Phosphorylation of 4.1N by CaMKII Regulates the Trafficking of GluA1-containing AMPA Receptors During Long-term Potentiation in Acute Rat Hippocampal Brain Slices.

OBJECTIVE: GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) inserted into postsynaptic membranes are key to the process of long-term potentiation (LTP). Some evidence has shown that 4.1N plays a critical role in the membrane trafficking of AMPARs. However, the underlying mechanism behind this is still unclear. We investigated the role of 4.1N-mediated membrane trafficking of AMPARs during theta-burst stimulation long-term potentiation (TBS-LTP), to illustrate the molecular mechanism behind LTP. METHODS: LTP was induced by TBS in rat hippocampal CA1 neuron. Tat-GluA1 (MPR), which disrupts the association of 4.1N-GluA1, and autocamtide-2-inhibitory peptide, myristoylated (Myr-AIP), a CaMKII antagonist, were used to explore the role of 4.1N in the AMPARs trafficking during TBS-induced LTP. Immunoprecipitation (IP) and immunoblotting (IB)were used to detect protein expression, phosphorylation, and the interaction of p-CaMKII-4.1N-GluA1. RESULTS: We found that Myr-AIP attenuated increases of p-CaMKII (T286), p-GluA1 (ser831), and 4.1N phosphorylation after TBS-LTP, and decreased the association of p-CaMKII-4.1N-GluA1, along with the expression of GluA1, at postsynaptic densities during TBS-LTP. We also designed interfering peptides to disrupt the interaction between 4.1N and GluA1, which showed that Tat-GluA1 (MPR) or Myr-AIP inhibited TBS-LTP and attenuated increases of GluA1 at postsynaptic sites, while Tat-GluA1 (MPR) or Myr-AIP had no effects on miniature excitatory postsynaptic currents (mEPSCs) in non-stimulated hippocampal CA1 neurons. CONCLUSION: Active CaMKII enhanced the phosphorylation of 4.1N and facilitated the association of p-CaMKII with 4.1N-GluA1, which in turn resulted in GluA1 trafficking during TBS-LTP. The association of 4.1N-GluA1 is required for LTP, but not for basal synaptic transmission.

Transcription factor EBF1 mitigates neuropathic pain by rescuing Kv1.2 expression in primary sensory neurons.

Nerve injury-induced alternations of gene expression in primary sensory neurons of the dorsal root ganglion (DRG) are molecular basis of neuropathic pain genesis. Transcription factors regulate gene expression. In this study, we examined whether early B cell factor 1 (EBF1), a transcription factor, in the DRG, participated in neuropathic pain caused by chronic constriction injury (CCI) of the sciatic nerve. EBF1 was distributed exclusively in the neuronal nucleus and coexpressed with cytoplasmic/membrane Kv1.2 in individual DRG neurons. The expression of Ebf1 mRNA and protein was time-dependently downregulated in the ipsilateral lumbar (L) 3/4 DRGs after unilateral CCI. Rescuing this downregulation through microinjection of the adeno-associated virus 5 expressing full-length Ebf1 mRNA into the ipsilateral L3/4 DRGs reversed the CCI-induced decrease of DRG Kv1.2 expression and alleviated the development and maintenance of mechanical, heat and cold hypersensitivities. Conversely, mimicking the downregulation of DRG EBF1 through microinjection of AAV5-expressing Ebf1 shRNA into unilateral L3/4 DRGs produced a reduction of Kv1.2 expression in the ipsilateral L3/4 DRGs, spontaneous pain, and the enhanced responses to mechanical, heat and cold stimuli in naive mice. Mechanistically, EBF1 not only bound to the Kcna2 gene (encoding Kv1.2) promoter but also directly activated its activity. CCI decreased the EBF1 binding to the Kcna2 promoter in the ipsilateral L3/4 DRGs. Our findings suggest that DRG EBF1 downregulation contributes to neuropathic pain likely by losing its binding to Kcna2 promoter and subsequently silencing Kv1.2 expression in primary sensory neurons. Exogenous EBF1 administration may mitigate neuropathic pain by rescuing DRG Kv1.2 expression.

miR-181-5p/KLHL5 Promoted Proliferation and Migration of Gastric Cancer Through Activating METTL3-Mediated m6A Process.

