The impact of the COVID-19 outbreak on the connectedness of the BRICS's term structure.
This study aims to examine the impact of the different waves of the COVID-19 pandemic on the connectedness of the BRICS (Brazil, Russia, India, China, and South Africa) term structure of interest rates and its components (level, slope and curvature). For that purpose, this research applies the time-varying parameter vector autoregression (TVP-VAR) approach in order to assess the direction of spillovers among countries and factors and measure their contribution to the connectedness system. Our results show that the total connectedness measure changes over time, and the level and curvature components show connectedness that persists longer than the slope component, both in the first wave of the COVID-19 pandemic. Brazil and South Africa would appear as net transmitters of shocks, whereas China and India are net receivers. Finally, the most significant differences in the net dynamic connectedness between transmitters and receivers were focused on before and during the first wave of the COVID-19 pandemic crisis. Some additional impacts were observed during the last waves of the coronavirus pandemic. To our best knowledge, this is the first study on the connectedness between the yield curves of the BRICS economies and the COVID-19 crisis uncertainty according to the coronavirus MCI, by decomposing the yield curve into its factors (level, slope, and curvature).


Extracting drug indication information from structured product labels using natural language processing.
To extract drug indications from structured drug labels and represent the information using codes from standard medical terminologies. We used MetaMap and other publicly available resources to extract information from the indications section of drug labels. Drugs and indications were encoded by RxNorm and UMLS identifiers respectively. A sample was manually reviewed. We also compared the results with two independent information sources: National Drug File-Reference Terminology and the Semantic Medline project. A total of 6797 drug labels were processed, resulting in 19 473 unique drug-indication pairs. Manual review of 298 most frequently prescribed drugs by seven physicians showed a recall of 0.95 and precision of 0.77. Inter-rater agreement (Fleiss κ) was 0.713. The precision of the subset of results corroborated by Semantic Medline extractions increased to 0.93. Correlation of a patient's medical problems and drugs in an electronic health record has been used to improve data quality and reduce medication errors. Authoritative drug indication information is available from drug labels, but not in a format readily usable by computer applications. Our study shows that it is feasible to use publicly available natural language processing resources to extract drug indications from drug labels. The same method can be applied to other sections of the drug label-for example, adverse effects, contraindications. It is feasible to use publicly available natural language processing tools to extract indication information from freely available drug labels. Named entity recognition sources (eg, MetaMap) provide reasonable recall. Combination with other data sources provides higher precision.


Micronutrients and cancer aetiology: the epidemiological evidence.
Micronutrient deficiencies occur most commonly in poor countries and, therefore, are most likely to be associated with cancers common in these countries. Epidemiological studies are hampered by inaccurate measurement of micronutrient intake and by the correlations between intakes of many nutrients. The strongest evidence for a protective effect of micronutrients is for oesophageal cancer. The identity of the micronutrients is not certain, but may include retinol, riboflavin, ascorbic acid and Zn; alcohol, smoking and dietary nitrosamines increase the risk for oesophageal cancer. For stomach cancer there is good evidence that fruit and vegetables are protective. The protective effect of these foods might be largely due to ascorbic acid, but other nutrients and non-nutrients may also be important; the risk for stomach cancer is increased by salt, some types of preserved foods, and by infection of the stomach with the bacterium Helicobacter pylori. The risk for lung cancer appears to be reduced by a high intake of fruit and vegetables, but it is not clear which agents are responsible and the major cause of lung cancer is cigarette smoking. Diet is probably the major determinant of the risk for colo-rectal cancer; there is evidence that fruit and vegetables and fibre reduce risk and that meat and animal fat increase risk, but there is no convincing evidence that these relationships are mediated by micronutrients. The risk for cervical cancer is inversely related to fruit and vegetable consumption and, therefore, to consumption of carotenoids and ascorbic acid, but the major cause of this cancer is human papillomavirus and it is not yet clear whether the dietary associations indicate a true protective effect or whether they are due to confounding by other variables. The evidence that micronutrients are important in the aetiology of either breast cancer or prostate cancer is weak, but the possible roles of 1,25-dihydroxycholecalciferol and alpha-tocopherol in prostate cancer require further study.


Array-based DNA methylation profiling in male infertility reveals allele-specific DNA methylation in PIWIL1 and PIWIL2.
To identify CpG sites differentially methylated in peripheral blood of men with idiopathic infertility due to impaired spermatogenesis as compared with fertile controls. DNA methylation profiling on peripheral blood samples using the HumanMethylation450 BeadChip (Illumina) in patients and controls, single-nucleotide polymorphism (SNP) typing by Sanger sequencing. University institute in cooperation with genetic and infertility clinics. 30 infertile men with normal CFTR and AZF tests and karyotype, and 10 fertile male controls. None. DNA methylation levels at CpG sites. We identified 471 CpGs (287 genes) as differentially methylated between patients and controls. These were significantly enriched for the gene ontology functions MHC class II receptor activity and piwi-interacting (piRNA) binding. The latter was associated with two methylation-sensitive SNPs in the genes PIWIL1 and PIWIL2, respectively, which showed significant allele distribution skewing in the infertile cohort. We found that 445 (94.5%) of 471 differentially methylated CpGs were associated with SNPs, but 26 (15 genes) were not genomically templated, including the ENO1, MTA2, BRSK2, and LBX2 genes previously associated with fertility and spermatogenesis. Our study identifies surrogate DNA methylation markers for idiopathic infertility in peripheral blood and suggests that allele-specific DNA methylation differences at regulatory sites of genes involved in piRNA regulation are associated with disturbed spermatogenesis.


The karyotype of the yellow dung fly, Scathophaga stercoraria, a model organism in studies of sexual selection.
Knowledge of karyotypical characteristics of a species is essential for understanding how sexually selected and sexually antagonistic traits evolve. The yellow dung fly Scathophaga stercoraria L. (Diptera: Scathophagidae) is an established model system for studies of sexual selection and sexual conflict, but karyotypical data are lacking to date. Here, the karyotype of S. stercoraria was characterized using conventional Giemsa-staining and C-banding techniques. The diploid chromosome set consists of 6 pairs of bi-armed meta- or submetacentric chromosomes. The sex chromosomes are the largest chromosomes and constitute 30% of the total length of the diploid set in females and about 25% in males. Males are the heterogametic sex, and the length of the Y chromosome is about three-quarters of that of the X chromosome. C-banding revealed that both sex chromosomes are largely heterochromatic. In contrast, in the five autosome pairs, heterochromatin is limited to narrow bands in the centromeric regions. This karyotypic information will help provide a more profound understanding of the inheritance of phenotypic variation in reproductive traits and the chromosomal locations of underlying genes.


[Next generation of anti-immune checkpoints antibodies].
Immune checkpoints balance initial antigen-driven T cell stimulation by enhancing or dampening activation, allowing co-existence of efficient immune responses and maintenance of self-tolerance. In oncology, checkpoints currently targeted by inhibitors to amplify activity of T cell, NK cells or myeloid cells responses comprise CTLA-4 (cytolytic T-lymphocyte-associated antigen 4 or CD152), PD-1 (programmed cell death 1, or CD279), PD-L1 ( programmed cell death-ligand 1, or CD274), LAG-3 (Lymphocyte-activation gene 3, or CD223), TIM3 (T-cell immunoglobulin and mucin-domain containing-3), TIGIT (T cell immunoreceptor with Ig and ITIM domains ), VISTA (V-domain Ig suppressor of T cell activation), B7/H3 (or CD276), KIR (killer-cell immunoglobulin-like receptor), NKG2A, CD39, CD73, CSF1R (colony-stimulating factor 1 receptor), CD47 or CD172a. Other "checkpoints" are being pharmacologically triggered in order to directly amplify T cell co-stimulation. Among these molecules, CD28, CD137 (also called 4-1BB), OX40 [also called tumor necrosis factor receptor superfamily, member 4 (TNFRSF4)], GITR (Glucocorticoid-induced tumor necrosis factor receptor family-related protein) or CD40 are also tested in oncology, most often in combination with an inhibitory checkpoint inhibitor. In autoimmune and inflammatory diseases, checkpoint inhibitors or activators (LAG-3, CD28, CD40L) are also being tested. In this review, we focus on some modulators of immune checkpoints for which the mechanism of action has been particularly studied. As this description cannot be exhaustive, we have grouped in Table I all monoclonal antibodies (MAbs) or recombinant proteins in clinical use (to our knowledge), modulating the action of a control point of the immune system.


Triple-phase 99mTc-3P-RGD2 imaging of peripheral primitive neuroectodermal tumor in the hip muscle group with bone metastasis.
Peripheral primitive neuroectodermal tumors (pPNETs) are a group of aggressive neoplasms that are most commonly encountered in pediatric patients and may be located in the abdomen, pelvis, thoracopulmonary region and, rarely, in the head and neck region. pPNETs in adults are extremely rare. The present study reports a case of pPNET located in the hip muscles with bone metastasis. The patient was a 44-year-old woman who complained of progressive pain and swelling with a mass near the left hip. Computed tomography (CT) and enhanced CT revealed a soft tissue mass lesion in the hip muscle group measuring 4.3×4.3×4.4 cm. The lesion was ill-defined, heterogeneous, exhibiting mild post-contrast enhancement. There was a large number of bent neovessels and several branches from the left internal iliac artery and deep femoral artery on enhanced CT scan. Triple-phase dynamic imaging with integrin αvβ3-targeted 99mTc-3P-RGD2 as the radiotracer revealed increased blood perfusion and radiotracer aggregation in the large, ill-defined, heterogeneous, hypodense mass and adjacent bone. The patient was suspected of having pPNET with bone metastasis, which was confirmed by histological examination of a sample obtained by needle aspiration. Due to the high blood perfusion of primary pPNETs and high RGD uptake by the primary and metastatic lesions, chemoembolization and anti-angiogenic therapy were considered to be the optimal therapeutic choice. This also suggested that 177Lu-labeled RGD has great potential for the targeted treatment of pPNETs with multiple metastases.


