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Objective Recent studies have examined the extent to which alcohol dependence (AD) criteria prospectively predict the course of AD. Critically, these studies have lacked a developmental perspective. However, the differential performance of criteria by age might indicate overendorsement in younger individuals. The current study examined AD criteria in terms of persistence and prediction of AD course and alcohol use by age in order to identify criteria that are likely to be overly endorsed by younger individuals. Method The current study used longitudinal data from the National Epidemiologic Survey on Alcohol and Related Conditions to depict age differences in rates of new onset, recurrence, and persistence for each AD criterion, thereby showing how these three factors contribute to the overall age-prevalence curve of each criterion. Additionally, we tested age moderation of the predictive association between each criterion at baseline and new onset, recurrence, and persistence of syndromal AD. Results Some criteria (particularly, persistent desire or unsuccessful efforts to cut down or control drinking, and drinking despite physical/psychological problems) are both less persistent and less predictive of AD course among younger adults compared to older adults. Conclusions These findings raise the possibility of elevated rates of false-positive AD among younger adults and suggest ways to improve the assessment of AD criteria. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The Rho kinase (ROCK) pathway is implicated in the pathogenesis of several conditions, including neurological diseases. In Huntington's disease (HD), ROCK is implicated in mutant huntingtin (HTT) aggregation and neurotoxicity, and members of the ROCK pathway are increased in HD mouse models and patients. To validate this mode of action as a potential treatment for HD, we sought a potent, selective, central nervous system (CNS)-penetrant ROCK inhibitor. Identifying a compound that could be dosed orally in mice with selectivity against other AGC kinases, including protein kinase G (PKG), whose inhibition could potentially activate the ROCK pathway, was paramount for the program. We describe the optimization of published ligands to identify a novel series of ROCK inhibitors based on a piperazine core. Morphing of the early series developed in-house by scaffold hopping enabled the identification of a compound exhibiting high potency and desired selectivity and demonstrating a robust pharmacodynamic (PD) effect by the inhibition of ROCK-mediated substrate (MYPT1) phosphorylation after oral dosing.

Objective International Classification of Diseases (ICD) codes in electronic health records (EHRs) are increasingly used for health services research, in spite of unknown diagnostic accuracy. The accuracy of ICD codes to identify bronchopulmonary dysplasia (BPD) is unknown. Study design Retrospective cohort study in a single-center NICU (n = 166) to evaluate sensitivity and specificity of ICD-10 codes for the diagnosis of BPD. Analysis of large insurance claims database (n = 7887) to determine date of assignment of the code. Results The sensitivity of any BPD-related ICD codes ranged from 0.82 to 0.95, while the specificity ranged from 0.25 to 0.36. In a large national insurance database, the most common date of ICD-9 or ICD-10 code assignment was the day of birth, which is inconsistent with the clinical definition. Conclusions ICD codes registered for BPD are unlikely to accurately reflect the current clinical definition and should be interpreted with caution.

Novel dimethyl and dimethoxy ring-substituted octyl phenylcyanoacrylates, RPhCH=C(CN)CO2CH2(CH2)6CH3 (where R is 2,3-dimethyl, 2,4-dimethyl, 2,5-dimethyl, 2,6-dimethyl, 3,4-dimethyl, 3,5-dimethyl, 2,3-dimethoxy, 2,4-dimethoxy, 2,5-dimethoxy, 2,6-dimethoxy, 3,4-dimethoxy, 3,5-dimethoxy) were prepared and copolymerized with styrene. The acrylates were synthesized by the piperidine catalyzed Knoevenagel condensation of ring-disubstituted benzaldehydes and octyl cyanoacetate, and characterized by CHN analysis, IR, 1H and 13C NMR. All the acrylates were copolymerized with styrene in solution with radical initiation (ABCN) at 70C. The compositions of the copolymers were calculated from nitrogen analysis.

BRAF is among the most frequently mutated oncogenes in human cancers. Multiple small molecule BRAF kinase inhibitors have been approved for treating melanoma carrying BRAF-V600 mutations. However, the benefits of BRAF kinase inhibitors are generally short-lived. Small molecule-mediated targeted protein degradation has recently emerged as a novel pharmaceutical strategy to remove disease proteins through hijacking the cellular ubiquitin proteasome system (UPS). In this study, we developed thalidomide-based heterobifunctional compounds that induced selective degradation of BRAF-V600E, but not the wild-type BRAF. Downregulation of BRAF-V600E suppressed the MEK/ERK kinase cascade in melanoma cells and impaired cell growth in culture. Abolishing the interaction between degraders and cereblon or blocking the UPS significantly impaired the activities of these degraders, validating a mechanistic role of UPS in mediating targeted degradation of BRAF-V600E. These findings highlight a new approach to modulate the functions of oncogenic BRAF mutants and provide a framework to treat BRAF-dependent human cancers.

Alcohol use disorders (AUDs) are among the most prevalent mental disorders in the United States and elsewhere. Controversy exists regarding optimal classification of AUDs. Although observed across the lifespan, many ‘mature out’ of AUDs in young adulthood as they experience adult roles and personality maturation. Among etiological pathways to AUDs, foremost is a deviance proneness pathway shared by other externalizing disorders, with other pathways involving internalizing and individual differences in alcohol effects. All pathways likely involve genetic and environmental determinants. Numerous effective AUD prevention and treatment approaches exist, and basic research continues to further advances in behavior and drug treatments.

