Heat shock factor 1 promotes neurite outgrowth and suppresses inflammation in the severed spinal cord of geckos.

The low intrinsic growth capacity of neurons and an injury-induced inhibitory milieu are major contributors to the failure of sensory and motor functional recovery following spinal cord injury. Heat shock transcription factor 1 (HSF1), a master regulator of the heat shock response, plays neurogenetic and neuroprotective roles in the damaged or diseased central nervous system. However, the underlying mechanism has not been fully elucidated. In the present study, we used a gecko model of spontaneous nerve regeneration to investigate the potential roles of gecko HSF1 (gHSF1) in the regulation of neurite outgrowth and inflammatory inhibition of macrophages following spinal cord injury. gHSF1 expression in neurons and microglia at the lesion site increased dramatically immediately after tail amputation. gHSF1 overexpression in gecko primary neurons significantly promoted axonal growth by suppressing the expression of suppressor of cytokine signaling-3, and facilitated neuronal survival via activation of the mitogen-activated extracellular signal-regulated kinase/extracellular regulated protein kinases and phosphatidylinositol 3-kinase/protein kinase B pathways. Furthermore, gHSF1 efficiently inhibited the macrophage-mediated inflammatory response by inactivating IkappaB-alpha/NF-kappaB signaling. Our findings show that HSF1 plays dual roles in promoting axonal regrowth and inhibiting leukocyte inflammation, and provide new avenues of investigation for promoting spinal cord injury repair in mammals.

[A novel method for electroencephalography background analysis in neonates with hypoxic-ischemic encephalopathy]. / åº”ç”¨äºŽæ–°ç”Ÿå„¿ç¼ºæ°§ç¼ºè¡€æ€§è„‘ç— çš„è„‘ç”µèƒŒæ™¯åˆ†æžæ–°æ–¹æ³•.

OBJECTIVES: To explore a new method for electroencephalography (EEG) background analysis in neonates with hypoxic-ischemic encephalopathy (HIE) and its relationship with clinical grading and head magnetic resonance imaging (MRI) grading. METHODS: A retrospective analysis was performed for the video electroencephalography (vEEG) and amplitude-integrated electroencephalography (aEEG) monitoring data within 24 hours after birth of neonates diagnosed with HIE from January 2016 to August 2022. All items of EEG background analysis were enrolled into an assessment system and were scored according to severity to obtain the total EEG score. The correlations of total EEG score with total MRI score and total Sarnat score (TSS, used to evaluate clinical gradings) were analyzed by Spearman correlation analysis. The total EEG score was compared among the neonates with different clinical gradings and among the neonates with different head MRI gradings. The receiver operating characteristic (ROC) curve and the area under thecurve (AUC) were used to evaluate the value of total EEG score in diagnosing moderate/severe head MRI abnormalities and clinical moderate/severe HIE, which was then compared with the aEEG grading method. RESULTS: A total of 50 neonates with HIE were included. The total EEG score was positively correlated with the total head MRI score and TSS (rs=0.840 and 0.611 respectively, P<0.001). There were significant differences in the total EEG score between different clinical grading groups and different head MRI grading groups (P<0.05). The total EEG score and the aEEG grading method had an AUC of 0.936 and 0.617 respectively in judging moderate/severe head MRI abnormalities (P<0.01) and an AUC of 0.887 and 0.796 respectively in judging clinical moderate/severe HIE (P>0.05). The total EEG scores of ≤6 points, 7-13 points, and ≥14 points were defined as mild, moderate, and severe EEG abnormalities respectively, which had the best consistency with clinical grading and head MRI grading (P<0.05). CONCLUSIONS: The new EEG background scoring method can quantitatively reflect the severity of brain injury and can be used for the judgment of brain function in neonates with HIE.

Macrophage migration inhibitory factor facilitates astrocytic production of the CCL2 chemokine following spinal cord injury.

