Diurnal variation of the delta 13C of pine needle respired CO2 evolved in darkness.
The delta 13C of pine needle CO2 evolved in darkness (delta 13Cr) for slash pine trees (Pinus elliottii) was determined by placing recently collected pine needles in darkness and collecting respired CO2 over a short time period (<15 min). Delta 13Cr measurements were made over several 24 h periods to test the hypothesis that significant variation in delta 13Cr would be observed during a diurnal cycle. The delta 13Cr measurements from the 24 h time series trials showed a consistent midday 13C-enrichment (5-10 per thousand) relative to bulk biomass. The delta 13Cr values became more 13C-depleted at night and following shading, and approached bulk-biomass delta 13C values by dawn. The effect of night-time respired 13C-enriched CO2 on the delta 13C value of the remaining assimilate is shown to be minimal (13C depleted by 0.22 per thousand) under field conditions for P. elliottii needles.


The Starting Big approach to language learning.
The study of language acquisition has a long and contentious history: researchers disagree on what drives this process, the relevant data, and the interesting questions. Here, I outline the Starting Big approach to language learning, which emphasizes the role of multiword units in language, and of coarse-to-fine processes in learning. I outline core predictions and supporting evidence. In short, the approach argues that multiword units are integral building blocks in language; that such units can facilitate mastery of semantically opaque relations between words; and that adults rely on them less than children, which can explain (some of) their difficulty in learning a second language. The Starting Big approach is a theory of how children learn language, how language is represented, and how to explain differences between first and second language learning. I discuss the learning and processing models at the heart of the approach and their cross-linguistic implications.


Energy-loss return gate via liquid dielectric polarization.
There has been much research on renewable energy-harvesting techniques. However, owing to increasing energy demands, significant energy-related issues remain to be solved. Efforts aimed at reducing the amount of energy loss in electric/electronic systems are essential for reducing energy consumption and protecting the environment. Here, we design an energy-loss return gate system that reduces energy loss from electric/electronic systems by utilizing the polarization of liquid dielectrics. The use of a liquid dielectric material in the energy-loss return gate generates electrostatic potential energy while reducing the dielectric loss of the electric/electronic system. Hence, an energy-loss return gate can make breakthrough impacts possible by amplifying energy-harvesting efficiency, lowering the power consumption of electronics, and storing the returned energy. Our study indicates the potential for enhancing energy-harvesting technologies for electric/electronics systems, while increasing the widespread development of these systems.


Relationship between human leukocyte antigen (HLA)-DQA1*0102/HLA-DQB1*0602 polymorphism and preeclampsia.
Preeclampsia is a condition associated with systemic disorders in the mother and the fetus. However, the exact causes of preeclampsia are unknown, but several genetics and environmental factors play role in development of this disease. Major histocompatibility complex role is very important during pregnancy through which the fetus is not rejected by mother's immune system. In this study, we investigated the relationship of the human leukocyte antigen (HLA)-DQA1*0102/HLA-DQB1*0602 polymorphism with preeclampsia. Genomic DNA of 181 pregnant women with a history of preeclampsia as the case group and 228 pregnant women with no history of preeclampsia as the controls were extracted. The HLA-DQA1*0102/HLA-DQB1*0602 polymorphisms of all DNA samples were identified by the SSP-PCR method. Frequencies difference of variables between case and control groups were calculated by Chi-square test. The ethnic origin of the participants in this study was extracted from their medical records. There was a significant association between preeclampsia and Sistani ethnic group (p=0.031). Moreover, there was a significant association between preeclampsia and frequencies of allele HLA-DQB1*0602 (p<0.001), and genotypes of heterozygote (+0102/-0602) (p<0.001) and negative homozygote (-0102/-0602) (p=0.005). There also was an association between allele HLA-DQB1*0602 and preeclampsia in Fars ethnic group (p=0.028). It seems that immune incompatibility may have an important role in preeclampsia predisposition. According to our results, the lack of locus HLA-DQB1*0602 may be a risk factor for preeclampsia.


Two Nimrod receptors, NimC1 and Eater, synergistically contribute to bacterial phagocytosis in Drosophila melanogaster.
Eater and NimC1 are transmembrane receptors of the Drosophila Nimrod family, specifically expressed in haemocytes, the insect blood cells. Previous ex vivo and in vivoRNAi studies have pointed to their role in the phagocytosis of bacteria. Here, we have created a novel NimC1 null mutant to re-evaluate the role of NimC1, alone or in combination with Eater, in the cellular immune response. We show that NimC1 functions as an adhesion molecule ex vivo, but in contrast to Eater it is not required for haemocyte sessility in vivo. Ex vivo phagocytosis assays and electron microscopy experiments confirmed that Eater is the main phagocytic receptor for Gram-positive, but not Gram-negative bacteria, and contributes to microbe tethering to haemocytes. Surprisingly, NimC1 deletion did not impair phagocytosis of bacteria, nor their adhesion to the haemocytes. However, phagocytosis of both types of bacteria was almost abolished in NimC11 ;eater1 haemocytes. This indicates that both receptors contribute synergistically to the phagocytosis of bacteria, but that Eater can bypass the requirement for NimC1. Finally, we uncovered that NimC1, but not Eater, is essential for uptake of latex beads and zymosan particles. We conclude that Eater and NimC1 are the two main receptors for phagocytosis of bacteria in Drosophila, and that each receptor likely plays distinct roles in microbial uptake.


Distribution of lymphoma subtypes in Ukraine according to the WHO 2016 classification.
The Ukrainian Lymphoma Registry (ULR) was established in 2019 with the aim of monitoring the quality of diagnosis, staging, and treatment of lymphoma in Ukraine. Between September 2019 and October 2021, 546 patients with newly diagnosed lymphoma were prospectively registered. All cases were diagnosed according to the 2016 updated WHO lymphoma classification. The male-to-female ratio (M/F) for the whole population was 0.7, with a median age of 46 years (range 18-95). The adoption of the 2016 WHO classification resulted in the identification of 36 different lymphoma subtypes, with 132 cases (24.2%) classified differently compared to the 2008 WHO classification. Only 12 cases (2.8%) were true new entities, including seven cases of high-grade B-cell lymphoma NOS, three of anaplastic large B-cell lymphoma, ALK-negative, 1 case of HHV8+ DLBCL NOS, and 1 of high-grade B-cell lymphoma with C-MYC and BCL2/BCL6 rearrangement. Moreover, 55 (61.1%) entities, including 37 defined by WHO 2008 and 18 defined by WHO 2016, were not represented at all. The analysis of cases registered in the ULR provides a comprehensive breakdown of the subtypes, stage distribution, and treatment of malignant lymphomas (ML) in Ukraine, supporting the usefulness of prospective data collection and timely reporting. We believe that this study is the first step toward a better understanding of the real-life outcomes of patients with ML.


Oxidative and hydrolytic properties of beta-amyloid.
beta-Amyloid protein is the major component of senile plaques found in the brains of Alzheimer's patients. Previously, a new biochemical property of amyloid, its ability to disrupt ester and peptide bonds, was described [Elbaum, D., Brzyska, M., Bacia, A. & Alkon, D. (2000) Biochem. Biophys. Res. Commun. 267, 733-738]. In the present work we compare the ability of beta-amyloid to hydrolyse and oxidize model fluorescent derivatives of dichlorofluorescein [dichlorodihydrofluorescein (H2DCF) or dichlorofluorescein diacetate (DCF-DA), respectively] to the same final product (dichlorofluorescein). Although there is accumulating evidence of oxidative properties of beta-amyloid, little is known about its hydrolytic abilities. Chemical modification studies revealed that hydrolytic properties are related to a His, Ser and Asp/Glu triad, while residues of His, Tyr and Met are involved in the oxidative activity of amyloid. Studies with the rat homologue of human beta-amyloid (1-40), containing three amino-acid substitutions (Arg5-->Gly, Tyr10-->Phe and His13-->Arg) confirmed a role of His in the studied processes. Reduction of the hydrolysis product caused by inhibitors of Ser esterases (phenylmethylsulphonyl fluoride and eserine) suggests that beta-amyloid-mediated hydrolysis is Ser sensitive. Antioxidants and metal chelators that reduced H2DCF oxidation did not change or increase DCF-DA hydrolysis. Solvent isotope effects suggest the involvement of hydrogen bonds in the hydrolysis reaction. Hydrolysis was inhibited by redox-active metal ions and was practically oxygen independent while the oxidation process was redox-active-metal enhanced [Cu(II) and Fe(II) primarily], and oxygen dependent. Product formation was significantly inhibited by catalase and superoxide dismutase as well as benzoquinone, a specific superoxide anion radical scavenger. Increase of fluorescence by oxidation was strongly inhibited by azide and His and enhanced in samples prepared with deuterated phosphate buffer, suggesting singlet oxygen intermediacy. Our data are consistent with superoxide-mediated singlet oxygen intermediate in this Fenton mechanism-driven reaction. These results indicate that hydrolytic and oxidative properties of beta-amyloid are distinct features of this peptide and probably require different mechanisms to occur, but both of them may contribute to beta-amyloid toxicity.


Combination of diabetes mellitus and lack of habitual physical activity is a risk factor for functional disability in Japanese.
Declining healthy life expectancy due to functional disability is relevant and urgent because of its association with decreased quality of life and also for its enormous socioeconomic impact. The aim of this study is to examine the impact of diabetes, hypertension, dyslipidemia and physical activity habits on functional disability among community-dwelling Japanese adults. This is a population-based retrospective cohort study including 9673 people aged 39-98 years in Japan (4420, men). Functional disability was defined as a condition meeting Japan's new long-term care insurance certification requirements for the need of assistance in the activities of daily living whether by caregivers or assistive devices. Cox proportional-hazards regression model identified variables related to functional disability. Median follow-up was 3.7 years. During the study period, 165 disabilities occurred in the overall study population. Multivariate analysis showed that diabetes (HR 1.74 (95% CI 1.12 to 2.68)) and no physical activity habit (HR 1.83 (1.27 to 2.65)) presented increased risks for disability. HR for disability increased with the number of risk factors (HR of individuals with four conditions, 3.96 (1.59 to 9.99) vs individuals with none of those conditions as a reference). HR for disability among patients with diabetes with and without a physical activity habit was 1.68 (0.70 to 4.04) and 3.19 (1.79 to 5.70), respectively, compared with individuals without diabetes with a physical activity habit. The combination of diabetes and lack of habitual physical activity is predictive of functional disability in Japanese. Habitual physical activity attenuates the risk of functional disability in patients with diabetes.


