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1.
Small ; : e1903739, 2019 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-31565845

RESUMO

Single-cell analysis offers unprecedented resolution for the investigation of cellular heterogeneity and the capture of rare cells from large populations. Here, described is a simple method named interfacial nanoinjection (INJ), which can miniaturize various single-cell assays to be performed in nanoliter water-in-oil droplets on standard microwell plates. The INJ droplet handler can adjust droplet volumes for multistep reactions on demand with high precision and excellent monodispersity, and consequently enables a wide range of single-cell assays. Importantly, INJ can be coupled with fluorescence-activated cell sorting (FACS), which is currently the most effective and accurate single-cell sorting and isolation method. FACS-INJ pipelines for high-throughput plate well-based single-cell analyses, including single-cell proliferation, drug-resistance testing, polymerase chain reaction (PCR), reverse-transcription PCR, and whole-genome sequencing are introduced. This FACS-INJ pipeline is compatible with a wide range of samples and can be extended to various single-cell analysis applications in microbiology, cell biology, and biomedical diagnostics.

2.
Cancer Res ; 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575549

RESUMO

Lung cancer is the leading cause of cancer-related deaths worldwide. Cytological examination is the current "gold standard" for lung cancer diagnosis, however this has low sensitivity. Here, we identified a typical methylation signature of histone genes in lung cancer by whole-genome DNA methylation analysis, which was validated by a TCGA lung cancer cohort (n=907) and was further confirmed in 265 bronchoalveolar lavage fluid (BALF) samples with specificity and sensitivity of 96.7% and 87.0%, respectively. More importantly, HIST1H4F was universally hypermethylated in all seventeen tumor types from TCGA datasets (n=7344), which was further validated in nine different types of cancer (n=243). These results demonstrate that HIST1H4F can function as a Universal-Cancer-Only Methylation (UCOM) marker, which may aid in understanding general tumorigenesis and improve screening for early cancer diagnosis.

3.
Sci Data ; 6(1): 188, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575853

RESUMO

Larimichthys crocea is an endemic marine fish in East Asia that belongs to Sciaenidae in Perciformes. L. crocea has now been recognized as an "iconic" marine fish species in China because not only is it a popular food fish in China, it is a representative victim of overfishing and still provides high value fish products supported by the modern large-scale mariculture industry. Here, we report a chromosome-level reference genome of L. crocea generated by employing the PacBio single molecule sequencing technique (SMRT) and high-throughput chromosome conformation capture (Hi-C) technologies. The genome sequences were assembled into 1,591 contigs with a total length of 723.86 Mb and a contig N50 length of 2.83 Mb. After chromosome-level scaffolding, 24 scaffolds were constructed with a total length of 668.67 Mb (92.48% of the total length). Genome annotation identified 23,657 protein-coding genes and 7262 ncRNAs. This highly accurate, chromosome-level reference genome of L. crocea provides an essential genome resource to support the development of genome-scale selective breeding and restocking strategies of L. crocea.

4.
J Cell Biochem ; 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31595558

RESUMO

The bioactivity of microRNA-1827 (miR-1827) in lung adenocarcinoma cells would be explored. The expression level of gene and miR-1827 in 76 pairs of lung adenocarcinoma tissues and adjacent counterparts were analyzed by a quantitative real-time polymerase chain reaction. Primary lung adenocarcinoma cells were derived from patients' tissues. These cells were treated with miR-1827 agomir to mimic the upregulation of endogenous miR-1827. The malignant degree of lung adenocarcinoma cells in vitro was evaluated by cell proliferation, colony formation, transwell invasion, and apoptosis assays. Western blot analysis was used to observe the transition of lung adenocarcinoma cells from epithelial-to-mesenchymal. Target genes of miR-1827 were predicted by bioinformatics analysis. In addition, the interaction between miR-1827 and candidate messenger RNAs was verified by dual-luciferase reporter assay and AGO2-RNA immunoprecipitation. Besides, the effect of miR-1827 on tumors was verified by in vivo experiments. Transient gene overexpression was achieved by plasmids transfection. In this study, we found that the expression of miR-1827 was downregulated in lung adenocarcinoma, and its low expression was significantly correlated with the progression of lung adenocarcinoma and poor prognosis of patients. miR-1827 overexpression remarkably reduced the malignancy of primary lung adenocarcinoma cells in vitro. MYC and FAM83F were identified as two targeted genes of miR-1827 in lung adenocarcinoma cells. The levels of these two genes were upregulated in lung adenocarcinoma, and their high expression was significantly associated with the progression of lung adenocarcinoma and poor prognosis of patients. Overexpression of MYC or FAM83F attenuated the effects of miR-1827 on primary lung adenocarcinoma cells in vitro. In addition, in vivo experiments showed that miR-1827 inhibited tumor growth by reducing the levels of MYC and FAM83F. In conclusion, miR-1827 might repress the development of lung adenocarcinoma by targeting oncogenic genes MYC and FAM83F.

