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The mild hypothermia response (MHR) maintains organismal homeostasis during cold exposure and is thought to be critical for the neuroprotection documented with therapeutic hypothermia. To date, little is known about the transcriptional regulation of the MHR. We utilize a forward CRISPR-Cas9 mutagenesis screen to identify the histone lysine methyltransferase SMYD5 as a regulator of the MHR. SMYD5 represses the key MHR gene SP1 at euthermia. This repression correlates with temperature-dependent levels of histone H3 lysine 26 trimethylation (H3K36me3) at the SP1 locus and globally, indicating that the mammalian MHR is regulated at the level of histone modifications. We have identified 37 additional SMYD5-regulated temperature-dependent genes, suggesting a broader MHR-related role for SMYD5. Our study provides an example of how histone modifications integrate environmental cues into the genetic circuitry of mammalian cells and provides insights that may yield therapeutic avenues for neuroprotection after catastrophic events.

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Organisms have homeostatic mechanisms to respond to cold temperature to ensure survival including the activation of the mammalian neuroprotective mild hypothermia response (MHR) at 32°C. We show activation of the MHR at euthermia by an FDA-approved medication Entacapone, proof-of-principle that the MHR can be medically manipulated. Utilizing a forward CRISPR-Cas9 mutagenesis screen, we identify the histone lysine methyltransferase SMYD5 as an epigenetic gatekeeper of the MHR. SMYD5 represses the key MHR gene SP1 at euthermia but not at 32°C. This repression is mirrored by temperature-dependent levels of H3K36me3 at the SP1-locus and globally indicating that the mammalian MHR is regulated at the level of histone modifications. We identified 45 additional SMYD5-temperature dependent genes suggesting a broader MHR-related role for SMYD5. Our study provides an example of how the epigenetic machinery integrates environmental cues into the genetic circuitry of mammalian cells and suggests novel therapeutic avenues for neuroprotection after catastrophic events.

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Wiedemann-Steiner syndrome (WDSTS) is a neurodevelopmental disorder caused by de novo variants in KMT2A, which encodes a multi-domain histone methyltransferase. To gain insight into the currently unknown pathogenesis of WDSTS, we examined the spatial distribution of likely WDSTS-causing variants across the 15 different domains of KMT2A. Compared to variants in healthy controls, WDSTS variants exhibit a 61.9-fold overrepresentation within the CXXC domain-which mediates binding to unmethylated CpGs-suggesting a major role for this domain in mediating the phenotype. In contrast, we find no significant overrepresentation within the catalytic SET domain. Corroborating these results, we find that hippocampal neurons from Kmt2a-deficient mice demonstrate disrupted histone methylation (H3K4me1 and H3K4me3) preferentially at CpG-rich regions, but this has no systematic impact on gene expression. Motivated by these results, we combine accurate prediction of the CXXC domain structure by AlphaFold2 with prior biological knowledge to develop a classification scheme for missense variants in the CXXC domain. Our classifier achieved 92.6% positive and 92.9% negative predictive value on a hold-out test set. This classification performance enabled us to subsequently perform an in silico saturation mutagenesis and classify a total of 445 variants according to their functional effects. Our results yield a novel insight into the mechanistic basis of WDSTS and provide an example of how AlphaFold2 can contribute to the in silico characterization of variant effects with very high accuracy, suggesting a paradigm potentially applicable to many other Mendelian disorders.

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PURPOSE: Providing effective treatment for immigrants is an increasing challenge for mental health services across Europe. Yet, little is known as to whether current practice is associated with different outcomes in migrant and non-migrant patients. We compared outcomes of inpatient psychiatric treatment for migrants and non-migrants in a sample from five European countries. METHODS: Patients with psychotic disorders, affective disorders or anxiety/somatisation disorders admitted to routine psychiatric inpatient treatment were assessed in hospitals in Belgium, Germany, Italy, Poland and the United Kingdom. Treatment outcomes were satisfaction with care during hospitalisation, length of stay, readmission to hospital (any and, specifically, involuntary re-hospitalisation), as well as untoward incidents in a 1-year follow-up period. Outcomes were compared between patients born inside (non-migrants) and outside (migrants) the country of treatment, through mixed regression models. RESULTS: Across all sites, 985 migrant patients and 6298 non-migrant patients were included. After accounting for the influence of confounding patient characteristics, migrants reported significantly lower treatment satisfaction, but there were no significant differences for length of stay and re-hospitalisations, in general and involuntary ones. Migrants had a lower rate of suicide attempts, but there was no significant difference in other types of untoward incidents in the year following the index admission. CONCLUSION: The study suggests that migrants are less satisfied with their hospital treatment, there is no evidence that routine inpatient care as currently provided results overall in poorer objective outcomes for migrants than in non-migrant populations.