RAQET: Large-scale two-component relativistic quantum chemistry program package.
The Relativistic And Quantum Electronic Theory (RAQET) program is a new software package, which is designed for large-scale two-component relativistic quantum chemical (QC) calculations. The package includes several efficient schemes and algorithms for calculations involving large molecules which contain heavy elements in accurate relativistic formalisms. These calculations can be carried out in terms of the two-component relativistic Hamiltonian, wavefunction theory, density functional theory, core potential scheme, and evaluation of electron repulsion integrals. Furthermore, several techniques, which have frequently been used in non-relativistic QC calculations, have been customized for relativistic calculations. This article introduces the brief theories and capabilities of RAQET with several calculation examples. © 2018 Wiley Periodicals, Inc.


Changes in neuromuscular performance and muscle fiber characteristics of elite power athletes self-administering androgenic and anabolic steroids.
The influence of androgenic-anabolic steroid-induced changes in measures of body composition, muscle fiber characteristics and various aspects of the neuromuscular performance of the leg extensor muscles was investigated in five experimental and six control power athletes during the 24-week programmed strength training followed by the additional six week training without hormone drugs. The mean values of the dosages of self-administration during the 24-week period were 31.0 +/- 14.3 mg/day for anabolic steroids (methandienone, stanozolol, nandrolone) and 178.4 +/- 82.7 mg/week for testosterone. During the 24-week hormone period the experimental group gained in fat-free weight (p less than 0.01) and in the mean muscle fiber areas (p less than 0.01) of the vastus lateralis muscle while the corresponding gains in the control group were minor (NS). The increases of maximal isometric force in the experimental and control groups were 14.7% (p less than 0.01) and 6.1% (NS), respectively, and the values obtained in average load-vertical jumping height curves were improved significantly (p less than 0.05) only in the experimental group. Increases of 18.2% (p less than 0.001) and 12.9% (p less than 0.01) took place in the squat lift in the experimental and control groups, respectively. Both groups demonstrated similar (p less than 0.05) improvements in isometric fast force production. During the additional six week programmed training without hormone drugs significant (p less than 0.05) increases were observed in the experimental group in addition to maximal isometric force and the squat-lift but also in isometric fast force production, while the corresponding changes in the control group were minor (NS). It is suggested that strength training in combination with administration of androgenic-anabolic steroids causes improvements in selected neuromuscular parameters. These changes may be greater than those of caused by the strength training alone.


Genome wide selection in Citrus breeding.
Genome wide selection (GWS) is essential for the genetic improvement of perennial species such as Citrus because of its ability to increase gain per unit time and to enable the efficient selection of characteristics with low heritability. This study assessed GWS efficiency in a population of Citrus and compared it with selection based on phenotypic data. A total of 180 individual trees from a cross between Pera sweet orange (Citrus sinensis Osbeck) and Murcott tangor (Citrus sinensis Osbeck x Citrus reticulata Blanco) were evaluated for 10 characteristics related to fruit quality. The hybrids were genotyped using 5287 DArT_seqTM (diversity arrays technology) molecular markers and their effects on phenotypes were predicted using the random regression - best linear unbiased predictor (rr-BLUP) method. The predictive ability, prediction bias, and accuracy of GWS were estimated to verify its effectiveness for phenotype prediction. The proportion of genetic variance explained by the markers was also computed. The heritability of the traits, as determined by markers, was 16-28%. The predictive ability of these markers ranged from 0.53 to 0.64, and the regression coefficients between predicted and observed phenotypes were close to unity. Over 35% of the genetic variance was accounted for by the markers. Accuracy estimates with GWS were lower than those obtained by phenotypic analysis; however, GWS was superior in terms of genetic gain per unit time. Thus, GWS may be useful for Citrus breeding as it can predict phenotypes early and accurately, and reduce the length of the selection cycle. This study demonstrates the feasibility of genomic selection in Citrus.


Gamma-secretase exists on the plasma membrane as an intact complex that accepts substrates and effects intramembrane cleavage.
Research on Alzheimer's disease led to the identification of a novel proteolytic mechanism in all metazoans, the presenilin/gamma-secretase complex. This unique intramembrane-cleaving aspartyl protease is required for the normal processing of Notch, Jagged, beta-amyloid precursor protein (APP), E-cadherin, and many other receptor-like proteins. We recently provided indirect evidence of gamma-secretase activity at the cell surface in HeLa cells following inhibition of receptor-mediated endocytosis. Here, we directly identify and isolate gamma-secretase as an intact complex (Presenilin, Nicastrin, Aph-1, and Pen-2) from the plasma membrane, both in overexpressing cell lines and endogenously. Inhibition of its proteolytic activity allowed cell surface gamma-secretase to be captured in association with its plasma membrane-localized APP substrates (C83 and C99). Moreover, non-denaturing isolation of the intact enzyme complex revealed that cell surface gamma-secretase can specifically generate amyloid beta-protein from an APP substrate and similarly cleave a Notch substrate. These data directly establish the proteolytic function of gamma-secretase on the plasma membrane, independent of a hypothesized substrate trafficking role. We conclude that presenilin/gamma-secretase exists as a mature complex at the cell surface, where it interacts with and can cleave its substrates, consistent with an essential function in processing many adhesion molecules and receptors required for cell-cell interaction or intercellular signaling.


Peptidoglycan-induced IL-6 production in RAW 264.7 macrophages is mediated by cyclooxygenase-2, PGE2/PGE4 receptors, protein kinase A, I kappa B kinase, and NF-kappa B.
In this study, we investigated the signaling pathway involved in IL-6 production caused by peptidoglycan (PGN), a cell wall component of the Gram-positive bacterium, Staphylococcus aureus, in RAW 264.7 macrophages. PGN caused concentration- and time-dependent increases in IL-6, PGE(2), and cAMP production. PGN-mediated IL-6 production was inhibited by a nonselective cyclooxygenase (COX) inhibitor (indomethacin), a selective COX-2 inhibitor (NS398), a PGE(2) (EP2) antagonist (AH6809), a PGE(4) (EP4) antagonist (AH23848), and a protein kinase A (PKA) inhibitor (KT5720), but not by a nonselective NO synthase inhibitor (N(G)-nitro-l-arginine methyl ester). Furthermore, PGE(2), an EP2 agonist (butaprost), an EP2/PGE(3) (EP3)/EP4 agonist (misoprostol), and misoprostol in the presence of AH6809 all induced IL-6 production, whereas an EP1/EP3 agonist (sulprostone) did not. PGN caused time-dependent activations of IkappaB kinase alphabeta (IKKdbeta) and p65 phosphorylation at Ser(276), and these effects were inhibited by NS398 and KT5720. Both PGE(2) and 8-bromo-cAMP also caused IKKdbeta kinase alphabeta phosphorylation. PGN resulted in two waves of the formation of NF-kappaB-specific DNA-protein complexes. The first wave of NF-kappaB activation occurred at 10-60 min of treatment, whereas the later wave occurred at 2-12 h of treatment. The PGN-induced increase in kappaB luciferase activity was inhibited by NS398, AH6809, AH23848, KT5720, a protein kinase C inhibitor (Ro31-8220), and a p38 MAPK inhibitor (SB203580). These results suggest that PGN-induced IL-6 production involves COX-2-generated PGE(2), activation of the EP2 and EP4 receptors, cAMP formation, and the activation of PKA, protein kinase C, p38 MAPK, IKKdbeta, kinase alphabeta, p65 phosphorylation, and NF-kappaB. However, PGN-induced NO release is not involved in the signaling pathway of PGN-induced IL-6 production.


Morphological, Mechanical and Gas Penetration Properties of Elastomer Composites with Hybrid Fillers.
Ethylene-propylene-diene monomer (EPDM)-based composites including four different types of graphene nanoplatelets (GnPs) were prepared to evaluate the size effects of GnPs in terms of both specific surface area and lateral size on the morphological, mechanical, and viscoelastic properties, swelling ratio, crosslink density, and oxygen permeability. EPDM-based hybrid composites with GnPs and carbon black (CB) fillers were prepared, with the concentrations of 20 and 50 phr of CB and GnPs up to 7 phr. All samples were prepared using the melt mixing method, followed by compression molding. The specific surface area of GnPs is a more important key factor for mechanical and viscoelastic properties than its lateral size. The presence of GnPs leads to a decrease in the swelling ratio and oxygen permeability of the matrix while an increase in the crosslinking density. For a given specific surface area of GnPs (170 m2/g) and the same thickness (5 nm), the optimum lateral size for mechanical properties, swelling ratio, and crosslinking density is about 30 µm. There is a distinct synergic effect on the mentioned properties when hybrid fillers are used. For hybrid composites, the optimum total and each filler concentration are found to be important for achieving the best performance in terms of mechanical properties, swelling ratio, and crosslink density.


Myocardial infarction temporally related to ephedra--a possible role for the coronary microcirculation.
Myocardial infarction has been reported with ephedrine and pseudoephedrine use. It has been suggested that these agents may induce coronary artery spasm, hypercoagulable states, or oxygen demand imbalance. We report a 25-year-old male with myocardial infarction after receiving a diet pill containing ephedra. Coronary angiography revealed normal coronary arteries with very slow flow, suggestive of microcirculation abnormalities. The flow responded promptly to intracoronary verapamil.


Selective killing of human immunodeficiency virus infected cells by non-nucleoside reverse transcriptase inhibitor-induced activation of HIV protease.
Current antiretroviral therapy against human immunodeficiency virus (HIV-1) reduces viral load and thereby prevents viral spread, but it cannot eradicate proviral genomes from infected cells. Cells in immunological sanctuaries as well as cells producing low levels of virus apparently contribute to a reservoir that maintains HIV persistence in the presence of highly active antiretroviral therapy. Thus, accelerated elimination of virus producing cells may represent a complementary strategy to control HIV infection. Here we sought to exploit HIV protease (PR) related cytotoxicity in order to develop a strategy for drug induced killing of HIV producing cells. PR processes the viral Gag and Gag-Pol polyproteins during virus maturation, but is also implicated in killing of virus producing cells through off-target cleavage of host proteins. It has been observed previously that micromolar concentrations of certain non-nucleoside reverse transcriptase inhibitors (NNRTIs) can stimulate intracellular PR activity, presumably by enhancing Gag-Pol dimerization. Using a newly developed cell-based assay we compared the degree of PR activation displayed by various NNRTIs. We identified inhibitors showing higher potency with respect to PR activation than previously described for NNRTIs, with the most potent compounds resulting in ~2-fold increase of the Gag processing signal at 250 nM. The degree of enhancement of intracellular Gag processing correlated with the compound's ability to enhance RT dimerization in a mammalian two-hybrid assay. Compounds were analyzed for their potential to mediate specific killing of chronically infected MT-4 cells. Levels of cytotoxicity on HIV infected cells determined for the different NNRTIs corresponded to the relative degree of drug induced intracellular PR activation, with CC50 values ranging from ~0.3 μM to above the tested concentration range (10 μM). Specific cytotoxicity was reverted by addition of PR inhibitors. Two of the most active compounds, VRX-480773 and GW-678248, were also tested in primary human cells and mediated cytotoxicity on HIV-1 infected peripheral blood mononuclear cells. These data present proof of concept for targeted drug induced elimination of HIV producing cells. While NNRTIs themselves may not be sufficiently potent for therapeutic application, the results provide a basis for the development of drugs exploiting this mechanism of action.


