Functional comparisons of different tumour necrosis factor receptor/IgG fusion proteins.
Nine different IgG fusion proteins and one non-fusion protein, all containing sequences from the extracellular domain of either of two human TNF receptors, were compared for their ability to bind and inhibit human TNF-alpha or TNF-beta. The fusion proteins differed with respect to TNF receptor type (p55 or p75 TNF receptor), receptor valency (one, two or four receptor domains per molecule), the presence or absence of a CH1 domain in the IgG constant region, and the proportion of the extracellular domain included in the construct. In vitro TNF binding assays and cytotoxicity assays indicated that, of the constructs that bound TNF, the greatest difference in affinity and neutralizing capability was between monovalent and bivalent receptor constructs. Differences were also noted between tetravalent and bivalent versions of p55 fusion proteins, as well as between a p75 fusion protein comprising the complete extracellular domain and one lacking the C-terminal 53 amino acids of the extracellular domain. p55 constructs that included only the second cysteine-rich domain (CRD) or only the second and third CRDs showed no TNF binding activity. The presence or absence of an IgG CH1 domain made no difference in the ability of fusion proteins to neutralize TNF-alpha or TNF-beta. Animal experiments comparing the tetravalent and bivalent p55 fusions and the effects of the CH1 domain did not show significant differences in their ability to protect mice from endotoxin-induced lethality, although the p55 fusion proteins appeared to be more protective than the p75 fusion proteins. Thus, this study has identified structural modifications to TNF receptor/IgG fusion proteins which have differing effects on their neutralizing ability towards TNF-alpha or TNF-beta.


The GS (genetic selection) Principle.
The GS (Genetic Selection) Principle states that biological selection must occur at the nucleotide-sequencing molecular-genetic level of 3'5' phosphodiester bond formation. After-the-fact differential survival and reproduction of already-living phenotypic organisms (ordinary natural selection) does not explain polynucleotide prescription and coding. All life depends upon literal genetic algorithms. Even epigenetic and "genomic" factors such as regulation by DNA methylation, histone proteins and microRNAs are ultimately instructed by prior linear digital programming. Biological control requires selection of particular configurable switch-settings to achieve potential function. This occurs largely at the level of nucleotide selection, prior to the realization of any integrated biofunction. Each selection of a nucleotide corresponds to the setting of two formal binary logic gates. The setting of these switches only later determines folding and binding function through minimum-free-energy sinks. These sinks are determined by the primary structure of both the protein itself and the independently prescribed sequencing of chaperones. The GS Principle distinguishes selection of existing function (natural selection) from selection for potential function (formal selection at decision nodes, logic gates and configurable switch-settings).


Correlation between G2m(n) immunoglobulin allotype and human antibody response and susceptibility to polysaccharide encapsulated bacteria.
To determine whether genetic factors influence the human antibody response to polysaccharides, we correlated Ig allotypes with the concentrations of antibody to 14 bacterial capsular antigens in 130 actively immunized Caucasian adults. The 88 individuals possessing G2m(n), an allotype antigen of IgG2 subclass heavy chains, had significantly higher postimmunization antibody levels to Haemophilus influenzae type b (Hib) and 8 of 11 pneumococcal types (P less than 0.05) than the 42 lacking this antigen. For Hib, pneumococcus type 14, and meningococcus group C, an increased response was observed in IgG class but not in IgM or IgA classes of antibody. The G2m(n) positive individuals also had higher preimmunization antibody levels to most polysaccharide antigens. Total IgG2 concentrations were correlated with the mean postimmunization antibody concentrations to pneumococci (P = 0.005), but this correlation was independent of G2m(n) by multiple regression analysis. To determine if the lack of G2m(n) was associated with increased susceptibility to infection, we compared the frequencies of various Ig allotypes in 98 children infected with Hib and 98 matched controls. Caucasian children with Hib infections other than epiglottitis were significantly more likely to lack the G2m(n) allotype than controls (P less than 0.05). G2m(n) negative Caucasian children less than or equal to 18 mo old have a 5.1-fold higher risk of nonepiglottitic Hib infections than G2m(n) positive children (P less than 0.01). We conclude that allotypic variants of the gamma-2 heavy chain genes, or genes in linkage equilibrium with them, exert a regulatory influence on the caucasian antibody response to a variety of immunologically distinct bacterial polysaccharide antigens. Young Caucasian children of the low responder phenotype, i.e., those lacking the G2m(n) allotype, are genetically predisposed to Hib and perhaps other bacterial infections.


Liver endothelium mediates the hepatocyte's uptake of ceruloplasmin.
The mode of transport of ceruloplasmin (CP) into the liver was investigated in fractionated liver cell suspensions. Incubation of 125I-CP at 4 degrees C with these different fractions led to its binding only to endothelial cells but not Kupffer cells and hepatocytes. Incubation at 37 degrees C led to rapid uptake of 125I-CP by endothelium, but cell-associated radioactivity declined after 15 min, which suggests the release of the labeled substance. Internalization was confirmed by fractionation of surface-bound and internalized ligand. The released label now acquired binding potential for fresh target hepatocytes, and the binding was inhibitable with asialoceruloplasmin but not native CP. This suggested that the released molecule was modified in the endothelium by desialation. Desialation was confirmed by incubation of endothelium with double-labeled CP (3H label on sialic acid and 125I on the protein part). We conclude that in the liver, CP is first recognized and taken up by endothelial cells that are endowed with appropriate surface receptors for the protein. Endothelium then modifies the molecule by desialation to expose the penultimate galactosyl residues. The modified molecule is then released, recognized, and taken up by hepatocytes through their membrane galactosyl-recognition system. These findings are consistent with the role of endothelium as an active mediator of molecular transport between blood and tissue, and further assign a biological role for the galactosyl-recognition system in hepatocytes.


Autophagy-dependent regulation of tumor metastasis by myeloid cells.
Autophagy is a vital process controlling the lysosomal degradation of cellular organelles and thereby regulating tissue homeostasis in an environment-dependent fashion. Recent studies have unveiled the critical role of tumor cell-derived autophagy in regulating pro-tumor and anti-tumor processes depending on different stages and tumor microenvironments. However, the precise mechanism whereby autophagy regulates tumor progression remains largely unclear. Since myeloid cells contribute to tumor progression and metastasis, we evaluated the role of myeloid cell-specific autophagy in the regulation of tumor progression. We found that the number and size of metastatic lesions were smaller in myeloid cell-specific autophagy-deficient mice. Furthermore, autophagy-mediated regulation of TGF-β in myeloid cells was associated with the induction of epithelial-mesenchymal transition (EMT), which increases the invasive and metastatic potentials of tumor cells. Myeloid-derived autophagy also plays a critical role in impairing antitumor immune responses and promoting the survival and accumulation of M2 macrophages in tumor tissues in a CSF-1 and TGF-β-dependent manner. Taken together, our findings elucidate previously unrecognized mechanisms by which myeloid cells promote tumor progression through autophagy-mediated regulation of malignancy and immune tolerance.


Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium.
Tumor progression alters the composition and physical properties of the extracellular matrix. Particularly, increased matrix stiffness has profound effects on tumor growth and metastasis. While endothelial cells are key players in cancer progression, the influence of tumor stiffness on the endothelium and the impact on metastasis is unknown. Through quantitative mass spectrometry, we find that the matricellular protein CCN1/CYR61 is highly regulated by stiffness in endothelial cells. We show that stiffness-induced CCN1 activates β-catenin nuclear translocation and signaling and that this contributes to upregulate N-cadherin levels on the surface of the endothelium, in vitro This facilitates N-cadherin-dependent cancer cell-endothelium interaction. Using intravital imaging, we show that knockout of Ccn1 in endothelial cells inhibits melanoma cancer cell binding to the blood vessels, a critical step in cancer cell transit through the vasculature to metastasize. Targeting stiffness-induced changes in the vasculature, such as CCN1, is therefore a potential yet unappreciated mechanism to impair metastasis.


Social epidemiology and Eastern Wisdom.
Social epidemiology is the field of study that attempts to understand the social determinants of health and the dynamics between societal settings and health. In the past 3 decades, large-scale studies in the West have accumulated a range of measures and methodologies to pursue this goal. We would like to suggest that there may be conceptual gaps in the science if Western research models are applied uncritically in East Asian studies of socioeconomic, gender, and ethnic inequalities in health. On one hand, there are common concerns, including population aging and gendered labor market participation. Further, international comparison must be built on shared concepts such as socioeconomic stratification in market economies. On the other hand, some aspects of health, such as common mental disorders, may have culturally specific manifestations that require development of perspectives (and perhaps novel measures) in order to reveal Eastern specifics. Exploring and debating commonalities and differences in the determinants of health in Oriental and Occidental cultures could offer fresh inspiration and insight for the next phase of social epidemiology in both regions.


Detecting reports of unsafe foods in consumer product reviews.
Access to safe and nutritious food is essential for good health. However, food can become unsafe due to contamination with pathogens, chemicals or toxins, or mislabeling of allergens. Illness resulting from the consumption of unsafe foods is a global health problem. Here, we develop a machine learning approach for detecting reports of unsafe food products in consumer product reviews from Amazon.com. We linked Amazon.com food product reviews to Food and Drug Administration (FDA) food recalls from 2012 to 2014 using text matching approaches in a PostGres relational database. We applied machine learning methods and over- and under-sampling methods to the linked data to automate the detection of reports of unsafe food products. Our data consisted of 1 297 156 product reviews from Amazon.com. Only 5149 (0.4%) were linked to recalled food products. Bidirectional Encoder Representation from Transformations performed best in identifying unsafe food reviews, achieving an F1 score, precision and recall of 0.74, 0.78, and 0.71, respectively. We also identified synonyms for terms associated with FDA recalls in more than 20 000 reviews, most of which were associated with nonrecalled products. This might suggest that many more products should have been recalled or investigated. Challenges to improving food safety include, urbanization which has led to a longer food chain, underreporting of illness and difficulty in linking contaminated food to illness. Our approach can improve food safety by enabling early identification of unsafe foods which can lead to timely recall thereby limiting the health and economic impact on the public.


