The transition from physical sibling abuse to bullying perpetration through trait anger: A longitudinal study.

OBJECTIVES: Experiencing physical sibling abuse is a form of family violence that is common but understudied. While it is often perceived as a normative aspect of sibling relationships, there are apparent behavioral consequences. The current study aims to advance the literature by utilizing the displaced aggression model and I3 theory to longitudinally examine trait anger as a pathway linking physical sibling abuse to bullying perpetration. METHODS: Using data from the Bullying, Sexual, and Dating Violence Trajectories from Early to Late Adolescence in the Midwestern United States, 2008-2013, adolescents (n = 851, M = 14.8 years) completed questionnaires at baseline and were reassessed 6 months later. RESULTS: Results suggested that when adolescents experience physical sibling abuse, they are more likely to engage in bullying perpetration. Mediation analyses indicated that as adolescents were physically abused by a sibling at home, they were more likely to report higher levels of trait anger, which subsequently increased their risk of engaging in bullying perpetration. CONCLUSION: These results suggest that experiencing physical sibling abuse has long-term detrimental consequences, including elicitation of trait anger, subsequently predicting bullying perpetration.

Developing expert scientific consensus on the environmental and societal effects of marine artificial structures prior to decommissioning.

Thousands of artificial ('human-made') structures are present in the marine environment, many at or approaching end-of-life and requiring urgent decisions regarding their decommissioning. No consensus has been reached on which decommissioning option(s) result in optimal environmental and societal outcomes, in part, owing to a paucity of evidence from real-world decommissioning case studies. To address this significant challenge, we asked a worldwide panel of scientists to provide their expert opinion. They were asked to identify and characterise the ecosystem effects of artificial structures in the sea, their causes and consequences, and to identify which, if any, should be retained following decommissioning. Experts considered that most of the pressures driving ecological and societal effects from marine artificial structures (MAS) were of medium severity, occur frequently, and are dependent on spatial scale with local-scale effects of greater magnitude than regional effects. The duration of many effects following decommissioning were considered to be relatively short, in the order of days. Overall, environmental effects of structures were considered marginally undesirable, while societal effects marginally desirable. Experts therefore indicated that any decision to leave MAS in place at end-of-life to be more beneficial to society than the natural environment. However, some individual environmental effects were considered desirable and worthy of retention, especially in certain geographic locations, where structures can support improved trophic linkages, increases in tourism, habitat provision, and population size, and provide stability in population dynamics. The expert analysis consensus that the effects of MAS are both negative and positive for the environment and society, gives no strong support for policy change whether removal or retention is favoured until further empirical evidence is available to justify change to the status quo. The combination of desirable and undesirable effects associated with MAS present a significant challenge for policy- and decision-makers in their justification to implement decommissioning options. Decisions may need to be decided on a case-by-case basis accounting for the trade-off in costs and benefits at a local level.

To what extent can decommissioning options for marine artificial structures move us toward environmental targets?

Switching from fossil fuels to renewable energy is key to international energy transition efforts and the move toward net zero. For many nations, this requires decommissioning of hundreds of oil and gas infrastructure in the marine environment. Current international, regional and national legislation largely dictates that structures must be completely removed at end-of-life although, increasingly, alternative decommissioning options are being promoted and implemented. Yet, a paucity of real-world case studies describing the impacts of decommissioning on the environment make decision-making with respect to which option(s) might be optimal for meeting international and regional strategic environmental targets challenging. To address this gap, we draw together international expertise and judgment from marine environmental scientists on marine artificial structures as an alternative source of evidence that explores how different decommissioning options might ameliorate pressures that drive environmental status toward (or away) from environmental objectives. Synthesis reveals that for 37 United Nations and Oslo-Paris Commissions (OSPAR) global and regional environmental targets, experts consider repurposing or abandoning individual structures, or abandoning multiple structures across a region, as the options that would most strongly contribute toward targets. This collective view suggests complete removal may not be best for the environment or society. However, different decommissioning options act in different ways and make variable contributions toward environmental targets, such that policy makers and managers would likely need to prioritise some targets over others considering political, social, economic, and ecological contexts. Current policy may not result in optimal outcomes for the environment or society.

The Identification of GPR52 Agonist HTL0041178, a Potential Therapy for Schizophrenia and Related Psychiatric Disorders.

