Risk and protective factors for offending among UK Armed Forces personnel after they leave service: a data linkage study.

BACKGROUND: A proportion of ex-military personnel who develop mental health and social problems end up in the Criminal Justice System. A government review called for better understanding of pathways to offending among ex-military personnel to improve services and reduce reoffending. We utilised data linkage with criminal records to examine the patterns of offending among military personnel after they leave service and the associated risk (including mental health and alcohol problems) and socio-economic protective factors. METHOD: Questionnaire data from a cohort study of 13 856 randomly selected UK military personnel were linked with national criminal records to examine changes in the rates of offending after leaving service. RESULTS: All types of offending increased after leaving service, with violent offending being the most prevalent. Offending was predicted by mental health and alcohol problems: probable PTSD, symptoms of common mental disorder and aggressive behaviour (verbal, property and threatened or actual physical aggression). Reduced risk of offending was associated with post-service socio-economic factors: absence of debt, stable housing and relationship satisfaction. These factors were associated with a reduced risk of offending in the presence of mental health risk factors. CONCLUSIONS: Ex-military personnel are more likely to commit violent offences after leaving service than other offence-types. Mental health and alcohol problems are associated with increased risk of post-service offending, and socio-economic stability is associated with reduced risk of offending among military veterans with these problems. Efforts to reduce post-service offending should encompass management of socio-economic risk factors as well as mental health.

Post-deployment family violence among UK military personnel.

BACKGROUND: Research into violence among military personnel has not differentiated between stranger- and family-directed violence. While military factors (combat exposure and post-deployment mental health problems) are risk factors for general violence, there has been limited research on their impact on violence within the family environment. This study aims to compare the prevalence of family-directed and stranger-directed violence among a deployed sample of UK military personnel and to explore risk factors associated with both family- and stranger-directed violence. METHOD: This study utilised data from a large cohort study which collected information by questionnaire from a representative sample of randomly selected deployed UK military personnel (n = 6711). RESULTS: The prevalence of family violence immediately following return from deployment was 3.6% and 7.8% for stranger violence. Family violence was significantly associated with having left service, while stranger violence was associated with younger age, male gender, being single, having a history of antisocial behaviour as well as having left service. Deployment in a combat role was significantly associated with both family and stranger violence after adjustment for confounders [adjusted odds ratio (aOR) = 1.92 (1.25-2.94), p = 0.003 and aOR = 1.77 (1.31-2.40), p < 0.001, respectively], as was the presence of symptoms of post-traumatic stress disorder, common mental disorders and aggression. CONCLUSIONS: Exposure to combat and post-deployment mental health problems are risk factors for violence both inside and outside the family environment and should be considered in violence reduction programmes for military personnel. Further research using a validated measurement tool for family violence would improve comparability with other research.

Systematic review of mental health disorders and intimate partner violence victimisation among military populations.

PURPOSE: There is growing awareness of the problem of intimate partner violence (IPV) among military populations. IPV victimisation has been shown to be associated with mental disorder. A better understanding of the link between IPV and mental disorder is needed to inform service development to meet the needs of military families. We aimed to systematically review the literature on the association between IPV victimisation and mental health disorders among military personnel. METHODS: Searches of four electronic databases (Embase, Medline, PsycINFO, and Web of Science) were supplemented by reference list screening. Heterogeneity among studies precluded a meta-analysis. RESULTS: Thirteen studies were included. There was stronger evidence for an association between IPV and depression/alcohol problems than between IPV and PTSD. An association between IPV and mental health problems was more frequently found among veterans compared to active duty personnel. However, the link between IPV and alcohol misuse was more consistently found among active duty samples. Finally, among active duty personnel psychological IPV was more consistently associated with depression/alcohol problems than physical/sexual IPV. The review highlighted the lack of research on male IPV victimisation in the military. CONCLUSIONS: There is evidence that the burden of mental health need may be significant among military personnel who are victims of IPV. The influence of attitudes towards gender in the military on research in this area is discussed. Further research is needed to inform development of services and policy to reduce IPV victimisation and the mental health consequences among military personnel.

Violent behavior among military reservists.