The pesticide azamethiphos used by the salmon industry to treat sea lice, is applied as a bath and subsequently discharged into the sea. The effects of azamethiphos concentration (0, 15 and 100 μg L

The disposal of antibiotics in the aquatic environment favors the selection of bacteria exhibiting antibiotic resistance mechanisms. Quinolones are bactericidal antimicrobials extensively used in both human and animal medicine. Some of the quinolone-resistance mechanisms are encoded by different bacterial genes, whereas others are the result of mutations in the enzymes on which those antibiotics act. The worldwide occurrence of quinolone resistance genes in aquatic environments has been widely reported, particularly in areas impacted by urban discharges. The most commonly reported quinolone resistance gene, qnr, encodes for the Qnr proteins that protect DNA gyrase and topoisomerase IV from quinolone activity. It is important to note that low-level resistance usually constitutes the first step in the development of high-level resistance, because bacteria carrying these genes have an adaptive advantage compared to the highly susceptible bacterial population in environments with low concentrations of this antimicrobial group. In addition, these genes can act additively with chromosomal mutations in the sequences of the target proteins of quinolones leading to high-level quinolone resistance. The occurrence of qnr genes in aquatic environments is most probably caused by the release of bacteria carrying these genes through anthropogenic pollution and maintained by the selective activity of antimicrobial residues discharged into these environments. This increase in the levels of quinolone resistance has consequences both in clinical settings and the wider aquatic environment, where there is an increased exposure risk to the general population, representing a significant threat to the efficacy of quinolone-based human and animal therapies. In this review the potential role of aquatic environments as reservoirs of the qnr genes, their activity in reducing the susceptibility to various quinolones, and the possible ways these genes contribute to the acquisition and spread of high-level resistance to quinolones will be discussed.

Novel trisubstituted ethylenes, dimethyl and dimethoxy ring-substituted octyl phenylcyanoacrylates, RPhCH=C(CN)CO2CH2(CH2)6CH3 (where R is 2,3-dimethyl, 2,4-dimethyl, 2,5-dimethyl, 2,6-dimethyl, 3,4-dimethyl, 3,5-dimethyl, 2,3-dimethoxy, 2,4-dimethoxy, 2,5-dimethoxy, 2,6-dimethoxy, 3,4-dimethoxy, 3,5-dimethoxy) were prepared and copolymerized with styrene. The ethylenes were synthesized by the piperidine catalyzed Knoevenagel condensation of ring-disubstituted benzaldehydes and octyl cyanoacetate, and characterized by CHN analysis, IR, 1H and 13C NMR. All the ethylenes were copolymerized with styrene in solution with radical initiation (ABCN) at 70C. The compositions of the copolymers were calculated from nitrogen analysis.

A recent study of the meiofauna from several intertidal sites along the coast of Chile yielded several gastrotrich specimens. The number of specimens was too small to assess the ecology of the individual species; however, as there are no published records of Gastrotricha in Chile until recently, it is important to document the presence of this group in order to stimulate further research. We report specimens of the genera Lepidodasys , Cephalodasys , Macrodasys , Tetranchyroderma , Xenotrichula and several morphotypes of Turbanella . Additionally, we provide some initial data on the population density of Lepidodasys sp. at Coihuin (Puerto Montt) and an observation of them feeding on nematodes. Normal 0 21 false false false /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Normale Tabelle"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; mso-bidi-font-size:12.0pt; font-family:"Liberation Serif","serif"; mso-ansi-language:EN-GB; mso-fareast-language:ZH-CN; mso-bidi-language:HI;} Normal 0 21 false false false /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Normale Tabelle"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; mso-bidi-font-size:12.0pt; font-family:"Liberation Serif","serif"; mso-ansi-language:EN-GB; mso-fareast-language:ZH-CN; mso-bidi-language:HI;}

Objective:The aim of this study was to (1) assess the long-term mental and behavioral health outcomes of the Deepwater Horizon Oil Spill of residents in the Gulf Coast and to (2) identify populations that may be particularly vulnerable to future disasters.Methods:The Survey of Trauma, Resilience, and Opportunity in Neighborhoods in the Gulf (STRONG) is a population-representative sample of 2520 coastal residents surveyed in Texas, Louisiana, Alabama, Mississippi, and Florida in 2016. We present prevalence estimates for positive screens of depression, anxiety, and alcohol misuse, as well as receipt of health care services. We examine differences in these outcomes across states, affected occupational groups, and demographic groups.Results:Resource loss attributed to the spill was associated with positive screens for depression and anxiety. Almost 50% of adults screened positive for depression, anxiety, or alcohol misuse, but less than 20% of these currently access mental health care. Black residents were less likely to have health insurance and a usual source of care but were more likely to have visited the emergency room in the past 12 months.Conclusions:Surveillance data from STRONG can help policy-makers and other stakeholders develop targeted approaches to foster resilience, particularly among vulnerable populations, and thereby mitigate the effects of future disasters.

While a wide body of research has indicated that social resources may be enhanced through religious practice, few studies have explored how social resources are impacted by the intersection of the social and individual domains of religion. Using data from the recently conducted Survey of Trauma, Resilience, and Opportunity among Neighborhoods in the Gulf, this study employs multilevel analysis to examine the impact of religious context on alcohol misuse among individuals impacted by the Deepwater Horizon Oil Spill. Our findings indicate that residence in areas that have high levels of religious concentration may magnify the risk of problem drinking among disaster-affected individuals for whom religion is not very salient, suggesting that religious context may influence the distribution of social resources differently between the religious and irreligious.