Profiling lipoxygenase metabolism in specific steps of colorectal tumorigenesis.
Lipoxygenases (LOX) are key enzymes for the oxidative metabolism of polyunsaturated fatty acids into biologically active products. Clinical data on comparative levels of various LOX products in tumorigenesis are lacking. Therefore, we examined the profiles of several LOX products (5-LOX, 12-LOX, 15-LOX-1, and 15-LOX-2) by liquid chromatography/tandem mass spectrometry in the major steps of colorectal tumorigenesis (normal, polyp, and cancer) in a clinical study of 125 subjects (49 with normal colon, 36 with colorectal polyps, and 40 with colorectal cancer) who underwent prospective colorectal biopsies to control for various potential confounding factors (e.g., diet, medications). Mean 13-hydroxyoctadecadienoic acid (13-HODE) levels were significantly higher in normal colon [mean, 36.11 ng/mg protein; 95% confidence interval (95% CI), 31.56-40.67] than in paired colorectal cancer mucosa (mean, 27.01 ng/mg protein; 95% CI, 22.00-32.02; P = 0.0002), and in normal colon (mean, 37.15 ng/mg protein; 95% CI, 31.95-42.34) than in paired colorectal polyp mucosa (mean, 28.07 ng/mg protein; 95% CI, 23.66-32.48; P < 0.001). Mean 13-HODE levels, however, were similar between the left (mean, 37.15 ng/mg protein; 95% CI, 31.95-42.35) and the right normal colon (mean, 32.46 ng/mg protein; 95% CI, 27.95-36.98; P = 0.09). No significant differences with regard to 12- or 15-hydroxyeicosatetraenoic acid or leukotriene B(4) levels were detected between normal, polyp, and cancer mucosae. 15-LOX-1 inhibited interleukin-1beta expression. This study establishes that reduced 13-HODE levels are a specific alteration in the LOX product profile associated with human colorectal tumorigenesis.


Validation of genome-wide intervertebral disk calcification associations in dachshund and further investigation of the chromosome 12 susceptibility locus.
Herniation of the intervertebral disk is a common cause of neurological dysfunction in the dog, particularly in the Dachshund. Using the Illumina CanineHD BeadChip, we have previously identified a major locus on canine chromosome 12 nucleotide positions 36,750,205-38,524,449 that strongly associates with intervertebral disk calcification in Danish wire-haired Dachshunds. In this study, targeted resequencing identified two synonymous variants in MB21D1 and one in the 5'-untranslated region of KCNQ5 that associates with intervertebral disk calcification in an independent sample of wire-haired Dachshunds. Haploview identified seven linkage disequilibrium blocks across the disease-associated region. The effect of haplotype windows on disk calcification shows that all haplotype windows are significantly associated with disk calcification. However, our predictions imply that the causal variant(s) are most likely to be found between nucleotide 36,750,205-37,494,845 as this region explains the highest proportion of variance in the dataset. Finally, we develop a risk prediction model for wire-haired Dachshunds. We validated the association of the chromosome 12 locus with disk calcification in an independent sample of wire-haired Dachshunds and identify potential risk variants. Additionally, we estimated haplotype effects and set up a model for prediction of disk calcifications in wire-haired Dachshunds based on genotype data. This genetic prediction model may prove useful in selection of breeding animals in future breeding programs.


The E-selectin-ligand ESL-1 is located in the Golgi as well as on microvilli on the cell surface.
Neutrophils and subsets of lymphocytes bind to E-selectin, a cytokine inducible adhesion molecule on endothelial cells. The E-selectin-ligand-1 (ESL-1) is a high affinity glycoprotein ligand which participates in the binding of mouse myeloid cells to E-selectin. The sequence of mouse ESL-1 is highly homologous to the cysteine rich FGF receptor (CFR) in chicken and the rat Golgi protein MG160. We have analysed the subcellular distribution of ESL-1 by indirect immunofluorescence, flow cytometry, various biochemical techniques and by immunogold scanning electron microscopy. We could localize ESL-1 in the Golgi as well as on the cell surface of 32Dc13 cells and neutrophils. Cell surface staining was confirmed by cell surface biotinylation and by cell surface immunoprecipitations in which antibodies only had access to surface proteins on intact cells. In addition, ESL-1(high) and ESL-1(low) expressing cells, sorted by flow cytometry, gave rise to high and low immunoprecipitation signals for ESL-1, respectively. Based on immunogold labeling of intact cells, we localized ESL-1 on microvilli of 32Dc13 cells and of the lymphoma cell line K46. Quantitative evaluation determined 80% of the total labeling for ESL-1 on microvilli of K46 cells while 69% of the labeling for the control antigen B220 was found on the planar cell surface. These data indicate that ESL-1 occurs at sites on the leukocyte cell surface which are destined for the initiation of cell contacts to the endothelium.


Stilbenoids and cannabinoids from the leaves of Cannabis sativa f. sativa with potential reverse cholesterol transport activity.
Three new stilbenoids (1-3) and 16 known stilbenoids (4-6) and cannabinoids (7-19) were isolated from the leaves of hemp (Cannabis sativa L.). The structures of the three new compounds were identified as α,α'-dihydro-3',4,5'-trihydroxy-4'-methoxy-3-isopentenylstilbene (HM1), α,α'-dihydro-3,4',5-trihydroxy-4-methoxy-2,6-diisopentenylstilbene (HM2), and α,α'-dihydro-3',4,5'-trihydroxy-4'-methoxy-2',3-diisopentenylstilbene (HM3) by 1D and 2D NMR spectroscopy, LC-MS, and HRESIMS. The known α,α'-dihydro-3,4',5-trihydroxy-4,5'-diisopentenylstilbene (5) and combretastatin B-2 (6) were isolated for the first time from C. sativa f. sativa. These isolated compounds exhibited cytotoxic effects on human cancer cells via inhibiting the proliferation of cancer cells and inducing cell death. Among them, compounds 4, 5, 10, 12, 13, 15, and 19 displayed broad-spectrum cytotoxicity, and 1, 7, and 11 displayed selectivity in inhibition efficiency on MCF-7 and A549 cells, which suppressed the proliferation of cancer cells significantly by inducing cell death. The effects of compounds 1-3 on improving reverse cholesterol transport (RCT) were evaluated by isotope-tracing and western blotting. Results showed that the three stilbenoids showed a cytotoxicity above 1.0 mg L-1, especially that of HM3. They could improve [3H]-cholesterol efflux from Raw 264.7 macrophages to high density lipoproteins by enhancing the protein expression of ABCG1 and SR-B1, and HM1 and HM2 showed a significant difference compared with fenofibrate at 1.0 mg L-1. The three stilbenoids could also significantly improve the protein expression of ABCA1. Further study on HepG2 cells indicated that they improve the protein expression of LDLR, SR-B1 and CYP7A1, especially that of HM1 and HM3. However, they showed no significant effect on PCSK9. The above results indicated that these stilbenoids may elevate the transfer of cholesterol to hepatocytes by improving the protein expression of SR-B1 and LDLR, and the synthesis of bile acid by increasing the protein expression of CYP7A1. In conclusion, HM1 showed lower cytotoxicity and higher activity in improving the RCT-related protein expression. Our study suggests that it may be explored as a novel lipid-lowering drug and as a beneficial ingredient in health functional foods and pharmaceuticals.


Induction of autophagy during extracellular matrix detachment promotes cell survival.
Autophagy has been proposed to promote cell death during lumen formation in three-dimensional mammary epithelial acini because numerous autophagic vacuoles are observed in the dying central cells during morphogenesis. Because these central cells die due to extracellular matrix (ECM) deprivation (anoikis), we have directly interrogated how matrix detachment regulates autophagy. Detachment induces autophagy in both nontumorigenic epithelial lines and in primary epithelial cells. RNA interference-mediated depletion of autophagy regulators (ATGs) inhibits detachment-induced autophagy, enhances apoptosis, and reduces clonogenic recovery after anoikis. Remarkably, matrix-detached cells still exhibit autophagy when apoptosis is blocked by Bcl-2 overexpression, and ATG depletion reduces the clonogenic survival of Bcl-2-expressing cells after detachment. Finally, stable reduction of ATG5 or ATG7 in MCF-10A acini enhances luminal apoptosis during morphogenesis and fails to elicit long-term luminal filling, even when combined with apoptotic inhibition mediated by Bcl-2 overexpression. Thus, autophagy promotes epithelial cell survival during anoikis, including detached cells harboring antiapoptotic lesions.


Minimum detectable change in gait velocity during acute rehabilitation following hip fracture.
Early ambulation and rehabilitation are recommended for patients undergoing surgical fixation of hip fracture. Gait velocity may be used as an outcome measure for these patients during acute rehabilitation. As an outcome measure, an estimate of meaningful change (responsiveness) in gait velocity for these patients, however, has not been described. The minimum detectable change (MDC) is a value that represents true change in a measure beyond that accounted for by measurement error. The purpose of this study was to quantify MDC in gait velocity as an index of responsiveness for persons in the acute stage of rehabilitation following hip fracture. The study design was a descriptive cohort study with one repeated measure. A volunteer sample of 16 subjects over the age of 65, at a mean of 4.7 days postsurgical fixation of unilateral hip fracture, participated in the study. The study was conducted in an acute care rehabilitation practice in a large, tertiary care hospital. We measured gait velocity with the 10-meter walk test, estimated test-retest reliability with an intraclass correlation coefficient and quantified responsiveness of gait velocity as the MDC at a 95% level of confidence. Mean gait velocity was 15 cm/s and the test-retest reliability coefficient was equal to 0.823. The MDC in gait velocity during acute rehabilitation following surgical repair for hip fracture was 8.2 cm/s. Self-selected gait velocity in patients during acute rehabilitation following surgical fixation for hip fracture must improve by 8.2 cm/s or more to designate the change as being real change beyond the bounds of measurement error.


