Network-based pharmacology and UHPLC-Q-Exactive-Orbitrap-MS reveal Jinhua Qinggan granule's mechanism in reducing cellular inflammation in COVID-19.

Introduction: The outbreak of SARS-CoV-2, leading to COVID-19, poses a major global health threat. While specific treatments and vaccines are under development, Traditional Chinese Medicine (TCM) has historically been effective against pandemics, including viral pneumonias. Our study explores the efficacy and mechanisms of Jinhua Qinggan Granules (JHQG) in treating COVID-19. Methods: We analyzed JHQG's components using UHPLC-Q-Exactive-Orbitrap-MS, identifying 73 compounds. Network pharmacology and single-cell RNA sequencing (scRNA-seq) were used to assess JHQG's effects on immune cells from peripheral blood mononuclear cells (PBMCs). Literature review supported the antiviral and anti-inflammatory effects of JHQG. Results: JHQG targets were found to interact with immune cells, including neutrophils, monocytes, plasmablasts, and effector T cells, reducing their overactivation in severe COVID-19. JHQG's modulation of these cells' activity likely contributes to reduced inflammation and improved clinical outcomes. Discussion: Our findings provide insights into JHQG's mechanism of action, highlighting its potential in controlling the inflammatory response in COVID-19 patients. The study supports the use of JHQG as a safe and effective treatment for COVID-19 and similar viral infections, leveraging its ability to modulate immune cell activity and reduce inflammation.

The clinical effect of gratitude extension-construction theory nursing program on bladder cancer patients with fear of cancer recurrence.

Objective: To explore the clinical effect of bladder cancer patients with Fear of Cancer Recurrence (FCR) after applying the gratitude extension construction theory nursing program. Methods: 168 patients with bladder cancer hospitalized in the Department of Urology from December 2021 to June 2023 in a hospital are study subjects. The experimental subjects are uniformly designed as an experimental group and a control group, with 52 participants in each group. The former receives routine nursing care, while the later receives nursing interventions based on gratitude extension construction theory. The baseline data, Quality of life Questionnaire-core 30, Quality of Life Questionnaire-non Invasive Bladder Cancer 24, Fear of Progression Questionnaire-Short Form, gratitude level questionnaire, Self-Rating Depression Scale, Self-rating Anxiety Scale, patient compliance behavior score, Overall Survival, and Progression-free Survival are evaluated. Results: The basic data revealed no statistical significance. The quality of life questionnaire-core 30 and quality of life questionnaire-noninvasive bladder cancer 24 was no significant difference before treatment and after treatment for 1 month. After 9 months, There was a significant difference in pre-treatment scores. The experimental group had no significant difference before and after treatment. For the overall survival rates, the two groups were 67.25% and 79.56%. The progression-free survival rates were 56.35% and 72.35%, respectively, with statistical difference. The compliance rates were 86.54% and 98.08%. The compliance rate of the experimental group exceeded the control group. After 3, 6, and 12 months, the gratitude level questionnaire score and the fear of progression questionnaire-short form in the experimental group were improved. After 3, 6, and 12 months, the control group had no statistically significant difference in the gratitude level questionnaire and the fear of progression questionnaire-short form scores. Compared with the control group, the scores on the gratitude level questionnaire and the fear of progression questionnaire-short form were significantly higher after 3, 6, and 12 months of intervention. Conclusion: After applying the gratitude extension construction theory nursing program, the FCR of bladder cancer patients is significantly reduced. The quality of life and compliance rate are significantly improved, and anxiety and depression are relieved.

Enhanced interfacial effect via acid theory with boosted photocatalytic performance of nitenpyram removal.

Surface reaction is a prominent aspect that affects the efficiency of photocatalysis. In this work, acid theory was employed to facilitate the reaction dynamics and enhance the interfacial effect between photocatalysts and target molecules. The photocatalytic removal efficiency of NTP was 66 % for bare CdS in 50 min with apparent rate constants of 0.023 compare to 96 % with apparent rate constants of 0.065 for 5% Ce-CdS. The introduced Ce atom as bifunctional active site reduces the energy barrier of O2 adsorption, strengthens the interfacial effect and accelerates the electrons transfer, which could facilitate surface reaction process and boost the photocatalytic performance.