Spinal cord injury causes accumulation of a large number of leukocytes at the lesion site where they contribute to excessive inflammation. Overproduced chemokines are responsible for the migratory process of the leukocytes, but the regulatory mechanism underlying the production of chemokines from resident cells of the spinal cord has not been fully elucidated. We examined the protein levels of macrophage migration inhibitory factor and chemokine C-C motif chemokine ligand 2 in a spinal cord contusion model at different time points following spinal cord injury. The elevation of macrophage migration inhibitory factor at the lesion site coincided with the increase of chemokine C-C motif chemokine ligand 2 abundance in astrocytes. Stimulation of primary cultured astrocytes with different concentrations of macrophage migration inhibitory factor recombinant protein induced chemokine C-C motif chemokine ligand 2 production from the cells, and the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine attenuated the stimulatory effect. Further investigation into the underlying mechanism on macrophage migration inhibitory factor-mediated astrocytic production of chemokine C-C motif chemokine ligand 2 revealed that macrophage migration inhibitory factor activated intracellular JNK signaling through binding with CD74 receptor. Administration of the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine following spinal cord injury resulted in the reduction of chemokine C-C motif chemokine ligand 2-recruited microglia/macrophages at the lesion site and remarkably improved the hindlimb locomotor function of rats. Our results have provided insights into the functions of astrocyte-activated chemokines in the recruitment of leukocytes and may be beneficial to develop interventions targeting chemokine C-C motif chemokine ligand 2 for neuroinflammation after spinal cord injury.

Aquaporin-4 Antibody Dynamics and Relapse Risk in Seropositive Neuromyelitis Optica Spectrum Disorder Treated with Immunosuppressants.

OBJECTIVE: To investigate aquaporin-4 antibody (AQP4-IgG) dynamics and relapse risk in patients with seropositive neuromyelitis optica spectrum disorder treated with immunosuppressants. METHODS: This observational cohort study with prospectively collected data included 400 neuromyelitis optica spectrum disorder patients seropositive for AQP4-IgG and treated with immunosuppressants. Serum AQP4-IgG was detected by fixed cell-based assay every 6 months. RESULTS: After treatment with immunosuppressants, 128 patients became AQP4-IgG seronegative. The median time to become seronegative for 400 patients was 76.4 months (61.4 months, NA). Among those patients with negative change of AQP4-IgG, the mean annualized relapse rate significantly decreased after patients became seronegative (0.20 vs 0.77, p < 0.001), and a positive correlation was observed between time to become seronegative and relapse (OR 1.018, 95% CI 1.001-1.035, p < 0.05). Independent risk factors for AQP4-IgG becoming seronegative were older age at onset, initiation of immunosuppressants at onset, and shorter disease duration before maintenance therapy. Independent risk factors for relapse included younger age (≤46.4 years) at onset, poly-system involvement in the first attack, and unchanged or increased AQP4-IgG titer. The relapse risk was not associated with sex, combination with connective tissue disease, seropositivity for systemic autoimmune antibodies, or incomplete recovery from the first attack. INTERPRETATION: Patients with younger age at onset, poly-system involvement in the first attack, and unchanged or increased titer of AQP4-IgG are most likely to experience relapse under treatment with immunosuppressants. Time to AQP4-IgG becoming seronegative and change of AQP4-IgG titer may become the surrogate efficacy biomarkers in clinical trials. ANN NEUROL 2023.

A synergistic therapeutic nano-eyedrop for dry eye disease based on ascorbic acid-coupled exosomes.

Dry eye disease (DED), a complex ocular surface disease with a high prevalence rate, is associated with corneal injury, excess oxidative stress and inflammation. Current therapeutic strategies, including artificial tears and anti-inflammatory agents, are unable to address all the deleterious factors or to achieve a clinical cure due to their temporary or side effects. Here, we prepared a multiple-functional eyedrop based on the deposition of gold nanoparticles (AuNPs) reduced by ascorbic acid (AA) onto the exosomal phospholipid membrane of mesenchymal stem cell (mExo)-derived exosomes in situ (mExo@AA). The therapeutic value of mExo@AA for DED was demonstrated in a mouse DED model. Combining the benefits of mExo and AA, mExo@AA effectively improves corneal epithelium recovery and anti-inflammation capacity, decreases corneal reactive oxygen species, and restores tear secretion without adverse effects. Thus, this study suggests that mExo@AA is effective and safe as a therapeutic agent for the treatment of DED.

Rapid evolution of unimodal but not of linear thermal performance curves in Daphnia magna.

