A chemocentric approach to the identification of cancer targets.
A novel chemocentric approach to identifying cancer-relevant targets is introduced. Starting with a large chemical collection, the strategy uses the list of small molecule hits arising from a differential cytotoxicity screening on tumor HCT116 and normal MRC-5 cell lines to identify proteins associated with cancer emerging from a differential virtual target profiling of the most selective compounds detected in both cell lines. It is shown that this smart combination of differential in vitro and in silico screenings (DIVISS) is capable of detecting a list of proteins that are already well accepted cancer drug targets, while complementing it with additional proteins that, targeted selectively or in combination with others, could lead to synergistic benefits for cancer therapeutics. The complete list of 115 proteins identified as being hit uniquely by compounds showing selective antiproliferative effects for tumor cell lines is provided.


Research into food portion size: methodological aspects and applications.
Portion sizes for certain foods have been increasing dramatically in recent years alongside obesity rates, concurring with the phenomenon of the portion size effect (more is consumed when more is offered). Portion size may be defined based on different purposes such as for dietary assessment, or therapeutic advice or food labelling, resulting in a variety of measurement methods and specifications. This situation has resulted in disagreements on establishing portion size recommendations by manufacturers, food distributors, restaurants, health professionals and policy makers, contributing to confusion amongst consumers on the amounts of food to be consumed, and potentially increasing the likelihood of overeating and other obesity-related behaviours. Such variability is also reflected in the research field making comparison across studies on portion size difficult. The aim of this review is to provide an overview of definitions and methods used in research to evaluate portion-size related outcomes, including methods to estimate amounts consumed by individuals as part of dietary assessment; methods to analyse cognitive mechanisms related to portion size behaviour; and methods to evaluate the impact of portion size manipulations as well as individual plus environmental factors on portion size behaviour. Special attention has been paid to behavioural studies exploring portion size cognitive processes given the lack of previous methodological reviews in this area. This information may help researchers, clinicians and other stakeholders to establish clearer definitions of portion size in their respective areas of work and to standardise methods to analyse portion size effects.


Disaster waste management: a review article.
Depending on their nature and severity, disasters can create large volumes of debris and waste. The waste can overwhelm existing solid waste management facilities and impact on other emergency response and recovery activities. If poorly managed, the waste can have significant environmental and public health impacts and can affect the overall recovery process. This paper presents a system overview of disaster waste management based on existing literature. The main literature available to date comprises disaster waste management plans or guidelines and isolated case studies. There is ample discussion on technical management options such as temporary storage sites, recycling, disposal, etc.; however, there is little or no guidance on how these various management options are selected post-disaster. The literature does not specifically address the impact or appropriateness of existing legislation, organisational structures and funding mechanisms on disaster waste management programmes, nor does it satisfactorily cover the social impact of disaster waste management programmes. It is envisaged that the discussion presented in this paper, and the literature gaps identified, will form a basis for future comprehensive and cohesive research on disaster waste management. In turn, research will lead to better preparedness and response to disaster waste management problems.


Heterocyclic homoprostanoid derivative attenuates monoarthritis in rats: An in vitro and in vivo preclinical paradigm.
From our lab, among the nineteen heterocyclic homoprostanoids (HHPs), three derivatives (compounds 3, 3b and 3c) exerted antioxidant and anti-inflammatory activity. Present study is an extension of the earlier work, and, is designed to establish their therapeutic potential in monoarthritis in rats. In addition, their possible mechanism of action would be investigated. A battery of in vitro tests such as lipopolysaccharide (LPS)-induced nitrite (NO)/reactive oxygen species (ROS) and NO/interleukin (IL)-6 generation in murine macrophages and whole blood (WhB), respectively were conducted. Later, in vitro cyclooxygenase (COX) enzyme inhibitory activity was also evaluated. All the tested compounds showed comparable efficacy against ROS and NO in LPS-stimulated murine macrophages. However, compound 3 did not exert inhibitory effect on LPS-induced NO/IL-6 generation in WhB assay. Compounds (3b and 3c) inhibited the NO generation in LPS-stimulated WhB. However, only compound 3b reversed the raised IL-6 levels in this assay. None of the test compounds inhibited COX iso-enzymes in the in vitro assay. All three HHPs showed comparable efficacy against carrageenan-induced paw inflammation. However, none of them exhibited any dose-dependent effect in this model. Based upon previous reports, compound 3c was explored against adjuvant-induced monoarthritis (AIA) in male Sprague-Dawley rats, where it exerted promising therapeutic effect. In addition to radiological and histological examinations of tibio-tarsal joint, various parameters such as chronic inflammation/pain, clinical score, interleukin (IL)-6 levels and complete blood cell profile were evaluated in AIA rats. Chronic treatment with 3c halted the disease progression in rats, improved the overall health of animals, as demonstrated by haematological, clinical scoring and joint examinations (radiological and histopathological). Inhibitory effect on elevated IL-6 in AIA rats suggested the possible mechanism of 3c on cytokine signalling. Overall, the study supports the anti-arthritic potential of compound 3c.


An acoustic study of multiple lateral consonants in three Central Australian languages.
This study presents dental, alveolar, retroflex, and palatal lateral /̪ll ɭ ʎ/ data from three Central Australian languages: Arrernte, Pitjantjatjara, and Warlpiri. Formant results show that the laminal laterals (dental /̪l/ and palatal /ʎ/) have a relatively low F1, presumably due to a high jaw position for these sounds, as well as higher F4. In addition, the palatal /ʎ/ has very high F2. There is relatively little difference in F3 between the four lateral places of articulation. However, the retroflex /ɭ/ appears to have slightly lower F3 and F4 in comparison to the other lateral sounds. Importantly, spectral moment analyses suggest that centre of gravity and standard deviation (first and second spectral moments) are sufficient to characterize the four places of articulation. The retroflex has a concentration of energy at slightly lower frequencies than the alveolar, while the palatal has a concentration of energy at higher frequencies. The dental is characterized by a more even spread of energy. These various results are discussed in light of different acoustic models of lateral production, and the possibility of spectral cues to place of articulation across manners of articulation is considered.


District nurses' experience of supervising nursing students in primary health care: A pre- and post-implementation questionnaire study.
Nursing students go through clinical supervision in primary health care settings but district nurses' (DNs) circumstances when supervising them are only briefly described in the literature. The aim of this study was to investigate DNs experience of supervising nursing students before and after the implementation of a new supervision model. Ninety-eight (74%) DNs answered a questionnaire before and 84 (65%) after implementation of the new supervision model. The study showed that DNs in most cases felt that conditions for supervision in the workplace were adequate. But about 70% lacked training for the supervisory role and 20% had no specialist district nurse training. They also experienced difficulty in keeping up-to-date with changes in nurse education programmes, in receiving support from the university and from their clinic managers, and in setting aside time for supervision. Improvements after the implementation of a new model chiefly concerned organisation; more DNs stated that one person had primary responsibility for students' clinical practice, that information packages for supervisors and students were available at the health care centres, and that conditions were in place for increasing the number of students they supervised. DNs also stated that supervisors and students benefited from supervision by more than one supervisor. To conclude, implementation of a new supervision model resulted in some improvements.


Dairy Propionibacterium extends the mean lifespan of Caenorhabditis elegans via activation of the innate immune system.
Dairy Propionibacterium freudenreichii is a candidate non-lactic acid probiotic. However, little information is available on the effect of P. freudenreichii on lifespan extension in humans. The aim of this study was to evaluate the effects of P. freudenreichii on lifespan extension and to elucidate the mechanism of P. freudenreichii-dependent lifespan extension in Caenorhabditis elegans. The results showed that P. freudenreichii significantly (p < 0.05) extended the lifespan of C. elegans compared with Escherichia coli OP50, a standard food for the worm. Analysis of age-related biomarkers showed that P. freudenreichii retards ageing. Moreover, P. freudenreichii increased resistance against a human pathogen, Salmonella typhimurium, through the activation of skn-1, which is involved in pathogen resistance in C. elegans. Furthermore, P. freudenreichii-fed daf-16, jnk-1, skn-1 or daf-7 loss-of-function mutants showed an extended mean lifespan compared with E. coli OP50-fed worms. However, the increase in lifespan was not observed in pmk-1, sek-1, mek-1, dbl-1, daf-12 or daf-2 mutants, which suggests potential roles for these genes in P. freudenreichii-induced longevity in C. elegans. In conclusion, P. freudenreichii extends the lifespan of C. elegans via the p38 MAPK pathway involved in stress response and the TGF-β pathways associated with anti-inflammation processes in the immune system.


Hedgehog signaling regulates imaginal cell differentiation in a basally branching holometabolous insect.
The evolution of imaginal cells, or stem cell-like cells, contributed to the spectacular diversification of holometabolous insects, which undergo complete metamorphosis. The proliferation and differentiation of these imaginal cells is under the control of juvenile hormone (JH), but which patterning genes respond to JH is currently unknown. Here, the role of Hedgehog (Hh) signaling in the development of imaginal cells was investigated. RNA interference-mediated knockdown of the components of the Hh signaling pathway showed that Hh is required for the proliferation of polymorphic and imaginal cells in Tribolium castaneum. Hh was also necessary for the regeneration of larval appendages. In contrast, knockdown of Hh signaling antagonists, patched and costal 2 led to the overgrowth and precocious maturation of structures derived from imaginal cells and the occasional appearance of ectopic appendages from the head epidermis. In addition, JH suppressed the expression of hh both in vivo and in vitro. Our findings suggest that imaginal cells are created and maintained by modulating Hh signaling. Thus, Hh signaling may have played a critical role during the evolution of complete metamorphosis.


