Plos One
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Laminae I-III of the spinal dorsal horn contain many inhibitory interneurons that use GABA and/or glycine as a neurotransmitter. Distinct neurochemical populations can be recognised among these cells, and these populations are likely to have differing roles in inhibiting pain or itch. Quantitative studies in rat have shown that inhibitory interneurons account for 25-40% of all neurons in this region. ⋯ As in the rat, the sst2A receptor is only expressed by inhibitory interneurons in laminae I-II, and is present on just over half (54%) of these cells. Antibody against the neurokinin 1 receptor was used to define lamina I, and we found that although the receptor was concentrated in this lamina, it was expressed by many fewer cells than in the rat. By estimating the total numbers of neurons in each of these laminae in the L4 segment of the mouse, we show that there are around half as many neurons in each lamina as are present in the corresponding segment of the rat.
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High-mobility group box 1 (HMGB1) was initially discovered as a nuclear protein that interacts with DNA as a chromatin-associated non-histone protein to stabilize nucleosomes and to regulate the transcription of many genes in the nucleus. Once leaked or actively secreted into the extracellular environment, HMGB1 activates inflammatory pathways by stimulating multiple receptors, including Toll-like receptor (TLR) 2, TLR4, and receptor for advanced glycation end products (RAGE), leading to tissue injury. Although HMGB1's ability to induce inflammation has been well documented, no studies have examined the role of HMGB1 in wound healing in the gastrointestinal field. ⋯ TLR4 and RAGE deficiency enhanced ulcer healing and reduced the level of TNFα, whereas ulcer healing in TLR2 knockout (KO) mice was similar to that in wild-type mice. In TLR4 KO and RAGE KO mice, exogenous HMGB1 did not affect ulcer healing and TNFα expression. Thus, we showed that HMGB1 is a complicating factor in the gastric ulcer healing process, which acts through TLR4 and RAGE to induce excessive inflammatory responses.
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Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder. Current diagnosis time is about 12-months due to lack of objective methods. Previous brain white matter voxel based morphometry (VBM) studies in ALS reported inconsistent results. ⋯ FD correlated significantly with revised ALS functional rating scale (ALSFRS-R) score a clinical measure of function. Results suggest that brain WM shape complexity is more sensitive to ALS disease process when compared to volumetric VBM analysis and FD changes are dependent on the ALS phenotype. Correlation between FD and clinical measures suggests that FD could potentially serve as a biomarker of ALS pathophysiology, especially after confirmation by longitudinal studies.
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Missense mutations in ATP1A3 encoding Na(+),K(+)-ATPase α3 have been identified as the primary cause of alternating hemiplegia of childhood (AHC), a motor disorder with onset typically before the age of 6 months. Affected children tend to be of short stature and can also have epilepsy, ataxia and learning disability. The Na(+),K(+)-ATPase has a well-known role in maintaining electrochemical gradients across cell membranes, but our understanding of how the mutations cause AHC is limited. ⋯ Using molecular modelling, we show that the Myshkin and AHC mutations display similarly severe structural impacts on Na(+),K(+)-ATPase α3, including upon the K(+) pore and predicted K(+) binding sites. Behavioural analysis of Myshkin mice revealed phenotypic abnormalities similar to symptoms of AHC, including motor dysfunction and cognitive impairment. 2-DG imaging of Myshkin mice identified compromised thalamocortical functioning that includes a deficit in frontal cortex functioning (hypofrontality), directly mirroring that reported in AHC, along with reduced thalamocortical functional connectivity. Our results thus provide validation for missense mutations in Na(+),K(+)-ATPase α3 as a cause of AHC, and highlight Myshkin mice as a starting point for the exploration of disease mechanisms and novel treatments in AHC.
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The number of retracted scientific publications has risen sharply, but it is unclear whether this reflects an increase in publication of flawed articles or an increase in the rate at which flawed articles are withdrawn. ⋯ The increase in retracted articles appears to reflect changes in the behavior of both authors and institutions. Lower barriers to publication of flawed articles are seen in the increase in number and proportion of retractions by authors with a single retraction. Lower barriers to retraction are apparent in an increase in retraction for "new" offenses such as plagiarism and a decrease in the time-to-retraction of flawed work.