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PURPOSE: Strengthening the resilience of adolescents is central to promoting long-term mental health outcomes, but resilience is a widely used term, often applied in different ways. We explored how resilience is understood in the adolescent mental health literature and developed a framework that synthesizes the core characteristics of different resilience concepts. METHODS: Systematic searches of electronic databases, hand searches of reference lists and known work on resilience, and multidisciplinary team discussions were employed, and articles with explicit conceptualizations of resilience in adolescent mental health literature were included. After screening 9,562 articles, 105 articles were retained, analyzed and used to refine a framework. RESULTS: Three dimensions capture the various concepts of resilience, each with two end points: (1) resilience as withstanding adversity without any distress versus overcoming the distress resulting from adversity; (2) resilience as an existing trait versus as a process over time; and (3) resilience of individuals versus resilience of groups. CONCLUSION: Concepts of resilience in adolescence can be clearly categorized within three distinct dimensions. Referring to this framework may help to clarify and compare different concepts of resilience of adolescents in mental health research as well as at a policy level and in clinical contexts.

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Solid-phase extraction (SPE) is a widely-used and very well-established sample preparation technique for liquid samples. An area of on-going focus for innovation in this field concerns the development of new and improved SPE sorbents that can enhance the sensitivity and/or the selectivity of SPE processes. In this context, mixed-mode ion-exchange sorbents have been developed and commercialised, thereby allowing enhanced capacity and selectivity to be offered by one single material. The ion-selectivity of these materials is such that either anion-exchange or cation-exchange is possible, however one limitation to their use is that more than one sorbent type is required to capture both anions and cations. In this paper, we disclose the design, synthesis and exploitation of a novel SPE sorbent based on microporous polymer microspheres with amphoteric character. We show that it is possible to switch the ion-exchange retention mechanism of the sorbent simply by changing the pH of the loading solution; anion-exchange dominates at low pH, cation-exchange dominates at high pH, and both mechanisms can contribute to retention when the polymer-bound amphoteric species, which are based on the α-amino acid sarcosine (N-methylglycine), are in a zwitterionic state. This is an interesting and useful feature, since it allows distinctly different groups of analytes (acids and bases) to be fractionated using one single amphoteric sorbent with dual-functionality. The sarcosine-based sorbent was applied to the SPE of acidic, basic and amphoteric analytes from ultrapure water, river water and effluent wastewater samples. Under optimised conditions (loading 100 mL of sample at pH 6, washing with 1 mL of MeOH and eluting with an acidic or basic additive in MeOH) the recoveries for most of the compounds were from 57% to 87% for river water and from 61% to 88% for effluent wastewater. We anticipate that these results will lay the basis for the development of a new family of multifunctional sorbents, where two or more separation mechanisms can be embedded within one single, bespoke material optimised for application to challenging chemical separations to give significant selectivity advantages over essentially all other state-of-the-art SPE sorbents.