HTL0041178 (1), a potent GPR52 agonist with a promising pharmacokinetic profile and exhibiting oral activity in preclinical models, has been identified. This molecule was the outcome of a judicious molecular property-based optimization approach, focusing on balancing potency against metabolic stability, solubility, permeability, and P-gp efflux.

Novel Macrocyclic Antagonists of the CGRP Receptor Part 2: Stereochemical Inversion Induces an Unprecedented Binding Mode.

The diastereomeric macrocyclic calcitonin gene-related peptide (CGRP) antagonists HTL0029881 (3) and HTL0029882 (4), in which the stereochemistry of a spiro center is reversed, surprisingly demonstrate comparable potency. X-ray crystallographic characterization demonstrates that 3 binds to the CGRP receptor in a precedented manner but that 4 binds in an unprecedented, unexpected, and radically different manner. The observation of this phenomenon is noteworthy and may open novel avenues for CGRP receptor antagonist design.

The number of boundedly rational choices on four elements.

We use a combinatorial approach to identify and compute the number of non-isomorphic choices on four elements that can be explained by several models of bounded rationality. •These estimates offer a tool to analyze choice experiments designed on four-element sets.•The presented methodology allows the application of an algorithm to estimate the fraction of choices justifiable by these models on finite sets.•Our approach can be extended to evaluate other - existing or future - models of bounded rationality.

Inclusion of condition in natural capital assessments is critical to the implementation of marine nature-based solutions.

Current approaches to measure ecosystem services (ES) within natural capital (NC) and nature-based solutions (NbS) assessments are generally coarse, often using a single figure for ecosystem services (e.g., nutrient remediation or blue carbon sequestration) applied to the local or national habitat stock, which fails to take account of local ecosystem conditions and regional variability. As such, there is a need for improved understanding of the link between habitat condition and ES provision, using comparable indicators in order to take more informed management decisions. Here the UK, Solent Marine Sites (SEMS) is used as a case study system to demonstrate how Water Framework Directive (WFD) 'ecological status' and other indicators of ecosystem condition (state or quality) can be coupled with habitat extent information to deliver a more precise locally-tailored NC approach for active coastal and marine habitat restoration. Habitat extent and condition data are collected for seven NbS relevant coastal habitats (littoral sediment, mat-forming green macroalgae, subtidal sediment, saltmarsh, seagrass, reedbeds and native oyster beds). The workflow includes: 1) biophysical assessment of regulatory ES; 2) monetary valuation; and 3) compilation of future scenarios of habitat restoration and creation. The results indicate that incorporating classifications by condition indices into local NC extent accounts improved ES benefits by 11-67%. This suggests that omitting condition from NC assessments could lead to undervaluation of ES benefits. Future scenarios of restoration in the SEMS also show that the additional regulatory benefits of reaching 'Good' ecological status are £376 million annually, but could be as much as £1.218 billion if 'High'status and all habitat creation targets were met. This evidence of the potential value of restoration and importance of including condition indices in assessments is highly relevant to consider when investing in water ecosystems conservation and restoration as called for by the UN Decade on Ecosystem Restoration (2021-2030), and more generally in global nutrient neutrality and blue carbon policy strategies.

Novel Macrocyclic Antagonists of the Calcitonin Gene-Related Peptide Receptor: Design, Realization, and Structural Characterization of Protein-Ligand Complexes.

A series of macrocyclic calcitonin gene-related peptide (CGRP) receptor antagonists identified using structure-based design principles, exemplified by HTL0028016 (1) and HTL0028125 (2), is described. Structural characterization by X-ray crystallography of the interaction of two of the macrocycle antagonists with the CGRP receptor ectodomain is described, along with structure-activity relationships associated with point changes to the macrocyclic antagonists. The identification of non-peptidic/natural product-derived, macrocyclic ligands for a G protein coupled receptor (GPCR) is noteworthy.

Antiprothrombin antibodies induce platelet activation: A possible explanation for anti-FXa therapy failure in patients with antiphospholipid syndrome?

