Microglia regulate myelin growth and integrity in the central nervous system white matter

Disruption of myelin structure occurs with ageing and neurodegenerative disease, and involves myelin which is outfolding, unravelling, less compact, and thicker. This is associated with nerve dysfunction and cognitive decline; however, the mechanisms underpinning appropriate myelin structure, i.e. myelin integrity, are unclear. The central nervous system (CNS)-resident macrophages microglia are prime candidates, as they are considered to instruct maturation of the myelinproducing oligodendrocytes and thus, myelin formation in development and following demyelination, based on studies of microglial depletion following loss-of-function of the pro-survival colony stimulating factor 1 receptor (CSF1R). As this approach also targets other CNS macrophages which may contribute to these processes, I sought to investigate the specific roles of microglia in regulating myelin health. To achieve this, I utilised a recently developed transgenic mouse model, in which deletion of the FIRE super-enhancer of the Csf1r gene (FIREΔ/Δ) leads to an absence of microglia, while other CNS macrophages are present. FIREΔ/Δ mice had no impairment in oligodendrocyte maturation or myelin formation in the white matter, yet showed a loss of its integrity, with impaired compaction, increased thickness and outfoldings and unravelling of myelin, culminating in demyelination. Results were recapitulated by depleting microglia in adulthood, indicating a role for microglia in myelin maintenance rather than development. These myelin changes were associated with impaired cognitive flexibility. Loss of myelin integrity was also observed in a human condition (ALSP) where CSF1R mutations result in reduced white matter microglia and dementia. To identify the mechanism by which microglia regulate myelin integrity, singlecell RNA sequencing of FIREΔ/Δ mice was performed, which revealed a new oligodendrocyte subpopulation. The genes upregulated in this oligodendrocyte population were predicted to be regulated by transforming growth factor β 1 (TGFβ1), a factor primarily produced by microglia, which regulates expression ii of its receptors e.g., TGFβR1. Accordingly, TGFβ1 levels in FIREΔ/Δ white matter were reduced, and oligodendroglial TGFβR1 expression was downregulated. Additionally, the conditional knockout of Tgfbr1 in mature oligodendrocytes was sufficient to cause a loss of myelin integrity, mirroring the results in the FIREΔ/Δ mice. Reinstating TGFβ downstream signalling via administration of a small molecule agonist (SRI-011381) rescued the loss of myelin integrity in FIREΔ/Δ mice, significantly reducing inner tongue enlargement and myelin thickness versus vehicle-treated mice such that these were comparable to wildtype controls. My findings reveal that microglia regulate myelin health at later stages than previously thought, preserving the structural integrity of myelin rather than driving initial myelin formation. These findings have important implications for understanding the pathological mechanisms underpinning loss of myelin integrity in ageing and neurodegenerative diseases, where dysregulated microglia may represent key therapeutic targets to restore CNS health

Staff Stress and Interpersonal Conflict in Secondary Schools—Implications for School Leadership

The importance of school leadership and workplace stress is a recurring theme in educationbased research. The literature reports that workplace stress in teaching is a difficult matter to resolve, with mixed outcomes from interventions. The aim of this initial scoping study was to report on the experiences of school leaders with interpersonal conflict (IPC), a known cause of this workplace stress. Accordingly, a sample of twelve school leaders working in Irish post primary schools were recruited to participate in this study using semi-structured interviews. All twelve participants reported experiencing workplace stress and linked other people as a source of this stress. Nine out of twelve had experienced IPC as a school leader. School leaders also noted a fear of reporting workplace stress. Half of the participants reported becoming ill from workplace stress and had taken time off from work. Participants also reported ‘balkanisation’ of like-minded cliques that tried to exert control over other groups. None of the participants expressed confidence in organisational strategies to resolve workplace stress or IPC. This study demonstrates that resolutions for IPC were scant. Further research is needed to conceptualise this phenomenon in the school environment and to support school leaders to effectively manage IPC as a cause of workplace stress

Re-identifying residential mixing: emergent identity dynamics between incomers and existing residents in a mixed neighbourhood in Northern Ireland

Research on residential diversification has neglected its impact on neighbourhood identity and overlooked the very different identity‐related experiences of new and existing residents. The present research examines how incoming and established group members relate to their changing neighbourhood in the increasingly desegregated city of Belfast, Northern Ireland. Thematic analysis of interviews with 24 residents (12 Protestant long‐term residents, 12 Catholic incomers) from an increasingly mixed neighbourhood identified asymmetrical concerns and experiences: Incomers reported undergoing an ‘identity transition’ between local communities, while long‐term residents faced an ‘identity merger’ within their neighbourhood. Where their identity concerns diverged, emergent intergroup perceptions of the residents were negative and divisive; where they accorded, positive intergroup perceptions and a shared neighbourhood identity evolved. From this, we propose a Social Identity Model of Residential Diversification (SIMRD) to encourage future research into how different identity concerns shape emergent intergroup dynamics between long‐term residents and incomers within diversifying neighbourhoods

Targeting the 19S proteasomal subunit, Rpt4, for the treatment of colon cancer.

