SALL4, a Stem Cell Factor, Affects the Side Population by Regulation of the ATP-Binding Cassette Drug Transport Genes

Our previous work shows that the stem cell factor SALL4 plays a central role in embryonic and leukemic stem cells. In this study, we report that SALL4 expression was higher in drug resistant primary acute myeloid leukemic patients than those from drug-responsive cases. In addition, while overexpression of SALL4 led to drug resistance in cell lines, cells with decreased SALL4 expression were more sensitive to drug treatments than the parental cells. This led to our investigation of the implication of SALL4 in drug resistance and its role in side population (SP) cancer stem cells. SALL4 expression was higher in SP cells compared to non-SP cells by 2–4 fold in various malignant hematopoietic cell lines. Knocking down of SALL4 in isolated SP cells resulted in a reduction of SP cells, indicating that SALL4 is required for their self-renewal. The SP phenotype is known to be mediated by members of the ATP-binding cassette (ABC) drug transport protein family, such as ABCG2 and ABCA3. Using chromatin-immunoprecipitation (ChIP), quantitative reverse transcription polymerase chain reaction (qRT-PCR) and electrophoretic mobility shift assay(EMSA), we demonstrated that SALL4 was able to bind to the promoter region of ABCA3 and activate its expression while regulating the expression of ABCG2 indirectly. Furthermore, SALL4 expression was positively correlated to those of ABCG2 and ABCA3 in primary leukemic patient samples. Taken together, our results suggest a novel role for SALL4 in drug sensitivity, at least in part through the maintenance of SP cells, and therefore may be responsible for drug-resistance in leukemia. We are the first to demonstrate a direct link between stem cell factor SALL4, SP and drug resistance in leukemia

Black-Box Quantum State Preparation with Inverse Coefficients

Black-box quantum state preparation is a fundamental building block for many higher-level quantum algorithms, which is applied to transduce the data from computational basis into amplitude. Here we present a new algorithm for performing black-box state preparation with inverse coefficients based on the technique of inequality test. This algorithm can be used as a subroutine to perform the controlled rotation stage of the Harrow-Hassidim-Lloyd (HHL) algorithm and the associated matrix inversion algorithms with exceedingly low cost. Furthermore, we extend this approach to address the general black-box state preparation problem where the transduced coefficient is a general non-linear function. The present algorithm greatly relieves the need to do arithmetic and the error is only resulted from the truncated error of binary string. It is expected that our algorithm will find wide usage both in the NISQ and fault-tolerant quantum algorithms.Comment: 11 pages, 3 figure

Case report of a Li-Fraumeni syndrome-like phenotype with a de novo mutation in <i>CHEK2</i>

BACKGROUND: Cases of multiple tumors are rarely reported in China. In our study, a 57-year-old female patient had concurrent squamous cell carcinoma, mucoepidermoid carcinoma, brain cancer, bone cancer, and thyroid cancer, which has rarely been reported to date. METHODS: To determine the relationship among these multiple cancers, available DNA samples from the thyroid, lung, and skin tumors and from normal thyroid tissue were sequenced using whole exome sequencing. RESULTS: The notable discrepancies of somatic mutations among the 3 tumor tissues indicated that they arose independently, rather than metastasizing from 1 tumor. A novel deleterious germline mutation (chr22:29091846, G->A, p.H371Y) was identified in CHEK2, a Li–Fraumeni syndrome causal gene. Examining the status of this novel mutation in the patient's healthy siblings revealed its de novo origin. CONCLUSION: Our study reports the first case of Li–Fraumeni syndrome-like in Chinese patients and demonstrates the important contribution of de novo mutations in this type of rare disease

Highly time-resolved chemical characterization and implications of regional transport for submicron aerosols in the North China Plain

To investigate the regional transport and formation mechanisms of submicron aerosols in the North China Plan (NCP), for the first time, we conducted simultaneous combined observations of the non-refractory submicron aerosols (NR-PM1) chemical compositions using aerosol mass spectrometer at urban Beijing (BJ) and at regional background area of the NCP (XL), from November 2018 to January 2019. During the observation period, average mass concentrations of PM1 in BJ and XL were 26.6 +/- 31.7 and 16.0 +/- 18.7 mu g m(-3) respectively. The aerosol composition in XL showed a lower contribution of organic aerosol (33% vs. 43%) and higher fractions of nitrate (35% vs. 30%), ammonium (16% vs. 13%), and chlorine (2% vs. 1%) than in BJ. Additionally, a higher contribution of secondary organic aerosol (SOA) was also observed in XL, suggesting low primary emissions and highly oxidized OA in the background area. Nitrate displayed a significantly enhanced contribution with the aggravation of aerosol pollution in both BJ and XL, which was completely neutralized by excess ammonium at both sites, that the abundant ammonia emissions in the NCP favor nitrate formation on a regional scale. In addition, a higher proportion of nitrate in XL can be attributed to the more neutral and higher oxidation capacity of the background atmosphere. Heterogeneous aqueous reaction plays an important role in sulfate and SOA formation, and is more efficient in BJ which can be attributed to the higher aerosol surface areas at urban site. Regional transport from the southwestern regions of NCP showed a significant impact on the formation of haze episodes. Beside the invasion of transported pollutants, the abundant water vapor associated with the air mass to the downwind background area further enhanced local secondary transformation and expanded the regional scope of the haze pollution in the NCP. (C) 2019 Elsevier B.V. All rights reserved.Peer reviewe