Species may cope with warming through both rapid evolutionary and plastic responses. While thermal performance curves (TPCs), reflecting thermal plasticity, are considered powerful tools to understand the impact of warming on ectotherms, their rapid evolution has been rarely studied for multiple traits. We capitalized on a 2-year experimental evolution trial in outdoor mesocosms that were kept at ambient temperatures or heated 4°C above ambient, by testing in a follow-up common-garden experiment, for rapid evolution of the TPCs for multiple key traits of the water flea Daphnia magna. The heat-selected Daphnia showed evolutionary shifts of the unimodal TPCs for survival, fecundity at first clutch and intrinsic population growth rate toward higher optimum temperatures, and a less pronounced downward curvature indicating a better ability to keep fitness high across a range of high temperatures. We detected no evolution of the linear TPCs for somatic growth, mass and development rate, and for the traits related to energy gain (ingestion rate) and costs (metabolic rate). As a result, also the relative thermal slope of energy gain versus energy costs did not vary. These results suggest the overall (rather than per capita) top-down impact of D. magna may increase under rapid thermal evolution.

The lymphatic drainage systems in the brain: a novel target for ischemic stroke?

Recent studies have proposed three lymphatic drainage systems in the brain, that is, the glymphatic system, the intramural periarterial drainage pathway, and meningeal lymphatic vessels, whose roles in various neurological diseases have been widely explored. The glymphatic system is a fluid drainage and waste clearance pathway that utilizes perivascular space and aquaporin-4 protein located in the astrocyte endfeet to provide a space for exchange of cerebrospinal fluid and interstitial fluid. The intramural periarterial drainage pathway drives the flow of interstitial fluid through the capillary basement membrane and the arterial tunica media. Meningeal lymphatic vessels within the dura mater are involved in the removal of cerebral macromolecules and immune responses. After ischemic stroke, impairment of these systems could lead to cerebral edema, accumulation of toxic factors, and activation of neuroinflammation, while restoration of their normal functions can improve neurological outcomes. In this review, we summarize the basic concepts of these drainage systems, including drainage routes, physiological functions, regulatory mechanisms, and detection technologies. We also focus on the roles of lymphatic drainage systems in brain injury after ischemic stroke, as well as recent advances in therapeutic strategies targeting these drainage systems. These findings provide information for potential novel strategies for treatment of stroke.

A model-informed approach to assess the risk of immune checkpoint inhibitor-induced autoimmune myocarditis.

Immune checkpoint inhibitors (ICIs), as a novel immunotherapy, are designed to modulate the immune system to attack malignancies. Despite their promising benefits, immune-related adverse events (IRAEs) may occur, and incidences are bound to increase with surging demand of this class of drugs in treating cancer. Myocarditis, although rare compared to other IRAEs, has a significantly higher fatal frequency. Due to the overwhelming complexity of the immune system, this condition is not well understood, despite the significant research efforts devoted to it. To better understand the development and progression of autoimmune myocarditis and the roles of ICIs therein, we suggest a new approach: mathematical modelling. Mathematical modelling of myocarditis has enormous potential to determine which parts of the immune system are critical to the development and progression of the disease, and therefore warrant further investigation. We provide the immunological background needed to develop a mathematical model of this disease and review relevant existing models of immunology that serve as the mathematical inspiration needed to develop this field.

[Risk factors for acute kidney injury after hematopoietic stem cell transplantation in children: a retrospective study]. / å„¿ç«¥é€ è¡€å¹²ç»†èƒžç§»æ¤åŽæ€¥æ€§è‚¾æŸä¼¤ç›¸å ³å±é™©å› ç´ çš„å›žé¡¾æ€§ç ”ç©¶.