5.
Sci Data ; 6(1): 187, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31570724

RESUMO

Takifugu bimaculatus is a native teleost species of the southeast coast of China where it has been cultivated as an important edible fish in the last decade. Genetic breeding programs, which have been recently initiated for improving the aquaculture performance of T. bimaculatus, urgently require a high-quality reference genome to facilitate genome selection and related genetic studies. To address this need, we produced a chromosome-level reference genome of T. bimaculatus using the PacBio single molecule sequencing technique (SMRT) and High-through chromosome conformation capture (Hi-C) technologies. The genome was assembled into 2,193 contigs with a total length of 404.21 Mb and a contig N50 length of 1.31 Mb. After chromosome-level scaffolding, 22 chromosomes with a total length of 371.68 Mb were constructed. Moreover, a total of 21,117 protein-coding genes and 3,471 ncRNAs were annotated in the reference genome. The highly accurate, chromosome-level reference genome of T. bimaculatus provides an essential genome resource for not only the genome-scale selective breeding of T. bimaculatus but also the exploration of the evolutionary basis of the speciation and local adaptation of the Takifugu genus.

6.
Viruses ; 11(9)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487941

RESUMO

Adenoviral viral vectors have been widely used for gene-based therapeutics, but commonly used serotype 5 shows poor transduction efficiency into hematopoietic cells. In this study, we aimed to generate a recombinant adenovirus serotype 5 (rAd5) vector that has a high efficiency in gene transfer to megakaryocytic leukemic cells with anticancer potential. We first modified the rAd5 backbone vector with a chimeric fiber gene of Ad5 and Ad11p (rAd5F11p) to increase the gene delivery efficiency. Then, the nonstructural protein NS1 of human parvovirus B19 (B19V), which induces cell cycle arrest at the G2/M phase and apoptosis, was cloned into the adenoviral shuttle vector. As the expression of parvoviral NS1 protein inhibited Ad replication and production, we engineered the cytomegalovirus (CMV) promoter, which governs NS1 expression, with two tetracycline operator elements (TetO2). Transfection of the rAd5F11p proviral vectors in Tet repressor-expressing T-REx-293 cells produced rAd in a large quantity. We further evaluated this chimeric rAd5F11p vector in gene delivery in human leukemic cells, UT7/Epo-S1. Strikingly, the novel rAd5F11p-B19NS1-GFP vector, exhibited a transduction efficiency much higher than the original vector, rAd5-B19NS1-GFP, in UT7/Epo-S1 cells, in particular, when they were transduced at a relatively low multiplicity of infection (100 viral genome copies/cell). After the transduction of rAd5F11p-B19NS1-GFP, over 90% of the UT7/Epo-S1 cells were arrested at the G2/M phase, and approximately 40%-50% of the cells were undergoing apoptosis, suggesting the novel rAd5F11P-B19NS1-GFP vector holds a promise in therapeutic potentials of megakaryocytic leukemia.