The plasticity of mesenchymal stem cells in regulating surface HLA-I

Summary A low surface expression level of human leukocyte antigen class I(HLA-I) ensures the mesenchymal stem cells’(MSCs) escape from the allogeneic recipients’ immunological surveillance. Here, we discovered that both transcriptional and synthesis levels of HLA-I in MSCs increased continuously after IFN-γ treatment, while interestingly, their surface HLA-I expression was downregulated after reaching an HLA-I surface expression peak. Microarray data indicated the post-transcriptional process plays an important role in downregulation of surface HLA-I. Further studies identified that IFN-γ-treated MSCs accelerated HLA-I endocytosis through a Clathrin–independent Dynamin-dependent endocytosis pathway. Furthermore, the cells which have self-downregulated surface HLA-I expression elicit a weaker immune response than they previously could. Thus, uncovering the plasticity of MSCs in the regulation of HLA-I surface expression would reveal insights into the membrane-transportation events leading to the maintenance of low surface HLA-I expression, providing more evidence for selecting and optimizing low immunogenic MSCs to improve the therapeutic efficiency.Peer reviewe

Manipulations of phenylnorbornyl palladium species for multicomponent construction of a bridged polycyclic privileged scaffold

Hexahydromethanocarbazole is a privileged scaffold in the discovery of new drugs and photoactive organic materials due to its good balance between structural complexity and minimized entropy penalty upon receptor binding. To address the difficulty of synthesizing this highly desirable bridged polycyclic scaffold, we designed a convenient multicomponent reaction cascade as intercepted Heck addition/C-H activation/C-palladacycle formation/electrophilic attack of ANP/N-palladacycle formation/Buchwald amination. A distinguishing feature of this sophisticated strategy is the successive generation of two key phenylnorbornyl palladium species to control the reaction flow towards desired products. DFT calculations further reveal the crucial roles of Cs2CO3 and 5,6-diester substitutions on the norbornene reactant in preventing multiple side-reactions. This innovative method exhibits a broad scope with good yields, and therefore will enable the construction of natural-product-like compound libraries based on hexahydromethanocarbazole

Individual Professional Practice in the Company

Import 23/08/2017Cílem této bakalářské práce je popsat absolvování odborné praxe ve firmě HS Interactive s.r.o. Praxe byla zaměřena na vývoj mobilní aplikace pro operační systém Android. Aplikace je mobilním klientem pro sociální síť MatchToMe. V úvodu popisuji důvody, které vedly k výběru odborné praxe. Dále se věnuji úkolům, které mi byly zadány s jejich implementací a postupem řešení problémů, které se objevily při vývoji. Závěr práce je věnován zhodnocení získaných zkušeností a dosažených výsledků.Purpose of this bachelor thesis is to describe a professional practice in company HS Interactive s.r.o. Practice was focused on the development of mobile application for the operating system Android. The application is a mobile client for social network MatchToMe. In the introduction I describe reasons that led to the selection of professional practice. Then I describe tasks that I have been awarded with their implementations and process of solution issues that have emerged during development. The conclusion of thesis is dedicated to the evaluation of the experience gained and the results achieved.440 - Katedra telekomunikační technikyvýborn

Investigations on the intramolecular (4+3) cycloadditions of epoxy enolsilanes, and applications towards the asymmetric synthesis of himandrine

The intramolecular (4+3) cycloadditions of epoxy enolsilane substrates 1.89 generated polycyclic cycloadducts 1.90 having bicyclo[5.3.0]decane frameworks, a skeleton which is common among terpenoid natural products (Scheme 1). Each cycloadduct has been fully characterized, and two cycloaddition models have been proposed to rationalize their formation. Epimerization has been observed to generate an additional diastereomer which did not directly result from cycloaddition. Cycloaddition of optically enriched (+)-1.89b produced 1.90b with conserved ee. Tethered pyrroles having a range of N-protecting groups and substituents have been synthesized and their cycloadditions examined (Scheme 2). The intramolecular (4+3) cycloadditions of pyrrolyl enolsilanes such as 2.171 has been observed to proceed with good yields and diastereoselectivities. The endo cycloadducts (type i) were the major diastereomers in all cycloadditions, except when the pyrrole is substituted at C3. Cycloaddition models have been proposed to explain the stereochemical outcomes. Cycloaddition of enantiomerically pure (+)-2.106 also provided (–)-2.113a and (+)-2.114 with conserved ee. Based on these results, we have pursued the asymmetric synthesis of 3.77, the BCDEF rings of himandrine, a Type II Galbulimima alkaloid. The intramolecular (4+3) cycloaddition of optically enriched pyrrole (+)-3.127 to generate cycloadduct (–)-3.138ii, was the key step to construct the BCF ring system of the himandrine core (Scheme 3). From (–)-3.138ii, the methoxycarbonyl group was introduced by a palladium-catalyzed carbonylation, and further transformations provided cyclic amine (–)-3.159. Ring E was formed by the aza-Michael/Mukaiyama aldol sequence, and the resultant alcohols 3.167 were reduced by a Barton-McCombie deoxygenation. For constructing ring D, a metal-halogen exchange and intramolecular carbonyl addition were employed. Finally, the target molecule (–)-3.77 has been successfully achieved in 19 (or 20) steps.published_or_final_versionChemistryDoctoralDoctor of Philosoph