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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.comnet.2009.07.008 Byline: Jing Fu, Peter Sjodin, Gunnar Karlsson Keywords: Routing convergence; Centralized control; Link-state routing protocols Abstract: The decentralized control scheme for routing in current IP networks has been questioned, and a centralized routing scheme has been proposed as an alternative. In this paper, we compare the convergence of centralized control scheme with decentralized link-state routing protocols. We first review the architectural advantages and challenges of centralized control. Thereafter, we identify and discuss the components of the convergence time in both schemes. We present how to achieve fast routing convergence in networks with centralized control. In particular, we analyze how to distribute forwarding information efficiently. Finally, we perform simulation studies on the convergence time for both real and synthetic network topologies and study the impact of control element location, link weights, and number of failures on the convergence time. The results show that the centralized control scheme can provide faster routing convergence than link-state routing protocols. Author Affiliation: KTH, Royal Institute of Technology, SE-100 44 Stockholm, Sweden Article History: Received 9 July 2008; Revised 18 February 2009; Accepted 16 July 2009 Article Note: (miscellaneous) Responsible Editor: S. Kasera

Due to differences in chemical properties and half-lives, best practices for exposure assessment may differ for legacy versus novel brominated flame retardants (BFRs). Our objective was to identify the environment matrix that best predicted biomarkers of children's BFR exposures. Paired samples were collected from children aged 3–6 years and their homes, including dust, a small piece of polyurethane foam from the furniture, and a handwipe and wristband from each child. Biological samples collected included serum, which was analyzed for 11 polybrominated diphenyl ethers (PBDEs), and urine, which was analyzed for tetrabromobenzoic acid (TBBA), a metabolite of 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB). Significant positive correlations were typically observed between BFRs measured in dust, handwipes and wristbands, though wristbands and handwipes tended to be more strongly correlated with one another than with dust. PBDEs, EH-TBB and BEH-TEBP were detected in 30% of the sofa foam samples, suggesting that the foam was treated with PentaBDE or Firemaster® 550/600 (FM 550/600). PBDEs were detected in all serum samples and TBBA was detected in 43% of urine samples. Statistically significant positive correlations were observed between the environmental samples and serum for PBDEs. Urinary TBBA was 6.86 and 6.58 times more likely to be detected among children in the highest tertile of EH-TBB exposure for handwipes and wristbands, respectively (95 % CI: 2.61, 18.06 and 1.43, 30.05 with p < 0.001 and 0.02, respectively). The presence of either PentaBDE or FM 550/600 in furniture was also associated with significantly higher levels of these chemicals in dust, handwipes and serum (for PBDEs) and more frequent detection of TBBA in urine (p = 0.13). Our results suggest that children are exposed to a range of BFRs in the home, some of which likely originate from residential furniture, and that silicone wristbands are a practical tool for evaluating external exposure to both legacy and novel BFRs. [Display omitted] • EH-TBB and BEH-TEBP, along with BDE-209, BDE-47 and BDE-99, were the most abundant BFRs in environmental samples. • PentaBDE and Firemaster® 550/600 were the most common BFRs detected in sofa foam. • BFRs in foam were associated with higher levels of exposure biomarkers. • Wristbands are an effective exposure assessment tools for a variety of BFRs. [ABSTRACT FROM AUTHOR]

We have examined the murine embryonic expression pattern of the cell adhesion molecule R-cadherin in muscle, kidney, thymus, and lung. In developing muscle, R-cadherin was first seen at 10.5-11.5 days postcoitum in the somitic myotome. Consistently, we found R-cadherin expressed at the highest levels in the myotome, early skeletal muscle, and smooth muscle (both vascular and visceral), while very low levels of R-cadherin were detected in the heart. The expression pattern and subcellular localization of R-cadherin in developing skeletal muscle indicate a possible role in myoblast cell-cell interactions during both primary and secondary myogenesis. In the developing kidney, R-cadherin was first detected at 10.5 days postcoitum in the mesonephric epithelial tubule cells. In the metanephric kidney, it was specifically expressed in the pretubular aggregates, comma- and S-shaped bodies, proximal tubules, and collecting ducts. Thus, in the kidney, R-cadherin was associated with the mesenchymal - epithelial transition. R-cadherin was also found in other developing epithelia, for example in the thymic epithelial cells. In the lung, R-cadherin was expressed at the highest levels in the smooth muscle surrounding the lung epithelial tubules. To test whether R-cadherin can direct formation of tissues, we constitutively expressed R-cadherin in E-cadherin-/- ES cells and examined histogenesis in teratomas derived from these cells. R-cadherin exclusively rescued formation of striated muscle and epithelia in the teratomas. R-cadherin's ability to form epithelia in vivo was substantiated by its ability to rescue formation of cystic embryoid bodies in vitro. By comparing our data with the previously reported embryonic expression patterns and histogenetic activities of E- and N-cadherin, we suggest that R-cadherin plays an important role in the formation of striated muscle and possibly also of epithelia.