Diagnostic and clinical relevance of the number of circulating CD34(+) cells in myelofibrosis with myeloid metaplasia.
The absolute content of CD34(+) cells in the peripheral blood of 84 patients with myelofibrosis with myeloid metaplasia (MMM) and 23 patients with other Philadelphia-negative (Ph(-)) chronic myeloproliferative disorders (CMDs) was investigated. In MMM, the median absolute number of circulating CD34(+) cells was consistently high (91.6 x 10(6)/L; range, 0-2460 x 10(6)/L). Receiver operating characteristic curve analysis showed that 15 x 10(6)/L as a decision criterion for CD34(+) cells produced an almost complete discrimination between MMM patients out of therapy and other Ph(-) CMDs (positive predictive value, 98.4%; negative predictive value, 85.0%). MMM patients with higher numbers of CD34(+) cells had a significantly longer disease duration (P =.019) and higher spleen volume index (P =.014), liver volume (P =.000), percentage of circulating immature myeloid cells (P =.020), and percentage of myeloid blasts (P =.000). When CD34(+) cells were correlated with the use of Dupriez risk stratification, CD34(+) cells increased significantly from low-risk (median, 68.1 x 10(6)/L) to intermediate-risk (median, 112.8 x 10(6)/L) and high-risk patients (median 666.1 x 10(6)/L) (F = 4.95; P =.009). When CD34(+) cells were correlated with a severity score on the basis of both myeloproliferative and myelodepletive characteristics of the disease, only the myeloproliferation index was significantly associated with CD34(+) cell level (F = 5.7; P =.000). Overall survival and interval to blast transformation from the time of CD34(+) cell analysis were significantly shorter in patients with more than 300 x 10(6)/L CD34(+) cells (P =.005 and.0005, respectively). In conclusion, the absolute number of CD34(+) circulating cells allows MMM to be distinguished from other Ph(-) CMDs; it is strongly associated with the extent of myeloproliferation and predicts evolution toward blast transformation.


The Spatial Overlap of Police Calls Reporting Street-Level and Behind-Closed-Doors Crime: A Bayesian Modeling Approach.
Traditionally, intimate-partner violence has been considered a special type of crime that occurs behind closed doors, with different characteristics from street-level crime. The aim of this study is to analyze the spatial overlap of police calls reporting street-level and behind-closed-doors crime. We analyzed geocoded police calls in the 552 census-block groups of the city of Valencia, Spain, related to street-level crime (N = 26,624) and to intimate-partner violence against women (N = 11,673). A Bayesian joint model was run to analyze the spatial overlap. In addition, two Bayesian hierarchical models controlled for different neighborhood characteristics to analyze the relative risks. Results showed that 66.5% of the total between-area variation in risk of reporting street-level crime was captured by a shared spatial component, while for reporting IPVAW the shared component was 91.1%. The log relative risks showed a correlation of 0.53, with 73.6% of the census-block groups having either low or high values in both outcomes, and 26.4% of the areas with mismatched risks. Maps of the shared component and the relative risks are shown to detect spatial differences. These results suggest that although there are some spatial differences between police calls reporting street-level and behind-closed-doors crime, there is also a shared distribution that should be considered to inform better-targeted police interventions.


Association Between Conditioning Capacities and Shooting Performance in Professional Basketball Players: An Analysis of Stationary and Dynamic Shooting Skills.
Pojskic, H, Sisic, N, Separovic, V, and Sekulic, D. Association between conditioning capacities and shooting performance in professional basketball players: an analysis of stationary and dynamic shooting skills. J Strength Cond Res 32(7): 1981-1992, 2018-Little is known about the influence of conditioning capacities on shooting performance in basketball. The aim of this study was to examine the relationship between different conditioning capacities and shooting performance in professional basketball players. In this investigation, we examined 38 males (all perimeter players; height: 185.5 ± 6.73 cm; mass: 78.66 ± 10.35 kg). Conditioning capacities were evaluated by tests of muscular strength, aerobic endurance, jumping and throwing capacities, sprinting speed, preplanned agility, anaerobic endurance, and fatigue resistance. Shooting performance was evaluated using game statistics, as well as 6 tests of shooting performance performed in controlled settings: (a) 3 tests of static (i.e., nonfatigued) shooting performance (standardized execution of 1- [S1], 2- [S2] and 3-point shots [S3] in stationary conditions), and (b) 3 tests of dynamic (i.e., fatigued) shooting performance (standardized execution of 1- [D1], 2- (D2), and 3-point shots [D3] in dynamic conditions). All 3 dynamic shooting tests and the S1 test were significantly (p ≤ 0.05) correlated with corresponding game statistics. Multiple regression indicated that conditioning capacities were significantly related to D1 (R = 0.36; p = 0.03), D2 (R = 0.44; p = 0.03), S3 (R = 0.41; p = 0.02), and D3 (R = 0.39; p = 0.03) tests. Players with a higher fatigue resistance achieved better results on the D1 test (β = -0.37, p = 0.03). Preplanned agility (β = -0.33, p = 0.04), countermovement jump (β = 0.42, p = 0.03), and fatigue resistance (β = -0.37, p = 0.02) were significant predictors of D2 performance. The countermovement jump (β = 0.39, p = 0.04), medicine ball toss (β = 0.34, p = 0.04), and anaerobic endurance (β = 0.46, p = 0.04) predicted the results of D3 performance. Jumping, throwing, and anaerobic endurance capacities were good determinants of the skill of dynamic shooting over a long distance. These findings emphasize the importance of explosive power and anaerobic capacity as determinants of shooting performance in high-level basketball players.


Stromal cells expressing hedgehog-interacting protein regulate the proliferation of myeloid neoplasms.
Aberrant reactivation of hedgehog (Hh) signaling has been described in a wide variety of human cancers including cancer stem cells. However, involvement of the Hh-signaling system in the bone marrow (BM) microenvironment during the development of myeloid neoplasms is unknown. In this study, we assessed the expression of Hh-related genes in primary human CD34(+) cells, CD34(+) blastic cells and BM stromal cells. Both Indian Hh (Ihh) and its signal transducer, smoothened (SMO), were expressed in CD34(+) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)-derived cells. However, Ihh expression was relatively low in BM stromal cells. Remarkably, expression of the intrinsic Hh-signaling inhibitor, human Hh-interacting protein (HHIP) in AML/MDS-derived stromal cells was markedly lower than in healthy donor-derived stromal cells. Moreover, HHIP expression levels in BM stromal cells highly correlated with their supporting activity for SMO(+) leukemic cells. Knockdown of HHIP gene in stromal cells increased their supporting activity although control cells marginally supported SMO(+) leukemic cell proliferation. The demethylating agent, 5-aza-2'-deoxycytidine rescued HHIP expression via demethylation of HHIP gene and reduced the leukemic cell-supporting activity of AML/MDS-derived stromal cells. This indicates that suppression of stromal HHIP could be associated with the proliferation of AML/MDS cells.


Recent developments in atmospheric pressure photoionization-mass spectrometry.
Recent developments in atmospheric pressure photoionization (APPI), which is one of the three most important ionization techniques in liquid chromatography-mass spectrometry, are reviewed. The emphasis is on the practical aspects of APPI analysis, its combination with different separation techniques, novel instrumental developments - especially in gas chromatography and ambient mass spectrometry - and the applications that have appeared in 2009-2014. © 2015 Wiley Periodicals, Inc. Mass Spec Rev 36:423-449, 2017.


Impact of Hispanic ethnicity on the likelihood of developing postoperative atrial fibrillation.
A recent multicenter observational study of 4,657 patients reported a 52% lower risk of postcardiothoracic surgery (CTS) atrial fibrillation (AF) among South American vs United States patients. This study did not evaluate whether the decreased incidence in AF was attributable to differing ethnicity (Hispanic vs Caucasian) or to another cause. A cohort study of CTS patients at Hartford Hospital was undertaken to evaluate whether Hispanic patients had a lower incidence of post-CTS AF than Caucasians. First, Hispanic patients were compared to the total Caucasian population. Then differences in important baseline predictors of AF were probed between groups. Finally, Hispanic patients undergoing CTS were matched (1:4 matching) with Caucasian patients based upon known predictors of post-CTS AF including age >70 years, valvular surgery, AF history, previous CTS, peripheral vascular disease, gender, pre-CTS digoxin and beta-blocker intolerance. In the total population [n = 2,739, with 97 (3.5%) Hispanics, 66.6 +/- 11.6 years, 70.9% male, 66.9% valve surgery], Hispanics were 38% less likely to develop AF (15.5% vs 24.8%, P = 0.035). However, the Hispanic patients were 11.9 years younger (P< 0.001) with 14.7% more women (P = 0.002) which reduces the risk of post-CTS AF; they also had a 12.8% higher risk of valvular surgery (P = 0.009) which is known to enhance the risk. When these factors and other important variables were matched for, a total of 485 patients (n = 97 Hispanics, 388 Caucasian) were evaluated (55.8 +/- 13.1 years, 57.3% male, 45.4% valvular surgery). Hispanic and Caucasian patients had a similar incidence of post-CTS AF (15.5% vs 18.3%, P = 0.513). Hispanic patients do not have an innately lower risk of post-CTS AF than Caucasians.