Impact of ERAS on Hysteromyomectomy: A Study on Anxiety, Depression, and Ovarian Function.

Objective: To analyze the application of the Enhanced Recovery After Surgery (ERAS) nursing mode in patients undergoing radical cystectomy with urinary diversion. Methods: A retrospective analysis was conducted on clinical data of 72 patients with bladder cancer who underwent "robot-assisted laparoscopic radical cystectomy + urinary diversion" in Nanjing University Medical College Affiliated Gulou Hospital between January 2021 and January 2023. All patients met the complete inclusion criteria. They were divided into a control group (n=35) and a observation group (n=37). Patients in the control group received routine rehabilitation nursing intervention, while patients in the study group received ERAS nursing mode intervention. The outcomes include time to first intake, time to first defecation, duration of enteral nutrition, duration of antibiotic use, duration of drainage tube placement, length of hospital stay, psychological status Self-rating Depression Scale (SDS), Self-rating Anxiety Scale (SAS), quality of life (SF-36) scores, sexual function assessment Arizona Sexual Experience Scale (ASEX), International Index of Erectile Function-5 (IIEF-5), and occurrence of complications were compared between the two groups. Results: In the observation group, perioperative indicators, psychological status, quality of life, sexual function, and complication rates were notably improved compared to the control group (all P < .05). Conclusion: ERAS nursing mode intervention in bladder cancer patients exhibited significant effectiveness, enhancing postoperative recovery, reducing anxiety and depression, improving quality of life and sexual function, and lowering complication risks. These findings support the clinical merit and applicability of ERAS nursing in urinary diversion for bladder cancer patients.

[Design and application of distal radial artery hemostat].

Transradial approach is the classical access for coronary angiography and percutaneous coronary intervention (PCI). With the increase in the number of interventional procedures, some disadvantages of the transradial approach have also been found, it is easy to lead to various complications, such as radial artery occlusion, radial nerve injury, and puncture difficulties after radial artery spasm. Therefore, some experts put forward the approach of distal radial artery approach for interventional therapy, which has the advantages of convenient positioning, easy postoperative hemostasis, less damage to the proximal radial artery and improving patients' comfort. However, there is no special distal radial artery hemostat in clinic, which limits the development of this approach to a certain extent. Therefore, based on the principles of anatomy and physics, cardiovascular physician at Jiading District District Central Hospital in Shanghai designed and invented a distal radial artery hemostatic device, which is convenient for clinical hemostasis of distal radial artery puncture, and obtained the National Utility Model Patent (patent number: ZL 2021 2 2097829.6). The hemostatic device consists of a glove body with a silicone gasket protruding towards the skin on the inner surface and a binding component. The patient's hand is inserted into the glove body, and after being fixed by the restraint component, the silicone gasket can effectively compress the location of the radial artery puncture point, and play a good hemostatic effect with less pressure, avoid the common complications of proximal radial artery hemostatic, and reduce the discomfort of the patient. Has good application value.

Channel Features and API Frequency-Based Transformer Model for Malware Identification.

Malicious software (malware), in various forms and variants, continues to pose significant threats to user information security. Researchers have identified the effectiveness of utilizing API call sequences to identify malware. However, the evasion techniques employed by malware, such as obfuscation and complex API call sequences, challenge existing detection methods. This research addresses this issue by introducing CAFTrans, a novel transformer-based model for malware detection. We enhance the traditional transformer encoder with a one-dimensional channel attention module (1D-CAM) to improve the correlation between API call vector features, thereby enhancing feature embedding. A word frequency reinforcement module is also implemented to refine API features by preserving low-frequency API features. To capture subtle relationships between APIs and achieve more accurate identification of features for different types of malware, we leverage convolutional neural networks (CNNs) and long short-term memory (LSTM) networks. Experimental results demonstrate the effectiveness of CAFTrans, achieving state-of-the-art performance on the mal-api-2019 dataset with an F1 score of 0.65252 and an AUC of 0.8913. The findings suggest that CAFTrans improves accuracy in distinguishing between various types of malware and exhibits enhanced recognition capabilities for unknown samples and adversarial attacks.

Effects of sinomenine on a rat orthotopic liver carcinoma model.

