UHRF1 Deficiency Inhibits Alphaherpesvirus through Inducing RIG-I-IRF3-Mediated Interferon Production.

Type I interferon (IFN-I) response plays a prominent role in innate immunity, which is frequently modulated during viral infection. Here, we report DNA methylation regulator UHRF1 as a potent negative regulator of IFN-I induction during alphaherpesvirus infection, whereas the viruses in turn regulates the transcriptional expression of UHRF1. Knockdown of UHRF1 in cells significantly increases interferon-ß (IFN-ß)-mediated gene transcription and viral inhibition against herpes simplex virus 1 (HSV1) and pseudorabies virus (PRV). Mechanistically, UHRF1 deficiency promotes IFN-I production by triggering dsRNA-sensing receptor RIG-I and activating IRF3 phosphorylation. Knockdown of UHRF1 in cells upregulates the accumulation of double-stranded RNA (dsRNA), including host endogenous retroviral sequence (ERV) transcripts, while the treatment of RNase III, known to specifically digest dsRNA, prevents IFN-ß induction by siUHRF1. Furthermore, the double-knockdown assay of UHRF1 and DNA methyltransferase DNMT1 suggests that siUHRF1-mediated DNA demethylation may play an important role in dsRNA accumulation and subsequently IFN induction. These findings establish the essential role of UHRF1 in IFN-I-induced antiviral immunity and reveal UHRF1 as a potential antivrial target. IMPORTANCE Alphaherpesviruses can establish lifelong infections and cause many diseases in humans and animals, which rely partly on their interaction with IFN-mediated innate immune response. Using alphaherpesviruses PRV and HSV-1 as models, we identified an essential role of DNA methylation regulator UHRF1 in IFN-mediated immunity against virus replication, which unravels a novel mechanism employed by epigenetic factor to control IFN-mediated antiviral immune response and highlight UHRF1, which might be a potential target for antiviral drug development.

Giant Effect of CO2 Injection on Multiphase Fluid Adsorption and Shale Gas Production: Evidence from Molecular Dynamics.

Carbon dioxide (CO2) injection in unconventional gas-bearing shale reservoirs is a promising method for enhancing methane recovery efficiency and mitigating greenhouse gas emissions. The majority of methane is adsorbed within the micropores and nanopores (≤50 nm) of shale, which possess extensive surface areas and abundant adsorption sites for the sequestration system. To comprehensively discover the underlying mechanism of enhanced gas recovery (EGR) through CO2 injection, molecular dynamics (MD) provides a promising way for establishing the shale models to address the multiphase, multicomponent fluid flow behaviors in shale nanopores. This study proposes an innovative method for building a more practical shale matrix model that approaches natural underground environments. The grand canonical Monte Carlo (GCMC) method elucidates gas adsorption and sequestration processes in shale gas reservoirs under various subsurface conditions. The findings reveal that previously overlooked pore slits have a significant impact on both gas adsorption and recovery efficiency. Based on the simulation comparisons of absolute and excess uptakes inside the kerogen matrix and the shale slits, it demonstrates that nanopores within the kerogen matrix dominate the gas adsorption while slits dominate the gas storage. Regarding multiphase, multicomponent fluid flow in shale nanopores, moisture negatively influences gas adsorption and carbon storage while promoting methane recovery efficiency by CO2 injection. Additionally, saline solution and ethane further impede gas adsorption while facilitating displacement. Overall, this work elucidates the substantial effect of CO2 injection on fluid transport in shale formations and advances the comprehensive understanding of microscopic gas flow and recovery mechanisms with atomic precision for low-carbon energy development.

Bclaf1 regulates c-FLIP expression and protects cells from TNF-induced apoptosis and tissue injury.

TNF stimulation generates pro-survival signals through activation of NF-κB that restrict the build-in death signaling triggered by TNF. The competition between TNF-induced survival and death signals ultimately determines the fate of a cell. Here, we report the identification of Bclaf1 as a novel component of the anti-apoptotic program of TNF. Bclaf1 depletion in multiple cells sensitizes cells to TNF-induced apoptosis but not to necroptosis. Bclaf1 exerts its anti-apoptotic function by promoting the transcription of CFLAR, a caspase 8 antagonist, downstream of NF-κB activation. Bclaf1 binds to the p50 subunit of NF-κB, which is required for Bclaf1 to stimulate CFLAR transcription. Finally, in Bclaf1 siRNA administered mice, TNF-induced small intestine injury is much more severe than in control mice with aggravated signs of apoptosis and pyroptosis. These results suggest Bclaf1 is a key regulator in TNF-induced apoptosis, both in vitro and in vivo.

