Microglia have long been the focus of much attention due to their strong proliferative response (microgliosis) to essentially any kind of damage to the CNS. More recently, we reached the realization ...that these cells play specific roles in determining progression and outcomes of essentially all CNS disease. Thus, microglia has ceased to be viewed as an accessory to underlying pathologies and has now taken center stage as a therapeutic target. Here, we review how our understanding of microglia’s involvement in promoting or limiting the pathogenesis of diseases such as amyotrophic lateral sclerosis, Alzheimer’s disease, Huntington’s disease, multiple sclerosis, X-linked adrenoleukodystrophy (X-ALD) and lysosomal storage diseases (LSD) has changed over time. While strategies to suppress the deleterious and promote the virtuous functions of microglia will undoubtedly be forthcoming, replacement of these cells has already proven its usefulness in a clinical setting. Over the past few years, we have reached the realization that microglia have a developmental origin that is distinct from that of bone marrow-derived myelomonocytic cells. Nevertheless, microglia can be replaced, in specific situations, by the progeny of hematopoietic stem cells (HSCs), pointing to a strategy to engineer the CNS environment through the transplantation of modified HSCs. Thus, microglia replacement has been successfully exploited to deliver therapeutics to the CNS in human diseases such as X-ALD and LSD. With this outlook in mind, we will discuss the evidence existing so far for microglial involvement in the pathogenesis and the therapy of specific CNS disease.
To examine the awareness and perceptions of local government staff about the social determinants of health (SDoH) and health inequity and use of these ideas to shape policy and practice.
96 staff at ...17 councils in South Australia or New South Wales responded to questions in a pilot online survey concerning: sources of knowledge about, familiarity with the evidence on, attitudes towards, and uses of ideas about the social determinants of health. Eight of 68 SA councils and 16 of 152 NSW councils were randomly selected stratified by state and metropolitan status. Differences between states and metropolitan/non‐metropolitan status were explored.
The majority of respondents (88.4%) reported some familiarity with ideas about the broad determinants of health and 90% agreed that the impact of policy action on health determinants should be considered in all major government policy and planning initiatives. Research articles, government/professional reports, and professional contacts were rated as important sources of knowledge about the social determinants of health.
Resources need to be dedicated to systematic research on practical implementation of interventions on social determinants of health inequities and towards providing staff with more practical information about interventions and tools to evaluate those interventions.
The findings suggest there is support for action addressing the social determinants of health in local government. The findings extend similar research regarding SDoH and government in NZ and Canada to Australian local government.
In zebrafish larvae, the first response when detecting prey is an oculomotor behavior; eye convergence. Eye convergence increases the overlap between the visual fields of the left and right eyes to ...prepare for tracking prey. A high vergence angle is maintained throughout the prey-tracking and capture swim phases, enhancing binocular depth. Since the discovery of eye convergence, hundreds of articles reporting on this behavior in zebrafish have been published. In this study, we found that the larvae of blind tetra cavefish, Astyanax mexicanus, despite being adapted to the absence of visual stimuli due to the lack of light in the cave, have retained the oculomotor behavior of eye convergence in their vestigial eyes. In Astyanax, eye convergence responses can be triggered singlehandedly by vibrations elicited with a glass rod at frequencies similar to those generated by its prey (10-35 Hz). The blind cave tetra offers an intriguing combination of regression of the eye structure, while retaining several of the physiological functions and actions performed in the eye, including light-entrained retinomotor rhythms and eye convergence.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
4.
Clinical/Scientific Notes NUMIS, Adam L; ANGRIMAN, Marco; SULLIVAN, Joseph E ...
Neurology,
01/2014, Letnik:
82, Številka:
4
Journal Article
Neonatal-onset epilepsies are rare conditions, mostly genetically determined, that can have a benign or severe phenotype.(1,2) There is recent recognition of de novo KCNQ2 mutations in patients with ...severe neonatal-onset epilepsy with intractable seizures and severe psychomotor impairment, termed KCNQ2 encephalopathy.(3,4) This is a rare condition and all patients reported so far were diagnosed well after the neonatal period.(3,4) We report on 3 new cases of KCNQ2 encephalopathy diagnosed in the neonatal period and studied with continuous video-EEG recording. We describe a distinct electroclinical phenotype and report on efficacy of antiepileptic drug (AED) therapies.