Internet-based Self-Management Support for Patients With Well-Controlled Type 2 Diabetes: A Real-Life Study.
Little attention has been paid to self-management support of patients with well-controlled type 2 diabetes mellitus (T2DM). Most studies evaluated the addition of self-management support to regular diabetes care, but self-management as an alternative for part of regular diabetes care has hardly been studied. In this study, we offered patients with well-controlled T2DM the opportunity to perform the 3 quarterly monitoring sessions at home using an Internet-based self-management program, resulting in online personalized advice. The aim of our study was to assess the reach and feasibility of an Internet-based diabetes self-management support program for patients with well-controlled T2DM, addressing both primary care providers' (PCPs) opinions and patients' willingness to participate in such a support program. PCPs assessed patients' eligibility for Internet-based self-management, and patients were offered the opportunity to participate. Characteristics of eligible and ineligible patients were compared, as well as those of participants and nonparticipants, also with regard to quality of life, treatment satisfaction, and illness perceptions. Multivariate logistic regression models were performed and odds ratios (ORs) calculated with 95% CIs. Almost half (128/282, 45.4%) of the patients with well-controlled T2DM were considered ineligible by their PCPs mainly because of cognitive impairment and language barriers (8.2% and 8.9%). Older patients (OR for each year 1.06, 95% CI 1.03-1.09, P<.001), non-Western European patients (OR 3.64, 95% CI 1.67-7.92, P=.001), and patients with a longer diabetes duration (OR for each year 1.56, 95% CI 1.04-2.34, P=.03) were more often regarded as ineligible. Of the 154 patients considered eligible, 57 (37.0%) consented to participate and 30 (10.6%) started the program. Of 57 participants, 45 returned the 3 questionnaires; 21 of 97 nonparticipants returned the questionnaires. Nonparticipants less often thought that their disease would last their entire life (median 8.0 vs 10.0, P=.03) and they were more satisfied with their current treatment than participants (DTSQ total score 44.0 vs 40.0, P=.05). There was no significant difference in quality of life between the 2 groups. PCPs considered half of their patients with well-controlled T2DM incapable of Internet-based self-management mainly because of cognitive impairment and language barriers; of the selected patients, about 1 out of 3 was willing to participate. Older patients, non-Western European patients, and patients with a higher BMI were less likely to participate. Predominantly, practical issues (such as Internet problems) hindered implementation of the Internet-based self-management program.


Phospholipase C zeta (PLCζ): oocyte activation and clinical links to male factor infertility.
Mounting scientific and clinical evidence supports the key role played by phospholipase C zeta (PLCζ), a sperm-specific protein, in the activation of oocytes following fertilisation. Lacking a pleckstrin homology domain, PLCζ remains the smallest known mammalian PLC and was first identified in 2002. Since then, PLCζ has been the target for a multitude of studies in both mammalian and non-mammalian species focused upon its fundamental biochemical activity and crucial role as the mediator of oocyte activation. The earliest event subsequent to gamete fusion is the onset of a series of intracellular calcium oscillations within the oocyte, which are known to modulate cortical granule exocytosis, release meiotic arrest, regulate gene expression, recruit maternal mRNA, and initiate embryogenesis. Collectively these processes are known as 'oocyte activation' and together, represent a fundamental mechanism for early embryonic development. Evidence suggests that these processes are initiated and controlled by calcium release from ooplasmic sources in response to PLCζ activity via the inositol-1,4,5-triphosphate (IP3) pathway. While the biochemical action of PLCζ has been extensively studied, especially in relation to the EF-hands, X-Y linker, and C2 domain, all of which play critical roles for in vivo activity, there are still key gaps in our knowledge, particularly in terms of regulation and interaction with other proteins within the oocyte. Moreover, increasing clinical evidence has revealed a strong correlation between certain types of male infertility and the aberrant expression, localisation, structure and function of PLCζ in human sperm, particularly in cases of recurrent intracytoplasmic sperm injection (ICSI) failure, globozoospermia, and oocyte activation deficiency (OAD). In addition, two heterozygous substitution mutations have been identified in the coding sequence of PLCζ in one particular patient causing disruption to the catalytic X and Y domains and resulting in infertility. Although, such cases can be treated via the use of artificial oocyte activators (AOAs) such as calcium ionophores, significant concern remains over the use of such chemical agents, largely due to the fact that calcium release manifests as a single transient, rather than a series of oscillations as observed during normal fertilisation. Current interest in PLCζ is thus to develop a series of prognostic, diagnostic and therapeutic approaches which could first identify male patients that are deficient in PLCζ and then rescue oocyte activation ability via assisted reproductive technology (ART) and a pure, functionally-active, recombinant human PLCζ protein. While significant progress has been made in such areas over recent years, there is a clear need to translate scientific findings to clinical settings in order to maximise successful outcome for patients.


Willingness to Pay for Community-Based Healthcare Insurance Schemes in Developing Countries: A Case of Lahore, Pakistan.
Healthcare costs and poverty are significant barriers to achieving universal access to healthcare. Thus, Community-Based Health Insurance Schemes (CBHIS) are regarded as an influential instrument for providing access to healthcare. For this purpose, this study was carried out in order to assess the community's Willingness to Pay (WTP) for CBHIS and its determinants among the residents of Lahore City. A cross-sectional study was adopted during the period of May 2018 to August 2018 to conduct a standardized questionnaire survey among targeted population of Lahore. A total of 250 households from lower, middle and upper-middle-class areas were approached randomly from which 200 participated in the survey, rendering a response rate of 90.9%. Sample size was determined by using single population proportion formula assuming 5% margin of error and 95% Confidence Interval (CI). Moreover, multiple regression analysis, Pearson's correlation and t-test were employed to determine relationships between different variables affecting WTP. Sixty-four percent of the respondents were willing to pay for CBHIS. Among the remaining thirty-six% of unwilling the community, income level (p< 0.05, CI=0.34 to 1.11) and education level (p< 0.05, CI=0.52-1.37) were significant predictors of WTP. Moreover, strong positive relation (p<0.05) between people's awareness and WTP for CBHIS was witnessed. The findings further suggested that the larger population of the willing community was not willing to pay more than 5000 Rs annually. Henceawareness level of the community regarding the benefits of CBHIS is a major hindrance. The key policy priority is to increase the community's awareness regarding the benefits of CBHIS and to increase willingness to pay rate among public.


Nature, content and shifts over time of the most impactful unruptured intracranial aneurysms articles: a bibliometric analysis.
The management of unruptured intracranial aneurysms (UIAs) has evolved significantly over the last few decades. Our objective was to evaluate the 100 most cited UIA articles by bibliometric analysis to identify nature, content and shifts over time. Elsevier's Scopus database was interrogated for the 100 most cited articles that focused on UIA. Older versus newer articles were compared, with categorical data analyzed using Pearson's Chi-square, and continuous data analyzed using Wilcoxon's rank-sum test. The 100 most cited articles were published between 1975 and 2015, with the majority of these reporting patient clinical outcomes (n=69). There were 47/69 (68%) articles that described surgical intervention, with 38/47 (81%) and 18/47 (38%) including endovascular and open approaches, respectively . Publications peaked in 2004 (n=8), and the most common country of correspondence was the United States (n=59). Compared to older articles, newer articles had statistically higher citation rates (P<0.01), higher number of authors (P<0.01) with more multiple institution collaborations (P=0.01), greater disclosures of funding (P<0.01), more focus on endovascular treatments (P=0.04), in more journals with a clinical, non-surgical focus (P<0.01) published under open access policies (P<0.01). In the 100 most cited articles about UIAs to date, there is a distinct shift towards more co-authored efforts utilizing multi-institutional efforts focused on endovascular approaches supported by funding. The emergence of endovascular techniques has refreshed the need for more contemporary rupture risk prediction models and natural history data to validate current attitudes towards clinical management after these minimally invasive procedures for UIAs.


MicroRNA-24 regulates vascularity after myocardial infarction.
Myocardial infarction leads to cardiac remodeling and development of heart failure. Insufficient myocardial capillary density after myocardial infarction has been identified as a critical event in this process, although the underlying mechanisms of cardiac angiogenesis are mechanistically not well understood. Here, we show that the small noncoding RNA microRNA-24 (miR-24) is enriched in cardiac endothelial cells and considerably upregulated after cardiac ischemia. MiR-24 induces endothelial cell apoptosis, abolishes endothelial capillary network formation on Matrigel, and inhibits cell sprouting from endothelial spheroids. These effects are mediated through targeting of the endothelium-enriched transcription factor GATA2 and the p21-activated kinase PAK4, which were identified by bioinformatic predictions and validated by luciferase gene reporter assays. Respective downstream signaling cascades involving phosphorylated BAD (Bcl-XL/Bcl-2-associated death promoter) and Sirtuin1 were identified by transcriptome, protein arrays, and chromatin immunoprecipitation analyses. Overexpression of miR-24 or silencing of its targets significantly impaired angiogenesis in zebrafish embryos. Blocking of endothelial miR-24 limited myocardial infarct size of mice via prevention of endothelial apoptosis and enhancement of vascularity, which led to preserved cardiac function and survival. Our findings indicate that miR-24 acts as a critical regulator of endothelial cell apoptosis and angiogenesis and is suitable for therapeutic intervention in the setting of ischemic heart disease.


The impact of mid-treatment MRI on defining boost volumes in the radiation treatment of glioblastoma multiforme.
Radiation therapy is a central modality in the treatment of glioblastoma multiforme (GBM). Integral to adequate radiation therapy delivery is the appropriate determination of tumor volume and extent at the time treatment is being delivered. As a matter of routine practice, radiation therapy treatment fields are designed based on tumor volumes evident on pre-operative or immediate post-operative MRIs; another MRI is generally not obtained for planning boost fields. In some instances the time interval from surgery to radiotherapy initiation is up to 5 weeks and the boost or "cone-down phase" commences 4-5 weeks later. The contrast enhanced T1 MRI may not be a totally reliable indicator of active tumor, especially in regions where such blood-brain barrier breakdown has not occurred. Moreover, these volumes may change during the course of treatment. This may lead to a geographic miss when mid-treatment boost volumes are designed based on a pre-radiotherapy MRI. The goal of this study is to examine how a mid-treatment MRI impacts the delineation and definition of the boost volume in GBM patients in comparison to the pre-treatment MRI scan, particularly when the tumor-specific agent Motexafin-Gadolinium is used.