OBJECTIVES: To investigate the risk factors for acute kidney injury (AKI) after hematopoietic stem cell transplantation (HSCT) in children. METHODS: A retrospective analysis was performed on the medical data of 111 children who underwent HSCT from January 2018 to January 2020. A multivariate logistic regression analysis was used to identify the risk factors for AKI. The Kaplan-Meier survival analysis was used to compare the prognosis in children with different grades of AKI. RESULTS: Graft-versus-host disease (grade Ⅱ-Ⅳ) (OR=4.406, 95%CI: 1.501-12.933, P=0.007), hepatic veno-occlusive disease (OR=4.190, 95%CI: 1.191-14.740, P=0.026), and thrombotic microangiopathy (OR=10.441, 95%CI: 1.148-94.995, P=0.037) were closely associated with the development of AKI after HSCT. The children with stage Ⅲ AKI had a lower 1-year survival rate than those without AKI or with stage Ⅰ AKI or stage Ⅱ AKI (28.6%±12.1% vs 82.8%±5.2%/81.7%±7.4%/68.8%±11.6%; P<0.05). CONCLUSIONS: Children with stage Ⅲ AKI after HSCT have a higher mortality rate. Graft-versus-host disease, hepatic veno-occlusive disease, and thrombotic microangiopathy are closely associated with the development of AKI after HSCT.

Pharmacokinetics of Herb-Drug Interactions of Plumbagin and Tazemetostat in Rats by UPLC-MS/MS.

Objective: A sensitive and rapid UPLC-MS/MS method for determination of tazemetostat in rat plasma was developed, and the pharmacokinetics of herb-drug interactions (HDIs) of plumbagin (PLB) and tazemetostat was investigated. Methods: After the rat plasma samples were precipitated by acetonitrile, tazemetostat and verubecestat (ISTD) were detected. Gradient elution was performed with 0.1% formic acid and acetonitrile as mobile phases. The multi-reaction monitoring was used with ESI+ source, and the ion pairs for tazemetostat and ISTD were m/z 573.12→135.99 and m/z 410.10→124.00, respectively. 12 SD rats were randomly divided into the control group and the experimental group, 6 rats in each group. The rats in the experimental group were given PLB 100 mg/kg by gavage once a day for 7 consecutive days. The rats in the control group were given the same amount of 0.1% sodium carboxymethyl cellulose solution by gavage once a day for 7 consecutive days. At the seventh day, tazemetostat (80 mg/kg) was given and the blood was collected at different time points. The main parameters of pharmacokinetics were calculated and the herb-drug interactions (HDIs) were evaluated. Results: In the calibrated range of 1-1000 ng/mL, tazemetostat had a good linearity. The extraction recovery was more than 84%, and the RSD of intra-batch and inter-batch precision were both less than 15%. The Cmax of tazemetostat in the experimental group was 32.48% higher than that in the control group, and the AUC(0-t) and AUC(0-∞) of tazemetostat in the experimental group were 46.24% and 46.67% higher than that in the control group, respectively, and the t1/2 was prolonged from 10.56 h to 11.73 h. Conclusion: A simple, rapid and sensitive UPLC-MS/MS method for the determination of tazemetostat in rat plasma was established. PLB can inhibit the metabolism of tazemetostat and increase the plasma exposure of tazemetostat in rats.

Actinomycin D: a novel Pseudomonas aeruginosa quorum sensing inhibitor from the endophyte Streptomyces cyaneochromogenes RC1.

The infections caused by Pseudomonas aeruginosa are difficult to treat due to its multidrug resistance. A promising strategy for controlling P. aeruginosa infection is targeting the quorum sensing (QS) system. Actinomycin D isolated from the metabolite of endophyte Streptomyces cyaneochromogenes RC1 exhibited good anti-QS activity against P. aeruginosa PAO1. Actinomycin D (50, 100, and 200 µg/mL) significantly inhibited the motility as well as reduced the production of multiple virulence factors including pyocyanin, protease, rhamnolipid, and siderophores. The images of confocal laser scanning microscopy and scanning electron microscopy revealed that the treatment of actinomycin D resulted in a looser and flatter biofilm structure. Real-time quantitative PCR analysis showed that the expression of QS-related genes lasI, rhlI, rhlR, pqsR, pslA, and pilA were downregulated dramatically. The production of QS signaling molecules N-(3-oxododecanoyl)-L-homoserine lactone and N-butanoyl-L-homoserine lactone were also decreased by actinomycin D. These findings suggest that actinomycin D, a potent in vitro anti-virulence agent, is a promising candidate to treat P. aeruginosa infection by interfering with the QS systems.

The Metacaspase TaMCA-Id Negatively Regulates Salt-Induced Programmed Cell Death and Functionally Links With Autophagy in Wheat.