Pim kinases are a family of constitutively active serine/threonine kinases that are partially redundant and regulate multiple pathways important for cell growth and survival. In human disease, high expression of the three Pim isoforms has been implicated in the progression of hematopoietic and solid tumor cancers, which suggests that Pim kinase inhibitors could provide patients with therapeutic benefit. Herein, we describe the structure-guided optimization of a series of quinazolinone-pyrrolodihydropyrrolone analogs leading to the identification of potent pan-Pim inhibitor 28 with improved potency, solubility, and drug-like properties. Compound 28 demonstrated on-target Pim activity in an in vivo pharmacodynamic assay with significant inhibition of BAD phosphorylation in KMS-12-BM multiple myeloma tumors for 16 h postdose. In a 2-week mouse xenograft model, daily dosing of compound 28 resulted in 33% tumor regression at 100 mg/kg.

The conceptualization of stress-responsive physiological systems as operating in an integrated manner is evident in several theoretical models of cross-system functioning. However, limited empirical research has modeled the complexity of multisystem activity. Moreover few studies have explored developmentally regulated changes in multisystem activity during early childhood when plasticity is particularly pronounced. The current study used latent profile analysis (LPA) to evaluate multisystem activity during fall and spring of children’s transition to kindergarten in three biological systems: the parasympathetic nervous system (PNS), sympathetic nervous system (SNS), and hypothalamic pituitary adrenal (HPA) axis. Latent transition analysis (LTA) was then used to examine the stability of profile classification across time. Across both timepoints, three distinct profiles of multisystem activity emerged. One profile was characterized by heightened HPA axis activity (HPA Axis Responders), a second profile was characterized by moderate, typically adaptive patterns across the PNS, SNS, and HPA axis (Active Copers/Mobilizers), and a third profile was characterized by heightened baseline activity, particularly in the PNS and SNS (Anticipatory Arousal/ANS Responders). LTA of fall-to-spring profile classifications indicated higher probabilities that children remained in the same profile over time compared to probabilities of profile changes, suggesting stability in certain patterns of cross-system responsivity. Patterns of profile stability and change were associated with socioemotional outcomes at the end of the school year. Findings highlight the utility of LPA and LTA to detect meaningful patterns of complex multisystem physiological activity across three systems and their associations with early adjustment during an important developmental transition.

This article presents an overview of the Louisiana Community Oil Spill Survey (COSS), the dataset used in "Community Sentiment following the Deepwater Horizon Oil Spill Disaster: A Test of Time, Systemic Community, and Corrosive Community Models" [1] as well as elsewhere [2-6]. The COSS, administered by the Louisiana State University's Public Policy Research Laboratory, consists of five waves of cross-sectional trend data attuned to the characteristics and effects of the 2010 BP Deepwater Horizon (BP-DH) oil spill on those coastal Louisiana residents most affected by the disaster. Respondents were randomly drawn from a list of nearly 6,000 households in the coastal Louisiana zip codes located in Lafourche Parish, Plaquemines Parish, Terrebonne Parish, and the community of Grand Isle. COSS data were initially collected in June 2010 when oil was still flowing from the wellhead, with additional data waves, collected in October 2010, April 2011, April 2012, and April 2013. The respective response rates were: June 2010, 20%; October 2010, 24%; April 2011, 25%; April 2012, 20%; and April 2013, 19%.

118 Background: To date, immune-checkpoint inhibition for microsatellite stable (MSS) mCRC has been ineffective, though targeted therapy combination strategies may be promising. This phase II, investigator-initiated trial (NCT03475004) was designed to evaluate the efficacy and safety of the three-drug combination of pembrolizumab (pembro), binimetinib, and bevacizumab in patients with advanced, MSS treatment-refractory colorectal cancer. Methods: Patients with mCRC locally determined to be MSS and whom have progressed on two prior lines of therapy were enrolled. Treatment consists of pembro (200 mg every 3 weeks), binimetinib (45 mg BID) and bevacizumab (7.5 mg/kg every 3 weeks) until disease progression or unacceptable toxicity. The primary endpoint is PFS using RECIST v1.1 by investigator review. Additional endpoints include objective response rate, disease control rate at time of first re-staging (2 mo), duration of response, and safety and tolerability. Results: 50 patients have been enrolled (accrual is completed). 53% of patients are male and the mean age is 53.6 (range 31-79). The mean number of prior therapies is 5.3. At the time of preliminary data review, 39 patients are evaluable for response data. The median PFS was 5.8 mo (95% CI 4.2 to 8.9). The objective response rate was 13% with 5 partial responses. 24 patients (62%) had stable disease and 10 (26%) had progressive disease as the best response. The disease control rate at the time of first re-staging was 74%. Median duration of response was 6.5 mo. 19 (40%) patients experienced serious adverse events; the most common grade ≥3 adverse events included transaminase elevation (15%), diarrhea (11%), acneiform rash (9%), hypertension (9%), and anemia (9%). Conclusions: Preliminary results from this phase II study indicate that this regimen of pembrolizumab, binimetinib, and bevacizumab has promising activity and acceptable tolerability in this heavily pre-treated population of patients with MSS metastatic colorectal cancer. Final results will be presented as well as ongoing correlative studies. Clinical trial information: NCT03475004.