Deregulation of the ubiquitin-proteasome pathway has been frequently observed in a number of malignancies. Using quantitative Western blotting of normal and matched tumour tissue, we here identified a significant increase in the 19S proteasome subunit Rpt4 in response to chemoradiation in locally advanced rectal cancer patients with unfavourable outcome. We therefore explored the potential of Rpt4 reduction as a therapeutic strategy in colorectal cancer (CRC). Utilizing siRNA to down regulate Rpt4 expression, we show that silencing of Rpt4 reduced proteasomal activity and induced endoplasmic reticulum stress. Gene silencing of Rpt4 also inhibited cell proliferation, reduced clonogenic survival and induced apoptosis in HCT-116 colon cancer cells. We next developed a cell penetrating peptide-based nanoparticle delivery system to achieve in vivo gene silencing of Rpt4. Administration of Rpt4 siRNA nanoparticles reduced tumour growth and improved survival in a HCT-116 colon cancer xenograft tumour model in vivo. Collectively, our data suggest that inhibition of Rpt4 represents a novel strategy for the treatment of CRC

How do people with eating disorders experience the stigma associated with their condition? A mixed-methods systematic review

Background: Public opinion research shows that eating disorders (EDs) are a major target of stigmatisation. To understand the implications of this stigma, research investigating how stigma is experienced by individuals with EDs is critical. Aims: This paper aims to collate, evaluate and synthesise the extant empirical research illuminating how people with EDs experience the stigma associated with their condition. Method: A systematic mixed-methods literature search was performed. Articles that met a specified set of inclusion criteria underwent a quality assessment and thematic synthesis. Results: 29 articles were included in the review. Studies were mostly qualitative and of reasonable methodological quality. The literature was characterised by five research themes, illuminating (i) the nature and prevalence of stigma experienced, (ii) stigma in families, (iii) stigma in healthcare contexts, (iv) self-stigmatisation and illness concealment, and (v) stigma resistance. Conclusions: The reviewed research showed that people with EDs have extensive experience of stigma in diverse settings. They report that stigma has negative implications for their psychological wellbeing and likelihood of help-seeking. However, research also shows that people with EDs actively seek to resist and challenge stigma. The review identifies the outstanding gaps and weaknesses in this literature

Calnexin, an ER-induced protein, is a prognostic marker and potential therapeutic target in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer mortality in the Western world and commonly treated with genotoxic chemotherapy. Stress in the endoplasmic reticulum (ER) was implicated to contribute to chemotherapeutic resistance. Hence, ER stress related protein may be of prognostic or therapeutic significance. METHODS: The expression levels of ER stress proteins calnexin, calreticulin, GRP78 and GRP94 were determined in n = 23 Stage II and III colon cancer fresh frozen tumour and matched normal tissue samples. Data were validated in a cohort of n = 11 rectal cancer patients treated with radiochemotherapy in the neoadjuvant setting. The calnexin gene was silenced using siRNA in HCT116 cells. RESULTS: There were no increased levels of ER stress proteins in tumour compared to matched normal tissue samples in Stage II or III CRC. However, increased calnexin protein levels were predictive of poor clinical outcome in the patient cohort. Data were validated in the rectal cancer cohort treated in the neoadjuvant setting. Calnexin gene-silencing significantly reduced cell survival and increased cancer cell susceptibility to 5FU chemotherapy. CONCLUSION: Increased tumour protein levels of calnexin may be of prognostic significance in CRC, and calnexin may represent a potential target for future therapies

Impact of therapeutic hypothermia on infantile spasms: an observational cohort study

Aim: To establish the incidence of infantile spasms in children in the southern region of the Republic of Ireland and to compare the incidence of infantile spasms before and after the introduction of therapeutic hypothermia in infants with hypoxic‐ischemic encephalopathy (HIE). Method: Children born between 2003 and 2015 and diagnosed with infantile spasms (epileptic spasms with or without hypsarrhythmia) in the first 2 years of life were identified through audits of electroencephalography reports and paediatric neurology patient lists. Data on live births were obtained from the regional hospital statistics databases. Medical charts of infantile spasm cases were reviewed for demographic information, diagnostic workup results, treatment response, disease course, and developmental outcome. Results: Forty‐two infants with infantile spasms were identified. The cumulative incidence of infantile spasms up to the age of 2 years was 4.01 per 10 000 live births. Difference due to sex was minimal (22 males, 20 females) and most infants were delivered at or near term with gestational ages ranging between 30.0 and 41.8 weeks (median [interquartile range] 39.6wks [38.1–40.0wks]). The aetiology for infantile spasms was identified in almost two‐thirds of cases, with HIE being the single most common cause (n=7). Other causes included chromosomal and monogenetic abnormalities (n=8). Infantile spasms occurred in moderate and severe grades of HIE, with a significantly higher incidence in those with severe HIE (p=0.029). Infants with severe HIE who did not receive therapeutic hypothermia were six times more likely to develop infantile spasms compared to those who did, but the difference was not statistically significant (4 out of 16 vs 1 out of 24, p=0.138). Interpretation: This study provides detailed information about infantile spasms before and after the introduction of therapeutic hypothermia. HIE severity is a risk factor for the development of infantile spasms. The introduction of therapeutic hypothermia may have had an impact, but the effect was hard to ascertain in this cohort due to the small number of infants

Erratum to: Calnexin, an ER stress-induced protein, is a prognostic marker and potential therapeutic target in colorectal cancer

Erratum to: Calnexin, an ER stress-induced protein, is a prognostic marker and potential therapeutic target in colorectal cancer

Microglia regulate myelin growth and integrity in the central nervous system

Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health(1), it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1–TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease(2,3)