Case report of the first Severe Acute Respiratory Syndrome patient in China: successful application of extracorporeal liver support MARS therapy in multiorgan failure possibly induced by Severe Acute Respiratory Syndrome.
A previously healthy patient was transferred to our infectious department with a 9-day-history of continued fever. The patient was placed on assisted respiration support in addition to anti-viral medication. The diagnosis of SARS (Severe Acute Respiratory Syndrome) was made in view of the severe hypoxemia and the characteristic symptoms exhibited by the patient. Despite the best intensive therapy, he clinically deteriorated into multiorgan dysfunction syndrome (MODS) including additional dysfunction of kidney, liver, and heart. We initiated MARS therapy (extracorporeal liver support utilizing albumin dialysis) with intention to positively influence the organ functions in his MODS on the basis of recently published studies which suggested a positive impact of MARS in multiorgan failure secondary to respiratory illnesses and the possible influence on inflammatory mediators and cytokines. The application of 4 intermittent MARS treatments (8 h each, mean blood flow rate 180 ml/min) on 4 consecutive days resulted in an immediate improvement of clinical conditions within the treatment days. The further improvement of organ functions allowed withdrawing the patient from ventilatory support 13 days after start of MARS, and 44 days after admission he was discharged home with completely resolved organ functions and laboratory abnormalities. SARS is a severe form of the epidemic outbreak of atypical pneumonia which remains poorly defined regarding etiology and special therapy recommendations. However, the development and aggravation of this ARDS-like severe acute respiratory syndrome is pathologically associated with the systemic inflammatory response syndrome (SIRS) which may then mediate or cause MODS. To our knowledge, this is the first report of an application of MARS therapy in MODS which was probably induced by SARS in a patient in China which improved the clinical condition of the patient in multi-organ failure secondary to respiratory failure indicating that MARS might be an additional therapeutic option in multiorgan failure induced by SARS.


Nuclear magnetic resonance solution structures of inter- and intrastrand adducts of DNA cross-linker SJG-136.
SJG-136 (1) is a sequence-selective DNA-interactive agent that is about to enter phase II clinical trials for the treatment of malignant disease. Previous studies on the pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimers, typified by SJG-136 and DSB-120 (2), have shown that these planar ligands react with the exocyclic NH(2) groups of two guanine bases in the base of the minor groove of DNA to form an irreversible interstrand cross-linked sequence-specific adduct. Using high-field NMR, we have characterized and modeled the previously predicted interstrand duplex adduct formed by SJG-136 with the self-complementary 5'-d(CICGATCICG)(2) duplex (4). This first SJG-136 NMR-refined adduct structure has been compared with previous high-field NMR studies of the adducts of the closely related PBD dimer DSB-120 with the same duplex and of the adduct of tomaymycin (3) formed with 5'-d(ATGCAT)(2). Surprisingly, the SJG-136 duplex adduct appears to be more closely related to the tomaymycin adduct than to the DSB-120 adduct with respect of the orientation and depth of insertion of the ligand within the minor groove. The intrastrand duplex adduct formed in the reaction of SJG-136 with the noncomplementary 5'-d(CTCATCAC)·(GTGATGAG) duplex (5) has also been synthesized and modeled. In this duplex adduct, the nature of the cross-link was confirmed, the central guanines were identified as the sites of alkylation, and the stereochemical configuration at C11 at both ends of the SJG-136 molecule was determined to be S. The NMR-refined solution structures produced for the intrastrand adduct confirm the previously proposed structure (which was based solely on mass spectroscopy). Both the inter- and intrastrand SJG-136 duplex adducts form with minimal distortion of the DNA duplex. These observations have an impact on the proposal for the mechanism of action of SJG-136 both in vitro and in vivo, on the repair of its adducts and mechanism of resistance in cells, and, potentially, on the type of pharmacodynamic assay to be used in clinical trials. SGJ-136 is currently in phase II clinical trials with several groups working on both dimeric cross-linking agents and monoalkylating ligands based on the PBD alkylating moiety. This study suggests subtle differences between the DNA binding of SJG-136 and the C2 unsubstituted analogue DSB-120 that are likely to be the origins of the differences in potency. Confirmation of the stereochemical configuration at the C11 position (particularly in the intrastrand adduct) provides confirmation of binding orientation that was previously only speculation in the HPLC MS study. Together, these observations are likely to be of value in the development of third-generation PBD-based cross-linkers and monoalkylating analogues.


Comparing multi-criteria decision analysis and integrated assessment to support long-term water supply planning.
We compare the use of multi-criteria decision analysis (MCDA)-or more precisely, models used in multi-attribute value theory (MAVT)-to integrated assessment (IA) models for supporting long-term water supply planning in a small town case study in Switzerland. They are used to evaluate thirteen system scale water supply alternatives in four future scenarios regarding forty-four objectives, covering technical, social, environmental, and economic aspects. The alternatives encompass both conventional and unconventional solutions and differ regarding technical, spatial and organizational characteristics. This paper focuses on the impact assessment and final evaluation step of the structured MCDA decision support process. We analyze the performance of the alternatives for ten stakeholders. We demonstrate the implications of model assumptions by comparing two IA and three MAVT evaluation model layouts of different complexity. For this comparison, we focus on the validity (ranking stability), desirability (value), and distinguishability (value range) of the alternatives given the five model layouts. These layouts exclude or include stakeholder preferences and uncertainties. Even though all five led us to identify the same best alternatives, they did not produce identical rankings. We found that the MAVT-type models provide higher distinguishability and a more robust basis for discussion than the IA-type models. The needed complexity of the model, however, should be determined based on the intended use of the model within the decision support process. The best-performing alternatives had consistently strong performance for all stakeholders and future scenarios, whereas the current water supply system was outperformed in all evaluation layouts. The best-performing alternatives comprise proactive pipe rehabilitation, adapted firefighting provisions, and decentralized water storage and/or treatment. We present recommendations for possible ways of improving water supply planning in the case study and beyond.


Effect in vitro on platelet function of two compounds developed from the pyrimido-pyrimidines.
VK 774 and VK 744, two new compounds developed from the pyrimido-pyrimidines, have been found to be powerful inhibitors of platelet function tested in vitro. They inhibit adenosine diphosphate (ADP)-induced platelet aggregation, and the release of platelet factor 3 by kaolin, and VK 774 also reduces platelet adhesiveness and inhibits platelet aggregation (;snowstorm' effect) in the Chandler tube system. Although measured percentage whole blood clot retraction was uninfluenced by these drugs the clot produced with VK 774 was friable and soft. VK 774 appears to be the most powerful of these compounds reported so far, being active in some test systems at 10(-6)M, and, if the results of toxicity testing are satisfactory, it should be an important agent for therapeutic trial.


Relationship between exercise-induced myocardial ischemia and reduced left ventricular distensibility in patients with nonobstructive hypertrophic cardiomyopathy.
Many studies have demonstrated that reduced left ventricular (LV) diastolic distensibility plays a key role in the pathophysiology of hypertrophic cardiomyopathy (HCM). However, the relationship between myocardial ischemia and reduced LV distensibility in HCM remains unclear. We aimed to clarify the relationship between exercise-induced ischemia and reduced LV distensibility in patients with HCM. Twenty patients with HCM and 5 age-matched control subjects underwent stress-redistribution (201)Tl myocardial scintigraphy and biventricular cardiac catheterization and echocardiography at rest and during exercise. Scintigraphic defect analysis was interpreted using Berman's 20-segment model. The summed stress score (SSS) was calculated as the sum of scores of the 20 LV segments and the summed difference score (SDS) was calculated as the sum of differences between each of the 20 LV segments on stress and rest images. Patients were divided into 2 groups according to the (201)Tl defect as follows: 9 patients with an SSS on (201)Tl of >or=10 and an SDS on (201)Tl of >or=5 (ischemic group) and 11 patients with an SSS of <10 or an SDS of <5 (nonischemic group). The absolute increases from rest to peak exercise in LV end-diastolic pressure (LVEDP) and pulmonary artery wedge pressure were significantly greater (15.5 +/- 5.2 vs. 7.6 +/- 5.5 mm Hg and 17.3 +/- 5.0 vs. 8.9 +/- 5.0 mm Hg, P < 0.01, respectively), and the percentage changes from rest to peak exercise in the maximum first derivative of LV pressure and LV pressure half-time were significantly smaller in the ischemic HCM group compared with the nonischemic HCM group (70% +/- 24% vs. 123% +/- 43% and -32% +/- 6.4% vs. -44% +/- 9.4%, P < 0.01, respectively). However, the end-diastolic dimensions did not differ between the 2 HCM groups. One of the 9 patients in the ischemic group, as revealed by fill-in on (201)Tl scintigraphy, showed increased (18)F-FDG uptake in the anteroseptal wall. Some HCM patients show a significant increase in LVEDP without chamber dilatation, indicating reduced LV diastolic distensibility. Myocardial ischemia may at least in part contribute to this condition.


One-year progression of diabetic subclinical macular edema in eyes with mild nonproliferative diabetic retinopathy: location of the increase in retinal thickness.
To characterize the 1-year progression of retinal thickness (RT) increase occurring in eyes with subclinical macular edema in type 2 diabetes. Forty-eight type 2 diabetic eyes/patients with mild nonproliferative diabetic retinopathy (NPDR; levels 20 and 35 in the Early Treatment Diabetic Retinopathy Study) classified as presenting subclinical macular edema at baseline completed the 1-year follow-up period, from a sample of 194 followed in a 12-month observational and prospective study (ClinicalTrials.gov identifier: NCT01145599). Automated segmentation of the retinal layers in these eyes was performed, followed by verification and correction by a human grader. The highest increase in RT over the 1-year follow-up period for the 48 eyes/patients with subclinical macular edema was found in the inner nuclear layer (INL). Progression to clinical macular edema was also associated with increased thickening of other retinal layers aside from the INL. The microvascular disease activity shown by microaneurysm (MA) turnover ≥6 was associated with progression from subclinical to clinical macular edema. Increases in RT occurring over a period of 1 year in diabetic eyes with mild NPDR and subclinical macular edema occur mainly in the INL. The development of clinical macular edema appears to be associated with increased thickening of other retinal layers and microvascular disease activity.


From diagnostics to therapy--conceptual basis for real-time movement feedback in rehabilitation medicine.
Recently, locomotion therapy on a treadmill has become part of rehabilitation programs for neurological gait disorders (spinal cord injury, hemiplegia). Instrumental gait analysis is an important tool for quantification of therapy progress in terms of functional changes in a patient's gait patterns. Whereas most of current applications focus on diagnostic assessment of gait, the current paper presents an extension of movement analysis offering enhanced therapeutic options. Specifically, the conceptual basis for application of real-time movement feedback in rehabilitation medicine is outlined and is put into context with recent developments in the field. A first technical realization of these concepts is presented and first results are reported. Furthermore, open questions towards a universal environment for movement feedback in rehabilitation medicine are discussed and future lines of research are identified.