Reef-associated predators are thought to influence the distribution of invertebrates of surrounding sediment habitats. In this study, we analyzed the predation pressure and the distributional patterns of macro- and meiofaunal assemblages in soft sediments surrounding two coral reef sites at Rapa Nui (Easter Island), in the central South Pacific. We tested the hypothesis that reef-associated predators negatively affect sediment-dwelling invertebrates, causing macro- and meiofauna to be less abundant and diverse in soft sediments near the reefs. As expected, predation intensity was greater nearer the reef than farther away, but macro- and meiofaunal assemblages did not differ significantly with distance from the reef. Taxon richness of macro- and meiofaunal assemblages were similar irrespective of distance from the reef. Only meiofauna showed significant variation in total abundance with distance from the reef, but this trend was not consistent between the two study sites. No gradient in sediment texture was observed with distance from the reef. Underwater video recordings at one study site also revealed that local hydrodynamics cause frequent disturbance and resuspension of the upper sediment layers. Our results suggest that soft-sediment assemblages are constantly reshuffled by oceanic waves, thereby blurring the potential effects of predation on invertebrate assemblages closer to the reef.

This article reviews literature aiming to explain the widespread reductions in binge and problem drinking that begin around the transition to young adulthood (i.e., "maturing out"). Whereas most existing literature on maturing out emphasizes contextual effects of transitions into adult roles and responsibilities, this article also reviews recent work demonstrating further effects of young adult personality maturation. As possible mechanisms of naturally occurring desistance, these processes could inform both public health and clinical interventions aimed at spurring similar types of drinking-related behavior change. This article also draws attention to evidence that the normative trend of age-related reductions in problem drinking extends well beyond young adulthood. Specific factors that may be particularly relevant to problem drinking desistance in these later periods are considered within a broader life span developmental framework.

This study examines the effects of geographically differentiated social network support resources on perceived household preparedness and resource adequacy for coping with environmental hazards. The guiding notion is that socially close but spatially distant network resources will become critical for resilience in disaster contexts when the efficacy of local network resources become compromised due to community-wide disruption. Results from a random sample household survey of 928 coastal Louisiana residents confirm that perceived preparedness and resource adequacy for coping with environmental hazards is higher among those with strong support resources that are more than 2 h away from where they live, whereas access to support from local neighbors plays a lesser role. The implication is that efforts intended to build resilient communities by way of enhancing social network resources can benefit from considering the importance of promoting regional, in addition to localized, social ties.

In recent decades, the alteration of coastal food webs (via aquaculture, fishing, and leisure activities), nutrient loading, and an expansion of monitoring programs have prompted an apparent worldwide rise in Harmful Algae Blooms (HABs). Over this time, a parallel increase in HABs has also been observed in the Chilean southern austral region (Patagonia fjords). HAB species like Alexandrium catenella—responsible for Paralytic Shellfish Poisoning (PSP)—are of great public concern due to their negative socioeconomic impacts and significant northward geographical range expansion. Many toxic dinoflagellate species (like A. catenella) produce benthic resting cysts, yet a holistic understanding of the physical-chemical and biological conditions influencing the distributions of cysts in this region is lacking. In this study, we measured a combination of hydrographic (temperature, salinity, and dissolved oxygen) and sediment physical-chemical properties (temperature, pH and redox potential), in addition to meiofaunal abundances –as sediment bioturbators and potential cyst predators– to determine the factors influencing dinoflagellate cyst distribution, with emphasis on A. catenella in and around a “hotspot” area of southern Chile. An analysis of similarities (ANOSIM) test revealed significant differences (p

This chapter aims to characterize and explain pathological substance use from a developmental perspective. We first review key definitions (e.g., substance use disorder) and epidemiologic findings (e.g., age patterns). We then discuss etiology of problematic substance use with an organizational framework that distinguishes three key risk pathways emphasizing (1) deviance proneness, (2) stress and negative affect, and (3) pharmacological effects, respectively. We highlight components of these pathways that represent promising modifiable targets for prevention and treatment interventions. In addition to etiology, we also consider the normative trend toward “maturing out” of problematic substance use beginning in young adulthood. While most past literature on maturing out has emphasized young adult adoption of new roles and responsibilities, we also consider recent evidence for effects of young adult personality maturation. As possible mechanisms of naturally occurring desistance, these role- and personality-related processes could inform interventions aimed at goading similar changes in substance involvement. We also note that the normative trend toward maturing out in fact extends well beyond young adulthood, and we discuss factors that may be particularly salient to midlife and older adult desistance within a lifespan developmental framework (e.g., problem recognition, substance-related health concerns).

Background Due to the importance of both prostaglandins (PGs) and leukotrienes (LTs) as pro-inflammatory mediators, and the potential for eicosanoid shunting in the presence of pathway target inhibitors, we have investigated an approach to inhibiting the formation of both PGs and LTs as part of a multi-targeted drug discovery effort. Methods We generated ligand-protein X-ray crystal structures of known inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1) and the 5-Lipoxygenase Activating Protein (FLAP), with their respective proteins, to understand the overlapping pharmacophores. We subsequently used molecular modeling and structure-based drug design (SBDD) to identify hybrid structures intended to inhibit both targets. Results This work enabled the preparation of compounds 4 and 5, which showed potent in vitro inhibition of both targets. Significance Our findings enhance the structural understanding of mPGES-1 and FLAP's unique ligand binding pockets and should accelerate the discovery of additional dual inhibitors for these two important integral membrane protein drug targets.

