CoMPARA: Collaborative Modeling Project for Androgen Receptor Activity.
Endocrine disrupting chemicals (EDCs) are xenobiotics that mimic the interaction of natural hormones and alter synthesis, transport, or metabolic pathways. The prospect of EDCs causing adverse health effects in humans and wildlife has led to the development of scientific and regulatory approaches for evaluating bioactivity. This need is being addressed using high-throughput screening (HTS) in vitro approaches and computational modeling. In support of the Endocrine Disruptor Screening Program, the U.S. Environmental Protection Agency (EPA) led two worldwide consortiums to virtually screen chemicals for their potential estrogenic and androgenic activities. Here, we describe the Collaborative Modeling Project for Androgen Receptor Activity (CoMPARA) efforts, which follows the steps of the Collaborative Estrogen Receptor Activity Prediction Project (CERAPP). The CoMPARA list of screened chemicals built on CERAPP's list of 32,464 chemicals to include additional chemicals of interest, as well as simulated ToxCast™ metabolites, totaling 55,450 chemical structures. Computational toxicology scientists from 25 international groups contributed 91 predictive models for binding, agonist, and antagonist activity predictions. Models were underpinned by a common training set of 1,746 chemicals compiled from a combined data set of 11 ToxCast™/Tox21 HTS in vitro assays. The resulting models were evaluated using curated literature data extracted from different sources. To overcome the limitations of single-model approaches, CoMPARA predictions were combined into consensus models that provided averaged predictive accuracy of approximately 80% for the evaluation set. The strengths and limitations of the consensus predictions were discussed with example chemicals; then, the models were implemented into the free and open-source OPERA application to enable screening of new chemicals with a defined applicability domain and accuracy assessment. This implementation was used to screen the entire EPA DSSTox database of ∼875,000 chemicals, and their predicted AR activities have been made available on the EPA CompTox Chemicals dashboard and National Toxicology Program's Integrated Chemical Environment. https://doi.org/10.1289/EHP5580.


Gastric tubular adenocarcinoma with diffuse neutrophils infiltrating: characteristics and probable treatment strategy.
Gastric adenocarcinoma is a highly heterogeneous malignancy with varying prognoses. In clinicopathological practice, we noticed a special tubular adenocarcinoma with diffuse neutrophils infiltrating (TADNI). However, the proportion and characteristics of TADNI remain unclear. This study aimed to evaluate the features of TADNI and explore probable treatments. We divided 289 tubular adenocarcinoma cases into the TADNI and non-TADNI (nTADNI) groups by histological neutrophil quantity and performed immunohistochemistry of treatment-associated markers (CXCR1, CXCR2, PD-L1, CD8, HER2 and VEGFR2). Then we evaluated the clinical and morphological features in these cases. We also compared the value of histological features and peripheral blood neutrophil test. In addition, multiomics bioinformatic analyses were performed using the public datasets. In our cohort, TADNI accounted for 10.4% of all tubular adenocarcinoma cases. These cases had worse prognoses (especially the neutrophils mainly outside the tubes) than nTADNI cases. The histological identification of TADNI had more prognostic value than peripheral blood neutrophils. CXCR1/CXCR2 expression was significantly high in TADNI group which indicated that CXCR1/CXCR2 inhibitors might be beneficial for TADNI patients. There were no significant differences in the expression of PD-L1, CD8, HER2 and VEGFR2. The analyses of TCGA data confirmed that TADNI cases had poorer prognoses and higher CXCR1/CXCR2 expression. Bioinformatic results also revealed molecular features (more hsa-mir-223 expression, fewer CD8-positive T cells and regulatory T cells, tighter communication between tumor cells' CXCR1/CXCR2 and neutrophils' CXCL5/CXCL8) of this type. TADNI is a special morphological subtype with poorer prognoses and unique molecular characteristics, which might benefit from CXCR1/CXCR2 inhibitors.


In vitro toxicology of ambient particulate matter: correlation of cellular effects with particle size and components.
High concentrations of airborne particulate matter (PM) have been associated with increased rates of morbidity and mortality among exposed populations. Although certain components of PM were suggested to influence these effects, no clear-cut correlation was determined thus far. One of the possible modes of action is the induction of oxidative stress by inhaled PM triggering inflammatory responses. Therefore, the in vitro formation of reactive oxygen species (ROS) in three cell lines in the presence of five subfractions of PM(10), collected in Münster, Germany was investigated. The PM components chloride, nitrate, ammonium, sulfate, 68 chemical elements, and endotoxin were quantified. The highest concentration of endotoxin was found in particles of 0.42-1.2 μm aerodynamic diameters, and therefore probably subject to long-range transport. Intracellular ROS formation in three well established mammalian cell lines (CaCo2, human; MDCK, canine; RAW264.7, mouse) only correlated positively with particle size. The two smallest PM size fractions provoked the highest rise in ROS. However, the latter did not correlate with the concentration of any PM components investigated. The smallest PM size fractions significantly dominated the number of particles. Therefore, the particle number may be most effective in inducing oxidative stress in vitro.


Morphologic study of the testes from spontaneous unilateral and bilateral abdominal cryptorchid boars.
Macroscopical and histological characteristics were examined in both testes from three healthy boars, three boars with unilateral abdominal cryptorchidism on the right side, and three boars with bilateral abdominal cryptorchidism. Abdominal cryptorchidism, unilateral and bilateral, provoked a significant decrease of the weight and volume of the ectopic testes. The scrotal testis of the unilateral cryptorchid boars showed an increase in its volume and weight. Cryptorchidism also induced abnormalities in the histological structure of seminiferous tubules, lamina propria, and interstitial tissue of the abdominal testes. The number of seminiferous tubules decreased; the seminiferous epithelium was constituted by few spermatogonia with an atypical pattern and by abnormal Sertoli cells. The lamina propria showed a variable degree of thickening and collagenization. The interstitial tissue was very developed but displayed a decrease in the Leydig cell population. These abnormalities were more critical in bilateral cryptorchidism than in unilateral cryptorchidism. The scrotal testis of the unilateral cryptorchid boars showed normal appearance, but a decrease of the number of seminiferous tubules was observed. Moreover, the seminiferous tubules showed impaired spermatid maturation. The alterations observed in the abdominal testes of the unilateral and bilateral cryptorchid boars were attributed to defective proliferation and differentiation of Sertoli cells and Leydig cells. The anomalies in the scrotal testis of the unilateral cryptorchid boars were due to disturbances in the Sertoli cell activity.


FKBP52 overexpression accelerates hippocampal-dependent memory impairments in a tau transgenic mouse model.
Abnormal accumulation of hyperphosphorylated tau induces pathogenesis in neurodegenerative diseases, like Alzheimer's disease. Molecular chaperones with peptidyl-prolyl cis/trans isomerase (PPIase) activity are known to regulate these processes. Previously, in vitro studies have shown that the 52 kDa FK506-binding protein (FKBP52) interacts with tau inducing its oligomerization and fibril formation to promote toxicity. Thus, we hypothesized that increased expression of FKBP52 in the brains of tau transgenic mice would alter tau phosphorylation and neurofibrillary tangle formation ultimately leading to memory impairments. To test this, tau transgenic (rTg4510) and wild-type mice received bilateral hippocampal injections of virus overexpressing FKBP52 or GFP control. We examined hippocampal-dependent memory, synaptic plasticity, tau phosphorylation status, and neuronal health. This work revealed that rTg4510 mice overexpressing FKBP52 had impaired spatial learning, accompanied by long-term potentiation deficits and hippocampal neuronal loss, which was associated with a modest increase in total caspase 12. Together with previous studies, our findings suggest that FKBP52 may sensitize neurons to tau-mediated dysfunction via activation of a caspase-dependent pathway, contributing to memory and learning impairments.


Gut microbiota and butyrate level changes associated with the long-term administration of proton pump inhibitors to old rats.
The association between adverse effects of PPI and gut microbiota in old age has yet to be elucidated. We assessed changes in the gut microbiota and butyrate levels following the long-term administration of PPIs to old rats and investigated their associations. F344 aged male rats were fed a PPI-supplemented diet for 50 weeks. The ileal microbiota was analysed by metagenomic sequencing of the 16S rRNA, while the butyrate concentration was measured by high-performance liquid chromatography. We observed a significant decrease in microbial diversity following PPI administration in the 2-year-old rats but not in the 74-week-old rats. PPI treatment reduced both commensal bacteria and opportunistic pathogens, particularly in the 2-year-old rats. Enterotypes comprising the majority of the control samples were enriched in Lactobacillus, while other enterotypes in the PPI group were dominated by Turicibacter or Romboutsia. The PPI treatment reduced the butyrate concentrations in the intestines and colons of 74-week-old rats compared to the control group. The abundance of Lactobacillus significantly correlated with butyrate concentrations in 74-week-old rats. In conclusion, long-term administration of PPIs alters the gut microbiota and butyrate concentrations in rats, particularly in old age, which may be an underlying mechanism of PPI-induced adverse effects such as pseudomembranous colitis.


Enantio- and diastereoselective Michael addition reactions of unmodified aldehydes and ketones with nitroolefins catalyzed by a pyrrolidine sulfonamide.
Chiral (S)-pyrrolidine trifluoromethanesulfonamide has been shown to serve as an effective catalyst for direct Michael addition reactions of aldehydes and ketones with nitroolefins. A wide range of aldehydes and ketones as Michael donors and nitroolefins as acceptors participate in the process, which proceeds with high levels of enantioselectivity (up to 99 % ee) and diastereoselectivity (up to 50:1 d.r.). The methodology has been employed successfully in an efficient synthesis of the potent H(3) agonist Sch 50917. In addition, a practical three-step procedure for the preparation of (S)-pyrrolidine trifluoromethanesulfonamide has been developed. The high levels of stereochemical control attending Michael addition reactions catalyzed by this pyrrolidine sulfonamide, have been investigated by using ab initio and density functional methods. Transition state structures for the rate-limiting C--C bond-forming step, corresponding to re- and si-face addition to the reactive conformation of the key enamine intermediates have been calculated. Analysis of these structures indicates that hydrogen bonding plays an important role in catalysis and that the energy barrier for si-face attack in reactions of aldehydes to form 2R,3S products is lower than that for the re-face attack leading to 2S,3R products. In contrast, the energy barrier for re-face addition is lower than that for si-face addition in reactions of ketones. The computational results, which are in good agreement with the experimental observations, are discussed in the context of the stereochemical course of these Michael addition reactions.