An Assessment of Outpatient Satisfaction with Hospital Pharmacy Quality and Influential Factors in the Context of the COVID-19 Pandemic.
The study aims to evaluate outpatient satisfaction (OS) with health insurance drug dispensing at the central hospital in Vietnam and to explore the influential factors. A cross-sectional survey was conducted on adult outpatients via an adjusted SERVQUAL questionnaire. The questionnaire's internal consistency (Cronbach alpha) and construct validity (exploratory factor analysis) were considered. The difference between groups was solved using a t-test or ANOVA-test. The multiple-regression analysis determined the influence levels of each factor. A p-value less than 0.05 was statistically significant. A total of 210 participants participated, with most being over 55 years old, female, with a high school education, and freelancers. The mean general satisfaction score was 3.42 (SD = 0.79). The reliability obtained the highest satisfaction score, and the guarantee was the lowest. The final questionnaire, including five factors (reliability, responsiveness, assurance, sympathy, and tangible) with 26 observational variables, had an internal consistency reliability and construct validity. These five factors had a statistically significant correlation and influence on the general satisfaction of the outpatients. The reliability factor had the strongest influence, and assurance had the weakest. Training staff about communication, counseling, and consolidating the facilities are the core solutions for increasing OS.


Identification of Putative Vaccine and Drug Targets against the Methicillin-Resistant Staphylococcus aureus by Reverse Vaccinology and Subtractive Genomics Approaches.
Methicillin-resistant Staphylococcus aureus (MRSA) is an opportunistic pathogen and responsible for causing life-threatening infections. The emergence of hypervirulent and multidrug-resistant (MDR) S. aureus strains led to challenging issues in antibiotic therapy. Consequently, the morbidity and mortality rates caused by S. aureus infections have a substantial impact on health concerns. The current worldwide prevalence of MRSA infections highlights the need for long-lasting preventive measures and strategies. Unfortunately, effective measures are limited. In this study, we focus on the identification of vaccine candidates and drug target proteins against the 16 strains of MRSA using reverse vaccinology and subtractive genomics approaches. Using the reverse vaccinology approach, 4 putative antigenic proteins were identified; among these, PrsA and EssA proteins were found to be more promising vaccine candidates. We applied a molecular docking approach of selected 8 drug target proteins with the drug-like molecules, revealing that the ZINC4235426 as potential drug molecule with favorable interactions with the target active site residues of 5 drug target proteins viz., biotin protein ligase, HPr kinase/phosphorylase, thymidylate kinase, UDP-N-acetylmuramoyl-L-alanyl-D-glutamate-L-lysine ligase, and pantothenate synthetase. Thus, the identified proteins can be used for further rational drug or vaccine design to identify novel therapeutic agents for the treatment of multidrug-resistant staphylococcal infection.


Evaluation of glucose uptake by skeletal muscle tissue and subcutaneous fat in HIV-infected patients with and without lipodystrophy using FDG-PET.
To evaluate differences in glucose uptake by skeletal muscle tissue and subcutaneous fat in HIV patients on highly active antiretroviral therapy (HAART) presenting with and without lipodystrophy as well as in drug-naive HIV patients using F-fluorodeoxyglucose (FDG) positron emission tomography. Thirty-nine consecutive patients suffering from HIV: seven drug-naive patients, 21 nonlipodystrophic patients on HAART and 11 patients on HAART, respectively, suffering from lipodystrophy were prospectively included. All patients underwent a whole-body FDG positron emission tomography examination. Standardized uptake values (SUV values) of muscle and subcutaneous fat were compared and related to demographic and biochemical variables. SUV mean values of subcutaneous fat were significantly higher in patients under HAART presenting with lipodystrophy when compared with untreated and treated, nonlipodystrophic patients (P=0.000). SUV mean values of subcutaneous fat significantly correlated with treatment duration (r=0.56, P=0.000) and CD4 count (r=0.51, P=0.001) and inversely correlated with viral load (r=-0.61, P=0.000). Finally, SUV mean values of thigh muscles were not significantly different between the three different patient groups under study. Quantitative FDG uptake by subcutaneous fat proved significantly higher in HIV patients under HAART presenting with lipodystrophy. HAART did not influence FDG uptake by human skeletal muscle tissue under basal conditions.


Frequency of Home Numeracy Activities Is Differentially Related to Basic Number Processing and Calculation Skills in Kindergartners.
Home numeracy has been shown to play an important role in children's mathematical performance. However, findings are inconsistent as to which home numeracy activities are related to which mathematical skills. The present study disentangled between various mathematical abilities that were previously masked by the use of composite scores of mathematical achievement. Our aim was to shed light on the specific associations between home numeracy and various mathematical abilities. The relationships between kindergartners' home numeracy activities, their basic number processing and calculation skills were investigated. Participants were 128 kindergartners (Mage = 5.43 years, SD = 0.29, range: 4.88-6.02 years) and their parents. The children completed non-symbolic and symbolic comparison tasks, non-symbolic and symbolic number line estimation tasks, mapping tasks (enumeration and connecting), and two calculation tasks. Their parents completed a home numeracy questionnaire. Results indicated small but significant associations between formal home numeracy activities that involved more explicit teaching efforts (i.e., identifying numerals, counting) and children's enumeration skills. There was no correlation between formal home numeracy activities and non-symbolic number processing. Informal home numeracy activities that involved more implicit teaching attempts, such as "playing games" and "using numbers in daily life," were (weakly) correlated with calculation and symbolic number line estimation, respectively. The present findings suggest that disentangling between various basic number processing and calculation skills in children might unravel specific relations with both formal and informal home numeracy activities. This might explain earlier reported contradictory findings on the association between home numeracy and mathematical abilities.


The virulence of the 1918 pandemic influenza virus: unraveling the enigma.
The 1918 influenza pandemic caused acute illness in 25-30% of the world's population and resulted in the death of up to 40 million people. Using lung tissue of 1918 influenza victims, the complete genomic sequence of the 1918 influenza virus is being deduced. Neither the 1918 hemagglutinin nor neuraminidase genes possess mutations known to increase tissue tropicity that account for virulence of other influenza virus strains, such as A/WSN/33 or the highly pathogenic avian influenza H5 or H7 viruses. Using reverse genetics approaches, influenza virus constructs containing the 1918 hemagglutinin and neuraminidase on an A/WSN/33 virus background were lethal in mice. The genotypic basis of this virulence has not yet been elucidated. The complete sequence of the non-structural (NS) gene segment of the 1918 virus was deduced and also tested to determine the validity of the hypothesis that enhanced virulence in 1918 could have been due to type I interferon inhibition by the NS1 protein. Results from these experiments suggest that in human cells the 1918 NS1 is a very effective interferon antagonist. Sequence analysis of the 1918 influenza virus is allowing us to test hypotheses as to the origin and virulence of this strain. This information should help elucidate how pandemic influenza virus strains emerge and what genetic features contribute to virulence in humans.


Protective Immunity Induced by an Eimeria tenella Whole Sporozoite Vaccine Elicits Specific B-Cell Antigens.
This study investigated protection against Eimeria tenella following the vaccination of chicks with 5.3 × 106 E. tenella whole-sporozoites emulsified in the nanoparticle adjuvant IMS 1313 N VG Montanide™ (EtSz-IMS1313). One-day-old specific pathogen-free (SPF) chicks were subcutaneously injected in the neck with EtSz-IMS1313 on the 1st and 10th days of age. Acquired immunity was assayed through a challenge with 3 × 104 homologous sporulated oocysts at 21 days of age. The anticoccidial index (ACI) calculated for every group showed the effectiveness of EtSz-IMS1313 as a vaccine with an ACI of 186; the mock-injected control showed an ACI of 18 and the unimmunized, challenged control showed an ACI of -28. In a comparison assay, antibodies from rabbits and SPF birds immunized with EtSz-IMS1313 recognized almost the same polypeptides in the blotting of E. tenella sporozoites and merozoites. However, rabbit antisera showed the clearest recognition pattern. Polypeptides of 120, 105, 94, 70, 38, and 19 kDa from both E. tenella life cycle stages were the most strongly recognized by both animal species. The E. tenella zoite-specific IgG antibodies from the rabbits demonstrated the feasibility for successful B cell antigen identification.


Cerenkov-Activated Sticky Tag for In Vivo Fluorescence Imaging.
A big challenge in the clinical use of Cerenkov luminescence (CL) imaging is its low signal intensity, which is several orders of magnitude below ambient light. Consequently, highly sensitive cameras, sufficient shielding from background light, and long acquisition times are required. To alleviate this problem, we hypothesized a strategy to convert the weak CL signal into a stronger fluorescence signal by using CL-activated formation of nitrenes from azides to locally fix a fluorescent probe in tissue by the formation of a covalent bond. CL-activated drug delivery was also evaluated using the same azide chemistry. The specific delivery of the CL-activated drug to cancer cells could reduce systemic toxicity, which is a limitation in chemotherapy. Methods: A cyanine-class near-infrared fluorescent dye, Cy7, and doxorubicin were synthetically attached to polyfluorinated aryl azide to form Cy7 azide and DOX azide, respectively. Fibrosarcoma cells were incubated with 18F-FDG and exposed to Cy7 azide with subsequent fluorescence imaging. For CL-activated tagging in vivo, tumor-bearing mice were injected first with 90Y-DOTA-RGD, targeting αvβ3 integrins, and then with the Cy7 azide. Fluorescence signal was imaged over time. Breast cancer cells were incubated with DOX azide and 68Ga, after which cell viability was quantified using an assay. Results: CL photoactivation of Cy7 azide in vitro showed significantly higher fluorescence signal from 18F-FDG-treated than untreated cells. In vivo, CL photoactivation could be shown by using the tumor-specific, integrin-targeting 90Y-DOTA-RGD and the localized activation of Cy7 azide. Here, localized CL-induced fluorescence was detected in the tumors and remained significantly higher over several days than in tumors without CL. We also established as a next step CL-activated drug delivery of DOX azide by showing significantly decreasing cell viability of breast cancer cells in a CL dose-dependent manner in vitro using CL photoactivation of DOX azide. Conclusion: We were able to develop a CL-activated "sticky tag" that converts the low CL signal into a stable and long-lasting, highly intense fluorescence signal. This fluorescent footprint of the radioactive signal might be clinically used for intraoperative surgery. The CL-targeted drug delivery strategy may potentially be used for dual-step targeted therapy.