Interdomain information transfer during substrate activation of yeast pyruvate decarboxylase: the interaction between cysteine 221 and histidine 92.
Oligonucleotide-directed site-specific mutagenesis was carried out on pyruvate decarboxylase (EC 184.108.40.206) from Saccharomyces cerevisiae at two cysteines on the beta domain (221 and 222) and at H92 on the alpha domain, across the domain divide from C221. While C221 has been shown to provide the trigger for substrate activation [Baburina, I., et al. (1994) Biochemistry 33, 5630-5635], the information must be transmitted from the substrate bound at this site [Arjunan, D., et al. (1996) J. Mol. Biol. 256, 590-600] to the active center thiamin diphosphate located at the interface of the alpha and gamma domains. Substitution at H92 with G, A, or C leads to great reduction of the Hill coefficient (from 2.0 in the wild-type enzyme to 1.2-1.3), while substitution for Lys affords an active enzyme with a Hill coefficient of 1.5-1.6. Iodoacetate at 10 mM reduced the Hill coefficient from 2.0 to 1.1, while also causing significant inactivation of the enzyme, presumably by carboxymethylation of C221. 1,3-Dibromoacetone, a potential cross-linker when added to the H92C/C222S variant at 0.1 mM, abolished substrate activation while reducing the activity only by 30%. Therefore, 1,3-dibromoacetone may cross-link C92 and C221. It was concluded that H92 is on the information transfer pathway during the substrate activation process and the interaction between C221 on the beta domain and H92 on the alpha domain is required for substrate activation. Extensive pH studies of the steady-state kinetic constants provide support for the interaction of C221 and H92 and the transmission of regulatory information to the active center via this pathway and pKaS for the two groups. This important interaction between the C221-bound pyruvate and His92 probably has both electrostatic and steric components.


Liver transplantation in the first three months of life.
Pediatric liver transplant recipients have traditionally been grouped according to age. Age-based classification schemes are useful in identifying clinical problems in selected age groups and also for developing solutions to these problems. Although infants in the first 3 months of life have not traditionally been considered a distinct age group, several features of these infants may distinguish them from other pediatric liver transplant recipients. The experience with liver transplantation in infants during the first 3 months of life in three large pediatric liver transplant programs (University of Chicago, Stanford University, and UCLA) was analyzed in order to characterize this group. A total of 23 liver transplants were performed at these three centers in children younger than 3 months of age. This group of patients comprised approximately 37% of the U.S. experience between 1988 and 1994 according to United Network for Organ Sharing statistics. Age distribution at the time of transplantation included the following: <1 month, 28%; 1-2 months, 35%; and 2-3 months, 36%. Median age at the time of transplantation was 37 days (range, 7-90 days), and mean age was 57+/-30 days. Mean weight at the time of transplantation was 3.8+/-1.0 kg. Etiology of liver disease included idiopathic hepatitis, 52%; iron storage disease, 17%; and other causes, 31%. Types of liver allografts used included cadaveric, 85% (reduced size, 60%, and full-size, 25%); living donor, 15%; ABO-identical, 65%; and ABO-compatible, 35%. Actuarial patient and graft survival rates were 60% and 60% at 1 year and 60% and 42% at 2 years, respectively. Median follow-up was 1.5 years. Rejection occurred in 42% of patients, with a median time to first rejection of 13 days. Of these patients, 28% required steroids only and 14% required OKT3. Three patients (14%) were retransplanted at a median time to retransplantation of 1.6 years. Vascular thrombosis occurred in three patients (14%). Liver transplantation performed in infants younger than 3 months of age (1) provides acceptable short- and long-term patient and graft survival, (2) is associated with significant rates of rejection, and (3) is not associated with excessive rates of vascular thrombosis. The etiology of end-stage liver disease occurring in the first 3 months of life is distinct from that in other pediatric liver transplant recipient age groups. These infants should be referred promptly for liver transplantation as reasonable survival can be expected.


Development of an 18S rRNA gene-targeted PCR-based diagnostic for the blue crab parasite Hematodinium sp..
The 18S rRNA gene from Hematodinum sp., a parasitic dinoflagellate that infects blue crabs, was amplified, cloned, and sequenced. The sequence showed a high similarity (95% at the nucleotide level) to sequences obtained from other dinoflagellate species, including both free-living and symbiotic species. Sequence similarity was much lower when compared with parasites of other marine invertebrates with similar life histories and with the 18S rRNA gene from the blue crab. Based on comparison of sequence alignments between Hematodinium, other dinoflagellate species, protozoan pathogens of oysters, and blue crab 18S rRNA gene sequences, 2 sets of PCR primers that specifically amplified fragments of the Hematodinium 18S rRNA gene were developed and tested. One of these primer sets (Hemat-F-1487 and Hemat-R-1654) amplified a 187 bp fragment that could be used routinely as a diagnostic test for the presence of Hematodinium in hemolymph from blue crabs. This fragment was consistently amplified from genomic DNA extracted from hemolymph of Hematodinium infected blue crabs. Comparison between the PCR technique and standard histological examination indicated that the PCR technique was reliable and provided 1000 times more sensitivity than the histological methods. The sensitivity of the PCR diagnostic was estimated to be one parasite cell among 300,000 crab hemocytes. Preliminary studies using the PCR diagnostic technique suggest that Hematodinium sp. is absent in crabs collected from waters with low salinity (5 to 10 ppt), but common in crabs from higher salinity environments in estuarine waters from southeastern Georgia (USA).


"On water" catalytic enantioselective sulfenylation of deconjugated butyrolactams.
The first catalytic enantioselective α-sulfenylation of deconjugated butyrolactams has been developed using dimeric cinchona alkaloids as catalysts in a water-enriched reaction medium. Highly substituted and densely functionalized γ-lactams, bearing a quaternary stereogenic center, are produced with up to 99.5 : 0.5 er. The applicability of the same catalyst system for the enantioselective α-selenylation and formal vinylogous γ-hydroxylation of deconjugated butyrolactam has also been described.


Regulation of cytosolic aspartate aminotransferase mRNAs in the Fao rat hepatoma cell line by dexamethasone, insulin and cyclic AMP.
Glucocorticoid hormones increase the activity of cytosolic aspartate aminotransferase (cAspAT) in the Fao rat hepatoma cell line. Maximal increase (6-10-fold) was observed 48 h following the addition of the glucocorticoid agonist dexamethasone at a concentration of 0.1 microM. The effect of dexamethasone was specific since it was not mimicked by sex steroids and was inhibited by the glucocorticoid antagonist RU 486. Insulin (0.1 microM) inhibited by more than 50% the induction of cAspAT by glucocorticoids. The cAMP analog, 8-bromoadenosine 3',5'-monophosphate (Br8cAMP, 0.5 mM), potentiated the effect of dexamethasone (2-3-fold) and partially relieved the inhibitory effect of insulin on the induction by dexamethasone. Both insulin and Br8-cAMP had no significant effect on basal activity. The mitochondrial isoenzyme was insensitive to the various hormonal treatments. Northern blot analysis revealed the presence of two major (2.1-kb and 1.8-kb) and one minor (4-kb) mRNA species hybridizing with a rat cAspAT probe. The regulation of these mRNAs by glucocorticoids, insulin and cAMP correlated with the variation of the cAspAT activity, suggesting that these hormones act at the pretranslational level. We compared the regulation of cAspAT mRNAs with those of tyrosine aminotransferase mRNA. Both were similarly increased by dexamethasone but the latter was also increased by cAMP even in the absence of the glucocorticoid agonist. In addition, the increase in tyrosine aminotransferase mRNA was inhibited by cycloheximide whereas the increase in cAspAT mRNAs was not. These results show that there are significant differences in the regulation of cAspAT and tyrosine aminotransferase by glucocorticoids and other hormones, although both enzymes probably contribute to the same metabolic pathway.


Branch-specific plasticity enables self-organization of nonlinear computation in single neurons.
It has been conjectured that nonlinear processing in dendritic branches endows individual neurons with the capability to perform complex computational operations that are needed to solve for example the binding problem. However, it is not clear how single neurons could acquire such functionality in a self-organized manner, because most theoretical studies of synaptic plasticity and learning concentrate on neuron models without nonlinear dendritic properties. In the meantime, a complex picture of information processing with dendritic spikes and a variety of plasticity mechanisms in single neurons has emerged from experiments. In particular, new experimental data on dendritic branch strength potentiation in rat hippocampus have not yet been incorporated into such models. In this article, we investigate how experimentally observed plasticity mechanisms, such as depolarization-dependent spike-timing-dependent plasticity and branch-strength potentiation, could be integrated to self-organize nonlinear neural computations with dendritic spikes. We provide a mathematical proof that, in a simplified setup, these plasticity mechanisms induce a competition between dendritic branches, a novel concept in the analysis of single neuron adaptivity. We show via computer simulations that such dendritic competition enables a single neuron to become member of several neuronal ensembles and to acquire nonlinear computational capabilities, such as the capability to bind multiple input features. Hence, our results suggest that nonlinear neural computation may self-organize in single neurons through the interaction of local synaptic and dendritic plasticity mechanisms.


Detection of nociceptive-related metabolic activity in the spinal cord of low back pain patients using 18F-FDG PET/CT.
Over the past couple of decades, a number of centers in the brain have been identified as important sites of nociceptive processing and are collectively known as the 'pain matrix.' Imaging tools such as functional magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) have played roles in defining these pain-relevant, physiologically active brain regions. Similarly, certain segments of the spinal cord are likely more metabolically active in the setting of pain conditions, the location of which is dependent upon location of symptoms. However, little is known about the physiologic changes in the spinal cord in the context of pain. This study aimed to determine whether uptake of 18F-FDG in the spinal cord on positron emission tomography/computed tomography (PET/CT) of patients with low back pain (LBP) differs from that of patients without LBP. We conducted a retrospective review of 18F-FDG PET/CT scans of 26 patients with non-central nervous system cancers, 13 of whom had reported LBP and 13 of whom were free of LBP (controls). No patients had spinal stenosis or significant 18F-FDG contribution of degenerative changes of the spine into the spinal canal. Circular regions of interests were drawn within the spinal canal on transaxial images, excluding bony or discal elements of the spine, and the maximum standardized uptake value (SUVmax) of every slice from spinal nerves C1 to S1 was obtained. SUVmax were normalized by subtracting the SUVmax of spinal nerve L5, as minimal neural tissue is present at this level. Normalized SUVmax of LBP patients were compared to those of LBP-free patients at each vertebral level. We found the normalized SUVmax of patients with LBP to be significantly greater than those of control patients when jointly tested at spinal nerves of T7, T8, T9 and T10 (p<0.001). No significant difference was found between the two groups at other levels of the spinal cord. Within the two groups, normalized SUVmax generally decreased cephalocaudally. Patients with LBP show increased uptake of 18F-FDG in the caudal aspect of the thoracic spinal cord, compared to patients without LBP. This paper demonstrates the potential of 18F-FDG PET/CT as a biomarker of increased metabolic activity in the spinal cord related to LBP. As such, it could potentially aid in the treatment of LBP by localizing physiologically active spinal cord regions and guiding minimally invasive delivery of analgesics or stimulators to relevant levels of the spinal cord.