Can the exceptional chilling tolerance of C4 photosynthesis found in Miscanthus × giganteus be exceeded? Screening of a novel Miscanthus Japanese germplasm collection.
A clone of the hybrid perennial C4 grass Miscanthus × giganteus (Mxg) is known for achieving exceptionally high rates of leaf CO2 uptake during chilling. This is a requisite of success in the early spring, as is the ability of the leaves to survive occasional frosts. The aim of this study was to search for genotypes with greater potential than Mxg for photosynthesis and frost survival under these conditions. A total of 864 accessions representing 164 local populations of M. sacchariflorus (Msa), M. sinensis (Msi) and M. tinctorius (Mti) collected across Japan were studied. Accessions whose leaves survived a natural late frost in the field were screened for high maximum photosystem II efficiency (Fv/Fm) following chilling weather, as an indicator of their capacity for light-limited photosynthesis. Those showing the highest Fv/Fm were transferred to a high-light-controlled environment and maintained at chilling temperatures, where they were further screened for their capacities for high-light-limited and light-saturated leaf uptake of CO2 (ΦCO2,max and Asat, respectively). For the first time, relatives of Mxg with significantly superior capacities for photosynthesis at chilling temperatures were identified. Msa accession '73/2' developed leaves in the spring that survived night-time frost, and during growth under chilling maintained a statistically significant 79 % higher ΦCO2,max, as a measure of light-limited photosynthesis, and a 70 % higher Asat, as a measure of light-saturated photosynthesis. A second Msa accession, '73/3' also showed significantly higher rates of leaf uptake of CO2. As remarkable as Mxg has proved in its chilling tolerance of C4 photosynthesis, this study shows that there is still value and potential in searching for yet more superior tolerance. Msa accession '73/2' shows rates of light-limited and light-saturated photosynthesis at chilling temperatures that are comparable with those of the most cold-tolerant C3 species. This adds further proof to the thesis that C4 photosynthesis is not inherently limited to warm climates.


A probabilistic model of visual working memory: Incorporating higher order regularities into working memory capacity estimates.
When remembering a real-world scene, people encode both detailed information about specific objects and higher order information like the overall gist of the scene. However, formal models of change detection, like those used to estimate visual working memory capacity, assume observers encode only a simple memory representation that includes no higher order structure and treats items independently from one another. We present a probabilistic model of change detection that attempts to bridge this gap by formalizing the role of perceptual organization and allowing for richer, more structured memory representations. Using either standard visual working memory displays or displays in which the items are purposefully arranged in patterns, we find that models that take into account perceptual grouping between items and the encoding of higher order summary information are necessary to account for human change detection performance. Considering the higher order structure of items in visual working memory will be critical for models to make useful predictions about observers' memory capacity and change detection abilities in simple displays as well as in more natural scenes.


Guidelines: Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline for the Management of Patients With Positional Plagiocephaly: The Role of Physical Therapy.
Evidence-based guidelines are not currently available for the treatment of positional plagiocephaly and, in particular, for the use of physical therapy for treatment. To answer the question: "does physical therapy provide effective treatment for positional plagiocephaly?" Treatment recommendations are created based on the available evidence. The PubMed and the Cochrane Library were queried using MeSH headings and key words relevant to the objective of this systematic review. Abstracts were reviewed, after which studies meeting the inclusion criteria were selected and graded according to their quality of evidence (Classes I-III). Evidentiary tables were constructed that summarized pertinent study results, and recommendations were made based on the quality of the literature (Levels I-III). Three studies met criteria for inclusion. Two randomized, controlled trials (Class I and Class II) and 1 prospective study assessing plagiocephaly as a secondary outcome measure (Class III) were included. Within the limits of this systematic review, physical therapy is significantly more effective than repositioning education as a treatment for positional plagiocephaly. There is no significant difference between physical therapy and a positioning pillow as a treatment for positional plagiocephaly. However, given the American Academy of Pediatrics' recommendation against soft pillows in cribs to ensure a safe sleeping environment for infants, physical therapy must be recommended over the use of a positioning pillow. The full guidelines document can be located at https://www.cns.org/guidelines/guidelines-management-patients-positional-plagiocephaly/Chapter_4.


Age-related findings on MRI in neurofibromatosis type 1.
T2 hyperintensities (T2H) on MRI are the most common CNS lesions in individuals with neurofibromatosis type 1 (NF1). The aim was to determine the frequency, signal characteristics and localization of T2H at different ages. In addition, we examined the sensitivity of different MR imaging sequences in detecting these lesions. We studied prospectively a cohort of children, adolescents and young adults with NF1 using T2-volume (T2-V) and conventional MRI sequences. Lesions were designated as either discrete or diffuse, and the region of signal abnormality was recorded. A total of 103 patients were studied (age range 8.0-25.4 years, mean 13.9 years). The frequency, size, and intensity of T2H decreased with age in the basal ganglia (BG) and the cerebellum/brainstem (CB/BS). The majority of thalamic and CB/BS lesions were diffuse. Of the total cohort, 80% had diffuse bilateral hippocampal hyperintensities and 18.4% had hemispheric lesions best demonstrated on FLAIR; there was no significant difference in the frequency or signal intensity of hemispheric lesions with age. Lesions in the cerebral hemispheres and hippocampus imaged by MR do not change in prevalence over time, suggesting a different pathological basis from the lesions in the in BG and CB/BS that resolve with age. FLAIR and T2-V sequences are more sensitive in detecting lesions than standard T2-weighted sequences.


Passive error concealment for wavelet-coded I-frames with an inhomogeneous Gauss-Markov random field model.
In video communication over lossy packet networks (e.g., the Internet), packet loss errors can severely damage the transmitted video. The damaged video can largely be repaired with passive error concealment, where neighboring information is used to estimate missing information. We address the problem of passive error concealment for wavelet coded data with dispersive packetization. The reported techniques of this kind have many problems and usually fail in the reconstruction of high-frequency content. This paper presents a novel locally adaptive error concealment method for subband coded I-frames based on an inhomogeneous Gaussian Markov random field model. We estimate the parameters of this model from a local context of each lost coefficient, and we interpolate the lost coefficients accordingly. The results demonstrate a significant improvement over the reported related methods both in terms of objective performance measures and visually. The biggest improvement of the proposed method compared to the state-of-the-art in the field is the correct reconstruction of high-frequency information such as textures and edges.


The perception of assimilation in newly learned novel words.
The present study investigated the mechanisms underlying perceptual compensation for assimilation in novel words. During training, participants learned canonical versions of novel spoken words (e.g., decibot) presented in isolation. Following exposure to a second set of novel words the next day, participants carried out a phoneme monitoring task. Here, the novel words were presented with final alternations (e.g., decibop) in carrier sentences that either licensed assimilation (viable context: Our decibop behaved badly) or did not (unviable context: Our decibop does very well). Listeners had to monitor for the underlying form of the assimilated consonant (e.g., /t/ in decibop). Results showed more responses corresponding to the underlying form in viable than in unviable contexts. This viability effect was equivalent for novel words learned on the same day and on the previous day but was absent for unexposed control items. The processing difference between exposed and control novel words supports the idea that compensation for assimilation interacts with newly acquired phonological information and suggests that contextual compensation for assimilation is enhanced by lexical knowledge.


Sorption and fractionation of dissolved organic matter and associated phosphorus in agricultural soil.
Mobility of dissolved organic matter (DOM) strongly affects the export of nitrogen (N) and phosphorus (P) from soils to surface waters. To study the sorption and mobility of dissolved organic C and P (DOC, DOP) in soil, the pH-dependent sorption of DOM to samples from Ap, EB, and Bt horizons from a Danish agricultural Humic Hapludult was investigated and a kinetic model applicable in field-scale models tested. Sorption experiments of 1 to 72 h duration were conducted at two pH levels (pH 5.0 and 7.0) and six initial DOC concentrations (0-4.7 mmol L(-1)). Most sorption/desorption occurred during the first few hours. Dissolved organic carbon and DOP sorption decreased strongly with increased pH and desorption dominated at pH 7, especially for DOC. Due to fractionation during DOM sorption/desorption at DOC concentrations up to 2 mmol L(-1), the solution fraction of DOM was enriched in P indicating preferred leaching of DOP. The kinetics of sorption was expressed as a function of how far the solution DOC or DOP concentrations deviate from "equilibrium." The model was able to simulate the kinetics of DOC and DOP sorption/desorption at all concentrations investigated and at both pH levels making it useful for incorporation in field-scale models for quantifying DOC and DOP dynamics.


Decolonization of psychiatric public policy in Jamaica.
Involuntary commitment and custodialization were the principal tenets of British colonial public policy provisions for the management of the violent, disturbed mentally ill in Jamaica and the West Indies. Over the fifty years following Jamaica's political independence from Britain, a community engagement mental health programme has developed through a decolonization process that has negated involuntary certification, incarceration and custodialization, has promoted family therapy and short stay treatment in conventional primary and secondary care health facilities, and has promoted reliance on traditional and cultural therapies that have been extremely successful in the treatment of mental illness and the reduction of stigma in Jamaica. Collaborations involving The University of the West Indies, the Jamaican Ministry of Health and the Pan American Health Organization have been seminal in the development of the decolonizing of public policy initiatives, negating the effects of involuntary certification that had been imposed on the population by slavery and colonization. This collaboration also catalysed the psychiatric training of medical, nursing and mental health practitioners and the execution of community mental health policy in Jamaica.


The brain's default network: anatomy, function, and relevance to disease.
Thirty years of brain imaging research has converged to define the brain's default network-a novel and only recently appreciated brain system that participates in internal modes of cognition. Here we synthesize past observations to provide strong evidence that the default network is a specific, anatomically defined brain system preferentially active when individuals are not focused on the external environment. Analysis of connectional anatomy in the monkey supports the presence of an interconnected brain system. Providing insight into function, the default network is active when individuals are engaged in internally focused tasks including autobiographical memory retrieval, envisioning the future, and conceiving the perspectives of others. Probing the functional anatomy of the network in detail reveals that it is best understood as multiple interacting subsystems. The medial temporal lobe subsystem provides information from prior experiences in the form of memories and associations that are the building blocks of mental simulation. The medial prefrontal subsystem facilitates the flexible use of this information during the construction of self-relevant mental simulations. These two subsystems converge on important nodes of integration including the posterior cingulate cortex. The implications of these functional and anatomical observations are discussed in relation to possible adaptive roles of the default network for using past experiences to plan for the future, navigate social interactions, and maximize the utility of moments when we are not otherwise engaged by the external world. We conclude by discussing the relevance of the default network for understanding mental disorders including autism, schizophrenia, and Alzheimer's disease.


