Structural basis for the role of inhibition in facilitating adult brain plasticity

Although inhibition has been implicated in mediating plasticity in the adult brain, the underlying mechanism remains unclear. Here we present a structural mechanism for the role of inhibition in experience-dependent plasticity. Using chronic in vivo two-photon microscopy in the mouse neocortex, we show that experience drives structural remodeling of superficial layer 2/3 interneurons in an input- and circuit-specific manner, with up to 16% of branch tips undergoing remodeling. Visual deprivation initially induces dendritic branch retractions, and this is accompanied by a loss of inhibitory inputs onto neighboring pyramidal cells. The resulting decrease in inhibitory tone, also achievable pharmacologically using the antidepressant fluoxetine, provides a permissive environment for further structural adaptation, including addition of new synapse-bearing branch tips. Our findings suggest that therapeutic approaches that reduce inhibition, when combined with an instructive stimulus, could facilitate restructuring of mature circuits impaired by damage or disease, improving function and perhaps enhancing cognitive abilities

The Genome Sequence of 'Mycobacterium massiliense' Strain CIP 108297 Suggests the Independent Taxonomic Status of the Mycobacterium abscessus Complex at the Subspecies Level

Members of the Mycabacterium abscessus complex are rapidly growing mycobacteria that are emerging as human pathogens. The M. abscassus complex was previously composed of three species, namely M. abscessus sensu strict, 'M. massiliense', and M. bolletii', In 2011, 'M. massiliense' and 'M. bolletre' were united and reclassified as a single subspecies within M. abscessus: M. abscessus subsp. bolletii. However, the placement of 'M. massiliense' Within the boundary of M. abscessus subsp. balletii remains highly controversial with regard to clinical aspects. In this study, we revisited the taxonomic status of members of the M. abscessus complex based on comparative analysis of he whole-genome sequences of 53 strains, The genome sequence of the previous type strain of 'Mycobacterium massiliense' (CIP 108297) was determined using next-generation sequencing. The genome tree based on average nucleotide identity (AN I) values supported the differentiation of M. bolletii' and M. massiliense' at the subspecies level. The genome tree also clearly illustrated that 'M. bolletil' and 'M. massiliense' form a distinct phylogenetic clade within the radiation of the M. abscessus complex. The genomic distances observed in this study suggest that the current M. abscessus subsp. bolletii taxon should be divided into two subspecies, M. abscessus subsp. massiliense subsp. nov. and M. abscessus subsp. bolletii, to correspondingly accommodate the previously known 'M. assiliense' and 'M. bolletii' strains.

Dual Therapy with Cidofovir and Mirtazapine for Progressive Multifocal Leukoencephalopathy in a Sarcoidosis Patient

Background: Progressive multifocal leukoencephalopathy (PML) is a demyelinating central nervous system disease caused by JC virus (JCV) reactivation in immunocompromised patients. The disease course of PML is often progressive, fatal and at present, there are few reports on successful treatment outcomes. Case Report: A 45-year-old man with systemic sarcoidosis presented with rapidly progressive dementia and right hemiparesis. The patient was diagnosed with PML as confirmed via brain biopsy and JCV PCR. With a combination treatment of cidofovir and mirtazapine, there was significant improvement of neurological symptoms without measurable functional deficit. Conclusion: This case suggests that dual therapy with cidofovir and mirtazapine might be an effective treatment option in PML patients with sarcoidosis

Comprehensive and unbiased multiparameter high-throughput screening by compaRe finds effective and subtle drug responses in AML models

Large-scale multiparameter screening has become increasingly feasible and straightforward to perform thanks to developments in technologies such as high-content microscopy and high-throughput flow cytometry. The automated toolkits for analyzing similarities and differences between large numbers of tested conditions have not kept pace with these technological developments. Thus, effective analysis of multiparameter screening datasets becomes a bottleneck and a limiting factor in unbiased interpretation of results. Here we introduce compaRe, a toolkit for large-scale multiparameter data analysis, which integrates quality control, data bias correction, and data visualization methods with a mass-aware gridding algorithm-based similarity analysis providing a much faster and more robust analyses than existing methods. Using mass and flow cytometry data from acute myeloid leukemia and myelodysplastic syndrome patients, we show that compaRe can reveal interpatient heterogeneity and recognizable phenotypic profiles. By applying compaRe to high-throughput flow cytometry drug response data in AML models, we robustly identified multiple types of both deep and subtle phenotypic response patterns, highlighting how this analysis could be used for therapeutic discoveries. In conclusion, compaRe is a toolkit that uniquely allows for automated, rapid, and precise comparisons of large-scale multiparameter datasets, including high-throughput screens.Peer reviewe

A metabolite-derived protein modification integrates glycolysis with KEAP1-NRF2 signalling.