BACKGROUND: Arterial and venous thrombosis are both common in antiphospholipid syndrome (APS). Recent studies have shown that anti-factor Xa (FXa) therapy in APS patients leads to a greater number of patients with arterial thrombosis than with warfarin. We hypothesize that this may be due to the lowering of prothrombin levels by warfarin. OBJECTIVES: To investigate whether antiprothrombin antibodies induce platelet aggregation and to identify the platelet receptors involved. A second aim was to investigate the effect of reduced prothrombin levels on antiprothrombin antibody-induced platelet aggregation. METHODS: Enzyme-linked immunosorbent assays were performed to measure binding of antiprothrombin antibodies to prothrombin fragment 1+2 and prothrombin. Platelet aggregation assays in washed platelets were performed. FcγRIIA was immunoprecipitated and tyrosine-phosphorylated FcγRIIA was measured by western blot. RESULTS: The antiprothrombin antibodies 28F4 and 3B1 had lupus anticoagulant (LAC) activity and caused platelet aggregation in the presence of Ca2+ and prothrombin. Antiprothrombin antibodies without LAC activity did not activate platelets. Inhibition of Syk and Src kinases and FcγRIIA blocked platelet aggregation. Fab and F(ab')2 fragments of 28F4 were unable to induce platelet aggregation. Immunoprecipitations showed that whole 28F4 immunoglobulin G induced tyrosine phosphorylation of FcγRIIA. Platelet aggregation was significantly reduced when prothrombin levels were reduced from 1 µM to 0.2 µM. CONCLUSIONS: Antiprothrombin antibodies with LAC activity are able to activate platelets via FcγRIIA. Decreased prothrombin levels resulted in less antiprothrombin antibody-mediated platelet aggregation. This may explain the lower incidence of arterial thrombosis in patients treated with warfarin than with anti-FXa therapy.

Ecological restoration of agricultural land can improve its contribution to economic development.

Given the negative environmental impacts of intensive agriculture, there is an urgent need to reduce the impact of food production on biodiversity. Ecological restoration of farmland could potentially contribute to this goal. While the positive impacts of ecological restoration on biodiversity are well established, less evidence is available regarding impacts on economic development and employment. Potentially, prospects for economic development could be enhanced by ecological restoration though increased provision of ecosystem services, on which some economic activity depends. Here we examined this issue through the development of contrasting land use scenarios for the county of Dorset, southern England. Two scenarios of future agricultural expansion were compared with two scenarios of landscape-scale ecological restoration and the current situation. Impacts on provision of multiple ecosystem services (ES) were explored using InVEST models and proxy values for different land cover types. Impacts on economic employment were examined using an economic input-output model, which was adjusted for variation in ES flows using empirically determined ES dependency values for different economic sectors. Using the unadjusted input-output model, the scenarios had only a slight economic impact (≤ 0.3% Gross Value Added, GVA). Conversely, when the input-output model was adjusted to take account of ES flows, GVA increased by up to 5.4% in the restoration scenarios, whereas under the scenario with greatest agricultural expansion, GVA was reduced by -4.5%. Similarly, employment increased by up to 6.7% following restoration, compared to declines of up to -5.6% following maximum agricultural expansion. These results show that the economic contribution of rural land is far greater than that attributable to agricultural production alone. Landscape-scale restoration of agricultural land can potentially increase the contribution of farmland to economic development and employment, by increasing flows of multiple ES to the many economic sectors that depend on them.

Is the endogenous ligand for PEAR1 a proteoglycan: clues from the sea.

Platelet Endothelial Aggregation Receptor 1 (PEAR1) is an orphan receptor of unknown function which mediates powerful activation of platelets and endothelial cells in response to crosslinking by antibodies and sulfated polysaccharides belonging to the dextran and fucoidan families. PEAR1 is a single transmembrane protein composed of 15 epidermal growth factor-like repeat sequences and with a conserved binding motif, YXXM, which when phosphorylated binds to phosphoinositide 3-kinase (PI3K). The 13th of the repeats has a heparin-binding sequence that is the site of interaction with the sulfated fucoidans and the only known endogenous ligand FcεRIα. Crosslinking of PEAR1 drives Src family kinase phosphorylation of the cytosolic tail leading to binding and activation of PI3K. In this Opinion Article, we summarize the literature on PEAR1 expression, structure and signaling, and the search for further endogenous ligands. We highlight one article in which phosphorylation of a 150 kDa platelet protein by heparin-containing ligands has been reported and propose that PEAR1 is a receptor for one or more glycosaminoglycan-conjugated proteins (proteoglycans). The up-regulation of PEAR1 at sites of inflammation in the vasculature and its role in angiogenesis suggests a role in the interplay of inflammation, platelets, coagulation, and thromboinflammation. We speculate that this may explain the link between single nucleotide variants in PEAR1 and cardiovascular disease.