RECQL5 and BLM exhibit divergent functions in cells defective for the Fanconi anemia pathway.
Fanconi anemia (FA) patients exhibit bone marrow failure, developmental defects and cancer. The FA pathway maintains chromosomal stability in concert with replication fork maintenance and DNA double strand break (DSB) repair pathways including RAD51-mediated homologous recombination (HR). RAD51 is a recombinase that maintains replication forks and repairs DSBs, but also rearranges chromosomes. Two RecQ helicases, RECQL5 and Bloom syndrome mutated (BLM) suppress HR through nonredundant mechanisms. Here we test the impact deletion of RECQL5 and BLM has on mouse embryonic stem (ES) cells deleted for FANCB, a member of the FA core complex. We show that RECQL5, but not BLM, conferred resistance to mitomycin C (MMC, an interstrand crosslinker) and camptothecin (CPT, a type 1 topoisomerase inhibitor) in FANCB-defective cells. RECQL5 suppressed, while BLM caused, breaks and radials in FANCB-deleted cells exposed to CPT or MMC, respectively. RECQL5 protected the nascent replication strand from MRE11-mediated degradation and restarted stressed replication forks in a manner additive to FANCB. By contrast BLM restarted, but did not protect, replication forks in a manner epistatic to FANCB. RECQL5 also lowered RAD51 levels in FANCB-deleted cells at stressed replication sites implicating a rearrangement avoidance mechanism. Thus, RECQL5 and BLM impact FANCB-defective cells differently in response to replication stress with relevance to chemotherapeutic regimes.


Brain MRI white matter hyperintensities and one-carbon cycle metabolism in non-geriatric outpatients with major depressive disorder (Part II).
The objective of this study was to investigate the relative impact of brain white matter hyperintensities (WMHs), cardiovascular risk factors and elements of the one-carbon cycle metabolism (including serum folate, vitamin B12 and homocysteine levels) on the outcome of antidepressant treatment in non-elderly subjects with major depressive disorder (MDD). Fifty MDD subjects were administered brain magnetic resonance imaging (MRI) scans at 1.5 T to detect T2 WMHs. The severity of brain WMHs was classified with the Fazekas scale (range=0-3). We assessed cardiovascular risk factors in all MDD subjects (age, gender, smoking, diabetes, family history, hypertension, cholesterol). MDD patients also had serum folate, vitamin B12 and homocysteine levels measured. All MDD subjects received treatment with fluoxetine 20 mg/day for 8 weeks. In a logistic regression, the severity of subcortical WMHs and the presence of hypofolatemia were independent predictors of lack of clinical response to antidepressant treatment. Separately, hypofolatemia also predicted lack of remission to antidepressant treatment. These associations were independent of the presence of smoking, diabetes, family history, hypercholesterolemia, hyperhomocysteinemia and low B12 levels. Although preliminary, the results of the present work suggest that subcortical brain WMHs and hypofolatemia may have an independent negative impact on the likelihood of responding to antidepressant treatment in non-geriatric subjects with MDD.


Independent replication and meta analysis of association studies establish TNFSF4 as a susceptibility gene preferentially associated with the subset of anticentromere-positive patients with systemic sclerosis.
Independent replication with large cohorts and metaanalysis of genetic associations are necessary to validate genetic susceptibility factors. The known tumor necrosis factor (ligand) superfamily, member 4 gene (TNFSF4) systemic lupus erythematosus (SLE) risk locus has been found to be associated with systemic sclerosis (SSc) in 2 studies, but with discrepancies between them for genotype-phenotype correlation. Our objective was to validate TNFSF4 association with SSc and determine the subset with the higher risk. Known SLE and SSc TNFSF4 susceptibility variants (rs2205960, rs1234317, rs12039904, rs10912580, and rs844648) were genotyped in 1031 patients with SSc and 1014 controls of French white ancestry. Genotype-phenotype association analysis and meta analysis of available data were performed, providing a population study of 4989 patients with SSc and 4661 controls, all of European white ancestry. Allelic and genotypic associations were observed for the 5 single-nucleotide polymorphisms (SNP) with the subset of patients with SSc who are positive for anticentromere antibodies (ACA) and only a trend for association with SSc and limited cutaneous SSc. Rs2205960 exhibited the strongest allelic association in ACA+ patients with SSc [p = 0.0015; OR 1.37 (1.12-1.66)], with significant intra-cohort association when compared to patients with SSc positive for ACA. Metaanalysis confirmed overall association with SSc but also raised preferential association with the ACA+ subset and strongest effect with rs2205960 [T allele p = 0.00013; OR 1.33 (1.15-1.54) and TT genotype p = 0.00046; OR 2.02 (1.36-2.98)]. We confirm TNFSF4 as an SSc susceptibility gene and rs2205960 as a putative causal variant with preferential association in the ACA+ SSc subphenotype.


In vitro antioxidant activity and total phenolic content of the inflorescences, leaves and fruits of Sorbus torminalis (L.) Crantz.
The antioxidant potential of 70% methanolic extracts from the inflorescences, leaves and fruits of Sorbus torminalis (L.) Crantz was evaluated using three in vitro test systems: the DPPH (2,2-diphenyl-1-picryl-hydrazyl) and the ABTS [2,2-azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid)] free radical scavenging assays, and the AAPH [2,2'-azobis-(2-amidinopropane) dihydrochloride]-induced [corrected] linoleic acid (LA) peroxidation test. The results were compared with the activity of the extracts obtained from the model antioxidant Sorbus species (Sorbus aucuparia L.), and also with the activity of phenolic standards such as quercetin, Trolox [(+/-)-6-hydroxy-2,2,7,8-tetramethylchroman-2-carboxylic acid], BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene) and TBHQ (tert-butylhydroquinone). The radical scavenging capacities of the S. torminalis extracts towards the DPPH radical were in the range of 62.0-244.1 micromolar Trolox equivalents/g d.w. of plant material. They were significantly (p < 0.05) correlated with the results of the ABTS test (r = 0.8535), and with the chain-breaking activities determined in the LA-peroxidation test (r = 0.9831). In comparison with the synthetic standards, the free radical scavenging capacity of the Sorbus extracts was remarkably higher than their chain-breaking activity. Both kinds of antioxidant effects of the extracts were significantly (R2 > 0.8097, p < 0.05) influenced by the total phenolic content (TPC) as determined by the Folin-Ciocalteu method. The plant tissues derived from S. torminalis exhibited lower antioxidant potentials than those of S. aucuparia by a factor of 1.5-3.2, partially due to the lower TPC levels (multiplicity factors of 1.2-1.9). After the original antioxidant capacities of the extracts were recalculated according to the TPC levels, the resulting antioxidant capacities of the phenolic fractions in the S. torminalis extracts were lower than those from S. aucuparia by a factor of 1.1-1.6, suggesting that the distinctive chemistry of the phenolic constituents also influences the antioxidant power of the two species.


Transferability of a coarse-grained atactic polystyrene model: the non-bonded potential effect.
In this paper, we construct an efficient and simple coarse grained (CG) model for atactic polystyrene (PS) by using a 1 : 1 mapping scheme at 463 K and 1 atm pressure and derive the corresponding bonded and non-bonded potentials in the CG force field (FF) via a direct Boltzmann inversion approach and a combined structure-based and thermodynamic quantities-based CG method, respectively. For computational considerations, the non-bonded interaction between CG particles is described by Lennard-Jones (LJ) type potentials, and both the radial distribution function (RDF) and the bulk density of the atomistic simulations are taken as target properties in the parameterization of the two LJ parameters. To shed light on the choice of LJ forms of CG non-bonded potentials when designing the CG models, a series of CG models with different LJ potentials are constructed and compared in order to understand how the quality of a CG model in reproducing the structure and thermodynamic properties of chemically realistic systems is affected by the choice of non-bonded potentials. We find that with our structural and thermodynamics combined CG method to construct the CG FF at a single thermodynamic state point without any temperature dependent LJ potential correction and/or pressure optimization, the resulting CG models possess good temperature transferability in a wide range of temperatures 300-600 K, where both the target properties and several other static properties (such as thermal expansion coefficient and mean-square radius of gyration) are generally reproduced. Furthermore, the non-bonded LJ potential influences the density response of CG models to the temperature change, i.e., CG models with harder LJ potentials show better temperature transferability than the softer ones. Meanwhile, the derived Tg increases with increasing LJ repulsion strength while thermal expansion coefficients in both melt and glass states are lowered as the LJ potential hardens. With regard to the local conformation and local packing distribution functions, varying non-bonded LJ potential hardness influences only the magnitude of the peak height but does not affect the peak position, in particular the magnitude of the non-bonded potential effect on local distribution functions becomes stronger at lower temperatures. More specifically, this effect on the local chain conformation statistics at the CG level is different for the distribution of bond-lengths, bond angles and dihedrals. As a result, the size of the CG chains is fairly insensitive to the non-bonded LJ potentials within 300-600 K. In short, the CG model with the harder LJ-type non-bonded CG potential is a more realistic representation of excluded volume interactions of the underlying atomistic PS monomer and thus has the potential to generate a higher Tg to match with the atomistic systems.


Interplay between many body effects and Coulomb screening in the optical bandgap of atomically thin MoS2.
Due to its unique layer-number dependent electronic band structure and strong excitonic features, atomically thin MoS2 is an ideal 2D system where intriguing photoexcited-carrier-induced phenomena can be detected in excitonic luminescence. We perform micro-photoluminescence (PL) measurements and observe that the PL peak redshifts nonlinearly in mono- and bi-layer MoS2 as the excitation power is increased. The excited carrier-induced optical bandgap shrinkage is found to be proportional to n4/3, where n is the optically-induced free carrier density. The large exponent value of 4/3 is explicitly distinguished from a typical value of 1/3 in various semiconductor quantum well systems. The peculiar n4/3 dependent optical bandgap redshift may be due to the interplay between bandgap renormalization and reduced exciton binding energy.


[Mechanisms of the anti-anginal effect of obzidan].
Using the blind method, a group of 91 coronary heart disease patients were studied. A two-week course of obsidan therapy proved to be most effective in patients with two impaired vessels and also in patients with a simultaneous decrease in the heart rate and in the systolic blood pressure during the threshold exercise. A parallel increase in the stroke index during exercise and a decrease in the myocardial contractile function at rest (by echocardiographic findings) suggest that the decrease in the systolic arterial pressure is associated with a negative inotropic effect of the drug. A decrease in the heart rate and myocardial contractility was observed only in patients with initial tachycardia and the intact functional state of the cardiac muscle. The best antianginal response occurs when these effects are combined.


