Nanobugs as Drugs: Bacterial Derived Nanomagnets Enhance Tumor Targeting and Oncolytic Activity of HSV-1 Virus.

The survival strategies of infectious organisms have inspired many therapeutics over the years. Indeed the advent of oncolytic viruses (OVs) exploits the uncontrolled replication of cancer cells for production of their progeny resulting in a cancer-targeting treatment that leaves healthy cells unharmed. Their success against inaccessible tumors however, is highly variable due to inadequate tumor targeting following systemic administration. Coassembling herpes simplex virus (HSV1716) with biocompatible magnetic nanoparticles derived from magnetotactic bacteria enables tumor targeting from circulation with magnetic guidance, protects the virus against neutralizing antibodies and thereby enhances viral replication within tumors. This approach additionally enhances the intratumoral recruitment of activated immune cells, promotes antitumor immunity and immune cell death, thereby inducing tumor shrinkage and increasing survival in a syngeneic mouse model of breast cancer by 50%. Exploiting the properties of such a nanocarrier, rather than tropism of the virus, for active tumor targeting offers an exciting, novel approach for enhancing the bioavailability and treatment efficacy of tumor immunotherapies for disseminated neoplasms.

PROTOCOL: Mental disorder, psychological problems and terrorist behaviour: A systematic review.

This is the protocol for a Campbell systematic review. The objectives are as follows: the first objective of the review (Objective 1-Prevalence) is to present a synthesis of the reported prevalence rates of mental health difficulties in terrorist samples. Where sufficient data is available, the synthesis will be sensitive to the heterogeneity of the terrorism phenomenon by exploring the rates of mental health difficulties for different forms of terrorism and for different terrorist roles (e.g., bombing, logistics, finance, etc.). The second objective (Objective 2-Temporality) will synthesise the extent to which mental health difficulties pre-date involvement in terrorism within prevalence studies. Finally, the third objective (Objective 3-Risk) aims to further establish temporality by examining the extent to which the presence of mental disorder is associated with terrorist involvement by comparing terrorist and non-terrorist samples.

Mental disorder, psychological problems and terrorist behaviour: A systematic review and meta-analysis.

Background: The link between mental health difficulties and terrorist behaviour has been the subject of debate for the last 50 years. Studies that report prevalence rates of mental health difficulties in terrorist samples or compare rates for those involved and not involved in terrorism, can inform this debate and the work of those responsible for countering violent extremism. Objectives: To synthesise the prevalence rates of mental health difficulties in terrorist samples (Objective 1-Prevalence) and prevalence of mental health disorders pre-dating involvement in terrorism (Objective 2-Temporality). The review also synthesises the extent to which mental health difficulties are associated with terrorist involvement compared to non-terrorist samples (Objective 3-Risk Factor). Search Methods: Searches were conducted between April and June 2022, capturing research until December 2021. We contacted expert networks, hand-searched specialist journals, harvested records from published reviews, and examined references lists for included papers to identify additional studies. Selection Criteria: Studies needed to empirically examine mental health difficulties and terrorism. To be included under Objective 1 (Prevalence) and Objective 2 (Temporality), studies had to adopt cross-sectional, cohort, or case-control design and report prevalence rates of mental health difficulties in terrorist samples, with studies under Objective 2 also needing to report prevalence of difficulties before detection or involvement in terrorism. For Objective 3 (Risk Factor) studies where there was variability in terrorist behaviour (involved vs. not involved) were included. Data Collection and Analysis: Captured records were screened in DisillterSR by two authors. Risk of bias was assessed using Joanna Briggs Institute checklists, and random-effects meta-analysis conducted in Comprehensive Meta-Analysis software. Results: Fifty-six papers reporting on 73 different terrorist samples (i.e., studies) (n = 13,648) were identified. All were eligible for Objective 1. Of the 73 studies, 10 were eligible for Objective 2 (Temporality) and nine were eligible for Objective 3 (Risk Factor). For Objective 1, the life-time prevalence rate of diagnosed mental disorder in terrorist samples (k = 18) was 17.4% [95% confidence interval (CI) = 11.1%-26.3%]. When collapsing all studies reporting psychological problems, disorder, and suspected disorder into one meta-analyses (k = 37), the pooled prevalence rate was 25.5% (95% CI = 20.2%-31.6%). When isolating studies reporting data for any mental health difficulty that emerged before either engagement in terrorism or detection for terrorist offences (Objective 2: Temporality), the life-time prevalence rate was 27.8% (95% CI = 20.9%-35.9%). For Objective 3 (Risk Factor), it was not appropriate to calculate a pooled effect size due the differences in comparison samples. Odds ratios for these studies ranged from 0.68 (95% CI = 0.38-1.22) to 3.13 (95% CI = 1.87-5.23). All studies were assessed as having high-risk of bias which, in part, reflects challenges conducting terrorism research. Author's Conclusions: This review does not support the assertion that terrorist samples are characterised by higher rates of mental health difficulties than would be expected in the general population. Findings have implications for future research in terms of design and reporting. There are also implications for practice with regards the inclusion of mental health difficulties as indicators of risk.

