Dearomatization provides numerous possibilities for the development of new transformative modes of aromatic compounds. A conceptually novel metal-free multicomponent domino reaction of the ...dearomatized products of 2-alkynylanilines is developed. The reaction involves the secondary amine-mediated transimination with α-amino nitriles and subsequent aromatization-triggered cascade rearrangement, nucleophilic cyclization, and retro-Strecker reaction. This process provided a new practical method for the rapid synthesis of polyfunctionalized 4-aminoquinolines from readily available starting materials.
Tumor heterogeneity presents a challenge for inferring clonal evolution and driver gene identification. Here, we describe a method for analyzing the cancer genome at a single-cell nucleotide level. ...To perform our analyses, we first devised and validated a high-throughput whole-genome single-cell sequencing method using two lymphoblastoid cell line single cells. We then carried out whole-exome single-cell sequencing of 90 cells from a JAK2-negative myeloproliferative neoplasm patient. The sequencing data from 58 cells passed our quality control criteria, and these data indicated that this neoplasm represented a monoclonal evolution. We further identified essential thrombocythemia (ET)-related candidate mutations such as SESN2 and NTRK1, which may be involved in neoplasm progression. This pilot study allowed the initial characterization of the disease-related genetic architecture at the single-cell nucleotide level. Further, we established a single-cell sequencing method that opens the way for detailed analyses of a variety of tumor types, including those with high genetic complex between patients.
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► Building a new whole-genome SCS of high genome coverage, sensitivity, and specificity ► Whole-exome SCS of a typical JAK2-negative myeloproliferative neoplasm patient ► Depicting intratumoral genetics of the neoplasm at a single-cell nucleotide level ► Provision of evidence for monoclonal evolution of the neoplasm
A new high-throughput method based on non-PCR amplification allows whole-exome sequencing of single cells at the nucleotide level. Sequencing of 90 individual tumor cells from a JAK2-negative myeloproliferative neoplasm provides evidence for monoclonal evolution of the cancer.
Hepatocellular carcinoma (HCC) has emerged as one of the most prevalent life‐threatening cancers, and the high mortality rate is largely due to the metastasis. The sustained activation of Smad4 and ...transforming growth factor‐β (TGF‐β) is closely associated with advanced HCC metastasis. However, the regulatory mechanism underlying the aberrant activation of Smad4 and TGF‐β pathway remains elusive. In this study, using a functional screen of USPs siRNA library, we identified ubiquitin‐specific proteases USP10 as a deubiquitinating enzyme (DUB) that sustains the protein level of Smad4 and activates TGF‐β signaling. Further analysis showed that USP10 directly interacts with Smad4 and stabilizes it through the cleavage of its proteolytic ubiquitination, thus promoting HCC metastasis. The suppression of USP10 by either shRNAs or catalytic inhibitor Spautin‐1 significantly inhibited the migration of HCC cells, whereas the reconstitution of Smad4 was able to efficiently rescue this defect. Overall, our study not only uncovers the regulatory effect of USP10 on the protein abundance of Smad4, but also indicates that USP10 could be regarded as a potential intervention target for the metastatic HCC in Smad4‐positive patients.
Ubiquitin‐specific protease USP10 was shown to activate TGF‐β signaling and promote the metastasis of advanced HCC by deubiquitinating and stabilizing Smad4. Depletion of USP10 or inhibition of the USP10 catalytic activity by use of the small‐molecule inhibitor Spautin‐1 significantly repressed HCC metastasis, whereas reconstitution with Smad4 could efficiently rescue the metastatic phenotype.