Large numbers of British and American Reservists have been deployed to operations in Iraq and Afghanistan. Little is known about the impact of deployment and combat exposure on violent behavior in Reservists. The purpose of this study was to determine the prevalence of self-reported violent behavior among a representative sample of United Kingdom Reservists, the risk factors associated with violence and the impact of deployment and combat exposure on violence. This study used data from a large cohort study of randomly selected UK military personnel and included Reservists who were in service at the time of sampling (n = 1710). Data were collected by questionnaires that asked about socio-demographic and military characteristics, pre-enlistment antisocial behavior, deployment experiences, post-deployment mental health, and self-reported interpersonal violent behavior. The prevalence of violence among Reservists was 3.5%. Deployment was found to be a risk factor for violent behavior even after adjustment for confounders. The association with violence was similar for those deployed in either a combat role or non-combat role. Violence was also strongly associated with mental health risk factors (PTSD, common mental disorders, and alcohol misuse). This study demonstrated higher levels of self-reported post-deployment violence in UK Reservists who had served in either Iraq or Afghanistan. Deployment, irrespective of the role was associated with higher levels of violent behavior among Reservists. The results also emphasize the risk of violent behavior associated with post-deployment mental health problems. Aggr. Behav. 43:273-280, 2017. © 2016 Wiley Periodicals, Inc.

A lack of peptide binding and decreased thermostability suggests that the CASKIN2 scaffolding protein SH3 domain may be vestigial.

BACKGROUND: CASKIN2 is a neuronal signaling scaffolding protein comprised of multiple ankyrin repeats, two SAM domains, and one SH3 domain. The CASKIN2 SH3 domain for an NMR structural determination because its peptide-binding cleft appeared to deviate from the repertoire of aromatic enriched amino acids that typically bind polyproline-rich sequences. RESULTS: The structure demonstrated that two non-canonical basic amino acids (K290/R319) in the binding cleft were accommodated well in the SH3 fold. An K290Y/R319W double mutant restoring the typical aromatic amino acids found in the binding cleft resulted in a 20 °C relative increase in the thermal stability. Considering the reduced stability, we speculated that the CASKIN2 SH3 could be a nonfunctional remnant in this scaffolding protein. CONCLUSIONS: While the NMR structure demonstrates that the CASKIN2 SH3 domain is folded, its cleft has suffered two substitutions that prevent it from binding typical polyproline ligands. This observation led us to additionally survey and describe other SH3 domains in the Protein Data Bank that may have similarly lost their ability to promote protein-protein interactions.

A new mode of SAM domain mediated oligomerization observed in the CASKIN2 neuronal scaffolding protein.

BACKGROUND: CASKIN2 is a homolog of CASKIN1, a scaffolding protein that participates in a signaling network with CASK (calcium/calmodulin-dependent serine kinase). Despite a high level of homology between CASKIN2 and CASKIN1, CASKIN2 cannot bind CASK due to the absence of a CASK Interaction Domain and consequently, may have evolved undiscovered structural and functional distinctions. RESULTS: We demonstrate that the crystal structure of the Sterile Alpha Motif (SAM) domain tandem (SAM1-SAM2) oligomer from CASKIN2 is different than CASKIN1, with the minimal repeating unit being a dimer, rather than a monomer. Analytical ultracentrifugation sedimentation velocity methods revealed differences in monomer/dimer equilibria across a range of concentrations and ionic strengths for the wild type CASKIN2 SAM tandem and a structure-directed double mutant that could not oligomerize. Further distinguishing CASKIN2 from CASKIN1, EGFP-tagged SAM tandem proteins expressed in Neuro2a cells produced punctae that were distinct both in shape and size. CONCLUSIONS: This study illustrates a new way in which neuronal SAM domains can assemble into large macromolecular assemblies that might concentrate and amplify synaptic responses.

The solution structures of two prophage homologues of the bacteriophage λ Ea8.5 protein reveal a newly discovered hybrid homeodomain/zinc-finger fold.

