Cold atom microwave clock based on intracavity cooling in China space station.

Atomic clocks with higher frequency stability and accuracy than traditional space-borne atomic clocks are the cornerstone of long-term autonomous operation of space-time-frequency systems. We proposed a space cold atoms clock based on an intracavity cooling scheme, which captures cold atoms at the center of a microwave cavity and then executes in situ interactions between the cold atoms and microwaves. As a result of the microgravity environment in space, the cold atoms can interact with the microwaves for a longer time, which aids in realizing a high-precision atomic clock in space. This paper presents the overall design, operational characteristics, and reliability test results of the space atomic clock based on the intracavity cooling scheme designed for the operation onboard the China space station. In addition, the engineering prototype performance of the space cold atoms microwave clock is also presented. The ground test results for the clock show a fractional frequency stability of 1.1 × 10-12 τ-1/2 reaching 2.5 × 10-15 at 200,000 s, providing solid technical and data support for its future operation in orbit.

A PANoptosis pattern to predict prognosis and immunotherapy response in head and neck squamous cell carcinoma.

Individuals diagnosed with head and neck squamous cell carcinoma (HNSCC) experience a significant occurrence rate and are susceptible to premature spreading, resulting in a bleak outlook. Therapeutic approaches, such as chemotherapy, targeted therapy, and immunotherapy, may exhibit primary and acquired resistance during the advanced phases of HNSCC. There is currently no viable solution to tackle this issue. PANoptosis-a type of non-apoptotic cell death-is a recently identified mechanism of cellular demise that entails communication and synchronization among thermal apoptosis, apoptosis, and necrosis mechanisms. However, the extent to which PANoptosis-associated genes (PRG) contribute to the forecast and immune reaction of HNSCC remains mostly undisclosed. The present study aimed to thoroughly analyze the potential importance of PRG in HNSCC and report our discoveries. We systematically analyzed 19 PRG from previous studies and clinical data from HNSCC patients to establish a PAN-related signature and assess its prognostic, predictive potential. Afterward, the patient information was separated into two gene patterns that corresponded to each other, and the analysis focused on the connection between patient prognosis, immune status, and cancer immunotherapy. The PAN score was found to correlate with survival rates, immune systems, and cancer-related pathways. We then validated the malignant role of CD27 among them in HNSCC. In summary, we demonstrated the effectiveness of PAN.Score-based molecular clustering and prognostic features in predicting the outcome of HNSCC. The discovery we made could enhance our comprehension of the significance of PAN.Score in HNSCC and facilitate the development of more effective treatment approaches.

Hippo-signaling-controlled MHC class I antigen processing and presentation pathway potentiates antitumor immunity.

The major histocompatibility complex class I (MHC class I)-mediated tumor antigen processing and presentation (APP) pathway is essential for the recruitment and activation of cytotoxic CD8+ T lymphocytes (CD8+ CTLs). However, this pathway is frequently dysregulated in many cancers, thus leading to a failure of immunotherapy. Here, we report that activation of the tumor-intrinsic Hippo pathway positively correlates with the expression of MHC class I APP genes and the abundance of CD8+ CTLs in mouse tumors and patients. Blocking the Hippo pathway effector Yes-associated protein/transcriptional enhanced associate domain (YAP/TEAD) potently improves antitumor immunity. Mechanistically, the YAP/TEAD complex cooperates with the nucleosome remodeling and deacetylase complex to repress NLRC5 transcription. The upregulation of NLRC5 by YAP/TEAD depletion or pharmacological inhibition increases the expression of MHC class I APP genes and enhances CD8+ CTL-mediated killing of cancer cells. Collectively, our results suggest a crucial tumor-promoting function of YAP depending on NLRC5 to impair the MHC class I APP pathway and provide a rationale for inhibiting YAP activity in immunotherapy for cancer.

The CK1ε/SIAH1 axis regulates AXIN1 stability in colorectal cancer cells.