Can 3 mg·kg-1 of Caffeine Be Used as An Effective Nutritional Supplement to Enhance the Effects of Resistance Training in Rugby Union Players?
The present study uniquely examined the effect of 3 mg·kg-1 chronic caffeine consumption on training adaptations induced by 7-weeks resistance training and assessed the potential for habituation to caffeine's ergogenicity. Thirty non-specifically resistance-trained university standard male rugby union players (age (years): 20 ± 2; height (cm): 181 ± 7; body mass (kg): 92 ± 17) completed the study), who were moderate habitual caffeine consumers (118 ± 110 mg), completed the study. Using a within-subject double-blind, placebo-controlled experimental design, the acute effects of caffeine intake on upper and lower limb maximal voluntary concentric and eccentric torque were measured using isokinetic dynamometry (IKD) prior to and immediately following a resistance training intervention. Participants were split into strength-matched groups and completed a resistance-training program for seven weeks, consuming either caffeine or a placebo before each session. Irrespective of group, acute caffeine consumption improved peak eccentric torque of the elbow extensors (p < 0.013), peak concentric torque of the elbow flexors (p < 0.005), total eccentric work of the elbow flexors (p < 0.003), total concentric work of the knee extensors (p < 0.001), and total concentric and eccentric work of the knee flexors (p < 0.046) following repeated maximal voluntary contractions. Many of these acute caffeine effects were still prevalent following chronic exposure to caffeine throughout the intervention. The training intervention resulted in significant improvements in upper and lower body one-repetition maximum strength (p < 0.001). For the most part, the effect of the training intervention was equivalent in both the caffeine and placebo groups, despite a small but significant increase (p < 0.037) in the total work performed in the participants that consumed caffeine across the course of the intervention. These results infer that caffeine may be beneficial to evoke acute improvements in muscular strength, with acute effects prevalent following chronic exposure to the experimental dose. However, individuals that consumed caffeine during the intervention did not elicit superior post-intervention training- induced adaptations in muscular strength.


Gestalt Reasoning with Conjunctions and Disjunctions.
Reasoning, solving mathematical equations, or planning written and spoken sentences all must factor in stimuli perceptual properties. Indeed, thinking processes are inspired by and subsequently fitted to concrete objects and situations. It is therefore reasonable to expect that the mental representations evoked when people solve these seemingly abstract tasks should interact with the properties of the manipulated stimuli. Here, we investigated the mental representations evoked by conjunction and disjunction expressions in language-picture matching tasks. We hypothesised that, if these representations have been derived using key Gestalt principles, reasoners should use perceptual compatibility to gauge the goodness of fit between conjunction/disjunction descriptions (e.g., the purple and/ or the green) and corresponding binary visual displays. Indeed, the results of three experimental studies demonstrate that reasoners associate conjunction descriptions with perceptually-dependent stimuli and disjunction descriptions with perceptually-independent stimuli, where visual dependency status follows the key Gestalt principles of common fate, proximity, and similarity.


Health of Immigrant Children: The Role of Immigrant Generation, Exogamous Family Setting, and Family Material and Social Resources.
Although the children of first-generation immigrants tend to have better health than the native population, the health advantage of the children of immigrant families deteriorates over generations. It is, however, poorly understood where on the generational health assimilation spectrum children with one immigrant and one native parent (i.e., exogamous families) lie, to what extent family resources explain health assimilation, and whether the process of assimilation varies across health conditions. We seek to extend our understanding of the process of health assimilation by analyzing the physical and mental health of immigrant generations, assessing the role of exogamous family arrangements, and testing the contributions of family material and social resources to children's outcomes. We use register-based longitudinal data on all children residing in Finland, born in 1986-2000, and alive in 2000; these data are free of reporting bias and loss to follow-up. We estimate the risk of receiving inpatient and outpatient care for somatic conditions, psychopathological disorders, and injuries by immigrant generation status. Our results show evidence of a negative health assimilation process, with both first- and second-generation immigrant children having a higher prevalence of physical problems and particularly mental health problems than native children that is only partially explained by family resources. We find that the children of exogamous families are at especially high risk of developing psychopathological disorders. These results provide strong support for the hypothesis that children of exogamous families constitute a specific health risk group and that the impact on children's health of family social and material resources seems to be secondary to other unobserved factors.


Tricks an IRES uses to enslave ribosomes.
In eukaryotes, mRNAs are primarily translated through a cap-dependent mechanism whereby initiation factors recruit the 40S ribosomal subunit to a cap structure at the 5' end of the mRNA. However, some viral and cellular messages initiate protein synthesis without a cap. They use a structured RNA element termed an internal ribosome entry site (IRES) to recruit the 40S ribosomal subunit. IRESs were discovered over 20 years ago, but only recently have studies using a model IRES from dicistroviruses expanded our understanding of how a 3D RNA structure can capture and manipulate the ribosome to initiate translation.


Breaking the Law of Valgus: the surprising and unexplained prevalence of medial patellofemoral cartilage damage.
To compare the prevalence of medial and lateral patellofemoral (PF) cartilage damage in three large osteoarthritis (OA) studies and determine the relationship of this damage to varus, neutral and valgus knee alignment. In the Boston OA of the Knee, Framingham OA and Multicenter OA studies, MRIs were read for cartilage morphology at the medial and lateral patella and trochlea femoris using Whole-Organ MRI Scores (WORMS). WORMS scores ≥2 (any cartilage defect), ≥3 (areas of partial thickness loss), ≥4 (diffuse partial thickness loss) and ≥5 (extensive full thickness loss) were all variously considered as thresholds to identify damage that may indicate OA. Full-limb radiographs were measured for mechanical alignment, and varus (<-2°), neutral (-2° to 2°) and valgus (>2°) knees were identified. The prevalence of medial PF cartilage damage exceeded that of lateral damage in all three studies and according to nearly every threshold. Only among severely involved knees (WORMS ≥4 or ≥5) did the prevalence of lateral PF cartilage damage approximate that of medial damage. The high prevalence of medial PF damage persisted in all strata of knee alignment. Even among knees with valgus alignment, the prevalence of lateral PF cartilage damage equalled or surpassed that of medial PF damage only when the threshold was specific to severely involved knees. Medial PF cartilage damage is at least as prevalent within these older adult populations as lateral PF cartilage damage.


Experiences of older people following an acute exacerbation of chronic obstructive pulmonary disease: A phenomenological study.
To explore the experience of patients affected by chronic obstructive pulmonary disease following hospitalisation due to an acute exacerbation event. Chronic obstructive pulmonary disease is a progressively debilitating disease, often with very burdensome symptoms such as acute and chronic breathlessness and fatigue. Acute exacerbation often creates a life-threatening event. Exacerbation can also have substantial psychological effects including anxiety and depression although this aspect is less well researched-especially amongst people with chronic obstructive pulmonary disease recovering from an acute event and facing a return home. A descriptive phenomenological study. In-depth interviews were conducted with 12 chronic obstructive pulmonary disease patients recently recovering from an acute exacerbation of their chronic obstructive pulmonary disease. Data were analysed using Colaizzi's phenomenological framework. Four themes were identified from the data: a sense of loss and frustration, hopelessness, uncertainty about the future and fear of becoming a burden. Participants expressed quite negative views including a loss of hope, uncertainty about their future care and the burden they may become on their families. They appeared stressed and anxious as a result of the acute event they had experienced. This study shows that an acute episode of illness can generate a sense of hopelessness and uncertainty about their future care in people with chronic obstructive pulmonary disease. This occurs as they recover physically and think about the future, often in quite negative terms. For healthcare professionals, it is important to take into account the potential feelings of loss, hopelessness and uncertainty that people can experience following an acute exacerbation of their chronic obstructive pulmonary disease and ensure that psychological care is available as physical recovery takes place. Such care to include good discharge planning, giving patients time to express concerns and referral to counselling services if appropriate.


Mucin-rich variant of traditional serrated adenoma: a distinct morphological variant.
Traditional serrated adenomas (TSAs) account for 5% of serrated polyps, and have a villiform architecture, eosinophilic cells with a brush border, and indented, flat-topped luminal serrations. However, some are composed of mucin-filled goblet cells (GCs): mucin-rich TSA (MrTSA). The aim of this study was to determine whether this variant has unique features as compared with classic TSA (cTSA). One hundred and fifty-six TSAs were retrieved from the period 2010-2016. Patient demographics, site of polyps and 16 microscopic variables were evaluated. TSAs containing ≥50% GCs were classified as MrTSAs. Ectopic crypt foci (ECFs) were quantified as low (1-10) or high (>10), counted at ×200 magnification, and the average was taken for 10 fields. Twenty-four fulfilled the criteria for MrTSA. In males, MrTSAs (65%) were more prevalent than cTSAs (55%). There was no age difference, and both variants had a predilection for the left colon, although, in the right colon, MrTSAs were more frequent (39%) than cTSAs (10%) (P = 0.012). Adenomatous dysplasia was present in four of 24 MrTSAs (low grade, 3; high grade, 1). The most distinctive features of MrTSAs were: a variable growth pattern [endophytic (9%), mixed (30%), or villiform/exophytic (61%)], and a lower frequency of ECFs (P = 0.001) and more intraepithelial lymphocytes (P < 0.05) than in cTSAs. MrTSAs retain characteristic luminal serrations, at least focally. Inflamed MrTSAs can mimic inflammatory polyps and hamartomatous polyps (when there are >95% GCs). MrTSA is characterized by >50% GCs, and fewer ECFs than cTSA, but with preservation of archetypal luminal serrations. Awareness of this variant will prevent misdiagnosis, given the association of TSA with the accelerated pathway to colorectal cancer.