Genetic deficiency of the tumor suppressor protein p53 influences erythrocyte survival.
The transcription factor p53 suppresses tumor growth by inducing nucleated cell apoptosis and cycle arrest. Because of its influence on primitive erythroid cell differentiation and survival, p53 is an important determinant of erythropoiesis. However, the impact of p53 on the fate of erythrocytes, cells lacking nucleus and mitochondria, during their post-maturation phase in the circulation remained elusive. Erythrocyte survival may be compromised by suicidal erythrocyte death or eryptosis, which is hallmarked by phosphatidylserine translocation and stimulated by increase of cytosolic Ca2+ concentration. Here, we comparatively examined erythrocyte homeostasis in p53-mutant mice (Trp53tm1Tyj/J) and in corresponding WT mice (C57BL/6J) by analyzing eryptosis and erythropoiesis. To this end, spontaneous cell membrane phosphatidylserine exposure and cytosolic Ca2+ concentration were higher in erythrocytes drawn from Trp53tm1Tyj/J mice than from WT mice. Eryptosis induced by glucose deprivation, a pathophysiological cell stressor, was slightly, but significantly more prominent in erythrocytes drawn from Trp53tm1Tyj/J mice as compared to WT mice. The loss of erythrocytes by eryptosis was fully compensated by enhanced erythropoiesis in Trp53tm1Tyj/J mice, as reflected by increased reticulocytosis and abundance of erythroid precursor cells in the bone marrow. Accordingly, erythrocyte number, packed cell volume and hemoglobin were similar in Trp53tm1Tyj/J and WT mice. Taken together, functional p53 deficiency enhances the turnover of circulating erythrocytes by parallel increase of eryptosis and stimulated compensatory erythropoiesis.


Prenatal management with digoxin and sotalol combination for fetal supraventricular tachycardia: case report and review of literature.
Sustained fetal supraventricular tachycardia (SVT) with a heart rate of approximately 210 bpm may lead to increased atrial and venous pressures and congestive heart failure. There is no clear consensus regarding the best drug-treatment regimens for fetal SVT. However, considerable nonrandomized experience in the transmaternal treatment of fetal SVT is available with a number of antiarrhythmic agents. We report a case of fetal supraventricular tachyarrhythmia with hydrops detected at 32 weeks that was managed with combination of oral digoxin and sotalol and review management guidelines available in the literature.


Toward the Fourth Industrial Revolution among E7 Economies: Assessment of the Combined Impact of Institutional Quality, Bank Funding, and Foreign Direct Investment.
Technological innovation and its paradigm, that is, the Fourth Industrial Revolution-4IR, have shown strong impact on income levels of adopters across the globe. To this end, this analysis examines the impact of bank funding and institutional quality on technological advancement. This study adds additional variables such as high-technology exports and foreign direct investment (FDI) as control variable. Our study period spans from 2000 to 2018 on an annual frequency for E7 economies (Brazil, Indonesia, Mexico, India, Turkey, Russia, and China). This study leverages on cross-sectional ARDL, Augmented Mean Group (AMG), and Common Correlated Effects Mean Group Estimates (CCEMG) estimation techniques to examine long-run relationship between the outlined variables. Empirical findings show that institution quality, bank finance, income, high-technology exports, and foreign direct investments exert a positive effect on advancements in technology. Furthermore, the interaction between bank finance and institution quality on technological advancement is also positive and statistically significant. Based on the findings, it is concluded that large-scale funding is crucial for businesses to leverage revolutionary technology. Likewise, access to large capital sources if made easier encourages technology affordance as well as innovation and operational excellence. Thus, economies with established legal and financial systems stand to offer businesses such security, which encourages business innovation. Consequently, E7 economies ought to improve their financial and legal systems to boost financial security, creativity, and competitiveness of businesses.


Prostate cancer: preliminary results of a case finding campaign.
The objective of this study was to evaluate the feasibility of applying a case finding programme for prostate carcinoma based on a questionnaire which was sent by post to the male population of a Northern Italian region. In November 2000 a questionnaire containing prostate related questions was sent to all men aged 55 or older residing in the area served by our hospital. Information provided by the answers was included in a specific data base. Subjects considered at risk for prostate carcinoma were invited for clinical consultation and prostate biopsy when appropriate. 41,627 questionnaires were sent and 7,732 were completed and returned. 960 subjects (12.4%) were considered at risk. Presently, 816 patients have been examined and 116 were biopsied. Thirty-six cases of prostate cancer were found (4.4%). The value of mass screening programmes for prostate carcinoma is still under debate and mature data from controlled screening trials must be obtained before definitive conclusions can be drawn. In the meanwhile, considering the growing public awareness, it may be advisable to activate programmes asking for information through questionnaires about prostate disease in order to find cases of undetected prostate cancer.


EMA: a differentiation antigen related to node metastatic capacity of breast carcinomas.
Epithelial membrane antigen (EMA), also known as MUC1, is a mucinous glycoprotein fixed to the luminal domain of the epithelial cell membrane of normal breast ducts. However, in breast cancer cells, it is usually dispersed in the cytoplasm. EMA staining patterns of 330 breast carcinomas were examined, and three groups formed: lineal (16%), cytoplasmic (75%), and negative (9%). Although these patterns were somewhat related to histological cancer types, this was not statistically significant. However, EMA showed statistically significant univariate relationships to tumor grade, tumor size, estrogen and progesterone receptors, and nodal stage. Logistic regression analysis showed that among these variables, all of which were univariately related to node metastasis, only tumor size and EMA were independent nodal stage predictors. A combined analysis of these two factors revealed that the statistical probability of a tumor metastasizing to four or more nodes increased in each tumor size group from 0.9% to 12% for pT1, from 2% to 29% for pT2 and from 10% to 63% for pT3, depending on the EMA staining. The tumors showing a lineal pattern were the least metastasizing, while the EMA-negative tumors were the most. After recognizing these relationships between EMA staining patterns and other well-known differentiation markers and the lymph node metastatic capacity of carcinomas, and considering the results obtained by others on survival, one might conclude that EMA is both a differentiation marker and a histological prognostic factor.


Finite element assessment of block-augmented total knee arthroplasty.
Loosening and migration of tibial prostheses have been identified as causes of early total knee replacement (TKR) failure. The problem is made more complex when defects occur in the proximal tibia compromising fixation and alignment. Clinical studies using metal augments have shown these to be an alternative to other means of defect treatment. Finite element (FE) analysis can be used to identify regions that may be prone to loosening and migration. In the current work, 3D FE models of TKR uncontained type-2 defects treated with block augments have been constructed and analysed. It has been shown that a metal augment is the most suitable. The use of bone cement (PMMA) to fill proximal defects is not considered suitable as stresses carried by the cement block exceed those of the fatigue limit of bone cement. It has been shown that the stresses in the proximal cancellous bone of block-augmented models are significantly below levels likely to cause damage due to overloading. Furthermore, the use of stem extensions has been shown to reduce the cancellous bone stresses in the proximal region thus increasing the likelihood of bone resorption. Given this, it is recommended that stem extensions are not required unless necessary to mitigate some other problem.


Potential therapeutic benefits of unconventional oils: assessment of the potential in vitro biological properties of some Rubiaceae, Cucurbitaceae, and Brassicaceae seed oils.
Seed oils are versatile in the food sector and for pharmaceutical purposes. In recent years, their biological properties aroused the interest of the scientific world. We studied the composition of fatty acids (FAs) and some in vitro potential therapeutic benefits of five cold-pressed commercial oils obtained from broccoli, coffee, green coffee, pumpkin, and watermelon seeds. In particular, we assayed the antioxidant activity (using diphenyl-1-picrylhydrazyl (DPPH) and azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS) assays). In addition, through the fatty acid composition, we calculated the atherogenicity index (AI) and thrombogenicity index (TI) to evaluate the potential impact of such oils on cardiovascular diseases. Furthermore, we assessed the in vitro anti-inflammatory capacity of the oils (evaluated through their effectiveness in preventing protein degradation, using bovine serum albumin as protein standard) and the ability of the oils to inhibit in vitro activity of three among the essential enzymes, cholinesterases and tyrosinase, involved in the Alzheimer's and Parkinson's neurodegenerative diseases. Finally, we evaluated the capacity of the oils to inhibit the biofilm of some pathogenic bacteria. The unsaturated fatty acids greatly predominated in broccoli seed oil (84.3%), with erucic acid as the main constituent (33.1%). Other unsaturated fatty acids were linolenic (20.6%) and linoleic (16.1%) acids. The saturated fatty acids fraction comprised the palmitic (6.8%) and stearic acids (0.2%). Broccoli seed oil showed the best AI (0.080) and TI (0.16) indexes. The oils expressed a good antioxidant ability. Except for the watermelon seed oil, the oils exhibited a generally good in vitro anti-inflammatory activity, with IC50 values not exceeding 8.73 micrograms. Broccoli seed oil and green coffee seed oil showed the best acetylcholinesterase inhibitory activity; coffee seed oil and broccoli seed oil were the most effective in inhibiting butyrylcholinesterase (IC50 = 15.7 μg and 20.7 μg, respectively). Pumpkin and green coffee seed oil showed the best inhibitory activity against tyrosinase (IC50 = 2 μg and 2.77 μg, respectively). In several cases, the seed oils inhibited the biofilm formation and the mature biofilm of some gram-positive and gram-negative bacteria, with Staphylococcus aureus resulting in the most sensitive strain. Such activity seemed related only in some cases to the capacity of the oils to act on the sessile bacterial cells' metabolism, as indicated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric method.


Mechanisms of bronchial hyperreactivity in cystic fibrosis.
We studied 14 patients with cystic fibrosis (CF) who had evidence of bronchial hyperreactivity on a standardized histamine challenge. Patients had a histamine challenge on the first day. Then they were pretreated with either 0.25 mg ipratropium bromide or 0.5 mg fenoterol hydrobromide on 2 separate days, and the histamine challenge was repeated. Baseline forced expiratory volume in 1 sec was similar on the 3 days; however, there was a small but significant (P less than 0.05) improvement after fenoterol. Mean PC20 on the control day was 1.50 mg/ml, which increased significantly after pretreatment with ipratropium (2.88 mg/ml, P less than 0.01) and fenoterol (3.64 mg/ml, P less than 0.005), indicating protection against histamine-induced bronchial hyperreactivity. The six CF patients with "coexistent asthma," as defined by recurrent episodes of wheezing responsive clinically to bronchodilator therapy, had no significant protection from ipratropium, whereas the eight "nonasthmatic" CF patients were protected by both ipratropium and fenoterol. We postulate that at least two mechanisms contribute to histamine-induced bronchial hyperreactivity in patients with CF, one related to vagally mediated reflex bronchoconstriction and another that acts independently of this mechanism.