Casein kinase 1ε (CK1ε) and axis inhibitor 1 (AXIN1) are crucial components of the ß-catenin destruction complex in canonical Wnt signaling. CK1ε has been shown to interact with AXIN1, but its physiological function and role in tumorigenesis remain unknown. In this study, we found that CK1δ/ε inhibitors significantly enhanced AXIN1 protein level in colorectal cancer (CRC) cells through targeting CK1ε. Mechanistically, CK1ε promoted AXIN1 degradation by the ubiquitin-proteasome pathway by promoting the interaction of E3 ubiquitin-protein ligase SIAH1 with AXIN1. Genetic or pharmacological inhibition of CK1ε and knockdown of SIAH1 downregulated the expression of Wnt/ß-catenin-dependent genes, suppressed the viability of CRC cells, and restrained tumorigenesis and progression of CRC in vitro and in vivo. In summary, our results demonstrate that CK1ε exerted its oncogenic role in CRC occurrence and progression by regulating the stability of AXIN1. These findings reveal a novel mechanism by which CK1ε regulates the Wnt/ß-catenin signaling pathway and highlight the therapeutic potential of targeting the CK1ε/SIAH1 axis in CRC.

Proteomic and metabolomic analysis of the serum of patients with tick-borne encephalitis.

Tick-borne encephalitis virus (TBEV) is a common virus in Europe and Asia, causing around 10,000 to 10,500 infections annually. It affects the central nervous system and poses threats to public health. However, the exact molecular mechanisms of TBE pathogenesis are not yet fully understood due to the complex interactions between the virus and its host. In this study, a comprehensive analysis was conducted to characterize the serum metabolome and proteome of adult patients infected with TBEV, in comparison to a control group of healthy individuals. Liquid chromatography tandem mass spectrometry (LC-MS) was employed to monitor metabolic and proteomic alternations throughout the progression of the disease, significant physiological changes associated with different stages of the disease were identified. A total of 44 proteins and 115 metabolites exhibited significantly alternations in the sera of patients diagnosed with TBE. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses of these metabolites and proteins revealed differential enrichment of genes associated with the extracellular matrix, complement binding, hemostasis, lipid metabolism, and amino acid metabolism between TBE patients and healthy controls. We gained valuable understanding of the specific metabolites implicated in the host's responses to TBE, establishing a basis for further research on TBE disease. SIGNIFICANCE: The current investigation revealed a comprehensive and systematic differences on TBE using LC-MS platform from human serum samples of TBE patients and healthy individuals providing the immune response to the invasion of TBE.

R-spondin-1 induces Axin degradation via the LRP6-CK1ε axis.

R-spondins (RSPOs) are secreted signaling molecules that potentiate the Wnt/ß-catenin pathway by cooperating with Wnt ligands. RSPO1 is crucial in tissue development and tissue homeostasis. However, the molecular mechanism by which RSPOs activate Wnt/ß-catenin signaling remains elusive. In this study, we found that RSPOs could mediate the degradation of Axin through the ubiquitin-proteasome pathway. The results of Co-IP showed that the recombinant RSPO1 protein promoted the interaction between Axin1 and CK1ε. Either knockout of the CK1ε gene or treatment with the CK1δ/CK1ε inhibitor SR3029 caused an increase in Axin1 protein levels and attenuated RSPO1-induced degradation of the Axin1 protein. Moreover, we observed an increase in the number of associations of LRP6 with CK1ε and Axin1 following RSPO1 stimulation. Overexpression of LRP6 further potentiated Axin1 degradation mediated by RSPO1 or CK1ε. In addition, recombinant RSPO1 and Wnt3A proteins synergistically downregulated the protein expression of Axin1 and enhanced the transcriptional activity of the SuperTOPFlash reporter. Taken together, these results uncover the novel mechanism by which RSPOs activate Wnt/ß-catenin signaling through LRP6/CK1ε-mediated degradation of Axin.

CK1δ/ε inhibition induces ULK1-mediated autophagy in tumorigenesis.