OBJECTIVE: Liver carcinoma is a common malignant tumor. In this study, an orthotopic liver carcinoma model was established by B-ultrasound, and the therapeutic effect of sinomenine (Sin) on the disease was investigated. METHODS: SD rats were randomly divided into control, Sin, Sorafenib (Sor), and combination (Sin+Sor) groups (n=8). An orthotopic liver carcinoma model was established by inoculating N1-S1 cells into the rat liver by B-ultrasound-guided, and tumor volume was monitored three times by B-ultrasound after inoculation. After drug treatment, the tumor tissues were stained with HE and TUNEL, and the levels of inflammatory cytokines, ALT and AST were detected by ELISA. The numbers of erythrocytes, leukocytes and platelets were detected. Immunohistochemistry and immunofluorescence were used to detect the expression of Ki-67, CD44, VEGF and CD31. The levels of cell cycle, apoptosis-related proteins were detected by western blot. RESULTS: B-ultrasound monitoring found that Sin reduced tumor volume. Moreover, Sin improved tissue lesions, and promoted cancer cell apoptosis. Sin decreased the levels of inflammatory cytokines, AST and ALT, and decreased the numbers of erythrocytes, leukocytes and platelets. Simultaneously, the expressions of Ki-67, CD44, VEGF and CD31 were decreased in the Sin group. Furthermore, Sin decreased the Bcl-2, Cyclin D1, CDK4, CDK6 and Survivin levels, but increased Bax, Cleaved-caspase3/pro-caspase3, P21 and P27 levels. More importantly, the combination of Sin and Sor treatment was more effective than treatment alone. CONCLUSION: A rat orthotopic liver carcinoma model was established under the guidance of B-ultrasound, and Sin had a therapeutic effect on orthotopic liver carcinoma.

In Situ Fabrication of CdS/Cd(OH)2 for Effective Visible Light-Driven Photocatalysis.

Photocatalytic hydrogen production is a promising technology that can generate renewable energy. However, light absorption and fast electron transfer are two main challenges that restrict the practical application of photocatalysis. Moreover, most of the composite photocatalysts that possess better photocatalytic performance are fabricated by various methods, many of which are complicated and in which, the key conditions are hard to control. Herein, we developed a simple method to prepare CdS/Cd(OH)2 samples via an in situ synthesis approach during the photocatalytic reaction process. The optimal hydrogen generation rate of CdS/Cd(OH)2 that could be obtained was 15.2 mmol·h-1·g-1, greater than that of CdS, which generates 2.6 mmol·h-1·g-1 under visible light irradiation. Meanwhile, the CdS-3 sample shows superior HER performance during recycling tests and exhibits relatively steady photocatalytic performance in the 10 h experiment. Expanded absorption of visible light, decreased recombination possibility for photo-induced carriers and a more negative conduction band position are mainly responsible for the enhanced photocatalytic hydrogen evolution performance. Photo-induced electrons will be motivated to the conduction band of CdS under the irradiation of visible light and will further transfer to Cd(OH)2 to react with H+ to produce H2. The in situ-formed Cd(OH)2 could effectively facilitate the electron transfer and reduce the recombination possibility of photo-generated electron-hole pairs.

Crocin exerts anti-tumor effect in colon cancer cells via repressing the JAK pathway.

Crocin has been reported to have therapeutic effects on multiple cancers including colon cancer, but its specific mechanism is still ambiguous and needs to be further explored. Human colorectal adenocarcinoma cells (HCT-116) and human normal colonic epithelial cells (CCD841) were first treated with increasing concentrations of crocin. Subsequently, with 150 and 200 µM of crocin, the cell vitality was examined by cell counting kit 8. Cell apoptosis and proliferation were tested by TUNEL staining and colony formation assay, respectively. The expression of Ki-67 was assessed by immunofluorescence. Enzyme-linked immunosorbent assay was used to evaluate the level of inflammation- and oxidative-related factors. The reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) were examined by flow cytometer. Janus kinase (JAK), signal transducer and activator of transcription 3 (STAT3), and extracellular regulated protein kinases (ERK) in HCT-116 cells were tested by Western blot. Different concentrations of crocin barely affected the CCD841 cell vitality, while crocin restrained the HCT-116 cells vitality, proliferation and the expression of Ki-67, while inducing apoptosis in a concentration-dependent manner. Moreover, the contents of inflammation- and oxidative-related factors in HCT-116 cells were largely blunted by crocin that enhanced ROS and restrained the MMP and suppressed p-JAK2/JAK2, p-STAT3/STAT3, and p-ERK/ERK expression in HCT-116 cells. Crocin induced apoptosis and restored mitochondrial function in HCT-116 cells via repressing the JAK pathway. If the threptic effect works in patients, it could herald a new, effective treatment for colon cancer, improving the patients' prognosis and quality of life.