Early-childhood biomonitoring of persistent organic pollutants (POPs) is challenging due to the logistic and ethical limitations associated with blood sampling. We investigated using faeces as a non-invasive matrix to estimate internal exposure to POPs. The concentrations of selected POPs were measured in matched plasma and faecal samples collected from 20 infants/toddlers (aged 13 ± 4.8 months), including a repeat sample time point for 13 infants (~ 5 months apart). We observed higher rates of POP quantification in faeces (2 g dry weight) than in plasma (0.5 mL). Among the five chemicals that had quantification frequencies over 50% in both matrices, except for HCB, log concentration in faeces (C f ) and blood (C b ) were correlated (r > 0.74, P < 0.05) for p . p ′-dichlorodiphenyldichloroethylene ( p , p ′-DDE), 2,3′,4,4′,5-pentachlorobiphenyl (PCB118), 2,2′,3,4,4′,5′-pentachlorobiphenyl (PCB138) and 2,2′,4,4′,5,5′-pentachlorobiphenyl (PCB153). We determined faeces:plasma concentration ratios (K fb ), which can be used to estimate C b from measurements of C f for infants/toddlers. For a given chemical, the variation in K fb across individuals was considerable (CV from 0.46 to 0.70). Between 5% and 50% of this variation was attributed to short-term intra-individual variability between successive faecal samples. This variability could be reduced by pooling faeces samples over several days. Some of the remaining variability was attributed to longer-term intra-individual variability, which was consistent with previously reported observations of a decrease in K fb over the first year of life. The strong correlations between C f and C b demonstrate the promise of using faeces for biomonitoring of these compounds. Future research on the sources of variability in K fb could improve the precision and utility of this technique. [ABSTRACT FROM AUTHOR]

Objective To assess the impact of prenatal exposure to polybrominated diphenyl ethers (PBDEs) and polyfluoroalkyl chemicals (PFCs) on early infant neurobehavior. Study design In a cohort of 349 mother/infant pairs, we measured maternal serum concentrations during pregnancy of PBDEs, including BDE-47 and other related congeners, as well as 2 common PFCs, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid. When the infants were 5 weeks of age, we measured their neurobehavior by using the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS). Results Neither PBDE nor PFC exposures during gestation were associated with the 11 individual NNNS outcomes included in our study; however, when we used latent profile analysis to categorize infants into neurobehavioral profiles based on performance on the NNNS (social/easygoing, high arousal/difficult, or hypotonic), a 10-fold increase in prenatal PFOA concentrations significantly increased the odds of being categorized as hypotonic compared with social/easygoing (aOR 3.79; 95% CI 1.1-12.8). Conclusions Infants of mothers with greater serum concentrations of PFOA during pregnancy were more likely to be categorized as hypotonic. No association between PBDE concentrations and hypotonia was found. Additional studies should further investigate possible associations of prenatal PFC exposure and muscle tone in infants and children. [ABSTRACT FROM AUTHOR]

An aminoquinazoline series targeting the essential bacterial enzyme GlmU (uridyltransferase) were previously reported ( Biochem. J. 2012 , 446 , 405). In this study, we further explored SAR through a combination of traditional medicinal chemistry and structure-based drug design, resulting in a novel scaffold (benzamide) with selectivity against protein kinases. Virtual screening identified fragments that could be fused into the core scaffold, exploiting additional binding interactions and thus improving potency. These efforts resulted in a hybrid compound with target potency increased by a 1000-fold, while maintaining selectivity against selected protein kinases and an improved level of solubility and protein binding. Despite these significant improvements no significant antibacterial activity was yet observed within this class. [ABSTRACT FROM AUTHOR]

Twenty-four hour PM2.5 samples from a rural site, an urban site, and a suburban site (next to a major highway) in the metropolitan Atlanta area in December 2003 and June 2004 were analyzed for 19 polycyclic aromatic hydrocarbons (PAH). Extraction of the air samples was conducted using an accelerated solvent extraction method followed by isotope dilution gas chromatography/mass spectrometry determination. Distinct seasonal variations were observed in total PAH concentration (i.e. significantly higher concentrations in December than in June). Mean concentrations for total particulate PAHs in December were 3.16, 4.13, and 3.40ngm−3 for the urban, suburban and rural sites, respectively, compared with 0.60, 0.74, and 0.24ngm−3 in June. Overall, the suburban site, which is impacted by a nearby major highway, had higher PAH concentration than did the urban site. Total PAH concentrations were found to be well correlated with PM2.5, organic carbon (OC), and elemental carbon (EC) in both months (r 2 =0.36–0.78, p <0.05), although the slopes from the two months were different. PAHs represented on average 0.006% of total PM2.5 mass and 0.017% of OC in June, compared with 0.033% of total PM2.5 and 0.14% of OC in December. Total PAH concentrations were also correlated with potassium ion (r 2 =0.39, p =0.014) in December, but not in June, suggesting that in winter biomass burning can potentially be an important source for particulate PAH. Retene was found at a higher median air concentration at the rural site than at the urban and suburban sites—unlike the rest of the PAHs, which were found at lower levels at the rural site. Retene also had a larger seasonal difference and had the weakest correlation with the rest of the PAHs measured, suggesting that retene, in particular, might be associated with biomass burning. [Copyright &y& Elsevier]

