Search

Lung inflammation indicated by 18F-labeled fluorodeoxyglucose (FDG) in patients with tuberculosis is associated with disease severity and relapse risk upon treatment completion. We revealed the heterogeneity and intercellular crosstalk in lung tissues with 18F-FDG avidity and adjacent uninvolved tissues from 6 tuberculosis patients by single-cell RNA-sequencing. Tuberculous lungs had an influx of regulatory T cells (Treg), exhausted CD8 T cells, immunosuppressive myeloid cells, conventional DC, plasmacytoid DC, and neutrophils. Immune cells in inflamed lungs showed general up-regulation of ATP synthesis and interferon-mediated signaling. Immunosuppressive myeloid and Treg cells strongly displayed transcriptions of genes related to tuberculosis disease progression. Intensive crosstalk between IL4I1 -expressing myeloid cells and Treg cells involving chemokines, costimulatory molecules, and immune checkpoints, some of which are specific in 18F-FDG-avid lungs, were found. Our analysis provides insights into the transcriptomic heterogeneity and cellular crosstalk in pulmonary tuberculosis and guides unveiling cellular and molecular targets for tuberculosis therapy. • Single-cell RNA sequencing reveals cellular landscape in inflamed human TB lungs. • Inflamed TB lungs show disease-linked transcriptional changes in myeloid and Treg cells. • Treg cells and immunosuppressive myeloid cells feature extensive crosstalk potential. [ABSTRACT FROM AUTHOR]

Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor sensory neuropathy, is a group of rare genetically heterogenous diseases characterized by progressive muscle weakness and atrophy, along with sensory deficits. Despite extensive pre-clinical and clinical research, no FDA-approved therapy is available for any CMT type. We previously identified C1ORF194, a novel causative gene for CMT, and found that both C1orf194 knock-in (I121N) and knockout mice developed clinical phenotypes similar to those in patients with CMT. Encouraging results of adeno-associated virus (AAV)-mediated gene therapy for spinal muscular atrophy have stimulated the use of AAVs as vehicles for CMT gene therapy. Here, we present a gene therapy approach to restore C1orf194 expression in a knockout background. We used C1orf194-/- mice treated with AAV serotype 9 (AAV9) vector carrying a codon-optimized WT human C1ORF194 cDNA whose expression was driven by a ubiquitously expressed chicken β-actin promoter with a CMV enhancer. Our preclinical evaluation demonstrated the efficacy of AAV-mediated gene therapy in improving sensory and motor abilities, thus achieving largely normal gross motor performance and minimal signs of neuropathy, on the basis of neurophysiological and histopathological evaluation in C1orf194-/- mice administered AAV gene therapy. Our findings advance the techniques for delivering therapeutic interventions to individuals with CMT. [ABSTRACT FROM AUTHOR]

Neutrophils constitute a considerable proportion of all leukocytes found in tumors and are essential for promoting tumor growth. In this issue, Linde et al. demonstrate that an antibody cocktail therapy consisting of tumor necrosis factor (TNF), anti-CD40 monoclonal antibody, and tumor-binding antibody can boost the anti-tumor activity of neutrophils. [ABSTRACT FROM AUTHOR]

Abstract: A highly efficient and selective rearrangement reaction of bromohydrins to aldehydes mediated by CF3CO2ZnEt was described. The secondary and tertiary aldehydes were prepared under mild conditions in good to excellent yields (85–99%). The scope and limitations of this rearrangement process were also investigated. [Copyright &y& Elsevier]

[Display omitted] • The tartary buckwheat roots polysaccharide (TBRP) may play a hypoglycemic role. • TBRP could elevate the expression of IRS1 by suppressing SOCS3 expression to enhance the insulin sensibility. • SOCS3 is considered as a potential target for the treatment of T2DM. Tartary buckwheat is an alternative cereal crop. This study sought to establish the mechanisms whereby tartary buckwheat root polysaccharide (TBRP-1) treatment can alleviate diabetes mellitus. TBRP-1 was extracted and purified by hot water and gel permeation column chromatography. Its structure was determined by Fourier transform-infrared spectroscopy (FT-IR), monosaccharide analysis, and nuclear magnetic resonance (NMR) spectroscopy. TBRP-1 was composed of fucose, arabinose, rhamnose, galactose, glucose, xylose, mannose, galacturonic acid, and glucuronic acid. The molecular weight was 2.731 × 104 Da. In addition, for in vitro , HepG2 cells were treated with high insulin concentrations to establish a model of insulin resistance. For in vivo modeling, diabetic mice were established by injecting with streptozotocin (STZ). Body weight, blood glucose levels, glycosylated hemoglobin (HbA1c) levels, and changes in hepatic lipids were analyzed. The expression of suppressor of cytokine signaling 3 (SOCS3), insulin receptor substrate 1 (IRS1), and glucose transporter type 4 (GLUT4) was assessed via qPCR and western blotting. TBRP-1 treatment was sufficient to enhance the ability of insulin resistant HepG2 cells to take up glucose. TBRP-1 also lowered levels of blood glucose, HbA1c, and hepatic lipids in diabetic mice. The underlying molecular mechanisms suggested that TBRP-1 was able to suppress SOCS3 expression to thereby enhance IRS1 expression, thus alleviating insulin resistance. [ABSTRACT FROM AUTHOR]