Early steatohepatitis in hyperlipidemic mice with endothelial-specific gain of TRPC3 function precedes changes in aortic atherosclerosis.
Nonalcoholic fatty liver disease (NAFLD) and its more advanced form nonalcoholic steatohepatitis (NASH) are the most common chronic liver diseases in developed countries. Moreover, NAFLD and NASH are considerable risk factors for atherosclerosis, the most frequent vascular pathology in these and other metabolic diseases. Despite this strong connection, current knowledge of the relationship between NAFLD/NASH and atherosclerosis is scarce. Recently, we studied hyperlipidemic Apoe knockout mice with endothelial-specific gain of transient receptor potential canonical 3 channel function (TgESTRPC3/ApoeKO) and found that these animals had increased burden of advanced aortic atherosclerosis (16 wk on high-fat diet) compared with nontransgenic ApoeKO littermate controls (non-Tg/ApoeKO), whereas early lesions (10 wk on high-fat diet) were not different. Here, we report that at the early stage when differences in aortic atherosclerosis are not yet manifest, the livers of TgESTRPC3/ApoeKO mice show steatosis, fibrosis, and altered hepatic enzymes compared with non-Tg/ApoeKO animals. Because differences in liver pathology were noticeable long before differences in atherosclerosis were evident, our studies suggest that TRPC3-related endothelial mechanisms that promote steatohepatitis may also contribute to atherosclerosis progression. In vitro, downregulation of TRPC3 in liver sinusoid endothelial cells reduces their susceptibility to endoplasmic reticulum stress-induced apoptosis, suggesting that a proapoptotic effect of TRPC3 may add to other fibrogenic factors in vivo. These novel findings show a positive association between augmented expression of an endothelial TRPC channel, development of early steatohepatitis, and atherosclerotic burden in a hyperlipidemic mouse model of NAFLD fed conventional Western-type diet.


3. Adhesion molecules and receptors.
Adhesion molecules are necessary for leukocyte trafficking and differentiation. They serve to initiate cell-cell interactions under conditions of shear, and they sustain the cell-cell and cell-matrix interactions needed for cellular locomotion. They also can serve directly as signaling molecules activating pathways critical to cell functions, and they can act as accessory molecules maintaining cellular contacts necessary for signaling through other receptors. Given their critical role in the emigration of leukocytes into sites of inflammation, genetic mutations that thwart adhesion molecule expression or function can produce profound disruptions in host defense. Adhesion molecules might serve as therapeutic targets for inflammatory diseases.


RANTES: a versatile and controversial chemokine.
The activity of the chemokine RANTES is not restricted merely to chemotaxis. It is a powerful leukocyte activator, a feature potentially relevant in a range of inflammatory disorders. RANTES has attracted attention because it can potently suppress and, in some circumstances, enhance HIV replication. These characteristics are critically dependent on its ability to self-aggregate and bind to glycosaminoglycans.


Impacts of invasive plants on carbon pools depend on both species' traits and local climate.
Invasive plants can alter ecosystem properties, leading to changes in the ecosystem services on which humans depend. However, generalizing about these effects is difficult because invasive plants represent a wide range of life forms, and invaded ecosystems differ in their plant communities and abiotic conditions. We hypothesize that differences in traits between the invader and native species can be used to predict impacts and so aid generalization. We further hypothesize that environmental conditions at invaded sites modify the effect of trait differences and so combine with traits to predict invasion impacts. To test these hypotheses, we used systematic review to compile data on changes in aboveground and soil carbon pools following non-native plant invasion from studies across the World. Maximum potential height (Hmax ) of each species was drawn from trait databases and other sources. We used meta-regression to assess which of invasive species' Hmax , differences in this height trait between native and invasive plants, and climatic water deficit, a measure of water stress, were good predictors of changes in carbon pools following invasion. We found that aboveground biomass in invaded ecosystems relative to uninvaded ones increased as the value of Hmax of invasive relative to native species increased, but that this effect was reduced in more water stressed ecosystems. Changes in soil carbon pools were also positively correlated with the relative Hmax of invasive species, but were not altered by water stress. This study is one of the first to show quantitatively that the impact of invasive species on an ecosystem may depend on differences in invasive and native species' traits, rather than solely the traits of invasive species. Our study is also the first to show that the influence of trait differences can be altered by climate. Further developing our understanding of the impacts of invasive species using this framework could help researchers to identify not only potentially dangerous invasive species, but also the ecosystems where impacts are likely to be greatest.


Increased mesolimbic GABA concentration blocks heroin self-administration in the rat.
Opiate reinforcement has been hypothesized to be mediated by an inhibition of mesolimbic gamma-aminobutyric acid (GABA) release that subsequently disinhibits ventral tegmental area (VTA) dopamine neurons. In support of this hypothesis, this study demonstrates that when administered directly into the lateral ventricle, the VTA, or the ventral pallidum, but not the nucleus accumbens, gamma-vinyl-GABA (GVG, an irreversible GABA-transaminase inhibitor, 20-50 microg) dose dependently blocked heroin (0.06 mg/kg) self-administration (SA), as assessed by an increase in heroin SA at low doses of GVG and an initial increase followed 1 to 2 h later by a blockade of heroin SA at higher GVG doses. This effect lasted 3 to 5 days. In drug-naïve rats, intra-VTA GVG pretreatment also prevented or delayed acquisition of heroin SA for 2 days. This GVG effect was prevented or reversed by systemic or intra-VTA pretreatment with the GABA(B) antagonist 2-hydroxysaclofen, but not the GABA(A) antagonist bicuculline. Similarly, coadministration of heroin with aminooxy-acetic acid (1-4 mg/kg) or ethanolamine-O-sulfate (50-100 mg/kg), two reversible GABA transaminase inhibitors, dose dependently reduced heroin reinforcement. Coadministration of (+/-)-nipecotic acid (0.1-5 mg/kg) with heroin, or intra-VTA or -ventral pallidum pretreatment with (+/-)-nipecotic acid (10 microg) or NO-711 (2 microg), two GABA uptake inhibitors, significantly increased heroin SA behavior, an effect also blocked by systemic 2-hydroxysaclofen, but not bicuculline. Taken together, these experiments, for the first time, demonstrate that pharmacological elevation of mesolimbic GABA concentration blocks heroin reinforcement by activating GABA(B) receptors, supporting the GABAergic hypothesis of opiate reinforcement and the incorporation of GABA agents in opiate abuse treatment.


Comparison of four schistosome excretory-secretory antigens: phenol sulfuric test active peak, cathodic circulating antigen, gut-associated proteoglycan, and circulating anodic antigen.
Several carbohydrate-containing antigens of schistosomes have been characterized and tests for these antigens or for the corresponding antibodies are increasingly being used for the diagnosis and clinical analysis of human schistosomiasis. Phenol sulfuric active peak (PSAP) and cathodic circulating antigen (CCA) are 2 soluble glycoproteins found in adult worms of Schistosoma mansoni. These antigens have some similar characteristics including solubility in trichloroacetic acid and non-binding or weak binding to DEAE cellulose which suggests these 2 compounds to be identical. PSAP and CCA were therefore compared using radioimmunoassays employing monoclonal antibodies to CCA and radiolabeled PSAP as well as inhibitory assays using the original glycoproteins as inhibitors. By these criteria PSAP and CCA were found to be different glycoproteins. Using similar techniques, 2 anodic schistosome compounds, gut-associated proteoglycan (GASP) and circulating anodic antigen (CAA) were found to be identical. We now propose to call this later material GASCAP (gut-associated circulating anodic proteoglycan).


Accuracy analysis of fMRI and MEG activations determined by intraoperative mapping.
By looking at how the accuracy of preoperative brain mapping methods vary according to differences in the distance from the activation clusters used for the analysis, the present study aimed to elucidate how preoperative functional neuroimaging may be used in such a way that maximizes the mapping accuracy. The eloquent function of 19 patients with a brain tumor or cavernoma was mapped prior to resection with both functional MRI (fMRI) and magnetoencephalography (MEG). The mapping results were then validated using direct cortical stimulation mapping performed immediately after craniotomy and prior to resection. The subset of patients with equivalent MEG and fMRI tasks performed for motor (n = 14) and language (n = 12) were evaluated as both individual and combined predictions. Furthermore, the distance resulting in the maximum accuracy, as evaluated by the J statistic, was determined by plotting the sensitivities and specificities against a linearly increasing distance threshold. fMRI showed a maximum mapping accuracy at 5 mm for both motor and language mapping. MEG showed a maximum mapping accuracy at 40 mm for motor and 15 mm for language mapping. At the standard 10-mm distance used in the literature, MEG showed a greater specificity than fMRI for both motor and language mapping but a lower sensitivity for motor mapping. Combining MEG and fMRI showed a maximum accuracy at 15 mm and 5 mm-MEG and fMRI distances, respectively-for motor mapping and at a 10-mm distance for both MEG and fMRI for language mapping. For motor mapping, combining MEG and fMRI at the optimal distances resulted in a greater accuracy than the maximum accuracy of the individual predictions. This study demonstrates that the accuracy of language and motor mapping for both fMRI and MEG is heavily dependent on the distance threshold used in the analysis. Furthermore, combining MEG and fMRI showed the potential for increased motor mapping accuracy compared to when using the modalities separately.Clinical trial registration no.: NCT01535430 (clinicaltrials.gov).