KLHL5 was a member of kelch-repeat protein family and was involved in the initiation of progression of a plethora of cancers. However, its specific role in gastric cancer was not explicitly illustrated. In this context, we aimed to investigate the biological role and mechanisms about KLHL5 in gastric cancer. qRT-PCR and western blot were used to investigate the expression of KLHL5 and EMT biomarkers. Wound healing assay, CCK-8, and Transwell assay were used to investigate the biological function of KLHL5. We found that KLHL5 was highly expressed in gastric cancer both in vivo and in vitro; besides, its high expression led to a shorter overall survival. Following statistical analysis showed that KLHL5 was associated with M stage. As for molecular experiments, we found that KLHL5 knockdown significantly reduced the proliferation, migration, and invasion ability of gastric cancer cell line MKN45 and SGC-7901. Furthermore, we found that miR-181-5p targeted KLHL5 to regulate m6A level through METTL3. In addition, KLHL5 knockdown could significantly reduce the lung metastasis rate in mice. In conclusion, we found that miR-181-5p/KLHL5 could promote the proliferation, migration, and invasion of gastric cancer by activating m6A process through regulating METTL3.

Markedly Improved Catalytic Dehydration of Sorbitol to Isosorbide by Sol-Gel Sulfated Zirconia: A Quantitative Structure-Reactivity Study.

Isosorbide, a bicyclic C6 diol, has considerable value as a precursor for the production of bio-derived polymers. Current production of isosorbide from sorbitol utilizes homogeneous acid, commonly H2SO4, creating harmful waste and complicating separation. Thus, a heterogeneous acid catalyst capable of producing isosorbide from sorbitol in high yield under mild conditions would be desirable. Reported here is a quantitative investigation of the liquid-phase dehydration of neat sorbitol over sulfated zirconia (SZ) solid acid catalysts produced via sol-gel synthesis. The catalyst preparation allows for precise surface area control (morphology) and tunable catalytic activity. The S/Zr ratio (0.1-2.0) and calcination temperature (425-625 °C) were varied to evaluate their effects on morphology, acidity, and reaction kinetics and, as a result, to optimize the catalytic system for this transformation. With the optimal SZ catalyst, complete conversion of sorbitol occurred in <2 h under mild conditions to give isosorbide in 76% yield. Overall, the quantitative kinetics and structure-reactivity studies provided valuable insights into the parameters that govern product yields and SZ catalyst activity, central among these being the relative proportion of acid site types and Brønsted surface density.

The Early Warning Mechanism of Public Health Emergencies Through Whistleblowing: A Perspective Based on Considering the Uncertainty of Risk Perception.

Purpose: During the early warning period of public health emergencies, the information released by whistleblowers on the risk posed by the given event can reduce uncertainty in the public's risk perception and help governments take timely actions to contain the large-scale dissemination of risk. The purpose of this study is to give full play to whistleblowers and draw attention to the risk events, forming a pluralistic model of the risk governance during the early warning period of public health emergencies. Methods: We construct an evolutionary game model of the early warning of public health emergencies through whistleblowing that involves the government, whistleblowers, and the public, discussing the mechanism of interaction between these subjects under the uncertainty of risk perception. Furthermore, we use numerical simulations to analyze the influence of changes in the relevant parameters on the evolutionary trajectory of the subjects' behaviors. Results: The results of the research are obtained by numerical simulation of the evolutionary game model. The results show that the public's cooperation with the government encourages the latter to take a positive guidance strategy. Increasing the reward for whistleblowers within an acceptable cost, strengthening the propaganda of the mechanism and the higher level of risk perception of the government and whistleblowers will promote whistleblowers' vocalization actively. When the government's reward for whistleblowers is lower, the whistleblowers choose negative vocalization with the improvement of the public's risk perception. If there is no mandatory guidance from the government at this point, the public is prone to passively cooperating with the government owing to a lack of risk-related information. Conclusion: Establishing an early warning mechanism through whistleblowing is important for containing risk in the early warning period of public health emergencies. Building the whistleblowing mechanism in daily work can improve the effectiveness of the mechanism and enhance the public's risk perception better when the public health emergencies arise.