Resveratrol Enhances the Radiosensitivity by Inducing DNA Damage and Antitumor Immunity in a Glioblastoma Rat Model under 3 T MRI Monitoring.

Glioblastoma (GBM) is the most common intracranial tumor with characteristic of malignancy. Resveratrol, a natural originated polyphenolic compound, has been reported to act as a potential radiosensitizer in cancer therapy. Magnetic resonance imaging (MRI) is the first choice for the diagnosis, pathological grading, and efficacy evaluation of GBM. In this study, MRI was applied to observe whether resveratrol could intensify the anti-GBM tumor effect by enhancing antitumor immunity during radiotherapy. We established an intracranial C6 GBM model in SD rats, treated with radiation and resveratrol. The increased body weight, the inhibition on mortality, and tumor volume in radiated- GBM rats were further enhanced by resveratrol addition, while the pathological damage of brain was alleviated. The modulation of radiation on inflammation, cell cycle, and apoptosis was strengthened by resveratrol; and Ki-67, PD-L1, and cell cycle- and apoptosis-related protein expressions were also improved by cotreatment. Besides, cotreatment attenuated DNA damage and induced G0/G1-phase cell arrest of GBM rats, accompanied with the changed expression of ATM-AKT-STAT3 pathway-related proteins. Moreover, the percentages of CD3+CD8+T cells and IFN-γ +CD8+T cells were enhanced, while (CD4+CD25+Foxp3)/CD4+T cells were decreased by radiation or resveratrol, which was strengthened by cotreatment. The modulation effect of cotreatment on CD3, Foxp3, and IFN-γ levels was also stronger than radiation or resveratrol alone. To conclude, resveratrol enhanced the effect of radiotherapy by inducing DNA damage and antitumor immunity in the intracranial C6 GBM.

High salt activates p97 to reduce host antiviral immunity by restricting Viperin induction.

High-salt diets have recently been implicated in hypertension, cardiovascular disease, and autoimmune disease. However, whether and how dietary salt affects host antiviral response remain elusive. Here, we report that high salt induces an instant reduction in host antiviral immunity, although this effect is compromised during a long-term high-salt diet. Further studies reveal that high salt stimulates the acetylation at Lys663 of p97, which promotes the recruitment of ubiquitinated proteins for proteasome-dependent degradation. p97-mediated degradation of the deubiquitinase USP33 results in a deficiency of Viperin protein expression during viral infection, which substantially attenuates host antiviral ability. Importantly, switching to a low-salt diet during viral infection significantly enhances Viperin expression and improves host antiviral ability. These findings uncover dietary salt-induced regulation of ubiquitinated cellular proteins and host antiviral immunity, and could offer insight into the daily consumption of salt-containing diets during virus epidemics.

Construction of a New Tumor Immunity-Related Signature to Assess and Classify the Prognostic Risk of Colorectal Cancer.

PURPOSE: Although immunotherapy and checkpoint inhibitors contribute to the treatment of colorectal cancer (CRC), few patients can benefit from these treatments. Therefore, our goal was to develop a marker based on immune-related genes to predict the prognosis of patients with CRC to guide treatment strategies. METHODS: Gene expression data from colorectal cancer patients in the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas were analyzed systematically. We used Cox regression to identify immune-related genes with potential prognostic value. The expression of immune genes, infiltration level of immune cells, and several immune-related molecules were further compared between the high-risk and low-risk groups. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analyses were used for functional analysis. RESULTS: Five GEO datasets were integrated into a merged GEO dataset, which showed obvious survival in StromalScore and ESTIMATEScore. WGCNA showed that 749 genes of the pink module are related to immunity, 95 of which are related to prognosis, correlating with cytokine-cytokine receptor interaction and natural killer cell-mediated cytotoxicity. Among these genes, an 11-gene signature was developed through stability selection and LASSO Cox regression. Univariate and multifactorial Cox regression analyses demonstrated that gene signature was an independent prognostic factor for predicting survival in patients with colorectal cancer. Samples from the low-risk group may be more sensitive to immunotherapy. In addition, the nomogram risk prediction model effectively predicted the prognosis of CRC patients by appropriately stratifying the risk scores. CONCLUSION: In conclusion, we developed a novel immune-related gene signature that may be useful in predicting cancer progression and prognosis, thus contributing to the individualized management of colorectal cancer patients.