Health economic value of an innovation: delimiting the scope and framework of future market entry agreements.
The objective of our paper is to offer a new, payer-friendly taxonomy of market entry agreements (MEAs) that aims to twin contracts with their methodological designs in an effort to clarify the distinction between contracts that are based on performance and those that are based on demonstrated effect. Our analysis proceeds in two stages: First, we delimit the scope and framework of pay for performance (P4P) and pay for demonstrated effect (P4E) agreements. Second, we distinguish the methodological designs supporting the implementation of each of these contracts. We elucidate why P4P contracts prevent the payer from funding the true effectiveness of an innovation by expanding on their limitations. These include: 1) the normative nature of comparisons, 2) the impossibility of true effect imputability for each individual, and 3) the use of intermediary outcome measures. We then explore three main criticisms that payers must take into account when reasoning in terms of performance rather than in terms of the product effectiveness. The potential effect that performance-based reimbursements may have on dissociating the components of the cost-effectiveness ratio constitutes an obstacle to a true health economic reasoning.


Effect of estradiol on human breast cancer cells in culture.
Conditions are described for growing and maintaining the estradiol sensitivity of the human breast cancer cell line ZR-75-1 both in monolayer and suspension cultures. Either newborn calf or fetal calf serum can be used in the culture medium, but an effect of estradiol on growth of the cells was only observed reproducibly if the serum was first treated with dextran-charcoal. Sulfatase treatment of the sera prior to dextran-charcoal treatment did not decrease cell growth in the absence of added estradiol, indicating that estrogen sulfates are unlikely to contribute to cell growth in dextran-charcoal-treated sera. In monolayer cultures, estradiol increased both the growth rate and final saturation density of the cells for each individual plating density tested in a dose-dependent manner with maximal stimulation occurring between 10(-10) and 10(-8) M estradiol. Estradiol also markedly increased the ability of the cells to grow both in suspension and semisolid Methocel cultures. In suspension, the cells grew as tight balls which clustered together to give small organoid-like structures reaching diameters of 4 mm and composed of an outer shell of living cells containing a central cavity of necrotic cells. In the absence of estradiol in both monolayer and suspension, the cells went through a limited and constant number of divisions and then stopped, such that the final cell number was determined by the initial plating density. In the presence of estradiol, this block was removed such that in monolayer cultures the final cell number was independent of plating density. A major loss of estradiol response was found if the cells were grown for 7 to 14 days in the absence of estradiol. This loss of response appeared to be due to a loss of ability to grow rather than to selective cell death within the population.


Sensemaking, stakeholder discord, and long-term risk communication at a US Superfund site.
Risk communication can help reduce exposures to environmental contaminants, mitigate negative health outcomes, and inform community-based decisions about hazardous waste sites. While communication best practices have long guided such efforts, little research has examined unintended consequences arising from such guidelines. As rhetoric informs stakeholder sensemaking, the language used in and reinforced by these guidelines can challenge relationships and exacerbate stakeholder tensions. This study evaluates risk communication at a U.S. Superfund site to identify unintended consequences arising from current risk communication practices. This qualitative case study crystallizes data spanning 6 years from three sources: 1) local newspaper coverage of site-related topics; 2) focus-group transcripts from a multi-year project designed to support future visioning of site use; and 3) published blog entries authored by a local environmental activist. Constant comparative analysis provides the study's analytic foundation, with qualitative data analysis software QSR NVivo 8 supporting a three-step process: 1) provisional coding to identify broad topic categories within datasets, 2) coding occurrences of sensemaking constructs and emergent intra-dataset patterns, and 3) grouping related codes across datasets to examine the relationships among them. Existing risk communication practices at this Superfund site contribute to a dichotomous conceptualization of multiple and diverse stakeholders as members of one of only two categories: the government or the public. This conceptualization minimizes perceptions of capacity, encourages public commitment to stances aligned with a preferred group, and contributes to negative expectations that can become self-fulfilling prophecies. Findings indicate a need to re-examine and adapt risk communication guidelines to encourage more pluralistic understanding of the stakeholder landscape.


New developments in tube shunt surgery.
This article reviews recent studies related to tube shunt surgery. Medical claims data and surveys of glaucoma surgeons demonstrate that tube shunts are being selected with increasing frequency as an alternative to trabeculectomy. A 5-year pooled analysis of the Ahmed Baerveldt comparison study and Ahmed versus Baerveldt study found a higher rate of surgical success with the Baerveldt glaucoma implant compared with the Ahmed glaucoma valve, but Baerveldt implantation carried a higher risk of hypotony. The primary tube versus trabeculectomy study showed trabeculectomy with mitomycin C produced greater intraocular pressure reduction with fewer glaucoma medications compared with tube shunt surgery as a primary procedure at 1 year, but trabeculectomy had a higher rate of postoperative complications. Adjunctive use of antifibrotic agents may enhance the success of tube shunt surgery. Implantation of a second tube shunt is effective in lowering intraocular pressure following primary tube shunt failure, but good results have also been reported with cyclophotocoagulation. Endothelial cell loss, diplopia, and tube shunt erosion are complications associated with these devices. The popularity of tube shunts has grown in recent years. Clinical trials and retrospective studies have provided valuable information to guide surgeons in the use of tube shunts. Increased efficacy of glaucoma procedures generally occurs at the cost of a higher risk of surgical complications.


Open "back door" in a molecular dynamics simulation of acetylcholinesterase.
The enzyme acetylcholinesterase generates a strong electrostatic field that can attract the cationic substrate acetylcholine to the active site. However, the long and narrow active site gorge seems inconsistent with the enzyme's high catalytic rate. A molecular dynamics simulation of acetylcholinesterase in water reveals the transient opening of a short channel, large enough to pass a water molecule, through a thin wall of the active site near tryptophan-84. This simulation suggests that substrate, products, or solvent could move through this "back door," in addition to the entrance revealed by the crystallographic structure. Electrostatic calculations show a strong field at the back door, oriented to attract the substrate and the reaction product choline and to repel the other reaction product, acetate. Analysis of the open back door conformation suggests a mutation that could seal the back door and thus test the hypothesis that thermal motion of this enzyme may open multiple routes of access to its active site.


Genome-scale phylogenetic function annotation of large and diverse protein families.
The Statistical Inference of Function Through Evolutionary Relationships (SIFTER) framework uses a statistical graphical model that applies phylogenetic principles to automate precise protein function prediction. Here we present a revised approach (SIFTER version 2.0) that enables annotations on a genomic scale. SIFTER 2.0 produces equivalently precise predictions compared to the earlier version on a carefully studied family and on a collection of 100 protein families. We have added an approximation method to SIFTER 2.0 and show a 500-fold improvement in speed with minimal impact on prediction results in the functionally diverse sulfotransferase protein family. On the Nudix protein family, previously inaccessible to the SIFTER framework because of the 66 possible molecular functions, SIFTER achieved 47.4% accuracy on experimental data (where BLAST achieved 34.0%). Finally, we used SIFTER to annotate all of the Schizosaccharomyces pombe proteins with experimental functional characterizations, based on annotations from proteins in 46 fungal genomes. SIFTER precisely predicted molecular function for 45.5% of the characterized proteins in this genome, as compared with four current function prediction methods that precisely predicted function for 62.6%, 30.6%, 6.0%, and 5.7% of these proteins. We use both precision-recall curves and ROC analyses to compare these genome-scale predictions across the different methods and to assess performance on different types of applications. SIFTER 2.0 is capable of predicting protein molecular function for large and functionally diverse protein families using an approximate statistical model, enabling phylogenetics-based protein function prediction for genome-wide analyses. The code for SIFTER and protein family data are available at http://sifter.berkeley.edu.


Contribution of semi-arid ecosystems to interannual variability of the global carbon cycle.
The land and ocean act as a sink for fossil-fuel emissions, thereby slowing the rise of atmospheric carbon dioxide concentrations. Although the uptake of carbon by oceanic and terrestrial processes has kept pace with accelerating carbon dioxide emissions until now, atmospheric carbon dioxide concentrations exhibit a large variability on interannual timescales, considered to be driven primarily by terrestrial ecosystem processes dominated by tropical rainforests. We use a terrestrial biogeochemical model, atmospheric carbon dioxide inversion and global carbon budget accounting methods to investigate the evolution of the terrestrial carbon sink over the past 30 years, with a focus on the underlying mechanisms responsible for the exceptionally large land carbon sink reported in 2011 (ref. 2). Here we show that our three terrestrial carbon sink estimates are in good agreement and support the finding of a 2011 record land carbon sink. Surprisingly, we find that the global carbon sink anomaly was driven by growth of semi-arid vegetation in the Southern Hemisphere, with almost 60 per cent of carbon uptake attributed to Australian ecosystems, where prevalent La Niña conditions caused up to six consecutive seasons of increased precipitation. In addition, since 1981, a six per cent expansion of vegetation cover over Australia was associated with a fourfold increase in the sensitivity of continental net carbon uptake to precipitation. Our findings suggest that the higher turnover rates of carbon pools in semi-arid biomes are an increasingly important driver of global carbon cycle inter-annual variability and that tropical rainforests may become less relevant drivers in the future. More research is needed to identify to what extent the carbon stocks accumulated during wet years are vulnerable to rapid decomposition or loss through fire in subsequent years.


Sound localization with bilateral cochlear implants in noise: how much do head movements contribute to localization?
Bilateral cochlear implant (CI) users encounter difficulties in localizing sound sources in everyday environments, especially in the presence of background noise and reverberation. They tend to show large directional errors and front-back confusions compared to normal hearing (NH) subjects in the same conditions. In this study, the ability of bilateral CI users to use head movements to improve sound source localization was evaluated. Speech sentences of 0.5, 2, and 4.5 seconds were presented in noise to the listeners in conditions with and without head movements. The results show that for middle and long signal durations, the CI users could significantly reduce the number of front-back confusions. The angular accuracy, however, did not improve. Analysis of head trajectories showed that the CI users had great difficulties in moving their head towards the position of the source, whereas the NH listeners targeted the source loudspeaker correctly.