Management of tracheal rupture involving both bronchi.
A patient with a rupture of the lower trachea and both bronchi is presented. A review of the significant clinical findings is presented, and the anaesthetic management is discussed. The necessity of early bronchoscopy in these patients and the ready availability of experienced medical staff in assessing all severe trauma is emphasized.


Generation and Characterization of Acid Tolerant Fibrobacter succinogenes S85.
Microorganisms are key components for plant biomass breakdown within rumen environments. Fibrobacter succinogenes have been identified as being active and dominant cellulolytic members of the rumen. In this study, F. succinogenes type strain S85 was adapted for steady state growth in continuous culture at pH 5.75 and confirmed to grow in the range of pH 5.60-5.65, which is lower than has been reported previously. Wild type and acid tolerant strains digested corn stover with equal efficiency in batch culture at low pH. RNA-seq analysis revealed 268 and 829 genes were differentially expressed at pH 6.10 and 5.65 compared to pH 6.70, respectively. Resequencing analysis identified seven single nucleotide polymorphisms (SNPs) in the sufD, yidE, xylE, rlmM, mscL and dosC genes of acid tolerant strains. Due to the absence of a F. succinogenes genetic system, homologues in Escherichia coli were mutated and complemented and the resulting strains were assayed for acid survival. Complementation with wild-type or acid tolerant F. succinogenes sufD restored E. coli wild-type levels of acid tolerance, suggesting a possible role in acid homeostasis. Recent genetic engineering developments need to be adapted and applied in F. succinogenes to further our understanding of this bacterium.


The repeated bout effect: is the blunted creatine kinase response an effect of an altered enzyme inactivation kinetic?
If unaccustomed lengthening contractions are repeated within a certain period of time, muscle damage symptoms are blunted. This observation, often referred to as the repeated bout effect (RBE), also holds true for the response of muscle damage markers like creatine kinase (CK). However, measuring plasma enzyme activity rather than the concentration of enzyme protein might conceal the actual amount of damaged tissue. Therefore, the primary aim of the study was to investigate if the RBE of CK can partially be explained by enzyme inactivation. Ten healthy male subjects performed two bouts of 100 drop-to-vertical jumps (DVJs) from a 70-cm high platform at an interval of three weeks. CK activity, CK concentration, and neutrophils were measured prior to, and on four consecutive days after the interventions. Besides significant main effects, there was a significant group by time interaction for the specific CK activity (CK activity in blood [U/L] divided by the enzyme concentration [ng/mL]). Higher values following the first bout (133.1±99.4 U/µg) than the second bout (94.7±63.0 U/µg) indicate that the ratio of inactive to active CK molecules increased. Neutrophil levels were similar following both bouts and differed only at 8 hours (7.0±2.5 bout 1, 5.1±1.6 bout 2). The findings of the present study support the hypothesis that the blunted response of CK activity after a repeated bout of eccentric exercise is not solely the result of tissue protection, but can be at least partially attributed to enzyme inactivation.


RRP6/EXOSC10 is required for the repair of DNA double-strand breaks by homologous recombination.
The exosome acts on different RNA substrates and plays important roles in RNA metabolism. The fact that short non-coding RNAs are involved in the DNA damage response led us to investigate whether the exosome factor RRP6 of Drosophila melanogaster and its human ortholog EXOSC10 play a role in DNA repair. Here, we show that RRP6 and EXOSC10 are recruited to DNA double-strand breaks (DSBs) in S2 cells and HeLa cells, respectively. Depletion of RRP6/EXOSC10 does not interfere with the phosphorylation of the histone variant H2Av (Drosophila) or H2AX (humans), but impairs the recruitment of the homologous recombination factor RAD51 to the damaged sites, without affecting RAD51 levels. The recruitment of RAD51 to DSBs in S2 cells is also inhibited by overexpression of RRP6-Y361A-V5, a catalytically inactive RRP6 mutant. Furthermore, cells depleted of RRP6 or EXOSC10 are more sensitive to radiation, which is consistent with RRP6/EXOSC10 playing a role in DNA repair. RRP6/EXOSC10 can be co-immunoprecipitated with RAD51, which links RRP6/EXOSC10 to the homologous recombination pathway. Taken together, our results suggest that the ribonucleolytic activity of RRP6/EXOSC10 is required for the recruitment of RAD51 to DSBs.


Connexin 36 in bovine retina: lack of phosphorylation but evidence for association with phosphorylated proteins.
In vertebrate retina interneuronal communication through gap junctions is involved in light adaptation and in the transfer of visual information from the rod pathway to the cone pathway. Reports over the last two decades have indicated that these gap junctions are regulated by cyclic nucleotide-dependent protein kinases suggesting that the gap junction proteins, connexins, are phosphorylated. Though all the connexins involved in light adaptation and information transfer from rod to cone pathway are not yet known, connexin 36 has been shown to be definitively involved in the latter process. We have therefore attempted to investigate the cyclic nucleotide-dependent phosphorylation of this connexin in bovine retina. We found several soluble and membrane proteins in bovine retina whose phosphorylation was regulated by cyclic nucleotides. However, no protein of about 36 kDa with cyclic nucleotide-regulated phosphorylation was found in gap junction-enriched membrane preparations. A 36-kDa phosphorylated protein was found in gap junction-enriched membranes phosphorylated in the presence of calcium. However, this protein was not immunoprecipitated by anti-connexin 36 antibodies indicating that it was not connexin 36 in spite of its similarity in molecular weight. Immunoprecipitation did reveal phosphorylated proteins coimmunoprecipitated with connexin 36. Two of these proteins were identified as beta and alpha tubulin subunits. Though cyclic GMP and calcium did not greatly influence the association of these proteins with connexin 36, the results suggest the possibility of connexin 36 associating with other proteins. Together, these observations indicate that interneuronal communication at gap junctions made by connexin 36 may not be regulated by direct phosphorylation of connexin 36, but possibly by phosphorylation of associated proteins.


Low flow active antipollution systems. An evaluation of two systems with automatic ventilators.
The performance of two low-flow antipollution systems has been assessed by making measurements of the nitrous oxide pollution levels with four automatic ventilators. The effectiveness of the antipollution system is dependent on the volume of gas discharged, the peak expiratory flow, the airway pressure and to a lesser extent the ventilator settings. Both systems coped adequately with the clinical conditions where inflation pressures were below 4 kPa for two ventilators. Only one system coped with these conditions for the third ventilator. The fourth ventilator, which discharged driving gas to the respired volume, was not adequately scavenged.


Cordycepin delays postovulatory aging of oocytes through inhibition of maternal mRNAs degradation via DCP1A polyadenylation suppression.
Postovulatory aging leads to the decline in oocyte quality and subsequent impairment of embryonic development, thereby reducing the success rate of assisted reproductive technology (ART). Potential preventative strategies preventing oocytes from aging and the associated underlying mechanisms warrant investigation. In this study, we identified that cordycepin, a natural nucleoside analogue, promoted the quality of oocytes aging in vitro, as indicated by reduced oocyte fragmentation, improved spindle/chromosomes morphology and mitochondrial function, as well as increased embryonic developmental competence. Proteomic and RNA sequencing analyses revealed that cordycepin inhibited the degradation of several crucial maternal proteins and mRNAs caused by aging. Strikingly, cordycepin was found to suppress the elevation of DCP1A protein by inhibiting polyadenylation during postovulatory aging, consequently impeding the decapping of maternal mRNAs. In humans, the increased degradation of DCP1A and total mRNA during postovulatory aging was also inhibited by cordycepin. Collectively, our findings demonstrate that cordycepin prevents postovulatory aging of mammalian oocytes by inhibition of maternal mRNAs degradation via suppressing polyadenylation of DCP1A mRNA, thereby promoting oocyte developmental competence.


Role and levels of real-time monitoring for successful anti-fouling strategies--an overview.
Biofouling is a biofilm problem and any anti-fouling strategy will be greatly improved if the site and extent of biofilm growth can be monitored. A suitable monitoring system will provide early warning capacity and allow for specific optimization of countermeasures. As water samples do not give reliable information about biofilms, surface sampling is mandatory. Conventional biofilm monitoring techniques rely on removal of material from representative sites or on analysis of test surfaces which have been exposed. This procedure is time consuming and, depending on the parameters to be measured, requires skilled laboratory personnel. There is a strong demand for direct, on-line, in situ, continuous, non-destructive real-time information about biofilms in a system. Such demands can only be fulfilled by physical or physico-chemical methods, a number of which have already been successfully applied for biofilm monitoring. It is important, however, to be aware of the actual parameter they refer to in order to interpret the data properly. Three levels of information can be identified: (i) systems which detect increase and decrease of material accumulating on a surface but cannot differentiate between biomass and other components of a deposit, (ii) systems which provide biological information and distinguish between biotic and abiotic material, and (iii) systems which provide detailed chemical information. Examples for all three levels are presented and discussed.


An evidence synthesis approach to estimating the incidence of symptomatic pertussis infection in the Netherlands, 2005-2011.
Despite high vaccination coverage, infection with Bordetella pertussis is a current public health concern in the Netherlands and other European Union member states. Because surveillance data are subject to extensive under-ascertainment and under-reporting, incidence is difficult to determine. Our objective was to estimate the age-group specific incidence of symptomatic pertussis infection in the Netherlands over the period 2005-2011, using multi-parameter evidence synthesis. Age-specific seroconversion probabilities were estimated for 2007 using Netherlands population data stratified by age-group and cross-sectional population-wide serosurvey (PIENTER-2) data, with a sero-diagnostic cut-off of 125 EU/ml as a proxy for recent infection. Symptomatic probabilities were derived from a study of household contacts and from PIENTER-2. The annual number of symptomatic infected (SI) persons was estimated using evidence synthesis methods in a Bayesian framework, by combining the estimated incidence of infection with notification data and symptomatic probabilities. An incidence rate of 128 SI cases per 10,000 population (95 % credible interval [CrI]: 110-150) was estimated for 2005, which decreased to 107 per 10,000 (95 % CrI: 91-126) for 2011. The degree of underestimation in statutory notified cases was age-dependent, ranging from 10-fold (10-19 years) to 69-fold (60+ years). The largest annual decreases in SI incidence rate over the study period were in the 1-4 and 5-9 years age-groups (24.3 %, 15.9 % per year, respectively). By synthesising all available data, the incidence of symptomatic pertussis and the extent to which SI is underrepresented by notification data can be estimated. Such estimates are essential for disease burden computation and for informing public health priority-setting.