The impact on the meiofaunal assemblage of the bioturbation caused by Chilean Flamingos (Phoenicopterus chilensis) feeding on the tidal flat at Caulin, southern Chile was investigated. The flamingos walk in circles in shallow water, moving their feet up and down in order to suspend the sediment which is then filtered through the lamellae in their beaks in order to capture their prey. Which component of the benthos the flamingos are targeting has yet to be unequivocally determined. Meiofauna are one potential food source as they are extremely abundant at the site and the filtering capacity of the flamingos could potentially retain meiofauna. Two possible hypotheses concerning the impact of flamingo feeding activity on the meiofaunal assemblage were tested: hypothesis 1 that the flamingos are feeding on the meiofaunal assemblage, and hypothesis 2 that the flamingos are displacing the meiofaunal assemblage over short distances. Meiofaunal samples were collected on four occasions (autumn, winter, spri...

We report the performance of protein-protein docking predictions by our group for recent rounds of the Critical Assessment of Prediction of Interactions (CAPRI), a community-wide assessment of state-of-the-art docking methods. Our prediction procedure uses a protein-protein docking program named LZerD developed in our group. LZerD represents a protein surface with 3D Zernike descriptors (3DZD), which are based on a mathematical series expansion of a 3D function. The appropriate soft representation of protein surface with 3DZD makes the method more tolerant to conformational change of proteins upon docking, which adds an advantage for unbound docking. Docking was guided by interface residue prediction performed with BindML and cons-PPISP as well as literature information when available. The generated docking models were ranked by a combination of scoring functions, including PRESCO, which evaluates the native-likeness of residues' spatial environments in structure models. First, we discuss the overall performance of our group in the CAPRI prediction rounds and investigate the reasons for unsuccessful cases. Then, we examine the performance of several knowledge-based scoring functions and their combinations for ranking docking models. It was found that the quality of a pool of docking models generated by LZerD, that is whether or not the pool includes near-native models, can be predicted by the correlation of multiple scores. Although the current analysis used docking models generated by LZerD, findings on scoring functions are expected to be universally applicable to other docking methods. Proteins 2017; 85:513-527. © 2016 Wiley Periodicals, Inc.

The high expression of proviral insertion site of Moloney murine leukemia virus kinases (Pim-1, -2, and -3) in cancers, particularly the hematopoietic malignancies, is believed to play a role in promoting cell survival and proliferation while suppressing apoptosis. The three isoforms of Pim protein appear largely redundant in their oncogenic functions. Thus, a pan-Pim kinase inhibitor is highly desirable. However, cell active pan-Pim inhibitors have proven difficult to develop because Pim-2 has a low Km for ATP and therefore requires a very potent inhibitor to effectively block the kinase activity at cellular ATP concentrations. Herein, we report a series of quinazolinone-pyrrolopyrrolones as potent and selective pan-Pim inhibitors. In particular, compound 17 is orally efficacious in a mouse xenograft model (KMS-12 BM) of multiple myeloma, with 93% tumor growth inhibition at 50 mg/kg QD upon oral dosing.

One of the challenges for targeting B-Raf(V600E) with small molecule inhibitors had been achieving adequate selectivity over the wild-type protein B-Raf(WT), as inhibition of the latter has been associated with hyperplasia in normal tissues. Recent studies suggest that B-Raf inhibitors inducing the 'DFG-in/αC-helix-out' conformation (Type IIB) likely will exhibit improved selectivity for B-Raf(V600E). To explore this hypothesis, we transformed Type IIA inhibitor (1) into a series of Type IIB inhibitors (sulfonamides and sulfamides 4-6) and examined the SAR. Three selectivity indices were introduced to facilitate the analyses: the B-Raf(V600E)/B-Raf(WT) biochemical ((b)S), cellular ((c)S) selectivity, and the phospho-ERK activation ((p)A). Our data indicates that α-branched sulfonamides and sulfamides show higher selectivities than the linear derivatives. We rationalized this finding based on analysis of structural information from the literature and provided evidence for a monomeric B-Raf-inhibitor complex previously hypothesized to be responsible for the desired B-Raf(V600E) selectivity.

BACKGROUND: Delay discounting is a potential etiological factor in adolescents' alcohol use, making it important to understand its antecedents. Family disorganization might contribute to delay discounting, but few studies have tested this relation. Moreover, because delay discounting is heritable, the effects of family disorganization on delay discounting might be moderated by adolescents' genetic risk for delay discounting. Thus, the current study examined the role of family disorganization, in interaction with genetic risk, in predicting adolescents' delay discounting and subsequent alcohol use. METHODS: Adolescents participated in 4 waves of data collection. Adolescents self-reported their family disorganization at T1, completed a delay discounting questionnaire at T3, and self-reported their alcohol use both at T2 (covariate) and T4 (outcome). Using results from an independent sample, we created a polygenic risk score consisting of dopaminergic genes to index genetic risk for delay discounting. RESULTS: Greater family disorganization predicted adolescents' greater delay discounting, but only for adolescents with low levels of genetic risk for delay discounting. Adolescents with high and mean levels of genetic risk for delay discounting showed elevated delay discounting regardless of their family's disorganization. Greater delay discounting prospectively predicted adolescents' greater alcohol use. Finally, the effects of family disorganization on adolescents' alcohol use were mediated through delay discounting, but only for adolescents with low levels of genetic risk. CONCLUSIONS: Results suggest multiple pathways to delay discounting. Although there are genetically influenced pathways to delay discounting, family disorganization might represent an environmental pathway to delay discounting (and subsequent alcohol use) for a subset of adolescents at low genetic risk. These findings reinforce the utility of family interventions for reducing adolescents' delay discounting and alcohol use, at least for a subgroup of adolescents. Because higher family organization did not buffer against delay discounting among adolescents with high genetic risk, future research should explore other early environmental influences that could protect these high-risk adolescents from developing these risky behaviors. Language: en