Pre-deployment programmes for building resilience in military and frontline emergency service personnel.

BACKGROUND: Military personnel and frontline emergency workers may be exposed to events that have the potential to precipitate negative mental health outcomes such as depression, symptoms of post-traumatic stress and even post-traumatic stress disorder (PTSD). Programmes have been designed to build psychological resilience before staff are deployed into the field. This review presents a synthesis of the literature on these "pre-deployment resilience-building programmes". OBJECTIVES: The objective of this review was to assess the effectiveness of programmes that seek to build resilience to potentially traumatic events among military and frontline emergency service personnel prior to their deployment. These resilience programmes were compared to other interventions, treatment as usual or no intervention. SEARCH METHODS: Studies were identified through searches of electronic databases including Ovid MEDLINE, Embase, PsycINFO, Web of Science and Google Scholar. The initial search took place in January 2019, with an updated search completed at the end of September 2020. SELECTION CRITERIA: Only studies that used a randomised controlled trial (RCT)/cluster-RCT methodology were included. The programmes being evaluated must have sought to build resilience prior to exposure to trauma. Study participants must have been 18 years or older and be military personnel or frontline emergency workers. DATA COLLECTION AND ANALYSIS: Studies that met the inclusion criteria were assembled. Data extracted included methods, participants' details, intervention details, comparator details, and information on outcomes. The primary outcomes of interest were resilience, symptoms of post-traumatic stress and PTSD. Secondary outcomes of interest included acute stress disorder, depression, social support, coping skills, emotional flexibility, self-efficacy, social functioning, subjective levels of aggression, quality of sleep, quality of life and stress. Assessment of risk of bias was also completed. A total of 28 studies were included in a narrative synthesis of results. MAIN RESULTS: All 28 included studies compared an experimental resilience building intervention versus a control or no intervention. There was a wide range of therapeutic modalities used, including cognitive behavioural therapy (CBT) informed programmes, biofeedback based programmes, stress-management programmes, mindfulness and relaxation programmes, neuropsychological-based programmes, and psychoeducational-informed programmes. The main outcomes are specified here, secondary outcomes such as depression, social support, coping skills, self-efficacy, subjective levels of aggression and stress are reported in text. No studies reported on the following pre-specified outcomes; acute stress disorder, emotional flexibility, social functioning, quality of sleep and quality of life. Resilience Eight studies reported resilience as an outcome. We narratively synthesised the data from these studies and our findings show that five of these interventions had success in building resilience in their respective samples. Two of the studies that reported significant results utilised a CBT approach to build resilience, while the other three successful programmes were mindfulness-based interventions. Symptoms of post-traumatic stress Our narrative synthesis of results included eight studies. Two of the eight studies produced significant reductions in symptoms of post traumatic stress compared to controls. These interventions used neuropsychological and biofeedback intervention models respectively. PTSD caseness Four studies reported PTSD caseness as an outcome. Our narrative synthesis of results suggests that evidence is mixed as to the effectiveness of these interventions in reducing clinical diagnosis of PTSD. One study of a neuropsychology-orientated Attention Bias Modification Training (AMBT) programme had success in reducing both symptoms of post-traumatic stress and numbers of participants receiving a diagnosis of PTSD. A stress-management programme reported that, when baseline differences in rates of pre-deployment mental health issues were controlled for, participants in the control condition were at 6.9 times the risk of a diagnosis of PTSD when compared to the intervention group. Given the diversity of intervention designs and theoretical orientations used (which included stress-management, neuropsychological and psychoeducational programmes), a definitive statement on the efficacy of pre-deployment programmes at reducing symptoms of post-traumatic stress and PTSD cannot be confidently offered. AUTHORS' CONCLUSIONS: While a number of evaluations of relevant programmes have been published, the quality of these evaluations limits our ability to determine if resilience-building programmes 'work' in terms of preventing negative outcomes such as depression, symptoms of post-traumatic stress and diagnoses of PTSD. Based on our findings we recommend that future research should: a) report pre-/post-means and standard deviation scores for scales used within respective studies, b) take the form of large, RCTs with protocols published in advance, and c) seek to measure defined psychological facets such as resilience, PTSD and stress, and measure these concepts using established psychometric tools. This will provide more certainty in future assessments of the evidence base. From a clinical implications point of view, overall there is mixed evidence that the interventions included in this review are effective at safe guarding military personnel or frontline emergency workers from experiencing negative mental health outcomes, including PTSD, following exposure to potentially traumatic events. Based on this, practitioners seeking to build resilience in their personnel need to be aware of the limitations of the evidence base. Practitioners should have modest expectations in relation to the efficacy of resilience-building programmes as a prophylactic approach to employment-related critical incident traumas.