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Lebanon hosts over one million refugees displaced from Syria as a result of the armed conflict-of whom, approximately 15% are adolescents aged between 12 and 17 years of age. Many female adolescent migrants report a decrease in quality of life and an increase in family tensions. This study sought to investigate the emotional well-being of adolescent Syrian girls in Lebanon. We hypothesized that married girls may experience additional hardships and thus greater feelings of dissatisfaction in daily life, given their young marriage and responsibilities at home. This study was part of a large mixed-methods study on the experiences of Syrian refugee girls in Lebanon (n = 1422). Using line-by-line coding and thematic analysis, 188 first-person narratives from Syrian girls were analysed. Our results highlight poor emotional well-being among married and unmarried girls, with sadness, fear and anger commonly mentioned. Some participants expressed feelings of hope, happiness, gratefulness and empowerment. Unmarried girls (n = 111) were more likely to associate their shared stories with negative feelings such as sadness (47% vs. 22%), disappointment (30% vs. 19%), and frustration (32% vs. 22%) than were married girls (n = 77). Four themes emerged as important determinants: access to education, perceived safety, peer support, and longing for life back in Syria. Continued efforts to improve emotional well-being for married and unmarried refugee girls are needed in Lebanon, in particular those that address the nuances for these groups.

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Waldenström's macroglobulinemia (WM) is a non-Hodgkin lymphoma, resulting in antibody-secreting lymphoplasmacytic cells in the bone marrow and pathologies resulting from high levels of monoclonal immunoglobulin M (IgM) in the blood. Despite the key role for BLIMP1 in plasma cell maturation and antibody secretion, its potential effect on WM cell biology has not yet been explored. Here we provide evidence of a crucial role for BLIMP1 in the survival of cells from WM cell line models and further demonstrate that BLIMP1 is necessary for the expression of the histone methyltransferase EZH2 in both WM and multiple myeloma cell lines. The effect of BLIMP1 on EZH2 levels is post-translational, at least partially through the regulation of proteasomal targeting of EZH2. Chromatin immunoprecipitation analysis and transcriptome profiling suggest that the two factors co-operate in regulating genes involved in cancer cell immune evasion. Co-cultures of natural killer cells and cells from a WM cell line further suggest that both factors participate in immune evasion by promoting escape from natural killer cell-mediated cytotoxicity. Together, the interplay of BLIMP1 and EZH2 plays a vital role in promoting the survival of WM cell lines, suggesting a role for the two factors in Waldenström's macroglobulinaemia.

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Traditional foods contribute to the health and well-being of Indigenous Peoples. Many Indigenous Peoples within Canada have expressed a desire to consume more traditional foods; however, there are a number of barriers to doing so. Southern and urban communities face unique challenges associated with traditional food consumption. To address these concerns and build on community interests in a Haudenosaunee community in Southern Ontario, a participatory research project was initiated. This community-based study utilized Photovoice methodology to explore the perceptions of and experiences with traditional foods among local youth. Participants ranging in age from 15-22 (n = 5) took photos of their local food environments, including locations where foods were acquired, consumed, prepared, or shared during two seasons of the year. Semi-structured interviews were conducted to collect participants' stories behind 8-10 self-selected images. A thematic analysis was subsequently utilized to identify patterns and themes illustrated by the photos and interview content. The youth conveyed contextual understandings of traditional foods and a preference for these items, despite their limited consumption, preparation or harvesting of these foods. The youth also identified the important influence of families and communities on their individual perceptions and experiences with traditional foods. Recommendations to reduce barriers to traditional food choices among youth are made.

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The ability of a parent to step back from their own experiences in order to understand those of their child, reflective functioning (RF), can be impacted by myriad factors. We explored RF among refugee mothers in the context of having a child born of sexual violence (CBSV). A sample of 10 mothers now residing in the Netherlands, both with (n = 5) and without (n = 5) a CBSV, were interviewed, seeking to explore parents' representations of their children, themselves as parents, and their relationship with their children. After deriving a score of RF, interview narratives were qualitatively analyzed using thematic analysis. An ordinary level of reflective functioning was identified in this sample overall (average score 4.5); which was reduced in the group with CBSV (average score 3.0). Trends within the qualitative analyses indicated that emotion regulation and ambivalence as well as parenting challenges are factors that affect RF capabilities for mothers with CBSV. Wider findings show that the asylum process and mental well-being also impinge on RF capabilities. Experiences of having a CBSV as well as those pertaining to being a refugee appear to interact and impact reflective functioning for some mothers. Further investigation would add weight to this pilot data.