Subacute CNS Demyelination after Treatment with Nivolumab for Melanoma.
Immunotherapy with monoclonal antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1) has improved the survival of patients with metastatic melanoma. These agents carry a certain risk of adverse immune-related events. We present a patient with widely metastatic melanoma who was initially treated with ipilimumab and subsequently with nivolumab. After four infusions of nivolumab, he developed subacute multifocal central nervous system (CNS) demyelination. Nivolumab was discontinued and, despite immunosuppressive therapy, the largest lesion progressed significantly, whereas another lesion showed radiographic improvement. After further progression, the patient succumbed to his CNS lesions 4 months later. Autopsy revealed extensive demyelination, a mild multifocal T-cell-rich perivascular lymphoid infiltrate, abundant macrophages, and necrosis. There was no metastatic melanoma in the brain. CNS demyelination has not been described in association with nivolumab. We hypothesize that the combination therapy of ipilimumab and subsequent nivolumab accounted for the severity of the demyelinating process in this patient. This case, with comprehensive clinical, molecular, and neuropathologic characterization, illustrates the need for awareness of these potential CNS complications with the use of multiple checkpoint inhibitors.


Temporal concentrations of cortisol and LH in virgin ewes acutely exposed to rams during the transition into the breeding season.
The objectives of this study were to determine if exposing seasonally anovular ewes to rams would alter patterns of cortisol concentrations, and if these changes are associated with changes in characteristics of LH concentrations. Seasonally anestrous ewes were assigned to be exposed to rams (RE; n=11) or wethers (NE; n=12). Blood samples were collected at 15-min intervals beginning 120 min before introduction of males (time=0 min), and continued for 360 min after male exposure. Characteristics of cortisol and LH concentrations included: mean and baseline concentrations, pulse amplitude, duration, frequency, and time to first pulse. Mean and baseline cortisol concentrations, and cortisol pulse amplitude, frequency, and time to first pulse after male exposure did not differ between RE and NE ewes. Cortisol pulse duration was longer (P<0.05) in RE ewes than in NE ewes. Mean LH and LH pulse amplitude, duration, and time to first pulse after male exposure did not differ between RE and NE ewes. Baseline LH concentrations and LH pulse frequency were greater (P<0.05) in RE than in NE ewes. In RE ewes, but not NE ewes, LH pulse frequency tended to increase (P=0.06) as pulse frequency of cortisol decreased. In conclusion, exposing ewes to mature rams during the transition into the breeding season increased LH pulse frequency which hastened ovulatory activity. However, the results do not support the hypothesis that changes in cortisol concentrations plays a significant role in the 'ram effect'.


The effect of fostering on the genetic expression of locomotor sensitivity to alcohol.
Steps were taken to eradicate endemic mouse coronavirus from a colony that was part of a behavioral project characterizing the genetics of alcohol sensitivity. This behavioral study was conducted to determine whether changing the uterine or rearing environment (as is integral to common rederivation methods) would have a significant effect on the expression of the behavioral traits in question. Selected breeding pairs of the affected lines were divided into four treatment groups: 1) transfer of embryos to pseudopregnant B6D2F1 female mice, 2) fostering offspring to B6D2F1 dams, 3) fostering offspring to a different dam of the same line, and 4) offspring raised by the birth dam. Embryo transfers were successful only in one affected line. At approximately 50 days of age, the offspring were tested for locomotor behavior after intraperitoneal administration of ethanol or normal saline. There were no statistically significant effects of embryo transfer on the ethanol phenotype (ethanol-induced locomotor depression). Fostering significantly reduced the stimulant response to ethanol of only one mouse line selectively bred for high sensitivity to ethanol-induced stimulation, although the stimulant response of the fostered groups was still quite robust. Overall, the results of this study showed that eradication efforts involving fostering of offspring have a modest impact on the stimulant response to ethanol, but there were insufficient data to draw conclusions regarding the use of embryo transfer.


Predictable adaptive trajectories of sexual coloration in the wild: Evidence from replicate experimental guppy populations.
The question of whether populations evolve predictably and consistently under similar selective regimes is fundamental to understanding how adaptation proceeds in the wild. We address this question with a replicated evolution experiment focused upon male sexual coloration in guppies (Poecilia reticulata). Fish were transplanted from a single high predation population in the Guanapo River to four replicate, guppy-free low predation headwater streams. Two streams had their canopies thinned to adjust the setting under which male coloration is displayed and perceived. We assessed evolutionary divergence using second-generation lab-bred offspring of fish sampled four to six years following translocation. A prior experiment of the same design, performed in an adjacent drainage, resulted in the evolution of more extensive orange, black, and iridescent markings. We however found evidence for expansion only in structural coloration (iridescent blue/green), no change in orange, and a reduction in black. This response amplifies earlier findings for Guanapo fish, revealing that trajectories of color elaboration differ among drainages. We also found that color phenotypes evolved more greatly at the thinned-canopy sites. Our findings support the predictability of sexual trait evolution in the wild, and underscore the importance of signaling conditions and ornamental starting points in shaping adaptive trajectories.


Metabolism of ovorubin, the major egg lipoprotein from the apple snail.
The site of synthesis of molluscs lipoproteins is little known and was investigated for the egg lipoprotein perivitellin 1 (PV 1) or ovorubin in the freshwater snail Pomacea canaliculata. Tissues (albumen gland, gonad-digestive gland complex and muscle) of vitellogenic females were incubated in vitro at 25 degrees C for 12 h with 14C Leucine. After that, soluble proteins from tissue homogenates and medium samples were analysed for de novo protein synthesis by electrophoresis and HPLC, and radiolabelled proteins quantified by liquid scintillation. Gonad-digestive gland complex did not synthesise ovorubin, in spite its high protein synthesis levels. Three albumen gland radiolabelled proteins (35, 32 and 28 kDa) comigrated with the subunits of ovorubin and represented 1.3% of the total labelled protein of that tissue. Western blot analysis with polyclonal antibodies confirmed that these were ovorubin subunits. In vivo experiments where vitellogenic females were injected with 3H Leucine, revealed that ovorubin was not present in hemolymph. ELISA analysis confirmed ovorubin presence only in albumen gland and developing eggs with levels of 800 and 582 mg/g protein, which represent 30.3 and 28.4 mg ovorubin/g of tissue, respectively. Therefore, albumen gland is the single site of ovorubin synthesis as no extragland synthesis, circulation or accumulation could be detected in the apple snail.


Sparse coding with an overcomplete basis set: a strategy employed by V1?
The spatial receptive fields of simple cells in mammalian striate cortex have been reasonably well described physiologically and can be characterized as being localized, oriented, and bandpass, comparable with the basis functions of wavelet transforms. Previously, we have shown that these receptive field properties may be accounted for in terms of a strategy for producing a sparse distribution of output activity in response to natural images. Here, in addition to describing this work in a more expansive fashion, we examine the neurobiological implications of sparse coding. Of particular interest is the case when the code is overcomplete--i.e., when the number of code elements is greater than the effective dimensionality of the input space. Because the basis functions are non-orthogonal and not linearly independent of each other, sparsifying the code will recruit only those basis functions necessary for representing a given input, and so the input-output function will deviate from being purely linear. These deviations from linearity provide a potential explanation for the weak forms of non-linearity observed in the response properties of cortical simple cells, and they further make predictions about the expected interactions among units in response to naturalistic stimuli.


Perceived injustice moderates the relationship between pain and depressive symptoms among individuals with persistent musculoskeletal pain.
Numerous investigations report that depressive symptoms frequently coexist with persistent pain. However, evidence suggests that symptoms of depression are not an inevitable consequence of pain. Diathesis-stress formulations suggest that psychological factors interact with the stress of pain to heighten the risk of depressive symptoms. Perceptions of injustice have recently emerged as a factor that may interact with the stress of pain to increase depressive symptoms. The purpose of the present study was to examine whether perceived injustice moderates the relationship between pain and depressive symptoms. A total of 107 individuals with persistent musculoskeletal pain completed self-report measures of pain severity, depressive symptoms, perceived injustice and catastrophizing. A hierarchical regression analysis revealed that the interaction between pain severity and perceived injustice uniquely contributed an additional 6% of the variance to the prediction of depressive symptoms, beyond the main effects of these variables. Post hoc probing indicated that pain was significantly related to depressive symptoms at high, but not low levels of perceived injustice. This finding remained statistically significant even when controlling for pain catastrophizing. The results suggest that perceived injustice augments the relationship between pain severity and depressive symptoms. The inclusion of techniques specifically targeting perceptions of injustice may enhance the effectiveness of interventions aimed at reducing symptoms of depression for individuals presenting with strong perceptions of injustice.


Multiple variations in the pelvic vasculature - a case report.
A thorough knowledge of possible variations of pelvic vasculature is very useful for surgeons, gynaecologists, radiologists, urologists and orthopaedic surgeons. We report multiple vascular variations in the left half of the pelvis of an adult male cadaver. Iliolumbar artery arose from the main trunk of the internal iliac artery. Posterior division of the internal iliac artery gave two lateral sacral arteries and a superior gluteal artery. The anterior division of the internal iliac artery gave origin to superior vesical, inferior vesical, inferior gluteal and internal pudendal arteries. The internal pudendal artery gave origin to a common trunk before leaving the pelvis. The common trunk divided into middle rectal artery and deep artery of the penis. The obturator artery took origin from the inferior epigastric artery and descended downward to the pelvis and left the pelvis by passing through the obturator foramen. Most of the other veins accompanying the arteries joined to form a plexus on the superior surface of the pelvic diaphragm. This plexus condensed to form anterior and posterior divisions of the internal iliac vein. Apart from this, the posterior part of the plexus drained directly into the common iliac vein through a large unnamed vein.


In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations.
Type IV hemochromatosis is associated with dominant mutations in the SLC40A1 gene encoding ferroportin (FPN). Known as the "ferroportin disease," this condition is typically characterized by high serum ferritin, reduced transferrin saturation, and macrophage iron loading. Previously FPN expression in vitro has been shown to cause iron deficiency in human cell lines and mediate iron export from Xenopus oocytes. We confirm these findings by showing that expression of human FPN in a human cell line results in an iron deficiency because of a 3-fold increased export of iron. We show that FPN mutations A77D, V162delta, and G490D that are associated with a typical pattern of disease in vivo cause a loss of iron export function in vitro but do not physically or functionally impede wild-type FPN. These mutants may, therefore, lead to disease by haploinsufficiency. By contrast the variants Y64N, N144D, N144H, Q248H, and C326Y, which can be associated with greater transferrin saturation and more prominent iron deposition in liver parenchyma in vivo, retained iron export function in vitro. Because FPN is a target for negative feedback in iron homeostasis, we postulate that the latter group of mutants may resist inhibition, resulting in a permanently "turned on" iron exporter.