Pseudorabies Virus EP0 Antagonizes the Type I Interferon Response via Inhibiting IRF9 Transcription.

The alphaherpesvirus pseudorabies virus (PRV) is the etiologic agent of swine Aujeszky's disease, which can cause huge economic losses to the pig industry. PRV can overcome a type I interferon (IFN)-induced antiviral state in host cells through its encoded EP0 protein. However, the exact role of EP0 in this process is poorly defined. Here, we report that EP0 transcriptionally represses IFN regulatory factor 9 (IRF9), a critical component in the IFN signaling pathway, thereby reducing the cellular levels of IRF9 and inhibiting IFN-induced gene transcription. This activity of EP0 is mediated by its C-terminal region independently of the RING domain. Moreover, compared with EP0 wild-type PRV, EP0-deficient PRV loses the ability to efficiently decrease cellular IRF9, while reintroducing the C-terminal region of EP0 back into the EP0-deficient virus restores the activity. Together, these results suggest that EP0 can transcriptionally modulate IRF9-mediated antiviral pathways through its C-terminal region, contributing to PRV innate immune evasion. IMPORTANCE Alphaherpesviruses can establish lifelong infections and cause many diseases in humans and animals. Pseudorabies virus (PRV) is a swine alphaherpesvirus that threatens pig production. Using PRV as a model, we found that alphaherpesvirus can utilize its encoded early protein EP0 to inhibit the IFN-induced upregulation of antiviral proteins by reducing the basal expression levels of IRF9 through repressing its transcription. Our findings reveal a mechanism employed by alphaherpesvirus to evade the immune response and indicate that EP0 is an important viral protein in pathogenesis and a potential target for antiviral drug development.

Structure of human MDM2 complexed with RPL11 reveals the molecular basis of p53 activation.

The central region of MDM2 is critical for p53 activation and tumor suppression. Upon ribosomal stress, this region is bound by ribosomal proteins, particularly ribosomal protein L11 (RPL11), leading to MDM2 inactivation and subsequent p53 activation. Here, we solved the complex structure of human MDM2-RPL11 at 2.4 Å. MDM2 extensively interacts with RPL11 through an acidic domain and two zinc fingers. Formation of the MDM2-RPL11 complex induces substantial conformational changes in both proteins. RPL11, unable to bind MDM2 mutants, fails to induce the activation of p53 in cells. MDM2 mimics 28S rRNA binding to RPL11. The C4 zinc finger determines RPL11 binding to MDM2 but not its homolog, MDMX. Our results highlight the essential role of the RPL11-MDM2 interaction in p53 activation and tumor suppression and provide a structural basis for potential new anti-tumor drug development.

Potential role of BAY11-7082, a NF-κB blocker inhibiting experimental autoimmune encephalomyelitis in C57BL/6J mice via declining NLRP3 inflammasomes.

Multiple sclerosis (MS) is an inflammatory autoimmune demyelinating disease of the central nervous system. NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is implicated in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the exact mechanism by which NLRP3 inflammasome is involved in the development of MS and EAE is not clear. NF-kappaB (NF-κB) is associated with the activity of NLRP3 inflammasomes, but the role of NF-κB is controversial. We sought to demonstrate that both NF-κB and NLRP3 contribute to development of MS and EAE, and NF-κB pathway is positively correlated with NLRP3 activation in EAE. The inhibitor of NF-κB and NLRP3, BAY11-7082, can prevent and treat EAE. BAY11-7082 (5 and 20 mg/kg/i.p.) was intraperitoneally administered to EAE mice at the time of second injection of pertussis toxin (BAY11-7082 prevention group) or at the onset of symptoms (BAY11-7082 treatment group). mRNA expressions of NLRP3 were determined by qPCR. Protein expressions of NLRP3, NF-κB p65, and phosphorylated p65 were determined by western blotting. Serum levels of inflammatory cytokines were measured by cytometric bead array. Mice treated with BAY11-7082 (both prevention and treatment groups) showed lower clinical scores and attenuated pathological changes. NLRP3 inflammasome and activity of NF-κB in spinal cord of EAE mice was higher than that in control group. However, the level of NLRP3 inflammasome decreased in BAY11-7082 prevention and treatment groups. BAY11-7082 is a promising therapeutic agent for MS. NLRP3 activation in EAE maybe related with NF-κB pathway.