A cluster of genes in the exoxis region of bacteriophage λ are capable of inhibiting the initiation of DNA synthesis in Escherichia coli. The most indispensible gene in this region is ea8.5. Here, we report the nuclear magnetic resonance structures of two ea8.5 orthologs from enteropathogenic E. coli and Pseudomonas putida prophages. Both proteins are characterized by a fused homeodomain/zinc-finger fold that escaped detection by primary sequence search methods. While these folds are both associated with a nucleic acid binding function, the amino acid composition suggests otherwise, leading to the possibility that Ea8.5 associates with other viral and host proteins.

Lam Qua and Peter Parker: Portraiture of Head and Neck Surgery in 19th-Century China.

In 1835, Peter Parker, an American surgeon and Presbyterian minister, established a hospital in Guangzhou and became the first Western head and neck surgeon in China. While Parker documented his most interesting cases in his journals, he also commissioned oil paintings of these patients from Lam Qua (), a prominent Chinese artist trained in British academic painting. Lam Qua produced 86 portraits of Dr Parker's patients, providing insight into not only the treatment of head and neck tumors but also the introduction of Western artistic techniques to 19th-century China. Parker's pioneering surgical accomplishments and Lam Qua's portraits document the role of art and medicine in America's cultural influence in Asia.

Third-generation genome sequencing implicates medium-sized structural variants in chronic schizophrenia.

Background: Schizophrenia (SCZ) is a heterogeneous psychiatric disorder, with significant contribution from genetic factors particularly for chronic cases with negative symptoms and cognitive deficits. To date, Genome Wide Association Studies (GWAS) and exome sequencing have associated SCZ with a number of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs), but there is still missing heritability. Medium-sized structural variants (SVs) are difficult to detect using SNP arrays or second generation sequencing, and may account for part of the missing heritability of SCZ. Aims and objectives: To identify SVs associated with severe chronic SCZ across the whole genome. Study design: 10 multiplex families with probands suffering from chronic SCZ with negative symptoms and cognitive deficits were recruited, with all their affected members demonstrating uni-lineal inheritance. Control subjects comprised one affected member from the affected lineage, and unaffected members from each paternal and maternal lineage. Methods: Third generation sequencing was applied to peripheral blood samples from 10 probands and 5 unaffected controls. Bioinformatic tools were used to identify SVs from the long sequencing reads, with confirmation of findings in probands by short-read Illumina sequencing, Sanger sequencing and visual manual validation with Integrated Genome Browser. Results: In the 10 probands, we identified and validated 88 SVs (mostly in introns and medium-sized), within 79 genes, which were absent in the 5 unaffected control subjects. These 79 genes were enriched in 20 biological pathways which were related to brain development, neuronal migration, neurogenesis, neuronal/synaptic function, learning/memory, and hearing. These identified SVs also showed evidence for enrichment of genes that are highly expressed in the adolescent striatum. Conclusion: A substantial part of the missing heritability in SCZ may be explained by medium-sized SVs detectable only by third generation sequencing. We have identified a number of such SVs potentially conferring risk for SCZ, which implicate multiple brain-related genes and pathways. In addition to previously-identified pathways involved in SCZ such as neurodevelopment and neuronal/synaptic functioning, we also found novel evidence for enrichment in hearing-related pathways and genes expressed in the adolescent striatum.

Screening of herbal extracts against multi-drug resistant Acinetobacter baumannii.

Antibiotic resistance is increasing resulting in a decreasing number of fully active antimicrobial agents available to treat infections with multi-drug resistant (MDR) bacteria. Herbal medicines may offer alternative treatment options. A direct inoculation method simulating the standard disc diffusion assay was developed to determine in vitro antimicrobial activity of sixty herbal extracts against MDR-Acinetobacter baumannii (A. baumannii). Eighteen herbal extracts inhibited MDR-A. baumannii on agar plates, although the magnitude and quality of bacterial inhibition differed considerably among the antibacterial herbal extracts. Next, minimal inhibitory concentration (MIC) of these antibacterial herbal extracts was calculated using a broth microdilution assay. For most herbal extracts, the larger the zone of inhibition on agar plates, the lower the MIC. In general, hetero-resistance on agar plates correlated with higher MIC. The skip well phenomenon was seen with two herbal extracts. In conclusion, 30% of the screened herbal extracts demonstrated in vitro antibacterial activity against MDR-A. baumannii using similar rigorous testing methods as those commonly employed for assessing antimicrobial activity of synthetic antibacterial agents. Characterization of a specific compound conferring this antibacterial activity of the herbal extracts may help to identify novel antimicrobial agents active against highly resistant bacteria.