Effect of occlusal interference on habitual activity of human masseter.
It has been suggested that occlusal interference may increase habitual activity in the jaw muscles and may lead to temporomandibular disorders (TMD). We tested these hypotheses by means of a double-blind randomized crossover experiment carried out on 11 young healthy females. Strips of gold foil were glued either on a selected occlusal contact area (active interference) or on the vestibular surface of the same tooth (dummy interference) and left for 8 days each. Electromyographic masseter activity was recorded in the natural environment by portable recorders under interference-free, dummy-interference, and active-interference conditions. The active occlusal interference caused a significant reduction in the number of activity periods per hour and in their mean amplitude. The EMG activity did not change significantly during the dummy-interference condition. None of the subjects developed signs and/or symptoms of TMD throughout the whole study, and most of them adapted fairly well to the occlusal disturbance.


Particle size distributions of organic aerosol constituents during the 2002 Yosemite Aerosol Characterization Study.
The Yosemite Aerosol Characterization Study (YACS) was conducted in the summer of 2002 to investigate sources of regional haze in Yosemite National Park. Organic carbon and molecular source marker species size distributions were investigated during hazy and clear periods. More than 75% of the organic carbon mass was associated with submicron aerosol particles. Most molecular marker species for wood smoke, an important source of particulate matter during the study, were contained in submicron particles, although on some fire influenced days, levoglucosan shifted toward larger sizes. Various wood smoke marker species exhibited slightly different size distributions in the samples, suggesting different, size dependent emission or atmospheric processing rates of these species. Secondary biogenic compounds including pinic and pinonic acids were associated with smaller particles. Pinonaldehyde, however, exhibited a broader distribution, likely due to its higher volatility. Dicarboxylic acids were associated mainly with submicron particles. Hopanes, molecular markers for vehicle emissions, were mostly contained in smaller particles but exhibited some tailing into larger size classes.


Oligohydramnios: a prospective study of fetal, neonatal and maternal outcomes in low-middle income countries.
Oligohydramnios is a condition of abnormally low amniotic fluid volume that has been associated with poor pregnancy outcomes. To date, the prevalence of this condition and its outcomes has not been well described in low and low-middle income countries (LMIC) where ultrasound use to diagnose this condition in pregnancy is limited. As part of a prospective trial of ultrasound at antenatal care in LMICs, we sought to evaluate the incidence of and the adverse maternal, fetal and neonatal outcomes associated with oligohydramnios. We included data in this report from all pregnant women in community settings in Guatemala, Pakistan, Zambia and the Democratic Republic of Congo (DRC) who received a third trimester ultrasound as part of the First Look Study, a randomized trial to assess the value of ultrasound at antenatal care. Using these data, we conducted a planned secondary analysis to compare pregnancy outcomes of women with to those without oligohydramnios. Oligohydramnios was defined as measurement of an Amniotic Fluid Index less than 5 cm in at least one ultrasound in the third trimester. The outcomes assessed included maternal morbidity and fetal and neonatal mortality, preterm birth and low-birthweight. We used pairwise site comparisons with Tukey-Kramer adjustment and multivariable logistic models using general estimating equations to account for the correlation of outcomes within cluster. Of 12,940 women enrolled in the clusters in Guatemala, Pakistan, Zambia and the DRC in the First Look Study who had a third trimester ultrasound examination, 87 women were diagnosed with oligohydramnios, equivalent to 0.7% of those studied. Prevalence of detected oligohydramnios varied among study sites; from the lowest of 0.2% in Zambia and the DRC to the highest of 1.5% in Pakistan. Women diagnosed with oligohydramnios had higher rates of hemorrhage, fetal malposition, and cesarean delivery than women without oligohydramnios. We also found unfavorable fetal and neonatal outcomes associated with oligohydramnios including stillbirths (OR 5.16, 95%CI 2.07, 12.85), neonatal deaths < 28 days (OR 3.18, 95% CI 1.18, 8.57), low birth weight (OR 2.10, 95% CI 1.44, 3.07) and preterm births (OR 2.73, 95%CI 1.76, 4.23). The mean birth weight was 162 g less (95% CI -288.6, - 35.9) with oligohydramnios. Oligohydramnos was associated with worse neonatal, fetal and maternal outcomes in LMIC. Further research is needed to assess effective interventions to diagnose and ultimately to reduce poor outcomes in these settings. NCT01990625.


Diagnosis of Brain Metastases from Lung Cancer Using a Modified Electromagnetism like Mechanism Algorithm.
Brain metastases are commonly found in patients that are diagnosed with primary malignancy on their lung. Lung cancer patients with brain metastasis tend to have a poor survivability, which is less than 6 months in median. Therefore, an early and effective detection system for such disease is needed to help prolong the patients' survivability and improved their quality of life. A modified electromagnetism-like mechanism (EM) algorithm, MEM-SVM, is proposed by combining EM algorithm with support vector machine (SVM) as the classifier and opposite sign test (OST) as the local search technique. The proposed method is applied to 44 UCI and IDA datasets, and 5 cancers microarray datasets as preliminary experiment. In addition, this method is tested on 4 lung cancer microarray public dataset. Further, we tested our method on a nationwide dataset of brain metastasis from lung cancer (BMLC) in Taiwan. Since the nature of real medical dataset to be highly imbalanced, the synthetic minority over-sampling technique (SMOTE) is utilized to handle this problem. The proposed method is compared against another 8 popular benchmark classifiers and feature selection methods. The performance evaluation is based on the accuracy and Kappa index. For the 44 UCI and IDA datasets and 5 cancer microarray datasets, a non-parametric statistical test confirmed that MEM-SVM outperformed the other methods. For the 4 lung cancer public microarray datasets, MEM-SVM still achieved the highest mean value for accuracy and Kappa index. Due to the imbalanced property on the real case of BMLC dataset, all methods achieve good accuracy without significance difference among the methods. However, on the balanced BMLC dataset, MEM-SVM appears to be the best method with higher accuracy and Kappa index. We successfully developed MEM-SVM to predict the occurrence of brain metastasis from lung cancer with the combination of SMOTE technique to handle the class imbalance properties. The results confirmed that MEM-SVM has good diagnosis power and can be applied as an alternative diagnosis tool in with other medical tests for the early detection of brain metastasis from lung cancer.


Addition of rye chromosome 4R to wheat increases anther length and pollen grain number.
The research identified rye chromosome 4R arms associated with good pollinator traits, and demonstrated possible use of rye genetic resources to develop elite pollinators for hybrid wheat breeding. Bread wheat (Triticum aestivum) is a predominantly self-pollinating plant which has relatively small-sized anthers and produces a low number of pollen grains. These features limit the suitability of most wheat lines as pollinators for hybrid seed production. One strategy for improving the pollination ability of wheat is to introgress cross-pollination traits from related species. One such species is rye (Secale cereale L.), which has suitable traits such as high anther extrusion, long anthers containing large amounts of pollen and long pollen viability. Therefore, introducing these traits into wheat is of great interest in hybrid wheat breeding. Here, we investigated wheat-rye chromosome addition lines for the effects of rye chromosomes on anther and pollen development in wheat. Using a single nucleotide polymorphism genotyping array, we detected 984 polymorphic markers that showed expected syntenic relationships between wheat and rye. Our results revealed that the addition of rye chromosomes 1R or 2R reduced pollen fertility, while addition of rye chromosome 4R increased anther size by 16% and pollen grain number by 33%. The effect on anther length was associated with increases in both cell size and the number of endothecium cells and was attributed to the long arm of chromosome 4R. In contrast, the effect on pollen grain number was attributed to the short arm of chromosome 4R. These results indicate that rye chromosome 4R contains at least two genetic factors associated with increased anther size and pollen grain number that can favourably affect pollination traits in wheat.


Estimation of treatment effects in matched-pair cluster randomized trials by calibrating covariate imbalance between clusters.
We address estimation of intervention effects in experimental designs in which (a) interventions are assigned at the cluster level; (b) clusters are selected to form pairs, matched on observed characteristics; and (c) intervention is assigned to one cluster at random within each pair. One goal of policy interest is to estimate the average outcome if all clusters in all pairs are assigned control versus if all clusters in all pairs are assigned to intervention. In such designs, inference that ignores individual level covariates can be imprecise because cluster-level assignment can leave substantial imbalance in the covariate distribution between experimental arms within each pair. However, most existing methods that adjust for covariates have estimands that are not of policy interest. We propose a methodology that explicitly balances the observed covariates among clusters in a pair, and retains the original estimand of interest. We demonstrate our approach through the evaluation of the Guided Care program.


Apelin targets gut contraction to control glucose metabolism via the brain.
The gut-brain axis is considered as a major regulatory checkpoint in the control of glucose homeostasis. The detection of nutrients and/or hormones in the duodenum informs the hypothalamus of the host's nutritional state. This process may occur via hypothalamic neurons modulating central release of nitric oxide (NO), which in turn controls glucose entry into tissues. The enteric nervous system (ENS) modulates intestinal contractions in response to various stimuli, but the importance of this interaction in the control of glucose homeostasis via the brain is unknown. We studied whether apelin, a bioactive peptide present in the gut, regulates ENS-evoked contractions, thereby identifying a new physiological partner in the control of glucose utilisation via the hypothalamus. We measured the effect of apelin on electrical and mechanical duodenal responses via telemetry probes and isotonic sensors in normal and obese/diabetic mice. Changes in hypothalamic NO release, in response to duodenal contraction modulated by apelin, were evaluated in real time with specific amperometric probes. Glucose utilisation in tissues was measured with orally administrated radiolabeled glucose. In normal and obese/diabetic mice, glucose utilisation is improved by the decrease of ENS/contraction activities in response to apelin, which generates an increase in hypothalamic NO release. As a consequence, glucose entry is significantly increased in the muscle. Here, we identify a novel mode of communication between the intestine and the hypothalamus that controls glucose utilisation. Moreover, our data identified oral apelin administration as a novel potential target to treat metabolic disorders.