Metacaspases (MCAs), a family of caspase-like proteins, are important regulators of programmed cell death (PCD) in plant defense response. Autophagy is an important regulator of PCD. This study explored the underlying mechanism of the interaction among PCD, MCAs, and autophagy and their impact on wheat response to salt stress. In this study, the wheat salt-responsive gene TaMCA-Id was identified. The open reading frame (ORF) of TaMCA-Id was 1,071 bp, coding 356 amino acids. The predicted molecular weight and isoelectric point were 38,337.03 Da and 8.45, respectively. TaMCA-Id had classic characteristics of type I MCAs domains, a typical N-terminal pro-domain rich in proline. TaMCA-Id was mainly localized in the chloroplast and exhibited nucleocytoplasmictrafficking under NaCl treatment. Increased expression of TaMCA-Id in wheat seedling roots and leaves was triggered by 150 mM NaCl treatment. Silencing of TaMCA-Id enhanced sensitivity of wheat seedlings to NaCl stress. Under NaCl stress, TaMCA-Id-silenced seedlings exhibited a reduction in activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), higher accumulation of H2O2 and O 2 . - , more serious injury to photosystem II (PSII), increase in PCD level, and autophagy activity in leaves of wheat seedlings. These results indicated that TaMCA-Id functioned in PCD through interacting with autophagy under NaCl stress, which could be used to improve the salt tolerance of crop plants.

Engineered Chimeric Peptides with IGF-1 and Titanium-Binding Functions to Enhance Osteogenic Differentiation In Vitro under T2DM Condition.

Due to the complexity of the biomolecules and titanium (Ti) combination, it is a challenge to modify the implant surface with biological cytokines. The study proposed a new method for immobilizing cytokines on implant surface to solve the problem of low osseointegration under type 2 diabetes mellitus (T2DM) condition. This new modified protein that connected Ti-binding artificial aptamer minTBP-1 with Insulin-like growth factor I (IGF-I), had a special strong affinity with Ti and a therapeutic effect on diabetic bone loss. According to the copies of minTBP-1, three proteins were prepared, namely minTBP-1-IGF-1, 2minTBP-1-IGF-1 and 3minTBP-1-IGF-1. Compared with the other modified proteins, 3minTBP-1-IGF-1 adsorbed most on the Ti surface. Additionally, this biointerface demonstrated the most uniform state and the strongest hydrophilicity. In vitro results showed that the 3minTBP-1-IGF-1 significantly increased the adhesion, proliferation, and mineralization activity of osteoblasts under T2DM conditions when compared with the control group and the other modified IGF-1s groups. Real-time PCR assay results confirmed that 3minTBP-1-IGF-1 could effectively promote the expression of osteogenic genes, that is, ALP, BMP-2, OCN, OPG, and Runx2. All these data indicated that the 3minTBP-1-IGF-1 had the most efficacious effect in promoting osteoblasts osteogenesis in diabetic conditions, and may be a promising option for further clinical use.

The Effect of a Local Injection of Flurbiprofen Ester Microspheres on Systemic Inflammatory Model Rats With a Closed Femoral Shaft Fracture.

Background: Periarticular injections with a combination of local anesthetics, non-steroidal anti-inflammatory analgesics (NSAIDs), and epinephrine are becoming increasingly popular in the perioperative analgesia of artificial joint replacement. However, data on the efficacy and safety of local injection NSAIDs are still scarce. The purpose of this study was to investigate the efficacy and safety of a local injection of Flurbiprofen Ester Lipid microspheres into the inflammatory model of femoral shaft closed fractures in rats. Methods: A systemic inflammatory model was induced in SD rats (60) by closed femoral shaft fracture; 12 non-fractured rats were used as the blank control group (group A). The systemic inflammation model of 60 rats was divided into 5 groups (12 in each group); Group B: intramuscular injectionof the same amount of normal saline at different time points as a negative control; Group C: intravenous injection of Flurbiprofen Ester microspheres (4.5 mg/kg) at different time points; Group D: intramuscular injection of Flurbiprofen Ester microspheres (2.25 mg/kg) at different time points; Group E: intramuscular injection of Flurbiprofen Ester microspheres (4.5 mg/kg) at different time points; Group F: intramuscular injection of Flurbiprofen Ester microspheres (9 mg/kg) at different time points. The behavioral test observed the behavior of the rats. Then, the inflammation factors of CRP, IL-6, COX-1, COX-2 and TNF-αby ELISA were recorded. Results: Through the behavioral test it could be found that the effect of the intramuscular and intravenous injections of Flurbiprofen Ester microspheres was similar. Fracture rats with a local injection of Flurbiprofen Ester microspheres showed lower inflammation levels measured by COX-1, CRP, and TNF-α compared with the control group. Pathological sections at 24, 48, and 96 h after surgery did not display any local muscle necrosis at the local injection site. These findings suggested that a Flurbiprofen Ester microsphere muscular injection exhibited a similar effect to an intravenous injection. Conclusion: The local injection of Flurbiprofen Ester microspheres significantly reduced the inflammatory response in fracture rats and did not increase the risk of muscle necrosis, suggesting its feasibility in local injection analgesia.