Inhibition of ribosomal RNA processing 15 Homolog (RRP15), which is overexpressed in hepatocellular carcinoma, suppresses tumour growth via induction of senescence and apoptosis.

Recent studies suggest that RRP15 (Ribosomal RNA Processing 15 Homolog) might be a potential target for cancer therapy. However, the role of RRP15 in hepatocarcinogenesis remains poorly delineated. In this study, we aimed to evaluate the expression and biological function of RRP15 in human hepatocellular carcinoma (HCC). We show that RRP15 was up regulated in HCC cell lines and tumours. Up-regulation of RRP15 in HCC tumours was also correlated with unfavorable prognosis. We further show that the frequent up-regulation of RRP15 in HCCs is at least partly driven by recurrent gene copy gain at chromosome 1q41. Functional studies indicated that RRP15 knockdown suppresses HCC proliferation and growth both in vitro and in vivo. Mechanistically, RRP15 depletion in p53-wild-type HepG2 cells induced senescence via activation of the p53-p21 signalling pathway through enhanced interaction of RPL11 with MDM2, as well as inhibition of SIRT1-mediated p53 deacetylation. Moreover, RRP15 depletion in p53-mutant PLC5 and p53-deleted Hep3B cells induced metabolic shift from the glycolytic pentose-phosphate to mitochondrial oxidative phosphorylation via regulating a series of key genes such as HK2 and TIGAR, and thus, promoted the generation of ROS and apoptosis. Taken together, our findings provide evidence for an important role of the RRP15 gene in hepatocarcinogenesis through regulation of HCC proliferation and growth, raising the possibility that targeting RRP15 may represent a potential therapeutic strategy for HCC treatment.

Elevated post-ischemic ubiquitination results from suppression of deubiquitinase activity and not proteasome inhibition.

Cerebral ischemia-reperfusion increases intraneuronal levels of ubiquitinated proteins, but the factors driving ubiquitination and whether it results from altered proteostasis remain unclear. To address these questions, we used in vivo and in vitro models of cerebral ischemia-reperfusion, in which hippocampal slices were transiently deprived of oxygen and glucose to simulate ischemia followed by reperfusion, or the middle cerebral artery was temporarily occluded in mice. We found that post-ischemic ubiquitination results from two key steps: restoration of ATP at reperfusion, which allows initiation of protein ubiquitination, and free radical production, which, in the presence of sufficient ATP, increases ubiquitination above pre-ischemic levels. Surprisingly, free radicals did not augment ubiquitination through inhibition of the proteasome as previously believed. Although reduced proteasomal activity was detected after ischemia, this was neither caused by free radicals nor sufficient in magnitude to induce appreciable accumulation of proteasomal target proteins or ubiquitin-proteasome reporters. Instead, we found that ischemia-derived free radicals inhibit deubiquitinases, a class of proteases that cleaves ubiquitin chains from proteins, which was sufficient to elevate ubiquitination after ischemia. Our data provide evidence that free radical-dependent deubiquitinase inactivation rather than proteasomal inhibition drives ubiquitination following ischemia-reperfusion, and as such call for a reevaluation of the mechanisms of post-ischemic ubiquitination, previously attributed to altered proteostasis. Since deubiquitinase inhibition is considered an endogenous neuroprotective mechanism to shield proteins from oxidative damage, modulation of deubiquitinase activity may be of therapeutic value to maintain protein integrity after an ischemic insult.

Prohibitin S-Nitrosylation Is Required for the Neuroprotective Effect of Nitric Oxide in Neuronal Cultures.