The development of cell therapy for repairing damaged or diseased skeletal muscle has been hindered by the inability to significantly expand immature, transplantable myogenic stem cells (MuSCs) ...in culture. To overcome this limitation, a deeper understanding of the mechanisms regulating the transition between activated, proliferating MuSCs and differentiation-primed, poorly engrafting progenitors is needed. Here, we show that methyltransferase Setd7 facilitates such transition by regulating the nuclear accumulation of β-catenin in proliferating MuSCs. Genetic or pharmacological inhibition of Setd7 promotes in vitro expansion of MuSCs and increases the yield of primary myogenic cell cultures. Upon transplantation, both mouse and human MuSCs expanded with a Setd7 small-molecule inhibitor are better able to repopulate the satellite cell niche, and treated mouse MuSCs show enhanced therapeutic potential in preclinical models of muscular dystrophy. Thus, Setd7 inhibition may help bypass a key obstacle in the translation of cell therapy for muscle disease.
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•Deletion of Setd7 impairs myogenic differentiation and skeletal muscle regeneration•Setd7 is localized to the cytoplasm of MuSCs and primes β-catenin for nuclear entry•Small-molecule targeting of Setd7 enhances expansion of transplantable MuSCs•Inhibition of Setd7 improves therapeutic potential of cultured mouse and human MuSCs
Judson et al. show that lysine-methyltransferase Setd7 acts cytoplasmically to regulate the differentiation of skeletal muscle stem cells (MuSCs) by priming β-catenin for nuclear import. Pharmacological inhibition of Setd7 can provide a strategy to enhance the in vitro expansion and transplantation potential of murine and human MuSCs.
The dispositions of 50 marketed central nervous system (CNS) drugs into the brain have been examined in terms of their rat in situ (P) and in vitro apparent membrane permeability (P(app)) alongside ...lipophilicity and free fraction in rat brain tissue. The inter-relationship between these parameters highlights that both permeability and brain tissue binding influence the uptake of drugs into the CNS. Hydrophilic compounds characterized by low brain tissue binding display a strong correlation (R(2) = 0.82) between P and P(app), whereas the uptake of more lipophilic compounds seems to be influenced by both P(app) and brain free fraction. A nonlinear relationship is observed between logP(oct) and P over the 6 orders of magnitude range in lipophilicity studied. These findings corroborate recent reports in the literature that brain penetration is a function of both rate and extent of drug uptake into the CNS.
Myeloablative preconditioning using irradiation is the most commonly used technique to generate rodents having chimeric bone marrow, employed for the study of bone marrow-derived cell accumulation in ...the healthy and diseased central nervous system. However, irradiation has been shown to alter the blood-brain barrier, potentially creating confounding artefacts. To better study the potential of bone marrow-derived cells to function as treatment vehicles for neurodegenerative diseases alternative preconditioning regimens must be developed. We treated transgenic mice that over-express human mutant superoxide dismutase 1, a model of amyotrophic lateral sclerosis, with busulfan to determine whether this commonly used chemotherapeutic leads to stable chimerism and promotes the entry of bone marrow-derived cells into spinal cord. Intraperitoneal treatment with busulfan at 60 mg/kg or 80 mg/kg followed by intravenous injection of green fluorescent protein-expressing bone marrow resulted in sustained levels of chimerism (~80%). Bone marrow-derived cells accumulated in the lumbar spinal cord of diseased mice at advanced stages of pathology at both doses, with limited numbers of bone marrow derived cells observed in the spinal cords of similarly treated, age-matched controls; the majority of bone marrow-derived cells in spinal cord immunolabelled for macrophage antigens. Comparatively, significantly greater numbers of bone marrow-derived cells were observed in lumbar spinal cord following irradiative myeloablation. These results demonstrate bone marrow-derived cell accumulation in diseased spinal cord is possible without irradiative preconditioning.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD).
This study describes the molecular and clinical characterisation ...of 28 probands with NDD harbouring heterozygous
coding variants, occurring de novo for all those whose transmission could have been verified (26/28).
A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del).
encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations.
Our study establishes that de novo coding variants in
are involved in a novel monogenic form of NDD, highly similar to the recently reported
-related NDD.
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