E74-like factor 1 contributes to nerve trauma-induced nociceptive hypersensitivity through transcriptionally activating matrix metalloprotein-9 in dorsal root ganglion neurons.

ABSTRACT: Nerve trauma-induced alternations of gene expression in the neurons of dorsal root ganglion (DRG) participate in nerve trauma-caused nociceptive hypersensitivity. Transcription factors regulate gene expression. Whether the transcription factor E74-like factor 1 (ELF1) in the DRG contributes to neuropathic pain is unknown. We report here that peripheral nerve trauma caused by chronic constriction injury (CCI) of unilateral sciatic nerve or unilateral fourth lumbar spinal nerve ligation led to the time-dependent increases in the levels of Elf1 mRNA and ELF1 protein in injured DRG, but not in the spinal cord. Preventing this increase through DRG microinjection of adeno-associated virus 5 expressing Elf1 shRNA attenuated the CCI-induced upregulation of matrix metallopeptidase 9 (MMP9) in injured DRG and induction and maintenance of nociceptive hypersensitivities, without changing locomotor functions and basal responses to acute mechanical, heat, and cold stimuli. Mimicking this increase through DRG microinjection of AAV5 expressing full-length Elf1 upregulated DRG MMP9 and produced enhanced responses to mechanical, heat, and cold stimuli in naive mice. Mechanistically, more ELF1 directly bond to and activated Mmp9 promoter in injured DRG neurons after CCI. Our data indicate that ELF1 participates in nerve trauma-caused nociceptive hypersensitivity likely through upregulating MMP9 in injured DRG. E74-like factor 1 may be a new target for management of neuropathic pain.

Face beauty or soul beauty? The influence of facial attractiveness and moral judgment on pain empathy.

Previous studies indicated that both facial attractiveness (face beauty) and moral judgment (soul beauty) would impact the responses to others' pain, however, the effects from facial attractiveness were in controversial. Furthermore, whether facial attractiveness would increase or decrease the effects of moral judgment on pain empathy were still unknown. Based on the videos in which actors with high versus low facial attractiveness under pain or non-pain conditions, study 1 recruited 26 undergraduates to assess the effects of facial attractiveness on participants' pain intensity rating scores. Then study 2 recruited 85 undergraduates to examine the effects of facial attractiveness and moral judgment on pain empathy by assessing pain intensity and self-uncomfortableness rating scores. Study 1 found that participants rated higher pain intensity scores to actors with high facial attractiveness compared to low facial attractive actors under pain condition. Study 2 found that participants showed higher pain empathic responses for actors with high moral judgment, no matter their facial attractiveness were high or low. For actors with low moral judgment under pain condition, participants showed higher pain empathy to those with high facial attractiveness compared to those with low facial attractiveness. In conclusion, facial attractiveness could facilitate the empathy responses for other's pain. High facial attractiveness would increase the pain empathic responses to individuals with low moral judgment, however, low facial attractiveness would not decrease the pain empathic responses to individuals with high moral judgment.

The viscoelastic characteristics of in-vitro carotid plaque by Kelvin-Voigt fractional derivative modeling.