Prohibitin (PHB) is a critical protein involved in many cellular activities. In brain, PHB resides in mitochondria, where it forms a large protein complex with PHB2 in the inner TFmembrane, which serves as a scaffolding platform for proteins involved in mitochondrial structural and functional integrity. PHB overexpression at moderate levels provides neuroprotection in experimental brain injury models. In addition, PHB expression is involved in ischemic preconditioning, as its expression is enhanced in preconditioning paradigms. However, the mechanisms of PHB functional regulation are still unknown. Observations that nitric oxide (NO) plays a key role in ischemia preconditioning compelled us to postulate that the neuroprotective effect of PHB could be regulated by NO. Here, we test this hypothesis in a neuronal model of ischemia-reperfusion injury and show that NO and PHB are mutually required for neuronal resilience against oxygen and glucose deprivation stress. Further, we demonstrate that NO post-translationally modifies PHB through protein S-nitrosylation and regulates PHB neuroprotective function, in a nitric oxide synthase-dependent manner. These results uncover the mechanisms of a previously unrecognized form of molecular regulation of PHB that underlies its neuroprotective function.SIGNIFICANCE STATEMENT Prohibitin (PHB) is a critical mitochondrial protein that exerts a potent neuroprotective effect when mildly upregulated in mice. However, how the neuroprotective function of PHB is regulated is still unknown. Here, we demonstrate a novel regulatory mechanism for PHB that involves nitric oxide (NO) and shows that PHB and NO interact directly, resulting in protein S-nitrosylation on residue Cys69 of PHB. We further show that nitrosylation of PHB may be essential for its ability to preserve neuronal viability under hypoxic stress. Thus, our study reveals a previously unknown mechanism of functional regulation of PHB that has potential therapeutic implications for neurologic disorders.

Prohibitin levels regulate OMA1 activity and turnover in neurons.

The GTPase OPA1 and the AAA-protease OMA1 serve well-established roles in mitochondrial stress responses and mitochondria-initiated cell death. In addition to its role in mitochondrial membrane fusion, cristae structure, and bioenergetic function, OPA1 controls apoptosis by sequestering cytochrome c (cyt c) in mitochondrial cristae. Cleavage of functional long OPA1 (L-OPA1) isoforms by OMA1 inactivates mitochondrial fusion and primes apoptosis. OPA1 cleavage is regulated by the prohibitin (PHB) complex, a heteromeric, ring-shaped mitochondrial inner membrane scaffolding complex composed of PHB1 and PHB2. In neurons, PHB plays a protective role against various stresses, and PHB deletion destabilizes OPA1 causing neurodegeneration. While deletion of OMA1 prevents OPA1 destabilization and attenuates neurodegeneration in PHB2 KO mice, how PHB levels regulate OMA1 is still unknown. Here, we investigate the effects of modulating neuronal PHB levels on OMA1 stability and OPA1 cleavage. We demonstrate that PHB promotes OMA1 turnover, effectively decreasing the pool of OMA1. Further, we show that OMA1 binds to cardiolipin (CL), a major mitochondrial phospholipid. CL binding promotes OMA1 turnover, as we show that deleting the CL-binding domain of OMA1 decreases its turnover rate. Since PHB is known to stabilize CL, these data suggest that PHB modulates OMA1 through CL. Furthermore, we show that PHB decreases cyt c release induced by tBID and attenuates caspase 9 activation in response to hypoxic stress in neurons. Taken together, our results suggest that PHB-mediated CL stabilization regulates stress responses and cell death through OMA1 turnover and cyt c release.

Small-molecule inhibitors of ubiquitin-specific protease 7 enhance type-I interferon antiviral efficacy by destabilizing SOCS1.