Functional role of dorsolateral prefrontal cortex in the modulation of cognitive bias.
Human cognition is often biased. It is a fundamental question in psychology how cognitive bias is modulated in the human brain. Automatic action tendency is a typical cognitive bias. The dorsolateral prefrontal cortex (DLPFC) is a crucial area for processing various behavioral tasks. We investigated the functional role of DLPFC in the modulation of cognitive bias by testing the automatic action tendency during automatic and regulated behavioral tasks. Unilateral intermittent or continuous theta burst stimulation (excitatory iTBS or inhibitory cTBS) was used to manipulate the left or right DLPFC excitability and assess the changes in automatic action tendency during a manikin task. An approaching behavior with positive stimulus and avoiding behavior with negative stimulus were performed in an automatic task. An approaching behavior with negative stimulus and avoiding behavior with positive stimulus were performed in a regulated task. Reaction time was measured. We confirmed the automatic action tendency that reaction time for performing an automatic task was shorter than that for performing a regulated task. The automatic action tendency was enhanced after left DLPFC excitatory iTBS and was abolished after left DLPFC inhibitory cTBS stimulation. On the other hand, right DLPFC excitatory iTBS accelerated the avoiding behaviors and right DLPFC inhibitory cTBS accelerated approaching behaviors. The results suggest that left DLPFC modulates the automatic action tendency while the right DLPFC modulates the direction of behavioral tasks. We conclude that left DLPFC and right DLPFC are key nodes in modulating the cognitive bias while their functional roles are different.


Reconciling modern machine-learning practice and the classical bias-variance trade-off.
Breakthroughs in machine learning are rapidly changing science and society, yet our fundamental understanding of this technology has lagged far behind. Indeed, one of the central tenets of the field, the bias-variance trade-off, appears to be at odds with the observed behavior of methods used in modern machine-learning practice. The bias-variance trade-off implies that a model should balance underfitting and overfitting: Rich enough to express underlying structure in data and simple enough to avoid fitting spurious patterns. However, in modern practice, very rich models such as neural networks are trained to exactly fit (i.e., interpolate) the data. Classically, such models would be considered overfitted, and yet they often obtain high accuracy on test data. This apparent contradiction has raised questions about the mathematical foundations of machine learning and their relevance to practitioners. In this paper, we reconcile the classical understanding and the modern practice within a unified performance curve. This "double-descent" curve subsumes the textbook U-shaped bias-variance trade-off curve by showing how increasing model capacity beyond the point of interpolation results in improved performance. We provide evidence for the existence and ubiquity of double descent for a wide spectrum of models and datasets, and we posit a mechanism for its emergence. This connection between the performance and the structure of machine-learning models delineates the limits of classical analyses and has implications for both the theory and the practice of machine learning.


Hindlimb net joint energies during swing phase as a function of trotting velocity.
Net joint powers and energies have been described in walking horses during the swing phase of the stride in the fore- and hindlimb (Clayton et al. 2001). During trotting, swing phase net joint powers have been described in the forelimb but not in the hindlimb. The effects of velocity on power profiles and energy patterns are important in relation to locomotor energetics. The objective of this study was to evaluate velocity-dependent changes in hindlimb net energy profiles of the swing phase during trotting. Inverse dynamic analysis was used to calculate net joint energies at the hindlimb joints of 6 horses trotting overground at velocities ranging from 2.27-5.17 m/s. At all velocities, there was net energy generation at the hip and tarsus and net energy absorption at the stifle, fetlock and coffin joints. Velocity-dependent bursts of energy generation at the hip actively protracted the limb in early swing and initiated retraction in late swing. Synchronous with the bursts of energy generation at the hip were velocity-dependent bursts of energy absorption across the stifle that acted to control flexion in early swing and extension in late swing. The distal limb was raised and lowered by velocity-dependent bursts of energy generation that flexed the tarsus in early swing and extended it in late swing. The energy bursts in early swing increased linearly with velocity, whereas the energy bursts in late swing increased as a function of the square or cube of velocity. The results contribute to understanding the mechanisms used to accelerate and decelerate the limbs more rapidly as velocity increases, which is an important consideration in racing and sporting performance.


Periodic Visual Stimulation Induces Resting-State Brain Network Reconfiguration.
Periodic visual stimulation can evoke the steady-state visual potential (SSVEP) in the brain. Owing to its superior characteristics, the SSVEP has been widely used in neural engineering and cognitive neuroscience studies. However, the underlying mechanisms of the SSVEP are not well understood. In this study, we introduced a brain reconfiguration methodology to explore the possible mechanisms of the SSVEP. The EEG data from five periodic stimuli consistently indicated that the periodic visual stimulation could induce resting-state brain network reconfiguration and that the responses evoked by the stimuli were correlated to the network reconfiguration indexes. For each stimulus frequency, larger response amplitudes corresponded to higher reconfiguration indexes from the resting-state network to a stimulus-evoked network. These findings demonstrate that an external periodic visual stimulation can induce the modification of intrinsic oscillatory activities by reconfiguring resting-state activity at a network level, which could facilitate the responses evoked by the stimulus. These findings provide new insights into the response mechanisms of periodic visual stimulation.


Treatment and outcomes of iatrogenic colon perforations at a community teaching hospital.
Despite the growing expertise in colonoscopy, it remains subject to complications. The previously published rate of colonoscopic perforation is 0.82 per 1000 examinations. The objective of this study was to describe the experience and management of colonoscopic perforations. A retrospective review of cases from a database of surgical complications was searched for perforations postcolonoscopy from January 1, 2001, to December 31, 2010 at a 527-bed community teaching hospital. Eighteen patients were identified, 11 of whom underwent examination at our institution. Ages ranged from 40 to 91 years with a mean age of 71 years. Eleven of the 18 patients were female and seven were male. Main outcome measures were treatment approach, treatment complications, and mortality. A total of 18 patients were identified in this database. Of these 18 patients, 11 underwent colonoscopy at our institution. During the studied time period, 7578 colonoscopies were performed at our hospital. The majority of the perforations were located in the rectosigmoid colon. Seventeen patients were treated with surgical exploration of the abdomen. Ten patients experienced complications postoperatively. There were two deaths in our series. Only cases in which the colonoscopy was performed at our institution were used when making incidence calculations. The incidence of perforation in our series was significantly higher than previously reported rates. When the perforation was discovered and treated within 24 hours, the patient was rescued. Timely recognition of surgical complications is critical in preventing patient mortality.


Janus Iron Oxides @ Semiconducting Polymer Nanoparticle Tracer for Cell Tracking by Magnetic Particle Imaging.
Iron oxides nanoparticles tailored for magnetic particle imaging (MPI) have been synthesized, and their MPI signal intensity is three-times that of commercial MPI contrast (Ferucarbotran, also called Vivotrax) and seven-times that of MRI contrast (Feraheme) at the same Fe concentration. MPI tailored iron oxide nanoparticles were encapsulated with semiconducting polymers to produce Janus nanoparticles that possessed optical and magnetic properties for MPI and fluorescence imaging. Janus particles were applied to cancer cell labeling and in vivo tracking, and as few as 250 cells were imaged by MPI after implantation, corresponding to an amount of 7.8 ng of Fe. Comparison with MRI and fluorescence imaging further demonstrated the advantages of our Janus particles for MPI-super sensitivity, unlimited tissue penetration, and linear quantitativity.


Ipratropium bromide in the treatment of the 'rhinorrhoea syndrome'.
Conventional treatments for non-allergic perennial rhinitis have proven somewhat unsuccessful in the control of rhinorrhoea when it is the predominant symptom. Hence, a double-blind cross-over trial of Ipratropium, a parasympatholytic, and placebo were carried out over a 12-week period. There was a significant reduction in rhinorrhoea during active treatment, with the most noticeable effect being in the moderate-to-severe rhinorrhoea group. No significant effect was noted on nasal obstruction or sneezing and no serious side-effects were seen. A carry-on effect was noted when active treatment was used initially. However, the group given active treatment following placebo had a better result overall. A strong placebo effect was also noted in both groups, in keeping with a trial of this order.


The Witness Credibility Scale: an outcome measure for expert witness research.
The judge or jury makes a subjective determination of when an expert is credible. However, no published measure exists for assessment of the credibility of expert witnesses. The current study addressed this gap by developing and cross-validating the Witness Credibility Scale (WCS). Drawing on the narrative literature, we hypothesized that credibility was a product of four factors: "likeability," "believability," "trustworthiness," and "intelligence." A 41-item measure was initially constructed based on successive iterations of ratings by a panel of judges using items from the Osgood Semantic Differential measure and was subsequently administered to 264 undergraduates. A factor analysis of the data yielded a factor structure that consisted of four factors labeled, "knowledge," "likeability," "trustworthiness," and "confidence." The final version of the WCS used 20 adjectives with four subscales of five items, each subscale reflecting high loadings on the respective factors. The scale was then tested in five additional studies, in which the scale successfully differentiated between groups of videotaped experts testifying in manipulated conditions. The empirical data from these studies permit a foundation for comparing outcome data in future research investigations.


Left Ovarian Cyst With Overlying Sigmoid Colon.
Ovarian cysts are usually asymptomatic and self-resolvable, but large cysts can increase the risk of ovarian torsion or rupture and may be indicated for surgical intervention. We present the case of a large left ovarian cyst in which laparoscopic left salpingo-oophorectomy was challenged by an overlying sigmoid colon with dense adhesions. A 47-year-old female patient presented to the emergency department with abdominal pain in the right lower quadrant. Ultrasound and computed tomography scans found a large left ovarian cyst and multiple small right ovarian cysts. Due to the size of the left ovarian cyst increasing the risk for torsion, the patient was indicated for laparoscopic left salpingo-oophorectomy. However, the cyst was inaccessible due to the overlying sigmoid colon and dense adhesions on all sides. The surgeons elected to drain the cyst, and the patient was counseled that it was safe to monitor for postoperative recurrence over the next three months. Though laparoscopic surgery is considered a gold standard modality for minimally-invasive ovarian cystectomy/oophorectomy, our case illustrates how it can be challenging when treating left-sided adnexal masses in post-hysterectomy patients due to rectosigmoid and adhesional obstruction. In the context of this challenge, our case further demonstrates the importance of preoperative ovarian cancer screening and favoring conservative treatment options whenever possible.