Prevalence of Self-Reported Intimate Partner Violence Victimization Among Military Personnel: A Systematic Review and Meta-Analysis.

BACKGROUND: Research on intimate partner violence (IPV) in the military has tended to focus on military personnel as perpetrators and civilian partners/spouses as victims. However, studies have found high levels of IPV victimization among military personnel. This article systematically reviews studies of the prevalence of self-reported IPV victimization among military populations. METHODS: Searches of four electronic databases (Embase, Medline, PsycINFO, and Web of Science) were supplemented by reference list screening. Meta-analyses of the available data were performed, where possible, using the random effects model. RESULTS: This review included 28 studies with a combined sample of 69,808 military participants. Overall, similar or higher prevalence rates of physical IPV victimization were found among males compared to females and this was supported by a meta-analytic subgroup analysis: pooled prevalence of 21% (95% confidence interval [CI] = [17.4, 24.6]) among males and 13.6% among females (95% CI [9.5, 17.7]). Psychological IPV was the most prevalent type of abuse, in keeping with findings from the general population. There were no studies on sexual IPV victimization among male personnel. Evidence for the impact of military factors, such as deployment or rank, on IPV victimization was conflicting. DISCUSSION: Prevalence rates varied widely, influenced by methodological variation among studies. The review highlighted the lack of research into male IPV victimization in the military and the relative absence of research into impact of IPV. It is recommended that future research disaggregates results by gender and considers the impact of IPV, in order that gender differences can be uncovered.

HACS1 signaling adaptor protein recognizes a motif in the paired immunoglobulin receptor B cytoplasmic domain.

Hematopoietic adaptor containing SH3 and SAM domains-1 (HACS1) is a signaling protein with two juxtaposed protein-protein interaction domains and an intrinsically unstructured region that spans half the sequence. Here, we describe the interaction between the HACS1 SH3 domain and a sequence near the third immunoreceptor tyrosine-based inhibition motif (ITIM3) of the paired immunoglobulin receptor B (PIRB). From surface plasmon resonance binding assays using a mouse and human PIRB ITIM3 phosphopeptides as ligands, the HACS1 SH3 domain and SHP2 N-terminal SH2 domain demonstrated comparable affinities in the micromolar range. Since the PIRB ITIM3 sequence represents an atypical ligand for an SH3 domain, we determined the NMR structure of the HACS1 SH3 domain and performed a chemical shift mapping study. This study showed that the binding site on the HACS1 SH3 domain for PIRB shares many of the same amino acids found in a canonical binding cleft normally associated with polyproline ligands. Molecular modeling suggests that the respective binding sites in PIRB ITIM3 for the HACS1 SH3 domain and the SHP2 SH2 domain are too close to permit simultaneous binding. As a result, the HACS1-PIRB partnership has the potential to amalgamate signaling pathways that influence both immune and neuronal cell fate.

Essential Gene Profiles for Human Pluripotent Stem Cells Identify Uncharacterized Genes and Substrate Dependencies.

Human pluripotent stem cells (hPSCs) provide an invaluable tool for modeling diseases and hold promise for regenerative medicine. For understanding pluripotency and lineage differentiation mechanisms, a critical first step involves systematically cataloging essential genes (EGs) that are indispensable for hPSC fitness, defined as cell reproduction in this study. To map essential genetic determinants of hPSC fitness, we performed genome-scale loss-of-function screens in an inducible Cas9 H1 hPSC line cultured on feeder cells and laminin to identify EGs. Among these, we found FOXH1 and VENTX, genes that encode transcription factors previously implicated in stem cell biology, as well as an uncharacterized gene, C22orf43/DRICH1. hPSC EGs are substantially different from other human model cell lines, and EGs in hPSCs are highly context dependent with respect to different growth substrates. Our CRISPR screens establish parameters for genome-wide screens in hPSCs, which will facilitate the characterization of unappreciated genetic regulators of hPSC biology.