Living donor lobar grafts improve pediatric lung retransplantation survival.
Lung retransplantation is a controversial practice due to increased morbidity and mortality and the scarcity of available donor organs. Living donor lobar lung transplantation increases the number of available donor organs and facilitates a more organized procedure than traditional cadaveric donation for this complex reoperation. The purpose of this study was to evaluate our experience with pediatric lung retransplantation and to compare the outcomes of living donor lobar lung transplantation with cadaveric donation. Retrospective review of a prospectively collected database identified 39 children who underwent lung retransplantation from 1991 to 2004. Retransplantation was performed with living donor lobar lung transplantation in 13 patients and cadaveric donation in 26 patients. Short- and long-term outcomes were compared between the 2 groups. Perioperative mortality was 1/13 (7.7%) in the patients who had living donor lobar lung transplantation versus 11/26 (42.3%) in the cadaveric donation group (P = .03). Five-year survival for living donor lobar lung transplantation and cadaveric donation was 40.4% and 29.7%, respectively (P = .27). Both groups had a significant improvement in their forced expiratory volume in 1 second 6 months after retransplantation (P < .001). Multivariate analysis identified the use of cadaveric donation (relative risk = 6.16, P = .001) and early graft dysfunction (relative risk = 6.19, P = .001) as the major independent predictors of decreased survival following retransplantation. Living donor lobar lung transplantation reduces perioperative mortality and is an independent predictor of improved survival following pediatric lung retransplantation. This strategy offers significant benefit for this high-risk group and preserves the limited supply of donor lungs for other children at risk of dying while waiting for lung transplantation.


Childhood adversity, depression, age and gender effects on white matter microstructure: a DTI study.
Previous diffusion tensor imaging (DTI) studies have shown that various factors can affect white matter (WM) tract diffusivity. The aim of the present study was to investigate the effects of childhood adversity (CA), age and gender on WM diffusivity in tracts that are thought to be involved in emotional regulation in individuals with major depressive disorder (MDD) and healthy controls (HC). DTI was obtained from 46 subjects with MDD and 46 HC subjects. Data were pre-processed and deterministic tractography was applied in the cingulum, uncinate fasciculus (UF), fornix, superior longitudinal fasciculus (SLF) and fronto-occipital fasciculus (FOF). In subjects with a history of CA, fractional anisotropy (FA) was greater in the rostral cingulum (RC) and dorsal cingulum, whereas radial diffusivity (RD) was smaller in the RC when compared with subjects with no history of CA. In the UF, FOF and parahippocampal cingulum, FA was greater in the left hemisphere in the subjects with CA when compared with those without CA. Age affected FA, longitudinal diffusivity and RD in the UF, fornix, FOF and SLF, reflecting axonal and myelin degeneration with increasing age. Depression or gender did not have any effects on the diffusivity measures. Due to the cross-sectional nature of the study, a recall bias for CA and possible effects of medical treatment on diffusivity measures could have played a role. CA and age could increase the likelihood to develop WM microstructural anomalies in the brain affective network. Moreover, subjects with CA could be more vulnerable to FA changes.


Determination of hand soil loading, soil transfer, and particle size variations after hand-pressing and hand-mouthing activities.
Hand-pressing trials and hand-to-mouth soil transfer experiments were conducted to better understand soil loadings, soil transfer ratios for three mouthing activities, and variations in particle size distributions under various conditions. Results indicated that sand caused higher soil loadings on the hand than clay. When the moisture level of clay soil exceeded its liquid limit, soil loadings also increased. Greater pressing pressures also led to larger clay loadings. Clay with a moisture content close to its plastic limit caused the smallest soil loadings due to strong soil cohesion. Particle sizes of the transferred clay were larger than that of the original clay, indicating that hand-pressing and the pressure exerted may have enhanced clay particles of larger sizes adhering onto the hand. Nevertheless, the sizes of most particles that adhered to the hand were still smaller than 150 μm. Higher pressing pressures and greater moisture contents resulted in larger soil loadings on the hand, and transfer ratios became smaller. Transfer ratios from palm-licking with clay particles were smaller than those from finger-mouthing, which may have been due to finer particles that more readily adhered to the skin of the palm and that were transferred from the hand to the mouth with greater difficulty.


"Angle to Be Corrected" in Preoperative Evaluation for Hallux Valgus Surgery: Analysis of a New Angular Measurement.
The most common methods for assessing severity of hallux valgus deformity and the effects of an operative procedure are the angular measurements in weightbearing radiographs, specifically the hallux valgus angle and intermetatarsal angle (IMA). Our objective was to analyze the interobserver variability in hallux valgus patients of a new angle called the "angle to be corrected" (ATC), and to compare its capacity to differentiate between different deformities against IMA. We included 28 symptomatic hallux valgus patients with 48 weightbearing foot x-rays. Three trained observers measured the 1 to 2 IMA and the ATC. We then identified retrospectively 45 hallux valgus patients, which were divided into 3 operative technique groups having used the ATC as reference, and analyzed the capacity of the IMA to differentiate between them. The IMA average value was 13.6 degrees, and there was a significant difference between observer 3 and observer 1 (P = .001). The average value for the ATC was 8.9 degrees, and there was no difference between observers. Both angles showed a high intraclass correlation. Regarding the capacity to differentiate between operative technique groups, the ATC was different between the 3 operative technique groups analyzed, but the IMA showed differences only between 2. The ATC was at least as reliable as the intermetatarsal angle for hallux valgus angular measurements, showing a high intraclass correlation with no interobserver difference. It can be suggested that the ATC was better than the IMA to stratify hallux valgus patients when deciding between different operative treatments. Level III, comparative study.


A Gossypium BAC clone contains key repeat components distinguishing sub-genome of allotetraploidy cottons.
Dissecting genome organization is indispensable for further functional and applied studies. As genome sequences data shown, cotton genomes contain more than 60 % repetitive sequences, so study on repetitive sequences composition, structure, and distribution is the key step to dissect cotton genome. In this study, a bacterial artificial chromosome (BAC) clone enriched in repetitive sequences, was discovered initiatively by fluorescence in situ hybridization (FISH). FISHing with allotetraploidy cotton as target DNA, dispersed signals on most regions of all A sub-genome chromosomes, and only middle regions of all D sub-genome chromosomes were detected. Further FISHing with other cotton species bearing A or D genome as target DNA, specific signals were viewed. After BAC sequencing and bioinformational analysis, 129 repeat elements, size about 57,172 bp were found, accounting for more than 62 % of the BAC sequence (91,238 bp). Among them, a type of long terminal repeat-retrotransposon (LTR-RT), LTR/Gypsy was the key element causing the specific FISH results. Using the fragments of BAC matching with the identified Gypsy-like LTR as probes, the BAC-57I23-like FISH signals were reappeared. Running BLASTN, the fragments had good match with all chromosomes of G. arboreum (A2) genome and A sub-genome of G. hirsutum (AD1), and had relatively inferior match with all chromosomes of D sub-genome of AD1, but had little match with the chromosomes of G. raimondii (D5) genome, which was consistent with the FISH results. A repeats-enriched cytogenetic marker to identify A and D sub-genomes of Gossypium was discovered by FISH. Combined sequences analysis with FISH verification, the assembly quality of repetitive sequences in the allotetraploidy cotton draft genome was assessed, and better chromosome belonging was verified. We also found the genomic distribution of the identified Gypsy-LTR-RT was similar to the distribution of heterochromatin. The expansion of this type of Gypsy-LTR-RT in heterochromatic regions may be one of the major reasons for the size gap between A and D genome. The findings showed here will help to understand the composition, structure, and evolution of cotton genome, and contribute to the further perfection of the draft genomes of cotton.


The neglected significance of "antioxidative stress".
Oxidative stress arises when there is a marked imbalance between the production and removal of reactive oxygen species (ROS) in favor of the prooxidant balance, leading to potential oxidative damage. ROSs were considered traditionally to be only a toxic byproduct of aerobic metabolism. However, recently, it has become apparent that ROS might control many different physiological processes such as induction of stress response, pathogen defense, and systemic signaling. Thus, the imbalance of the increased antioxidant potential, the so-called antioxidative stress, should be as dangerous as well. Here, we synthesize increasing evidence on "antioxidative stress-induced" beneficial versus harmful roles on health, disease, and aging processes. Oxidative stress is not necessarily an un-wanted situation, since its consequences may be beneficial for many physiological reactions in cells. On the other hand, there are potentially harmful effects of "antioxidative stress," especially in the cases of overconsumption of synthetic antioxidants. Antioxidants can neutralize ROS and decrease oxidative stress; however, this is not always beneficial in regard to disease formation or progression (of, e.g., cancer) or for delaying aging.


Grazing resistant freshwater bacteria profit from chitin and cell-wall-derived organic carbon.
The rise of grazing resistant planktonic bacteria in freshwater lakes during vernal phytoplankton blooms is favoured by predation of heterotrophic nanoflagellates (HNF). The spring period is also characterized by increased availability of organic carbon species that are in parts derived from cellular debris generated during bacterivory or viral lysis, such as peptidoglycan, chitin and their subunit N-acetylglucosamine (NAG). We tested the hypothesis that two dominant grazing resistant bacterial taxa, the ac1 tribe of Actinobacteria (ac1) and filamentous bacteria from the LD2 lineage (Saprospiraceae), profit from such carbon sources during periods of intense HNF predation. The abundances of ac1 and LD2 rose in parallel with HNF, and disproportionally high fractions of cells from both lineages were involved in NAG uptake. Members of ac1 and LD2 were significantly more enriched after NAG addition to lake water. However, highest growth rates of both bacterial lineages were found on chitin and peptidoglycan. Moreover, the direct or indirect transfer of organic carbon from peptidoglycan to LD2 filaments could be demonstrated. We thus provide evidence that these taxa may benefit twofold from protistan predation: by removal of their competitors, and by specific physiological adaptations to utilize carbon sources that are released during grazing or viral lysis.