Pharmacokinetics of cocaine and metabolites in human oral fluid and correlation with plasma concentrations after controlled administration.
Oral fluid is an attractive alternative matrix for drug testing with a noninvasive and directly observed collection, but there are few controlled cocaine administration studies to guide interpretation. While residing on a closed research unit for up to 10 weeks under constant medical supervision, 19 participants were administered 75 mg/70 kg subcutaneous cocaine and 14 received 150 mg/70 kg. The disposition of cocaine, benzoylecgonine (BE), and ecgonine methyl ester (EME) into oral fluid was determined by gas chromatography-mass spectrometry for 0.08 to 48 hours after administration. In oral fluid collected by citric acid candy-stimulated expectoration, cocaine first appeared in oral fluid 0.08 to 0.32 hours after dosing and was rapidly eliminated with half-lives of 1.1 to 3.8 hours. BE and EME were first detected 0.08 to 1.0 hours after dosing with longer half-lives of 3.4 to 13.8 (BE) and 2.4 to 15.5 hours (EME) (P < 0.05). Oral fluid and plasma concentrations were significantly correlated for cocaine, BE, and EME (P < 0.0001). There were no significant differences (P > 0.05) in first and last detection times with the 8-μg/L cutoff proposed by the Substance Abuse and Mental Health Services Administration or the 10-μg/L cutoff from the European initiative, Driving Under the Influence of Drugs, Alcohol and Medicines. Metabolite:cocaine ratios increased after cocaine administration, potentially helpful for interpreting time of last use. Comparison of oral fluid collection through citric acid candy-stimulated expectoration, citric acid-treated Salivette, and neutral cotton Salivette devices did not reveal significant differences between devices for areas under the curve for cocaine, BE, or EME (P > 0.05). These results provide additional evidence for interpreting cocaine and metabolite concentrations in oral fluid and oral fluid's usefulness as an alternative matrix for drug testing.


Lessons from sea louse and salmon epidemiology.
Effective disease management can benefit from mathematical models that identify drivers of epidemiological change and guide decision-making. This is well illustrated in the host-parasite system of sea lice and salmon, which has been modelled extensively due to the economic costs associated with sea louse infections on salmon farms and the conservation concerns associated with sea louse infections on wild salmon. Consequently, a rich modelling literature devoted to sea louse and salmon epidemiology has been developed. We provide a synthesis of the mathematical and statistical models that have been used to study the epidemiology of sea lice and salmon. These studies span both conceptual and tactical models to quantify the effects of infections on host populations and communities, describe and predict patterns of transmission and dispersal, and guide evidence-based management of wild and farmed salmon. As aquaculture production continues to increase, advances made in modelling sea louse and salmon epidemiology should inform the sustainable management of marine resources.


Rac1 regulates neuronal polarization through the WAVE complex.
Neuronal migration and axon growth, key events during neuronal development, require distinct changes in the cytoskeleton. Although many molecular regulators of polarity have been identified and characterized, relatively little is known about their physiological role in this process. To study the physiological function of Rac1 in neuronal development, we have generated a conditional knock-out mouse, in which Rac1 is ablated in the whole brain. Rac1-deficient cerebellar granule neurons, which do not express other Rac isoforms, showed impaired neuronal migration and axon formation both in vivo and in vitro. In addition, Rac1 ablation disrupts lamellipodia formation in growth cones. The analysis of Rac1 effectors revealed the absence of the Wiskott-Aldrich syndrome protein (WASP) family verprolin-homologous protein (WAVE) complex from the plasma membrane of knock-out growth cones. Loss of WAVE function inhibited axon growth, whereas overexpression of a membrane-tethered WAVE mutant partially rescued axon growth in Rac1-knock-out neurons. In addition, pharmacological inhibition of the WAVE complex effector Arp2/3 also reduced axon growth. We propose that Rac1 recruits the WAVE complex to the plasma membrane to enable actin remodeling necessary for axon growth.


What Are Nursing Facilities Doing to Reduce Potentially Avoidable Hospitalizations?
Hospitalizations among nursing facility residents are frequent and often potentially avoidable. A number of initiatives and interventions have been developed to reduce excessive hospitalizations; however, little is known about the specific approaches nursing facilities use to address this issue. The objective of this study is to better understand which types of interventions nursing facilities have introduced to reduce potentially avoidable hospitalizations of long-stay nursing facility residents. Cross-sectional survey. 236 nursing facilities from 7 states. Nursing facility administrators. Web-based survey to measure whether facilities introduced any policies or procedures designed specifically to reduce potentially avoidable hospitalizations of long-stay nursing facility residents between 2011 and 2015. We surveyed facilities about seven types of interventions and quality improvement activities related to reducing avoidable hospitalizations, including use of Interventions to Reduce Acute Care Transfers (INTERACT) and American Medical Directors Association tools. Ninety-five percent of responding nursing facilities reported having introduced at least one new policy or procedure to reduce nursing facility resident hospitalizations since January 2011. The most common practice reported was hospitalization rate tracking or review, followed by standardized communication tools, such as Situation, Background, Assessment, Recommendation (SBAR). We found some variation in the extent and types of these reported interventions. Nearly all facilities surveyed reported having introduced a variety of initiatives to reduce potentially avoidable hospitalizations, likely driven by federal, state, and corporate initiatives to decrease hospital admissions and readmissions.


Dose-Exposure Simulation for Piperacillin-Tazobactam Dosing Strategies in Infants and Young Children.
Extended piperacillin-tazobactam (TZP) infusions have been associated with favourable outcomes. There are currently no pediatric dosing recommendations. To determine appropriate TZP dosing strategies in children 2 months - 6 years according to age and different minimal inhibitory concentrations (MICs). Age and weight were simulated for 1000 children. Post-hoc pharmacokinetic parameter estimates were generated using published clearance and volume of distribution data. For different dosing regimens, we estimated the probability of target attainment (PTA) over a range of MICs from 4 to 128 mg/L. The pharmacodynamic (PD) target was defined as free piperacillin concentrations above the MIC for ≥ 50% of the dosing interval. A PTA ≥ 90% was defined as optimal. PTA decreased as MIC and age increased. In all age groups, standard dosing regimens (240-300 mg/kg/day, 0.5h infusions) failed to reach PTAs ≥ 90% at MICs ≥ 16 mg/L. Standard 0.5h infusions reached PTAs ≥ 90% at MICs up to 8 mg/L in infants > 2 to 6m. No 0.5h infusion reached PTAs ≥ 90% for MICs ≥ 4 mg/L in children > 6m. While none of the tested regimens were optimal at MICs > 16 mg/L in children > 6m, 100 mg/kg/dose every 6h as a 3h infusion reached PD target at MICs of 32 mg/L in infants > 2 to 6m. Up to MICs of 16 mg/L, 90 mg/kg/dose every 8h as a 2h infusion in infants > 2 to 6m and 100 mg/kg/dose every 8h as a 4h infusion in children > 6m-6y achieved PTAs ≥ 90%.


If PBMs Guard Access to Drugs, Then Quis Custodiet Ipsos Custodies? (Who Will Guard the Guardians?).
Insulin prices in the United States have risen dramatically in recent years, yet pharmacies cannot provide a stable price for a given insulin due to factors that are not widely understood. This commentary discusses the complex and obscure factors that drive today's insulin prices with a discussion of the other players, besides the insulin manufacturer, who benefit from higher prices. An open discussion is critical regarding this drug and others that are essential to the lives of millions of people with diabetes. We'll also explore whether the market introduction of biosimilar insulin will impact insulin prices.


Tumor dormancy and cell signaling. II. Antibody as an agonist in inducing dormancy of a B cell lymphoma in SCID mice.
Tumor dormancy can be induced in a murine B cell lymphoma (BCL1) by immunizing BALB/c mice with the tumor immunoglobulin (Ig) before tumor cell challenge. In this report, we have investigated the immunological and cellular mechanisms underlying the induction of dormancy. BCL1 tumor cells were injected into SCID mice passively immunized with antibody against different epitopes on IgM or IgD with or without idiotype (Id)-immune T lymphocytes. Results indicate that antibody to IgM is sufficient to induce a state of dormancy. Antibodies against other cell surface molecules including IgD and CD44 (Pgp1) had no effect on tumor growth. Id-immune T cells by themselves also had no effect on tumor growth in SCID mice. However, simultaneous transfer of anti-Id and Id-immune T cells enhanced both the induction and duration of the dormant state. In vitro studies indicated that antibody to IgM induced apoptosis within several hours and cell cycle arrest by 24 h. Hyper cross-linking increased apoptosis. The Fc gamma RII receptor played little or no role in the negative signaling. Antibodies that did not negatively signal in vitro did not induce dormancy in vivo. The results suggest that anti-IgM plays a decisive role in inducing tumor dormancy to BCL1 by acting as an agonist of IgM-mediated signal transduction pathways.


Cue-invariant shape selectivity of macaque inferior temporal neurons.
The perception of shape is independent of the size and position of the shape and also of the visual cue that defines it. The same shape can be recognized whether defined by a difference in luminance, by motion, or by texture. Experiments showed that the shape selectivity of individual cells in the macaque inferior temporal cortex did not vary with the size and position of a shape and also did not vary with the visual cue used to define the shape. This cue invariance was true for static luminance and texture cues as well as for relative motion cues--that is, for cues that are processed in ventral and dorsal visual pathways. The properties of these inferior temporal cells meet the demands of cue-invariant shape coding.


Silver nanoparticles and their orthopaedic applications.
Implant-associated infection is a major source of morbidity in orthopaedic surgery. There has been extensive research into the development of materials that prevent biofilm formation, and hence, reduce the risk of infection. Silver nanoparticle technology is receiving much interest in the field of orthopaedics for its antimicrobial properties, and the results of studies to date are encouraging. Antimicrobial effects have been seen when silver nanoparticles are used in trauma implants, tumour prostheses, bone cement, and also when combined with hydroxyapatite coatings. Although there are promising results with in vitro and in vivo studies, the number of clinical studies remains small. Future studies will be required to explore further the possible side effects associated with silver nanoparticles, to ensure their use in an effective and biocompatible manner. Here we present a review of the current literature relating to the production of nanosilver for medical use, and its orthopaedic applications.