INTRODUCTION: Autophagy is an important mechanism of cell homeostasis maintenance. As essential serine/threonine-protein kinases, casein kinase I family members affect tumorigenesis by regulating a variety of cellular progression. However, the mechanism by which they regulate autophagy remains unclear. MATERIALS AND METHODS: We silenced CK1δ/ε in cancer cells and observed cell morphology, the expression of autophagy-related genes, and its impact on cancer cell growth and viability. By inhibiting CK1δ/ε-induced upregulation of autophagy genes, we profiled the regulatory mechanism of CK1δ/ε on autophagy and cancer cell growth. The impact of CK1δ/ε inhibition on tumor cell growth was also assessed in vivo. RESULTS: Here, we found that CK1δ/ε played an important role in ULK1-mediated autophagy regulation in both lung cancer and melanoma cells. Mechanically, silencing CK1δ/ε increased ULK1 expression with enhanced autophagic flux and suppressed cancer cell proliferation, while ULK1 knockdown blocked the activation of autophagy caused by CK1δ/ε inhibition. By silencing CK1δ/ε in syngeneic mouse model bearing LLC1 murine lung cancer cells in vivo, we observed tumor growth suppression mediated by CK1δ/ε inhibition. CONCLUSION: Our results provide evidence for the role of CK1δ/ε in the regulation of tumorigenesis via the ULK1-mediated autophagy, and also suggest the impact of CK1δ/ε inhibition on tumor growth and its significance as a potential therapeutic target.

ISX9 loaded thermoresponsive nanoparticles for hair follicle regrowth.

There is a high demand for an optimal drug delivery system to treat androgenetic alopecia. Topical application of ISX9, which is a neurogenesis inducer, has been found to stimulate hair follicle (HF) regrowth by upregulating the Wnt/ß-catenin signaling pathway, an essential pathway involved in initiating HF growth and development. In the present study, a temperature-sensitive, biopolymer-based, biocompatible, and eco-friendly drug-delivery system was synthesized. This system comprised chitosan-grafted poly(glycidyl methacrylate-co-N-isopropyl acrylamide) (Poly(GMA-co-NIPAAm)@CS-PGNCS) as the shell component and PF127 as the core polymer. The hydrophobic nature of the PF127 block copolymer efficiently dissolved the partially water-soluble drug, ISX9, and the thermos-responsive shell polymer effectively released the drug at a definite skin temperature. The optimized spherical nanoparticles demonstrated the lowest critical solution temperature (LCST) at 32 ± 2 °C with a diameter of 100-250 nm, which delivered encapsulated ISX9 with greater precision than topical ISX9. In a series of in vivo experiments, we demonstrated that ISX9-coated TBNPs upregulated the expression of ß-catenin, active ß-catenin, Wnt target genes, stemness marker genes, proliferating cell nuclear antigen, HF stem cell markers, and HF markers including VEGF, TGF, and IGF-1 more effectively than topical ISX9. These results suggest that TBNPs could be employed as a platform for effective transdermal delivery of various hydrophobic drugs.

Antimicrobial agent chloroxylenol targets ß­catenin­mediated Wnt signaling and exerts anticancer activity in colorectal cancer.

Chloroxylenol is the active ingredient of the antibacterial agent Dettol. The anticancer effect and underlying mechanisms of this compound and other common antimicrobial agents have not been clearly elucidated. In the present study, the effects of chloroxylenol, benzalkonium chloride, benzethonium chloride, triclosan and triclocarban on ß­catenin­mediated Wnt signaling in colorectal cancer were evaluated using the SuperTOPFlash reporter assay. It was demonstrated that chloroxylenol, but not the other antimicrobial agents tested, inhibited the Wnt/ß­catenin signaling pathway by decreasing the nuclear translocation of ß­catenin and disrupting ß­catenin/T­cell factor 4 complex, which resulted in the downregulation of the Wnt target genes Axin2, Survivin and Leucine­rich G protein­coupled receptor­5. Chloroxylenol effectively inhibited the viability, proliferation, migration and invasion, and sphere formation, and induced apoptosis in HCT116 and SW480 cells. Notably, chloroxylenol attenuated the growth of colorectal cancer in the MC38 cell xenograft model and inhibited organoid formation by the patient­derived cells. Chloroxylenol also demonstrated inhibitory effects on the stemness of colorectal cancer cells. The results of the present study demonstrated that chloroxylenol could exert anti­tumor activities in colorectal cancer by targeting the Wnt/ß­catenin signaling pathway, which provided an insight into its therapeutic potential as an anticancer agent.

YBX1 as an oncogenic factor in T-cell acute lymphoblastic leukemia.