Seasonal variations in the contractile behaviour of gastrocnemius muscles of Uromastix hardwickii.
Seasonal variations in the isometric activity of the isolated gastrocnemius muscle of Uromastix hardwickii was studied from winter to summer in Karachi, Pakistan. A constant 20 degrees C temperature was maintained during experimentation to avoid influence of this factor on seasonal changes. The twitch and tetanic tensions recorded at resting lengths showed a significant rise from winter to summer (p less than 0.0005) with a greater effect on tetanic tensions. The rate of rise of tensions also showed a significant elevation (p less than 0.0005) from winter to summer, while the duration of active state decreased by 66% during spring and summer. The results are discussed in terms of speed of summation of active state, cross bridge interaction, and characteristic expression of gastrocnemius muscle morphology on its mechanical behaviour from winter to summer.


Epidermal proliferation of the skin in metallothionein-null mice.
Metallothionein (MT) is a low-molecular weight metal-binding protein. Although the physiologic function of MT is not fully known, it is present in various species and various organs including the skin. MT is strongly stained in hyperplastic epidermal tissues in normal skin and in hyperplastic skin lesions, and increased expression of mRNA of the MT gene has been demonstrated in skin stimulated by proliferative agents, suggesting that MT is involved in the proliferation of epidermal keratinocytes. To improve our understanding of the role of MT in epidermal hyperplasia, mice with null mutations in their MT-1 and MT-2 genes were used in this study. We compared the epidermal hyperplasia in MT-null mice and in normal C57BL/6 J mice after treatments with cholera toxin, 12-0-tetradecanoylphorbol-13-acetate, and ultraviolet B irradiation, which stimulate epidermal proliferation. Immunostaining of MT was not detected in the skin of MT-null mice, and these mice developed significantly less epidermal hyperplasia than the normal mice after exposure to each stimulator. We determined the metal contents of skin samples by the proton-induced x-ray emission method. The zinc content of the skin of the MT-null mice was lower than that of the control mice before stimulation. After stimulation of epidermal hyperplasia, MT-null and normal mice showed significantly reduced levels of zinc. These findings indicate that cellular MT is involved in the proliferative process of the epidermis induced by cholera toxin, 12-0-tetradecanoylphorbol-13-acetate, and ultraviolet B light through its regulatory action on the metal metabolism required for cell growth.


Antidepressants use in pediatric populations.
In October of 2003, the FDA issued a public health warning stating that preliminary evidence showed selective serotonin re-uptake inhibitors (SSRIs) and related antidepressants might be associated with excess reports of suicidality. In 2004, the FDA convened a committee of neuropsychiatric and pediatric subcommittee members and expert consultants to evaluate the safety of antidepressants in children and adolescents. The committee reviewed a meta-analysis of antidepressant use in pediatric patients and concluded that there was a causal link between pediatric antidepressant use and suicidality. In response, the FDA mandated that a 'black box' warning be added to the prescribing and promotional information for all antidepressants. The warning specifically states 'antidepressants increase the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders'. Interestingly, the FDA tempered the warning with the following statement: 'Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide'. Therefore, in effect, the FDA has warned that both untreated depression and treatments for depression lead to suicidality. Now, 4 years later, the repercussions of the black box warning are becoming evident.


Comparison of radiography, computed tomography, and magnetic resonance imaging for evaluation of appendicular osteosarcoma in dogs.
To determine which imaging modality best determines the microscopic extent of primary appendicular osteosarcoma in amputated limbs in dogs. Case series. 10 dogs with appendicular osteosarcoma. 10 dogs with appendicular osteosarcoma that did not receive neoadjuvent chemotherapy were treated by use of limb amputation. Amputated limbs were imaged by use of radiography, computed tomography (CT), and magnetic resonance imaging (MRI) and examined microscopically to determine longitudinal extent of neoplastic cell involvement and length of associated intramedullary fibrosis. Changes detected by use of the various imaging studies were compared with the actual tumor length determined microscopically. Data were analyzed to determine which imaging technique most closely predicted tumor length. Measurements obtained by use of craniocaudal radiographic views were most accurate at predicting tumor length but underestimated tumor length substantially in 1 limb and slightly in another limb. Measurements made by use of CT were most accurate at predicting tumor length when intramedullary fibrosis was taken into account but underestimated tumor length in 1 limb. Measurements made by use of MRI were least accurate but did not underestimate tumor length in any of the limbs. Although radiography is used in diagnosis of osteosarcoma in dogs, additional imaging studies to confirm the extent of neoplasia prior to limb-sparing ostectomy may be beneficial. Underestimation of tumor length would be associated with higher incidence of incomplete excision and local tumor recurrence.


Prevalence and associated risk factors of hypertension and pre-hypertension among the adult population: findings from the Dubai Household Survey, 2019.
Minimal data is available on the prevalence and correlates of hypertension and prehypertension in Dubai. The study aims to measure the prevalence of hypertension and pre-hypertension and the associated socio-demographic characteristics, behavioral risk factors and comorbidities among the adult population of Dubai. This study used data from the Dubai Household Health Survey, 2019. A cross-sectional population survey based on a complex stratified cluster random design. The total eligible sample included 2530 adults (18+). Sociodemographic and behavioral factors were considered as independent covariates. The main study outcome variables, pre-hypertension and hypertension, were ordinal, with normotension as the reference group. The overall prevalence of hypertension in adults was 32.5% (38.37% in males and 16.66% in females). Prehypertension was prevalent in 29.8% of adults in Dubai (28.85% in males and 32.31% in females). The multivariate logistic regression analysis revealed that age groups, gender, occupation, and high Body Mass Index were significantly associated with a higher risk of hypertension at the level of P < 0.05. No clear trend toward a higher correlation of hypertension was noted with the increase in age, except after the age of 50 years. Males were five- times more likely to be hypertensive than females. Participants enrolled in skilled and service works had a five times higher risk of hypertension, compared with the reference group (professionals). Obese subjects had a 5.47-times greater correlation of hypertension compared with normal-weight subjects. Physically active individuals were less likely to develop hypertension. For the correlates with prehypertension in the present analysis, skilled and service workers and those working in elementary jobs had a higher risk of prehypertension, compared with the reference group (professionals) Individuals with a status of overweight were associated with a higher prevalence of prehypertension compared with people of normal weight. This study showed a high prevalence of prehypertension and hypertension among adults in Dubai. Some socio-demographic and behavioral risk factors were correlated with prehypertension and hypertension among the studied population. Interventions aiming at increasing public awareness about such risk factors are essential.


Transition-metal-catalyzed asymmetric allylic dearomatization reactions.
Dearomatization reactions serve as powerful methods for the synthesis of highly functionalized, three-dimensional structures starting with simple planar aromatic compounds. Among processes of this type, catalytic asymmetric dearomatization (CADA) reactions are attractive owing to the large number of aromatic compounds that are readily available and the fact that they enable direct access to enantiopure polycycles and spirocycles, which frequently are key structural motifs in biologically active natural products and pharmaceuticals. However, as a consequence of their high stabilities, arenes only difficultly participate in dearomatization reactions that take place with high levels of enantioselectivity. Transition-metal-catalyzed asymmetric allylic substitution reactions have been demonstrated to be powerful methods for enantioselective formation of C-C and C-X (X = O, N, S, etc.) bonds. However, the scope of these processes has been explored mainly using soft carbon nucleophiles, some hard carbon nucleophiles such as enolates and preformed organometallic reagents, and heteroatom nucleophiles. Readily accessible aromatic compounds have been only rarely used directly as nucleophiles in these reactions. In this Account, we present the results of studies we have conducted aimed at the development of transition-metal-catalyzed asymmetric allylic dearomatization reactions. By utilizing this general process, we have devised methods for direct dearomatization of indoles, pyrroles, phenols, naphthols, pyridines, and pyrazines, which produce various highly functionalized structural motifs bearing all-carbon quaternary stereogenic centers in a straightforward manner. In mechanistic investigations of the dearomatization process, we found that the five-membered spiroindolenines serve as intermediates, which readily undergo stereospecific allylic migration to form corresponding tetrahydro-1H-carbazoles upon treatment with a catalytic amount of TsOH. It is worth noting that no notable loss of the enantiomeric excess of the spiroindolenine derivatives takes place during the rearrangement process as a consequence of the intervention of a "three-center-two-electron"-type transition state, a proposal that has gained support from the results of DFT calculations. Equally intriguing, upon tuning of the electronic nature of the tethers, pyrroles or indoles undergo unprecedented Ir or Ru catalyzed intramolecular allylic alkylation promoted dearomatization/migration reactions. The operation of this novel reaction pathway provides additional information leading to a greater mechanistic understanding of the transition-metal-catalyzed enantioselective intramolecular functionalizations of pyrroles and indoles. The combined results of this effort provide not only methods for the efficient synthesis of highly enantioenriched fused and spiro polycycles but also novel strategies in the field of asymmetric catalysis.


Vitamin B12 Added as a Fortificant to Flour Retains High Bioavailability when Baked in Bread.
Vitamin B12 deficiency and depletion are common world-wide, particularly in populations that consume low amounts of animal source foods. WHO and the Food Fortification Initiative recommend that wheat flour be fortified with vitamin B12 in regions where intake of B12 is low. The purpose of this pilot study in five participants was to determine if fortification of flour with B12 produced a bread product with intact B12 still present and to determine if healthy elderly absorb sufficient B12 from bread fortified in this manner. High-purity crystalline 14C-B12 was dissolved in water and added to flour (2 μg B12 /100 g flour) in a bread maker and made into rolls (average 1.17 kBq (31.5 nCi) 14C-B12 in a total of 0.8 µg B12 per roll). Excess 14C first appeared in plasma 4 h after ingestion of the 14C fortified bread and plasma levels returned almost to background by 72 h. Measurement of 14C in plasma verified that the dose was absorbed into the systemic circulation. The cumulative % dose recovered in urine was 4.8-37.0% (mean = 20.1%). Most of the 14C label in the stool appeared by day 4, and the cumulative % dose recovered in stool was 24.5- 43.0% (mean = 31.8%). Bioavailability among the 5 participants, calculated by subtracting the sum of urinary and fecal 14C excretion from the administered dose, was 28.4-63.7% (mean = 48.0%). This study showed that when B12 is added as a fortificant to flour it survives the fermentation and baking processes, and retains ~ 50% bioavailability when fed in small doses to healthy subjects. The Recommended Dietary Allowance of B12 for adults is 2.4 μg/d. This recommendation assumes that usual bioavailability of low doses of the vitamin in the crystalline form is 60%, while for the same amount in foods such as meat and fish it is 50%. Our pilot study shows that B12 added to bread as a fortificant in flour was absorbed as well as it is from endogenous food sources such as meat and fish.