Proposal for High-Energy Cutoff Extension of Optical Harmonics of Solid Materials Using the Example of a One-Dimensional ZnO Crystal.

We propose a novel approach based on the subcycle injection of carriers to extend the high-energy cutoff in solid-state high harmonics. The mechanism is first examined by employing the standard single-cell semiconductor Bloch equation (SC SBE) method for one-dimensional (1D) Mathieu potential model for ZnO subjected to the intense linearly polarized midinfrared laser field and extreme-ultraviolet pulse. Then, we use coupled solution of Maxwell propagation equation and SC SBE to propagate the fundamental laser field through the sample, and find that the high-harmonics pulse train from the entrance section of the sample can inject carriers to the conduction bands with attosecond timing, subsequently leading to a dramatic extension of high-energy cutoff in harmonics from the backside. We predict that for a peak intensity at 2×10^{11} W/cm^{2}, as a result of the self-seeding, the high-energy cutoff shifts from 20th (7.75 eV) order to around 50th (19.38 eV) order harmonics.

Identifying the Phenotypes of Sepsis that will Benefit from Red Blood Cell Transfusion Using Unsupervised Cluster Analysis.

BACKGROUND: Sepsis is a heterogeneous syndrome. Previous studies have shown controversial results of the effects of red blood cell transfusion (RBC) on the clinical outcomes of septic patients. This study aimed to identify the phenotypes of sepsis that will benefit from RBC transfusion. METHODS: Clinical data were extracted from the Medical Information Mart for Intensive Care III database. The study population included adult (age ≥ 18 years) septic patients with moderate non-bleeding anemia (hemoglobin ≤ 10 g/dL) within 24 hours after admission to the intensive care unit (ICU) between 2001 and 2012. After data preprocessing, partitioning around medoids function was used for unsupervised cluster analysis. We used Kaplan-Meier survival analysis and multivariable Cox proportional hazard models to explore the relationship between RBC transfusion and mortality. RESULTS: In total, 6,821 septic patients with moderate non-bleeding anemia within 24 hours after ICU admission, and 3,874 patients (56.8%) received RBC transfusion during their stay in the ICU. Using unsupervised cluster analysis, we identified three phenotypes of septic patients with moderate non-bleeding anemia: cluster A (n = 1,835) was characterized by advanced age and heart issues; cluster B (n = 3,043) was characterized by mild disease and relatively high hemoglobin levels; and cluster C (n = 1,943) was characterized by severe disease, low mean arterial pressure, bloodstream infection, coagulopathy, high lactate levels, and high mortality. Only for patients in cluster C, RBC transfusion exhibited protective effects in terms of the 14-day [hazard ratio (HR), 0.50; 95% confidence interval (CI), 0.41 - 0.61; p < 0.001], 28-day (HR, 0.61; 95% CI, 0.51 - 0.72; p < 0.001), and 90-day (HR, 0.67; 95% CI, 0.58 - 0.78; p < 0.001) mortality after adjusting the confounding variables. CONCLUSIONS: Utilizing unsupervised cluster analysis, we identified three phenotypes of septic patients with moderate non-bleeding anemia who had different responses to RBC transfusion. In the future, randomized controlled trials about prognostic outcomes of RBC transfusions can focus on the specific phenotype of sepsis.

Candesartan Reduces Neuronal Apoptosis Caused by Ischemic Stroke via Regulating the FFAR1/ITGA4 Pathway.

Ischemic stroke (IS) is a general term for necrosis of brain tissue caused by stenosis, occlusion of arteries supplying blood to the brain (carotid artery and vertebral artery), and insufficient blood supply to the brain. Cerebral ischemia is the main kind of IS causing cell damage. However, the underlying mechanism still needs to be clarified further. In this study, it was demonstrated that FFAR1 was a hub gene in IS. The expression of FFAR1 was increased in PC12 cells with OGD/R treatment. FFAR1 deficiency inhibited cell viability and induced cell apoptosis, which was reversed by FFAR1 overexpression. Moreover, candesartan, as a compound targeting FFAR1, facilitated cell viability and reduced cell apoptosis. The expression of ITGA4 was also high in OGD/R-PC12 cells as FFAR1. Furthermore, FFAR1 deficiency retarded the increasing of cell viability and inhibition of cell apoptosis by downregulation of Bax and Cleaved Caspase-3 in OGD/R-PC12 cells with candesartan treatment. In conclusion, candesartan may regulate neuronal apoptosis through FFAR1/ITGA4 axis.

