Summary Selective neuronal loss is a hallmark of neurodegenerative diseases, which counter-intuitively are often caused by mutations in widely-expressed genes1. Charcot-Marie-Tooth (CMT) diseases are the most common hereditary peripheral neuropathies, for which there are no effective therapies2,3. A subtype of the diseases—CMT2D—is caused by dominant mutations in GARS, encoding the ubiquitously expressed enzyme glycyl-tRNA synthetase (GlyRS). Despite the broad requirement of GlyRS for protein biosynthesis in all cells, mutations in this gene cause a selective degeneration of peripheral axons leading to deficits in distal motor function4. How mutations in GlyRS (GlyRSCMT2D) are linked to motor neuron vulnerability has remained elusive. Here we report that GlyRSCMT2D acquires a neomorphic binding activity that directly antagonizes an essential signaling pathway for motor neuron survival. We find that CMT2D mutations alter the conformation of GlyRS, enabling GlyRSCMT2D to bind the Neuropilin 1 (Nrp1) receptor. This aberrant interaction competitively interferes with the binding of the cognate ligand vascular endothelial growth factor (VEGF) to Nrp1. Genetic reduction of Nrp1 in mice worsens CMT2D symptoms, whereas enhanced expression of VEGF improves motor function. These findings link the selective pathology of CMT2D to the neomorphic binding activity of GlyRSCMT2D that antagonizes the VEGF/Nrp1 interaction, and indicate the VEGF/Nrp1 signaling axis is an actionable target for treating CMT2D.
Understanding the survival mechanism of metastatic cancer cells in circulation will provide new perspectives on metastasis prevention and also shed new light on metastasis-derived drug resistance. In this study, we made it feasible to detect apoptosis of circulating tumor cells (CTCs) in real-time by integrating a fluorescence resonance energy transfer (FRET)-based caspase sensor into one in vitro microfluidic circulatory system, and two in vivo models: zebrafish circulation and mouse lung metastatic model. Our study demonstrated that fluid shear stresses triggered apoptosis of breast cancer cells in circulation by elevating the mitochondrial production of the primary free radical, superoxide anion. Cancer cells with high levels of manganese superoxide dismutase (MnSOD) exhibited stronger resistance to shear force-induced apoptosis and formed more lung metastases in mice. These metastasized cells further displayed higher resistance to chemotherapeutic agent doxorubicin, which also generates superoxide in mitochondria. Specific siRNA-mediated MnSOD knockdown reversed all three phenotypes. Our findings therefore suggest that MnSOD plays an important integrative role in supporting cancer cell survival in circulation, metastasis, and doxorubicin resistance. MnSOD can serve as a new biomarker for identifying metastatic CTCs and a novel therapeutic target for inhibiting metastasis and destroying doxorubicin-resistant breast cancer cells.
Background Gut microbiota has been suggested to play a role in stroke patients. Nevertheless, little is known about gut microbiota and the clinical indexes in stroke patients. Methods Total of 30 cerebral ischemic stroke (CI) patients and 30 healthy control were enrolled in this study and the fecal gut microbiota was profiled via Illumina sequencing of the 16S rRNA V1-V2. The National Institutes of Health Stroke Scale (NIHSS) were used to quantify stroke severity and modified Rankin scale (mRS) to assess outcome for CI patients. The correlations between the clinical indexes and microbiota were evaluated. Results Though the microbial α-diversity and structure is similar between CI patients and healthy controls, the gut microbiota of CI patients had more short chain fatty acids producer including Odoribacter , Akkermansia, Ruminococcaceae_ UCG_005 and Victivallis . We also found that the special microbes were correlation with serum index, such as norank_O _ _Mollicutes_RF9 , Enterobacter , Ruminococcaceae _UCG-002 were negative correlation with LDL (r = − 0.401, P < 0.01), HDL (r = − 0.425, P < 0.01) and blood glucose (r = − 0.439, P < 0.001), while the HDL was significantly positive correlation with the genus Ruminococcus _1 (r = 0.443, P < 0.001). The Christensenellaceae _R-7_group and norank_f_ Ruminococcaceae was significantly positive correlation with NIHSS1M (r = 0.514, P < 0.05; r = 0.449, P < 0.05) and mRS (r = 0.471, P < 0.05, r = 0.503, P < 0.01), respectively. On the other hand, the genus Enterobacter was significantly negative correlation with NIHSS1M (r = 0.449, P < 0.05) and mRS (r = 0.503, P < 0.01). Conclusions This study suggests that CI patients showed significant dysbiosis of the gut microbiota with enriched short chain fatty acids producer, including Odoribacter , Akkermansia . This dysbiosis was correlation with the outcomes and deserves further study. Electronic supplementary material The online version of this article (10.1186/s12866-019-1552-1) contains supplementary material, which is available to authorized users.
