mGluR5/ERK signaling regulated the phosphorylation and function of glycine receptor α1ins subunit in spinal dorsal horn of mice.

Inhibitory glycinergic transmission in adult spinal cord is primarily mediated by glycine receptors (GlyRs) containing the α1 subunit. Here, we found that α1ins, a longer α1 variant with 8 amino acids inserted into the intracellular large loop (IL) between transmembrane (TM)3 and TM4 domains, was expressed in the dorsal horn of the spinal cord, distributed at inhibitory synapses, and engaged in negative control over nociceptive signal transduction. Activation of metabotropic glutamate receptor 5 (mGluR5) specifically suppressed α1ins-mediated glycinergic transmission and evoked pain sensitization. Extracellular signal-regulated kinase (ERK) was critical for mGluR5 to inhibit α1ins. By binding to a D-docking site created by the 8-amino-acid insert within the TM3-TM4 loop of α1ins, the active ERK catalyzed α1ins phosphorylation at Ser380, which favored α1ins ubiquitination at Lys379 and led to α1ins endocytosis. Disruption of ERK interaction with α1ins blocked Ser380 phosphorylation, potentiated glycinergic synaptic currents, and alleviated inflammatory and neuropathic pain. These data thus unraveled a novel, to our knowledge, mechanism for the activity-dependent regulation of glycinergic neurotransmission.

The impact of air pollution on the transmission of pulmonary tuberculosis.

In this paper, we investigate the relationship between the air pollution and tuberculosis cases and its prediction in Jiangsu, China by using the time-series analysis method, and find that the seasonal ARIMA(1, 1, 0)×(0, 1, 1)12 model is the preferred model for predicting the TB cases in Jiangsu, China. Furthermore, we evaluate the relationship between AQI, PM2.5, PM10 and the number of TB cases, and find that the prediction accuracy of the ARIMA model is improved by adding monthly PM2.5 with 0-month lag as an external variable, i.e., ARIMA(1, 1, 0)×(0, 1, 1)12+PM2.5. The results show that ARIMAX model can be a useful tool for predicting TB cases in Jiangsu, China, and it can provide a scientific basis for the prevention and treatment of TB.

SNAP25/syntaxin4/VAMP2/Munc18-1 Complexes in Spinal Dorsal Horn Contributed to Inflammatory Pain.

Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) have been implicated in the trafficking of postsynaptic glutamate receptors, including N-methyl-d-aspartate (NMDA)-subtype glutamate receptors (NMDARs) that are critical for nociceptive plasticity and behavioral sensitization. However, the components of SNAREs complex involved in spinal nociceptive processing remain largely unknown. Here we found that SNAP25, syntaxin4, VAMP2 and Munc18-1 were localized at postsynaptic sites and formed the complex in the superficial lamina of spinal cord dorsal horn of rats. The complex formation between these SNAREs components were accelerated after intraplantar injection of complete Freund's adjuvant (CFA), pharmacological removal of GABAergic inhibition or activation of NMDAR in intact rats. The increased SNAP25/syntaxin4/VAMP2/Munc18-1 interaction facilitated the surface delivery and synaptic accumulation of NMDAR during inflammatory pain. Disruption of the molecular interaction between SNAP25 with its SNARE partners by using a blocking peptide derived from the C-terminus of SNAP25 effectively repressed the surface and synaptic accumulation of GluN2B-containing NMDARs in CFA-injected rats. This peptide also alleviated inflammatory mechanical allodynia and thermal hypersensitivity. These data suggested that SNAREs complex assembly in spinal cord dorsal horn was involved in the inflammatory pain hypersensitivity through promoting NMDAR synaptic trafficking.

Current trends and future prediction of novel coronavirus disease (COVID-19) epidemic in China: a dynamical modeling analysis.

