant governance instruments from multiple countries to identify how these instruments linked fisheries, aquaculture and food security and nutrition, including the policy framing and evidence of political commitment. Of the documents connecting the sectors (65%), the majority did so in the context of developing the fisheries/aquaculture sector to increase aquatic food availability and/or access (51%), followed by developing the fisheries/aquaculture sector as a livelihoods approach to indirectly improve food security (33%), for example, through income generation. Sectoral links established in the context of nutrition-sensitive approaches to fisheries and aquaculture were less common (5%). Almost one third (29%) of instruments supported the connection between aquatic foods and food security and nutrition across three or more different contexts relevant to food security or food systems, while 12% indicated a very high level of commitment. We recommend some key attributes for future policy development to help build coherence between sectors and to help frame coherent food system-based policies.


Frequency of hyponatremia and nonosmolar vasopressin release in the acquired immunodeficiency syndrome.
The frequency and pathophysiology of hyponatremia were studied in the acquired immunodeficiency syndrome. Of 71 hospitalized patients surveyed retrospectively, hyponatremia was observed in 37 (52%). Of 48 patients studied prospectively, 27 (56%) were hyponatremic. In 16 hyponatremic patients, volume status; serum and urine osmolalities; renal, adrenal, and thyroid function; and plasma vasopressin levels were assessed. Urine osmolalities were inappropriately elevated (mean, 377 mmol/kg of water) relative to serum osmolalities (mean, 268 mmol/kg of water). Four patients had moderate renal insufficiency. Plasma vasopressin levels were elevated in 15 patients, with the highest levels seen in patients who died (median, 7.08 pmol/L). Hyponatremia of multiple etiologies occurred in a majority of inpatients with the acquired immunodeficiency syndrome, often following the administration of hypotonic fluids, and was associated with a 30% (8/27) short-term mortality.


Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38alpha MAPK pathway.
Patients with primary (AL) cardiac amyloidosis suffer from progressive cardiomyopathy with a median survival of less than 8 months and a 5-year survival of <10%. Contributing to this poor prognosis is the fact that these patients generally do not tolerate standard heart failure therapies. The molecular mechanisms underlying this deadly form of heart disease remain unclear. Although interstitial amyloid fibril deposition of Ig light chain proteins is a major cause of cardiac dysfunction in AL cardiac amyloidosis, we have previously shown that amyloid precursor proteins directly impair cardiac function at the cellular and isolated organ levels, independent of fibril formation. In this study, we report that amyloidogenic light chain (AL-LC) proteins provoke oxidative stress, cellular dysfunction, and apoptosis in isolated adult cardiomyocytes through activation of p38 mitogen-activated protein kinase (MAPK). AL-LC-induced p38 activation was found to be independent of the upstream MAPK kinase, MKK3/6, and instead depends upon transforming growth factor-beta-activated protein kinase-1 binding protein-1 (TAB1)-mediated p38alpha MAPK autophosphorylation. Treatment of cardiomyocytes with SB203580, a selective p38 MAPK inhibitor, significantly attenuated AL-LC-induced oxidative stress, cellular dysfunction, and apoptosis. Our data provide a unique mechanistic insight into the pathogenesis of AL-LC cardiac toxicity and suggest that TAB1-mediated p38alpha MAPK autophosphorylation may serve as an important event leading to cardiac dysfunction and subsequent heart failure.


Theoretical study of signal-to-noise ratio on near-field photochromic memory with fluorescence readout.
The signal-to-noise ratio (SNR) on the fluorescence readout of a near-field photochromic memory was theoretically studied. Under various conditions the shot-noise-limited SNR was analyzed. SNR by bright spot recording (BSR) that was better than that by dark spot recording (DSR) was obtained under the condition of low writing power or wide bandwidth. Under the condition of bandwidth W = 1 MHz and P(write) = 10(-8) W only BSR can attain sufficiently high SNR, and the SNR was greater by as much as 30 dB than that of DSR. It was concluded that BSR is a promising method for high-density near-field photochromic memory with a fluorescence readout.


Hepatitis B virus treatment beyond the guidelines: special populations and consideration of treatment withdrawal.
The goal of chronic hepatitis B (CHB) treatment is to improve survival by preventing disease progression to decompensated cirrhosis and hepatocellular carcinoma which is the cause of over 1 million deaths annually. The risk of disease progression is reduced when a sustained reduction of hepatitis B virus (HBV) DNA to undetectable levels and suppression of HBV replication are obtained which can result in regression of liver fibrosis and may even reverse cirrhosis. However, even if HBsAg loss occurs, HBV is not completely eradicated by treatment, and long-term therapy is required in patients who are HBeAg(-) and HBeAg(+) who do not maintain off-treatment virological suppression and in those with advanced liver disease. The recently updated European Association of the Study of the Liver (EASL) clinical practical guidelines for HBV have clarified, first, how to treat HBV (interferon or the most potent oral drugs with optimal resistance profiles, i.e. entecavir and tenofovir disoproxil fumarate, should be used as first-line monotherapies); second, who should be treated (CHB in patients with significant liver disease but also patients who are HBsAg(+) and are receiving immunosuppressive treatment, patients coinfected with HBV and human immunodeficiency virus, mothers who are HBsAg(+) with high viral load in late pregnancy associated with sero vaccination to reduce the risk of vertical transmission of HBV; and third, when to stop antiviral therapies. The aim of this review was to clarify how to treat HBV and who should be treated, as well as when to stop treatment. Although the answer to these questions is clear for pegylated interferon, it is more debatable for nucleos(t)ide analogues (anti-HBe seroconversion, HBsAg loss or anti-HBs seroconversion with undetectable HBV DNA are clear indications to discontinue treatment but sustained undetectable HBV DNA in patients who are anti-HBe(+) without significant fibrosis might be another indication).