A key theoretical concept in the study of technological disasters is “recreancy,” which refers to perception that institutional actors have failed to carry out their responsibilities in a manner that engenders societal trust. Using household survey data from the Community Oil Spill Survey (COSS) to assess recreancy in the context of the Deepwater Horizon oil spill, we analyze four waves of the COSS collected between 2010 and 2013 to explore respondents’ perceptions of blame and distrust in relation to key institutional actors associated with the disaster, paying special attention to the influence of time and employment in natural resource occupations. We show that BP is clearly viewed as the principal responsible party at fault for the disaster and that the odds of blaming BP and the federal government have held relatively steady over time, while the odds of blaming state government increased over time. We find high levels of distrust of BP and the federal government, but show that odds of being distrustful of both institutional actors was significantly lower three years after the spill. Fishing households were significantly more likely to blame and be distrustful of institutional actors, a finding that is strongly consistent with theoretical expectations.

4031 Background: The majority of pts with mCRC have microsatellite stable (MSS) tumors with minimal response to PD-L1/PD-1 blockade. MEK inhibition and VEGF inhibition have immunomodulatory effects (upregulation of tumor major histocompatibility complex-I expression, enhanced T-cell infiltration, reduced MDSCs and Tregs in tumors) supporting clinical evaluation of combined MEKi (B), anti–PD-1 (P), and anti-VEGF (BV) in pts with mCRC. We hypothesize that the combination of binimetinib, pembrolizumab, and bevacizumab (BPBV) will result in greater clinical benefit than pembrolizumab alone. Methods: Patients with chemotherapy-refractory mCRC were evaluated (20 planned in the safety lead-in and 50 planned for total accrual). B was dosed at 45mg PO BID, P was administered at 200mg IV Q21 days, and BV was administered at 7.5mg/kg IV Q21 days. Primary objectives were safety, tolerability, and investigator-assessed ORR by RECIST 1.1. Clinical benefit rate (CR+PR+SD) and progression-free survival were secondary endpoints. Descriptive statistics were used to summarize safety and clinical activity. Results: As of January 9, 2020, 21 pts (10 KRAS/NRASmt, 11 RASwt, 21 MSS) were enrolled into the safety lead-in and were evaluable. The median number of prior therapies was 6. The BPBV combination was tolerable. Treatment-related Gr 1-2 and Gr 3-4 AEs occurred at 60% and 38%, respectively. The most frequent related Gr 3-4 AEs were aceniform rash, diarrhea, and hypertension (19%, 14%, 14% respectively). No treatment-related Gr 5 AEs occurred. A total of 17 patients were evaluable for response. Confirmed PR was observed in 2 pts (12%). SD was noted in 14 patients (82%) leading to a clinical benefit rate of 94%. 1 patient had PD as the best response to treatment. Median PFS was 6.4 months (95% CI 4.2-8.9). Molecular determinants, immune biomarkers, and updated tumor assessments of response will be presented. Conclusions: B + P + BV demonstrated a tolerable safety profile and improvements in ORR and clinical benefit rate compared to those reported with SOC in heavily pretreated pts with mCRC. Objective responses observed in pts were durable, suggesting benefit of this novel combination in a patient population refractory to immune therapies. Clinical trial information: NCT03475004 .

The Chilean salmon industry has undergone a rapid development making the country the world’s second largest producer of farmed salmon, but this growth has been accompanied by an intensive use of antibiotics. This overuse has become so significant that Chilean salmon aquaculture currently has one of the highest rates of antibiotic consumption per ton of harvested fish in the world. This review has focused on discussing use of antibiotics and current status of scientific knowledge regarding to incidence of antimicrobial resistance and associated genes in the Chilean salmonid farms. Over recent years there has been a consistent increase in the amount of antimicrobials used by Chilean salmonid farms, from 143.2 tons in 2010 to 382.5 tons in 2016. During 2016, Chilean companies utilized approximately 0.53 kg of antibiotics per ton of harvested salmon, 363.4 tons (95%) were used in marine farms, and 19.1 tons (5%) in freshwater farms dedicated to smolt production. Florfenicol and oxytetracycline were by far the most frequently used antibiotics during 2016 (82.5 and 16.8%, respectively), mainly being used to treat Piscirickettsia salmonis, currently considered the main bacterial threat to this industry. However, the increasing development of this industry in Chile, as well as the intensive use of antimicrobials, has not been accompanied by the necessary scientific research needed to understand the impact of the intensive use of antibiotics in this industry. Over the last two decades several studies assessing antimicrobial resistance and the resistome in the freshwater and marine environment impacted by salmon farming have been conducted, but information on the ecological and environmental consequences of antibiotic use in fish farming is still scarce. In addition, studies reporting the antimicrobial susceptibility of bacterial pathogens, mainly P. salmonis, have been developed, but a high number of these studies were aimed at setting their epidemiological cut-off values. In conclusion, further studies are urgently required, mainly focused on understanding the evolution and epidemiology of resistance genes in Chilean salmonid farming, and to investigate the feasibility of a link between these genes among bacteria from salmonid farms and human and fish pathogens.