Atherosclerotic plaque with a thin fibrous cap can be ruptured by shear force. Exploiting the mechanical properties of plaques within different histological regions can help to better understand the physical mechanisms of the plaque. The association between the plaque components and viscoelasticity was studied when mapping the viscoelasticity to histological features. Eleven in-vitro carotid plaques were tested with ramp-hold relaxation nanoindentation tests. Viscoelasticity (elastic modulus E0, fluidity α, and viscosity τ) was characterized by Kelvin-Voigt fractional derivative (KVFD) modeling. There is a significant difference (p < 0.001) on E0, α, and τ between the collagen-rich (CR) group and the non-collagen-rich (NCR) group. In the CR group, the elastic modulus E0 was higher but the fluidity α and viscosity τ were lower than those of the NCR group. Receiver operating characteristic (ROC) analysis revealed that combinations of E0 and α can be used as a CR indicator with an area under the curve (AUC) of 0.770. There was a negative correlation between E0 and the percentages of myxoid degeneration (r = -0.160, p < 0.001), necrosis (r = -0.229, p < 0.001) and inflammatory cells (r = -0.130, p < 0.001), and a positive correlation between elasticity E0 and the percentage of foam cells (r = 0.121, p < 0.001). There was a positive correlation between fluidity α and the percentage of necrosis (r = 0.308, p < 0.001). The results confirmed the clinical evidence that the CR group with higher elasticity and lower fluidity has higher resisting ability, whereas the NCR group with lower elasticity and higher fluidity has accompanied with more myxoid degeneration, extracellular lipids and necrosis.

TRPV1 SUMOylation suppresses itch by inhibiting TRPV1 interaction with H1 receptors.

The molecular mechanism underlying the functional interaction between H1R and TRPV1 remains unclear. We show here that H1R directly binds to the carboxy-terminal region of TRPV1 at residues 715-725 and 736-749. Cell-penetrating peptides containing these sequences suppress histamine-induced scratching behavior in a cheek injection model. The H1R-TRPV1 binding is kept at a minimum at rest in mouse trigeminal neurons due to TRPV1 SUMOylation and it is enhanced upon histamine treatment through a transient TRPV1 deSUMOylation. The knockin of the SUMOylation-deficient TRPV1K823R mutant in mice leads to constitutive enhancement of H1R-TRPV1 binding, which exacerbates scratching behaviors induced by histamine. Conversely, SENP1 conditional knockout in sensory neurons enhances TRPV1 SUMOylation and suppresses the histamine-induced scratching response. In addition to interfering with binding, TRPV1 SUMOylation promotes H1R degradation through ubiquitination. Our work unveils the molecular mechanism of histaminergic itch by which H1R directly binds to deSUMOylated TRPV1 to facilitate the transduction of the pruritogen signal to the scratching response.

The psychological factors mediating/moderating the association between childhood adversity and depression: A systematic review.

Accumulating evidence suggests that individuals with a history of childhood adversity are at greater risk for developing depression. Potential psychological mechanisms have not been well-established. Our study aims to identify psychological variables consistently mediating/moderating the link between childhood adversity to depression. We systematically searched articles from 1990 to October 2021 on online databases including PubMed, Web of Science and PsycINFO. Studies that examined a mediating/moderating role of psychological variables between childhood adversities and depression were included. Totally, 33 records were included. The review identified maladaptive schema, negative automatic thoughts, and avoidance as mediators of the relationship between childhood adversity and depression. Additionally, resilience was identified as both a mediator and moderator of the association between childhood adversity and depression. In general, cognitive dysfunction, avoidance behaviors and impaired resilience may be a by-product of childhood adversity and may contribute to increased risk for depression. Interventions that target at challenging negative cognition and improving resilience may be effective to prevent or treat depression in individuals with a history of childhood adversity.

The interplay between SUMOylation and phosphorylation of PKCδ facilitates oxidative stress-induced apoptosis.