Type-I interferons (IFN-I) are used as common antiviral drugs for a range of viral diseases in clinic. However, the antiviral efficacy of IFN-I is largely restricted by negative regulators of IFN-I signaling in cells. Therefore, identification of intracellular inhibitors of IFN-I signaling is important for developing novel targets to improve IFN-I antiviral therapy. In this study, we report that the deubiquitinase ubiquitin-specific protease 7 (USP7) negatively regulates IFN-I-mediated antiviral activity. USP7 physically interacts with suppressor of cytokine signaling 1 (SOCS1) and enhances SOCS1 protein stability by deubiquitination effects, which in turn restricts IFN-I-induced activation of Janus kinase-signal transducer and activator of transcription 1 signaling. Interestingly, viral infection up-regulates USP7 and therefore facilitates viral immune evasion. Importantly, the USP7 small-molecule inhibitors P5091 and P22077 inhibit SOCS1 expression and enhance IFN-I antiviral efficacy. Our findings identify a novel regulator of IFN-I antiviral activity and reveal that USP7 inhibitors could be potential enhancement agents for improving IFN-I antiviral therapy.

Targeting UBE4A Revives Viperin Protein in Epithelium to Enhance Host Antiviral Defense.

Mutation and prevalence of pathogenic viruses prompt the development of broad-spectrum antiviral strategies. Viperin is a potent antiviral protein that inhibits a broad range of viruses. Unexpectedly, we found that Viperin protein production in epithelium is defective in response to both viruses and interferons (IFNs). We further revealed that viruses and IFNs stimulate expression of the acetyltransferase HAT1, which induces Lys197-acetylation on Viperin. Viperin acetylation in turn recruits UBE4A that stimulates K6-linked polyubiquitination at Lys206 of Viperin, leading to Viperin protein degradation. Importantly, UBE4A deficiency restores Viperin protein production in epithelium. We then designed interfering peptides (IPs) to inhibit UBE4A binding with Viperin. We found that VIP-IP3 rescues Viperin protein production in epithelium and therefore enhances cellular antiviral activity. VIP-IP3 renders mice more resistant to viral infection. These findings could provide strategies for both enhancing host broad-spectrum antiviral response and improving the efficacy of IFN-based antiviral therapy.

Alpha-synuclein is strategically positioned for afferent modulation of midbrain dopamine neurons and is essential for cocaine preference.

Alpha-synuclein (α-syn) is an abundant neuroprotein elevated in cocaine addicts, linked to drug craving, and recruited to axon terminals undergoing glutamatergic plasticity - a proposed mechanism for substance abuse. However, little is known about normal α-syn function or how it contributes to substance abuse. We show that α-syn is critical for preference of hedonic stimuli and the cognitive flexibility needed to change behavioral strategies, functions that are altered with substance abuse. Electron microscopic analysis reveals changes in α-syn targeting of ventral tegmental area axon terminals that is dependent upon the duration of cocaine exposure. The dynamic changes in presynaptic α-syn position it to control neurotransmission and fine-tune the complex afferent inputs to dopamine neurons, potentially altering functional dopamine output. Cocaine also increases postsynaptic α-syn where it is needed for normal ALIX function, multivesicular body formation, and cocaine-induced exosome release indicating potentially similar α-syn actions for vesicle release pre- and post-synaptically.

Lack of patient education is risk factor of disease flare in patients with systemic lupus erythematosus in China.

BACKGROUND: To explore the inadequacies of health service and its impact on clinical outcomes of patients with systemic lupus erythematosus (SLE) in China. METHODS: A total of 210 SLE patients were randomly recruited between January 2017 and January 2018. Each patient received self-report questionnaires to assess medication adherence [Compliance Questionnaire for Rheumatology (CQR)], beliefs about medicines [Beliefs about Medicines Questionnaire (BMQ)] and satisfaction about medicine information [the Satisfaction with Information about Medicines Scale (SIMS)]. Associations between SLE disease activity index (SLEDAI-2 K) and observed factors were analyzed by multiple logistic regression. RESULTS: Based on CQR, only 28.10% patients were adherent. The score of BMQ was 2.85 ± 5.42, and merely 32.38% patients were satisfied with the information about their prescribed medicines. Disease activity was associated with SIMS, EuroQol five-dimensions [EQ5D], Systemic Lupus International Collaborating Clinics (SLICC), depression, use of NSAID (P ≤ 0.05). Remission of disease was positively correlated with SIMS (OR = 0.16, 95% CI: [0.06, 0.40]), and BMQ (OR = 0.64, 95%CI: [0.43, 0.94]). CONCLUSION: In this study, the scores of BMQ and SIMS were low, implying defects in the patient education of health service system, which led to disease flare in Chinese SLE patients. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03024307 . Registered January 18, 2017.