Latissimus dorsi muscle flap transfer through endoscopic approach combined with the implant after tissue expansion for breast reconstruction of mastectomy patients.

BACKGROUND: Implant-based breast reconstruction is easy to be performed but has flaws that an unnatural appearance might be presented when no sufficient coverage existing. While autologous tissue reconstruction also has disadvantages like donor site scar and skin patch effect. There is a demand for a new method to obtain natural and aesthetic appearance while surmounting drawbacks of conventional breast reconstruction surgery. METHODS: A retrospective review of thirty-one patients undergoing tissue expander (TE)/implant two-stage breast reconstruction with latissimus dorsi muscle flap (LDMF) transfer through endoscopic approach in Peking University Third Hospital from April 2016 to August 2020 was performed. The LDMF harvest time, drain time, and complications were reviewed. The 3D volume was obtained to assess the volume symmetry of bilateral breasts. The BREAST-Q reconstruction module was used to evaluate the satisfaction. RESULTS: The mean endoscopic LDMF harvest time was 90.4 min. In the mean follow-up of 11.2 months, there were no severe capsular contracture happened. The reconstructed side achieved good volume symmetry to the contralateral side (P = 0.256). Based on the evaluation of the BREAST-Q scores, the outcome of Satisfaction with Breasts was excellent or good in 87.1% of the cases. CONCLUSIONS: The novel type of two-stage breast reconstruction protocol, which includes tissue expansion followed by implant insertion with endoscopy-assisted LDMF transfer, could effectively reduce visible scars, avoid the patch effect, while require short time for LDMF harvest and present low incidence of complications. It is a promising method for breast reconstruction because it achieves good outcomes in the mastectomy patients.

Swine Promyelocytic Leukemia Isoform II Inhibits Pseudorabies Virus Infection by Suppressing Viral Gene Transcription in Promyelocytic Leukemia Nuclear Bodies.

Promyelocytic leukemia nuclear bodies (PML-NBs) possess an important intrinsic antiviral activity against alphaherpesvirus infection. PML is the structural backbone of NBs, comprising different isoforms. However, the contribution of each isoform to alphaherpesvirus restriction is not well understood. Here, we report the role of PML-NBs and swine PML (sPML) isoforms in pseudorabies virus (PRV) infection in its natural host swine cells. We found that sPML-NBs exhibit an anti-PRV activity in the context of increasing the expression level of endogenous sPML. Of four sPML isoforms cloned and examined, only isoforms sPML-II and -IIa, not sPML-I and -IVa, expressed in a sPML knockout cells inhibit PRV infection. Both the unique 7b region of sPML-II and the sumoylation-dependent normal formation of PML-NBs are required. 7b possesses a transcriptional repression activity and suppresses viral gene transcription during PRV infection with the cysteine residues 589 and 599 being critically involved. We conclude that sPML-NBs inhibit PRV infection partly by repressing viral gene transcription through the 7b region of sPML-II.IMPORTANCE PML-NBs are nuclear sites that mediate the antiviral restriction of alphaherpesvirus gene expression and replication. However, the contribution of each PML isoform to this activity of PML-NBs is not well characterized. Using PRV and its natural host swine cells as a system, we have discovered that the unique C terminus of sPML isoform II is required for PML-NBs to inhibit PRV infection by directly engaging in repression of viral gene transcription. Our study not only confirms in swine cells that PML-NBs have an antiviral function but also presents a mechanism to suggest that PML-NBs inhibit viral infection in an isoform specific manner.

Nuclear factor kappa B inhibitor suppresses experimental autoimmune neuritis in mice via declining macrophages polarization to M1 type.