Childhood conduct disorder (CD) and adult psychopathic traits according to the Psychopathy Checklist Revised (PCL-R) were the closest psychiatric covariates to repeated violent crimes and aggression among offenders under forensic psychiatric investigation in Sweden. As psychopathy is not included in the present psychiatric diagnostic systems, we compared total and factor PCL-R scores to Axis I disorders, including childhood-onset neuropsychiatric disorders, and to Axis II personality disorders, to establish the convergence of psychopathic traits with other psychiatric diagnoses, and to identify possible unique features. Psychopathic traits were positively correlated with bipolar mood disorder and negatively with unipolar depression. The total PCL-R scores as well as the Factor 2 (unemotionality) and Factor 3 (behavioral dyscontrol) scores were significantly correlated with attention-deficit/hyperactivity disorder, Asperger's syndrome/high-functioning autistic traits, CD, substance abuse, and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Cluster B personality disorders. The interpersonal Factor 1 showed none of these correlations and may capture features that are specific to psychopathy, distinguishing core psychopathy from other diagnostic definitions. [ABSTRACT FROM AUTHOR]

To describe lifetime mental disorders among perpetrators of severe inter-personal crimes and to identify the problem domains most closely associated with aggression and a history of repeated violent criminality, we used structured interviews, clinical assessments, analyses of intellectual functioning, medical and social files, and collateral interviews in 100 consecutive subjects of pretrial forensic psychiatric investigations. Childhood-onset neuropsychiatric disorders [attention-deficit/hyperactivity disorder (AD/HD), learning disability, tics and autism spectrum disorders] affected 55% of the subjects and formed complex comorbidity patterns with adult personality disorders [including psychopathic traits according to the Psychopathy Checklist (PCL-R)], mood disorders and substance abuse. The closest psychiatric covariates to high Lifetime History of Aggression (LHA) scores and violent recidivism were the PCL-R scores and childhood conduct disorder (CD). Behavioral and affective PCL-R factors were closely associated with childhood AD/HD, CD, and autistic traits. The results support the notion that childhood-onset social and behavioral problems form the most relevant psychiatric symptom cluster in relation to pervasive adult violent behavior, while late-onset mental disorders are more often associated with single acts of violent or sexual aggression. [Copyright &y& Elsevier]

The purpose of this study was to develop flexible and accurate multicompartment equations to calculate body composition and compare the results with methods using common two-compartment equations. Twenty-two healthy male volunteers 22-59 y of age were studied. Body volume was measured by underwater weighing (UWW) or with a skinfold caliper, bone mineral by dual-energy X-ray absorptiometry (DXA), and body water by bioelectrical impedance analysis (BIA). The percentage of water and bone mineral in fat-free mass (FFM) had a significant effect on the difference in percentage fat obtained by the two-compartment model compared with a four-compartment model. FFM density was negatively (r =-0.76, P < 0.001) and percentage water in FFM was positively correlated with age (r = 0.75, P < 0.001). The three-compartment model based on field-adapted methods (skinfold thickness + BIA) to calculate percentage body fat correlated significantly with the more complex four-compartment model (UWW + BIA + DXA; r = 0.95, P < 0.001). The advantages of three- and four-compartment equations are that they compensate for differences in body content of bone mineral and water. [ABSTRACT FROM AUTHOR]

Polychlorinated biphenyls (PCBs) are synthetic chemicals that bioaccumulate in the food chain. PCBs were used primarily for industrial applications due to their insulating and fire retardant properties, but were banned in the 1970s in the United States and in the 1980s in the United Kingdom, as adverse health effects following exposure were identified. Previous studies of populations with high PCB exposure have reported inverse associations with birth weight and gestational length. Birth weight is a powerful predictor of infant survival, and low birth weight can predispose infants to chronic conditions in adult life such as diabetes and cardiovascular diseases. Using data from the Avon Longitudinal Study of Parents and Children, we investigated the association between prenatal exposure to PCBs and fetal growth in a sample of 448 mother-daughter dyads. Concentrations of three common PCB analytes, PCB-118, PCB-153 and PCB-187, were measured in maternal serum collected during pregnancy, and fetal growth was measured by birth weight and birth length. Multivariable linear regression was used to examine the associations between PCB analytes and measures of fetal growth, after adjusting for parity, maternal age, pre-pregnancy BMI, educational status, tobacco use and gestational age of infant at sample collection. Birth length, ponderal index and gestational age were not associated with any of the PCB analytes. Mothers' educational status modified associations for PCB analytes with birthweight. We observed significant inverse associations with birth weight only among daughters of mothers with less education. Daughter's birth weight was −138.4 g lower (95% CI: −218.0, −58.9) for each 10 ng/g lipid increase in maternal serum PCB-118. Similarly, every 10 ng/g lipid increase in maternal serum PCB-153 was associated with a −41.9 g (95% CI: −71.6, −12.2) lower birth weight. Every 10 ng/g lipids increase in maternal serum PCB-187, was associated with a −170.4 g (95% CI: −306.1, −34.7) lower birth weight, among girls with mothers in the lowest education group. Our findings suggest that prenatal exposure to PCBs is inversely associated with daughters' birth weight and that mothers' education, which is a possible marker for socioeconomic status, significantly modified the association between maternal PCB concentrations and birth weight in female newborns. [ABSTRACT FROM AUTHOR]