Superchannel transmission system based on multi-channel equalization.
We proposed a new method for superchannel transmission based on the newly proposed multi-channel equalization technique. This method allows us to realize tight channel spacing (equal to the baud rate) without using frequency-locked lasers and complex spectral shaping techniques at the transmitter. The inter-channel interference originated from the tight channel spacing is removed at the receiver by joint equalization of multiple adjacent channels. When the channel spacing is equal to the baud rate, our simulation results show that, with conventional oversample ratio (2 samples per symbol), realistic laser frequency offset and laser linewidth, the proposed multi-channel-equalization based method can achieve better performance than the traditional method using spectral shaping plus single channel equalization, although at the expense of a moderate increase in DSP complexity. The paper also gives a simple method to process the data after conventional chromatic dispersion compensation, which enables subsequent multi-channel equalization for long-haul transmissions.


The role of abscisic acid in disturbed stomatal response characteristics of Tradescantia virginiana during growth at high relative air humidity.
In this study, the role of abscisic acid (ABA) in altered stomatal responses of Tradescantia virginiana leaves grown at high relative air humidity (RH) was investigated. A lower ABA concentration was found in leaves grown at high RH compared with leaves grown at moderate RH. As a result of a daily application of 20 microM ABA to leaves for 3 weeks during growth at high RH, the stomata of ABA-treated leaves grown at high RH showed the same behaviour as did the stomata of leaves grown at moderate RH. For example, they closed rapidly when exposed to desiccation. Providing a high RH around a single leaf of a plant during growth at moderate RH changed the stomatal responses of this leaf. The stomata in this leaf grown at high RH did not close completely in response to desiccation in contrast to the stomata of the other leaves from the same plant. The ABA concentration on a fresh weight basis, though not on a dry weight basis, of this leaf was significantly lower than that of the others. Moreover, less closure of stomata was found in the older leaves of plants grown at high RH in response to desiccation compared with younger leaves. This was correlated with a lower ABA concentration in these leaves on a fresh weight basis, though not on a dry weight basis. Stomata of leaves grown at moderate RH closed in response to short-term application of ABA or sodium nitroprusside (SNP), while for leaves grown at high RH there was a clear difference in stomatal responses between the leaf margins and main-vein areas. The stomatal aperture in response to short-term application of ABA or SNP at the leaf margins of leaves grown at high RH remained significantly wider than in the main-vein areas. It was concluded that: (i) a long-term low ABA concentration in well-watered plants during growth at high RH could be a reason for less or no stomatal closure under conditions of drought stress; and (ii) the long-term ABA concentration on a fresh weight basis rather than on a dry weight basis is likely to be responsible for structural or physiological changes in stomata during leaf growth.


Microsatellite markers to assess the influence of population size, isolation and demographic change on the genetic structure of the UK butterfly Polyommatus bellargus.
Five microsatellite DNA markers were isolated and used to quantify population genetic structure among a subset of UK populations of the Adonis blue (Polyommatus bellargus Rottemburg). Specifically, whether population size, degree of isolation or history of bottlenecking in 1976-1978 can explain current patterns of genetic variation. The butterfly is at its northern range limit in the UK, where it exists as a highly fragmented metapopulation on isolated pockets of calcareous grassland. Most populations were affected by a severe bottleneck in the late 1970s, when a drought caused the host plant (Hippocrepis comosa) to wilt. Mantel tests and spatial autocorrelation analysis indicated a significant effect of isolation by distance among the UK populations, a relationship that broke down at greater geographical scales (> 23.85 km), probably because of large areas of unsuitable habitat presenting barriers to gene flow. Similarly, amova revealed that variation among geographical regions was almost double that observed within regions. Larger populations were found to support significantly higher levels of genetic diversity, suggesting that small populations may lose genetic diversity through drift. If, as in other butterfly species, low genetic diversity increases the probability of population extinction, then these populations are likely to be under threat. Neither isolation nor a history of bottlenecks appeared to influence genetic diversity. The results indicate that adequate population size a crucial factor in the conservation of genetic diversity in P. bellargus in the UK.


Molecular genetic mapping of the multiple endocrine neoplasia type 1 locus.
Familial multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant disorder characterized by the combined occurrence of tumors of the parathyroid glands, the endocrine pancreas, and the pituitary gland. MEN 1 tumors have previously been shown to be associated with the loss of alleles on chromosome 11, and deletion mapping studies together with family linkage studies have localized the MEN 1 gene to 11q13. A detailed genetic map around the MEN 1 locus is required to facilitate further characterization and cloning of the gene (MEN1). We have characterized a panel of seven rodent-human somatic cell hybrids which contain fragments of human chromosome 11 with breakpoints in the pericentromeric region by using eight DNA sequences (D11S149, PGA, PYGM, D11S97, INT2, D11S37, D11S533, and D11S147) to define the region containing MEN1. This will facilitate the rapid localization of additional DNA sequences in this region. In addition, we have used a highly polymorphic repetitive degenerate hexanucleotide sequence, designated D11S533, for segregation studies in one family with MEN 1. These molecular genetic approaches will help to define a precise 1 to 2 centiMorgan map around MEN1.


Pregnancy level of estrogen attenuates experimental autoimmune encephalomyelitis in both ovariectomized and pregnant C57BL/6 mice through expansion of Treg and Th2 cells.
Pregnancy suppressive effect on autoimmune diseases including Multiple Sclerosis and Rheumatoid Arthritis may result from high levels of sex steroids such as estrogen and estriol. This study was designed to reveal the molecular and cellular mechanisms underlying the effect of estrogen on MS alleviation. Female C57BL/6 mice were immunized with MOG35-55. Clinical scores and other relevant parameters were monitored daily. Brain and spinal cord histology was performed to measure lymphocyte infiltration and central nervous system demyelination. Th1/Th2/Th17 and Treg cell profiles were determined through ELISA, flow cytometry, and real-time PCR. Transcription factor expression levels in the CNS were assessed by real-time PCR and T cell differentiation was explored through flow cytometry examination. Pregnancy and pregnancy level of estrogen alleviated clinical manifestations in EAE induced mice, reduced CNS demyelination and cell infiltration, suppressed spleen T cell proliferation, enhanced production of anti-inflammatory cytokines in splenocytes and increased the percentage of Th2 and Treg cells. Furthermore, the results of real-time PCR for transcription factors and related cytokines of Th1/Th2/Th17 and Treg cells in CNS showed reduced expression levels of Th1 and Th17 transcription factors, including T-bet and ROR-γt, and decreased Th1 and Th17 cytokines including IFN-γ, TNF-α, IL-17 and IL-23. These results are the first to indicate that pregnancy and pregnancy level of estrogen ameliorate the EAE condition by favoring Treg and Th2 differentiation through induced expression of Foxp3 and GATA3 in the CNS. Moreover, pregnancy and pregnancy level of estrogen decreased mRNA levels of T-bet and ROR-γt in the CNS.


Cell-free co-expression of functional membrane proteins and apolipoprotein, forming soluble nanolipoprotein particles.
Here we demonstrate rapid production of solubilized and functional membrane protein by simultaneous cell-free expression of an apolipoprotein and a membrane protein in the presence of lipids, leading to the self-assembly of membrane protein-containing nanolipoprotein particles (NLPs). NLPs have shown great promise as a biotechnology platform for solubilizing and characterizing membrane proteins. However, current approaches are limited because they require extensive efforts to express, purify, and solubilize the membrane protein prior to insertion into NLPs. By the simple addition of a few constituents to cell-free extracts, we can produce membrane proteins in NLPs with considerably less effort. For this approach an integral membrane protein and an apolipoprotein scaffold are encoded by two DNA plasmids introduced into cell-free extracts along with lipids. For this study reported here we used plasmids encoding the bacteriorhodopsin (bR) membrane apoprotein and scaffold protein Delta1-49 apolipoprotein A-I fragment (Delta49A1). Cell free co-expression of the proteins encoded by these plasmids, in the presence of the cofactor all-trans-retinal and dimyristoylphosphatidylcholine, resulted in production of functional bR as demonstrated by a 5-nm shift in the absorption spectra upon light adaptation and characteristic time-resolved FT infrared difference spectra for the bR --> M transition. Importantly the functional bR was solubilized in discoidal bR.NLPs as determined by atomic force microscopy. A survey study of other membrane proteins co-expressed with Delta49A1 scaffold protein also showed significantly increased solubility of all of the membrane proteins, indicating that this approach may provide a general method for expressing membrane proteins enabling further studies.


Swine manure cleanup criteria calculation for odor causing volatile organic compounds based on manure-to-ventilation air exposure pathway.
A mathematical model was derived to calculate swine manure cleanup criteria for odor causing volatile organic compounds (VOCs) so that acceptable total dose would not exceeded through the inhalation of ventilation air in swine housing for workers and pigs. A hypothetical scenario was used which assumed that subsurface contaminant in swine manure diffuses through a layer of manure-air interface then is swept into the ventilated airspace via advection, where long-term inhalation of contaminant was assumed to occur. The philosophy of the transport model is to incorporate the age distribution of contaminated air and a first-order decay of contaminant sources into the diffusion model for simulation of air concentrations of VOCs and total exposure dose. A closed-form solution is presented to allow a series of numerical experiments for investigating the effects of adsorption characteristics between manure gas and manure, the mean age of contaminated air, effective diffusivity, and degradation coefficient on total dose. Swine manure cleanup criteria based on non-exceedence of the total hazardous dose corresponding to an acceptable risk from indoor inhalation of four selected VOCs of p-cresol, hexane, toluene, and xylene were calculated in a typical pig unit. The model can be used in the future to compute the relative effectiveness of VOCs filtration systems and/or altered ventilation rates on the VOC exposure problem in animal housing.