The NMR structure of the gpU tail-terminator protein from bacteriophage lambda: identification of sites contributing to Mg(II)-mediated oligomerization and biological function.

During the late stages of lambda bacteriophage assembly, the protein gpU terminates tail polymerization and participates at the interface between the mature capsid and tail components. When it engages the lambda tail, gpU undergoes a monomer-hexamer transition to achieve its biologically active form. Towards understanding how gpU participates in multiple protein-protein interactions, we have solved the structure of gpU in its monomeric state using NMR methods. The structure reveals a mixed alpha/beta motif with several dynamic loops at the periphery. Addition of 20 mM MgCl(2) is known to oligomerize gpU in the absence of its protein partners. Multiple image analysis of electron micrographs revealed ring-like structures of magnesium ion saturated gpU with a 30 A pore, consistent with its function as a portal for the passage of viral DNA into the host bacterium. The ability of magnesium ions to promote oligomerization was lost when substitutions were made at a cluster of acidic amino acids in the vicinity of helix alpha2 and the beta1-beta2 loop. Furthermore, substitutions at these sites abolished the biological activity of gpU.

Education Research: Resident education through adult learning in neurology: Implementation and impact.

OBJECTIVE: To enhance residency education by implementing the 6 principles of adult learning theory (ALT) in a large academic neurology residency program. METHODS: We implemented a set of curricular interventions aimed at Resident Education through Adult Learning in Neurology (REAL Neurology), in a large, academic neurology residency program. Interventions included didactic reform, increasing resident-as-teacher activities, and enhancing residents' interaction. The primary outcome was the change in mean Residency In-service Training Examination (RITE) percentile between the preintervention and postintervention cohorts, adjusting for US Medical Licensing Examination step 1 and 2 score. Other analysis included evaluating the effect of the duration of intervention exposure on outcome and evaluating the intervention effect on the proportion of advanced performers. RESULTS: A total of 134 RITE score reports were evaluated (87 preintervention and 47 postintervention). The mean RITE score percentile postintervention was 11.7 points higher than preintervention (adjusted, longitudinal analysis: fit linear mixed model, p < 0.0001). Postgraduate year 3 learners who had 1 and 2 years of exposure scored 13.4 and 18.9 points higher than those with no exposure at all, respectively (analysis of covariance, p = 0.04). The adjusted odds of better performance with REAL Neurology was 5.77 (ordinal logistic regression, 95% confidence interval 2.37-14.07, p < 0.05). CONCLUSION: This study evaluated the efficacy and feasibility of an ALT-based curricular program in neurology education. The results show robust and sustainable benefit for residents in training without imposing a financial or logistical burden on programs. REAL Neurology could serve as a model for curricular reform in other programs across subspecialties.

Reduced Nonexercise Activity Attenuates Negative Energy Balance in Mice Engaged in Voluntary Exercise.

Exercise alone is often ineffective for treating obesity despite the associated increase in metabolic requirements. Decreased nonexercise physical activity has been implicated in this resistance to weight loss, but the mechanisms responsible are unclear. We quantified the metabolic cost of nonexercise activity, or "off-wheel" activity (OWA), and voluntary wheel running (VWR) and examined whether changes in OWA during VWR altered energy balance in chow-fed C57BL/6J mice (n = 12). Energy expenditure (EE), energy intake, and behavior (VWR and OWA) were continuously monitored for 4 days with locked running wheels followed by 9 days with unlocked running wheels. Unlocking the running wheels increased EE as a function of VWR distance. The metabolic cost of exercise (kcal/m traveled) decreased with increasing VWR speed. Unlocking the wheel led to a negative energy balance but also decreased OWA, which was predicted to mitigate the expected change in energy balance by ∼45%. A novel behavioral circuit involved repeated bouts of VWR, and roaming was discovered and represented novel predictors of VWR behavior. The integrated analysis described here reveals that the weight loss effects of voluntary exercise can be countered by a reduction in nonexercise activity.

Saccharomyces cerevisiae Ste50 binds the MAPKKK Ste11 through a head-to-tail SAM domain interaction.