Two novel compounds, pyridopyrimidines ( 1 ) and naphthyridines ( 2 ) were identified as potent inhibitors of bacterial NAD + -dependent DNA ligase (Lig) A in a fragment screening. SAR was guided by molecular modeling and X-ray crystallography. It was observed that the diaminonitrile pharmacophore made a key interaction with the ligase enzyme, specifically residues Glu114, Lys291, and Leu117. Synthetic challenges limited opportunities for diversification of the naphthyridine core, therefore most of the SAR was focused on a pyridopyrimidine scaffold. The initial diversification at R 1 improved both enzyme and cell potency. Further SAR developed at the R 2 position using the Negishi cross-coupling reaction provided several compounds, among these compounds 22g showed good enzyme potency and cellular potency. [ABSTRACT FROM AUTHOR]

Abstract: Although the production and use of some persistent organic pollutants (POPs) have been banned or highly restricted, human exposure remains a subject of investigation due to their environmental persistence. Physiological changes during pregnancy may affect the disposition of POPs in the mother’s body, and thus fetal exposure. Changes in serum concentrations of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) across pregnancy trimesters, and trans-placental transfer to the fetus were investigated. Seventy-nine pregnant women in Trujillo, Peru were recruited in the first trimester of pregnancy, and provided blood samples for the analysis of 35 PCB congeners, 9 OCPs, and 11 polybrominated biphenyl diethers (PBDEs). Subsequently, maternal blood samples were collected in the second (n =64) and third trimesters (n =59), and cord blood samples (n =50) were collected at delivery. There were statistically significant changes across trimesters (p <0.05) for both fresh weight (increase) and lipid adjusted concentrations (decrease) of hexachlorobenzene (HCB), 2,2-Bis(4-chlorophenyl)-1,1-dichloroethene (p,p′-DDE), PCB-74, 118, 138–158, 153, 170, 180 and 194. Fresh weight concentrations of these POPs increased from first to third trimester by 10–28%. On the other hand lipid adjusted concentrations decreased from first to third trimester by 16–28%. Serum lipids increased from first to third trimester by 53% indicating the dilution of the POPs in the lipids. Concentrations of 2,2-Bis(4-chlorophenyl)-1,1,1-trichloroethane (p,p′-DDT), its metabolite p,p′-DDE, PCB-118, 138–158, 153, 170 and 180 above their limits of detection were measured in >60% of cord serum samples. Intra-individual correlations in maternal serum concentrations were high for most of the POPs (ρ =0.62–0.99; p <0.05) while correlations between maternal and cord serum concentrations were also high (ρ =0.68–0.99; p <0.05). Results indicate that the disposition in the body and blood concentrations of POPs may change during pregnancy, and show trans-placental transfer of DDT, DDE and PCBs. [Copyright &y& Elsevier]

Abstract: The 4-(5-fluoro-6-methyl-pyridin-2-yl)-5-quinoxalin-6-yl-1H-imidazol-2-ylamine 3 is a potent and selective inhibitor of TGF-βR1. Substitution of the amino group of 3 typically led to a slight decrease in the affinity for the receptor and in TGF-β-inducted PAI-luciferase reporter activity. However, 2-acetamidoimidazoles were identified as attractive candidates for further optimization as a result of their significant activity combined to their superior pharmacokinetic profile. [Copyright &y& Elsevier]

We describe the discovery, using shape-based virtual screening, of a potent, ATP site-directed inhibitor of the TβRI kinase, an important and novel drug target for fibrosis and cancer. The first detailed report of a TβRI kinase small molecule co-complex confirms the predicted binding interactions of our small molecule inhibitor, which stabilizes the inactive kinase conformation. Our results validate shape-based screening as a powerful tool to discover useful leads against a new drug target. [Copyright &y& Elsevier]