Natural variation in the C-repeat binding factor cold response pathway correlates with local adaptation of Arabidopsis ecotypes.
The natural range of Arabidopsis thaliana (Arabidopsis) encompasses geographical regions that have greatly differing local climates, including harshness of winter temperatures. A question thus raised is whether differences in freezing tolerance might contribute to local adaptation in Arabidopsis. Consistent with this possibility is that Arabidopsis accessions differ in freezing tolerance and that those collected from colder northern latitudes are generally more tolerant to freezing than those collected from warmer southern latitudes. Moreover, recent studies with Arabidopsis genotypes collected from sites in Sweden (SW) and Italy (IT) have established that the two accessions are locally adapted, that the SW ecotype is more tolerant of freezing than the IT ecotype, and that genetic differences between the two ecotypes that condition local adaptation and freezing tolerance map to a region that includes the C-repeat binding factor (CBF) locus. The CBF locus includes three genes - CBF1, CBF2 and CBF3 - that are induced by low temperature and encode transcription factors that regulate a group of more than 100 genes, the CBF regulon, which impart freezing tolerance. Here we show that cold induction of most CBF regulon genes is lower in IT plants compared with SW plants, and that this is due to the IT CBF2 gene encoding a non-functional CBF2 protein. The non-functional IT CBF2 protein also contributes to the lower freezing tolerance of the IT plants compared with the SW plants. Taken together, studies on the SW and IT ecotypes provide evidence that natural variation in the CBF pathway has contributed to adaptive evolution in these Arabidopsis populations.


Janus nanocarrier-based co-delivery of doxorubicin and berberine weakens chemotherapy-exacerbated hepatocellular carcinoma recurrence.
Despite the rapid progress which has been made in hepatocellular carcinoma (HCC) chemotherapeutics, recurrence of liver cancer still remains a barrier to achieve satisfying prognosis. Herein, we aimed to decipher the role of berberine (BER) in chemotherapy-exacerbated HCC repopulation via developing a nanocarrier co-deliveries doxorubicin (DOX) and BER to achieve a synergic effect in HCC treatment. The underlying fact of chemotherapy that promotes HCC repopulation was firstly examined and corroborated by clinical samples and murine repopulation model. Then, hyaluronic acid (HA)-conjugated Janus nanocarrier (HA-MSN@DB) was developed to load DOX and BER simultaneously. The HCC targeting efficiency, pH-controlled drug-release and anti-cancer property of HA-MSN@DB were assessed in CD44-overexpressed HCCs and normal liver cells. Magnet resonance imaging, bio-distribution, biocompatibility, tumor and recurrence inhibition studies were performed in H22 tumor-bearing mice. BER significantly reduced doxorubicin (DOX)-triggered HCC repopulation in vitro and in vivo through inhibiting Caspase-3-iPLA2-COX-2 pathway. The delivery of HA-MSN@DB into HCCs through CD44 receptor-mediated targeting effect was demonstrated. The controlled release of DOX and BER in response to acidic tumor microenvironment was validated. Importantly, HA-MSN@DB drastically enhanced the antitumor activity of DOX and suppressed DOX-exacerbated HCC repopulation in vitro and in vivo. Furthermore, HA-MSN@DB exhibited enhanced tumor accumulation and biocompatibility. Our findings revealed the pivotal role of BER in overcoming chemotherapy-exacerbated HCC repopulation through Caspase-3-iPLA2-COX-2 pathway, thereby providing a promising and stable nanocarrier integrating DOX and BER for effective HCC chemotherapy without repopulation. STATEMENT OF SIGNIFICANCE: In this work, we have first demonstrated the fact that berberine (Ber) reduces chemotherapy-exacerbated HCC recurrence and studied its mechanism by the aid of a doxorubicin-induced mice HCC relapse model. We then developed a promising strategy that simultaneously inhibits HCC and its recurrence with an HCC-targeted co-delivery nanocarrier HA-MSN@DB and revealed that such an inhibition was related with the suppression of Caspase-3-iPLA2-COX-2 pathway by berberine.


Risk of gastrointestinal events in patients with rheumatoid arthritis after withdrawal of rofecoxib.
To examine the incidence of gastrointestinal (GI) events in patients with rheumatoid arthritis (RA) after the removal of rofecoxib from the market. Residents of British Columbia with a diagnosis of RA who were chronic users of cyclooxygenase 2 (COX-2) inhibitors or nonselective nonsteroidal antiinflammatory drugs (nsNSAID) as of September 30, 2004, were included. We studied the risk of GI events using incidence rates and adjusted HR from Cox proportional hazards regression using time-dependent covariates. The cohort comprised 4266 patients with a mean age of 60 years and over 72% women, of which 2034 (48%) were classified as COX-2 inhibitor users and 2232 (52%) as chronic nsNSAID users as of September 30, 2004. The 2 groups were well balanced on baseline covariates except for comorbid conditions. In the year following rofecoxib withdrawal, 174 patients (5.5%) experienced 1 or more GI events, defined as a GI-related physician visit or hospitalization. There was no statistically significant increase in the risk of a GI event between those classified as a COX-2 inhibitor or nsNSAID user at the time of withdrawal (HR 1.03, 95% CI 0.69-1.54). Considering the drug exposure at the time of the event, there was no increased risk of GI events associated with the use of either COX-2 inhibitors or nsNSAID, or with the use of oral corticosteroids, low-dose aspirin, or clopidogrel, after adjustment for potential confounders. In this cohort, withdrawal of rofecoxib did not result in a significant increase in GI events among patients with RA.


'You don't know which bits to believe': qualitative study exploring carers' experiences of seeking information on the internet about childhood eczema.
We sought to explore parents and carers' experiences of searching for information about childhood eczema on the internet. A qualitative interview study was carried out among carers of children aged 5 years or less with a recorded diagnosis of eczema. The main focus of the study was to explore carers' beliefs and understandings around eczema and its treatment. As part of this, we explored experiences of formal and informal information seeking about childhood eczema. Transcripts of interviews were analysed thematically. Participants were recruited from six general practices in South West England. Interviews were carried out with 31 parents from 28 families. Experiences of searching for eczema information on the internet varied widely. A few interviewees were able to navigate through the internet and find the specific information they were looking for (for instance about treatments their child had been prescribed), but more found searching for eczema information online to be a bewildering experience. Some could find no information of relevance to them, whereas others found the volume of different information sources overwhelming. Some said that they were unsure how to evaluate online information or that they were wary of commercial interests behind some information sources. Interviewees said that they would welcome more signposting towards high quality information from their healthcare providers. We found very mixed experiences of seeking eczema information on the internet; but many participants in this study found this to be frustrating and confusing. Healthcare professionals and healthcare systems have a role to play in helping people with long-term health conditions and their carers find reliable online information to support them with self-care.


Chikungunya fever: a re-emerging viral infection.
Chikungunya (CHIK) fever is a re-emerging viral disease characterized by abrupt onset of fever with severe arthralgia followed by constitutional symptoms and rash lasting for 1-7 days. The disease is almost self-limiting and rarely fatal. Chikungunya virus (CHIKV) is a RNA virus belonging to family Togaviridae, genus Alphavirus. Molecular characterization has demonstrated two distinct lineages of strains which cause epidemics in Africa and Asia. These geographical genotypes exhibit differences in the transmission cycles. In contrast to Africa where sylvatic cycle is maintained between monkeys and wild mosquitoes, in Asia the cycle continues between humans and the Aedes aegypti mosquito. CHIKV is known to cause epidemics after a period of quiescence. The first recorded epidemic occurred in Tanzania in 1952-1953. In Asia, CHIK activity was documented since its isolation in Bangkok, Thailand in 1958. Virus transmission continued till 1964. After hiatus, the virus activity re-appeared in the mid-1970s and declined by 1976. In India, well-documented outbreaks occurred in 1963 and 1964 in Kolkata and southern India, respectively. Thereafter, a small outbreak of CHIK was reported from Sholapur district, Maharashtra in 1973. CHIKV emerged in the islands of South West Indian Ocean viz. French island of La Reunion, Mayotee, Mauritius and Seychelles which are reporting the outbreak since February, 2005. After quiescence of about three decades, CHIKV re-emerged in India in the states of Andhra Pradesh, Karnataka, Maharashtra, Madhya Pradesh and Tamil Nadu since December, 2005. Cases have also been reported from Rajasthan, Gujarat and Kerala. The outbreak is still continuing. National Institute of Communicable Diseases has conducted epidemiological, entomological and laboratory investigations for confirmation of the outbreak. These have been discussed in detail along with the major challenges that the country faced during the current outbreak.


MRI in sarcoglycanopathies: a large international cohort study.
To characterise the pattern and spectrum of involvement on muscle MRI in a large cohort of patients with sarcoglycanopathies, which are limb-girdle muscular dystrophies (LGMD2C-2F) caused by mutations in one of the four genes coding for muscle sarcoglycans. Lower limb MRI scans of patients with LGMD2C-2F, ranging from severe childhood variants to milder adult-onset forms, were collected in 17 neuromuscular referral centres in Europe and USA. Muscle involvement was evaluated semiquantitatively on T1-weighted images according to a visual score, and the global pattern was assessed as well. Scans from 69 patients were examined (38 LGMD2D, 18 LGMD2C, 12 LGMD2E and 1 LGMD2F). A common pattern of involvement was found in all the analysed scans irrespective of the mutated gene. The most and earliest affected muscles were the thigh adductors, glutei and posterior thigh groups, while lower leg muscles were relatively spared even in advanced disease. A proximodistal gradient of involvement of vasti muscles was a consistent finding in these patients, including the most severe ones. Muscle involvement on MRI is consistent in patients with LGMD2C-F and can be helpful in distinguishing sarcoglycanopathies from other LGMDs or dystrophinopathies, which represent the most common differential diagnoses. Our data provide evidence about selective susceptibility or resistance to degeneration of specific muscles when one of the sarcoglycans is deficient, as well as preliminary information about progressive involvement of the different muscles over time.