Chemical Oxygen Demand (COD) composition in landfill leachate would vary as the disposal time extended. Leachates with different ages were collected from Laogang Refuse Landfill of Shanghai, the ...largest landfill in China with a placement scale of 7600 t refuse per day. To characterize COD composition in leachate, samples were size-fractioned into suspended fractions (>
0.45 μm), colloid fraction (0.45 μm
<
fraction
<
1 K Da MW) and dissolved fractions (<
1 KDa MW) based on the molecular weight distribution. The fractions <
0.45 μm (including colloid fraction and dissolved fractions) in leachate were further divided into 6 fractions, i.e. hydrophobic bases (Ho-base), hydrophobic acids (Ho-acid), hydrophobic neutral (Ho-neutral), hydrophilic bases (Hi-base), hydrophilic acids (Hi-acid) and hydrophilic neutral (Hi-neutral). It was found that the ratio of TOC/TC in leachate decreased over time, indicating that the percentage of organic matters in leachate decreased as the disposal time extended. It was also observed that the hydrophobic fraction accounted to about 50% of the total matters presented in the fraction <
0.45 μm of all leachate samples. The main components in <
0.45 μm fraction were the Ho-acid, Hi-acid and Hi-base fractions. The percentage of Ho-acid in leachate decreased from 60.8% (2 a) to 43.2% (12 a). In addition, leachate with different ages was categorized into 3 phases according to the results of Principle component analysis (PCA). TOC/COD ranges of leachate in periods I, II and III were 40–54.6%, 16.9–41.3% and 10–38.9%, respectively, indicating that the COD contribution of non-carbon reduction substances increased over time in leachate. Hence, the corresponding landfill leachate treatment process should be modified according to the leachate characterization. The results obtained in this study might provide the important information for modeling, design, and operation of landfill leachate treatment systems.
Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Here we sequenced the exomes of nine individuals with TCC and screened all the somatically mutated genes in a prevalence ...set of 88 additional individuals with TCC with different tumor stages and grades. In our study, we discovered a variety of genes previously unknown to be mutated in TCC. Notably, we identified genetic aberrations of the chromatin remodeling genes (UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A and CHD6) in 59% of our 97 subjects with TCC. Of these genes, we showed UTX to be altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. Our results provide an overview of the genetic basis of TCC and suggest that aberration of chromatin regulation might be a hallmark of bladder cancer.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Alloying technology usually improves the mechanical properties of alloys; however, the high cost of alloying elements limits their wider applicability to conventional cast aluminium alloys. In this ...work, a novel high-strength, ductile, and low-cost Al–11Si–3Cu alloy microalloyed with minor Sr + Sc was developed and shown to improve the ultimate tensile strength and elongation relative to the majority of developed Al–Si-(Cu) alloys to date. Atom probe tomography (APT) reconstruction showed that Sc atoms existed separately instead of being enriched with Al and Sr atoms in eutectic Si, which indicated that the growth of eutectic Si in different crystallographic directions was inhibited. Many interactive stacking fault planes were formed in the novel alloy, which, as a series of barriers, effectively prevented dislocations from passing through, thereby providing a significant boost to the alloy strength. Moreover, a large number of Al3Sc and AlSi2Sc2 nano-precipitates exerted positive effects on the alloy strength by effectively slowing the dislocation movement. In addition, the strengthening mechanisms of the novel high-strength ductility Al–11Si–3Cu alloy are discussed.
•A novel high strength-ductility Al alloy was developed by minor content of Sr and Sc micro-alloying.•The distribution of micro-alloyed atoms in the novel alloys were analyzed by APT.•The Sc and Sr atoms inhibited the growth of eutectic Si in different directions.•Many stacking faults, Al3Sc and AlSi2Sc2 nanoparticles are formed in the alloy.•Effect of eutectic refining, stacking fault and nanoparticle strengthen are discussed.
Metal-organic framework (MOF) exhibited potential in water purification, while the poor water stability limited its applications. In this study, the integration of KOH activation and high-temperature ...pyrolysis was applied to fabricate ZIF-L derived N-doped porous carbon (NPC) adsorbent. KOH concentration had effect on the physical structure and chemical property of NPC and the NPC-0.5 demonstrated the highest adsorption capacity. The morphology, crystalline phase, composition and pore structure were characterized. KOH activated treatment brought larger surface area and abundant porosity, which were beneficial for the adsorptive reaction. It turned out that the NPC-0.5 with the highest adsorption capacity of 330.98 mg g−1 towards tetracycline (TC). Effects of the adsorbent dosage, pH values, initial concentrations and co-existing ions on adsorption performance were investigated. The adsorption process was a combination of chemical and physical interactions. Moreover, the NPC-0.5 exhibited high efficiency in removal of various antibiotics (oxytetracycline and chlortetracycline) and can efficiently remove TC from different water bodies (deionized water, tap water and river water). More importantly, after reused for four times, the adsorption property of NPC-0.5 showed a negligible decline. This study proposed a design of fabricating ZIF-derived N-doped porous carbon adsorbent with high performance towards antibiotics-containing wastewater remediation.