Loss of mDia1 and Fhod1 impacts platelet formation but not platelet function.

An organized and dynamic cytoskeleton is required for platelet formation and function. Formins are a large family of actin regulatory proteins which are also able to regulate microtubule dynamics. There are four formin family members expressed in human and mouse megakaryocytes and platelets. We have previously shown that the actin polymerization activity of formin proteins is required for cytoskeletal dynamics and platelet spreading using a small molecule inhibitor. In the current study, we analyze transgenic mouse models deficient in two of these proteins, mDia1 and Fhod1, along with a model lacking both proteins. We demonstrate that double knockout mice display macrothrombocytopenia which is due to aberrant megakaryocyte function and a small decrease in platelet lifespan. Platelet function is unaffected by the loss of these proteins. This data indicates a critical role for formins in platelet and megakaryocyte function.

Assessing the natural capital value of water quality and climate regulation in temperate marine systems using a EUNIS biotope classification approach.

Using a natural capital framework to inform improvements to water quality and mitigation of climate change requires robust and spatially explicit ecosystem service data. Yet, for coastal habitats this approach is often constrained by a) sufficient and relevant habitat extent data and b) significant variability in baseline assessments used to quantify and value regulatory habitat services. Here, the European Nature Information System (EUNIS) habitat classification scheme is used to map seven key temperate coastal biotopes (littoral sediment, mat-forming green macroalgae, subtidal sediment, saltmarsh, seagrass, reedbeds and native oyster reefs) within the UK's Solent European Marine Site (SEMS). We then estimate the capacity of these biotopes to remove nitrogen (N) and phosphorus (P) and carbon (C), alongside monetary values associated with the resulting benefits. Littoral and sublittoral sediments (including those combined with macroalgae) were the largest contributors to total N, P and C removal, reflecting their large biotope area. However, our results also show considerable differences in relative biotope contributions to nutrient removal depending on how they are analysed and delineated over large spatial scales. When considered at a regional catchment level seagrass meadows, saltmarshes and reedbeds all had considerable N, P and C removal potential. Overall, we estimate that SEMS biotopes provide nutrient reductions and avoided climate damages equivalent to UK £1.1 billion, although this could be nearly £10 billion if water-treatment infrastructure costs and high carbon trading prices are utilised. Despite the variability in the final natural capital evaluations, the substantial regulatory value of N, P and C ecosystem services support a strong rational for restoring temperate coastal biotopes.

Critical redundant functions of the adapters Grb2 and Gads in platelet (hem)ITAM signaling in mice.

Platelets are essential for normal hemostasis; however, pathological conditions can also trigger unwanted platelet activation precipitating thrombosis and ischemic damage of vital organs such as the heart or brain. Glycoprotein (GP)VI- and C-type lectin-like receptor 2 (CLEC-2)-mediated (hem)immunoreceptor tyrosine-based activation motif (ITAM) signaling represents a major pathway for platelet activation. The two members of the Growth-factor receptor-bound protein 2 (Grb2) family of adapter proteins expressed in platelets - Grb2 and Grb2-related adapter protein downstream of Shc (Gads) - are part of the hem(ITAM) signaling cascade by forming an adapter protein complex with linker for activation of T cells (LAT). To date, a possible functional redundancy between these two adapters in platelet activation has not been investigated. We here generated megakaryocyte- and platelet-specific Grb2/Gads double knockout (DKO) mice and analyzed their platelet function in vitro and in vivo. The DKO platelets exhibited virtually abolished (hem)ITAM signaling whereas only partial defects were seen in Grb2 or Gads single-deficient platelets. This was based on impaired phosphorylation of key molecules in the (hem)ITAM signaling cascade and translated into impaired hemostasis and partially defective arterial thrombosis, thereby exceeding the defects in either Grb2 KO or Gads KO mice. Despite this severe (hem)ITAM signaling defect, CLEC-2 dependent regulation of blood-lymphatic vessel separation was not affected in the DKO animals. These results provide direct evidence for critically redundant roles of Grb2 and Gads for platelet function in hemostasis and thrombosis, but not development.

Job Opportunities in the Navy (JOIN).