Guillain-Barré syndrome (GBS) is an acute inflammatory and immune-mediated demyelinating disease of the peripheral nervous system (PNS). Macrophages play a central role in its animal model, experimental autoimmune neuritis (EAN), which has been well accepted. Additionally, nuclear factor (NF)-κB inhibitors have been used to treat cancers and have shown beneficial effects. Here, we investigated the therapeutic effect of M2 macrophage and the NF-κB pathway's correlation with macrophage activation in EAN in C57BL/6 mice. We demonstrate that M2 macrophage transfusion could alleviate the clinical symptoms of EAN by reducing the proportion of M1 macrophage in the peak period, inhibiting the phosphorylation of NF-κB p65. The NF-κB inhibitor (BAY-11-7082) could alleviate the clinical symptoms of EAN and shorten the duration of symptoms by reducing the proportion of M1 macrophages and the expression of proinflammatory cytokines. Consequently, BAY-11-7082 exhibits strong potential as a therapeutic strategy for ameliorating EAN by influencing the balance of M1/M2 macrophages and inflammatory cytokines.

Bclaf1 critically regulates the type I interferon response and is degraded by alphaherpesvirus US3.

Type I interferon response plays a prominent role against viral infection, which is frequently disrupted by viruses. Here, we report Bcl-2 associated transcription factor 1 (Bclaf1) is degraded during the alphaherpesvirus Pseudorabies virus (PRV) and Herpes simplex virus type 1 (HSV-1) infections through the viral protein US3. We further reveal that Bclaf1 functions critically in type I interferon signaling. Knockdown or knockout of Bclaf1 in cells significantly impairs interferon-α (IFNα) -mediated gene transcription and viral inhibition against US3 deficient PRV and HSV-1. Mechanistically, Bclaf1 maintains a mechanism allowing STAT1 and STAT2 to be efficiently phosphorylated in response to IFNα, and more importantly, facilitates IFN-stimulated gene factor 3 (ISGF3) binding with IFN-stimulated response elements (ISRE) for efficient gene transcription by directly interacting with ISRE and STAT2. Our studies establish the importance of Bclaf1 in IFNα-induced antiviral immunity and in the control of viral infections.

Parkinsonism and dysautonomia with anti-CV2/CRMP5 associated paraneoplastic neurological syndromes mimicking multiple system atrophy: a case report.

BACKGROUND: Paraneoplastic neurological syndromes (PNSs) are broad-spectrum disorders that can affect any part of the nervous system varying in core symptoms. Onconeural antibodies, including Hu, Yo, Ri, anti-CV2, amphiphysin, Ma2, and Tr are well-characterized and commonly used for the diagnosis of definite PNS. Generally, anti-CV2 antibodies have usually been associated with cerebellar ataxia, chorea, peripheral and autonomic neuropathies, myelopathy, optic neuritis, and retinitis. However, Parkinsonism has not been reported as the core symptom in patients with anti-CV2 antibodies. CASE PRESENTATION: We report a patient with anti-CV2 antibody manifested as Parkinsonism and autonomic dysfunction, which may lead to the diagnosis of multiple system atrophy with predominant Parkinsonism (MSA-P). A lumbar puncture examination was undergone to find a positive anti-CV2 antibody in cerebrospinal fluid. PET-CT showed no tumor. Immunotherapy was adopted and the symptoms were relieved for 5 months. However, with no evidence of tumor, he died after 8 months. CONCLUSIONS: Our findings indicate that PNS with anti-CV2 antibody can be shown as MSA-P mimic. Considering that MSA is a neurodegenerative disease with a poor prognosis, screening for other treatable or controllable factors like PNS presented in this case is necessary when encountering a rapid progressive MSA-mimic patient.

Clinical manifestations and polysomnography-based analysis in nine cases of probable sporadic Creutzfeldt-Jakob disease.

PURPOSE: To summarize the clinical characteristics of patients with sporadic Creutzfeldt-Jakob disease (sCJD), analyze its sleep disorder characteristics using polysomnography (PSG), and compare sleep disturbances with those of fatal familial insomnia (FFI). PATIENTS AND METHODS: We retrospectively reviewed the sleep disturbances; cerebrospinal fluid (CSF) protein 14-3-3 (CSF-14-3-3 protein); prion protein gene, PRNP; magnetic resonance imaging; and electroencephalogram (EEG) of nine sCJD patients RESULTS: Of the nine sCJD patients, six were positive for CSF-14-3-3 protein. In the eight patients who completed diffusion-weighted imaging, seven showed cortical "ribbons sign" and two showed high signal in the basal ganglia. All nine patients had an EEG, which showed an increase in background slow waves; moreover, four showed typical periodic sharp wave complexes. The codon diversity at position 129, 219 of nine patients were MM, EE. Almost all nine patients had sleep disturbances such as insomnia, hypersomnia, and periodic limb movement disorder (PLMD). Five patients completed PSG, which demonstrated severe sleep structure disorder, prolonged total waking time, significantly reduced sleep efficiency, and absent rapid eye movement in some severe patients. CONCLUSION: Sleep disturbances are common in sCJD patients, manifested as insomnia, lethargy, and PLMD. The sCJD patients often demonstrate severe sleep structure disorder through PSG, which is similar to patients with FFI.