7.
Bioorg Med Chem ; 27(20): 114938, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31488358

RESUMO

4-Anilinoquinazoline derivatives function as tyrosine kinase inhibitors (TKIs). Novel TKIs are needed for cancer mutations and drug-resistant cells. We designed and synthesized 4-anilinoquinazoline derivatives with substitutions at quinazoline positions 6, 7 and 4 using a binding model with multi-target receptor tyrosine kinases, and assessed their antitumor activity against five human tumor cell lines (HepG2, A549, MCF-7, DU145, SH-SY5Y). The majority of the compounds inhibited the proliferation of all the cancer cell types, with some compounds displaying selective inhibition. Compounds 21, 25, 27, and 37 displayed IC50 values of 7.588, 8.619, 6.936, and 8.516 µM, respectively, for A549 cells, which were much lower than that of Gefitinib (14.803 µM). Compound 32 displayed an IC50 value of 2.756 µM for DU145 cells. The representative compound 40 had unexceptionable broad-spectrum inhibition for all cancer cell types, and demonstrate inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFR-ß), and epidermal growth factor receptor (EGFR) with IC50 values of 46.4, 673.6 and 384.8 nM, respectively, which were similar to those of Sorafenib for VEGFR-2 and PDGFR-ß (140.6 and 582.7 nM, respectively). Molecular docking results supported the molecular level assay results. Data for production of reactive oxygen species and assessment of matrix metalloproteinase corroborated the strong anti-proliferative effect of compound 40. The compound also displayed robust antitumor efficacy and relativity lower toxicity in a xenograft model. These attributes were similar to those of Sorafenib. Compound 40 drug warrants further study as a candidate.

8.
Sci Rep ; 9(1): 13046, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506455

RESUMO

The fabella is a sesamoid bone of the knee that can degenerate in some patients with osteoarthritis. The purpose of this study was to examine the prevalence and degeneration grades of fabellae in the Chinese population and to analyse their relationships with subject ages and knee osteoarthritis grades. The anteroposterior and lateral knee roentgenograms of 1150 subjects were recruited from the institutional database. The Kellgren-Lawrence scoring system was used to evaluate knee osteoarthritis. The degeneration grades of fabellae were scored in lateral roentgenograms by screening their shapes, sizes, subchondral sclerosis and osteophyte formation. The prevalence and degeneration of fabellae among ages, genders and knee sides were analysed by the Pearson Chi-Square test, and their relationships with knee osteoarthritis were analysed by the Spearman nonparametric correlation test. The overall prevalence of fabellae was 48.6% in 1359 knees. There was no significant difference in fabellar prevalence between the two sides (χ² = 0.025, P = 0.87437) and genders (χ² = 3.647, P = 0.05617), while the prevalence increased with the increasing ages of the subjects (χ² = 213.868, P < 0.001). The fabellar degeneration grades were correlated with age (r = 0.5288, P < 0.001) and knee osteoarthritis scores (r = 0.6892, P < 0.001). These results suggested that the fabellar prevalence and degeneration grades were correlated with age and knee osteoarthritis scores.

9.
ACS Nano ; 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31532630

RESUMO

Structural dynamics and changes in electronic structures driven by photoexcited carriers are critical issues in both semiconducting and optoelectronic nanodevices. Herein, a phase diagram for the transient states and relevant dynamic processes in multiwalled boron nitride nanotubes (BNNTs) has been extensively studied for a full reversible cycle after a fs-laser excitation in ultrafast TEMs, and the significant structural features and evolution of electronic natures have been investigated using pulsed electron diffraction and femtosecond-resolved electron energy-loss spectroscopy (EELS). It is revealed that nonthermal anisotropic alterations of the lattice apparently precede the phonon-driven thermal transients along the radial and axial directions. Ab initio calculations support these findings and show that electrons excited from the π to π* orbitals in the BN nanotubes weaken the intralayer bonds while strengthening the interlayer bonds along the radial direction. Importantly, time-resolved EELS measurements show contraction of the energy bandgap after fs-laser excitation associated with nonthermal structural transients. This fact verifies that laser-induced bandgap renormalization in semiconductors can essentially be correlated with both the rapid processes of excited carriers and nonthermal lattice evolution.