The novel coronavirus disease 2019 (COVID-19) infection broke out in December 2019 in Wuhan, and rapidly overspread 31 provinces in mainland China on 31 January 2020. In the face of the increasing number of daily confirmed infected cases, it has become a common concern and worthy of pondering when the infection will appear the turning points, what is the final size and when the infection would be ultimately controlled. Based on the current control measures, we proposed a dynamical transmission model with contact trace and quarantine and predicted the peak time and final size for daily confirmed infected cases by employing Markov Chain Monte Carlo algorithm. We estimate the basic reproductive number of COVID-19 is 5.78 (95%CI: 5.71-5.89). Under the current intervention before 31 January, the number of daily confirmed infected cases is expected to peak on around 11 February 2020 with the size of 4066 (95%CI: 3898-4472). The infection of COVID-19 might be controlled approximately after 18 May 2020. Reducing contact and increasing trace about the risk population are likely to be the present effective measures.

Ubiquitination and functional modification of GluN2B subunit-containing NMDA receptors by Cbl-b in the spinal cord dorsal horn.

N-methyl-d-aspartate (NMDA) glutamate receptors (NMDARs) containing GluN2B subunits are prevalent early after birth in most brain regions in rodents. Upon synapse maturation, GluN2B is progressively removed from synapses, which affects NMDAR function and synaptic plasticity. Aberrant recruitment of GluN2B into mature synapses has been implicated in several neuropathologies that afflict adults. We found that the E3 ubiquitin ligase Cbl-b was enriched in the spinal cord dorsal horn neurons of mice and rats and suppressed GluN2B abundance during development and inflammatory pain. Cbl-b abundance increased from postnatal day 1 (P1) to P14, a critical time period for synapse maturation. Through its N-terminal tyrosine kinase binding domain, Cbl-b interacted with GluN2B. Ubiquitination of GluN2B by Cbl-b decreased the synaptic transmission mediated by GluN2B-containing NMDARs. Knocking down Cbl-b in vivo during P1 to P14 led to sustained retention of GluN2B at dorsal horn synapses, suggesting that Cbl-b limits the synaptic abundance of GluN2B in adult mice. However, peripheral inflammation induced by intraplantar injection of complete Freund's adjuvant resulted in the dephosphorylation of Cbl-b at Tyr363, which impaired its binding to and ubiquitylation of GluN2B, enabling the reappearance of GluN2B-containing NMDARs at synapses. Expression of a phosphomimic Cbl-b mutant in the dorsal horn suppressed both GluN2B-mediated synaptic currents and manifestations of pain induced by inflammation. The findings indicate a ubiquitin-mediated developmental switch in NMDAR subunit composition that is dysregulated by inflammation, which can enhance nociception.

Spinophilin negatively controlled the function of transient receptor potential vanilloid 1 in dorsal root ganglia neurons of mice.

Protein phosphatase-1 (PP1) is ubiquitously distributed in the nervous system and catalyzes the dephosphorylation of numerous substrates. The specificity and efficacy of PP1-mediated dephosphorylation depend on scaffolding proteins that anchor PP1 to the close vicinity of substrates. Spinophilin is one of the scaffolding proteins which are able to direct PP1 into postsynaptic density and regulate the synaptic transmission and plasticity. Here we found that spinophilin was enriched in dorsal root ganglia (DRG) neurons and engaged in the modification of nociceptive signaling processing. Disturbing spinophilin/PP1 interaction in DRG neurons led to the enhanced sensitivity of mice to heat and mechanical stimuli. The transient receptor potential vanilloid 1 (TRPV1) was identified as an important target for spinophilin modification. Our data showed that spinophilin physically interacted with TRPV1 and facilitated PP1 dephosphorylation of TRPV1 at Ser502. Disruption of spinophilin/PP1 complex enhanced Ser502 phosphorylation and boosted TRPV1 expression on plasma membrane. Peripheral inflammation induced by formalin disturbed spinophilin/PP1 interaction, which removed PP1-mediated inhibition and caused a marked increase of TRPV1 phosphorylation. Viral expression of wild-type spinophilin in DRG neurons repressed TRPV1 phosphorylation and alleviated formalin-induced inflammatory pain. These data suggested that spinophilin/PP1 complex negatively controlled TRPV1 function in DRG neurons.

A synthetic peptide disturbing GluN2A/SHP1 interaction in dorsal root ganglion attenuated pathological pain.