Y-box-binding protein 1 (YBX1), a member of the RNA-binding protein family, is a critical regulator of cell survival in various solid tumors and acute myeloid leukemia. However, the function of YBX1 in T-cell acute lymphoblastic leukemia (T-ALL) remains elusive. Here, we found that YBX1 was upregulated in patients with T-ALL, T-ALL cell lines, and NOTCH1-induced T-ALL mice. Furthermore, depletion of YBX1 dramatically reduced cell proliferation, induced cell apoptosis, and induced G0/G1 phase arrest in vitro. Moreover, YBX1 depletion significantly decreased the leukemia burden in the human T-ALL xenograft and NOTCH1-induced T-ALL mice model in vivo. Mechanistically, downregulation of YBX1 markedly inhibited the expression of total AKT serine/threonine kinase (AKT), p-AKT, total extracellular signal-regulated kinase (ERK), and p-ERK in T-ALL cells. Taken together, our results uncovered a critical role of YBX1 in the leukemogenesis of T-ALL, which may have great potential as a biomarker and therapeutic target in T-ALL.

WDR54 exerts oncogenic roles in T-cell acute lymphoblastic leukemia.

WDR54 has been recently identified as a novel oncogene in colorectal and bladder cancers. However, the expression and function of WDR54 in T-cell acute lymphoblastic leukemia (T-ALL) were not reported. In this study, we investigated the expression of WDR54 in T-ALL, as well as its function in T-ALL pathogenesis using cell lines and T-ALL xenograft. Bioinformatics analysis indicated high mRNA expression of WDR54 in T-ALL. We further confirmed that the expression of WDR54 was significantly elevated in T-ALL. Depletion of WDR54 dramatically inhibited cell viability and induced apoptosis and cell cycle arrest at S phase in T-ALL cells in vitro. Moreover, knockdown of WDR54 impeded the process of leukemogenesis in a Jurkat xenograft model in vivo. Mechanistically, the expression of PDPK1, phospho-AKT (p-AKT), total AKT, phospho-ERK (p-ERK), Bcl-2 and Bcl-xL were downregulated, while cleaved caspase-3 and cleaved caspase-9 were upregulated in T-ALL cells with WDR54 knockdown. Additionally, RNA-seq analysis indicated that WDR54 might regulate the expression of some oncogenic genes involved in multiple signaling pathways. Taken together, these findings suggest that WDR54 may be involved in the pathogenesis of T-ALL and serve as a potential therapeutic target for the treatment of T-ALL.

The analysis of cathepsin L that mediates cellular SARS-CoV-2 infection leading to COVID-19 in head and neck squamous cell carcinoma.

The vulnerability of the oral cavity to SARS-CoV-2 infection is well-known, and cancer patients are at a higher risk of COVID-19, emphasizing the need to prioritize this patient population. Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant cancers associated with early metastasis and poor prognosis. It has been established that cancerous tissues express Cathepsin L (CTSL), a proteinase that regulates cancer progression and SARS-CoV-2 entry. Therefore, it is essential to evaluate the correlation between disease outcomes and CTSL expression in cancer tissues and predict the susceptibility of cancer patients to SARS-CoV-2. In this study, we used transcriptomic and genomic data to profile CTSL expression in HNSCC and developed a CTSL signature that could reflect the response of HNSCC patients to chemotherapy and immunotherapy. Additionally, we investigated the relationship between CTSL expression and immune cell infiltration and established CTSL as a potential carcinogenic factor for HNSCC patients. These findings could aid in understanding the mechanisms underlying the increased susceptibility of HNSCC patients to SARS-CoV-2 and contribute to the development of therapy for both HNSCC and COVID-19.

KIF2C is a prognostic biomarker associated with immune cell infiltration in breast cancer.