Charcot-Marie-Tooth disease type 2D (CMT2D) is a peripheral nerve disorder caused by dominant, toxic, gain-of-function mutations in the widely expressed, housekeeping gene, GARS. The mechanisms underlying selective nerve pathology in CMT2D remain unresolved, as does the cause of the mild-to-moderate sensory involvement that distinguishes CMT2D from the allelic disorder distal spinal muscular atrophy type V. To elucidate the mechanism responsible for the underlying afferent nerve pathology, we examined the sensory nervous system of CMT2D mice. We show that the equilibrium between functional subtypes of sensory neuron in dorsal root ganglia is distorted by Gars mutations, leading to sensory defects in peripheral tissues and correlating with overall disease severity. CMT2D mice display changes in sensory behavior concordant with the afferent imbalance, which is present at birth and nonprogressive, indicating that sensory neuron identity is prenatally perturbed and that a critical developmental insult is key to the afferent pathology. Through in vitro experiments, mutant, but not wild-type, GlyRS was shown to aberrantly interact with the Trk receptors and cause misactivation of Trk signaling, which is essential for sensory neuron differentiation and development. Together, this work suggests that both neurodevelopmental and neurodegenerative mechanisms contribute to CMT2D pathogenesis, and thus has profound implications for the timing of future therapeutic treatments.aminoacyl-tRNA synthetase | Charcot-Marie-Tooth disease | distal spinal muscular atrophy type V | neuromuscular disease | neurodevelopment C harcot-Marie-Tooth disease (CMT) is a group of genetically diverse peripheral neuropathies that share the main pathological feature of progressive motor and sensory degeneration (1). Although lifespan is usually unaffected, patients display characteristic muscle weakness and wasting predominantly in the extremities, leading to difficulty walking, foot deformities, and reduced dexterity (2). CMT is traditionally divided into type 1/ demyelinating CMTs that display loss of peripheral nerve myelin causing reduced nerve conduction velocity (NCV), type 2/axonal CMTs typified by axon loss with relatively normal NCVs, and intermediate CMTs that share clinical features of CMT1 and -2 (1). Over 80 different genetic loci have been linked to CMT, which is known to affect ∼1/2,500 people, making it the most common group of hereditary neuromuscular disorders (3).Dominant mutations in the glycyl-tRNA synthetase (GlyRS) gene, GARS, are causative of CMT type 2D (CMT2D) [Online Mendelian Inheritance in Man (OMIM) 601472], which normally manifests during adolescence and presents with muscle weakness in the extremities (4). The 2D subtype is one of a number of CMTs associated with mutation of an aminoacyl-tRNA synthetase (ARS) gene (5-8). Humans possess 37 ARS proteins, which covalently link amino acids to their partner transfer RNAs (tRNAs), thereby charging and priming the tRNAs for protein synthesis.This housekeeping function of gl...
Dominant mutations in glycyl-tRNA synthetase (GlyRS) cause a subtype of Charcot-Marie-Tooth neuropathy (CMT2D). Although previous studies have shown that GlyRS mutants aberrantly interact with Nrp1, giving insight into the disease’s specific effects on motor neurons, these cannot explain length-dependent axonal degeneration. Here, we report that GlyRS mutants interact aberrantly with HDAC6 and stimulate its deacetylase activity on α-tubulin. A decrease in α-tubulin acetylation and deficits in axonal transport are observed in mice peripheral nerves prior to disease onset. An HDAC6 inhibitor used to restore α-tubulin acetylation rescues axonal transport deficits and improves motor functions of CMT2D mice. These results link the aberrant GlyRS-HDAC6 interaction to CMT2D pathology and suggest HDAC6 as an effective therapeutic target. Moreover, the HDAC6 interaction differs from Nrp1 interaction among GlyRS mutants and correlates with divergent clinical presentations, indicating the existence of multiple and different mechanisms in CMT2D.
Post-stroke depression (PSD) is a frequent problem in stroke rehabilitation. Several studies have evaluated association between the lesion location and the risk of depression. Different conclusions and contradictory findings have been published. The aim of the present study was to perform a systematic meta-analysis to evaluate the relationship between PSD and lesion location. We researched PubMed, ISI Web of Science, EMBASE, and systematically reviewed available publications reporting investigations on stroke location and risk of PSD. Subgroup analyses were performed according to the time since stroke onset to assessment for PSD or the source of patients. Odds ratios (ORs) and 95 % confidence intervals (CIs) were used for pooled analyses. Heterogeneity was assessed with Cochran's Q test and I (2) test. Begg's funnel plot and Egger's test were used to examine the publication bias. A total of 43 studies involving 5,507 patients suffering from stroke were included in this meta-analysis. The pooled OR with 95 % CI for the overall association of stroke location and depression risk was 0.99 (0.88-1.11). Subgroups analyses highlighted that only studies with subacute post-stroke group (1-6 months) showed a statistical association between right hemisphere stroke and risk of depression (OR = 0.79, 95 % CI 0.66-0.93). This systematic review offered no support for the hypothesis that lesion of the left hemisphere was associated with an increased risk of depression after stroke. We only find significant association between right hemisphere stroke and incidence of depression for studies within subacute post-stroke phase.
Multilayered semiconducting polymer nanoparticles are developed for in vivo imaging of lymph nodes and tumors with a high signal-to-noise ratio.
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