Src Homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1) interacts specifically with GluN2A subunit of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors in spinal cord dorsal horn. This molecular interaction is involved in the development of GluN2A-dependent spinal sensitization of nociceptive behaviors. Intrathecal application of a GluN2A-derived polypeptide (short for pep-GluN2A) has been shown to disturb spinal GluN2A/SHP1 interaction and inhibit inflammatory pain. Here we found that SHP1 was also located at dorsal root ganglion (DRG) neurons and formed complexes with GluN2A subunit. Peripheral inflammation activated SHP1 in DRG neurons, which promoted GluN2A tyrosine phosphorylation. The SHP1 binding to GluN2A facilitated the glutamate release from primary afferent fibers and exaggerated nociceptive synaptic transmission onto postsynaptic spinal cord neurons. Our data showed that intradermal application of pep-GluN2A disrupted GluN2A/SHP1 interaction in DRG neurons, attenuated the ability of GluN2A subunit-containing NMDA receptors to regulate the presynaptic glutamate release and more importantly, alleviated the pain hypersensitivity caused by carrageenan, complete Freund's adjuvant and formalin. The neuropathic pain induced by spared nerve injury was also ameliorated by intradermal pep-GluN2A application. These data suggested that disruption of GluN2A/SHP1 interaction in DRG neurons generated an effective analgesic action against pathological pain.

Ubiquitination and inhibition of glycine receptor by HUWE1 in spinal cord dorsal horn.

Glycine receptors (GlyRs) are pentameric proteins that consist of α (α1-α4) subunits and/or ß subunit. In the spinal cord of adult animals, the majority of inhibitory glycinergic neurotransmission is mediated by α1 subunit-containing GlyRs. The reduced glycinergic inhibition (disinhibition) is proposed to increase the excitabilities and spontaneous activities of spinal nociceptive neurons during pathological pain. However, the molecular mechanisms by which peripheral lesions impair GlyRs-α1-mediated synaptic inhibition remain largely unknown. Here we found that activity-dependent ubiquitination of GlyRs-α1 subunit might contribute to glycinergic disinhibition after peripheral inflammation. Our data showed that HUWE1 (HECT, UBA, WWE domain containing 1), an E3 ubiquitin ligase, located at spinal synapses and specifically interacted with GlyRs-α1 subunit. By ubiquitinating GlyRs-α1, HUWE1 reduced the surface expression of GlyRs-α1 through endocytic pathway. In the dorsal horn of Complete Freund's Adjuvant-injected mice, shRNA-mediated knockdown of HUWE1 blunted GlyRs-α1 ubiquitination, potentiated glycinergic synaptic transmission and attenuated inflammatory pain. These data implicated that ubiquitin modification of GlyRs-α1 represented an important way for peripheral inflammation to reduce spinal glycinergic inhibition and that interference with HUWE1 activity generated analgesic action by resuming GlyRs-α1-mediated synaptic transmission.

[Transurethral enucleation of the prostate for treatment of benign prostatic hyperplasia in patients less than 50 years old].

OBJECTIVE: To evaluate the therapeutic effect of transurethral enucleation of the prostate for treatment of benign prostatic hyperplasia in patients below 50 years of age. METHODS: Twelve patients with benign prostatic hyperplasia patients (mean age 48.2 years, range 46-49 years) underwent transurethral enucleation of the prostate. The middle lobe and two lateral lobes were enucleated with the preprosthetic sphincter and anterior fibromuscular stroma preserved during the operation. The patients were followed up to evaluate the lower urinary tract symptoms and sexual activity after the surgery. RESULTS: The 12 patients were followed up for 3 to 6 months. The symptoms of lower urinary tract obstruction were improved obviously after the surgery, and the International Prostate Symptom Score (IPSS) decreased from 24±5.1 to 8.8±1.4 and peak urine flow rate (Qmax) increased from 8.1±4.2 ml/s to 20.1±4.2 ml/s at 3 months postoperatively. All the 12 cases had residual urine (12-44 ml) preoperatively, but after the surgery, only 4 still had residual urine of less than 30 ml. All the patients had normal erection function postoperatively, and 10 had normal ejaculation; the other 2 patients recovered normal ejaculation 3 and 5 months after the operation, respectively. CONCLUSIONS: Transurethral enucleation can alleviate the low urinary tract obstruction symptom and improve the sexual function by avoiding preprosthetic sphincter injury in relatively young patients with benign prostatic hyperplasia.