Pyroptosis in Spinal Cord Injury: Implications for Pathogenesis and Therapeutic Approaches.

Traumatic spinal cord injury (SCI) is a serious disease of the central nervous system. Aside from the limited intrinsic regenerative capacity of neurons, complex microenvironmental disturbances can also lead to further cellular damage and growth inhibition. Programmed cell death regulated by pyroptosis has an important role in the pathogenesis of SCI. While there has been a wealth of new knowledge regarding cellular pyroptosis, a detailed understanding of its role in SCI and possible therapeutic strategies is still lacking. This review summarizes current advances in the regulatory role of pyroptosis-regulated cell death and inflammasome components in the inhibitory microenvironment following SCI, as well as recent therapeutic advances.

Comprehensive analysis of a pyroptosis-related gene signature of clinical and biological values in spinal cord injury.

Background: Since some of the clinical examinations are not suitable for patients with severe spinal cord injury (SCI), blood biomarkers have been reported to reflect the severity of SCI. The objective of this study was to screen out the potential biomarkers associated with the diagnosis of SCI by bioinformatics analysis. Methods: The microarray expression profiles of SCI were obtained from the Gene Expression Omnibus (GEO) database. Core genes correlated to pyroptosis were obtained by crossing the differential genes, and module genes were obtained by WGCNA analysis and lasso regression. The immune infiltration analysis and GSEA analysis revealed the essential effect of immune cells in the progression of SCI. In addition, the accuracy of the biomarkers in diagnosing SCI was subsequently evaluated and verified using the receiver operating characteristic curve (ROC) and qRT-PCR. Results: A total of 423 DEGs were identified, among which 319 genes were upregulated and 104 genes were downregulated. Based on the WGCNA analysis, six potential biomarkers were screened out, including LIN7A, FCGR1A, FGD4, GPR27, BLOC1S1, and GALNT4. The results of ROC curves demonstrated the accurate value of biomarkers related to SCI. The immune infiltration analysis and GSEA analysis revealed the essential effect of immune cells in the progression of SCI, including macrophages, natural killer cells, and neutrophils. The qRT-PCR results verified that FGD4, FCAR1A, LIN7A, BLOC1S1, and GPR27 were significantly upregulated in SCI patients. Conclusion: In this study, we identified and verified five immune pyroptosis-related hub genes by WGCNA and biological experiments. It is expected that the five identified potential biomarkers in peripheral white blood cells may provide a novel strategy for early diagnosis.

Regulation of Satiety by Bdnf-e2-Expressing Neurons through TrkB Activation in Ventromedial Hypothalamus.

The transcripts for Bdnf (brain-derived neurotrophic factor), driven by different promoters, are expressed in different brain regions to control different body functions. Specific promoter(s) that regulates energy balance remain unclear. We show that disruption of Bdnf promoters I and II but not IV and VI in mice (Bdnf-e1-/-, Bdnf-e2-/-) results in obesity. Whereas Bdnf-e1-/- exhibited impaired thermogenesis, Bdnf-e2-/- showed hyperphagia and reduced satiety before the onset of obesity. The Bdnf-e2 transcripts were primarily expressed in ventromedial hypothalamus (VMH), a nucleus known to regulate satiety. Re-expressing Bdnf-e2 transcript in VMH or chemogenetic activation of VMH neurons rescued the hyperphagia and obesity of Bdnf-e2-/- mice. Deletion of BDNF receptor TrkB in VMH neurons in wildtype mice resulted in hyperphagia and obesity, and infusion of TrkB agonistic antibody into VMH of Bdnf-e2-/- mice alleviated these phenotypes. Thus, Bdnf-e2-transcripts in VMH neurons play a key role in regulating energy intake and satiety through TrkB pathway.

Determining Surface Shape of Translucent Objects with the Combination of Laser-Beam-Based Structured Light and Polarization Technique.