Activation of free fatty acid receptor 1 (GPR40) by synthetic partial and full agonists occur via distinct allosteric sites. A crystal structure of GPR40-TAK-875 complex revealed the allosteric site for the partial agonist. Here we report the 2.76-Å crystal structure of human GPR40 in complex with a synthetic full agonist, compound 1, bound to the second allosteric site. Unlike TAK-875, which acts as a Gαq-coupled partial agonist, compound 1 is a dual Gαq and Gαs-coupled full agonist. compound 1 binds in the lipid-rich region of the receptor near intracellular loop 2 (ICL2), in which the stabilization of ICL2 by the ligand is likely the primary mechanism for the enhanced G protein activities. The endogenous free fatty acid (FFA), γ-linolenic acid, can be computationally modeled in this site. Both γ-linolenic acid and compound 1 exhibit positive cooperativity with TAK-875, suggesting that this site could also serve as a FFA binding site., GPR40 is a G-protein coupled receptor that binds to free fatty acids, mediating insulin and incretin secretion. Here, the authors present the crystal structure of human GPR40 with an agonist bound to an allosteric site located near the lipid-rich region that suggests a mechanism for biased agonism.

This chapter discusses relations between personality and alcohol use disorder (AUD). After reviewing basic terms and concepts in personality research, two major areas of contemporary research are discussed. The first area concerns how personality traits are implicated in etiologic pathways to AUD. This highlights the centrality of personality to conceptualizing AUD and related psychopathology. The second area is research emphasizing movement beyond a static view of personality, recognizing that personality traits are dynamic and change as a function of human development and life transitions. In particular, whereas past research on “maturing out” of AUD emphasized salutary effects of young adult role transitions, recent evidence reveals normative patterns of developmental personality maturation and supports these as additional influences on maturing out. The chapter discusses ways that contextual role effects and personality maturation can perhaps be integrated into a broader model of maturing out of AUD. Implications for future investigation are presented.

Key to an understanding of alcohol use disorder (AUD) are the drinking-related reductions that begin in young adulthood and continue throughout the adult lifespan. Research is needed to precisely characterize the form of these reductions, including possible developmental differences across the lifespan. Using U.S.-representative data, we estimated multiple-group Markov models characterizing longitudinal transitions among five drinking statuses and differences in transition patterns across six adult age periods. While past research indicates relative developmental stability in overall AUD-desistance rates, we found far higher rates of Severe AUD desistance in young adulthood relative to later ages. Especially considering the dramatic change reflected by Severe AUD desistance (from 6+ symptoms to 0–1 symptoms), this result indicates a substantial developmental shift, with Severe AUD desistance rates peaking at 43% to 50% across ages 25 to 34 and then dropping to 22% to 24% across ages 35 to 55. We discuss implications regarding practical significance of young-adult “maturing out” and predictions regarding lifespan variability in desistance mechanisms.

Research on Asian Americans’ experiences of racism has examined the impact of generation status and ethnicity. This study investigates how phenotypic and physical appearance characteristics are implicated in self-reports of racialization and social anxiety in Asian American college students (n 170) who completed measures of psychological distress, well-being, and racialization (e.g., Subtle and Blatant Racism Scale; Yoo, Steger, & Lee, 2010). Participants’ digital photographs were analyzed to test whether specific physical characteristics correlated with self-reported distress. Results suggest eyeglasses and darker skin tone are strongly associated with greater reports of racialization and psychological distress in Asian American college students.

Microsomal prostaglandin E synthase 1 (mPGES-1) is an α-helical homotrimeric integral membrane inducible enzyme that catalyzes the formation of prostaglandin E2 (PGE2) from prostaglandin H2 (PGH2). Inhibition of mPGES-1 has been proposed as a therapeutic strategy for the treatment of pain, inflammation, and some cancers. Interest in mPGES-1 inhibition can, in part, be attributed to the potential circumvention of cardiovascular risks associated with anti-inflammatory cyclooxygenase 2 inhibitors (coxibs) by targeting the prostaglandin pathway downstream of PGH2 synthesis and avoiding suppression of antithrombotic prostacyclin production. We determined the crystal structure of mPGES-1 bound to four potent inhibitors in order to understand their structure-activity relationships and provide a framework for the rational design of improved molecules. In addition, we developed a light-scattering-based thermal stability assay to identify molecules for crystallographic studies.

The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to tumorigenesis. As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Herein, we describe our efforts toward the development of a potent, pan-Pim inhibitor. The synthesis and hit-to-lead SAR development from a 3-(pyrazin-2-yl)-1H-indazole derived hit 2 to the identification of a series of potent, pan-Pim inhibitors such as 13o are described.

PIM kinases are a family of Ser/Thr kinases that are implicated in tumorigenesis. The discovery of a new class of PIM inhibitors, 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amines, is discussed with optimized compounds showing excellent potency against all three PIM isoforms.

The current study used two waves of data to investigate pathways through which adolescents’ response inhibition related to later externalizing problems. A polygenic risk score indexed genetic risk for poor response inhibition. Adolescents’ performance on a response inhibition task mediated the relation between adolescents’ polygenic risk scores and mother’s inconsistent parenting (i.e., evocative rGE), even after controlling for mothers’ genetic risk (i.e., passive rGE). Mothers’ inconsistent parenting subsequently prospectively predicted adolescents’ externalizing problems. Adolescents’ response inhibition also prospectively predicted later externalizing behaviors. These findings were subgroup-specific, with greater risk for non-Hispanic Caucasian boys with substance-disordered parents. Results suggest that poor response inhibition may increase risk for adolescents’ externalizing problems both directly and by evoking certain environmental conditions.