Physiological and Morphological Changes Induced by Nutrient Limitation of Pseudomonas fluorescens 378 in Continuous Culture.
Pseudomonas fluorescens 378 was studied in continuous culture at a dilution rate of 0.05 or 0.15 h and under a limitation of carbon/energy, nitrogen, phosphorus, iron(III), or oxygen. Cultures were examined for nutritional consumption, production of biosurfactant AP-6 and lipase, and electron microscopy morphology. Morphological features were lysis and plasmolysis of the cells, vacuoles in the cells, granules in cell nuclei, and DNA coagulation during transmission electron microscopy preparation. Biosurfactant and lipase production were lost after 8 to 15 retention times, but under iron limitation and at low dilution rate they were maintained for more than 30 retention times. Consumption of nutrients varied between different cultures. Between 2.4 and 6.0 g of succinic acid per g (dry weight) was consumed; the highest value was obtained under phosphorus limitation. The uptake of nitrogen was mostly about 0.16 g/g (dry weight), and that of phosphorus varied between 13 and 58 mg/g (dry weight). Phosphorus-limited cells reduced their phosphorus consumption by at least 50% compared with other limitations. Cell morphology varied among different cultures. Up to 25% cell lysis occurred at the higher dilution rate. The frequencies of plasmolysis varied between 0 and 85%. Granules in nuclei were found in 65 to 100% of the cells. Vacuoles appeared mostly in low numbers, but at the lower dilution rate under phosphorus or iron limitation the frequencies increased to between 25 and 85%. At high dilution rate, the DNA coagulated in 30 to 70% of the cells. Multivariate data analysis demonstrated a general difference between the two tested dilution rates; i.e., both nutritional and morphological features differed more between the two tested dilution rates than between the different limitations. Cultures at the lower dilution rate changed more with time; this was especially pronounced for phosphorus or iron limitation. The data analysis also showed a correlation between plasmolysis or vacuoles in the cells and an increased carbon uptake under phosphorus limitation.


Radiolytic production of Ag-containing nanocomposite colloids in presence of lithium ions.
This research is motivated to prepare homogeneous and less aggregated nanostructured composites for potential scintillators. Poly ethylene glycol (PEG)-protected approximately 5 nm and approximately 29 nm sized Ag nanoparticles and Ag-Zn nanocomposites were relatively prepared by electron-beam irradiation on Ag+ and Zn2+ solutions with the aids of stabilizers and 6Li+ at room temperature under atmospheric pressure. Especially the 6Li+, which was used for a neutron absorption purpose, played a part the Ag-Zn nanocolloids to less aggregate in the aqueous phase by making partial complexes with stabilizers containing Ag-Zn. To be a potential scintillator, the Ag-Zn nanocomposites have to show an optical response to radiation. Therefore, optical luminescence, which resembles the concept of detecting light without the requirement of a neutron absorbent (convertor) for a neutron scitillator, of the nanocomposites was tested.


Neuronal response to texture- and contrast-defined boundaries in early visual cortex.
Natural scenes contain a variety of visual cues that facilitate boundary perception (e.g., luminance, contrast, and texture). Here we explore whether single neurons in early visual cortex can process both contrast and texture cues. We recorded neural responses in cat A18 to both illusory contours formed by abutting gratings (ICs, texture-defined) and contrast-modulated gratings (CMs, contrast-defined). We found that if a neuron responded to one of the two stimuli, it also responded to the other. These neurons signaled similar contour orientation, spatial frequency, and movement direction of the two stimuli. A given neuron also exhibited similar selectivity for spatial frequency of the fine, stationary grating components (carriers) of the stimuli. These results suggest that the cue-invariance of early cortical neurons extends to different kinds of texture or contrast cues, and might arise from a common nonlinear mechanism.


Women with red hair report a slightly increased rate of bruising but have normal coagulation tests.
There is an anecdotal impression that redheads experience more perioperative bleeding complications than do people with other hair colors. We, therefore, tested the hypothesis that perceived problems with hemostasis could be detected with commonly used coagulation tests. We studied healthy female Caucasian volunteers, 18 to 40 yr of age, comparable in terms of height, weight, and age, with natural bright red (n = 25) or black or dark brown (n = 26) hair. Volunteers were questioned about their bleeding history and the following tests were performed: complete blood count, prothrombin time/international normalized ratio, activated partial thromboplastin time, platelet function analysis, and platelet aggregation using standard turbidimetric methodology. Agonists for aggregation were adenosine diphosphate, arachidonic acid, collagen, epinephrine, and two concentrations of ristocetin. The red-haired volunteers reported significantly more bruising, but there were no significant differences between the red-haired and dark-haired groups in hemoglobin concentration, platelet numbers, prothrombin time/international normalized ratio, or activated partial thromboplastin time. Furthermore, no significant differences in platelet function, as measured by platelet function analysis or platelet aggregometry, were observed. We conclude that if redheads have hemostasis abnormalities, they are subtle.


Is the bithiazole moiety of bleomycin a classical intercalator?
Bleomycin is a widespread anticancerous drug, the biological activity of which having been extensively studied. Its metal ion-chelating portion has been shown to cleave DNA whereas the role of the bithiazole moiety is still questionable. In order to elucidate this problem some 2', 4-disubstituted bithiazoles structurally related to the "tripeptide S" moiety of bleomycin were synthesized and their interaction with DNA was studied using delta Tm, fluorescence, EPR and viscometry techniques. The results of delta Tm and fluorescence quenching determinations were in favour of a binding of the bithiazole part by an intercalation process. Nevertheless, the use of the spin-label probes indicated only a partial intercalation of the ring between the base-pairs. Moreover, viscometry data which clearly exhibited a slight decrease of DNA length in the presence of bithiazole derivative led to the proposal of a binding model involving a partial insertion of a thiazole ring which wedges in between the bases at a bending point of DNA.


[Eukaryotic translation initiation factor 2B and leukoencephalopathy with vanishing white matter].
Leukoencephalopathy with vanishing white matter (VWM) is one of the most prevalent inherited white matter disorders in childhood, and it's the only known hereditary human disease due to the direct defects in protein synthesis process, with the gene defects in EIF2B1-5, encoding the five subunits of eukaryotic translation initiation factor (eIF2B alpha, beta, gamma, delta and epsilon ) respectively. eIF2B is essential for the protein translation initiation process, and its action is realized via eukaryotic translation initiation factor2 (eIF2). Phosphorylation of eIF2alpha and eIF2Bepsilon is an important way to regulate eIF2B function, and thus play a key role in control of the protein translation level under physiological condition. Mutant eIF2B results in functional defects and decrease of the overall protein translation in cells, but in increase the translation of proteins with multiple upstream open reading frames, such as activating transcription factor 4 (AFT4), which leads to the susceptibility to unfolded protein response under stress, and the following apoptosis. The exact pathogenic mechanisms of VWM are far from well understood. It's suggested that level of AFT4 in cells with eIF2B mutations is higher than in wild type cells under physiological condition, which makes the mutant cells more susceptible to endoplasmic reticulum (ER) stress and unfolded protein response (UPR). Under stress, the defect eIF2B leads to a vicious cycle of UPR activation, which may underlie the neurological aggravation in VWM patients after minor stress, a specific clinical feature of VWM. Elucidating the pathogenesis of VWM will be helpful to further understand the protein translation process in eukaryotic cells, and provide a clue for possible therapeutic targets and treatment strategies in the future.


Genetic analysis of a high-level vancomycin-resistant isolate of Staphylococcus aureus.
Vancomycin is usually reserved for treatment of serious infections, including those caused by multidrug-resistant Staphylococcus aureus. A clinical isolate of S. aureus with high-level resistance to vancomycin (minimal inhibitory concentration = 1024 microg/ml) was isolated in June 2002. This isolate harbored a 57.9-kilobase multiresistance conjugative plasmid within which Tn1546 (vanA) was integrated. Additional elements on the plasmid encoded resistance to trimethoprim (dfrA), beta-lactams (blaZ), aminoglycosides (aacA-aphD), and disinfectants (qacC). Genetic analyses suggest that the long-anticipated transfer of vancomycin resistance to a methicillin-resistant S. aureus occurred in vivo by interspecies transfer of Tn1546 from a co-isolate of Enterococcus faecalis.


Exertional leg pain as a manifestation of occult spondyloarthropathy in familial Mediterranean fever: an MRI evaluation.
Familial Mediterranean fever (FMF) is characterized by recurrent episodes of fever, peritonitis, arthritis, and pleuritis, caused by neutrophil-induced sterile serositis. Another clinical manifestation in patients with FMF is exertional leg and ankle pain that appears after minor exercise, for which the underlying mechanism is obscure. The purpose of the current study was to feature distal leg changes in FMF patients complaining of exertional leg pain, using magnetic resonance imaging (MRI). Eleven patients with FMF who suffer from exertional leg pain (eight males, three females; mean age 33 years) and six unaffected controls (three males, three females; mean age 39 years) underwent MRI (3 T) of the ankle, including conventional T1 and T2 with fat saturation sequences, before and after graded exercise on a treadmill. Clinical and genetic data and sacroiliac radiographs were obtained. Ten patients (91%) with FMF but none of the control group had signs compatible with enthesitis of the Achilles tendon, long plantar ligament, or the plantar fascia (including enthesophytes, erosions, and bone marrow oedema). Nine patients (80%) had radiographic signs of sacroiliitis on the pelvic radiograph. Exertional leg pain in FMF patients, shown to be associated with signs of enthesopathy on imaging, may be included within the spectrum of spondyloarthropathy.


Different consequences of beta1 integrin deletion in neonatal and adult mouse epidermis reveal a context-dependent role of integrins in regulating proliferation, differentiation, and intercellular communication.
There are conflicting reports of the consequences of deleting beta1 integrins from the epidermis of transgenic mice. Epidermal thinning with normal differentiation and lack of inflammation has been observed; conversely, epidermal thickening, abnormal differentiation, and dermal fibrosis can occur. beta1 integrin deletion results in decreased epidermal proliferation, yet on wounding the proliferative defect is overcome. To distinguish primary from secondary consequences of beta1 integrin loss, we compared epidermal beta1 deletion at E14.5 via K5Cre and 4-hydroxy-tamoxifen induced deletion in adulthood via K14CreER. As reported previously, there was dermo-epidermal splitting, inflammation, reduced proliferation, and hair follicle and sebaceous gland loss in 30-d-old K5Cre beta1-null mice. These changes were not observed 30 d after beta1 integrin deletion in adult epidermis, however, and there were no changes in the hair follicle stem cell compartment. Deletion in adult epidermis revealed a previously unreported correlation between the level of beta1 integrins and proliferation in the interfollicular epidermis that was remarkably consistent with human epidermis. In addition, the number of melanocytes in interfollicular epidermis was greatly increased. Our results highlight the context-dependent effects of beta1 integrin deletion and suggest that inflammation may be responsible for some of the K5Cre beta1-null phenotype.