Vanillin derivative VND3207 activates DNA-PKcs conferring protection against radiation-induced intestinal epithelial cells injury in vitro and in vivo.

Vanillin is a natural compound endowed with antioxidant and anti-mutagenic properties. We previously identified the vanillin derivative VND3207 with strong radio-protective and antioxidant effects and found that VND3207 confers survival benefit and protection against radiation-induced intestinal injury (RIII) in mice. We also observed that VND3207 treatment enhanced the expression level of the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) in human lymphoblastoid cells with or without γ-irradiation. DNA-PKcs is a critical component of DNA double strand break repair pathway and also regulates mitotic progression by stabilizing spindle formation and preventing mitotic catastrophe in response to DNA damage. In the present study, we found that VND3207 protected intestinal epithelial cells in vitro against ionizing radiation by promoting cell proliferation and inhibiting cell apoptosis. In addition, VND3207 promoted DNA-PKcs activity by increasing autophosphorylation at S2056 site. Consistent with this, VND3207 significantly decreased the number of γH2AX foci and mitotic catastrophe after radiation. DNA-PKcs deficiency abolished these VND3207 radio-protective effects, indicating that DNA-PKcs activation is essential for VND3207 activity. In conclusion, VND3207 promoted intestinal repair following radiation injury by regulating the DNA-PKcs pathway.

Clinical characteristics and prognostic analysis of anti-gamma-aminobutyric acid-B (GABA-B) receptor encephalitis in Northeast China.

OBJECTIVE: To investigate the clinical characteristics and prognosis of anti-gamma-aminobutyric acid-B (GABA-B) receptor encephalitis. METHODS: This retrospective study enrolled nineteen patients with anti-GABA-B receptor encephalitis. Clinical manifestations, radiological and electroencephalogram features, treatment and outcomes were collected and analyzed. The neurological function was evaluated according to the modified Rankin Scale (mRS). RESULTS: There were eleven patients in the favorable-prognosis group (mRS ≤ 2) and eight patients in the poor-prognosis group (mRS > 2). In the favorable-prognosis group, clinical symptoms included memory deterioration (n = 10; 90.9%), epileptic seizures (n = 9; 81.8%), psychiatric disorders (n = 9; 81.8%), and conscious disturbance (n = 5; 45.5%); magnetic resonance imaging (MRI) indicated an involvement of the limbic system in three (27.3%) cases in this group. Lung cancer was detected in one patient (9.1%). After an average follow-up period of 11.7 months, four (36.4%) patients were cured, and seven (63.6%) patients showed significant improvements. In the poor-prognosis group, all patients presented with memory deterioration, epileptic seizures, psychiatric disorders, and conscious disturbance; five (62.5%) patients had convulsive status epilepticus, and five (62.5%) patients developed respiratory failure; MRI indicated an involvement of the limbic system in seven (87.5%) cases. Malignant tumors were detected in five (62.5%) patients. After an average follow-up period of 14.8 months, seven (87.5%) patients died and one (12.5%) patient remained dependent in daily life. CONCLUSIONS: The clinical manifestations of anti-GABA-B receptor encephalitis include epileptic seizures, cognitive impairment and psychiatric disorders. Patients with convulsive status epilepticus or respiratory failure have poor outcomes. In anti-GABA-B receptor encephalitis, limbic system involvement is associated with a poor prognosis in and radiological examinations can reflect disease progression. Early diagnosis and appropriate treatment should be highlighted.

Renal tubules transcriptome reveals metabolic maladaption during the progression of ischemia-induced acute kidney injury.