This article describes the author's efforts to build a combined job-preference/job-preview measure as an alternative to conventional interest inventories for use in U.S. Navy recruiting, as most applicants have no previous exposure to Navy-specific jobs. Criteria for building a successful instrument (i.e., JOIN) that can identify the best match between the Sailor and his/her assigned job are presented. The resulting taxonomy (i.e., JOIN's classification of Navy jobs based on Community (e.g., aviation), Work Styles/Environments (e.g., outdoor), and specific Work Activity process-content pairs (e.g., maintain mechanical equipment)), is described. Psychometric properties of JOIN are presented based on data from 6,988 U.S. Navy Sailors, as well as gender differences and factor structure. Preliminary evidence of JOIN's predictive validity with five service-related outcome measures is presented, with modest yet significant findings. Although the development of JOIN may be considered non-traditional, JOIN promises to have a direct impact on training, promotion, and retention.

Critical role of the HDAC6-cortactin axis in human megakaryocyte maturation leading to a proplatelet-formation defect.

Thrombocytopenia is a major side effect of a new class of anticancer agents that target histone deacetylase (HDAC). Their mechanism is poorly understood. Here, we show that HDAC6 inhibition and genetic knockdown lead to a strong decrease in human proplatelet formation (PPF). Unexpectedly, HDAC6 inhibition-induced tubulin hyperacetylation has no effect on PPF. The PPF decrease induced by HDAC6 inhibition is related to cortactin (CTTN) hyperacetylation associated with actin disorganization inducing important changes in the distribution of megakaryocyte (MK) organelles. CTTN silencing in human MKs phenocopies HDAC6 inactivation and knockdown leads to a strong PPF defect. This is rescued by forced expression of a deacetylated CTTN mimetic. Unexpectedly, unlike human-derived MKs, HDAC6 and CTTN are shown to be dispensable for mouse PPF in vitro and platelet production in vivo. Our results highlight an unexpected function of HDAC6-CTTN axis as a positive regulator of human but not mouse MK maturation.

The design and SAR of a novel series of 2-aminopyridine based LRRK2 inhibitors.

Leucine-rich repeat kinase 2 (LRRK2) has attracted considerable interest as a therapeutic target for the treatment of Parkinson's disease. Compounds derived from a 2-aminopyridine screening hit were optimised using a LRRK2 homology model based on mixed lineage kinase 1 (MLK1), such that a 2-aminopyridine-based lead molecule 45, with in vivo activity, was identified.

The identification of novel acid isostere based inhibitors of the VPS10P family sorting receptor Sortilin.

Using fragment based and structure based drug discovery strategies a series of novel Sortilin inhibitors has been identified. The inhibitors are based on the N-substituted 1,2,3-triazol-4-one/ol heterocyclic template. X-ray crystallography shows that the 1,2,3-triazol-4-one/ol acts as a carboxylic acid isostere, making a bi-dentate interaction with an arginine residue of Sortilin, an interaction which has not been previously characterised for this heterocycle.

The actin binding proteins cortactin and HS1 are dispensable for platelet actin nodule and megakaryocyte podosome formation.

A dynamic, properly organised actin cytoskeleton is critical for the production and haemostatic function of platelets. The Wiskott Aldrich Syndrome protein (WASp) and Actin-Related Proteins 2 & 3 Complex (Arp2/3 complex) are critical mediators of actin polymerisation and organisation in many cell types. In platelets and megakaryocytes, these proteins have been shown to be important for proper platelet production and function. The cortactin family of proteins (Cttn & HS1) are known to regulate WASp-Arp2/3-mediated actin polymerisation in other cell types and so here we address the role of these proteins in platelets using knockout mouse models. We generated mice lacking Cttn and HS1 in the megakaryocyte/platelet lineage. These mice had normal platelet production, with platelet number, size and surface receptor profile comparable to controls. Platelet function was also unaffected by loss of Cttn/HS1 with no differences observed in a range of platelet function assays including aggregation, secretion, spreading, clot retraction or tyrosine phosphorylation. No effect on tail bleeding time or in thrombosis models was observed. In addition, platelet actin nodules, and megakaryocyte podosomes, actin-based structures known to be dependent on WASp and the Arp2/3 complex, formed normally. We conclude that despite the importance of WASp and the Arp2/3 complex in regulating F-actin dynamics in many cells types, the role of cortactin in their regulation appears to be fulfilled by other proteins in platelets.