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BACKGROUND: Conflict-related sexual violence (CRSV) was committed on a large scale against women across Bosnia and Herzegovina (BiH) during the 1990's war, and research has shown both negative and positive psychosocial outcomes following such acts of interpersonal violence. We aim to determine the capacity for posttraumatic growth (PTG) among a population of women who experienced CRSV, and to what extent it is impacted by factors such as coping and optimism. METHODS: This study sought to examine the relationship between PTG (posttraumatic growth inventory), symptoms of posttraumatic stress disorder (PTSD; Harvard Trauma Questionnaire) and dispositional factors such as coping (COPE) and optimism (Life-Orientation Test-Revised) in a sample of n = 104 women. We first conducted bivariate correlations and then hierarchical linear regression analyses, and hypothesized that approach coping strategies and optimism will act to enhance PTG. RESULTS: Findings showed that the average total score for PTG in this study was 58.94 (SD = 23.01), and current PTSD symptomatology above a threshold of > 2.5 was detected in 92.3% (n = 96) participants (mean score 3.18, SD = .45). Bivariate correlations showed that higher levels of PTG were associated with greater optimism, greater approach coping strategies positive reinterpretation and planning, and lower avoidance strategies behavioural disengagement and substance use. When entered into a regression model, only positive reinterpretation and behavioural disengagement remained, the R-square of the total set of predictors was 0.16, thus explaining 16% of PTG total score. CONCLUSION: Two types of coping (namely capacity of both greater positive reinterpretation and lower behavioural disengagement) most strongly predicted growth after trauma in this sample of CRSV survivors from BiH. These dimensions of coping confirm the role of coping strategies in the development of PTG. Further research would be useful in corroborating these findings in other post-conflict settings, and delving further into the possibility of a dual mechanism of growth and distress after CRSV.

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Metabolism alterations are hallmarks of cancer, but the involvement of lipid metabolism in disease progression is unclear. We investigated the role of lipid metabolism in prostate cancer using tissue from patients with prostate cancer and patient-derived xenograft mouse models. We showed that fatty acid uptake was increased in human prostate cancer and that these fatty acids were directed toward biomass production. These changes were mediated, at least partly, by the fatty acid transporter CD36, which was associated with aggressive disease. Deleting Cd36 in the prostate of cancer-susceptible Pten-/- mice reduced fatty acid uptake and the abundance of oncogenic signaling lipids and slowed cancer progression. Moreover, CD36 antibody therapy reduced cancer severity in patient-derived xenografts. We further demonstrated cross-talk between fatty acid uptake and de novo lipogenesis and found that dual targeting of these pathways more potently inhibited proliferation of human cancer-derived organoids compared to the single treatments. These findings identify a critical role for CD36-mediated fatty acid uptake in prostate cancer and suggest that targeting fatty acid uptake might be an effective strategy for treating prostate cancer.

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Mothers with children born of sexual violence often have complex needs that are seldom adequately addressed in social care settings. The authors' objective was to investigate the current care provisions for these mothers and children, and how these might be enhanced in the future. Twenty-one experts were asked about their current approaches and difficulties in treating this population and to suggest recommendations for improving care. The same group was asked to comment on the relevance and feasibility of implementing suggested options. The authors suggest that a holistic and community embedded approach that can be applied across settings will be most beneficial.

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Although a growing field, much is still unknown about how different clinical and social care services might improve outcomes for female victims of intimate partner violence (IPV) and their children who are indirectly exposed to it. This review sought to characterize the structure of programs that have been tested and documented in existing literature, and the mechanisms by which change, if any, may occur. Seventeen individual interventions and two follow-ups (n = 19) were included in the review. Findings suggest that a multileveled program of mothers and children working both separately and jointly together across sessions might generate the most successful psychosocial recovery for mothers and children who have experienced violence in the home. The mechanism by which this happens is likely a collaborative one, focused on enhancing the dyadic interaction. This article adds to the growing evidence base on IPV and confirms the positive impact on well-being that programs for IPV victims can have. The evidence-base overall could benefit from testing and replicating a combination of the results found in this review.

