A variety of cells and cytokines have been shown to be involved in the whole process of hypertension. Data from experimental and clinical studies on hypertension have confirmed the key roles of immune cells and inflammation in the process. Dysfunction of the thymus, which modulates the development and maturation of lymphocytes, has been shown to be associated with the severity of hypertension. Furthermore, gradual atrophy, functional decline or loss of the thymus has been revealed to be associated with aging. The restoration or enhancement of thymus function via upregulation in the expression of thymus transcription factors forkhead box N1 or thymus transplantation may provide an option to halt or reverse the pathological process of hypertension. Therefore, the thymus may be key in hypertension and associated target organ damage, and may provide a novel treatment strategy for the clinical management of patients with hypertension in addition to different commercial drugs. The purpose of this review is to summarize and discuss the advances in our understanding of the impact of thymus function on hypertension from data from animal and human studies, and the potential mechanisms.
How protein sequence codes for 3D structure remains a fundamental question in biology. One approach to understanding the folding code is to design a pair of proteins with maximal sequence identity but retaining different folds. Therefore, the nonidentities must be responsible for determining which fold topology prevails and constitute a fold-specific folding code. We recently designed two proteins, G(A)88 and G(B)88, with 88% sequence identity but different folds and functions [Alexander et al. (2007) Proc Natl Acad Sci USA 104:11963-11968]. Here, we describe the detailed 3D structures of these proteins determined in solution by NMR spectroscopy. Despite a large number of mutations taking the sequence identity level from 16 to 88%, G(A)88 and G(B)88 maintain their distinct wild-type 3-alpha and alpha/beta folds, respectively. To our knowledge, the 3D-structure determination of two monomeric proteins with such high sequence identity but different fold topology is unprecedented. The geometries of the seven nonidentical residues (of 56 total) provide insights into the structural basis for switching between 3-alpha and alpha/beta conformations. Further mutation of a subset of these nonidentities, guided by the G(A)88 and G(B)88 structures, leads to proteins with even higher levels of sequence identity (95%) and different folds. Thus, conformational switching to an alternative monomeric fold of comparable stability can be effected with just a handful of mutations in a small protein. This result has implications for understanding not only the folding code but also the evolution of new folds.
Background: Nonalcoholic steatohepatitis (NASH)-driven hepatocellular carcinoma (HCC) is becoming a major health-related problem. The exploration of NASH-related prognostic biomarkers and therapeutic targets is necessary. Methods: Data were downloaded from the GEO database. The "glmnet" package was used to identify differentially expressed genes (DEGs). The prognostic model was constructed by the univariate Cox and LASSO regression analyses. Validation of the expression and prognosis by immunohistochemistry (IHC) in vitro. Drug sensitivity and immune cell infiltration were analyzed by CTR-DB and ImmuCellAI. Results: We constructed a prognostic model that identified the NASH-related gene set (DLAT, IDH3B, and MAP3K4), which was validated in a real-world cohort. Next, seven prognostic transcription factors (TFs) were identified. The prognostic ceRNA network included three mRNAs, four miRNAs, and seven lncRNAs. Finally, we found that the gene set was associated with drug response which was validated in six clinical trial cohorts. Moreover, the expression level of the gene set was inversely correlated with CD8 T cell infiltration in HCC. Conclusions: We established a NASH-related prognostic model. Upstream transcriptome analysis and the ceRNA network provided clues for mechanism exploration. The mutant profile, drug sensitivity, and immune infiltration analysis further guided precise diagnosis and treatment strategies.
In this series of works, we develop a discrete-velocity-direction model (DVDM) with collisions of BGK-type for simulating gas flows, where the molecular motion is confined to some prescribed directions but the speed is still a continuous variable in each orientation. In this article, we introduce a weighted function in each orientation when recovering the macroscopic parameters. Moreover, the internal molecular degrees of freedom are considered. With this weighted DVDM, we develop three submodels by incorporating the discrete velocity method, the Gaussian-extended quadrature method of moments and the Hermite spectral method in each direction. These spatial-time submodels are novel multidimensional versions corresponding to the three approaches. Numerical tests with a series of 1-D and 2-D flow problems show the efficiency of the weighted DVDM.
This paper introduces the discrete-velocity-direction model (DVDM) in conjunction with the hyperbolic quadrature method of moments (HyQMOM) to develop a multidimensional spatial-temporal approximation of the BGK equation, termed DVD-HyQMOM. Serving as a multidimensional extension of HyQMOM, DVD-HyQMOM model achieves higher accuracy than other DVDM submodels, especially with an increased number of abscissas. The efficiency and effectiveness of this model are demonstrated through various numerical tests.