Structure, physical, and photophysical properties of platinum(II) complexes containing bidentate aromatic and bis(diphenylphosphino)methane as ligands.
This study focuses on a series of PtII(L-L')(dppm)n+ complexes, where dppm is bis(diphenylphosphino)methane and L-L' are C-C' (n = 0), C-N (n = 1), and N-N' (n = 2) aromatic ligands. Structural characteristics are as follows: for [Pt(phen)(dppm)](PF6)2, a N-N' derivative, monoclinic, C2/c, a = 33.583(6) A, b = 11.399(2) A, c = 22.158(4) A, Z = 8; for [Pt(phq)(dppm)](PF6), a C-N derivative, triclinic, P1, a = 11.415(3) A, b = 13.450(3) A, c = 14.210(4) A, Z = 2; for [Pt(phpy)(dppm)](PF6), a C-N derivative, triclinic, P1, a = 10.030(3) A, b = 13.010(2) A, c = 15.066(4) A, Z = 2; and for [Pt(bph)(dppm)], a C-C' derivative, P2(1)/c, a = 17.116(7) A, b = 21.422(6) A, c = 26.528(6) A, Z = 12, where phen is 1,10-phenanthroline, phq is 2-phenylquinoline, phpy is 2-phenylpyridine, and bph is 2,2'-biphenyl. Structural features indicate that the Pt-C bond distance is shorter than the Pt-N bond distance in symmetrical complexes and that the Pt-P bond distance trans to N is shorter than the Pt-P bond trans to C. This is consistent with the 31P NMR spectra where the chemical shift of the P trans to C is approximately 10 ppm less than found for P trans to N. The energy maxima of the metal-to-ligand charge-transfer band for the complexes containing various L-L' ligands occur in the near-UV region of the spectrum and fall into the energy series bpy > bph > phen > 2-phpy > 2-ptpy > 2-phq > 7,8-bzq, where bpy is 2,2'-bipyridine, 2-phpy is 2-phenylpyridine, 2-ptpy is 2-p-tolylpyridine, and 7,8-bzq is 7,8-benzoquinoline. The emission energy maxima, ascribed to variance in metal-perturbed triplet ligand centered emission, commence near 500 nm and follow the series phen > bpy > 7,8-bzq > 2-phpy > 2-ptpy > bph > 2-phq. In general, emission is observed at 77 K and in solution at low temperatures, but the temperature dependence of the emission lifetimes indicates thermal activation to another state occurs with an energy of approximately 1800 cm-1 for the complexes, with the exception of [Pt(bph)(dppm)], which has an activation energy of approximately 2300 cm-1.


Excretion of major odor-causing and acidifying compounds in response to dietary supplementation of chicory inulin in growing pigs.
The excretion of major odor-causing and acidifying compounds in response to dietary supplementation of chicory inulin extract was investigated with six Yorkshire barrows, with an average initial BW of 30 kg, according to a balanced two-period cross-over design. The animals were fed a control diet containing no inulin extract and a treatment diet with 5% inulin extract (as-fed basis) at the expense of cornstarch. Each diet was formulated (as-fed basis) to contain 16% CP from corn (51%) and soybean meal (29%). Each experimental period lasted 14 d, with 10 d for dietary adaptation and 4 d for collection of fecal and urine samples. The fecal samples were analyzed for four major classes of odor-causing and acidifying compounds: 1) VFA; 2) N-containing compounds, including total N and ammonia; 3) volatile sulfides measured as hydrogen sulfide units; and 4) phenols and indoles, including p-cresol, indole, and skatole. Supplementation of chicory inulin at 5% had no effects on the fecal excretion of VFA (P = 0.29), ammonia (P = 0.96), total volatile sulfides (P = 0.56), p-cresol (P = 0.56), and indole (P = 0.75). Fecal excretion of total N (inulin = 6.13 vs. control = 5.10 g/kg DMI) was increased (P < 0.05), whereas urinary total N excretion (inulin = 15.1 vs. control = 16.4 g/[pig x d]) was not affected (P = 0.17) by the inulin supplementation compared with the control group. Furthermore, fecal excretion of skatole (inulin = 9.07 vs. control = 18.93 mg/kg DMI) was decreased (P < 0.05) by the inulin supplementation compared with the control group. In conclusion, dietary supplementation of 5% chicory inulin extract is effective in decreasing the fecal excretion of skatole in growing pigs fed corn and soybean meal diets.


Systematic distortions in world fisheries catch trends.
Over 75% of the world marine fisheries catch (over 80 million tonnes per year) is sold on international markets, in contrast to other food commodities (such as rice). At present, only one institution, the Food and Agriculture Organization of the United Nations (FAO) maintains global fisheries statistics. As an intergovernmental organization, however, FAO must generally rely on the statistics provided by member countries, even if it is doubtful that these correspond to reality. Here we show that misreporting by countries with large fisheries, combined with the large and widely fluctuating catch of species such as the Peruvian anchoveta, can cause globally spurious trends. Such trends influence unwise investment decisions by firms in the fishing sector and by banks, and prevent the effective management of international fisheries.


Molecular Dynamics Simulations and Kinetic Measurements to Estimate and Predict Protein-Ligand Residence Times.
Ligand-target residence time is emerging as a key drug discovery parameter because it can reliably predict drug efficacy in vivo. Experimental approaches to binding and unbinding kinetics are nowadays available, but we still lack reliable computational tools for predicting kinetics and residence time. Most attempts have been based on brute-force molecular dynamics (MD) simulations, which are CPU-demanding and not yet particularly accurate. We recently reported a new scaled-MD-based protocol, which showed potential for residence time prediction in drug discovery. Here, we further challenged our procedure's predictive ability by applying our methodology to a series of glucokinase activators that could be useful for treating type 2 diabetes mellitus. We combined scaled MD with experimental kinetics measurements and X-ray crystallography, promptly checking the protocol's reliability by directly comparing computational predictions and experimental measures. The good agreement highlights the potential of our scaled-MD-based approach as an innovative method for computationally estimating and predicting drug residence times.


Higher frequency of anastomotic leakage with stapled compared to hand-sewn ileocolic anastomosis in a large population-based study.
The stapling technique was recommended in a recent Cochrane analysis based on relatively small randomized trials between 1970 and 2009. Data from a large Swedish population-based quality register were analyzed in order to compare the leakage frequency between stapled and hand-sewn ileocolic anastomoses in colon cancer surgery. Three-thousand four-hundred and twenty-eight patients with an ileocolic anastomosis were entered in a Swedish regional quality register for colon cancer, including the type of anastomosis used. The patients were analyzed by logistic regression regarding risk for leakage, and Cox proportional hazard regression for survival associated with the technique used for anastomosis. Analyses were made for gender, age, elective or emergency surgery, duration of surgery, bleeding, cancer stage, and local radicality. Most anastomoses were hand sewn (1,908 of 3,428, 55.7 %, p < 0.001), whereas stapling was more common among emergency cases (342 of 618, 55.3 %, p < 0.001). Clinically relevant leakage appeared in 58 patients (1.7 %), of whom 51 (87.9 %) were re-operated. Leakage was found to be more frequent after stapled anastomosis (2.4 vs. 1.2 %, p = 0.006), and in multivariate analysis, stapled anastomosis was the only risk factor (OR = 2.04 95 % CI 1.19-3.50). There was no difference in overall survival related to the technique. Hand-sewn anastomosis is not associated with a higher leakage rate when comparing to a stapling procedure and is recommended for routine and emergency right-sided colon cancer surgery. This recommendation is based on what appears to be a lower leakage rate, similar survival and lower material cost.


Thermal conductivity of graphene nanoribbons under shear deformation: A molecular dynamics simulation.
Tensile strain and compress strain can greatly affect the thermal conductivity of graphene nanoribbons (GNRs). However, the effect of GNRs under shear strain, which is also one of the main strain effect, has not been studied systematically yet. In this work, we employ reverse nonequilibrium molecular dynamics (RNEMD) to the systematical study of the thermal conductivity of GNRs (with model size of 4 nm × 15 nm) under the shear strain. Our studies show that the thermal conductivity of GNRs is not sensitive to the shear strain, and the thermal conductivity decreases only 12-16% before the pristine structure is broken. Furthermore, the phonon frequency and the change of the micro-structure of GNRs, such as band angel and bond length, are analyzed to explore the tendency of thermal conductivity. The results show that the main influence of shear strain is on the in-plane phonon density of states (PDOS), whose G band (higher frequency peaks) moved to the low frequency, thus the thermal conductivity is decreased. The unique thermal properties of GNRs under shear strains suggest their great potentials for graphene nanodevices and great potentials in the thermal managements and thermoelectric applications.


A Likelihood-Free Inference Framework for Population Genetic Data using Exchangeable Neural Networks.
An explosion of high-throughput DNA sequencing in the past decade has led to a surge of interest in population-scale inference with whole-genome data. Recent work in population genetics has centered on designing inference methods for relatively simple model classes, and few scalable general-purpose inference techniques exist for more realistic, complex models. To achieve this, two inferential challenges need to be addressed: (1) population data are exchangeable, calling for methods that efficiently exploit the symmetries of the data, and (2) computing likelihoods is intractable as it requires integrating over a set of correlated, extremely high-dimensional latent variables. These challenges are traditionally tackled by likelihood-free methods that use scientific simulators to generate datasets and reduce them to hand-designed, permutation-invariant summary statistics, often leading to inaccurate inference. In this work, we develop an exchangeable neural network that performs summary statistic-free, likelihood-free inference. Our framework can be applied in a black-box fashion across a variety of simulation-based tasks, both within and outside biology. We demonstrate the power of our approach on the recombination hotspot testing problem, outperforming the state-of-the-art.


Monoallelic Mutations in the Translation Initiation Codon of KLHL24 Cause Skin Fragility.
The genetic basis of epidermolysis bullosa, a group of genetic disorders characterized by the mechanically induced formation of skin blisters, is largely known, but a number of cases still remain genetically unsolved. Here, we used whole-exome and targeted sequencing to identify monoallelic mutations, c.1A>G and c.2T>C, in the translation initiation codon of the gene encoding kelch-like protein 24 (KLHL24) in 14 individuals with a distinct skin-fragility phenotype and skin cleavage within basal keratinocytes. Remarkably, mutation c.1A>G occurred de novo and was recurrent in families originating from different countries. The striking similarities of the clinical features of the affected individuals point to a unique and very specific pathomechanism. We showed that mutations in the translation initiation codon of KLHL24 lead to the usage of a downstream translation initiation site with the same reading frame and formation of a truncated polypeptide. The pathobiology was examined in keratinocytes and fibroblasts of the affected individuals and via expression of mutant KLHL24, and we found mutant KLHL24 to be associated with abnormalities of intermediate filaments in keratinocytes and fibroblasts. In particular, KLHL24 mutations were associated with irregular and fragmented keratin 14. Recombinant overexpression of normal KLHL24 promoted keratin 14 degradation, whereas mutant KLHL24 showed less activity than the normal molecule. These findings identify KLHL24 mutations as a cause of skin fragility and identify a role for KLHL24 in maintaining the balance between intermediate filament stability and degradation required for skin integrity.