Thermal plasticity and evolution shape predator-prey interactions differently in clear and turbid water bodies.

Warming and eutrophication negatively affect freshwater ecosystems by modifying trophic interactions and increasing water turbidity. We need to consider their joint effects on predator-prey interactions and how these depend on the thermal evolution of both predator and prey. We quantified how 4°C warming and algae-induced turbidity (that integrates turbidity per se and increased food for zooplankton prey) affect functional response parameters and prey population parameters in a common-garden experiment. We did so for all combinations of high- and low-latitude predator (damselfly larvae) and prey (water fleas) populations to assess the potential impact of thermal evolution of predators and/or prey at a high latitude under warming using a space-for-time substitution. We then modelled effects on the system stability (i.e. tendency to oscillate) under different warming, turbidity and evolutionary scenarios. Warming and turbidity had little effect on the functional response parameters of high-latitude predators. In contrast, warming and turbidity reduced the handling times of low-latitude predators. Moreover, warming increased the search rates of low-latitude predators in clear water but instead decreased these in turbid water. Warming increased stability (i.e. prevented oscillations) in turbid water (except for the 'high-latitude predator and high-latitude prey' system), mainly by decreasing the prey's carrying capacity and partly also by decreasing search rates, while it did not affect stability in clear water. Algae-induced turbidity generally decreased stability, mainly by increasing the prey's carrying capacity and partly also by increasing search rates. This resembles findings that nutrient enrichment can reduce the stability of trophic systems. The expected stability of the high-latitude trophic system under warming was dependent on the turbidity level: our results suggest that thermal plasticity tends to destabilize the high-latitude trophic system under warming in clear water but not in turbid water, and that thermal evolution of the predator will stabilize the high-latitude system under warming in turbid water but less so in clear water. The extent to which thermal plasticity and evolution shape trophic system stability under warming may strongly differ between clear and turbid water bodies, with their contributions having a more stabilizing role in turbid water.

Translational and post-translational control of human naïve versus primed pluripotency.

Deciphering the regulatory network for human naive and primed pluripotency is of fundamental theoretical and applicable significance. Here, by combining quantitative proteomics, phosphoproteomics, and acetylproteomics analyses, we revealed RNA processing and translation as the most differentially regulated processes between naive and primed human embryonic stem cells (hESCs). Although glycolytic primed hESCs rely predominantly on the eukaryotic initiation factor 4E (eIF4E)-mediated cap-dependent pathway for protein translation, naive hESCs with reduced mammalian target of rapamycin complex (mTORC1) activity are more tolerant to eIF4E inhibition, and their bivalent metabolism allows for translating selective mRNAs via both eIF4E-dependent and eIF4E-independent/eIF4A2-dependent pathways to form a more compact naive proteome. Globally up-regulated proteostasis and down-regulated post-translational modifications help to further refine the naive proteome that is compatible with the more rapid cycling of naive hESCs, where CDK1 plays an indispensable coordinative role. These findings may assist in better understanding the unrestricted lineage potential of naive hESCs and in further optimizing conditions for future clinical applications.

DNA repair proteins cooperate with SOX2 in regulating the transition of human embryonic stem cells to neural progenitor cells.