Abstract We have engineered switches between the three most common small folds, 3α, 4β+α, and α/β−plait, referred to here as A, B, and S, respectively. Mutations were introduced into the natural S protein until sequences were created that have a stable S-fold in their longer (∼90 amino acid) form and have an alternative fold (either A or B) in their shorter (56 amino acid) form. Five sequence pairs were designed and key structures were determined using NMR spectroscopy. Each protein pair is 100% identical in the 56 amino acid region of overlap. Several rules for engineering switches emerged. First, designing one sequence with good native state interactions in two folds requires care but is feasible. Once this condition is met, fold populations are determined by the stability of the embedded A- or B-fold relative to the S-fold and the conformational propensities of the ends that are generated in the switch to the embedded fold. If the stabilities of the embedded fold and the longer fold are similar, conformation is highly sensitive to mutation so that even a single amino acid substitution can radically shift the population to the alternative fold. The results provide insight into why dimorphic sequences can be engineered and sometimes exist in nature, while most natural protein sequences populate single folds. Proteins may evolve toward unique folds because dimorphic sequences generate interactions that destabilize and can produce aberrant functions. Thus, two-state behavior may result from nature’s negative design rather than being an inherent property of the folding code. Significance Statement We establish general rules for designing protein fold switches by engineering dimorphic sequences that link the three most common small folds. The fact that switches can be engineered in arbitrary and common protein folds, sheds light on several important questions: 1) What is the generality of fold switching? 2) What types of folds are amenable to switching? 3) What properties are shared by sequences that can fold into two completely different structures? This work has implications for understanding how amino acid sequence encodes structure, how proteins evolve, how mutation is related to disease, and how function is annotated to sequences of unknown structure. Classification Biological Sciences: Biochemistry; Physical Sciences: Biophysics and Computational Biology
Objective To evaluate the feasibility and efficacy of percutaneous intratumor injection of gene-immunotherapy combined with capacitive radio-frequency hyperthermia treatment for advanced lung carcinoma under CT guided.Methods Thirty-one unresectable peripheric lung carcinomas(29 men and 2 women,10 squamous carcinomas,15 denocarcinoma and 6 alveolus carcinomas) in clinical Ⅲ~Ⅳ stage were undergone percutaneous intrastumor injection of H101 and ⅠL~Ⅱ under CT guided,and repeated at 8,29,35,57 and 64 d respectively as one course.During interventional therapy,radio-frequency hyperthermia carried out twice one week,totally 12 times per-patient.After one course 4 weeks later,the blood TSGF levels and CT changes of the tumors were observed.Results The short period effect included:CR in 0 case,PR in 22 cases,NC in 6 cases and PD in 3 cases,the total short-term efficacy rate was 71 percent(22/31).Significant statistical difference was found in the positive rate and quantitative level of the blood TSGF after on cycle(P 0.05).4~48 h after the procedure,fever and local thorax pain occurred in 100% and 54.8% respectively.Conclusion CT guided percutaneous intratumor injection of gene-immunotherapy in combination with capacitive radio-frequency hyperthermia treatment for advanced lung carcinoma is an effective and minimally invasive method.
We discuss the capabilities of novel reporters which efficiently upconvert near infrared light and considerations for application of these reporters to immunoassay.
Background: Endometrial cancer (EC) is the sixth most common cancer in women. Annually 63,230 new cases are diagnosed with 11,350 deaths estimated in the USA. Currently, advanced EC therapies remain palliative and new therapeutic strategies are urgently needed. Common risk factors include exposure to high levels of estrogen, obesity, and alterations in genetic and epigenetic factors. The lysine-specific demethylase-1A (KDM1A/LSD1) regulates gene expression programs by changing the epigenetic histone marks at the gene promoters. Emerging studies provided the evidence that KDM1A is overexpressed in EC. In studies examining the synthetic lethality of KDM1A inhibition on chemotherapy drug sensitivity, we made an unexpected discovery that KDM1A inhibition potentiate activity of mTOR inhibitors. In this study, we tested the hypothesis that inhibition of KDM1A could sensitize EC to mTOR inhibitor therapy.Methods: To study the significance of KDM1A inhibition on chemotherapy drug sensitivity, we performed MTT assays to screen 119 FDA approved drugs using KDM1A knockdown HEC1A and RL95 EC cell lines. Effect of KDM1A knockdown or KDM1A inhibitor (NCD-38) therapy on EC cells was examined using MTT cell viability assays and clonogenic survival assays. The effect on cell migration was examined using scratch wound healing assay. Mechanistic studies were conducted using RNA-seq, western blot, qRT-PCR, and IHC analysis. The in vivo efficacy of NCD-38 and sirolimus on EC progression was studied using mouse xenograft models.Results: Studies using 119 FDA approved drugs identified that mTOR inhibitors sirolimus and temsirolimus has potent synthetic lethality on KDM1A knockdown cells compared to control cells. Cell viability and survival assays demonstrated that KDM1A knockdown or inhibition in combination with sirolimus synergistically reduced cell viability and the survival of EC cells. Further, combination of KDM1A inhibitor and sirolimus reduced the migration of EC cells. Western blot analysis demonstrated that knockdown or inhibition of KDM1A attenuated the activation of mTOR signaling cascade in EC cells. RNA-seq and gene set enrichment analysis identified the down regulation of E2F pathway and DNA replication pathways in KDM1A and mTOR inhibitor treated cells compared to control cells. Further, combination of NCD-38 and sirolimus significantly reduced the in vivo tumor progression in xenograft models. IHC analysis of tumors revealed the downregulation of proliferation marker Ki67 and phosphorylation of mTOR signaling molecules in combination treated tumors compared to vehicle treated tumors.Conclusions: The results from these studies provide compelling evidence that KDM1A inhibition sensitizes EC cells to mTOR inhibitors, and the use of KDM1A inhibitor in conjunction with mTOR inhibitors may be an attractive therapy for advanced EC patients.Citation Format: Prabhakar Pitta-Venkata, Bridgitte Palacios, Yihong Chen, Suryavathi Viswanadhapalli, Uday P. Pratap, Yiliao Luo, Mengxing Li, Kristin Altwegg, Xiaonan Li, Takayoshi Suzuki, Rajeshwar Rao Tekmal, Edward Kost, Gangadhara Reddy Sareddy. Synthetic lethality of KDM1A and mTOR inhibitors: A novel combination therapy for endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 280.
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