Inhibiting CSF1R alleviates cerebrovascular white matter disease and cognitive impairment

\ua9 2023 The Authors. GLIA published by Wiley Periodicals LLC. White matter abnormalities, related to poor cerebral perfusion, are a core feature of small vessel cerebrovascular disease, and critical determinants of vascular cognitive impairment and dementia. Despite this importance there is a lack of treatment options. Proliferation of microglia producing an expanded, reactive population and associated neuroinflammatory alterations have been implicated in the onset and progression of cerebrovascular white matter disease, in patients and in animal models, suggesting that targeting microglial proliferation may exert protection. Colony-stimulating factor-1 receptor (CSF1R) is a key regulator of microglial proliferation. We found that the expression of CSF1R/Csf1r and other markers indicative of increased microglial abundance are significantly elevated in damaged white matter in human cerebrovascular disease and in a clinically relevant mouse model of chronic cerebral hypoperfusion and vascular cognitive impairment. Using the mouse model, we investigated long-term pharmacological CSF1R inhibition, via GW2580, and demonstrated that the expansion of microglial numbers in chronic hypoperfused white matter is prevented. Transcriptomic analysis of hypoperfused white matter tissue showed enrichment of microglial and inflammatory gene sets, including phagocytic genes that were the predominant expression modules modified by CSF1R inhibition. Further, CSF1R inhibition attenuated hypoperfusion-induced white matter pathology and rescued spatial learning impairments and to a lesser extent cognitive flexibility. Overall, this work suggests that inhibition of CSF1R and microglial proliferation mediates protection against chronic cerebrovascular white matter pathology and cognitive deficits. Our study nominates CSF1R as a target for the treatment of vascular cognitive disorders with broader implications for treatment of other chronic white matter diseases

人間の海洋移動にともなう分散がフィリピン列島における媒介蚊ネッタイシマ蚊の集団遺伝構造に影響

長崎大学学位論文 [学位記番号]博（医歯薬）甲第794号 [学位授与年月日]平成27年9月18

Neurovascular dysfunction in vascular dementia, Alzheimer’s and atherosclerosis

Efficient blood supply to the brain is of paramount importance to its normal functioning and improper blood flow can result in potentially devastating neurological consequences. Cerebral blood flow in response to neural activity is intrinsically regulated by a complex interplay between various cell types within the brain in a relationship termed neurovascular coupling. The breakdown of neurovascular coupling is evident across a wide variety of both neurological and psychiatric disorders including Alzheimer’s disease. Atherosclerosis is a chronic syndrome affecting the integrity and function of major blood vessels including those that supply the brain, and it is therefore hypothesised that atherosclerosis impairs cerebral blood flow and neurovascular coupling leading to cerebrovascular dysfunction. This review will discuss the mechanisms of neurovascular coupling in health and disease and how atherosclerosis can potentially cause cerebrovascular dysfunction that may lead to cognitive decline as well as stroke. Understanding the mechanisms of neurovascular coupling in health and disease may enable us to develop potential therapies to prevent the breakdown of neurovascular coupling in the treatment of vascular brain diseases including vascular dementia, Alzheimer’s disease and stroke

The Developmental Potential of Frugal Innovation among Mobile Money Agents in Kitwe, Zambia

Existing conceptual debates on frugal innovation have either welcomed its contribution to development or have stressed its exploitative capitalist underpinnings. Based on a qualitative survey among 52 mobile money agents and tellers in Kitwe, Zambia, the developmental potential of frugal innovation will be empirically assessed. Can the frugal innovation of mobile money become an inclusive innovation for the agents and tellers in Kitwe? This question will be tackled by focusing on entrepreneurship and labour relations. It is argued that mobile money can indeed generate employment and foster entrepreneurship, but that it can simultaneously contribute to informalisation and create new socio-economic inequalities. Empirical studies, thus, provide an opportunity to reach a more nuanced understanding of the relationship between frugal innovation and development

The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients

We recently defined a high-molecular risk category (HMR) in primary myelofibrosis (PMF), based on the presence of at least one of the five 'prognostically detrimental' mutated genes (ASXL1, EZH2, SRSF2 and IDH1/2). Herein, we evaluate the additional prognostic value of the 'number' of mutated genes. A total of 797 patients were recruited from Europe (n=537) and the Mayo Clinic (n=260). In the European cohort, 167 (31%) patients were HMR: 127 (23.6%) had one and 40 (7.4%) had two or more mutated genes. The presence of two or more mutations predicted the worst survival: median 2.6 years (hazard ratio (HR) 3.8, 95% confidence interval (CI) 2.6-5.7) vs. 7.0 years (HR 1.9, 95% CI 1.4-2.6) for one mutation vs 12.3 years for no mutations. The results were validated in the Mayo cohort and prognostic significance in both cohorts was independent of International Prognostic Scoring System (IPSS; HR 2.4, 95% CI 1.6-3.6) and dynamic IPSS (DIPSS)-plus (HR 1.9, 95% CI 1.2-3.1), respectively. Two or more mutations were also associated with shortened leukemia-free survival (HR 6.2, 95% CI 3.5-10.7), also Mayo validated. Calreticulin mutations favorably affected survival, independently of both number of mutations and IPSS/DIPSS-plus. We conclude that the 'number' of prognostically detrimental mutations provides added value in the combined molecular and clinical prognostication of PMF

Whatever happened to non-monogamies? Critical reflections on recent research and theory

The last decade has seen an explosion of interest in consensually non-monogamous relationships. This article critically reviews current research and theory in this area, focusing particularly on polyamory, swinging, and gay open relationships. The sociohistorical context in which these forms of relating emerged is considered and discussed in order to better understand why there has been such a significant increase in scholarly work on non-monogamies at this moment. Furthermore, we categorize the extant literature into two groups, 'celebratory' and 'critical', and argue that such polarization frequently works to reinforce partial and dichotomizing understandings of the topic. Research so far has primarily concentrated on the rules and boundaries which people employ to manage such relationships and we contend that future work needs to pay more attention to diversities of meanings and practices, intersections with other identities and communities, and the troubling of dichotomous understandings