BACKGROUND: The kinesin-13 family member 2C (KIF2C) is a versatile protein participating in many biological processes. KIF2C is frequently up-regulated in multiple types of cancer and is associated with cancer development. However, the role of KIF2C in immune cell infiltration of tumor microenvironment and immunotherapy in breast cancer remains unclear. METHODS: The expression of KIF2C was analyzed using Tumor Immune Estimation Resource (TIMER) database and further verified by immunohistochemical staining in human breast cancer tissues. The correlation between KIF2C expression and clinical parameters, the impact of KIF2C on clinical prognosis and independent prognostic factors were analyzed by using TCGA database, the Kaplan-Meier plotter, and Univariate and multivariate Cox analyses, respectively. The nomograms were constructed according to independent prognostic factors and validated with C-index, calibration curves, ROC curves, and decision curve analysis. A gene set enrichment analysis (GSEA) was performed to explore the underlying molecular mechanisms of KIF2C. The degree of immune infiltration was assessed by the Estimation of Stromal and Immune cells in Malignant Tumor tissues using the Expression (ESTIMATE) algorithm and the single sample GSEA (ssGSEA). The Tumor mutational burden and Tumor Immune Dysfunction and Rejection (TIDE) were used to analyze immunotherapeutic efficiency. Finally, the KIF2C-related competing endogenous RNA (ceRNA) network was constructed to predict the putative regulatory mechanisms of KIF2C. RESULTS: KIF2C was remarkably up-regulated in 18 different types of cancers, including breast cancer. Kaplan-Meier survival analysis showed that high KIF2C expression was associated with poor overall survival (OS). KIF2C expression was associated with clinical parameters such as age, TMN stage, T status, and molecular subtypes. We identified age, stage, estrogen receptor (ER) and KIF2C expression as OS-related independent prognosis factors for breast cancer. An OS-related nomogram was developed based on these independent prognosis factors and displayed good predicting ability for OS of breast cancer patients. Finally, our results revealed that KIF2C was significantly related to immune cell infiltration, tumor mutational burden, and immunotherapy in patients with breast cancer. CONCLUSION: KIF2C was overexpressed in breast cancer and was positively correlated with immune cell infiltration and immunotherapy response. Therefore, KIF2C can serve as a potential biomarker for prognosis and immunotherapy in breast cancer.

Characterization of laser cooling in microgravity via long-term operations in TianGong-2 space lab.

The invention of laser cooling has fundamentally influenced the research frontier of atomic physics and quantum physics, and recently an intense focus has been on the studies of cold atom physics in microgravity environments. Herein, we report the results of our laser cooling experiment in TianGong-2 space lab, which operated for 34 consecutive months in orbit. Over such an extended operation time, the quality of laser cooling did not experience any significant decline, while the properties of laser cooling in orbital microgravity were systematically studied. In particular, we demonstrate magneto-optical trapping and polarization-gradient cooling in orbit and carefully examine their performances. A comparison of the in-orbit and on-ground results indicates that a higher cooling efficiency exists in microgravity, including a smaller loss rate during the trapping and cooling process and lower ultimate temperature of laser-cooled atoms. Our progress has laid the technical foundations for future applications of cold atoms in space missions with operation times of the order of years.

Isoxazole 9 (ISX9), a small molecule targeting Axin, activates Wnt/ß-catenin signalling and promotes hair regrowth.

BACKGROUND AND PURPOSE: Isoxazole 9 (ISX9) is a neurogenesis-promoting small molecule compound that can up-regulate the expression of NeuroD1 and induce differentiation of neuronal, cardiac and islet endocrine progenitors. So far, the molecular mechanisms underlying the action of ISX9 still remain elusive. EXPERIMENTAL APPROACH: To identify a novel agonist of the Wnt/ß-catenin, a cell-based SuperTOPFlash reporter system was used to screen known-compound libraries. An activation effect of ISX9 on the Wnt/ß-catenin pathway was analysed with the SuperTOPFlash or SuperFOPFlash reporter system. Effects of ISX9 on Axin1/LRP6 interaction were examined using a mammalian two-hybrid system, co-immunoprecipitation, microscale thermophoresis, emission spectra and mass spectrometry assays. The expression of Wnt target and stemmness marker genes were evaluated with real-time PCR and immunoblotting. In vivo hair regeneration abilities of ISX9 were analysed by immunohistochemical staining, real-time PCR and immunoblotting in hair regrowth model using C57BL/6J mice. KEY RESULTS: In this study, ISX9 was identified as a novel agonist of the Wnt/ß-catenin pathway. ISX9 targeted Axin1 by covalently binding to its N-terminal region and potentiated the LRP6-Axin1 interaction, thereby resulting in the stabilization of ß-catenin and up-regulation of Wnt target genes and stemmness marker genes. Moreover, the topical application of ISX9 markedly promoted hair regrowth in C57BL/6J mice and induced hair follicle transition from telogen to anagen via enhancing Wnt/ß-catenin pathway. CONCLUSIONS AND IMPLICATIONS: Taken together, our study unravelled that ISX9 could activate Wnt/ß-catenin signalling by potentiating the association between LRP6 and Axin1, and may be a promising therapeutic agent for alopecia treatment.