10.
BMJ Open ; 9(9): e026136, 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31542734

RESUMO

INTRODUCTION: Achieving efficacious and safe treatments for unstable angina pectoris (UAP) is still a challenging clinical problem. The availability of different oral Chinese patent medicines frequently poses a practical challenge to clinicians, namely, which one to choose as first-line regimen for treatment. This study aims to examine the comparative effectiveness and safety of oral Chinese patent medicines for UAP on the national essential drugs list of China. METHODS AND ANALYSIS: We will conduct a network meta-analysis (NMA) of all randomised controlled trials to evaluate the use of oral Chinese patent medicines as adjuvant for the treatment of UAP. We will explore eight electronic databases from their inception to June 2018 and search for grey literature. Primary outcomes include mortality and the cardiovascular events. Secondary outcomes include: (1) symptom improvement; (2) ECG improvement; (3) frequency of acute angina attack; (4) duration of angina; (5) adverse effects. Two independent authors will screen titles and abstracts, review full texts, extract data, assess the risk of bias using the Cochrane risk of bias tool and assess the quality of evidence and strength of the recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). If adequate data are available, NMA will be performed with Bayesian analysis methods. ETHICS AND DISSEMINATION: The NMA will help us to reduce the uncertainty of interventions and help clinicians to make optimal and more accurate therapeutic decisions for adults with UAP. Therefore, we will publish the findings of this study in a peer-reviewed journal. No ethics approval is necessary for this study based on the nature of its design. TRIAL REGISTRATION NUMBER: CRD42018092822.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31471691

RESUMO

Matriptase is a type II transmembrane serine protease, which has been suggested to play critical roles in numerous pathways of biological developments. Matriptase is the activator of several oncogenic proteins, including urokinase-type plasminogen activator (uPA), hepatocyte growth factor (HGF) and protease-activated receptor 2 (PAR-2). The activations of these matriptase substrates subsequently lead to the generation of plasmin, matrix metalloproteases (MMPs), and the triggers for many other signaling pathways related to cancer proliferation and metastasis. Accordingly, matriptase is considered an emerging target for the treatments of cancer. Thus far, inhibitors of matriptase have been developed as potential anti-cancer agents, which include small-molecule inhibitors, peptide-based inhibitors, and monoclonal antibodies. This review covers established literature to summarize the chemical and biochemical aspects, especially the inhibitory mechanisms and structure-activity relationships (SARs) of matriptase inhibitors with the goal of proposing the strategies for their future developments in anti-cancer therapy.

12.
J Invest Dermatol ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31476315

RESUMO

Distant metastases are responsible for the majority of melanoma mortalities. As a critical barrier against metastasis, anoikis is a distinct programmed cell death induced by the integrated stress from extracellular matrix (ECM) detachment. In order to survive, tumor cells employ various strategies for overcoming this barrier. Recently, Sestrin2(Sesn2) has been reported to play a protective role against integrated stress. In this study, we found ECM detachment triggered the up-regulation of Sesn2 in metastatic melanoma cells. Knockdown of Sesn2 impaired not only the cell viability but also the tumor sphere formation of melanoma cells in suspension cultures. Moreover, an elevated oxidative stress level was detected in Sesn2-silencing melanoma cells in suspension cultures, accompanied with an increased apoptosis rate. Last of all, in vivo studies indicated that Sesn2-knockdown remarkably reduced the formation of distant metastasis. Taken together, our findings illustrated that the up-regulation of Sesn2 in response to suspension stress plays a protective role in melanoma against anoikis by detoxifying oxidative stress.

13.
Immunity ; 51(3): 522-534.e7, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31471107

RESUMO

Although recent progress provides mechanistic insights into the pathogenesis of pulmonary fibrosis (PF), rare anti-PF therapeutics show definitive promise for treating this disease. Repeated lung epithelial injury results in injury-repairing response and inflammation, which drive the development of PF. Here, we report that chronic lung injury inactivated the ubiquitin-editing enzyme A20, causing progressive accumulation of the transcription factor C/EBPß in alveolar macrophages (AMs) from PF patients and mice, which upregulated a number of immunosuppressive and profibrotic factors promoting PF development. In response to chronic lung injury, elevated glycogen synthase kinase-3ß (GSK-3ß) interacted with and phosphorylated A20 to suppress C/EBPß degradation. Ectopic expression of A20 or pharmacological restoration of A20 activity by disturbing the A20-GSK-3ß interaction accelerated C/EBPß degradation and showed potent therapeutic efficacy against experimental PF. Our study indicates that a regulatory mechanism of the GSK-3ß-A20-C/EBPß axis in AMs may be a potential target for treating PF and fibroproliferative lung diseases.