Macrophages Mediate the Antitumor Effects of the Oncolytic Virus HSV1716 in Mammary Tumors.

Oncolytic viruses (OV) have been shown to activate the antitumor functions of specific immune cells like T cells. Here, we show OV can also reprogram tumor-associated macrophage (TAM) to a less immunosuppressive phenotype. Syngeneic, immunocompetent mouse models of primary breast cancer were established using PyMT-TS1, 4T1, and E0771 cell lines, and a metastatic model of breast cancer was established using the 4T1 cell line. Tumor growth and overall survival was assessed following intravenous administration of the OV, HSV1716 (a modified herpes simplex virus). Infiltration and function of various immune effector cells was assessed by NanoString, flow cytometry of dispersed tumors, and immunofluorescence analysis of tumor sections. HSV1716 administration led to marked tumor shrinkage in primary mammary tumors and a decrease in metastases. This was associated with a significant increase in the recruitment/activation of cytotoxic T cells, a reduction in the presence of regulatory T cells and the reprograming of TAMs towards a pro-inflammatory, less immunosuppressive phenotype. These findings were supported by in vitro data demonstrating that human monocyte-derived macrophages host HSV1716 replication, and that this led to immunogenic macrophage lysis. These events were dependent on macrophage expression of proliferating cell nuclear antigen (PCNA). Finally, the antitumor effect of OV was markedly diminished when TAMs were depleted using clodronate liposomes. Together, our results show that TAMs play an essential role in support of the tumoricidal effect of the OV, HSV1716-they both host viral replication via a novel, PCNA-dependent mechanism and are reprogramed to express a less immunosuppressive phenotype.

Counter-narratives for the prevention of violent radicalisation: A systematic review of targeted interventions.