Renal tubular epithelial cells (TECs) play a critical role in driving acute kidney injury (AKI) progression, but the key molecular features in TECs during this process is not clear. To better understand the molecular characteristics in renal TECs during AKI and renal fibrogenesis, an irreversible AKI mouse model induced by ischemia/reperfusion injury (IRI) was used in this study. The renal tubules were isolated and tubule specific transcriptome was detected by RNA-seq at different stages in the progression of AKI in this model. The overall transcriptome indicated injury and repair process of TEC after renal IRI. In addition, metabolism maladaption was observed during AKI progression to chronic fibrosis. Particularly, we found dysregulation of multiple steps of lipid metabolism in tubule transcriptomes. Oil red O staining revealed massive lipid droplets accumulation in TECs at day 10, thus confirming the defect of lipid metabolism. This is the first study to charaterize renal tubule specific transcriptome during AKI progression. The results shed light on the molecular features in TECs for progressive AKI.

Pseudorabies Virus dUTPase UL50 Induces Lysosomal Degradation of Type I Interferon Receptor 1 and Antagonizes the Alpha Interferon Response.

Alphaherpesviruses that establish persistent infections rely partly on their ability to evade host antiviral responses, notably the type I interferon (IFN) response. However, the mechanisms employed by alphaherpesviruses to avoid this response are not well understood. Pseudorabies virus (PRV) is an economically important pathogen and a useful model system for studying alphaherpesvirus biology. To identify PRV proteins that antagonize type I IFN signaling, we performed a screen by using an IFN-stimulated response element reporter in the swine cell line CRL. Unexpectedly, we identified the dUTPase UL50 as a strong inhibitor. We confirmed that UL50 has the ability to inhibit type I IFN signaling by performing ectopic expression of UL50 in cells and deletion of UL50 in PRV. Mechanistically, UL50 impeded type I IFN-induced STAT1 phosphorylation, likely by accelerating lysosomal degradation of IFN receptor 1 (IFNAR1). In addition, this UL50 activity was independent of its dUTPase activity and required amino acids 225 to 253 in the C-terminal region. The UL50 encoded by herpes simplex virus 1 (HSV-1) also possessed similar activity. Moreover, UL50-deleted PRV was more susceptible to IFN than UL50-proficient PRV. Our results suggest that in addition to its dUTPase activity, the UL50 protein of alphaherpesviruses possesses the ability to suppress type I IFN signaling by promoting lysosomal degradation of IFNAR1, thereby contributing to immune evasion. This finding reveals UL50 as a potential antiviral target.IMPORTANCE Alphaherpesviruses can establish lifelong infections and cause many diseases in humans and animals. Pseudorabies virus (PRV) is a swine alphaherpesvirus that threatens pig production. Using PRV as a model, we found that this alphaherpesvirus could utilize its encoded dUTPase UL50 to induce IFNAR1 degradation and inhibit type I IFN signaling in an enzymatic activity-independent manner. Our finding reveals a mechanism employed by an alphaherpesvirus to evade the immune response and indicates that UL50 is an important viral protein in pathogenesis and is a potential target for antiviral drug development.

The vanillin derivative 6-bromine-5-hydroxy-4-methoxybenzaldehyde induces aberrant mitotic progression and enhances radio-sensitivity accompanying suppression the expression of PLK1 in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is the most common form of esophageal cancer in China. Since chemotherapy is the standard clinical intervention for advanced ESCC, the development of highly effective and minimal/non-toxic drugs is essential to improve the clinical outcome and prognosis of the patients. A novel derivative of vanillin, 6-bromine-5-hydroxy-4-methoxybenzaldehyde (BVAN08), has been recently reported to activate different cell death pathways in cancer cells. In this study, we demonstrate that BVAN08 exhibits a potent anti-proliferation effect on ESCC cells (TE-1 and ECA-109) by inhibiting the expression of PLK1, an important mitotic kinase. Consistent with this, BVAN08 induces mitotic arrest and chromosomal misalignment in ESCC cells. The disruption of microtubule nucleation around centrosomes is also observed in BVAN08 treated ESCC cells. Furthermore, BVAN08 enhances radio-sensitivity of ESCC cells by prolonging DNA damage repair. These findings underscore the potential value of BVAN08 in cancer therapeutics and demonstrate the underlying mechanism by which BVAN08 induces mitotic catastrophe and enhances radio-sensitivity in ESCC cells.