14.
Phys Rev Lett ; 123(7): 073001, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31491105

RESUMO

We generate high-fidelity massively entangled states in an antiferromagnetic spin-1 Bose-Einstein condensate (BEC) by utilizing multilevel oscillations. Combining the multilevel oscillations with additional adiabatic drives, we greatly shorten the necessary evolution time and relax the requirement on the control accuracy of quadratic Zeeman splitting, from microgauss to milligauss, for a ^{23}Na spinor BEC. The achieved high fidelities over 96% show that two kinds of massively entangled states, the many-body singlet state and the twin-Fock state, are almost perfectly generated. The generalized spin squeezing parameter drops to a value far below the standard quantum limit even with the presence of atom number fluctuations and stray magnetic fields, illustrating the robustness of our protocol under real experimental conditions. The generated many-body entangled states can be employed to achieve the Heisenberg-limit quantum precision measurement and to attack nonclassical problems in quantum information science.

15.
J Phys Chem A ; 123(39): 8406-8416, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31497961

RESUMO

Many-body dispersion has gained considerable attention over the past decade, particularly for condensed phase systems. However, quantitatively accurate studies of many-body dispersion have only recently become feasible due to challenges in reliability and accuracy. Currently available methodologies for calculating many-body dispersion have been challenged, with recent evidence suggesting, for example, that dispersion-corrected density functional theory (DFT) schemes cannot consistently predict many-body dispersion accurately. This study evaluates many-body dispersion energies using a composite approach that employs singles and doubles coupled cluster theory with perturbative/noniterative triples, CCSD(T), combined with an extrapolation to the complete basis set (CBS) limit. The combined CCSD(T)/CBS approach is applied to Arn and (H2O)n, n = 3-10, clusters, and a new data set called S22(3), which includes trimers generated based on the S22 data set. In these systems, the many-body dispersion provides a very small contribution to the total interaction energy of all of the systems studied, generally 3% or less of the total interaction energy. Two-body dispersion is the dominant dispersion contribution and many-body dispersion contributes no more than 5.7% of the total dispersion energy, generally staying below 2%.

16.
World Neurosurg ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31521754

RESUMO

BACKGROUND: To investigate role of Low-dose, Early Fresh frozen plasma Transfusion (LEFT) therapy in preventing perioperative coagulopathy and improving long-term outcome after severe traumatic brain injury (TBI). METHODS: A prospective, single-center, parallel-group, randomized trial was designed. Patients with severe TBI were eligible. We used a computer-generated randomization list and closed opaque envelops to randomly allocate patients to treatment with fresh frozen plasma (5 mL/kg body weight; LEFT group) or normal saline (5 mL/kg body weight; NO LEFT group) after admission in the operating room. RESULTS: Between January 1, 2018, and November 31, 2018, 63 patients were included and randomly allocated to LEFT (n = 28) and NO LEFT (n = 35) groups. The final interim analysis included 20 patients in the LEFT group and 32 patients in the NO LEFT group. The study was terminated early for futility and safety reasons because a high proportion of patients (7 of 20; 35.0%) in the LEFT group developed new delayed traumatic intracranial hematoma after surgery compared with the NO LEFT group (3 of 32; 9.4%) (relative risk, 5.205; 95% confidence interval, 1.159-23.384; P = 0.023). Demographic characteristics and indexes of severity of brain injury were similar at baseline. CONCLUSIONS: LEFT therapy was associated with a higher incidence of delayed traumatic intracranial hematoma than normal fresh frozen plasma transfusion in patients with severe TBI. A restricted fresh frozen plasma transfusion protocol, in the right clinical setting, may be more appropriate in patients with TBIs.

17.
J Org Chem ; 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31553609

RESUMO

Herein, we describe a variety of chiral hybrid pyrroidine-indole polycyclic derivatives with quaternary and continuous chiral centers were synthesized in good yields with excellent stereoselectivities through an asymmetric, intermolecular, and formal [3 + 2] cyclization reaction catalyzed by a bifunctional catalyst. In addition, the selection of substituents of substrates is the key to success, and both the hydroxyl group and the trifluoromethyl group play essential roles in the reaction.