Pulmonary infection caused by Nocardia otitidiscaviarum a case report and literature review / 中国热带医学

@#Abstract: Objective　To investigate the clinical and laboratory characteristics of pulmonary infection caused by Nocardia otitidiscaviarum. Methods　The clinical data of a patient with pulmonary infection caused by Nocardia otitidiscaviarum were reported, and the clinical characteristics, laboratory characteristics and drug sensitivity of pulmonary infection caused by Nocardia otitidiscaviarum were summarized in combination with the relevant literature at home and abroad from January 2010 to December 2022. Results　A 67-year-old female patient was admitted to the hospital on June 30, 2020 because of "repeated chest tightness and shortness of breath for 3 years, aggravated cough, expectoration and fever". The sputum, alveolar lavage fluid and blood of the patient were collected for culture, and the detected pathogenic bacteria were identified. There are pathogenic bacteria growing in sputum and alveolar lavage fluid, which are identified as Nocardia otitidiscaviarum by Autof ms mass spectrometer. According to the results of pathogenic bacteria and the patient's condition, meropenem combined with compound sulfamethoxazole tablets were given anti-infection treatment, and the patient's condition improved and discharged. Conclusion　The clinical manifestations and imaging features of nocardiosis are lack of specificity, and are prone to misdiagnosis and missed diagnosis. Etiology is the key to disease diagnosis, and clinical examination and culture should be conducted in time.

Predictive value of serum initial brain natriuretic peptide and troponin on functional prognosis in noncardiogenic patients with anterior and posterior circulation cerebral infarction.

BACKGROUND: Brain natriuretic peptide (BNP) and troponin have a close relationship with cardiogenic cerebral embolism (CCE), but their relationship with noncardiogenic patients with anterior circulation ischemia (ACI) and posterior circulation ischemia (PCI) is not clear. OBJECTIVE: To explore the predictive value of serum initial BNP and troponin on the functional prognosis of patients with noncardiogenic ACI and PCI. METHODS: Consecutive patients with first-episode cerebral infarction within 12 hours of symptom onset were enrolled in the present 1-year prospective cohort study. Serum levels of BNP and troponin were collected within 12 hours of onset. Infarction location was classified as ACI and PCI by magnetic resonance imaging (MRI). According to the modified Rankin Scale (mRS) score at 90 days after onset, ACI and PCI cases were respectively divided into a good prognosis group (mRS score between 0 and 2) and a poor prognosis group (mRS score between 3 and 6). The general state of health and results of laboratory examinations and other auxiliary examinations of all patients were recorded. Single-factor analysis and multivariate logistic regression analysis were used to assess the relationship between serum levels of BNP, troponin, and functional outcome. RESULTS: The multivariate logistic regression found that higher levels of initial BNP (odds ratio [OR] = 1.024; 95% confidence interval [CI]: 1.006-1.041; p = 0.007) and C-reactive protein (CRP) (OR = 1.184; 95%CI: 1.024-1.369; p = 0.022) were independent predictors of poor functional prognosis of noncardiogenic PCI at 90 days after onset after adjusting for age, gender, ethnicity, history of hypertension and of diabetes. CONCLUSIONS: The levels of initial BNP and CRP were related to poor functional outcomes in noncardiogenic PCI patients at 3 months, independent of troponin.