In this study, we focus on the 3D surface measurement and reconstruction of translucent objects. The proposed approach of surface-shape determination of translucent objects is based on the combination of the projected laser-beam-based sinusoidal structured light and the polarization technique. The theoretical analyses are rigorously completed in this work, including the formation, propagation, and physical features of the generated sinusoidal signal by the designed optical system, the reflection and transmission of the projected monochromatic fringe pattern on the surface of the translucent object, and the formation and the separation of the direct-reflection and the global components of the surface radiance of the observed object. The results of experimental investigation designed in accordance with our theoretical analyses have confirmed that accurate reconstructions can be obtained using the one-shot measurement based on the proposed approach of this study and Fourier transform profilometry, while the monochromaticity and the linearly-polarized characteristic of the projected sinusoidal signal can be utilized by using a polarizer and an optical filter simultaneously for removing the global component, i.e., the noised signal contributed by multiply-scattered photons and the background illuminance in the frame of our approach. Moreover, this study has also revealed that the developed method is capable of getting accurate measurements and reconstructions of translucent objects when the background illumination exists, which has been considered as a challenging issue for 3D surface measurement and reconstruction of translucent objects.

A subpopulation of Bdnf-e1-expressing glutamatergic neurons in the lateral hypothalamus critical for thermogenesis control.

OBJECTIVE: Brown adipose tissue (BAT)-mediated thermogenesis plays a key role in energy homeostasis and the maintenance of body temperature. Previous work suggests that brain-derived neurotrophic factor (BDNF) is involved in BAT thermogenesis, but the underlying neural circuits and molecular mechanism remain largely unknown. This is in part due to the difficulties in manipulating BDNF expression in different brain regions through different promoters and the lack of tools to identify neurons in the brain specifically involved in BAT thermogenesis. METHODS: We have created several lines of mutant mice in which BDNF transcription from a specific promoter was selectively disrupted by replacing Bdnf with green fluorescent protein (GFP; Bdnf-e1, -e4, and -e6-/- mice). As such, cells expressing Bdnf-e1, -e4, or -e6 were labeled with GFP. To identify BAT-connected thermogenesis neurons in brain, we applied the retrograde pseudorabies virus labeling method from BAT. We also used chemogenetic tools to manipulate specific neurons coupled with BAT temperature recording. Moreover, we developed a new TrkB agonist antibody to rescue the BAT thermogenesis deficits. RESULTS: We show that selective disruption of Bdnf expression from promoter 1 (Bdnf-e1) resulted in severe obesity and deficits of BAT-mediated thermogenesis. Body temperature response to cold was impaired in Bdnf-e1-/- mice. BAT expression of Ucp1 and Pcg1a, genes known to regulate thermogenesis, was also reduced, accompanying a decrease in the sympathetic activity of BAT. Staining of cells expressing Bdnf-e1 transcript, combined with transsynaptic, retrograde-tracing labeling of BAT-connected neurons, identified a group of excitatory neurons in lateral hypothalamus (LH) critical for thermogenesis regulation. Moreover, an adaptive thermogenesis defect in Bdnf-e1-/- mice was rescued by injecting an agonistic antibody for TrkB, the BDNF receptor, into LH. Remarkably, activation of the excitatory neurons (VGLUT2+) in LH through chemogenetic tools resulted in a rise of BAT temperature. CONCLUSIONS: These results reveal a specific role of BDNF promoter I in thermogenesis regulation and define a small subset of neurons in LH that contribute to such regulation.

MagR Alone Is Insufficient to Confer Cellular Calcium Responses to Magnetic Stimulation.

Magnetic manipulation of cell activity offers advantages over optical manipulation but an ideal tool remains elusive. The MagR protein was found through its interaction with cryptochrome (Cry) and the protein in solution appeared to respond to magnetic stimulation (MS). After we initiated an investigation on the specific role of MagR in cellular response to MS, a subsequent study claimed that MagR expression alone could achieve cellular activation by MS. Here we report that despite systematically testing different ways of measuring intracellular calcium and different MS protocols, it was not possible to detect any cellular or neuronal responses to MS in MagR-expressing HEK cells or primary neurons from the dorsal root ganglion and the hippocampus. By contrast, in neurons co-expressing MagR and channelrhodopin, optical but not MS increased calcium influx in hippocampal neurons. Our results indicate that MagR alone is not sufficient to confer cellular magnetic responses.