Lessons learned from ten investigations of waterborne gastroenteritis outbreaks, France, 1998-2006.
Ten outbreaks of waterborne acute gastroenteritis (AGE) have been investigated in France since 1998. These outbreaks have affected populations of over 1,000 people, with generally high attack rates. The causal agents have been identified in six of these events. Aetiologies involved mainly noroviruses and Cryptosporidium sp. The point of entry of the contamination was located in the distribution network in five outbreaks (waste water backflows in four cases and one case of contamination induced by maintenance work) and at the water collection facilities in five other cases. Once the outbreak was detected, epidemiological and environmental investigations and crisis management followed well-established procedures. Further progress in public health surveillance will depend on more complete and rapid detection and reporting. Automated analysis of health insurance data on the reimbursement of drugs for AGE should help make detection more complete. Improved reactivity depends primarily on the operator immediately reporting incidents that indicate a possible massive contamination of the water network to health authorities - in particular complaints from the population, which are the only early-warning alerts in the case of waste water backflows.


Short Communication: Impact of Viral Load Use on Treatment Switch in Perinatally HIV-Infected Children in Asia.
We sought to assess the impact of routine HIV viral load (VL) monitoring on the incidence of switching from a first- to a second-line antiretroviral therapy (ART) regimen, and to describe factors associated with switch. Data from a regional cohort of 16 clinical programs in six Asian countries were analyzed. Second-line switch was defined as a change from a non-nucleoside reverse transcriptase inhibitor (NNRTI) to a protease inhibitor (PI) or vice versa, and ≥1 of the following: (1) reported treatment failure by local criteria, (2) switch of ≥1 additional drug, or (3) a preceding HIV VL ≥1,000 copies/ml. Routine VL was having ≥1 test after ≥24 weeks of ART and ≥1 time/year thereafter. Factors associated with time to switch were evaluated with death and loss to follow-up as competing risks. A total of 2,398 children were included in this analysis. At ART initiation, the median (interquartile range) age was 6.0 (3.3-8.9) years, more than half had WHO stage 3 or 4, the median CD4 was 189 (47-456) cells/mm3, 93% were on NNRTI-based first-line ART, and 34% had routine VL monitoring. Treatment switch occurred in 17.6% of patients, at a median of 35 (22-49) months. After adjusting for country, sex, first ART regimen, and CD4% at ART initiation, children with routine VL monitoring were 1.46 (95% confidence interval 1.11-1.93) times more likely to be switched (p = .007). Scale-up of VL testing will lead to earlier identification of treatment failure, and it can help guide earlier switches to prevent resistance.


Population Pharmacokinetics and Pharmacodynamics of Extended-Infusion Piperacillin and Tazobactam in Critically Ill Children.
The study objective was to evaluate the population pharmacokinetics and pharmacodynamics of extended-infusion piperacillin-tazobactam in children hospitalized in an intensive care unit. Seventy-two serum samples were collected at steady state from 12 patients who received piperacillin-tazobactam at 100/12.5 mg/kg of body weight every 8 h infused over 4 h. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed to estimate the piperacillin pharmacokinetic profiles for dosing regimens of 80 to 100 mg/kg of the piperacillin component given every 6 to 8 h and infused over 0.5, 3, or 4 h. The probability of target attainment (PTA) for a cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMIC) of ≥50% was calculated at MICs ranging from 0.25 to 64 mg/liter. The mean ± standard deviation (SD) age, weight, and estimated glomerular filtration rate were 5 ± 3 years, 17 ± 6.2 kg, and 118 ± 41 ml/min/1.73 m(2), respectively. A one-compartment model with zero-order input and first-order elimination best fit the pharmacokinetic data for both drugs. Weight was significantly associated with piperacillin clearance, and weight and sex were significantly associated with tazobactam clearance. Pharmacokinetic parameters (mean ± SD) for piperacillin and tazobactam were as follows: clearance, 0.22 ± 0.07 and 0.19 ± 0.07 liter/h/kg, respectively; volume of distribution, 0.43 ± 0.16 and 0.37 ± 0.14 liter/kg, respectively. All extended-infusion regimens achieved PTAs of >90% at MICs of ≤16 mg/liter. Only the 3-h infusion regimens given every 6 h achieved PTAs of >90% at an MIC of 32 mg/liter. For susceptible bacterial pathogens, piperacillin-tazobactam doses of ≥80/10 mg/kg given every 8 h and infused over 4 h achieve adequate pharmacodynamic exposures in critically ill children.


Frontline Science: Characterization of a novel mouse strain expressing human Siglec-8 only on eosinophils.
Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is a human cell surface protein expressed exclusively on eosinophils, mast cells, and basophils that, when engaged, induces eosinophil apoptosis and inhibits mast cell mediator release. This makes Siglec-8 a promising therapeutic target to treat diseases involving these cell types. However, preclinical studies of Siglec-8 targeting in vivo are lacking because this protein is only found in humans, apes, and some monkeys. Therefore, we have developed a mouse strain in which SIGLEC8 transcription is activated by Cre recombinase and have crossed this mouse with the eoCre mouse to achieve eosinophil-specific expression. We confirmed that Siglec-8 is expressed exclusively on the surface of mature eosinophils in multiple tissues at levels comparable to those on human blood eosinophils. Following ovalbumin sensitization and airway challenge, Siglec-8 knock-in mice generated a pattern of allergic lung inflammation indistinguishable from that of littermate controls, suggesting that Siglec-8 expression within the eosinophil compartment does not alter allergic eosinophilic inflammation. Using bone marrow from these mice, we demonstrated that, during maturation, Siglec-8 expression occurs well before the late eosinophil developmental marker C-C motif chemokine receptor 3, consistent with eoCre expression. Antibody ligation of the receptor induces Siglec-8 endocytosis and alters the phosphotyrosine profile of these cells, indicative of productive signaling. Finally, we demonstrated that mouse eosinophils expressing Siglec-8 undergo cell death when the receptor is engaged, further evidence that Siglec-8 is functional on these cells. These mice should prove useful to investigate Siglec-8 biology and targeting in vivo in a variety of eosinophilic disease models.


Use of biogas for cogeneration of heat and electricity for local application: performance evaluation of an engine power generator and a sludge thermal dryer.
A small unit of cogeneration of energy and heat was tested at the Centre for Research and Training on Sanitation UFMG/COPASA - CePTS, located at the Arrudas Sewage Treatment Plant, in Belo Horizonte, Minas Gerais, Brazil. The unit consisted of an engine power generator adapted to run on biogas, a thermal dryer prototype and other peripherals (compressor, biogas storage tank, air blower, etc.). The heat from engine power generator exhaust gases was directed towards the thermal dryer prototype to dry the sludge and disinfect it. The results showed that the experimental apparatus is self-sufficient in electricity, even producing a surplus, available for other uses. The tests of drying and disinfection of sludge lasted 7 h, leading to an increase in solids content from 4 to 8% (50% reduction in sludge volume). Although the drying of sludge was not possible (only thickening was achieved), the disinfection process proved very effective, enabling the complete inactivation of helminth eggs.


Entropy-driven crystal formation on highly strained substrates.
In heteroepitaxy, lattice mismatch between the deposited material and the underlying surface strongly affects nucleation and growth processes. The effect of mismatch is well studied in atoms with growth kinetics typically dominated by bond formation with interaction lengths on the order of one lattice spacing. In contrast, less is understood about how mismatch affects crystallization of larger particles, such as globular proteins and nanoparticles, where interparticle interaction energies are often comparable to thermal fluctuations and are short ranged, extending only a fraction of the particle size. Here, using colloidal experiments and simulations, we find particles with short-range attractive interactions form crystals on isotropically strained lattices with spacings significantly larger than the interaction length scale. By measuring the free-energy cost of dimer formation on monolayers of increasing uniaxial strain, we show the underlying mismatched substrate mediates an entropy-driven attractive interaction extending well beyond the interaction length scale. Remarkably, because this interaction arises from thermal fluctuations, lowering temperature causes such substrate-mediated attractive crystals to dissolve. Such counterintuitive results underscore the crucial role of entropy in heteroepitaxy in this technologically important regime. Ultimately, this entropic component of lattice mismatched crystal growth could be used to develop unique methods for heterogeneous nucleation and growth of single crystals for applications ranging from protein crystallization to controlling the assembly of nanoparticles into ordered, functional superstructures. In particular, the construction of substrates with spatially modulated strain profiles would exploit this effect to direct self-assembly, whereby nucleation sites and resulting crystal morphology can be controlled directly through modifications of the substrate.


A comparison and user-based evaluation of models of textual information structure in the context of cancer risk assessment.
Many practical tasks in biomedicine require accessing specific types of information in scientific literature; e.g. information about the results or conclusions of the study in question. Several schemes have been developed to characterize such information in scientific journal articles. For example, a simple section-based scheme assigns individual sentences in abstracts under sections such as Objective, Methods, Results and Conclusions. Some schemes of textual information structure have proved useful for biomedical text mining (BIO-TM) tasks (e.g. automatic summarization). However, user-centered evaluation in the context of real-life tasks has been lacking. We take three schemes of different type and granularity--those based on section names, Argumentative Zones (AZ) and Core Scientific Concepts (CoreSC)--and evaluate their usefulness for a real-life task which focuses on biomedical abstracts: Cancer Risk Assessment (CRA). We annotate a corpus of CRA abstracts according to each scheme, develop classifiers for automatic identification of the schemes in abstracts, and evaluate both the manual and automatic classifications directly as well as in the context of CRA. Our results show that for each scheme, the majority of categories appear in abstracts, although two of the schemes (AZ and CoreSC) were developed originally for full journal articles. All the schemes can be identified in abstracts relatively reliably using machine learning. Moreover, when cancer risk assessors are presented with scheme annotated abstracts, they find relevant information significantly faster than when presented with unannotated abstracts, even when the annotations are produced using an automatic classifier. Interestingly, in this user-based evaluation the coarse-grained scheme based on section names proved nearly as useful for CRA as the finest-grained CoreSC scheme. We have shown that existing schemes aimed at capturing information structure of scientific documents can be applied to biomedical abstracts and can be identified in them automatically with an accuracy which is high enough to benefit a real-life task in biomedicine.