The diversity of free-living nematodes in the beaches of two Antarctic islands, King George and Deception islands was investigated. We used morphological and molecular (LSU, and two fragments of SSU sequences) approaches to evaluate 236 nematodes. Specimens were assigned to at least genera using morphology and were assessed for the presence of cryptic speciation. The following genera were identified: Halomonhystera, Litoditis, Enoploides, Chromadorita, Theristus, Oncholaimus, Viscosia, Gammanema, Bathylaimus, Choanolaimus, and Paracanthonchus; along with specimens from the families Anticomidae and Linhomoeidae. Cryptic speciation was identified within the genera Halomonhystera and Litoditis. All of the cryptic species identified live sympatrically. The two cryptic species of Halomonhystera exhibited no significant morphological differences. However, Litoditis species 2 was significantly larger than Litoditis species 1. The utility of molecular data in confirming the identifications of some of the morphologically more challenging families of nematodes was demonstrated. In terms of which molecular sequences to use for the identification of free-living nematodes, the SSU sequences were more variable than the LSU sequences, and thus provided more resolution in the identification of cryptic speciation. Finally, despite the considerable amount of time and effort required to put together genetic and morphological data, the resulting advance in our understanding of diversity and ecology of free-living marine nematodes, makes that effort worthwhile.

Climate change due to increased anthropogenic CO2 in the atmosphere is causing an increase in seawater temperatures referred to as ocean warming and a decrease in seawater pH, referred to as ocean acidification. The meiofauna play an important role in the ecology of marine ecosystems and the functions they provide. Using microcosms, meiofaunal assemblages were exposed to two temperatures (15 and 19 °C) and two pHs (pCO2 of 400 and 1000 ppm), both individually and in combination, for a period of 90 days. The hypothesis that increased temperature will increase meiofaunal abundance was not supported. The hypothesis that a reduced pH will reduce meiofaunal abundance and species richness was supported. The combination of future conditions of temperature and pH (19 °C and pCO2 of 1000 ppm) did not affect overall abundance but the structure of the nematode assemblage changed becoming dominated by a few opportunistic species.

Civic community theory has emerged in the last 10 years as a middle range theory to explain community variation in rates of crime. It has proven to be particularly powerful for explaining variations in violent crime across rural communities in the U.S. This essay provides a review of the available published literature testing components of the theory. The three main conceptual dimensions of the civic community thesis are outlined, and the nature of the empirical evidence is evaluated. The essay concludes with several suggestions for future research.

The mystacocarid Ctenocheilocaris galvarini is a member of the intertidal meiofauna in exposed sandy beaches along the coast of Chile. Originally described by Dahl (1952) from sub-tidal sediment off Isla Guafo, the only other published record is from semi-fine intertidal sand in Las Cruces. This paper presents a variety of new records of C. galvarini based on both quantitative and qualitative sampling of the coast of Chile between 18°S and 54°S. Ctenocheilocaris galvarini is found primarily in southern Chile, south of 32°, in the intertidal zone of intermediate beaches, in fine sand (Wentworth scale) most likely distributed between the level of the water-table and the surface, but avoiding dry sand.

Free-living nematodes are an important component of the marine benthos. In Chile there have been few studies on this group, and the majority has focused on the morphological aspect only. In this study, ribosomal 18S RNA and mitochondrial COI genes were used as genetic markers to complement morphological analyses to study the continental and Antarctic Chilean marine nematofauna. Different protocols for fixing, extracting and amplifying DNA were also tested. Not all the possible combinations produced good results. In fact, only the 18S gene showed consistently results. Phylogenetic analyses showed some discordance between classical taxonomy (i.e., based on morphology) and molecular data. These results suggest that taxonomic classification using integrative approaches including morphological characteristics and molecular information is needed to study the diversity and evolution of this complex group.

Research has shown a developmental process of “maturing out” of alcohol involvement beginning in young adulthood, but the precise nature of changes characterizing maturing out is unclear. We used latent transition analysis to investigate these changes in a high-risk sample from a longitudinal study of familial alcoholism (N = 844; 51% children of alcoholics; 53% male, 71% non-Hispanic Caucasian, 27% Hispanic). Analyses classified participants into latent drinking statuses during late adolescence (ages 17–22), young adulthood (ages 23–28), and adulthood (ages 29–40), and characterized transitions among these statuses over time. The resulting four statuses were abstainers, low-risk drinkers who typically drank less than weekly and rarely binged or showed drinking problems, moderate-risk drinkers who typically binged less than weekly and showed moderate risk for drinking problems, and high-risk drinkers who typically binged at least weekly and showed high risk for drinking problems. Maturing out between late adolescence and young adulthood was most common among initial high-risk drinkers, but they typically declined to moderate-risk drinking rather than to nonrisky drinking statuses. This suggests that the developmental phenomenon of maturing out pertains primarily to relatively high-risk initial drinkers and that many high-risk drinkers who mature out merely reduce rather than eliminate their risky drinking.

This research study examines Asian American student perceptions of Asian American Studies courses from a large Midwestern university using survey data (n = 761) and in-depth interviews (n = 12). Student voices and perspectives are centered in order better understand strengths and challenges of Asian American Studies beyond identified institutional factors.