Exaggerated initial response to warfarin following heart valve replacement.
The response to initiation of oral anticoagulants at a usual dose of 5 mg of warfarin has been retrospectively evaluated in patients following heart valve replacement (HVR). Patients starting oral anticoagulants after HVR have a lower target International Normalized Ratio (INR) (1.5 to 2.6) until the pacing wires are removed after operation. The mean daily doses and INR responses after HVR and nonsurgical patients were retrospectively compared during the first 5 days of warfarin treatment. In a subset from both groups, the mean dose of warfarin was correlated with age, body weight, and albumin levels. Eighty-four HVR and 32 nonsurgical patients were studied. The mean daily warfarin dosage was 3.29 +/- 1.29 mg after HVR and 4.96 +/- 1.76 mg in controls (p <0.001), and the mean INRs 2.08 +/- 0.60 and 1.60 +/- 0.54, respectively (p <0.001). Of the HVR patients and controls, 48.8% and 21.8%, respectively, exceeded the upper level of the targeted range (p = 0.014), 86.9% and 40.6% had the dose reduced after the first 5 mg (p <0.001), and 54.7% and 28.1%, respectively, had warfarin withheld for at least 1 day (p = 0.015). Thirty-nine patients were included in the subset analysis. Patients with serum albumin levels <35 g/L required significantly less warfarin (3.84 mg/day) than patients with levels > or =35 g/L (5.37 mg/day; p <0.05). Thus, patients starting oral anticoagulation after HVR are significantly more sensitive to warfarin than nonsurgical patients. Patients with serum albumin levels below the normal values require less warfarin than patients with normal values during the initial phase of treatment.


The kinetics of urinary fumonisin B1 excretion in humans consuming maize-based diets.
Fumonisins (FB) are mycotoxins found in maize. The purpose of this study was to (i) determine the relationship between FB(1) , FB(2) , and FB(3) intake and urinary excretion in humans, (ii) validate a method to isolate urinary FB on C(18) -SPE cartridges for international shipment, and (iii) test the method using samples from Guatemala. Volunteers (n = 10) consumed 206 grams/day of tortillas and biscuits prepared from masa flour and a product containing maize flour. Volunteers estimated their daily urine output and samples were analyzed for FB(1) , FB(2) , and FB(3) and hydrolyzed FB(1) . Only FB(1) was detected in urine suggesting lower absorption of FB(2) and FB(3) . Excretion was highly variable peaking soon after consumption began and decreasing rapidly after consumption stopped. Within 5 days after consumption ended, FB(1) was not detected in urine. In a study with eight volunteers, the average total urinary FB(1) was 0.5% of the intake. FB(1) was detected in 61% (107/177) of the samples collected in Guatemala. The results support the use of urinary FB(1) to assess ongoing exposure in population-based studies. However, relating the FB(1) concentration in urine to dietary intake of FB by individual subjects will be complicated due to interindividual variability and the rapidity of clearance.


Role of Cystatin C in Predicting Disease Activity and Flare-Up in Systemic Lupus Erythematosus: A Longitudinal Follow-Up Study.
We aimed to determine the sensitivity of serum cystatin C (Cys-C) in predicting lupus flare-up. In a longitudinal study, 77 patients were followed-up for up to 15 months. Cys-C, physician global assessment (PGA), and lupus activity index (SLEDAI) were recorded during each visit. Flare-up was defined as an increase ≥4 scores in SLEDAI compared to the last visit. The predictability of flare-up by Cys-C was evaluated by generalized linear-mixed effect model (GLMM) and generalized estimating equation (GEE). Predictive power of Cys-C, SLEDAI, and PGA was compared by the area under the curves (AUC) and application of receiver operating characteristic (ROC) curves. Lupus flare-up was observed in 14 out of 77 patients on the 1st visit, 3 out of 41 patients on the 2nd visit, 2 out of 26 patients on the 3rd visit, 1 out of 14 patients on the 4th visit, and 1 out of 3 patients on the 5th visit. Mean Cys-C levels in patients with flare-up vs. those with no flare-up in the 1st, 2nd, and 3rd visits were 1769 vs. 1603 (P = 0.6), 5701 vs. 2117 (p = 0.2) and 1409 vs. 1731 (p = 0.9), respectively. Cys-C had lower predictive power than PGA and SLEDAI for either flare-up, active nephritis or SLEDAI in GLMM/GEE models. Cys-C also showed lower sensitivity (AUC = 0.701, 95%CI = 0.579-0.823, P = 0.003) than PGA and SLEDAI, to distinguish patients prone to flare-ups. Although Cys-C had some sensitivity for predicting flare-up, active nephritis or SLEDAI, its sensitivity was lower than that in PGA and SLEDAI.


Free radicals as possible mediators of the actions of interferon.
Interferons (IFNs), in addition to their antiviral action, have been shown to inhibit cell proliferation, induce differentiation of some tumor cells, activate NK cells and macrophages, and modulate phagocytosis. The exact mechanism(s) by which IFN can bring about these pleiotropic actions is not known. Recent studies, including our own (presented here), showed that IFN can augment free radical generation in the cells. Free radicals can stimulate lymphocytes mitogenically and activate macrophages and NK cells. It is also known that activated machophages and polymorphs produce oxidative metabolites, such as hydrogen peroxide, which is responsible for sterilizing action against microorganisms and cytotoxic activity against tumor cells. Free radicals are also known to inhibit cell division. Since IFN can augment free radical generation, it is suggested that free radicals mediate some of the actions of IFN.


Studies in osteoarthritis of the hip. II. Osteoarthritis of the hip and leg-length disparity.
An x-ray method is described for the determination of leg-length inequality in the standing subject, Its precision is compared to that of other methods in current use. The geometrical considerations which are inherent in any radiographic method of leg-length determination are summarized. Sixty-seven patients with OA hip were studied; 62 were considered to be idiopathic and 36 of these idiopathic cases were superolateral in type. Measurements in these 36 patients showed significant leg-length disparity, most of the diseased hips being found on the side of the longer leg. If allowance is made for shortening due to disease, the frequency and bias of the disparity are highly significant. The strong association between OA hip of this type and a long leg suggests a causal relationship.


Measurement of RBC agglutination with microscopic cell image analysis in a microchannel chip.
Since Landsteiner's discovery of ABO blood groups, RBC agglutination has been one of the most important immunohematologic techniques for ABO and RhD blood groupings. The conventional RBC agglutination grading system for RhD blood typings relies on macroscopic reading, followed by the assignment of a grade ranging from (-) to (4+) to the degree of red blood cells clumping. However, with the new scoring method introduced in this report, microscopically captured cell images of agglutinated RBCs, placed in a microchannel chip, are used for analysis. Indeed, the cell images' pixel number first allows the differentiation of agglutinated and non-agglutinated red blood cells. Finally, the ratio of agglutinated RBCs per total RBC counts (CRAT) from 90 captured images is then calculated. During the trial, it was observed that the agglutinated group's CRAT was significantly higher (3.77-0.003) than that of the normal control (0). Based on these facts, it was established that the microchannel method was more suitable for the discrimination between agglutinated RBCs and non-agglutinated RhD negative, and thus more reliable for the grading of RBCs agglutination than the conventional method.


Investigation of anteroposterior head-neck responses during severe frontal impacts using a brain-spinal cord complex FE model.
Injuries of the human brain and spinal cord associated with the central nervous system (CNS) are seen in automotive accidents. CNS injuries are generally categorized into severe injuries (AIS 3+). However, it is not clear how the restraint conditions affect the CNS injuries. This paper presents a newly developed three-dimensional (3D) finite element head-neck model in order to investigate the biomechanical responses of the brain-spinal cord complex. The head model consists of the scalp, skull, and a detailed description of the brain including the cerebrum, cerebellum, brainstem with distinct white and gray matter, cerebral spinal fluid (CSF), sagittal sinus, dura, pia, arachnoid, meninx, falx cerebri, and tentorium. Additionally, the neck model consists of the cervical vertebral bodies, intervertebral discs, muscles, ligaments, spinal cord with white and gray matter, cervical pia, and CSF. The two models were linked together to construct a finite element (FE) model of the brain-spinal cord complex. The material stiffness and failure properties of porcine cervical pia mater were measured from uniaxial tensile tests with various strain rates at Yamaguchi University. The head-neck model was validated against three sets of brain test data obtained by Nahum et al. (1977), Trosseille et al. (1992), and Hardy et al. (2001) and two sets of neck test data obtained from Thunnissen et al. (1995) and Pintar et al. (1995). Additionally, a series of parametric studies were conducted to investigate the effects of restraint conditions on CNS injuries. The injury criteria for brain injuries were based on Cumulative Strain Damage Measure, while those for spinal cord injuries were based on the ultimate strains of the spinal cord and pia mater. It was found that the brain-spinal cord model was useful to investigate the relationship between the restraint conditions and CNS injuries.


Chlamydial rRNA operons: gene organization and identification of putative tandem promoters.
We isolated and characterized the rRNA operons of murine Chlamydia trachomatis. By exhaustively screening a library of chlamydial DNA and by blot hybridization of genomic DNA, we showed that there are only two rRNA operons in C. trachomatis. S1 nuclease protection and primer extension analysis were used to map the 5' and 3' ends of the mature 16S and 23S transcripts in both rRNA cistrons and, additionally, to demonstrate the lack of intervening sequences in these genes. The 5' ends of the presumed primary rRNA transcript were located and found to originate at two tandem sites separated by 100 base pairs. The two tandem chlamydial rDNA transcripts were not differentially regulated. Their products were coordinately expressed and were detectable as early as 9 h postinfection. However, the upstream transcript was only 10% as abundant as the downstream transcript. The sequences surrounding the transcription initiation sites bore little homology with each other or with the classic Escherichia coli -10 and -35 promoter sequences. This finding suggests that chlamydial transcription signals may differ from those of previously studied procaryotes.