Genome-wide molecular characterization of central nervous system primitive neuroectodermal tumor and pineoblastoma.
Central nervous system primitive neuroectodermal tumor (CNS PNET) and pineoblastoma are highly malignant embryonal brain tumors with poor prognoses. Current therapies are based on the treatment of pediatric medulloblastoma, even though these tumors are distinct at both the anatomical and molecular level. CNS PNET and pineoblastoma have a worse clinical outcome than medulloblastoma; thus, improved therapies based on an understanding of the underlying biology of CNS PNET and pineoblastoma are needed. To this end, we characterized the genomic alterations of 36 pediatric CNS PNETs and 8 pineoblastomas using Affymetrix single nucleotide polymorphism arrays. Overall, the majority of CNS PNETs contained a greater degree of genomic imbalance than pineoblastomas, with gain of 19p (8 [27.6%] of 29), 2p (7 [24.1%] of 29), and 1q (6 [20.7%] of 29) common events in primary CNS PNETs. Novel gene copy number alterations were identified and corroborated by Genomic Identification of Significant Targets In Cancer (GISTIC) analysis: gain of PCDHGA3, 5q31.3 in 62.1% of primary CNS PNETs and all primary pineoblastomas and FAM129A, 1q25 in 55.2% of primary CNS PNETs and 50% of primary pineoblastomas. Comparison of our GISTIC data with publically available data for medulloblastoma confirmed these CNS PNET-specific copy number alterations. With use of the collection of 5 primary and recurrent CNS PNET pairs, we found that gain of 2p21 was maintained at relapse in 80% of cases. Novel gene copy number losses included OR4C12, 11p11.12 in 48.2% of primary CNS PNETs and 50% of primary pineoblastomas. Loss of CDKN2A/B (9p21.3) was identified in 14% of primary CNS PNETs and was significantly associated with older age among children (P = .05). CADPS, 3p14.2 was lost in 27.6% of primary CNS PNETs and was associated with poor prognosis (P = .043). This genome-wide analysis revealed the marked molecular heterogeneity of CNS PNETs and enabled the identification of novel genes and clinical associations potentially involved in the pathogenesis of these tumors.


Mutations in CCR5-coding sequences are not associated with SIV carrier status in African nonhuman primates.
African monkeys can be naturally infected with SIV but do not progress to AIDS. Since mutations in the human CCR5 gene have been shown to influence susceptibility to HIV infection and disease progression, we have now investigated whether mutations in CCR5-coding sequences in African nonhuman primates can explain species-specific differences in susceptibility to lentiviral infection. The animals studied comprise chronically infected monkeys corresponding to four natural hosts of SIV (Cercopithecus aethiops, Cercopithecus pygerythrus, Cercopithecus sabaeus, and Cercopithecus tantalus), noninfected animals from three species that are known to be susceptible to SIV infection (Cercopithecus patas, Cercopithecus Ihoesti, and Pan troglodytes), and monkeys of six species that do not carry SIV in the wild (Cercocebus galeritus, Cercocebus aterrimus, Cercopithecus ascanius, Cercopithecus nictitans, Cercopithecus neglectus, and Cercopithecus cephus). We observed a high degree of genetic divergence among the species. The rate of accumulation of amino acid mutations was, however, not higher in SIV carriers than in other nonhuman primates. No homozygous premature stop codons, deletions, or frameshift mutations were detected. In at least two animals, one infected AGM (Cercopithecus tantalus) and one noninfected monkey (Cercocebus aterrimus), the CCR5 alleles identified encode functional proteins, as they were identical in terms of amino acid sequence to that of functional CCR5 reported in the literature. We found no other consistent differences in the genetic variability of CCR5-coding sequences between the nonhuman primates that are carriers of SIV and those that are not.


Establishing the fundamentals for an elephant early warning and monitoring system.
The decline of habitat for elephants due to expanding human activity is a serious conservation problem. This has continuously escalated the human-elephant conflict in Africa and Asia. Elephants make extensive use of powerful infrasonic calls (rumbles) that travel distances of up to several kilometers. This makes elephants well-suited for acoustic monitoring because it enables detecting elephants even if they are out of sight. In sight, their distinct visual appearance makes them a good candidate for visual monitoring. We provide an integrated overview of our interdisciplinary project that established the scientific fundamentals for a future early warning and monitoring system for humans who regularly experience serious conflict with elephants. We first draw the big picture of an early warning and monitoring system, then review the developed solutions for automatic acoustic and visual detection, discuss specific challenges and present open future work necessary to build a robust and reliable early warning and monitoring system that is able to operate in situ. We present a method for the automated detection of elephant rumbles that is robust to the diverse noise sources present in situ. We evaluated the method on an extensive set of audio data recorded under natural field conditions. Results show that the proposed method outperforms existing approaches and accurately detects elephant rumbles. Our visual detection method shows that tracking elephants in wildlife videos (of different sizes and postures) is feasible and particularly robust at near distances. From our project results we draw a number of conclusions that are discussed and summarized. We clearly identified the most critical challenges and necessary improvements of the proposed detection methods and conclude that our findings have the potential to form the basis for a future automated early warning system for elephants. We discuss challenges that need to be solved and summarize open topics in the context of a future early warning and monitoring system. We conclude that a long-term evaluation of the presented methods in situ using real-time prototypes is the most important next step to transfer the developed methods into practical implementation.


On the existence of guided acoustic waves at rectangular anisotropic edges.
The existence of acoustic waves with displacements localized at the tip of an isotropic elastic wedge was rigorously proven by Kamotskii, Zavorokhin and Nazarov. This proof, which is based on a variational approach, is extended to rectangular anisotropic wedges. For two high-symmetry configurations of rectangular edges in elastic media with tetragonal symmetry, a criterion is derived that allows identifying the boundary between the regions of existence for wedge modes of even and odd symmetry in regions of parameter space, where even- and odd-symmetry modes do not exist simultaneously. Furthermore, rectangular edges with non-equivalent surfaces are analyzed, and it is shown that at rectangular edges of cubic elastic media with one (110) surface and one (001) surface, a tip-localized guided wave always exists, apart from special cases that are characterized.


Trends in oral corticosteroids use in severe asthma: a 14-year population-based study.
Oral corticosteroids are important components of pharmacotherapy in severe asthma. Our objective was to describe the extent, trends, and factors associated with exposure to oral corticosteroids (OCS) in a severe asthma cohort. We used administrative health databases of British Columbia, Canada (2000-2014) and validated algorithms to retrospectively create a cohort of severe asthma patients. Exposure to OCS within each year of follow-up was measured in two ways: maintenance use as receiving on average ≥ 2.5 mg/day (prednisone-equivalent) OCS, and episodic use as the number of distinct episodes of OCS exposure for up to 14 days. Trends and factors associated with exposure on three time axes (calendar year, age, and time since diagnosis) were evaluated using Poisson regression. 21,144 patients (55.4% female; mean entry age 28.7) contributed 40,803 follow-up years, in 8.2% of which OCS was used as maintenance therapy. Maintenance OCS use declined by 3.8%/calendar year (p < 0.001). The average number of episodes of OCS use was 0.89/year, which increased by 1.1%/calendar year (p < 0.001). Trends remained significant for both exposure types in adjusted analyses. Both maintenance and episodic use increased by age and time since diagnosis. This population-based study documented a secular downward trend in maintenance OCS use in a period before widespread use of biologics. This might have been responsible for a higher rate of exacerbations that required episodic OCS therapy. Such trends in OCS use might be due to changes in the epidemiology of severe asthma, or changes in patient and provider preferences over time.


Origin and evolution of GALA-LRR, a new member of the CC-LRR subfamily: from plants to bacteria?
The phytopathogenic bacterium Ralstonia solanacearum encodes type III effectors, called GALA proteins, which contain F-box and LRR domains. The GALA LRRs do not perfectly fit any of the previously described LRR subfamilies. By applying protein sequence analysis and structural prediction, we clarify this ambiguous case of LRR classification and assign GALA-LRRs to CC-LRR subfamily. We demonstrate that side-by-side packing of LRRs in the 3D structures may control the limits of repeat variability within the LRR subfamilies during evolution. The LRR packing can be used as a criterion, complementing the repeat sequences, to classify newly identified LRR domains. Our phylogenetic analysis of F-box domains proposes the lateral gene transfer of bacterial GALA proteins from host plants. We also present an evolutionary scenario which can explain the transformation of the original plant LRRs into slightly different bacterial LRRs. The examination of the selective evolutionary pressure acting on GALA proteins suggests that the convex side of their horse-shoe shaped LRR domains is more prone to positive selection than the concave side, and we therefore hypothesize that the convex surface might be the site of protein binding relevant to the adaptor function of the F-box GALA proteins. This conclusion provides a strong background for further functional studies aimed at determining the role of these type III effectors in the virulence of R. solanacearum.


Preferred viewing directions of bumblebees (Bombus terrestris L.) when learning and approaching their nest site.
Many bees and wasps learn about the immediate surroundings of their nest during learning flights, in which they look back towards the nest and acquire visual information that guides their subsequent returns. Visual guidance to the nest is simplified by the insects' tendency to adopt similar viewing directions during learning and return flights. To understand better the factors determining the particular viewing directions that insects choose, we have recorded the learning and return flights of a ground-nesting bumblebee in two visual environments--an enclosed garden with a partly open view between north and west, and a flat roof with a more open panorama. In both places, bees left and returned to an inconspicuous nest hole in the centre of a tabletop, with the hole marked by one or more nearby cylinders. In all experiments, bees adopted similar preferred orientations on their learning and return flights. Bees faced predominantly either north or south, suggesting the existence of two attractors. The bees' selection between attractors seems to be influenced both by the distribution of light, as determined by the shape of the skyline, and by the direction of wind. In the partly enclosed garden with little or no wind, bees tended to face north throughout the day, i.e. towards the pole in the brighter half of their surroundings. When white curtains, which distributed skylight more evenly, were placed around the table, bees faced both north and south. The bees on the roof tended to face south or north when the wind came from a wide arc of directions from the south or north, respectively. We suggest that bees switch facing orientation between north and south as a compromise between maintaining a single viewing direction for efficient view-based navigation and responding to the distribution of light for the easier detection of landmarks seen against the ground or to the direction of the wind for exploiting olfactory cues.