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BACKGROUND: Female survivors of sexual violence in conflict experience not only physical and psychological sequelae from the event itself, but often many negative social outcomes, such as rejection and ostracisation from their families and community. Male relatives - whether husbands, fathers, brothers - play a key role in determining how the family and community respond to a survivor of sexual violence. Understanding these perspectives could help improve services for survivors of sexual violence, as well as their families and communities. METHODS: This study draws on qualitative data gathered from focus groups of 68 men in the eastern region of Democratic Republic of Congo. Men were asked about their experiences as relatives of women who had experienced sexual violence. RESULTS: Two dominant themes arose throughout the focus groups: factors driving rejection and pathways to acceptance. Factors driving rejection included: fear of sexually transmitted infections, social stigma directed toward the husbands themselves, and an understanding of marriage and fidelity that is incompatible with rape. Men also touched on their own trauma, including struggling with witnessing a rape that took place in public, or caring for a survivor with a child from rape. They noted that the economic burden of medical treatment for survivors was a salient factor in the decision to reject. Pathways to acceptance included factors such as the love of their spouse or relative, survivors' potential to give continued financial contribution to the family, the need to keep the family together to care for children in the home, and pressure from people of importance in the community. CONCLUSION: This study provides unique insight into how male relatives respond to close family members who have experienced sexual violence. This is particularly critical since the reaction of a male relative after rape can be the most pivotal factor in promoting or impeding recovery for a survivor. These results emphasise the importance of services that focus not only on the survivor of violence herself, but also on key family members that can ideally help support her recovery.

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BACKGROUND: Social networks of patients with psychosis can provide social support, and improve health and social outcomes, including quality of life. However, patients with psychosis often live rather isolated with very limited social networks. Evidence for interventions targeting symptoms or social skills, are largely unsuccessful at improving social networks indirectly. As an alternative, interventions may directly focus on expanding networks. In this systematic review, we assessed what interventions have previously been tested for this and to what extent they have been effective. METHODS: A systematic review was conducted of randomised controlled trials, testing psychosocial interventions designed to directly increase the social networks of patients with psychosis. Searches of five online databases (PsycINFO, CINAHL, Cochrane Database, MEDLINE, Embase), hand searching of grey literature, and both forward and backward snowballing of key papers were conducted and completed on 12 December 2014. Trial reports were included if they were written in English, the social network size was the primary outcome, participants were ≥ 18 years old and diagnosed with a psychotic disorder. RESULTS: Five studies (n = 631 patients) met the complete inclusion criteria. Studies were from different countries and published since 2008. Four trials had significant positive results, i.e. an observable increase in patients' social network size at the end of the intervention. The interventions included: guided peer support, a volunteer partner scheme, supported engagement in social activity, dog-assisted integrative psychological therapy and psychosocial skills training. Other important elements featured were the presence of a professional, and a focus on friendships and peers outside of services and the immediate family. CONCLUSIONS: Despite the small number and heterogeneity of included studies, the results suggest that interventions directly targeting social isolation can be effective and achieve a meaningful increase in patients' networks. Thus, although limited, the existing evidence is encouraging, and the range of interventions used in the reported trials leave various options for future research and further improvements. Future research is needed to test the findings in different settings, identify which components are particularly effective, and determine to what extent the increased networks, over time, impact on patients' symptoms and quality of life.

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The function of the stress-responsive N-myc downstream-regulated gene 2 (NDRG2) in the control of myoblast growth, and the amino acids contributing to its function, are not well characterized. Here, we investigated the effect of increased NDRG2 levels on the proliferation, differentiation and apoptosis in skeletal muscle cells under basal and stress conditions. NDRG2 overexpression increased C2C12 myoblast proliferation and the expression of positive cell cycle regulators, cdk2, cyclin B and cyclin D, and phosphorylation of Rb, while the serine/threonine-deficient NDRG2, 3A-NDRG2, had less effect. The onset of differentiation was enhanced by NDRG2 as determined through the myogenic regulatory factor expression profiles and myocyte fusion index. However, the overall level of differentiation in myotubes was not different. While NDRG2 up-regulated caspase 3/7 activities during differentiation, no increase in apoptosis was measured by TUNEL assay or through cleavage of caspase 3 and PARP proteins. During H2O2 treatment to induce oxidative stress, NDRG2 helped protect against the loss of proliferation and ER stress as measured by GRP78 expression with 3A-NDRG2 displaying less protection. NDRG2 also attenuated apoptosis by reducing cleavage of PARP and caspase 3 and expression of pro-apoptotic Bax while enhancing the pro-survival Bcl-2 and Bcl-xL levels. In contrast, Mcl-1 was not altered, and NDRG2 did not protect against palmitate-induced lipotoxicity. Our findings show that NDRG2 overexpression increases myoblast proliferation and caspase 3/7 activities without increasing overall differentiation. Furthermore, NDRG2 attenuates H2O2-induced oxidative stress and specific serine and threonine amino acid residues appear to contribute to its function in muscle cells.