Although the increase in the number of identified posttranslational modifications (PTMs) has substantially improved our knowledge about substrate site specificity of single PTMs, the fact that different types of PTMs can crosstalk and act in concert to exert important regulatory mechanisms for protein function has not gained much attention. Here, we show that protein kinase Cδ (PKCδ) is SUMOylated at lysine 473 in its C-terminal catalytic domain, and the SUMOylation increases PKCδ stability by repressing its ubiquitination. In addition, we uncover a functional interplay between the phosphorylation and SUMOylation of PKCδ, which can strengthen each other through recruiting SUMO E2/E3 ligases and the PKCδ kinase, respectively, to the PKCδ complexes. We identified PIAS2ß as the SUMO E3 ligase of PKCδ. More importantly, by enhancing PKCδ protein stability and its phosphorylation through an interdependent interplay of the PTMs, the SUMOylation of PKCδ promotes apoptotic cell death induced by H2 O2 . We conclude that SUMOylation represents an important regulatory mechanism of PKCδ PTMs for the kinase's function in oxidative cell damage.

DUSP6 SUMOylation protects cells from oxidative damage via direct regulation of Drp1 dephosphorylation.

Imbalanced mitochondrial fission/fusion, a major cause of apoptotic cell death, often results from dysregulation of Drp1 phosphorylation of two serines, S616 and S637. Whereas kinases for Drp1-S616 phosphorylation are well-described, phosphatase(s) for its dephosphorylation remains unclear. Here, we show that dual-specificity phosphatase 6 (DUSP6) dephosphorylates Drp1-S616 independently of its known substrates ERK1/2. DUSP6 keeps Drp1-S616 phosphorylation levels low under normal conditions. The stability and catalytic function of DUSP6 are maintained through conjugation of small ubiquitin-like modifier-1 (SUMO1) and SUMO2/3 at lysine-234 (K234), which is disrupted during oxidation through transcriptional up-regulation of SUMO-deconjugating enzyme, SENP1, causing DUSP6 degradation by ubiquitin-proteasome. deSUMOylation underlies DUSP6 degradation, Drp1-S616 hyperphosphorylation, mitochondrial fragmentation, and apoptosis induced by H2O2 in cultured cells or brain ischemia/reperfusion in mice. Overexpression of DUSP6, but not the SUMOylation-deficient DUSP6K234R mutant, protected cells from apoptosis. Thus, DUSP6 exerts a cytoprotective role by directly dephosphorylating Drp1-S616, which is disrupted by deSUMOylation under oxidation.

Author Correction: TRPV1 SUMOylation regulates nociceptive signaling in models of inflammatory pain.

In the originally published version of this Article, the affiliation details for Yan Wang, Yingwei Gao, Qi Deng, Yangbo Wang, Tian Zhou, Yingping Wang, Huiqing Liu, Ruining Ma, Jinke Cheng and Yong Li incorrectly omitted 'Shanghai Jiao Tong University'. This has now been corrected in both the PDF and HTML versions of the Article.' Furthermore, the Supplementary Information file originally associated with this Article inadvertently omitted Supplementary Figure 9. The error has now been fixed and the corrected version Supplementary Information PDF is available to download from the HTML version of the Article.

TRPV1 SUMOylation regulates nociceptive signaling in models of inflammatory pain.

Although TRPV1 channels represent a key player of noxious heat sensation, the precise mechanisms for thermal hyperalgesia remain unknown. We report here that conditional knockout of deSUMOylation enzyme, SENP1, in mouse dorsal root ganglion (DRG) neurons exacerbated thermal hyperalgesia in both carrageenan- and Complete Freund's adjuvant-induced inflammation models. TRPV1 is SUMOylated at a C-terminal Lys residue (K822), which specifically enhances the channel sensitivity to stimulation by heat, but not capsaicin, protons or voltage. TRPV1 SUMOylation is decreased by SENP1 but upregulated upon peripheral inflammation. More importantly, the reduced ability of TRPV1 knockout mice to develop inflammatory thermal hyperalgesia was rescued by viral infection of lumbar 3/4 DRG neurons of wild-type TRPV1, but not its SUMOylation-deficient mutant, K822R. These data suggest that TRPV1 SUMOylation is essential for the development of inflammatory thermal hyperalgesia, through a mechanism that involves sensitization of the channel response specifically to thermal stimulation.