Individual Radiosensitivity in Oncological Patients: Linking Adverse Normal Tissue Reactions and Genetic Features.
Introduction: Adverse effects of radiotherapy (RT) significantly affect patient's quality of life (QOL). The possibility to identify patient-related factors that are associated with individual radiosensitivity would optimize adjuvant RT treatment, limiting the severity of normal tissue reactions, and improving patient's QOL. In this study, we analyzed the relationships between genetic features and toxicity grading manifested by RT patients looking for possible biomarkers of individual radiosensitivity. Methods: Early radiation toxicity was evaluated on 143 oncological patients according to the Common Terminology Criteria for Adverse Events (CTCAE). An individual radiosensitivity (IRS) index defining four classes of radiosensitivity (highly radiosensitive, radiosensitive, normal, and radioresistant) was determined by a G2-chromosomal assay on ex vivo irradiated, patient-derived blood samples. The expression level of 15 radioresponsive genes has been measured by quantitative real-time PCR at 24 h after the first RT fraction, in blood samples of a subset of 57 patients, representing the four IRS classes. Results: By applying univariate and multivariate statistical analyses, we found that fatigue was significantly associated with IRS index. Interestingly, associations were detected between clinical radiation toxicity and gene expression (ATM, CDKN1A, FDXR, SESN1, XPC, ZMAT3, and BCL2/BAX ratio) and between IRS index and gene expression (BBC3, FDXR, GADD45A, and BCL2/BAX). Conclusions: In this prospective cohort study we found that associations exist between normal tissue reactions and genetic features in RT-treated patients. Overall, our findings can contribute to the identification of biological markers to predict RT toxicity in normal tissues.


Statin Use in Primary Prevention: A Simple Trial-Based Approach Compared With Guideline-Recommended Risk Algorithms for Selection of Eligible Patients.
Cardiovascular disease risk assessment tools help identify individuals likely to benefit from preventative therapies. In this study we compared outcomes using the American College of Cardiology/American Heart Association (ACC/AHA) risk algorithm and the Framingham Risk Score (FRS) tool in the Heart Outcomes Prevention Evaluation (HOPE)-3 study. We compared outcomes using the ACC/AHA algorithm and the FRS with those seen in HOPE-3, which randomized participants to 10 mg rosuvastatin or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; second coprimary outcome additionally included heart failure, cardiac arrest, and revascularization. Relative risks using risk scores were similar to those observed in the HOPE-3. Hazards ratios for the first coprimary outcome according to risk categories of ≤ 10%, 10%-20%, and ≥ 20% using the ACC/AHA algorithm were 0.82 (95% confidence interval [CI], 0.53-1.28), 0.72 (95% CI, 0.53-0.96), and 0.72 (95% CI, 0.55-0.93), and absolute risk reduction (ARR) of 0.18%, 1.33%, and 1.85%, respectively, over a median of 5.6 years. Corresponding results using the FRS were 0.69 (95% CI, 0.36-1.35), 0.73 (95% CI, 0.52-1.01), and 0.75 (95% CI, 0.60- 0.94); and ARR of 1.32%, 0.61%, and 1.43%. Hazard ratios for the second coprimary outcome were 0.77 (95% CI, 0.51-1.14), 0.73 (95% CI, 0.56-0.95), and 0.74 (95% CI, 0.58-0.94); and ARR of 0.36%, 1.49%, and 1.85%, using the ACC/AHA algorithm and 0.76 (95% CI, 0.41-1.41), 0.70 (95% CI, 0.52-0.95), and 0.76 (95% CI, 0.62-0.94); and ARR of 1.08%, 0.83%, and 1.56% using the FRS. The pragmatic HOPE-3 trial approach identifies in an ethnically diverse primary prevention population individuals at intermediate risk who benefit from statin therapy using simple clinical characteristics without the need for complex, currently used risk assessment tools.


High-functioning autism and Asperger's disorder: utility and meaning for families.
We used framework analysis to investigate the utility of pervasive developmental disorder diagnoses, interviewing young people (aged 9-16 years) with high-functioning autistic disorder (AD) and Asperger's disorder (AsD), and their parents. Twenty two participants from ten families described both gains and costs resulting from diagnosis. Perceived advantages of AD and AsD diagnosis were increased understanding and practical support, and parental empowerment. Disadvantages included the effects of stigma and concerns about validity. Participants tended to consider AsD and AD as interchangeable terms. Findings suggest that the utility of AD and AsD depends upon both their validity and how these diagnoses are received in their cultural, economic and legislative context. Improvement of post-diagnostic services will improve the utility of AD and AsD.


Ureteral catheterization studies.
It is apparent that the split function study and renal vein renin determination are complementary and afford valuable information for selecting patients with potentially curable renovascular hypertension. The split function study, when interpreted with the recently defined split function ratio, offers the clinician a highly accurate means of diagnosing significant renal ischemia. Because the split function ratio shows the disparity between the ischemic and contralateral kidney to a greater degree, the chance of misdiagnosis due to laboratory or physician error is minimized. The split function study, however, is of limited value in patients with pyelonephritis since the water- and salt-losing characteristics of the pyelonephritic kidney may mask significant renal ischemia. In these patients, as well as those with a nonfunctioning kidney or hydronephrosis, the renal vein renin determination is the test of choice. In addition, the added morbidity of the split function study is not warranted in a patient with an elevated peripheral renin which, for interpretation, requires an accurate 24 hour urine for sodium, a renal vein renin ratio outside the range of patients with essential hypertension (renal vein renin ratio greater than 1.7) and evidence of suppression of renin secretion from the contralateral kidney. If, however, the renin determination does not afford convincing evidence of significant renal ischemia in a patient with radiographic evidence of renal arterial stenosis, a split function ratio definitely should be determined to more completely define the pathology. The attendant morbidity of a carefully performed split renal function study does not approach the morbidity and mortality associated with unnecessary surgery or inadequately treated hypertension.


[Epidemiologic evaluation of the diagnosis and treatment of extrauterine pregnancy at the ABC Hospital].
The objective of this study was to determine the frequency, risk factors, treatment and morbility of the ectopic pregnancy (EP) at the ABC Hospital. EP cases occurring between January 1992 and May 1995 were studied retrospectively analyzing the next variables: Number of live births and EP's, the patients age, obstetric history, previous EP, sterility, previous pelvic surgeries, gestational age at diagnosis, treatment and complications. The results showed that the frequency of EP was 2.06% There was a positive correlation between EP and infertility, nuliparity, and previous tubal surgery secondary to EP. We concluded that even though EP tends to be diagnosed and treated in early stages, the majority of the surgical procedures lower patients fertility.


Community engagement approaches for Indigenous health research: recommendations based on an integrative review.
Community engagement practices in Indigenous health research are promoted as a means of decolonising research, but there is no comprehensive synthesis of approaches in the literature. Our aim was to assemble and qualitatively synthesise a comprehensive list of actionable recommendations to enhance community engagement practices with Indigenous peoples in Canada, the USA, Australia and New Zealand. Integrative review of the literature in medical (Medline, Cumulative Index to Nursing and Allied Health Literature and Embase) and Google and WHO databases (search cut-off date 21 July 2020). Studies that contained details regarding Indigenous community engagement frameworks, principles or practices in the field of health were included, with exclusion of non-English publications. Two reviewers independently screened the articles in duplicate and reviewed full-text articles. Recommendations for community engagement approaches were extracted and thematically synthesised through content analysis. A total of 63 studies were included in the review, with 1345 individual recommendations extracted. These were synthesised into a list of 37 recommendations for community engagement approaches in Indigenous health research, categorised by stage of research. In addition, activities applicable to all phases of research were identified: partnership and trust building and active reflection. We provide a comprehensive list of recommendations for Indigenous community engagement approaches in health research. A limitation of this review is that it may not address all aspects applicable to specific Indigenous community settings and contexts. We encourage anyone who does research with Indigenous communities to reflect on their practices, encouraging changes in research processes that are strengths based.


Impact of controlled release urea on maize yield and nitrogen use efficiency under different water conditions.
Controlled release urea (CRU) has been widely adopted to increase nitrogen (N) use efficiency and maize production, but the impacts can range widely depending on water availability in the soil. In an experiment using Zhengdan 958 (a popular summer maize hybrid), three levels of water treatments (adequate water condition [W3], which maintained soil moisture at about 75% ± 5% of the soil's field capacity; mild water stress [W2], which maintained moisture content at 55% ± 5% of field capacity; and severe water stress [W1], which had a moisture content of 35% ± 5% of field capacity) and four levels of controlled release urea fertilizer (N0, N1, N2 and N3 were 0, 105, 210 and 315 kg N ha-1, respectively) were compared in a rainout shelter system with soil. The results revealed that CRU had significant effects on maize yields and N use efficiencies under different water conditions. The mean yields increased with increasing water levels and showed significant differences. Under W1, the accumulation of dry matter and N were limited, and N internal efficiency (NIE) and the apparent recovery efficiency of applied N (REN) decreased with N increases; yields of N1, N2, and N3 were similar. Under W2, the dry matter and N accumulation, as well as the yield, showed an increasing trend with an increase in N application, and the NIE and REN of N3 showed no difference from N2. Under W3, yields of N2 and N3 were similar and they were significantly higher than that of N1, but the agronomic N use efficiency (ANUE), REN, and the physiological NUE (PNUE) of N2 were 54.2, 34.9, and 14.4% higher, respectively, than those of N3. N application beyond the optimal N rate did not consistently increase maize yield, and caused a decrease in N use efficiencies. Highest overall dry matter, N accumulation, and yields were observed with N3 under W2, and those showed no differences with N2 and N3 under W3. Under this experimental condition, the CRU of 210 kg ha-1 was optimized when soil moisture content was 75% ± 5% of field capacity, but an N rate of 315 kg ha-1 was superior when soil moisture content during the entire growing season was maintained at 55% ± 5% of field capacity.