In Saccharomyces cerevisiae, signal transduction through pathways governing mating, osmoregulation, and nitrogen starvation depends upon a direct interaction between the sterile alpha motif (SAM) domains of the Ste11 mitogen-activated protein kinase kinase kinase (MAPKKK) and its regulator Ste50. Previously, we solved the NMR structure of the SAM domain from Ste11 and identified two mutants that diminished binding to the Ste50 SAM domain. Building upon the Ste11 study, we present the NMR structure of the monomeric Ste50 SAM domain and a series of mutants bearing substitutions at surface-exposed hydrophobic amino acid residues. The mid-loop (ML) region of Ste11-SAM, defined by helices H3 and H4 and the end-helix (EH) region of Ste50-SAM, defined by helix H5, were sensitive to substitution, indicating that these two surfaces contribute to the high-affinity interaction. The combination of two mutants, Ste11-SAM-L72R and Ste50-SAM-L69R, formed a high-affinity heterodimer unencumbered by competing homotypic interactions that had prevented earlier NMR studies of the wild-type complex. Yeast bearing mutations that prevented the heterotypic Ste11-Ste50 association in vitro presented signaling defects in the mating and high-osmolarity growth pathways.

The NMR and X-ray structures of the Saccharomyces cerevisiae Vts1 SAM domain define a surface for the recognition of RNA hairpins.

The SAM domain of the Saccharomyces cerevisiae post-transcriptional regulator Vts1 has a high affinity towards RNA hairpins containing a CUGGC pentaloop. We present the 1.6 Angstroms X-ray crystal structure of the Vts1 SAM domain in its unliganded state, and the NMR solution structure of this domain in its RNA-bound state. Both structures reveal a canonical five helix SAM domain flanked by additional secondary structural elements at the N and C termini. The two structures are essentially identical, implying that no major structural rearrangements occur upon RNA binding. Amide chemical shift changes map the RNA-binding site to a shallow, basic patch at the junction of helix alpha5 and the loop connecting helices alpha1 and alpha2.

The NMR structure of the murine DLC2 SAM domain reveals a variant fold that is similar to a four-helix bundle.

BACKGROUND: The tumor suppressor DLC2 (Deleted in Liver Cancer -2) participates in cell signaling at the mitochondrial membrane. DLC2 is characterized by a SAM (sterile alpha motif) domain, a Rho GTPase activating protein (GAP) domain, and a START lipid transfer domain. RESULTS: Towards understanding the function of DLC2, we have solved the NMR solution structure of the SAM domain. The DLC2-SAM domain structure reveals an atypical four-helix composition that is distinct from the five-helix SAM domain structures that have been determined to date. From structural alignments, helix 3 of the canonical SAM domain appears to be replaced by shorter, extended secondary structure that follows a similar path. Another difference is demonstrated by helices 1 and 2 that form a helical hairpin that is situated approximately parallel to the canonical helix 5. CONCLUSION: The DLC2-SAM domain adopts a structure that is topologically more similar to an anti-parallel four-helix bundle than a canonical SAM domain. This alternate topology may allow the DLC2-SAM domain to interact with a novel set of ligands.

A Model for Dimerization of the SOX Group E Transcription Factor Family.

Group E members of the SOX transcription factor family include SOX8, SOX9, and SOX10. Preceding the high mobility group (HMG) domain in each of these proteins is a thirty-eight amino acid region that supports the formation of dimers on promoters containing tandemly inverted sites. The purpose of this study was to obtain new structural insights into how the dimerization region functions with the HMG domain. From a mutagenic scan of the dimerization region, the most essential amino acids of the dimerization region were clustered on the hydrophobic face of a single, predicted amphipathic helix. Consistent with our hypothesis that the dimerization region directly contacts the HMG domain, a peptide corresponding to the dimerization region bound a preassembled HMG-DNA complex. Sequence conservation among Group E members served as a basis to identify two surface exposed amino acids in the HMG domain of SOX9 that were necessary for dimerization. These data were combined to make a molecular model that places the dimerization region of one SOX9 protein onto the HMG domain of another SOX9 protein situated at the opposing site of a tandem promoter. The model provides a detailed foundation for assessing the impact of mutations on SOX Group E transcription factors.