ANTECEDENTES: O peptídeo natriurético cerebral (BNP, na sigla em inglês) e a troponina estão intimamente relacionados com a embolia cerebral cardiogênica (CCE, na sigla em inglês), mas a relação com pacientes não cardioembólicos com isquemia de circulação anterior (ICA) e isquemia de circulação posterior (ICP) não é clara. OBJETIVO: Investigar o valor preditivo dos níveis séricos iniciais do BNP e da troponina no prognóstico de pacientes com AVC isquêmico não cardiogênico. MéTODOS: Os níveis séricos de BNP e de troponina foram recolhidos de pacientes com primeiro episódio de acidente vascular cerebral (AVC) isquêmico dentro de 12 horas após o início dos sintomas, com localização classificada como ICA e ICP de acordo com exame de ressonância magnética (RM). De acordo com a pontuação modificada da escala de Rankin (mRS), aos 90 dias após o início dos sintomas, ICA e ICP foram divididas respectivamente em um grupo de bom prognóstico (mRS entre 0 e2) e em um grupo de mau prognóstico (mRS entre 3 e 6). Foram registrados exames laboratoriais e outros exames complementares de todos os pacientes. Foram utilizadas análise fatorial única e análise de regressão logística multivariada para investigar a relação entre os níveis séricos de BNP e de troponina e o resultado funcional. RESULTADOS: A regressão logística multivariada evidenciou que os níveis mais altos de BNP inicial (odds ratio [OR] = 1,024, intervalo de confiança [IC] de 95%: 1,006­1,041; p = 0,007) e proteína C reativa (CRP, na sigla em inglês) (OR = 1,184; 95%CI: 1,024­1,369; p = 0,022) foram preditores independentes de mau prognóstico funcional da ICP não cardiogênica aos 90 dias após o início dos sintomas. CONCLUSõES: Os níveis iniciais de BNP e CRP se associaram a maus resultados funcionais em pacientes com ICP não cardiogênica aos três meses, independentemente da troponina.

Predictive value of serum initial brain natriuretic peptide and troponin on functional prognosis in noncardiogenic patients with anterior and posterior circulation cerebral infarction / Valor preditivo dos níveis séricos iniciais do peptídeo natriurético cerebral e da troponina no prognóstico funcional em pacientes não cardiogênicos com acidente vascular cerebral isquêmico de circulação anterior e posterior

Abstract Background Brain natriuretic peptide (BNP) and troponin have a close relationship with cardiogenic cerebral embolism (CCE), but their relationship with noncardiogenic patients with anterior circulation ischemia (ACI) and posterior circulation ischemia (PCI) is not clear. Objective To explore the predictive value of serum initial BNP and troponin on the functional prognosis of patients with noncardiogenic ACI and PCI. Methods Consecutive patients with first-episode cerebral infarction within 12 hours of symptom onset were enrolled in the present 1-year prospective cohort study. Serum levels of BNP and troponin were collected within 12 hours of onset. Infarction location was classified as ACI and PCI by magnetic resonance imaging (MRI). According to the modified Rankin Scale (mRS) score at 90 days after onset, ACI and PCI cases were respectively divided into a good prognosis group (mRS score between 0 and 2) and a poor prognosis group (mRS score between 3 and 6). The general state of health and results of laboratory examinations and other auxiliary examinations of all patients were recorded. Single-factor analysis and multivariate logistic regression analysis were used to assess the relationship between serum levels of BNP, troponin, and functional outcome. Results The multivariate logistic regression found that higher levels of initial BNP (odds ratio [OR] = 1.024; 95% confidence interval [CI]: 1.006-1.041; p = 0.007) and C-reactive protein (CRP) (OR = 1.184; 95%CI: 1.024-1.369; p = 0.022) were independent predictors of poor functional prognosis of noncardiogenic PCI at 90 days after onset after adjusting for age, gender, ethnicity, history of hypertension and of diabetes. Conclusions The levels of initial BNP and CRP were related to poor functional outcomes in noncardiogenic PCI patients at 3 months, independent of troponin.

Resumo Antecedentes O peptídeo natriurético cerebral (BNP, na sigla em inglês) e a troponina estão intimamente relacionados com a embolia cerebral cardiogênica (CCE, na sigla em inglês), mas a relação com pacientes não cardioembólicos com isquemia de circulação anterior (ICA) e isquemia de circulação posterior (ICP) não é clara. Objetivo Investigar o valor preditivo dos níveis séricos iniciais do BNP e da troponina no prognóstico de pacientes com AVC isquêmico não cardiogênico. Métodos Os níveis séricos de BNP e de troponina foram recolhidos de pacientes com primeiro episódio de acidente vascular cerebral (AVC) isquêmico dentro de 12 horas após o início dos sintomas, com localização classificada como ICA e ICP de acordo com exame de ressonância magnética (RM). De acordo com a pontuação modificada da escala de Rankin (mRS), aos 90 dias após o início dos sintomas, ICA e ICP foram divididas respectivamente em um grupo de bom prognóstico (mRS entre 0 e2) e em um grupo de mau prognóstico (mRS entre 3 e 6). Foram registrados exames laboratoriais e outros exames complementares de todos os pacientes. Foram utilizadas análise fatorial única e análise de regressão logística multivariada para investigar a relação entre os níveis séricos de BNP e de troponina e o resultado funcional. Resultados A regressão logística multivariada evidenciou que os níveis mais altos de BNP inicial (odds ratio [OR] = 1,024, intervalo de confiança [IC] de 95%: 1,006-1,041; p = 0,007) e proteína C reativa (CRP, na sigla em inglês) (OR = 1,184; 95%CI: 1,024-1,369; p = 0,022) foram preditores independentes de mau prognóstico funcional da ICP não cardiogênica aos 90 dias após o início dos sintomas. Conclusões Os níveis iniciais de BNP e CRP se associaram a maus resultados funcionais em pacientes com ICP não cardiogênica aos três meses, independentemente da troponina.