Dual Emission of a Novel (P,N) Re(I) Complex: A Computational and Experimental Study on [P,N-{(C6H5)2(C5H4N)P}Re(CO)3Br].
The spectroscopic, electrochemical, and photophysical properties of the new complex [P,N-{(C6H5)2(C5H4N)P}Re(CO)3Br] are reported. The UV-vis spectrum in dichloromethane shows an absorption maximum centered at 315 nm and a shoulder at 350 nm. These absorption bands have been characterized to have MLCT character. Excitation at both wavelengths (maximum and shoulder) leads to an emission band centered at 550 nm. Cyclic voltammetry experiments show two ill-defined irreversible oxidation waves around +1.50 and 1.80 V that are assigned to Re(I)/Re(II) and Re(II)/Re(III) couples whereas an irreversible reduction signal centered at -1.80 V is likewise assigned to a ligand reduction process. These results support the proposal of the MLCT nature of the states implied by the emission of the complex. The luminescent decay fits to a biexponential function, where the lifetimes and emission quantum yields are dependent on the solvent polarity. DFT calculations suggest that dπ → π*pyridine and dπ → π*phenyl excited states may account for the existence of two decay lifetimes.


Fast voltammetry of metals at carbon-fiber microelectrodes: copper adsorption onto activated carbon aids rapid electrochemical analysis.
Rapid, in situ trace metal analysis is essential for understanding many biological and environmental processes. For example, trace metals are thought to act as chemical messengers in the brain. In the environment, some of the most damaging pollution occurs when metals are rapidly mobilized and transported during hydrologic events (storms). Electrochemistry is attractive for in situ analysis, primarily because electrodes are compact, cheap and portable. Electrochemical techniques, however, do not traditionally report trace metals in real-time. In this work, we investigated the fundamental mechanisms of a novel method, based on fast-scan cyclic voltammetry (FSCV), that reports trace metals with sub-second temporal resolution at carbon-fiber microelectrodes (CFMs). Electrochemical methods and geochemical models were employed to find that activated CFMs rapidly adsorb copper, a phenomenon that greatly advances the temporal capabilities of electrochemistry. We established the thermodynamics of surface copper adsorption and the electrochemical nature of copper deposition onto CFMs and hence identified a unique adsorption-controlled electrochemical mechanism for ultra-fast trace metal analysis. This knowledge can be exploited in the future to increase the sensitivity and selectivity of CFMs for fast voltammetry of trace metals in a variety of biological and environmental models.


Classroom as clinic: a model for teaching clinical reasoning in occupational therapy education.
One way to help students transfer their academic skills of data gathering and analysis to clinical settings is to teach them the clinical reasoning process outlined by Joan Rogers. This paper describes a format for teaching that process through the use of carefully structured in-class evaluations of physically disabled guest speakers who role-model as clients. Pre- and posttesting of the performance of 78 students during these in-class evaluation sessions showed a significant improvement over a semester in students' abilities to accurately analyze preassessment data and to formulate appropriate treatment plans. Qualitative outcomes are also discussed.


Effects of calcium oxide treatment of dry and modified wet corn distillers grains plus solubles on growth performance, carcass characteristics, and apparent digestibility of feedlot steers.
The objectives of this study were to determine the effects of feeding dried corn distillers grains (DDGS) or modified wet corn distillers grains (MDGS) with or without CaO treatment to feedlot steers on 1) growth performance and carcass characteristics and 2) diet digestibility, pattern of intake, and meal distribution. In Exp. 1, steers (n = 139; average initial BW = 336 ± 75 kg) were used in a randomized complete block design. Treatments were arranged in a 2 × 2 factorial design, and pens were randomly allotted to 1 of the 4 dietary treatments (DM basis): 1) 50% DDGS untreated, 2) 48.8% DDGS treated with 1.2% CaO, 3) 50% MDGS untreated, or 4) 48.8% MDGS treated with 1.2% CaO. The remainder of the diet was corn husklage, dry rolled corn, and vitamin and mineral supplement. In Exp. 2, fistulated steers (n = 8; average initial BW = 540 ± 250 kg) were used in a replicated 4 × 4 Latin square design with the same dietary treatments as in Exp. 1. There was no interaction (P ≥ 0.14) between distillers grains plus solubles (DGS) and CaO inclusion for DMI, ADG, final BW, or USDA yield and quality grades. However, steers fed CaO-treated DGS had decreased (P < 0.01) DMI, regardless of DGS type. Because CaO treatment decreased DMI without affecting (P = 0.66) ADG, steers fed CaO-treated DGS had increased (P < 0.01) G:F compared to steers not fed CaO. The variation in DMI found in this experiment could be explained by differences in meal size and distribution. Steers fed CaO-treated DGS ate a similar (P = 0.36) number of meals but ate smaller (P < 0.01) meals. No effects (P ≥ 0.55) of CaO treatment or its interaction with DGS type were found for apparent total tract DM or NDF digestibility. However, steers fed MDGS had increased (P < 0.01) NDF digestibility compared to steers fed DDGS. In conclusion, CaO treatment of DGS improved feed efficiency when DGS-based diets were fed but did not improve digestibility.


Minimum information for reporting next generation sequence genotyping (MIRING): Guidelines for reporting HLA and KIR genotyping via next generation sequencing.
The development of next-generation sequencing (NGS) technologies for HLA and KIR genotyping is rapidly advancing knowledge of genetic variation of these highly polymorphic loci. NGS genotyping is poised to replace older methods for clinical use, but standard methods for reporting and exchanging these new, high quality genotype data are needed. The Immunogenomic NGS Consortium, a broad collaboration of histocompatibility and immunogenetics clinicians, researchers, instrument manufacturers and software developers, has developed the Minimum Information for Reporting Immunogenomic NGS Genotyping (MIRING) reporting guidelines. MIRING is a checklist that specifies the content of NGS genotyping results as well as a set of messaging guidelines for reporting the results. A MIRING message includes five categories of structured information - message annotation, reference context, full genotype, consensus sequence and novel polymorphism - and references to three categories of accessory information - NGS platform documentation, read processing documentation and primary data. These eight categories of information ensure the long-term portability and broad application of this NGS data for all current histocompatibility and immunogenetics use cases. In addition, MIRING can be extended to allow the reporting of genotype data generated using pre-NGS technologies. Because genotyping results reported using MIRING are easily updated in accordance with reference and nomenclature databases, MIRING represents a bold departure from previous methods of reporting HLA and KIR genotyping results, which have provided static and less-portable data. More information about MIRING can be found online at miring.immunogenomics.org.


Comparison of optic nerve head topography and visual field in eyes with open-angle and angle-closure glaucoma.
To compare the optic disc and visual field (VF) alterations in primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). Observational case series. A total of 146 persons (217 eyes), 110 with POAG and 36 with PACG, recruited from a university glaucoma service. Each subject underwent visual acuity measurement, applanation tonometry, gonioscopy, slit-lamp examination, dilated optic disc and retinal examination, axial eye length measurement, central corneal pachymetry, automated perimetry, optical coherence tomography (OCT) nerve fiber layer (NFL) examination, and Heidelberg Retina Tomograph (HRT) optic disc evaluation. Parameters of interest were studied by multivariate regression models. Heidelberg Retina Tomograph parameters compared between POAG and PACG. Primary open-angle glaucoma and PACG groups were similar in age, ethnic background, and treated intraocular pressure, but the PACG group had significantly more women, shorter eye length, more hyperopia, and a larger disc area (all Ps < 0.001). The VF average mean deviation (MD) did not significantly differ between POAG and PACG, but the PACG group had lower pattern standard deviation (PSD) for a given MD (P = 0.001). Although 3 HRT parameters differed somewhat between POAG and PACG (cup area, rim area, and cup-to-disc area ratio), they did not significantly differ after correction for multiple comparisons. Mean deviation and disc area were much more significant predictors of the HRT measures than was diagnosis. Similar results were obtained when using OCT NFL thickness as a structural measure of damage as opposed to MD as a functional measure. When controlling for MD, current IOP was not significantly associated with disc parameters in POAG. When the amount of optic nerve damage is taken into account by adjusting for VF MD or OCT NFL thickness, those with POAG and PACG have no significant differences in optic disc topography. Visual field damage in PACG was more diffuse than that in POAG, as measured by a lower PSD for a given level of MD. There was no corresponding difference in the uniformity of structural damage as measured by OCT NFL thickness.


Abiotic pyrite formation produces a large Fe isotope fractionation.
The iron isotope composition of sedimentary pyrite has been proposed as a potential proxy to trace microbial metabolism and the redox evolution of the oceans. We demonstrate that Fe isotope fractionation accompanies abiotic pyrite formation in the absence of Fe(II) redox change. Combined fractionation factors between Fe(II)(aq), mackinawite, and pyrite permit the generation of pyrite with Fe isotope signatures that nearly encapsulate the full range of sedimentary δ(56)Fe(pyrite) recorded in Archean to modern sediments. We propose that Archean negative Fe isotope excursions reflect partial Fe(II)(aq) utilization during abiotic pyrite formation rather than microbial dissimilatory Fe(III) reduction. Late Proterozoic to modern sediments may reflect greater Fe(II)(aq) utilization and variations in source composition.


Therapeutic efficacy of liposome-encapsulated gentamicin in rat Klebsiella pneumoniae pneumonia in relation to impaired host defense and low bacterial susceptibility to gentamicin.
Long-circulating liposomes (LCL) may be used as targeted antimicrobial drug carriers as they localize at sites of infection. As a result, LCL-encapsulated gentamicin (LE-GEN) has demonstrated superior antibacterial activity over the free drug in a single-dose study of immunocompetent rats with Klebsiella pneumoniae pneumonia. In the present study, the therapeutic efficacy of LE-GEN was evaluated by monitoring rat survival and bacterial counts in blood and lung tissue in clinically relevant models, addressing the issue of impaired host defense and low bacterial antibiotic susceptibility. The results show that in immunocompetent rats infected with the high-GEN-susceptibility K. pneumoniae strain, a single dose of LE-GEN is clearly superior to an equivalent dose of free GEN. Yet complete survival can also be obtained with multiple doses of free GEN. In leukopenic rats infected with the high-GEN-susceptible K. pneumoniae strain, free GEN at the maximum tolerated dose (MTD) was needed to obtain survival. However, with the addition of a single dose of LE-GEN to free-GEN treatment, complete survival can be obtained using a sevenfold-lower cumulative amount of GEN than with free-GEN treatment alone. In leukopenic rats infected with low-GEN-susceptible K. pneumoniae cells, free GEN at the MTD did not result in survival. The use of LE-GEN is needed for therapeutic success. Increasing LE-GEN bilayer fluidity resulted in an increased GEN release from the liposomes and hence improved rat survival, thus showing the importance of the liposome lipid composition for therapeutic efficacy. These results warrant further clinical studies of liposomal formulations of aminoglycosides in immunocompromised patients with severe infections.