Role of endogenous nitric oxide in the brain stem on the rapid adaptation of baroreflex.
It has been shown that nitric oxide in the brain stem plays an important role in the control of sympathetic nerve activity. We examined the role of endogenous nitric oxide in the brain stem in the rapid central adaptation of baroreflex control of sympathetic nerve activity in anesthetized rabbits. Bilateral carotid sinuses were isolated, and a stepwise increase in pressure of 25 or 50 mm Hg for 50 to 60 seconds was applied to the carotid sinuses while the arterial pressure and renal sympathetic nerve activity were recorded. The renal sympathetic nerve activity was inhibited by the stepwise increase in carotid sinus pressure, but thereafter it gradually returned toward the baseline level despite the fact that carotid sinus pressure was kept constant. This procedure was performed after intracisternal injection of N(omega)-nitro-L-arginine methyl ester (L-NAME, 8 micromol), N(omega)-nitro-D-arginine methyl ester (D-NAME, 8 micromol), L-arginine (40 micromol), or the vehicle solution. The magnitude of the immediate and maximal inhibition of renal sympathetic nerve activity caused by a stepwise increase in carotid sinus pressure was similar between the vehicle and L-NAME treatment, but the rate of recovery of the renal sympathetic nerve activity after immediate inhibition was faster after L-NAME than after vehicle. L-Arginine reversed the effects of L-NAME. However, D-NAME or L-arginine alone had no such effects on the rate of recovery of the nerve activity. These results thus suggest that endogenous nitric oxide in the brain stem attenuates rapid adaptation of the arterial baroreflex control of the sympathetic nerve activity in rabbits.


Effects of nano-micelles curcumin-based photodynamic therapy on expression of RUNX2 as an indicator of bone regeneration in orthodontic tooth movement.
The aim was to evaluate the impact of nano-micelles curcumin (NMCur) based photodynamic therapy (PDT) during compressive force application on human PDL-derived fibroblasts (HPDFs) in vitro for up to 6 days on the expression of RUNX2 as an indicator of bone development and remodeling. HPDFs viability during 2 g/cm2 compressive force application was investigated using membrane-impermeable DNA-binding stain propidium iodide (PI) in flow cytometry. Gene and protein expressions of RUNX2 were assessed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and flow cytometry, respectively, following NMCur-PDT at different concentrations of NMCur (25, 50, and 75 µM plus irradiation of 180 mW/cm2 diode laser at the wavelength of 450 ± 10 nm for 5 min) during the static compressive force of 2 g/cm2 on HPDFs via weight approach-based in-vitro loading model up to 6 days. One-way ANOVA and Tukey post hoc tests at a p-value equal to/or less than 0.05 were used to analyze the obtained data. After 6 days of application of compressive force, 99.21 ± 6.12% of HPDFs were PI negative and therefore considered alive, while only 0.89 ± 0.06% of the population were PI positive and considered dead. In comparison with controls (loaded HPDFs), expression of RUNX2 gene was dose-dependent and the highest expression (14.38-fold; P < 0.01) was observed at a concentration of 75 µM NMCur following 5 min of diode laser irradiation (i.e., 75 µM NMCur-PDT) during compressive force application on day 5. The greatest and lowest upregulations of RUNX2 protein were observed in 75 µM NMCur-PDT during compressive force application on HPDFs, on day 5 (3.19-fold; P < 0.01) and day 6 (2.09-fold; P < 0.05), respectively. NMCur-PDT during weight approach-based in-vitro loading model can promote orthodontic tooth movement by upregulating RUNX2 signaling pathway in HPDFs.


Self-compensation of thermally induced depolarization in CaF₂ and definite cubic single crystals.
Compensation of thermally induced depolarization in laser active elements at small birefringence without additional phase elements was proposed and observed experimentally. Requirements to the crystals were formulated. An order of magnitude reduction of depolarization degree was obtained experimentally. A further modification of the scheme was developed.


Real-time PCR detection of gyrA and parC mutations in Streptococcus pneumoniae.
Fluoroquinolone resistance in Streptococcus pneumoniae mainly involves stepwise mutations predominantly in the parC and gyrA genes. We have developed a single-run real-time PCR assay for detection of the four most common mutations in the quinolone resistance-determining regions of these genes. This assay provides a useful tool for both clinical and epidemiological use.


Micro- and Nanopillar Chips for Continuous Separation of Extracellular Vesicles.
Micro- and nanopillar chips are widely used to separate and enrich biomolecules, such as DNA, RNA, protein, and cells, as an analytical technique and to provide a confined nanospace for polymer science analyses. Herein, we demonstrated a continuous accurate and precise separation technique for extracellular vesicles (EVs), nanometer-sized vesicles (typically 50-200 nm) currently recognized as novel biomarkers present in biofluids, based on the principle of electroosmotic flow-driven deterministic lateral displacement in micro- and nanopillar array chips. Notably, the easy-to-operate flow control afforded by electroosmotic flow allowed nanoparticles 50-500 nm in size, including EVs, to be precisely separated and enriched in a continuous manner. By observation of the flow behavior of nanoparticles, we found that electroosmotic flow velocity in the nanopillar arrays did not solely depend on counterion mobility on the surface of nanopillar chips, but rather showed a parabolic flow profile. This hydrodynamic pressure-free and easy-to-use separation and enrichment technique, which requires only electrode insertion into the reservoirs and electric field application, may thus serve as a promising technique for future precise and accurate EV analysis, reflecting both size and composition for research and potential clinical diagnostic applications.


Manganese oxide octahedral molecular sieves: preparation, characterization, and applications.
A thermally stable 3 x 3 octahedral molecular sieve corresponding to natural todorokite (OMS-1) has been synthesized by autoclaving layer-structure manganese oxides, which are prepared by reactions of MnO(4)(-) and Mn(2+) under markedly alkaline conditions. The nature and thermal stability of products depend strongly on preparation parameters, such as the MnO(4)(-)/Mn(2+) ratio, pH, aging, and autoclave conditions. The purest and the most thermally stable todorokite is obtained at a ratio of 0.30 to 0.40. Autoclave treatments at about 150 degrees to 180 degrees C for more than 2 days yield OMS-1, which is as thermally stable (500 degrees C) as natural todorokite minerals. Adsorption data give a tunnel size of 6.9 angstroms and an increase of cyclohexane or carbon tetrachloride uptake with dehydration temperature up to 500 degrees C. At 600 degrees C, the tunnel structure collapses. Both Lewis and Brönsted acid sites have been observed in OMS-1. Particular applications of these materials include adsorption, electrochemical sensors, and oxidation catalysis.


Nucleation-Supersaturation Dual-Drive Crystallization Strategy Enables Efficient Protein Crystallization.
A rational crystallization strategy is essential to obtain high-quality protein crystals, yet the established methods suffer from different limitations arising from the single regulation on either nucleation or supersaturation. Herein, a nucleation-supersaturation dual-driven crystallization (DDC) strategy that realizes synergistic regulation of heterogeneous nucleation sites and solution supersaturation based on dual surface and confinement effects for efficient protein crystallization is reported. This strategy relies on a p(PEGDA-co-DMAA) hydrogel template with pre-filled NaCl under designed concentrations. Once dropping hen egg white lysozyme (HEWL) protein solution on the hydrogel, the wrinkled surface provides numerous nucleation sites, while the internal structure regulates the solution supersaturation in the crystallization region through diffusion. Finally, DDC strategy can create high-quality HEWL crystals with large sizes (100-300 µm), well-defined morphologies (hexagon and tetragon), and a significantly accelerated nucleation time (9-12 times faster than that achieved using the conventional hanging drop method). It also performs well at wider protein concentrations (10-50 mg mL-1 ) and categories (e.g., achieving fast crystallization and large-size crystals of trypsin), therefore demonstrating clear advantages and great potential for efficiently fabricating protein crystals desirable for diverse applications.


Recent advances in our understanding of risk-sensitive foraging preferences.
Many experiments have shown that foraging animals are sensitive to the riskiness, or variance, associated with alternative food sources. For example, when offered a choice of a constant feeding option that always offers three seeds, and a risky option that offers either no seeds or six seeds with equal probability, most animals tested will be either risk-averse or risk-prone, preferring either the fixed or variable option respectively. Whether animals are risk-averse or risk-prone appears to depend on a range of factors, including the energetic status of the forager, the type of variance associated with the feeding options and even the number of feeding options between which the animal is choosing. These behavioural phenomena have attracted much theoretical interest, and a range of different explanations have been suggested, some based on a consideration ofthe psychological mechanisms involved in decision making, and others on a consideration of the Darwinian fitness consequences of risk-averse or risk-prone behaviour for the forager. A brief review of the recent literature on risk-sensitive foraging will be presented, focusing on results from the two experimental systems with which I have been involved: wild rufous hummingbirds (Selasphorus rufus) foraging on artificial flowers; European starlings (Sturnus vulgaris) foraging in operant boxes in the laboratory. It will be argued that to understand the foraging decisions of animals account needs to be taken of both the psychological mechanisms underlying decision-making and the fitness consequences of different decisions for the forager.


High IL2RA/CD25 expression is a prognostic stem cell biomarker for pediatric acute myeloid leukemia without a core-binding factor.
CD25 is an aberrant marker expressed on the leukemic stem cell (LSC) surface and an immunotherapy target in acute myeloid leukemia (AML). However, the clinical prevalence and significance of CD25 expression in pediatric AML are unknown. High IL2RA/CD25 expression in pediatric AML showed a stem cell-like phenotype, and elevated CD25 expression was associated with lower overall survival (p < .001) and event-free survival (p < .001) in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study. This finding was reproduced in AML without a core-binding factor in the Children's Oncology Group study cohort. High CD25 expression has prognostic significance in pediatric AML.


[Congenital mega-urethra. Comments apropos of a case report].
Congenital megalourethra is a malformation of the male urethra with a major dilatation of its penile part without obstruction downwards. It is either due to hypoplasia ore agenesia of spongy tissue. Two types are described, scaphoide and fusiform types, according to the presence or the absence of erectile tissue. Megalourethra is a rare condition, and 55 cases were previously reported until 1987. A new case of this severe anomaly is reported and management discussed.