Abstract GIN (GFP-expressing inhibitory interneuron) transgenic mice are believed to express the enhanced GFP (eGFP) in a subset of somatostatin (SST)-expressing interneurons in the neocortex and have been widely used in the study on SST interneurons. Previous studies showed that eGFP+ neurons in the neocortex are distributed in the layer II-IV and upper layer V (cortical eGFP neurons) and contain SST. In this study, we reported a new group of eGFP+ neurons in GIN mice at early postnatal ages, which was located in the deep layer of the lateral neocortex as clusters (cluster eGFP neurons). Cluster eGFP neurons were noticeable at birth but disappeared within two months, in contrast to cortical eGFP neurons that started to appear around postnatal day 3 to 5 and existed through life. Cluster eGFP neurons were not immunoreactive for SST antibodies, contrary to cortical eGFP neurons. They were also not immunolabeled by parvalbumin, a marker for another major type of interneurons, and Ca2+/calmodulin-dependent kinases II, a commonly used marker for excitatory neurons. Firing rate, afterhyperpolarization, and excitatory synaptic activity significantly enhanced in cortical eGFP neurons during postnatal development, but these properties remained mostly unchanged in cluster eGFP neurons. Short-term plasticity of the excitatory synapse showed robust facilitation in cortical eGFP neurons but depression in cluster eGFP neurons. These results implied that eGFP might also be expressed in other types of cortical neurons in addition to SST-containing interneurons in GIN mice at early postnatal ages. Highlights • A new group of eGFP+ neurons, in addition to the previously reported one, is present in the neocortex of GIN mice. • Those eGFP+ neurons are distributed in the deep cortical layers as clusters and disappear mostly after the second postnatal month. • They are not immunoreactive for SST, PV, GAD, and CaMKII antibodies. • They display distinct intrinsic and synaptic properties and postnatal development. [ABSTRACT FROM AUTHOR]

Antagonists of the group II metabotropic glutamate (mGlu) 2/3 receptors have been shown to have a rapid antidepressant effect. GABAergic interneurons play a crucial role in major depressive disorder (MDD) and possibly mediate the rapid antidepressant effect. However, how mGlu2/3 receptors regulate synaptic activities to GABAergic interneurons is not fully understood. In the present work, we studied the effect of mGlu2/3 receptors on excitatory and inhibitory synaptic activities to somatostatin (SST)- and parvalbumin (PV)-expressing interneurons, two major types of GABAergic interneurons, in the anterior cingulate cortex (ACC) that is strongly indicated in MDD. We found that activation of mGlu2/3 receptors by (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl) glycine (DCG-IV), an agonist of mGlu2/3 receptors, remarkably reduced the frequency, but not the amplitude, of spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs) and the amplitude of evoked EPSCs in both types. The reduction in the frequency of sEPSCs and the amplitude of evoked EPSCs was more pronounced in SST interneurons. DCG-IV, however, did not affect spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) and evoked IPSCs in both types. LY341495, an antagonist of mGlu2/3 receptors, enhanced the amplitude of evoked EPSCs without affecting sEPSCs and mEPSCs in both types. It also did not affect sIPSCs and evoked IPSCs except slightly increasing the frequency of mIPSCs in SST interneurons. Our results indicate that mGlu2/3 receptors primarily regulate excitatory synaptic activities to the two types of GABAergic interneurons in the ACC. • DCG-IV reduced excitatory, but not inhibitory, synaptic activities to SST and PV interneurons in the ACC. • The reduction of excitatory synaptic activities by DCG-IV was more pronounced in SST interneurons. • LY341495 enhanced the amplitude of evoked EPSCs but did not affect sEPSCs and mEPSCs in SST and PV interneurons. • LY341495 did not affect inhibitory synaptic activities to SST and PV interneurons. [ABSTRACT FROM AUTHOR]