The CK1δ/ϵ-Tip60 Axis Enhances Wnt/ß-Catenin Signaling via Regulating ß-Catenin Acetylation in Colon Cancer.

Casein kinase 1δ/ϵ (CK1δ/ϵ) are well-established positive modulators of the Wnt/ß-catenin signaling pathway. However, the molecular mechanisms involved in the regulation of ß-catenin transcriptional activity by CK1δ/ϵ remain unclear. In this study, we found that CK1δ/ϵ could enhance ß-catenin-mediated transcription through regulating ß-catenin acetylation. CK1δ/ϵ interacted with Tip60 and facilitated the recruitment of Tip60 to ß-catenin complex, resulting in increasing ß-catenin acetylation at K49. Importantly, Tip60 significantly enhanced the SuperTopFlash reporter activity induced by CK1δ/ϵ or/and ß-catenin. Furthermore, a CK1δ/CK1ϵ/ß-catenin/Tip60 complex was detected in colon cancer cells. Simultaneous knockdown of CK1δ and CK1ϵ significantly attenuated the interaction between ß-catenin and Tip60. Notably, inhibition of CK1δ/ϵ or Tip60, with shRNA or small molecular inhibitors downregulated the level of ß-catenin acetylation at K49 in colon cancer cells. Finally, combined treatment with CK1 inhibitor SR3029 and Tip60 inhibitor MG149 had more potent inhibitory effect on ß-catenin acetylation, the transcription of Wnt target genes and the viability and proliferation in colon cancer cells. Taken together, our results revealed that the transcriptional activity of ß-catenin could be modulated by the CK1δ/ϵ-ß-catenin-Tip60 axis, which may be a potential therapeutic target for colon cancer.

Serum Metabolomics of Tick-Borne Encephalitis Based on Orbitrap-Mass Spectrometry.

BACKGROUND: Tick-borne encephalitis virus (TBEV), the most prevalent arbovirus, causes potentially fatal encephalitis in humans. Prevalent in northeast China, tick-borne encephalitis (TBE) poses a major threat to public health, local economies and tourism. There are no biomarkers for TBE, which is classified serologically and clinically. Due to sample heterogeneity of samples and different detection platforms, obtaining stable markers is a great challenge for metabolomics. Accurate annotation is vital for data mining and interpretation. OBJECTIVE: To identify reliable biomarkers of TBEV infection. METHODS: An untargeted metabolomics analysis of serum from 30 TBE patients and 30 healthy controls was carried out. Liquid chromatography-mass spectrometry (LC-MS)-based metabolomics methods were used to characterize the subjects' serum metabolic profiles and to screen and validate TBE biomarkers. RESULTS: A total of 3370 molecular features were extracted from each sample, and the peak intensity of each feature was obtained. Pattern analysis, principal component analysis, partial least squares discriminant analysis were used to screen for potential metabolites. Bilirubin, LysoPC (18:1[9Z]), palmitic acid, and CL (8:0/8:0/8:0/8:0) were significantly different. Pathway enrichment analysis showed that these metabolites were in the fatty acid biosynthesis and glycerophospholipid metabolism pathways. The phospholipid family had a significant difference in both the difference ratio and the abundance. CONCLUSION: Phospholipids may be used to distinguish TBEV patients from healthy controls. TBEV infection affects the normal metabolic activity of host cells, providing insight into the pathogenesis of TBE.