Alterations in estrogen levels during development affects the skeleton: use of an animal model.
Exposure to estrogens during various stages of development has been shown to irreversibly influence responsive target organs. The recent finding of the presence of estrogen receptor in both osteoblasts and osteoclasts has suggested a direct role of steroid hormones on bone tissue. Furthermore, estrogens have important effects on bone turnover in both humans and experimental animal models. Thus, this tissue is now regarded as a specific estrogen target tissue. To investigate whether a short-term developmental exposure to estrogens can influence bone tissue, we have injected female mice with diethylstilbestrol (DES) from day 1 through day 5 of life. Additionally, a group of pregnant female mice were injected with different doses of DES from day 9 through 16 of pregnancy. Mice were then weaned at 21 days of age, and effects on bone tissue of the female mice were evaluated in adulthood (7-12 months of age). These short-term treatments did not affect body weight of exposed mice. However, a dose-dependent increase in bone mass, both in the trabecular and compact compartments, was observed in the DES-exposed female offspring. Furthermore, femurs from DES-exposed females were shorter than femurs from controls. A normal skeletal mineralization accompanied these changes in the bone tissue. In fact, a parallel increase in total calcium content of the skeleton was found in concomitance with the increase in bone mass. Estrogen treatment induced an increase in the amount of mineralized skeleton when compared to untreated controls. In summary, this report shows that alterations of estrogen levels during development can influence the early phases of bone tissue development inducing permanent changes in the skeleton. These changes appear to be related to bone cell programming in early phases of life.


Improving depth resolution of diffuse optical tomography with a layer-based sigmoid adjustment method.
Diffuse optical tomography (DOT) has much lower sensitivity in deep tissues than in superficial tissues, which leads to poor depth resolution. In this paper, a layer-based sigmoid adjustment (LSA) method is proposed for reducing sensitivity contrast in the depth dimension. Using this method, differences in image quality between layers can be effectively reduced. As a result, positioning errors of less than 3 mm can be obtained in the depth dimension for all depths from -1 cm to -3 cm.


Sexual behavior: Extreme reduction of postejaculatory refractory period by midbrain lesions in male rats.
The refractory period that characteristically follows ejaculation was abolished or significantly reduced by rostral midbrain lesions in male rats. The postejaculatory vocalization was also abolished or reduced, but other aspects of copulatory performance were unaffected. The results were attributed to disruption of biogenic amine pathways that pass from the ventral part of the rostral midbrain into the posterior hypothalamus.


Photonic band engineering in absorbing media for spectrally selective optoelectronic films.
Spectrally selective materials are of great interest for optoelectronic devices in which wavelength-selectivity of the photoactive material is necessary for applications such as multi-junction solar cells, narrow-band photodetectors, transparent photovoltaics, and tailored emission sources. Achieving controlled transparency or opacity within multiple wavelength bands in the absorption, reflection, and transmission spectra are difficult to achieve in traditional semiconductors that typically absorb at all energies above their electronic band gap and is generally realized by the use of external bandpass filters. Here, we propose an alternate method for achieving spectral selectivity in optoelectronic thin films: the use of photonic band engineering within the absorbing region of a semiconductor in which resonant photonic bands are strongly coupled to the external reflectivity and transmission spectra. As a first step, we use optical simulations to systematically study the effect of material absorption on the properties of the photonic bands in a photonic crystal slab structure. We find that adding a weak loss to the materials model does not appreciably change the frequencies of the photonic bands but does reduce the quality factor of the associated photonic modes. Critically, the radiating photonic bands induce strong Fano resonance features in the transmission and reflection spectra, even in the presence of material absorption, due to coupling between the bands and external electromagnetic plane waves. These resonances can be tuned by adjusting the photonic crystal structural properties to induce spectral selectivity in the absorbing region of semiconductors. Lastly, we demonstrate this tuning method experimentally by fabricating a proof-of-principle photonic structure consisting of a self-assembled polystyrene bead monolayer infiltrated with PbS CQDs that displays both near-infrared absorption enhancement and visible transparency enhancement over a homogeneous control film, qualitatively matching predictions and showing promise for optoelectronic applications.


Treatment of visceral leishmaniasis with sodium stibogluconate in Sudan: management of those who do not respond.
Almost all (98%) of 1593 visceral leishmaniasis (VL) patients treated with sodium stibogluconate (Pentostam; Wellcome) in Sudan between 1989 and 1995 and follow-up responded well to treatment. However, the other 33 patients, all of whom were seronegative for HIV, showed partial or no response. The two main causes of unresponsiveness were primary drug resistance (39.3%) and low drug dosages given at peripheral dispensaries (30.3%). All of those who had been sub-optimal doses were cured when adequate doses of the drug were given. A third cause was concurrent disease, particularly pulmonary tuberculosis (18%). With treatment of the concurrent disease, patients responded well to Pentostam. Eight patients who failed to respond to repeated courses of Pentostam did not benefit from pentamidine or sterol inhibitors. Three of these patients responded to liposomal amphotericin B, two responded to splenectomy in association with Pentostam therapy, and three died. Pentostam, given in adequate doses, still appears to be the drug of choice for the treatment of VL in the Sudan Liposomal amphotericin B is a suitable second-line drug.


The biology and medical implications of interleukin-6.
Cytokines are soluble mediators, which aid cell-to-cell communication in immune responses, and interleukin-6 (IL-6) is a prototypical cytokine featuring redundant and pleiotropic activity. The complete elucidation of the IL-6-mediated signal transduction system has provided a molecular basis for the characteristic features of cytokines. When tissue damage or inflammation due to infections or injuries occurs, IL-6 synthesis is promptly induced, contributing to the host defense through the stimulation of acute-phase immune reactions and hematopoiesis. The production of IL-6 is terminated when tissue homeostasis is restored. The synthesis of IL-6 is tightly regulated transcriptionally and posttranscriptionally. However, the dysregulated continual synthesis of IL-6 has been implicated in the development of various diseases, including autoimmune and chronic inflammatory diseases and cancers. Clinical trials using the humanized anti-IL-6 receptor monoclonal antibody tocilizumab have demonstrated the efficacy of IL-6 blockade for the treatment of refractory inflammatory diseases, such as rheumatoid arthritis, systemic juvenile idiopathic arthritis, and Castleman disease. Moreover, favorable results from the off-label use of tocilizumab strongly suggest that it may be applicable for the treatment of other refractory immune-mediated diseases, including cancer. Therefore, the mechanisms for the dysregulated synthesis of IL-6 need to be elucidated to understand the pathogenesis of the resultant diseases and to facilitate the development of effective therapeutic strategies.


[Music dynamics: New methodological proposal at work with pregnant women during prenatal care].
It is qualitative research, using and Creative and Sensible Method and Content Analysis. It aimed to find out how pregnant women experience the use of music to understand the gestational process. Participants were seven primiparous pregnant women, during the third trimester of pregnancy. The study happened in the Basic Health Center in Ponta Grossa, Paraná, Brazil. For data collection, creativity and sensitivity dynamics were employed, called musical dynamics, as well as a semi-structured interviews and observation. Results have showed that music can be employed as a facilitating resource in the teaching/learning process, favoring educators/nurses in their educational activities.


The effects of diet on DNA bulky adduct levels are strongly modified by GSTM1 genotype: a study on 634 subjects.
Frequent consumption of fresh fruit and vegetables, and polymorphisms in the detoxifying enzyme glutathione S-transferase M1 (GSTM1) and other metabolic genes have been shown to modulate cancer risk at some sites. We have shown recently that DNA adducts, a reliable indicator of genotoxic damage and, possibly, of cancer risk, are modulated by plasma levels of selected micronutrients. Here we further investigate the association between DNA adduct levels and consumption of major food groups and foods, and the estimated dietary intake of nutrients, taking into account the possible modifying effect of metabolic polymorphisms, in a larger sample of 634 healthy adults enrolled in a prospective study in Italy. DNA adducts and five polymorphic metabolic genotypes (GSTM1, GSTT1, NAT2, CYP1A1 and MTHFR) were determined in peripheral leukocytes by using 32P-postlabeling technique and PCR methods. DNA bulky adducts (mean: 7.82 +/- 0.40/10(9) nt) were detected in 482/634 samples (76.0%). Overall, DNA adduct levels were significantly and inversely associated with the intake of raw leafy vegetables (P = 0.02), non-citrus fruits (P = 0.04), potassium (P = 0.01) and beta-carotene (P = 0.05). No association was evident with the five genotypes. Stratification by GSTM1 genotype showed strong inverse associations of DNA adduct levels with increasing consumption of all vegetables combined (P = 0.04), leafy vegetables (P = 0.004), raw leafy vegetables (P = 0.002) and fish (P = 0.03) among 307 GSTM1-null subjects; strong inverse associations also emerged with estimated dietary intakes of beta-carotene (P = 0.004), vitamin E (P = 0.004), niacin (P = 0.02) and potassium (P = 0.01). In contrast, no association emerged among 295 subjects with a GSTM1-wild genotype. Overall, statistically significant interactions in predicting DNA adduct levels were observed between the GSTM1-null genotype and consumption of leafy vegetables (P = 0.01), white meat (P = 0.04), and intake of vitamin C (P = 0.04), vitamin E (P = 0.05) and beta-carotene (P = 0.02). Our results suggest that the role of a diet rich in antioxidants in preventing or reducing DNA adduct formation is restricted to subjects lacking the detoxifying activity of GSTM1 isoenzyme (approximately 50% of the general population).


Evolution of R1 and R2 in the rDNA units of the genus Drosophila.
R1 and R2 are non-long terminal repeat (non-LTR) retrotransposable elements that specifically insert in the 28S ribosomal RNA (rRNA) genes of insects. Using the Drosophila genus, which includes some of the best characterized insect taxa, we have conducted a number of studies on the evolution of these elements. We find that R1 and R2 are subject to the same recombinational forces that give rise to the concerted evolution of the rDNA units. The turnover of R1 and R2 elements can be readily documented in different strains of D. melanogaster using 5' truncated elements as restriction-length polymorphisms. This turnover leads to uniform populations of elements with nucleotide sequence divergence of different copies averaging only 0.23% for the R2 and 0.47% for the R1 elements. Molecular phylogenetic analysis of elements from 16 different species of Drosophila suggests that these elements have been stable components of the rDNA locus for the 50-70 million year history of the Drosophila genus. Using changes at synonymous positions within the protein-encoding regions as estimates of the baseline substitution rate, it could be shown that R1 and R2 are evolving at rates similar to that of typical protein encoding genes provided corrections are made for the low codon bias of the elements. R1 and R2 are clearly well-adapted for their existence in the rDNA units of their host.