Polychlorinated biphenyls (PCBs) are synthetic, organochlorine compounds previously used in industrial processes. Although banned in 1980's across Europe, these chemicals persist in the environment and are associated with adverse health outcomes in children. We investigated the association between in utero concentrations of PCBs and girls' body fatness. Concentrations of various PCB congeners (PCB 118, PCB 138, PCB 153, PCB 170, and PCB 180) were measured in maternal serum samples collected in the early 1990's. Body fatness was measured in the daughters at 9 y of age using body mass index (BMI) and dual-energy x-ray absorptiometry (DXA) for percent body fat. Using multivariable linear regression, we explored associations between prenatal PCB congener concentrations and body fatness outcomes. Among 339 mother-daughter dyads, the median and interquartile range (IQR) for PCB congeners ranged between 15.0 ng g−1 (11.0–20.8) for PCB 118 to 64.6 ng g−1 (48.6–86.3) for PCB 153. Among daughters, the median was 27.5% (21.7–34.6) for percent body fat, 39.6% (36.4–43.5) for percent trunk fat, 4.9 kg m−2 (3.5–7.0) for fat mass index and 18.1 kg m−2 (16.3–20.6) for body mass index. Multivariable-adjusted regression analyses showed little or no association between prenatal PCB concentrations with daughters' body fatness measures. Prenatal concentrations of PCB congeners were not strongly associated with measures of body fatness in girls. • Polychlorinated biphenyls (PCBs) are synthetic, organochlorine compounds previously used in industrial processes. • In a UK-based birth cohort median (IQR) PCB congeners in prenatal maternal blood ranged between 15.0 ng g−1 (11.0–20.8) for PCB 118 to 64.6 ng g−1 (48.6–86.3) for PCB 153. • Prenatal concentrations of PCB congeners were not strongly associated with measures of body fatness in daughters at 9 years of age. [ABSTRACT FROM AUTHOR]

Abstract Background Animal studies suggest polybrominated diphenyl ethers (PBDEs) may be obesogens. However, epidemiologic studies investigating childhood exposure to PBDEs and adiposity are limited, with several reporting an inverse association. Objectives To investigate associations between repeated childhood PBDE concentrations and adiposity measures at age 8 years. Methods We examined 206 children from the Health Outcomes and Measures of the Environment Study, a birth cohort in Cincinnati, OH (2003–2006). Serum PBDEs were measured at ages 1, 2, 3, 5, and 8 years. We used multiple imputation to estimate missing PBDE concentrations. At 8 years, we measured weight, height, waist circumference, and body fat percentage. We used multiple informant models to estimate age-specific associations between PBDEs and adiposity measures. Results We observed significant inverse associations between BDE-153 with all adiposity measures that became increasingly stronger with later childhood measurements. A 10-fold increase in BDE-153 at ages 1 and 8 years was associated with 2% (95% CI −3.9, −0.1) and 7% (95% CI −9.1, −4.7) lower body fat, respectively. No statistically significant associations were found with BDE-28, -47, -99, or -100. Child sex modified some associations; inverse associations between BDE-153 and body fat were stronger among boys, while positive and null associations were noted among girls. Conclusions Childhood BDE-153 concentrations were inversely associated with adiposity measures and these associations became stronger as BDE-153 measurements were more proximal to adiposity measures. Inverse associations could be attributed to reverse causality arising from greater storage of PBDEs in adipose tissue of children with higher adiposity. Highlights • Findings do not support postnatal PBDEs are associated with increased adiposity. • BDE-28, -47, -99, -100, and ∑PBDEs were not associated with adiposity at 8 years. • There was a pattern of inverse associations between BDE-153 and adiposity measures. • Child sex modified BDE-153 associations, with decreases in body fat % in males, but not in females. • Reverse causality may have resulted in inverse associations. [ABSTRACT FROM AUTHOR]

In this study, we examined associations between serum concentrations of 35 polychlorinated biphenyl (PCB) congeners, pesticides, and indicators of thyroid function in participants of the Anniston Community Health Survey (ACHS). Study subjects lived in the vicinity of a former PCB production facility and had PCB concentrations 2 to 3 times higher than similar age and race groups from the general population. We investigated associations among serum levels of thyroid hormones (thyroxin [T4], free thyroxin [fT4], triiodothyronine [T3], thyroid stimulation hormone [TSH]) and auto-antibodies (thyroglobulin antibody [TgAb] or thyroperoxidase antibody [TPOAb]) and combined indicators of thyroid function with the sum of PCBs, varying PCB groups, individual PCB congeners, and 8 pesticides. Logistic and linear regression models were adjusted for log10 transformed total lipids, age, sex, ethnicity, BMI, smoking, and family history of thyroid disease. We also performed analyses stratified by ethnicity and sex. Linear regression showed inverse associations between TT3 and thyroid-like PCBs (sum of PCBs 28, 52, 74, 101, 105, and 118; p = .0004), two pesticides (hexachlorobenzene, and pp’-DDE), and individual congeners (PCBs 74, 105). Null associations were observed between PCBs, pesticides, TSH, TT4, and fT4. Logistic regression analyses did not provide support for TT3 findings and found no association with other thyroid hormones, antibodies, or combined indicator of thyroid function. These results suggest there is little evidence that these chemicals have any major clinical effect on thyroid function in this highly PCB exposed population. [ABSTRACT FROM AUTHOR]

Introduction Epidemiologic data supporting the role of organochlorine pesticides in pubertal development are limited. Methods Using a nested case-control design, serum collected during pregnancy from mothers of 218 girls who reported menarche before 11.5 years of age (cases) and 230 girls who reported menarche at or after 11.5 years of age (controls) was analyzed for 9 organochlorines and metabolites. We analyzed the association between in utero organochlorine concentrations and early menarche using multivariate logistic regression controlling for mother's age at menarche, or mother's prenatal BMI. Results We did not observe an association between in utero exposure to HCB, β-HCH, ϒ-HCH, p,p′-DDT, p,p′-DDE, oxychlordane or trans-nonachlor and early menarche. Conclusions This study is the first to examine the association between in utero exposure to HCB, β-HCH, ϒ-HCH, oxychlordane or trans-nonachlor and early menarche. In utero exposure to organochlorine pesticides does not appear to have a role in the timing of menarche in this study. [ABSTRACT FROM AUTHOR]