Systematic evaluation of the features influencing the accuracy of third order measurements.
The aims of this study were to evaluate the relationship of third order measurements on dental casts with those on lateral radiographs, and to identify those incisor features on radiographs which can best explain third order measurements on dental casts. Lateral cephalograms and corresponding dental casts were obtained from 39 untreated Caucasians (12 males, 27 females; mean age 19.5 years; standard deviation 3.7 years) with occlusal relationships considered to be 'normal'. The upper (U1) and lower (L1) incisors were assessed with reference to the occlusal plane perpendicular which was established on the lateral radiographs, including third order angles (U1TR, L1TR) which were also derived from direct dental cast measurements (U1TA, L1TA). Both single regression and multiple linear regression analysis with stepwise variable selection were performed using third order measurements on casts as the dependent variable and crown axis (U1C, L1C), root axis (U1R, L1R), tip-apex connecting line (U1E, L1E), and radiographic third order measurements as independent variables. Single regression analysis indicated an overall difference of 0.02 degrees between radiographic third order inclination and cast assessment in the maxilla (mandible: -2.83 degrees). A change of 1 degree in radiographic third order inclination would produce a change of 0.65 degrees for U1TA and 0.86 degrees for L1TA assessments. Third order measurements on dental casts can best be explained by a linear combination of U1TR and U1E (maxilla) and of L1TR and L1C (mandible) measurements. This study demonstrates the functional enmeshment between two different third order assessments and the most common incisor features on lateral radiographs. Both methods of third order evaluation show sufficient reliability and are appropriate for routine orthodontic practice.


Differentiation of Clear Cell Renal Cell Carcinoma From Other Renal Cortical Tumors by Use of a Quantitative Multiparametric MRI Approach.
The purpose of this study was to develop a quantitative multiparametric MRI approach to differentiating clear cell renal cell carcinoma (RCC) from other renal cortical tumors. This retrospective study included 119 patients with 124 histopathologically confirmed renal cortical tumors who underwent preoperative MRI including DWI, contrast-enhanced, and chemical-shift sequences before nephrectomy. Two radiologists independently assessed each tumor volumetrically, and apparent diffusion coefficient values, parameters from multiphasic contrast-enhanced MRI (peak enhancement, upslope, downslope, AUC), and chemical-shift indexes were calculated. Univariate and multivariable logistic regression analyses were performed to identify parameters associated with clear cell RCC. Interreader agreement was excellent (intraclass correlation coefficient, 0.815-0.994). The parameters apparent diffusion coefficient (reader 1 AUC, 0.804; reader 2, 0.807), peak enhancement (reader 1 AUC, 0.629; reader 2, 0.606), and downslope (reader 1 AUC, 0.575; reader 2, 0.561) were significantly associated with discriminating clear cell RCC from other renal cortical tumors. The combination of all three parameters further increased diagnostic accuracy (reader 1 AUC, 0.889; reader 2, 0.907; both p ≤ 0.001), yielding sensitivities of 0.897 for reader 1 and 0.897 for reader 2, and specificities of 0.762 for reader 1 and 0.738 for reader 2 in the identification of clear cell RCC. With maximized sensitivity, specificities of 0.429 and 0.262 were reached for readers 1 and 2, respectively. A quantitative multiparametric approach statistically significantly improves diagnostic performance in differentiating clear cell RCC from other renal cortical tumors.


"Asian" men on the scene: challenges to "gay communities".
This article examines common assumptions behind the notion of "gay community," contrasting these views with the experiences of homosexual men originating from Southeast Asia on the commercial gay scene in Melbourne, Australia. The narratives here reveal fragmented social networks involving various social groups, categories of people and an "In/Out" culture where informants were culturally marginal. Fitting into the scene culture involves processes of assimilation, and loss of connection even with supportive ethnic networks. While all men who look for a place to belong on the scene generally feel pressure to assimilate to a predominantly white middle-class gay culture, Southeast Asian men generally had more cultural distance to cover. Men who are not well assimilated face exclusion, invisibility and discrimination. Differences and discrimination within Southeast Asian based networks also contributed towards fragmented relations. This article raises questions about dominant gay cultural forms, assumptions of gay solidarity, and how ethnic minority men make sense of and negotiate their sexual and social experiences.


Rapid processing of neutral and angry expressions within ongoing facial stimulus streams: Is it all about isolated facial features?
Our visual system extracts the emotional meaning of human facial expressions rapidly and automatically. Novel paradigms using fast periodic stimulations have provided insights into the electrophysiological processes underlying emotional content extraction: the regular occurrence of specific identities and/or emotional expressions alone can drive diagnostic brain responses. Consistent with a processing advantage for social cues of threat, we expected angry facial expressions to drive larger responses than neutral expressions. In a series of four EEG experiments, we studied the potential boundary conditions of such an effect: (i) we piloted emotional cue extraction using 9 facial identities and a fast presentation rate of 15 Hz (N = 16); (ii) we reduced the facial identities from 9 to 2, to assess whether (low or high) variability across emotional expressions would modulate brain responses (N = 16); (iii) we slowed the presentation rate from 15 Hz to 6 Hz (N = 31), the optimal presentation rate for facial feature extraction; (iv) we tested whether passive viewing instead of a concurrent task at fixation would play a role (N = 30). We consistently observed neural responses reflecting the rate of regularly presented emotional expressions (5 Hz and 2 Hz at presentation rates of 15 Hz and 6 Hz, respectively). Intriguingly, neutral expressions consistently produced stronger responses than angry expressions, contrary to the predicted processing advantage for threat-related stimuli. Our findings highlight the influence of physical differences across facial identities and emotional expressions.


Prevention of lymphocyte apoptosis in septic mice with cancer increases mortality.
Lymphocyte apoptosis is thought to have a major role in the pathophysiology of sepsis. However, there is a disconnect between animal models of sepsis and patients with the disease, because the former use subjects that were healthy prior to the onset of infection while most patients have underlying comorbidities. The purpose of this study was to determine whether lymphocyte apoptosis prevention is effective in preventing mortality in septic mice with preexisting cancer. Mice with lymphocyte Bcl-2 overexpression (Bcl-2-Ig) and wild type (WT) mice were injected with a transplantable pancreatic adenocarcinoma cell line. Three weeks later, after development of palpable tumors, all animals received an intratracheal injection of Pseudomonas aeruginosa. Despite having decreased sepsis-induced T and B lymphocyte apoptosis, Bcl-2-Ig mice had markedly increased mortality compared with WT mice following P. aeruginosa pneumonia (85 versus 44% 7-d mortality; p = 0.004). The worsened survival in Bcl-2-Ig mice was associated with increases in Th1 cytokines TNF-α and IFN-γ in bronchoalveolar lavage fluid and decreased production of the Th2 cytokine IL-10 in stimulated splenocytes. There were no differences in tumor size or pulmonary pathology between Bcl-2-Ig and WT mice. To verify that the mortality difference was not specific to Bcl-2 overexpression, similar experiments were performed in Bim(-/-) mice. Septic Bim(-/-) mice with cancer also had increased mortality compared with septic WT mice with cancer. These data demonstrate that, despite overwhelming evidence that prevention of lymphocyte apoptosis is beneficial in septic hosts without comorbidities, the same strategy worsens survival in mice with cancer that are given pneumonia.


Monensin-resistant mouse Balb/3T3 cell mutant with aberrant penetration of vesicular stomatitis virus.
A mutant (MO-5) resistant to monensin (an ionophoric antibiotic) derived from the mouse Balb/3T3 cell line, was a poor host for vesicular stomatitis virus (VSV) or semliki forest virus (SFV) multiplication. The yield of VSV particles in MO-5 is one 100-fold reduced as is VSV-dependent RNA synthesis. In contrast to a pH-remedial mutant, the abortive production of infectious VSV particles in MO-5 cells was not restored by low pH treatment. The pH values in the endosome and the lysosome of MO-5 cells were 5.2 and 5.4, respectively, values that were comparable to the pH value in Balb/3T3 cells. Assays with [3H]uridine-labeled VSV indicated similar binding of VSV in MO-5: percoll gradient centrifugation analysis of [35S]methionine-labeled VSV-infected Balb/3T3 showed accumulation of VSV in the lysosome fraction 20 min after VSV infection, whereas VSV can be found mainly in endosome/Golgi fraction of MO-5 cells after 40 to 60 min on the percoll gradients. Degradation of [35S]methionine-labeled VSV was observed at a significant rate in Balb/3T3 cells, but not in MO-5 cells. The monensin-resistant somatic cell may thus provide a genetic route to study the mechanism of endocytosis or transport of enveloped viruses.


Performance study of magnesium-sulfur battery using a graphene based sulfur composite cathode electrode and a non-nucleophilic Mg electrolyte.
Here we report for the first time the development of a Mg rechargeable battery using a graphene-sulfur nanocomposite as the cathode, a Mg-carbon composite as the anode and a non-nucleophilic Mg based complex in tetraglyme solvent as the electrolyte. The graphene-sulfur nanocomposites are prepared through a new pathway by the combination of thermal and chemical precipitation methods. The Mg/S cell delivers a higher reversible capacity (448 mA h g(-1)), a longer cyclability (236 mA h g(-1) at the end of the 50(th) cycle) and a better rate capability than previously described cells. The dissolution of Mg polysulfides to the anode side was studied by X-ray photoelectron spectroscopy. The use of a graphene-sulfur composite cathode electrode, with the properties of a high surface area, a porous morphology, a very good electronic conductivity and the presence of oxygen functional groups, along with a non-nucleophilic Mg electrolyte gives an improved battery performance.