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OBJECTIVE: To explore responses to overground bionic ambulation (OBA) training from an interdisciplinary perspective including key components of neuromuscular activation, exercise conditioning, mobility capacity, and neuropathic pain. DESIGN: Case series. SETTING: Academic research center. PARTICIPANTS: Persons (N=3; 2 men, 1 woman) aged 26 to 38 years with complete spinal cord injury (SCI) (American Spinal Injury Association Impairment Scale grade A) between the levels of T1 and T10 for ≥1 year. INTERVENTION: OBA 3d/wk for 6 weeks. MAIN OUTCOME MEASURES: To obtain a comprehensive understanding of responses to OBA, an array of measures were obtained while walking in the device, including walking speeds and distances, energy expenditure, exercise conditioning effects, and neuromuscular and cortical activity patterns. Changes in spasticity and pain severity related to OBA use were also assessed. RESULTS: With training, participants were able to achieve walking speeds and distances in the OBA device similar to those observed in persons with motor-incomplete SCI (10-m walk speed, .11-.33m/s; 2-min walk distance, 11-33m). The energy expenditure required for OBA was similar to walking in persons without disability (ie, 25%-41% of peak oxygen consumption). Subjects with lower soleus reflex excitability walked longer during training, but there was no change in the level or amount of muscle activity with training. There was no change in cortical activity patterns. Exercise conditioning effects were small or nonexistent. However, all participants reported an average reduction in pain severity over the study period ranging between -1.3 and 1.7 on a 0-to-6 numeric rating scale. CONCLUSIONS: OBA training improved mobility in the OBA device without significant changes in exercise conditioning or in neuromuscular or cortical activity. However, pain severity was reduced and no severe adverse events were encountered during training. OBA therefore opens the possibility to reduce the common consequences of chronic, complete SCI such as reduced functional mobility and neuropathic pain.

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OBJECTIVES: Dust mass concentrations, temperatures, and carbon dioxide concentrations were mapped in a modern, 1048-pen swine gestation barn in winter, spring, and summer. METHODS: In each season, two technicians measured respirable mass concentrations with an aerosol photometer and temperatures and carbon dioxide concentrations with an indoor air quality monitor at 60 positions in the barn. Stationary photometers were also deployed to measure mass concentrations during mapping at five fixed locations. RESULTS: In winter when building ventilation rates were low (center-barn mean air velocity=0.34 m s(-1), 68 fpm) to conserve heat within the barn, mass and carbon dioxide concentrations were highest (mass geometric mean, GM=0.50 mg m(-3); CO2 GM=2060 ppm) and fairly uniform over space (mass geometric standard deviation, GSD=1.48; CO2 GSD=1.24). Concentrations were lowest in summer (mass GM=0.13 mg m(-3); CO2 GM=610 ppm) when ventilation rates were high (center-barn mean air velocity=0.99 m s(-1), 196 fpm) to provide cooling. Spatial gradients were greatest in spring (mass GSD=2.11; CO2 GSD=1.50) with low concentrations observed near the building intake, increasing to higher concentrations at the building exhaust. CONCLUSIONS: Mass concentrations obtained in mapping were generally consistent with those obtained from stationary monitors. A moderately strong linear relationship (R2=0.60) was observed between the log of photometer-measured mass concentration and the log of carbon dioxide concentration, suggesting that carbon dioxide may be an inexpensive alternative to assessing air quality in a swine barn. These results indicate that ventilation can effectively reduce contaminant levels in addition to controlling temperature.

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