SOX2, a well-established pluripotency factor supporting the self-renewal of pluripotent stem cells (PSCs), is also a crucial factor for maintaining the properties and functionalities of neural progenitor cells (NPCs). It regulates the transcription of target genes by forming complexes with its partner factors, but systematic comparison of SOX2 binding partners in human PSCs versus NPCs is lacking. Here, by deciphering and comparing the SOX2-protein interactomes in human embryonic stem cells (hESCs) versus the NPCs derived from them, we identified 23 proteins with high reproducibility that are most differentially associated with SOX2, of which 9 are DNA repair proteins (PARP1, PARP2, PRKDC, XRCC1, XRCC5, XRCC6, RPA1, LIG3, DDB1). Genetic knocking-down or pharmacological inhibiting two of the DNA repair proteins (PARP1 and PRKDC) significantly up-regulated certain NPC or ectodermal biomarkers that are transcriptionally-suppressed by the SOX2/DNA repair protein complexes. These findings point to a crucial role of DNA repair proteins in pluripotent state transition and neural induction.

Improved Perioperative Sleep Quality or Quantity Reduces Pain after Total Hip or Knee Arthroplasty: A Systematic Review and Meta-Analysis.

OBJECTIVE: To investigate the effects of improved perioperative sleep on pain, analgesic consumption, and postoperative nausea and vomiting (PONV) in patients who were undergoing total knee arthroplasty (TKA) or total hip arthroplasty (THA). METHODS: Original studies published from 1 January 1970 to 30 September 2020 were queried in three unique databases using a common search term. The searches sought randomized controlled trials (RCT) investigating the effectiveness of sleep quality or quantity interventions for pain control early after TKA or THA. Grey literature was also searched by screening trial registers. There was no limitation on published language and patients. Two reviewers then assessed studies for eligibility. Eligible studies should have primary outcomes including perioperativeWe have comfirmed the edits. visual analogue scale (VAS) pain score and analgesic consumption; and secondary outcomes including side effects, such as PONV. Data extracted from the literature were abstracted into a comma-separated database spreadsheet using Microsoft Excel. A meta-analysis was then performed. Pooled statistics were calculated with weighting by inverse variance assuming a random effect model. I2 was calculated as a quantifier of heterogeneity and interpreted according to the Cochrane manual. All data analysis was performed using Revman software. RESULTS: From a total of 1285 potential records identified in the electronic search, six studies eventually fulfilled the eligibility criteria. The six controlled RCTs consisted of 207 patients in the sleep-improving group and 209 patients in the control group. The severity of rest pain was significantly lower in the sleep-improving group compared with the control group at day 1 and day 3 postoperatively; the severity of active pain was significantly lower in the sleep-improving group compared with the control group at day 3 postoperatively. Data concerning analgesic drugs could not undergo a meta-analysis due to the difference of eligible studies. No significant difference was found in the incidence of PONV between the sleep-improving group and the control group. CONCLUSION: Improved perioperative sleep, regardless of quality or quantity, could significantly reduce the pain level at the early stage after TKA or THA, thus the total amount of analgesic drugs consumed was decreased, without significant increase in the incidence of PONV.

LSD1-mediated demethylation of OCT4 safeguards pluripotent stem cells by maintaining the transcription of PORE-motif-containing genes.

Reversible lysine methylation is essential for regulating histones and emerges to critically regulate non-histone proteins as well. Here we show that the master transcription factor OCT4 in pluripotent stem cells (PSCs) was methylated at multiple lysine residues. LSD1 that is highly expressed in PSCs can directly interact with and demethylate OCT4 at lysine 222 (K222) in the flexible linker region. Reduced LSD1 activity led to the methylation of OCT4-K222 that diminished the differentiation potential of PSCs while facilitating proteasome-independent degradation of OCT4 proteins. Furthermore, site-specifically replacing K222 with phenylalanine to mimic the constitutively methylated lysine promoted the 'locked-in' mode engagement of the OCT4 PORE-homodimers that tightly bind to and block the transcription of multiple PORE-motif-containing target genes regulating cell fate determination and cell junction organization, and thereby reducing the pluripotency of PSCs. Thus, LSD1-mediated demethylation of OCT4 plays a crucial role in restricting the 'locked-in' mode binding of OCT4 PORE-homodimers to the PORE-motif-containing genes and thereby maintaining their transcription to safeguard the pluripotency of PSCs.