Cold Atmospheric Plasma Apoptotic and Oxidative Effects on MCF7 and HCC1806 Human Breast Cancer Cells.
Breast cancer (BC) is a malignant neoplasia with the highest incidence and mortality rates in women worldwide. Currently, therapies include surgery, radiotherapy, and chemotherapy, including targeted therapies in some cases. However, treatments are often associated with serious adverse effects. Looking for new options in BC treatment, we evaluated the therapeutic potential of cold atmospheric plasma (CAP) in two cell lines (MCF7 and HCC1806) with distinct histological features. Apoptosis seemed to be the most prevalent type of death, as corroborated by several biochemical features, including phosphatidylserine exposure, the disruption of mitochondrial membrane potential, an increase in BAX/BCL2 ratio and procaspase 3 loss. Moreover, the accumulation of cells in the G2/M phase of the cell cycle points to the loss of replication ability and decreased survival. Despite reported toxic concentrations of peroxides in culture media exposed to plasma, intracellular peroxide concentration was overall decreased accompanying a reduction in GSH levels shortly after plasma exposure in both cell lines. In HCC1806, elevated nitric oxide (NO) concentration accompanied by reduced superoxide levels suggests that these cells are capable of converting plasma-derived nitrites into NO that competes with superoxide dismutase (SOD) for superoxide to form peroxinitrite. The concomitant inhibition of the antioxidative activity of cells during CAP treatment, particularly the inhibition of cytochrome c oxidase with sodium azide, synergistically increased plasma toxicity. Thus, this in vitro research enlightens the therapeutic potential of CAP in the treatment of breast cancer, elucidating its possible mechanisms of action.


System-based drug discovery within the human kinome.
For well over a decade, significant effort has been devoted to the search for inhibitors of the human protein kinase family. This is increasingly translating into success in the clinic, with five new kinase inhibitor drugs approved since 2011. However, despite encouraging signs in other areas, success has been largely restricted to oncology. This article reviews the prospects for kinase inhibitor drug discovery in oncology and other therapeutic areas. Major topics include the application of kinome profiling and lessons learned from kinase system-based research. With these fields nearing maturity, the validation of kinases as targets or their classification as liabilities is becoming increasingly pertinent. Other topics include a discussion of the properties required of good small molecule kinase probes. The tractability of protein kinases to small molecule discovery through system-based research is excellent, and adequate selectivity can often be achieved. With advances in screening methodology now enabling compound profiling across most of the kinome, researchers involved in drug discovery must decide what inhibition profiles are desirable. However, this assessment must be made on the basis of incomplete understanding of the disease biology of most kinases, and as a result there is a significant risk that drugs entering clinical trials will lack efficacy. Because of this, as well as greater effort to determine which kinases are therapeutically relevant for particular diseases, opportunities for quality pre-candidate compounds developed for specific indications to find alternative uses should be maximised by early screening through panels of phenotypic assays.


Sphygmomanometer calibration--why, how and how often?
Hypertension is the most commonly managed problem in general practice. Systematic errors in blood pressure measurements caused by inadequate sphygmomanometer calibration are a common cause of over- and underidentification of hypertension. This article reviews sphygmomanometer error and makes recommendations regarding in service maintenance and calibration of sphygmomanometers. Most sphygmomanometer surveys report high rates of inadequate calibration and other faults, particularly in aneroid sphygmomanometers. Automatic electronic sphygmomanometers produce systematic errors in some patients. All sphygmomanometers should be checked and calibrated by an accredited laboratory at least annually. Aneroid sphygmomanometers should be calibrated every 6 months. Only properly validated automatic sphygmomanometers should be used. Practices should perform regular in house checks of sphygmomanometers. Good sphygmomanometer maintenance and traceable sphygmomanometer calibration will contribute to reducing the burden of cardiovascular disease and the number of patients overtreated for hypertension in Australia.


Insights from the evaluation of a provincial healthy eating strategy in Nova Scotia, Canada.
Healthy Eating Nova Scotia represents the first provincial comprehensive healthy eating strategy in Canada and a strategy that is framed within a population-health model. Five years after strategy launch, our objective was to evaluate Healthy Eating Nova Scotia to determine perceptions of strategy implementation and strategy outputs. The focus of the current paper is on the findings of this evaluation. We conducted an evaluation of the strategy through three activities that included a document review, survey of key stakeholders and in-depth interviews with key strategy informants. The findings from each of the activities were integrated to determine what has worked well with strategy implementation, what could be improved and what outputs have resulted. The evaluation was conducted in the Canadian province of Nova Scotia. Participants for this evaluation included survey respondents (n 120) and key informants (n 16). A total of 156 documents were also reviewed. Significant investments have been made towards inter-sectoral partnerships and resourcing that has provided the necessary leadership and momentum for the strategy. Policy development has been leveraged through the strategy primarily in the health and education sectors and is perceived as a visible success. Clarity of human resource roles and funding within the context of a provincial strategy may be beneficial for continued strategy implementation, as is expansion of policy development. Known to be the first evaluation of its kind, these findings and related considerations will be of interest to policy makers developing and implementing similar strategies in their own jurisdictions.


Mutant and wild-type p53 form complexes with p73 upon phosphorylation by the kinase JNK.
The transcription factors p53 and p73 are critical to the induction of apoptotic cell death, particularly in response to cell stress that activates c-Jun N-terminal kinase (JNK). Mutations in the DNA-binding domain of p53, which are commonly seen in cancers, result in conformational changes that enable p53 to interact with and inhibit p73, thereby suppressing apoptosis. In contrast, wild-type p53 reportedly does not interact with p73. We found that JNK-mediated phosphorylation of Thr81 in the proline-rich domain (PRD) of p53 enabled wild-type p53, as well as mutant p53, to form a complex with p73. Structural algorithms predicted that phosphorylation of Thr81 exposes the DNA-binding domain in p53 to enable its binding to p73. The dimerization of wild-type p53 with p73 facilitated the expression of apoptotic target genes [such as those encoding p53-up-regulated modulator of apoptosis (PUMA) and Bcl-2-associated X protein (BAX)] and, subsequently, the induction of apoptosis in response to JNK activation by cell stress in various cells. Thus, JNK phosphorylation of mutant and wild-type p53 promotes the formation of a p53/p73 complex that determines cell fate: apoptosis in the context of wild-type p53 or cell survival in the context of the mutant. These findings refine our current understanding of both the mechanistic links between p53 and p73 and the functional role for Thr81 phosphorylation.


Ab initio exploration and prediction of AE-containing nitrido(litho/magneso)tetrelates (AE = Ca, Sr; Tt = Si, Ge) with [Si2N6]10- or [Ge2N6]10- units.
Recently, a number of different structurally related nitrides characterized by pairs of edge-sharing Si-N tetrahedra forming [Si2N6]10- units have emerged via different synthesis methods. Concurrently, upon doping with rare earth elements (e.g. Eu2+ and Ce3+), numerous applications in the field of luminescent materials were revealed, ranging from the visible spectrum to the near IR. This compound class in turn emphasizes the extraordinary large tuning range with respect to relative composition by formal cation exchange. In this contribution, we study the dynamical stabilities of the existing Si-based nitridotetrelates and hypothetical Ge analogues promising for future synthesis efforts of luminescent materials by means of extensive phonon calculations. Further calculations of electronic and mechanical properties corroborate the fundamental suitability of the predicted compounds for the applications of potential luminescent materials with regard to band gap (Eg) and Debye temperature (ΘD). Calculated enthalpies of the reaction provide further beneficial insights for future experimental attempts. Our study hence highlights a potential range of novel stable nitridogermanates with isotypic structures and suitable electronic properties for optoelectronic applications.


A preliminary evaluation of a reusable digital sterilization indicator prototype.
Sterilization of critical and semicritical instruments used in patient care must undergo a terminal process of sterilization. Use of chemical and physical indicators are important in providing information on the sterilizer's performance during each cycle. Regular and periodic monitoring of sterilizers using biological indicators is necessary in periodically validating performance of sterilizers. Data loggers or independent digital parametric indicators are innovative devices that provide more information than various classes chemical indicators. In this study we evaluated a prototype of an independent digital parametric indicator's use in autoclaves. The purpose of this study was to evaluate the performance of an independent digital indicator/data logger prototype (DS1922F) that could be used for multiple cycles within an autoclave.MG Materials and methods: Three batches of the DS1922F (150 samples) were used in this study that was conducted in a series. The first batch was challenged with 300 sterilization cycles within an autoclave and the data loggers evaluated to study failures and the reason for failure, make corrections and improve the prototype design. After changes made based on studying the first batch, the second batch of the prototype (150 samples) were challenged once again with 300 sterilization cycles within an autoclave and failure studied again in further improvement of the prototype. The final batch (3rd batch) of the prototype (150 samples) was challenged again but with 600 cycles to see how long they would last. Kaplan-Meier survival analysis analyses of all three batches was conducted (α = 0.05) and failed samples qualitatively studied in understanding the variables involved in the failure of the prototype, and in improving quality. Each tested batch provided crucial information on device failure and helped in improvement of the prototype. Mean lifetime survival of the final batch (Batch 3) of prototype was 498 (480, 516) sterilization cycles in an autoclave. In this study, the final batch of the DS1922F prototype data logger was found to be robust in withstanding the challenge of 600 autoclave cycles, with a mean lifetime of more than 450 cycles, multiple times more than prescribed number of cycles. Instrument reprocessing is among the important aspects of infection control. While stringent procedures are followed in instrument reprocessing within the clinic in assuring patient safety, regular use of sterilization process indicators and periodic biological validation of the sterilizer's performance is necessary. Chemical indicators for use in Autoclaves provide information on whether the particular cycle's parameters were achieved but do not provide at what specific point in time or temperature the failure occurred. Data loggers and associated reader software as the tested prototype in this evaluation (DS1922F), are designed to provide continuous information on time and temperature of the prescribed cycle. Data loggers provide immediate information on the process as opposed to Biological Indicators that take from days to a week in obtaining a confirmatory result. Further, many countries do not have the sterilization monitoring service infrastructure to meet the demands of the end users. In the absence of sterilization monitoring services, use of digital data loggers for each sterilization cycle is more pragmatic.