A review of pesticides sorption in biochar from maize, rice, and wheat residues: Current status and challenges for soil application.
The use of pesticides has been increasing in recent years for maintaining traditional agricultural practices. However, these chemicals are associated with several environmental impacts, demanding urgent remediation techniques. Biochar is a carbonaceous material produced by pyrolysis that has the potential for pesticide sorption and remediation. In this context, this interdisciplinary review systematically assessed the state of the knowledge of crop residues to produce biochar for pesticide sorption. We focused on maize, rice, and wheat residues since these are the three most-produced grains worldwide. Besides, we evaluated different biochar handling, storage, and soil dispersion techniques to ease its implementation in agriculture. In general, pyrolysis temperature influences biochar characteristics and its potential for pesticide sorption. Furthermore, biochar amended soils had greater pesticide sorption capacity, limiting potential leaching and runoff. Most studies showed that the feedstock and specific surface area influence the biochar sorption properties, among other factors. Also, biochar reduces pesticides' bioavailability, decreasing their toxicity to soil organisms and improving soil fertility and crop yields. Nonetheless, the retrieved papers assessed only 21 pesticides, mainly consisting of lab-scale batch experiments. Therefore, there is still a gap in studies evaluating biochar aging, its potential desorption, pesticide co-contaminations, the associated microbiological processes, and field applications. Determining flow properties for biochars of different sizes and pellets is vital for reliable handling equipment design, and performing techno-economic assessment under different farm contexts is encouraged. Ultimately, coupling biochar production with residue management could address this challenge on sustainable agricultural systems.


Computer imaging and workflow systems in the business office.
Computer imaging and workflow technology automates many business processes that currently are performed using paper processes. Documents are scanned into the imaging system and placed in electronic patient account folders. Authorized users throughout the organization, including preadmission, verification, admission, billing, cash posting, customer service, and financial counseling staff, have online access to the information they need when they need it. Such streamlining of business functions can increase collections and customer satisfaction while reducing labor, supply, and storage costs. Because the costs of a comprehensive computer imaging and workflow system can be considerable, healthcare organizations should consider implementing parts of such systems that can be cost-justified or include implementation as part of a larger strategic technology initiative.


Loss of c-Jun N-terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma.
Targeted inhibition of the c-Jun N-terminal kinases (JNKs) has shown therapeutic potential in intrahepatic cholangiocarcinoma (CCA)-related tumorigenesis. However, the cell-type-specific role and mechanisms triggered by JNK in liver parenchymal cells during CCA remain largely unknown. Here, we aimed to investigate the relevance of JNK1 and JNK2 function in hepatocytes in two different models of experimental carcinogenesis, the dethylnitrosamine (DEN) model and in nuclear factor kappa B essential modulator (NEMO)hepatocyte-specific knockout (Δhepa) mice, focusing on liver damage, cell death, compensatory proliferation, fibrogenesis, and tumor development. Moreover, regulation of essential genes was assessed by reverse transcription polymerase chain reaction, immunoblottings, and immunostainings. Additionally, specific Jnk2 inhibition in hepatocytes of NEMOΔhepa/JNK1Δhepa mice was performed using small interfering (si) RNA (siJnk2) nanodelivery. Finally, active signaling pathways were blocked using specific inhibitors. Compound deletion of Jnk1 and Jnk2 in hepatocytes diminished hepatocellular carcinoma (HCC) in both the DEN model and in NEMOΔhepa mice but in contrast caused massive proliferation of the biliary ducts. Indeed, Jnk1/2 deficiency in hepatocytes of NEMOΔhepa (NEMOΔhepa/JNKΔhepa) animals caused elevated fibrosis, increased apoptosis, increased compensatory proliferation, and elevated inflammatory cytokines expression but reduced HCC. Furthermore, siJnk2 treatment in NEMOΔhepa/JNK1Δhepa mice recapitulated the phenotype of NEMOΔhepa/JNKΔhepa mice. Next, we sought to investigate the impact of molecular pathways in response to compound JNK deficiency in NEMOΔhepa mice. We found that NEMOΔhepa/JNKΔhepa livers exhibited overexpression of the interleukin-6/signal transducer and activator of transcription 3 pathway in addition to epidermal growth factor receptor (EGFR)-rapidly accelerated fibrosarcoma (Raf)-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) cascade. The functional relevance was tested by administering lapatinib, which is a dual tyrosine kinase inhibitor of erythroblastic oncogene B-2 (ErbB2) and EGFR signaling, to NEMOΔhepa/JNKΔhepa mice. Lapatinib effectively inhibited cystogenesis, improved transaminases, and effectively blocked EGFR-Raf-MEK-ERK signaling. Conclusion: We define a novel function of JNK1/2 in cholangiocyte hyperproliferation. This opens new therapeutic avenues devised to inhibit pathways of cholangiocarcinogenesis.


Nucleotide sequence of the bacteriophage T4 gene 57 and a deduced amino acid sequence.
A 693 basepair cloned fragment of bacteriophage T4 DNA, which supports specifically growth of T4 amber mutants in gene 57, has been sequenced. A polypeptide can be deduced from this sequence, that is either 54 or 60 amino acids long depending which of two AUG codons, 18 nucleotides apart, are used for initiation. The size of this deduced polypeptide is compatible with the size of a single polypeptide (based on polyacrylamide gel electrophoresis) synthesized in vivo in E. coli under the direction of the cloned T4 DNA fragment.


External quality assessment for detection of colorectal cancer by Septin9 DNA methylation in clinical laboratories.
The incidence and mortality rate of colorectal cancer (CRC) are increasing worldwide. Septin9 methylated (mSEPT9) DNA in circulation can be used as a non-invasive detection method to assist in the early diagnosis of CRC; however, the detection methods and procedures are complicated. This study aimed to evaluate the ability of clinical laboratories to detect Septin9 methylation in plasma cell-free DNA (cfDNA). We prepared a sample panel consisting of positive and negative Septin9 methylation cells and CRC cells. Three positive samples with different methylation levels, one negative sample and one duplicate sample, two samples containing interference, three different CRC cell samples, and a fictitious case report were included. The panel was distributed to 59 laboratories for mSEPT9 analysis, result comparison, and scoring. The sample panel, validated by National Medical Products Administration (NMPA)-approved tests and targeted bisulfite sequencing, met expectations and could be used for external quality assessment (EQA). Among the 59 laboratories, 55 (93.22%) correctly reported the mSEPT9 results for all samples, while four (6.79%) reported 15 false negatives and were considered improvable. All false negatives originated from four laboratories using laboratory-developed tests (LDTs), with three failing to detect weakly positive samples, samples containing interference, and samples from different CRC cells, and one reported erroneous results on all positive samples. Our results illustrated that the detection of mSEPT9 in cfDNA is satisfactory in China. EQA is indispensable because it can help improve the diagnostic capability and quality management of the laboratories, and provide suggestions for the problems existing in mSEPT9 detection.


Barrios and burbs: residential context and health-risk behaviors among Angeleno adolescents.
The increasing size of the Latino immigrant population in the United States underscores the need for a more complete understanding of the role that social context plays in influencing the health of immigrants and their children. This analysis explores the possibility that residential location influences the health-risk behaviors of Latino youth in Los Angeles County, California. The data come from the Los Angeles Family and Neighborhood Survey. We apply multivariate, multilevel Rasch models to two scales of adolescent health-risk behaviors (substance use and delinquency). The findings suggest that residence in Census tracts characterized by above-county-average levels of Latinos and above-county-average levels of poverty is associated with increased odds of health-risk behaviors for Latino adolescents, particularly for those born in the United States. The findings lend support to the contention, put forth in the segmented assimilation literature, that disadvantaged urban contexts increase the risk that U.S.-born children of immigrants will experience downward assimilation.


Non-soy legume consumption lowers cholesterol levels: a meta-analysis of randomized controlled trials.
Studies evaluating the effect of legume consumption on cholesterol have focused on soybeans, however non-soy legumes, such as a variety of beans, peas, and some seeds, are commonly consumed in Western countries. We conducted a meta-analysis of randomized controlled trials evaluating the effects of non-soy legume consumption on blood lipids. Studies were retrieved by searching MEDLINE (from January 1966 through July 2009), EMBASE (from January 1980 to July 2009), and the Cochrane Collaboration's Central Register of Controlled Clinical Trials using the following terms as medical subject headings and keywords: fabaceae not soybeans not isoflavones and diet or dietary fiber and cholesterol or hypercholesterolemia or triglycerides or cardiovascular diseases. Bibliographies of all retrieved articles were also searched. From 140 relevant reports, 10 randomized clinical trials were selected which compared a non-soy legume diet to control, had a minimum duration of 3 weeks, and reported blood lipid changes during intervention and control. Data on sample size, participant characteristics, study design, intervention methods, duration, and treatment results were independently abstracted by 2 investigators using a standardized protocol. Data from 10 trials representing 268 participants were examined using a random-effects model. Pooled mean net change in total cholesterol for those treated with a legume diet compared to control was -11.8 mg/dL (95% confidence interval [CI], -16.1 to -7.5); mean net change in low-density lipoprotein cholesterol was -8.0mg/dL (95% CI, -11.4 to -4.6). These results indicate that a diet rich in legumes other than soy decreases total and LDL cholesterol.


Distinct microbial communities in the active and permafrost layers on the Tibetan Plateau.
Permafrost represents an important understudied genetic resource. Soil microorganisms play important roles in regulating biogeochemical cycles and maintaining ecosystem function. However, our knowledge of patterns and drivers of permafrost microbial communities is limited over broad geographic scales. Using high-throughput Illumina sequencing, this study compared soil bacterial, archaeal and fungal communities between the active and permafrost layers on the Tibetan Plateau. Our results indicated that microbial alpha diversity was significantly higher in the active layer than in the permafrost layer with the exception of fungal Shannon-Wiener index and Simpson's diversity index, and microbial community structures were significantly different between the two layers. Our results also revealed that environmental factors such as soil fertility (soil organic carbon, dissolved organic carbon and total nitrogen contents) were the primary drivers of the beta diversity of bacterial, archaeal and fungal communities in the active layer. In contrast, environmental variables such as the mean annual precipitation and total phosphorus played dominant roles in driving the microbial beta diversity in the permafrost layer. Spatial distance was important for predicting the bacterial and archaeal beta diversity in both the active and permafrost layers, but not for fungal communities. Collectively, these results demonstrated different driving factors of microbial beta diversity between the active layer and permafrost layer, implying that the drivers of the microbial beta diversity observed in the active layer cannot be used to predict the biogeographic patterns of the microbial beta diversity in the permafrost layer.