Lack of Association Between Genetic Variants at ACE2 and TMPRSS2 Genes Involved in SARS-CoV-2 Infection and Human Quantitative Phenotypes.
Coronavirus disease 2019 (COVID-19) shows a wide variation in expression and severity of symptoms, from very mild or no symptoms, to flu-like symptoms, and in more severe cases, to pneumonia, acute respiratory distress syndrome, and even death. Large differences in outcome have also been observed between males and females. The causes for this variability are likely to be multifactorial, and to include genetics. The SARS-CoV-2 virus responsible for the infection depends on two human genes: the human receptor angiotensin converting enzyme 2 (ACE2) for cell invasion, and the serine protease TMPRSS2 for S protein priming. Genetic variation in these two genes may thus modulate an individual's genetic predisposition to infection and virus clearance. While genetic data on COVID-19 patients is being gathered, we carried out a phenome-wide association scan (PheWAS) to investigate the role of these genes in other human phenotypes in the general population. We examined 178 quantitative phenotypes including cytokines and cardio-metabolic biomarkers, as well as usage of 58 medications in 36,339 volunteers from the Lifelines population cohort, in relation to 1,273 genetic variants located in or near ACE2 and TMPRSS2. While none reached our threshold for significance, we observed several interesting suggestive associations. For example, single nucleotide polymorphisms (SNPs) near the TMPRSS2 genes were associated with thrombocytes count (p = 1.8 × 10-5). SNPs within the ACE2 gene were associated with (1) the use of angiotensin II receptor blockers (ARBs) combination therapies (p = 5.7 × 10-4), an association that is significantly stronger in females (p dif f = 0.01), and (2) with the use of non-steroid anti-inflammatory and antirheumatic products (p = 5.5 × 10-4). While these associations need to be confirmed in larger sample sizes, they suggest that these variants could play a role in diseases such as thrombocytopenia, hypertension, and chronic inflammation that are often observed in the more severe COVID-19 cases. Further investigation of these genetic variants in the context of COVID-19 is thus promising for better understanding of disease variability. Full results are available at https://covid19research.nl.


[3H]bicuculline methochloride binding to low-affinity gamma-aminobutyric acid receptor sites.
The binding of [3H]bicuculline methochloride (BMC) to mammalian brain membranes was characterized and compared with that of [3H] gamma-aminobutyric acid ([3H]GABA). The radiolabeled GABA receptor antagonist showed significant displaceable binding in Tris-citrate buffer that was improved by high concentrations of chloride, iodide, or thiocyanate, reaching greater than 50% displacement in the presence of 0.1 M SCN-. An apparent single class of binding sites for [3H]BMC (KD = 30 nM) was observed in 0.1 M SCN- for fresh or frozen rat cortex or several regions of frozen and thawed bovine brain. The Bmax was about 2 pmol bound/mg of crude mitochondrial plus microsomal membranes from unfrozen washed and osmotically shocked rat cortex, similar to that for [3H]GABA. Frozen membranes, however, showed decreased levels of [3H]BMC binding with no decrease or an actual increase in [3H]GABA binding sites. [3H]BMC binding was inhibited by GABA receptor specific ligands, but showed a higher affinity for antagonists and lower affinity for agonists than did [3H]GABA binding. Kinetics experiments with [3H]GABA binding revealed that low- and high-affinity sites showed a similar pharmacological specificity for a series of GABA receptor ligands, but that whereas all agonists had a higher affinity for slowly dissociating high-affinity [3H]GABA sites, bicuculline had a higher affinity for rapidly dissociating low-affinity [3H]GABA sites. This reverse potency between agonists and antagonists during assay of radioactive antagonists or agonists supports the existence of agonist- and antagonist-preferring conformational states or subpopulations of GABA receptors. The differential affinities, as well as opposite effects on agonist and antagonist binding by anions, membrane freezing, and other treatments, suggest that [3H]BMC may relatively selectively label low-affinity GABA receptor agonist sites. This study, using a new commercially available preparation of [3H]bicuculline methochloride, confirms the report of bicuculline methiodide binding by Möhler and Okada (1978), and suggests that this radioactive GABA antagonist will be a valuable probe in analyzing various aspects of GABA receptors.