18.
Biomater Sci ; 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31524909

RESUMO

The size effect of mesoporous organosilica nanoparticles (MONs) on tumor penetration and accumulation remains poorly understood, which strongly affects the tumor therapeutic efficacy. Herein, four different-sized thioether-bridged MONs (20, 40, 60, and 100 nm) are synthesized; all the MONs have a spherical morphology, excellent dispersity, similar surface charge, uniform mesopores (3.2-3.5 nm), and large surface areas (709-1353 m2·g-1). Hematology and histopathology analyses demonstrate that the four MONs do not cause pathological changes in mice even at a dose of 20 mg kg-1 for 30 d. The penetration depth of the MONs for multicellular spheroids (MCSs) decreases with increasing particle sizes, and the 20 nm MONs are uniformly distributed in the MCSs at a depth of 60 µm, while the larger MONs are mainly restricted to peripheral areas. In vivo experiments show that the 40 nm MONs possess the longest mean residence times, leading to their highest accumulation in blood and tumors. However, the 20 nm MONs reach the deepest penetration depth of 1230 µm for xenograft tumors. In contrast, the penetration depths of 40, 60, and 100 nm MONs are 783, 105, and 40 µm, respectively. Overall, this work provides an important guideline for the rational design of nanoplatforms for tumor treatment.

19.
Clin Cancer Res ; 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444250

RESUMO

PURPOSE: Anti-CD19 chimeric antigen receptor (CAR) T cells represent a novel immunotherapy and are highly effective in treating relapsed/refractory B-cell non- Hodgkin's lymphoma (B-NHL). How tumor microenvironment influences clinical response to CAR T therapy remains great interests. EXPERIMENTAL DESIGN: Aphase 1, first-in-human, dose-escalation studyof anti-CD19 JWCAR029was conductedinrefractory B-NHL (NCT03355859)and 10 patients received CAR T cells at an escalating dose of 2.5X107(n=3), 5X107(n=4), and 1X108(n=3) cells.Core needle biopsy was performed on tumor samples collected from diffuse large B-cell lymphomapatients onDay -6 (one day before lymphodepletion) and on Day 11 after CAR T cell infusion when adequate CAR T cell expansion was detected. RESULTS: The overall response rate was 100%, with 6 of 9 (66.7%) evaluable patients achieved complete remission. The most common adverse events of grade 3 or higher were neutropenia (10/10, 100%), anemia (3/10, 30%), thrombocytopenia (3/10, 30%), and hypofibrinogenemia (2/10, 20%). Grade 1 CRS occurred in all patientsand grade 3 neurotoxicity in one patient. The average peak levels of peripheral blood CAR T cells and cytokines were similar in three different dose levels,but CART cells were significantly higher in patients achieved CR on Day 29. Meanwhile, RNA sequencing identified gene expression signatures differentially enriched in complete and partial remission patients.Increased tumor-associated macrophage infiltration was negatively associated with remission status. CONCLUSIONS: JWCAR029was effective and safe in treating refractory B-NHL. The composition of the tumor microenvironment has a potential impact inCAR T therapy response.

20.
Nat Commun ; 10(1): 3751, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434894

RESUMO

Synthetic biology aims to develop programmable tools to perform complex functions such as redistributing metabolic flux in industrial microorganisms. However, development of protein-level circuits is limited by availability of designable, orthogonal, and composable tools. Here, with the aid of engineered viral proteases and proteolytic signals, we build two sets of controllable protein units, which can be rationally configured to three tools. Using a protease-based dynamic regulation circuit to fine-tune metabolic flow, we achieve 12.63 g L-1 shikimate titer in minimal medium without inducer. In addition, the carbon catabolite repression is alleviated by protease-based inverter-mediated flux redistribution under multiple carbon sources. By coordinating reaction rate using a protease-based oscillator in E. coli, we achieve D-xylonate productivity of 7.12 g L-1 h-1 with a titer of 199.44 g L-1. These results highlight the applicability of programmable protein switches to metabolic engineering for valuable chemicals production.

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