The formation of NPC, NPC-0.25, NPC-0.5 and NPC-1 sample and their adsorption capacity towards TC. Display omitted
•NPC was prepared through KOH activation and high-temperature pyrolysis of ZIF-L.•The KOH activation brought larger surface area and abundant porosity to NPC adsorbent.•High adsorption capacity of 330.98 mg g−1 can be obtained by NPC-0.5 towards TC.•The NPC-0.5 with superb reusability showed potential in wastewater remediation.
Resveratrol, a polyphenol found in various plants, including grapes, plums and peanuts has shown various medIRInal properties, including antioxidant, protection of cardiovascular disease and cancer ...risk. However, the effects of resveratrol on spinal cord reperfusion injury have not been investigated. Hence, the present study was designed to evaluate the effect of resveratrol on nitric oxide synthase (iNOS)/p38MAPK signaling pathway and to elucidate its regulating effect on the protection of spinal cord injury. Spinal cord ischemia–reperfusion injury (IRI) was performed by the infrarenal abdominal aorta with mini aneurysm clip model. The expressions of iNOS and p38MAPK and the levels of biochemical parameters, including nitrite/nitrate, malondialdehyde (MDA), advanced oxidation products (AOPP), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were measured in control and experimental groups. IRI-induced rats treated with 10mg/kg resveratrol protected spinal cord from ischemia injury as supported by improved biological parameters measured in spinal cord tissue homogenates. The resveratrol treatment significantly decreased the levels of plasma nitrite/nitrate, iNOS mRNA and protein expressions and phosphorylation of p38MAPK in IRI-induced rats. Further, IRI-produced free radicals were reduced by resveratrol treatment by increasing enzymatic and non-enzymatic antioxidant levels such as GSH, SOD and CAT. Taken together, administration of resveratrol protects the damage caused by spinal cord ischemia with potential mechanism of suppressing the activation of iNOS/p38MAPK pathway and subsequent reduction of oxidative stress due to IRI.
HSP60 is a major mitochondrial chaperone for maintaining mitochondrial proteostasis. Our previous studies showed that HSP60 was significantly downregulated in clear cell renal cell carcinoma (ccRCC), ...the most common type of kidney cancer characterized by the classic Warburg effect. Here, we analyzed datasets in The Cancer Genome Atlas and revealed that higher HSP60 expression correlated with better overall survival in ccRCC patients. We also stably knocked down or overexpressed HSP60 in ccRCC cells to investigate the effects of HSP60 expression on the transition between oxidative phosphorylation and glycolysis. We confirmed that HSP60 knockdown increased cell proliferation, whereas its overexpression decreased cell growth. Proteomics and metabolomics revealed that HSP60 knockdown promoted Warburg-like phenotypes with enhanced glycolysis and decreased mitochondrial activity. Consistent with this finding, isotope tracing showed that the metabolic flow from glycolysis to TCA was reduced. However, HSP60 silencing enhanced mitochondrial functions in glutamine-directed biosynthesis with increased flow in two parts of the TCA cycle: Gln→αKG→OAA→Asp and Gln→αKG→ISO→acetyl-CoA, resulting in elevated de novo nucleotide synthesis and lipid synthesis. Proteomic analysis indicated that HSP60 silencing activated NRF2-mediated oxidative stress responses, while glutamate generated from glutamine increased glutathione synthesis for quenching excessive reactive oxygen species (ROS) produced upon elevated cell growth. We further found that HSP60 silencing activated the MEK/ERK/c-Myc axis to promote glutamine addiction, and confirmed that ccRCC cells were susceptible to oxidative stress and glutaminase inhibition. Collectively, our data show that HSP60 knockdown drives metabolic reprogramming in ccRCC to promote tumor progression and enhances mitochondrial-dependent biosynthesis.
We sequenced whole exomes of ten clear cell renal cell carcinomas (ccRCCs) and performed a screen of ∼1,100 genes in 88 additional ccRCCs, from which we discovered 12 previously unidentified genes ...mutated at elevated frequencies in ccRCC. Notably, we detected frequent mutations in the ubiquitin-mediated proteolysis pathway (UMPP), and alterations in the UMPP were significantly associated with overexpression of HIF1α and HIF2α in the tumors (P = 0.01 and 0.04, respectively). Our findings highlight the potential contribution of UMPP to ccRCC tumorigenesis through the activation of the hypoxia regulatory network.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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