Abstract: In an attempt to identify novel inhibitors of NAD+-dependent DNA ligase (LigA) that are not affected by a known resistance mutation in the adenosine binding pocket, a detailed analysis of the binding sites of a variety of bacterial ligases was performed. This analysis revealed several similarities to the adenine binding region of kinases, which enabled a virtual screen of known kinase inhibitors. From this screen, a thienopyridine scaffold was identified that was shown to inhibit bacterial ligase. Further characterization through structure and enzymology revealed the compound was not affected by a previously disclosed resistance mutation in Streptococcus pneumoniae LigA, Leu75Phe. A subsequent medicinal chemistry program identified substitutions that resulted in an inhibitor with moderate activity across various Gram-positive bacterial LigA enzymes. [Copyright &y& Elsevier]

Abstract: Thymidylate kinase (TMK) is an essential enzyme for DNA synthesis in bacteria, phosphorylating deoxythymidine monophosphate (dTMP) to deoxythymidine diphosphate (dTDP), and thus is a potential new antibacterial drug target. Previously, we have described the first potent and selective inhibitors of Gram-positive TMK, leading to in vivo validation of the target. Here, a structure-guided design approach based on the initial series led to the discovery of novel sulfonylpiperidine inhibitors of TMK. Formation of hydrogen bonds with Arg48 in Staphylococcus aureus TMK was key to obtaining excellent enzyme affinity, as verified by protein crystallography. Replacement of a methylene linker in the series by a sulfonamide was accomplished with retention of binding conformation. Further optimization of log D yielded phenol derivative 11, a potent inhibitor of TMK showing excellent MICs against a broad spectrum of Gram-positive bacteria and >105 selectivity versus the human TMK homologue. [Copyright &y& Elsevier]

Abstract: Brominated flame retardants, including hexabromocyclododecane (HBCD) and polybrominated diphenyl ethers (PBDEs) are used to reduce the flammability of a multitude of electrical and electronic products, textiles and foams. The use of selected PBDEs has ceased, however, use of decaBDE and HBCD continues. While elevated concentrations of PBDEs in humans have been observed in Australia, no data is available on other BFRs such as HBCD. This study aimed to provide background HBCD concentrations from a representative sample of the Australian population and to assess temporal trends of HBCD and compare with PBDE concentrations over a 16year period. Samples of human milk collected in Australia from 1993 to 2009, primarily from primiparae mothers were combined into 12 pools from 1993 (2 pools); 2001; 2002/2003 (4 pools); 2003/2004; 2006; 2007/2008 (2 pools); and 2009. Concentrations of ∑HBCD ranged from not quantified (nq) to 19ngg−1 lipid while α-HBCD and γ-HBCD ranged from nq to 10ngg−1 lipid and nq to 9.2ngg−1 lipid. β-HBCD was detected in only one sample at 3.6ngg−1 lipid while ∑4PBDE ranged from 2.5 to 15.8ngg−1 lipid. No temporal trend was apparent in HBCD concentrations in human milk collected in Australia from 1993 to 2009. In comparison, PBDE concentrations in human milk show a peak around 2002/03 (mean ∑4PBDEs=9.6ngg−1 lipid) and 2003/04 (12.4ngg−1 lipid) followed by a decrease in 2007/08 (2.7ngg−1 lipid) and 2009 (2.6ngg−1 lipid). In human blood serum samples collected from the Australian population, PBDE concentrations did not vary greatly (p =0.441) from 2002/03 to 2008/09. Continued monitoring including both human milk and serum for HBCD and PBDEs is required to observe trends in human body burden of HBCD and PBDEs body burden following changes to usage. [Copyright &y& Elsevier]

Abstract: We present the discovery and optimization of a novel series of bacterial topoisomerase inhibitors. Starting from a virtual screening hit, activity was optimized through a combination of structure-based design and physical property optimization. Synthesis of fewer than a dozen compounds was required to achieve inhibition of the growth of methicillin-resistant Staphyloccus aureus (MRSA) at compound concentrations of 1.56μM. These compounds simultaneously inhibit DNA gyrase and Topoisomerase IV at similar nanomolar concentrations, reducing the likelihood of the spontaneous occurrence of target-based mutations resulting in antibiotic resistance, an increasing threat in the treatment of serious infections. [Copyright &y& Elsevier]

Abstract: The pyrrolamides are a new class of antibacterial agents targeting DNA gyrase, an essential enzyme across bacterial species and inhibition results in the disruption of DNA synthesis and subsequently, cell death. The optimization of biochemical activity and other drug-like properties through substitutions to the pyrrole, piperidine, and heterocycle portions of the molecule resulted in pyrrolamides with improved cellular activity and in vivo efficacy. [Copyright &y& Elsevier]