Background: In the field of terrorism research, the violent radicalisation of individuals towards perpetrating acts of terror has been the subject of academic enquiry for some time. One core focus by social scientists has been the role of narratives in this process. Narratives have the ability to present a socially constructed version of reality which serves the interest of the narrator(s). In the context of terrorism, by depicting violence as a viable antidote to individual vulnerabilities, the narratives purported for propagandistic purposes have the potential to thwart perceptions of instrumentality (a key characteristic of violent radicalisation). In order to prevent this from happening, researchers and counter-terrorism practitioners have increasingly sought to explore the potential for counter-narratives; targeted interventions that challenge the rationalisation(s) of violence purported in dominant narratives which, in turn, reconstructs the story. However, there is overwhelming consensus in both government and academic spheres that the concept of the counter-narrative is underdeveloped and, to date, there has been no synthesis of its effectiveness at targeting violent radicalisation-related outcomes. Objectives: The objective of this review was to provide a synthesis of the effectiveness of counter-narratives in reducing the risk of violent radicalisation. Search Methods: After a scoping exercise, the literature was identified through four search stages, including key-word searches of 12 databases, hand searches of reference lists of conceptual papers or books on the topic of counter-narratives, as well as direct contact with experts and professional agencies in the field. Selection Criteria: Studies adopting an experimental or quasiexperimental design where at least one of the independent variables involved comparing a counter-narrative to a control (or comparison exposure) were included in the review. Data Collection and Analysis: Accounting for duplicates, a total of 2,063 records were identified across two searches. Nineteen studies across 15 publications met the inclusion criteria. These studies were largely of moderate quality and 12 used randomised control trial designs with varying types of controls. The publication years ranged from 2000 to 2018, with the majority of studies published after 2015. The studies represented a range of geographical locations, but the region most heavily represented was North America. In most cases, the dominant narrative(s) "to-be-countered" comprised of hostile social constructions of an adversary or "out-group". The majority of studies challenged these dominant narratives through the use of stereotype-challenging, prosocial, or moral "exemplars". Other techniques included the use of alternative accounts, inoculation and persuasion. Results: In terms of risk factors for violent radicalisation, there was some disparity on intervention effectiveness. Overall, when pooling all outcomes, the intervention showed a small effect. However, the observed effects varied across different risk factors. Certain approaches (such as counter-stereotypical exemplars) were effective at targeting realistic threat perceptions, in-group favouritism and out-group hostility. However, there was no clear reduction in symbolic threat perceptions or implicit bias. Finally, there was a sparse yet discouraging evidence on the effectiveness of counter-narrative interventions at targeting primary outcomes related to violent radicalisation, such as intent to act violently. Authors' Conclusions: The review contributes to existing literature on violent radicalisation-prevention, highlighting the care and complexity needed to design and evaluate narrative-based interventions which directly counter existing, dominant narratives. The authors note the challenges of conducting high-quality research in the area, but nonetheless encourage researchers to strive for experimental rigour within these confines.

Vigilin interacts with signal peptide peptidase.

BACKGROUND: Signal peptide peptidase (SPP), a member of the presenilin-like intra-membrane cleaving aspartyl protease family, migrates on Blue Native (BN) gels as 100 kDa, 200 kDa and 450 kDa species. SPP has recently been implicated in other non-proteolytic functions such as retro-translocation of MHC Class I molecules and binding of misfolded proteins in the endoplasmic reticulum (ER). These high molecular weight SPP complexes might contain additional proteins that regulate the proteolytic activity of SPP or support its non-catalytic functions. RESULTS: In this study, an unbiased iTRAQ-labeling mass spectrometry approach was used to identify SPP-interacting proteins. We found that vigilin, a ubiquitous multi-KH domain containing cytoplasmic protein involved in RNA binding and protein translation control, selectively enriched with SPP. Vigilin interacted with SPP and both proteins co-localized in restricted intracellular domains near the ER, biochemically co-fractionated and were part of the same 450 kDa complex on BN gels. However, vigilin does not alter the protease activity of SPP, suggesting that the SPP-vigilin interaction might be involved in the non-proteolytic functions of SPP. CONCLUSIONS: We have identified and validated vigilin as a novel interacting partner of SPP that could play an important role in the non-proteolytic functions of SPP. This data adds further weight to the idea that intramembrane-cleaving aspartyl proteases, such as presenilin and SPPs, could have other functions besides the proteolysis of short membrane stubs.

Depression and intelligence in patients with Parkinson's disease and deep-brain stimulation.

The goal of this study is to examine the association of depression with intelligence and education in patients with Parkinson's disease treated with bilateral subthalamic nucleus stimulation (STN-DBS). The literature has been contradictory concerning depression in Parkinson's disease patients. Some studies have shown less depression in Parkinson's disease patients with more education not treated with STN-DBS. Other recently published studies indicate that STN-DBS improves the depression associated with Parkinson's disease. No studies have examined the correlation of these factors with depression in Parkinson's disease patients treated with STN-DBS. We administered the Beck Depression Inventory (BDI) pre- and postoperatively to 21 Parkinson's disease patients (seven women, 14 men, ages 49-75) who underwent STN-DBS. The postoperative scores of the lower 50th percentile (n=8) of the Verbal Comprehensive Index of the Wechsler Adult Intelligence Scale (WAIS-III) decreased significantly (P=0.036), while the upper 50th percentile (n=13) remained nearly constant (P=0.802). Furthermore, as the education increased from highschool to graduate level, patients demonstrated less improvement in depressive symptoms postoperatively. These findings suggest that Parkinson's disease patients with lower intelligence test scores and less education benefit more with regards to depressive symptomatology after STN-DBS than patients with higher scores and education.