Tobacco etch virus infectivity in Capsicum spp. is determined by a maximum of three amino acids in the viral virulence determinant VPg.
Potyvirus resistance in Capsicum spp. has been attributed to amino acid substitutions at the pvr1 locus that cause conformational shifts in eukaryotic translation initiation factor eIF4E. The viral genome-linked protein (VPg) sequence was isolated and compared from three Tobacco etch virus (TEV) strains, highly aphid-transmissible (HAT), Mex21, and N, which differentially infect Capsicum genotypes encoding Pvr1(+), pvr1, and pvr1(2). Viral chimeras were synthesized using the TEV-HAT genome, replacing HAT VPg with Mex21 or N VPg. TEV HAT did not infect pepper plants homozygous for either the pvr1 or pvr1(2) allele. However, the novel chimeric TEV strains, TEVHAT(Mex21-VPg) and TEV-HAT(N-VPg), infected pvr1 and pvr1(2) pepper plants, respectively, demonstrating that VPg is the virulence determinant in this pathosystem. Three dimensional structural models predicted interaction between VPg and the susceptible eIF4E genotype in every case, while resistant genotypes were never predicted to interact. To determine whether there is a correlation between physical interaction of VPg with eIF4E and infectivity, the effects of amino acid variation within VPg were assessed. Interaction between pvr1(2) eIF4E and N VPg was detected in planta, implying that the six amino acid differences in N VPg relative to HAT VPg are responsible for restoring the physical interaction and infectivity.


How Do Military Family Caregivers Who Completed a Supportive Intervention Differ From Those Who Dropped Out?
Background. To create efficacious interventions for military family caregivers (MFCs), it is important to understand the characteristics and predictors of completers and dropouts of newly developed supportive interventions. Aim. The purpose of this study was to examine completion patterns in MFCs enrolled in an educational intervention feasibility study. Method. Baseline data are presented from MFC completers (n = 64) and dropouts (n = 60) of a national feasibility study for an innovative intervention. Measures include depression (Patient Health Questionnaire-2), anxiety (Generalized Anxiety Disorder-7), somatic symptoms (Patient Health Questionnaire-15), quality of life (World Health Organization Quality of Life-Brief), relationship satisfaction (Relationship Assessment Scale), and military care recipient number of injuries. Analysis of variance was used to evaluate differences between completers and dropouts and logistic regression was used to identify predictors of intervention completion. Results. Results indicated that MFCs with greater anxiety, χ2(3) = 10.33, p = .02; depression, χ2(1) = 8.18, p = .004; somatic symptoms, F(1, 106) = 6.26, p = .01; care recipient number of injuries, F(1, 118) = 16.31, p < .001; lower general satisfaction with treatment, F(1, 96) = 4.34, p = .04; and lower satisfaction with accessibility and convenience with treatment, F(1, 89) = 4.18, p = .04, were significantly more likely to complete the intervention. After multivariate analysis, the sole predictor of intervention completion was the number of care recipients' injuries, χ2(6) = 14.89, N = 77, p < .05. Conclusions. Overall, findings indicate that MFCs who were more "at risk" were more likely to complete the intervention. Findings present patterns of intervention completion and provide insight on areas in need of further investigation on intervention development supporting the needs of MFCs.


(2Z,6Z)-N,N-Bis(2,6-diisopropyl-phen-yl)-N,N-bis-(2-methoxy-ethyl)pyridine-2,6-dicarboxamidine.
In the title compound, C(37)H(53)N(5)O(2), the benzene rings make dihedral angles of 84.61 (8) and 67.10 (9)° with the pyridine ring. The crystal structure is stabilized by strong intra-molecular inter-actions. The two (2-methoxyethyl)amine groups are disordered over two positions; the site occupancies are ca 0.6 and 0.4.


Microbial dark matter ecogenomics reveals complex synergistic networks in a methanogenic bioreactor.
Ecogenomic investigation of a methanogenic bioreactor degrading terephthalate (TA) allowed elucidation of complex synergistic networks of uncultivated microorganisms, including those from candidate phyla with no cultivated representatives. Our previous metagenomic investigation proposed that Pelotomaculum and methanogens may interact with uncultivated organisms to degrade TA; however, many members of the community remained unaddressed because of past technological limitations. In further pursuit, this study employed state-of-the-art omics tools to generate draft genomes and transcriptomes for uncultivated organisms spanning 15 phyla and reports the first genomic insight into candidate phyla Atribacteria, Hydrogenedentes and Marinimicrobia in methanogenic environments. Metabolic reconstruction revealed that these organisms perform fermentative, syntrophic and acetogenic catabolism facilitated by energy conservation revolving around H2 metabolism. Several of these organisms could degrade TA catabolism by-products (acetate, butyrate and H2) and syntrophically support Pelotomaculum. Other taxa could scavenge anabolic products (protein and lipids) presumably derived from detrital biomass produced by the TA-degrading community. The protein scavengers expressed complementary metabolic pathways indicating syntrophic and fermentative step-wise protein degradation through amino acids, branched-chain fatty acids and propionate. Thus, the uncultivated organisms may interact to form an intricate syntrophy-supported food web with Pelotomaculum and methanogens to metabolize catabolic by-products and detritus, whereby facilitating holistic TA mineralization to CO2 and CH4.


Psychological state estimation from physiological recordings during robot-assisted gait rehabilitation.
Robot-assisted treadmill training is an established intervention used to improve walking ability in patients with neurological disorders. Although it has been shown that attention to the task is a key factor for successful rehabilitation, the psychological state of patients during robot-assisted gait therapy is often neglected. We presented 17 nondisabled subjects and 10 patients with neurological disorders a virtual-reality task with varying difficulty levels to induce feelings of being bored, excited, and overstressed. We developed an approach to automatically estimate and classify a patient's psychological state, i.e., his or her mental engagement, in real time during gait training. We used psychophysiological measurements to obtain an objective measure of the current psychological state. Automatic classification was performed by a neural network. We found that heart rate, skin conductance responses, and skin temperature can be used as markers for psychological states in the presence of physical effort induced by walking. The classifier achieved a classification error of 1.4% for nondisabled subjects and 2.1% for patients with neurological disorders. Using our new method, we processed the psychological state data in real time. Our method is a first step toward real-time auto-adaptive gait training with potential to improve rehabilitation results by optimally challenging patients at all times during exercise.


Effects of colloidal fouling and gas sparging on microfiltration of yeast suspension.
Cross-flow microfiltration is an important step in separating Baker's yeast (Saccharomyces cerevisiae) from aqueous suspension in many processes. However the permeate flux often declines rapidly due to colloidal fouling of membranes and concentration polarisation. The present work explores the possibility of maintaining acceptable permeate flux by co-current sparging of gas along with the feed, which would scour away colloidal deposits and reduce concentration polarisation of membranes. In this work, both washed and unwashed yeast were used to study the effect of washing to reduce protein fouling of membranes. It was found that permeate flux increased by 45% for liquid throughput of 75 kg/h for a feed concentration of 2.0 kg/m3 of washed yeast as compared with unwashed yeast suspension without gas sparging. For washed yeast suspension, the increase in gas flow rate from 0.5 lpm to 1.5 lpm (30 l/h to 90 l/h) had beneficial effect on permeate flux. It is concluded that in the present case, the gas flow rate should be less than or equal to the liquid flow rate for enhancement of permeates flux.


Visualization of the left extraperitoneal space and spatial relationships to its related spaces by the visible human project.
The major hindrance to multidetector CT imaging of the left extraperitoneal space (LES), and the detailed spatial relationships to its related spaces, is that there is no obvious density difference between them. Traditional gross anatomy and thick-slice sectional anatomy imagery are also insufficient to show the anatomic features of this narrow space in three-dimensions (3D). To overcome these obstacles, we used a new method to visualize the anatomic features of the LES and its spatial associations with related spaces, in random sections and in 3D. In conjunction with Mimics® and Amira® software, we used thin-slice cross-sectional images of the upper abdomen, retrieved from the Chinese and American Visible Human dataset and the Chinese Virtual Human dataset, to display anatomic features of the LES and spatial relationships of the LES to its related spaces, especially the gastric bare area. The anatomic location of the LES was presented on 3D sections reconstructed from CVH2 images and CT images. What calls for special attention of our results is the LES consists of the left sub-diaphragmatic fat space and gastric bare area. The appearance of the fat pad at the cardiac notch contributes to converting the shape of the anteroexternal surface of the LES from triangular to trapezoidal. Moreover, the LES is adjacent to the lesser omentum and the hepatic bare area in the anterointernal and right rear direction, respectively. The LES and its related spaces were imaged in 3D using visualization technique for the first time. This technique is a promising new method for exploring detailed communication relationships among other abdominal spaces, and will promote research on the dynamic extension of abdominal diseases, such as acute pancreatitis and intra-abdominal carcinomatosis.


Direct inhibition of PI3K in combination with dual HER2 inhibitors is required for optimal antitumor activity in HER2+ breast cancer cells.
Despite multiple advances in the treatment of HER2+ breast cancers, resistance develops even to combinations of HER2 targeting agents. Inhibition of PI3K pathway signaling is critical for the efficacy of HER2 inhibitors. Activating mutations in PIK3CA can overlap with HER2 amplification and have been shown to confer resistance to HER2 inhibitors in preclinical studies. Lapatinib-resistant cells were profiled for mutations in the PI3K pathway with the SNaPshot assay. Hotspot PIK3CA mutations were retrovirally transduced into HER2-amplified cells. The impact of PIK3CA mutations on the effect of HER2 and PI3K inhibitors was assayed by immunoblot, proliferation and apoptosis assays. Uncoupling of PI3K signaling from HER2 was investigated by ELISA for phosphoproteins in the HER2-PI3K signaling cascade. The combination of HER2 inhibitors with PI3K inhibition was studied in HER2-amplified xenograft models with wild-type or mutant PIK3CA. Here we describe the acquisition of a hotspot PIK3CA mutation in cells selected for resistance to the HER2 tyrosine kinase inhibitor lapatinib. We also show that the gain of function conferred by these PIK3CA mutations partially uncouples PI3K signaling from the HER2 receptor upstream. Drug resistance conferred by this uncoupling was overcome by blockade of PI3K with the pan-p110 inhibitor BKM120. In mice bearing HER2-amplified wild-type PIK3CA xenografts, dual HER2 targeting with trastuzumab and lapatinib resulted in tumor regression. The addition of a PI3K inhibitor further improved tumor regression and decreased tumor relapse after discontinuation of treatment. In a PIK3CA-mutant HER2+ xenograft, PI3K inhibition with BKM120 in combination with lapatinib and trastuzumab was required to achieve tumor regression. These results suggest that the combination of PI3K inhibition with dual HER2 blockade is necessary to circumvent the resistance to HER2 inhibitors conferred by PIK3CA mutation and also provides benefit to HER2+ tumors with wild-type PIK3CA tumors.