Abstract: Interruption of TGFβ signaling through inhibition of the TGFβR1 kinase domain may prove to have beneficial effect in both fibrotic and oncological diseases. Herein we describe the SAR of a novel series of TGFβR1 kinase inhibitors containing a pyrazolone core. Most TGFβR1 kinase inhibitors described to date contain a core five-membered ring bearing N as H-bond acceptor. Described herein is a novel strategy to replace the core structure with pyrazolone ring, in which the carbonyl group is designed as an H-bond acceptor to interact with catalytic Lys 232. [Copyright &y& Elsevier]

Abstract: LFA-1 ICAM inhibitors based on ortho- and meta-phenol templates were designed and synthesized by Mitsunobu chemistry. The selection of targets was guided by X-ray co-crystal data, and led to compounds which showed an up to 30-fold increase in potency over reference compound 1 in the LFA-1/ICAM1-Ig assay. The most active compound exploited a new hydrogen bond to the I-domain and exhibited subnanomolar potency. [Copyright &y& Elsevier]

Abstract: The vitamin D receptor (VDR) is a critical mediator of the cellular effects of vitamin D. The associations between four common VDR polymorphisms (BSMI, APAI, TAQI, and FOKI) and risk of epithelial ovarian cancer (EOC) were assessed in a case-control study nested within two prospective cohorts. One hundred seventy incident cases of EOC and 323 individually matched controls were genotyped. Overall, no associations were observed in genotype analyses. Haplotypes combining three SNPs in high linkage disequilibrium (BSMI, APAI, and TAQI) were also not associated with risk. These observations do not support a role for BSMI, APAI, TAQI, and FOKI polymorphisms in epithelial ovarian cancer in a predominantly Caucasian population. [Copyright &y& Elsevier]

Abstract: Spontaneously adsorbed monolayers of [Co(ttp-CH2-SH)2](PF6)2 have been formed on platinum microelectrodes by exposure to micromolar solutions of the complex in 0.1M TBABF4 in acetonitrile, ttp-CH2-SH is 4′-(p-(thiolmethyl)-phenyl)-2,2′:6′,2″-terpyridine. Resonance Raman spectroscopy on roughened polycrystalline platinum macro electrodes show that the molecule undergoes adsorption through the sulphur atom onto the platinum surface. The monolayers show reversible and well defined cyclic voltammetry when switched between Co2+ and Co3+ forms, with a peak to peak splitting of 0.040±0.005V up to 200Vs−1 and an FWHM of 0.138±0.010V. Adsorption is irreversible leading to the maximum surface coverage, 6.3±0.3×10−11 molcm−2 for 2.5≤[Co(ttp-CH2-SH)2]≤10μM. The rate of monolayer formation appears to be controlled not by mass transport or interfacial binding but by surface diffusion of the complex. The surface diffusion coefficient is 5.5±1.1×10−7 cm2 s−1 indicating that prior to formation of an equilibrated monolayer, the adsorbates have significant mobility on the surface. The electron transfer process across the monolayer–electrode interface has been probed by high speed chronoamperometry and the standard heterogeneous electron transfer rate constant, k°, is approximately 3.06±0.03×104 s−1. The reorganization energy is at least 18.5kJmol−1. [Copyright &y& Elsevier]

Firefighters may encounter items containing flame retardants (FRs), including organophosphate flame retardants (OPFRs) and polybrominated diphenyl ethers (PBDEs), during structure fires. This study utilized biological monitoring to characterize FR exposures in 36 firefighters assigned to interior, exterior, and overhaul job assignments, before and after responding to controlled residential fire scenarios. Firefighters provided four urine samples (pre-fire and 3-h, 6-h, and 12-h post-fire) and two serum samples (pre-fire and approximately 23-h post-fire). Urine samples were analyzed for OPFR metabolites, while serum samples were analyzed for PBDEs, brominated and chlorinated furans, and chlorinated dioxins. Urinary concentrations of diphenyl phosphate (DPhP), a metabolite of triphenyl phosphate (TPhP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP), a metabolite of tris(1,3-dichloro-2-propyl) phosphate (TDCPP), and bis(2-chloroethyl) phosphate (BCEtP), a metabolite of tris(2-chloroethyl) phosphate (TCEP), increased from pre-fire to 3-hr and 6-hr post-fire collection, but only the DPhP increase was statistically significant at a 0.05 level. The 3-hr and 6-hr post-fire concentrations of DPhP and BDCPP, as well as the pre-fire concentration of BDCPP, were statistically significantly higher than general population levels. BDCPP pre-fire concentrations were statistically significantly higher in firefighters who previously participated in a scenario (within the past 12 days) than those who were responding to their first scenario as part of the study. Similarly, firefighters previously assigned to interior job assignments had higher pre-fire concentrations of BDCPP than those previously assigned to exterior job assignments. Pre-fire serum concentrations of 2,3,4,7,8-pentachlorodibenzofuran (23478-PeCDF), a known human carcinogen, were also statistically significantly above the general population levels. Of the PBDEs quantified, only decabromodiphenyl ether (BDE-209) pre- and post-fire serum concentrations were statistically significantly higher than the general population. These results suggest firefighters absorbed certain FRs while responding to fire scenarios. [ABSTRACT FROM AUTHOR]