Mechanisms that integrate the metabolic state of a cell with regulatory pathways are necessary to maintain cellular homeostasis. Endogenous, intrinsically reactive metabolites can form functional, covalent modifications on proteins without the aid of enzymes1,2, and regulate cellular functions such as metabolism3-5 and transcription6. An important 'sensor' protein that captures specific metabolic information and transforms it into an appropriate response is KEAP1, which contains reactive cysteine residues that collectively act as an electrophile sensor tuned to respond to reactive species resulting from endogenous and xenobiotic molecules. Covalent modification of KEAP1 results in reduced ubiquitination and the accumulation of NRF27,8, which then initiates the transcription of cytoprotective genes at antioxidant-response element loci. Here we identify a small-molecule inhibitor of the glycolytic enzyme PGK1, and reveal a direct link between glycolysis and NRF2 signalling. Inhibition of PGK1 results in accumulation of the reactive metabolite methylglyoxal, which selectively modifies KEAP1 to form a methylimidazole crosslink between proximal cysteine and arginine residues (MICA). This posttranslational modification results in the dimerization of KEAP1, the accumulation of NRF2 and activation of the NRF2 transcriptional program. These results demonstrate the existence of direct inter-pathway communication between glycolysis and the KEAP1-NRF2 transcriptional axis, provide insight into the metabolic regulation of the cellular stress response, and suggest a therapeutic strategy for controlling the cytoprotective antioxidant response in several human diseases

VEGF-A regulated by progesterone governs uterine angiogenesis and vascular remodelling during pregnancy

Peer reviewe

The bracteatus pineapple genome and domestication of clonally propagated crops

Domestication of clonally propagated crops such as pineapple from South America was hypothesized to be a 'one-step operation'. We sequenced the genome of Ananas comosus var. bracteatus CB5 and assembled 513 Mb into 25 chromosomes with 29,412 genes. Comparison of the genomes of CB5, F153 and MD2 elucidated the genomic basis of fiber production, color formation, sugar accumulation and fruit maturation. We also resequenced 89 Ananas genomes. Cultivars 'Smooth Cayenne' and 'Queen' exhibited ancient and recent admixture, while 'Singapore Spanish' supported a one-step operation of domestication. We identified 25 selective sweeps, including a strong sweep containing a pair of tandemly duplicated bromelain inhibitors. Four candidate genes for self-incompatibility were linked in F153, but were not functional in self-compatible CB5. Our findings support the coexistence of sexual recombination and a one-step operation in the domestication of clonally propagated crops. This work guides the exploration of sexual and asexual domestication trajectories in other clonally propagated crops

The impact of education on cortical thickness in amyloid-negative subcortical vascular dementia: cognitive reserve hypothesis

Background: The protective effect of education has been well established in Alzheimer's disease, whereas its role in patients with isolated cerebrovascular diseases remains unclear. We examined the correlation of education with cortical thickness and cerebral small vessel disease markers in patients with pure subcortical vascular mild cognitive impairment (svMCl) and patients with pure subcortical vascular dementia (SVaD). Methods: We analyzed 45 patients with svMCl and 47 patients with SVaD with negative results on Pittsburgh compound B positron emission tomographic imaging who underwent structural brain magnetic resonance imaging. The main outcome was cortical thickness measured using surface-based morphometric analysis. We also assessed the volumes of white matter hyperintensities (WMH) and numbers of lacunes as other outcomes. To investigate the correlation of education with cortical thickness, WMH volume, and number of lacunes, multiple linear regression analyses were performed after controlling for covariates, including Mini Mental State Examination, in the svMCl and SVaD groups. Results: In the SVaD group, higher education was correlated with more severe cortical thinning in the bilateral dorsolateral frontal, left medial frontal, and parahippocampal areas, whereas there was no correlation of education with cortical thickness in the svMCl group. There was no correlation between education and cerebral small vessel disease, including WMH and lacunes, in both patients with svMCl and patients with SVaD. Conclusions: Our findings suggest that the compensatory effects of education on cortical thinning apply to patients with SVaD, which might be explained by the cognitive reserve hypothesis