• PBDEs and PFAS during pregnancy may play a role in the pathogenesis of depression. • BDI-II was used to assess pregnancy and postpartum depressive symptoms. • PBDEs during pregnancy were associated with higher depressive symptoms in mothers. • ∑PBDEs were associated with higher risk of mothers having a high BDI-II trajectory. • Findings between PFAS during pregnancy and BDI-II scores were not significant. Experimental studies in rodents suggest that polybrominated diphenyl ethers (PBDEs) and poly- and perfluoroalkyl substances (PFAS) may contribute to depressive symptoms. Few studies have examined the impact of these chemicals on depression in adults. Objective : To examine the associations between serum PBDE and PFAS concentrations during pregnancy and repeated measures of depressive symptoms in women assessed from pregnancy to 8 years postpartum. Methods : This study was based on 377 women from the Health Outcomes and Measures of the Environment Study, a birth cohort in Cincinnati, OH (USA). PBDEs (BDE-28, -47, -99, -100, -153, and ∑PBDEs) and PFAS (perfluorooctanoate [PFOA], perfluorooctane sulfonate [PFOS], perfluorohexane sulfonate [PFHxS], perfluorononanoate [PFNA]) were quantified in maternal serum at 16 ± 3 weeks gestation. Depressive symptoms were measured using the Beck Depression Inventory-II (BDI-II) at ~20 weeks gestation and up to seven times during postpartum visits (4 weeks, 1, 2, 3, 4, 5, and 8 years). We used linear mixed models to estimate covariate-adjusted associations between chemical concentrations and repeated measures of BDI-II. Multinomial logistic regression models were used to estimate the relative risk ratios of having a medium or high depression trajectory. Results : We found that a 10-fold increase in BDE-28 at 16 ± 3 weeks gestation was associated with significantly increased BDI-II scores (β = 2.5 points, 95% confidence interval [CI] 0.8, 4.2) from pregnancy to 8 years postpartum. Significant positive associations were also observed with BDE-47, -100, -153, and ∑PBDEs. A 10-fold increase in ∑PBDEs was associated with a 4.6-fold increased risk (95% CI 1.8, 11.8) of a high trajectory for BDI-II compared to a low trajectory. We observed no significant associations between PFAS and BDI-II scores. Conclusion : PBDEs during pregnancy were associated with more depressive symptoms among women in this cohort. [ABSTRACT FROM AUTHOR]

• We found that certain clusters and principal components were inversely associated with infant birth length. • Individual chemcial biomarkers in these clusters or PCs were associated with lower birth length. • Cluster, PCs, and individual biomarker were not associated with other birth outcomes. • The consistency of these metrics suggests that these results are not method dependent. Exposure to mixtures of environmental chemicals are prevalent among pregnant women and may be associated with altered fetal growth and gestational age. To date, most research regarding environmental chemicals and neonatal outcomes has focused on the effect of individual agents. In a prospective cohort of 380 pregnant women from Cincinnati, OH (enrolled 2003–2006), we used biomarkers to estimate exposure to 43 phenols, phthalates, metals, organophosphate/pyrethroid/organochlorine pesticides, polychlorinated biphenyls, polybrominated diphenyl ethers, perfluoroalkyl substances (PFAS), and environmental tobacco smoke. Using three approaches, we estimated covariate-adjusted associations of chemical mixtures or individual chemicals with gestational-age-specific birth weight z-scores, birth length, head circumference, and gestational age: k-means clustering, principal components (PC), and one-chemical-at-a-time regression. We identified three chemical mixture profiles using k-means clustering. Women in cluster 1 had higher concentrations of most phenols, three phthalate metabolites, several metals, organophosphate/organochlorine pesticides, polychlorinated biphenyls, and several PFAS than women in clusters 2 and 3. On average, infants born to women in clusters 1 (−1.2 cm; 95% CI: −1.9, −0.5) and 2 (−0.5 cm; 95% CI: −1.1, 0.1) had lower birth length than infants in cluster 3. Six PCs explained 50% of the variance in biomarker concentrations and biomarkers with similar chemical structures or from shared commercial/industrial settings loaded onto commons PCs. Each standard deviation increase in PC 1 (organochlorine pesticides, some phenols) and PC 6 (cadmium, bisphenol A) was associated with 0.2 cm (95% CI: −0.4, 0.0) and 0.1 cm (95% CI: −0.4, 0.1) lower birth length, respectively. Organochlorine compounds, parabens, and cadmium were inversely associated with birth length in the one-chemical-at-a-time analysis. Cluster membership, PC scores, and individual chemicals were not associated with other birth outcomes. All three methods of characterizing multiple chemical exposures in this cohort identified inverse associations of select organochlorine compounds, phenols, and cadmium with birth length, but not other neonatal outcomes. [ABSTRACT FROM AUTHOR]