Selective quantum Zeno effect of ultracold atom-molecule scattering in dynamic magnetic fields

We demonstrated that final states of ultracold scattering between atom and molecule can be selectively produced using dynamic magnetic fields of multiple frequencies. The mechanism of the dynamic magnetic field control is based on a generalized quantum Zeno effect for the selected scattering channels. In particular, we use an atom-molecule spin flip scattering to show that the transition to the selected final spin projection of the molecule in the inelastic scattering can be suppressed by dynamic modulation of coupling between the Floquet engineered initial and final states

Resistance mechanisms and population structure of highly drug resistant Klebsiella in Pakistan during the introduction of the carbapenemase NDM-1.

Klebsiella pneumoniae is a major threat to public health with the emergence of isolates resistant to most, if not all, useful antibiotics. We present an in-depth analysis of 178 extended-spectrum beta-lactamase (ESBL)-producing K. pneumoniae collected from patients resident in a region of Pakistan, during the period 2010-2012, when the now globally-distributed carbapenemase bla-NDM-1 was being acquired by Klebsiella. We observed two dominant lineages, but neither the overall resistance profile nor virulence-associated factors, explain their evolutionary success. Phenotypic analysis of resistance shows few differences between the acquisition of resistance genes and the phenotypic resistance profile, including beta-lactam antibiotics that were used to treat ESBL-positive strains. Resistance against these drugs could be explained by inhibitor-resistant beta-lactamase enzymes, carbapenemases or ampC type beta-lactamases, at least one of which was detected in most, but not all relevant strains analysed. Complete genomes for six selected strains are reported, these provide detailed insights into the mobile elements present in these isolates during the initial spread of NDM-1. The unexplained success of some lineages within this pool of highly resistant strains, and the discontinuity between phenotypic resistance and genotype at the macro level, indicate that intrinsic mechanisms contribute to competitive advantage and/or resistance

Berberine Induces Caspase-Independent Cell Death in Colon Tumor Cells through Activation of Apoptosis-Inducing Factor

Berberine, an isoquinoline alkaloid derived from plants, is a traditional medicine for treating bacterial diarrhea and intestinal parasite infections. Although berberine has recently been shown to suppress growth of several tumor cell lines, information regarding the effect of berberine on colon tumor growth is limited. Here, we investigated the mechanisms underlying the effects of berberine on regulating the fate of colon tumor cells, specifically the mouse immorto-Min colonic epithelial (IMCE) cells carrying the Apcmin mutation, and of normal colon epithelial cells, namely young adult mouse colonic epithelium (YAMC) cells. Berberine decreased colon tumor colony formation in agar, and induced cell death and LDH release in a time- and concentration-dependent manner in IMCE cells. In contrast, YAMC cells were not sensitive to berberine-induced cell death. Berberine did not stimulate caspase activation, and PARP cleavage and berberine-induced cell death were not affected by a caspase inhibitor in IMCE cells. Rather, berberine stimulated a caspase-independent cell death mediator, apoptosis-inducing factor (AIF) release from mitochondria and nuclear translocation in a ROS production-dependent manner. Amelioration of berberine-stimulated ROS production or suppression of AIF expression blocked berberine-induced cell death and LDH release in IMCE cells. Furthermore, two targets of ROS production in cells, cathepsin B release from lysosomes and PARP activation were induced by berberine. Blockage of either of these pathways decreased berberine-induced AIF activation and cell death in IMCE cells. Thus, berberine-stimulated ROS production leads to cathepsin B release and PARP activation-dependent AIF activation, resulting in caspase-independent cell death in colon tumor cells. Notably, normal colon epithelial cells are less susceptible to berberine-induced cell death, which suggests the specific inhibitory effects of berberine on colon tumor cell growth

Phylogenetic Analysis of Klebsiella pneumoniae from Hospitalized Children, Pakistan.

Klebsiella pneumoniae shows increasing emergence of multidrug-resistant lineages, including strains resistant to all available antimicrobial drugs. We conducted whole-genome sequencing of 178 highly drug-resistant isolates from a tertiary hospital in Lahore, Pakistan. Phylogenetic analyses to place these isolates into global context demonstrate the expansion of multiple independent lineages, including K. quasipneumoniae.This work was supported by National Health and Medical Research Council program grants (0606788 to R.A.S. and T. L.; 1092262 to R.A.S., G.D., and T.L.); the Wellcome Trust (206194); and the Higher Education Commission of Pakistan and The Children’s Hospital & The Institute of Child Health, Lahore, Pakistan. H.E. was supported by a scholarship from Higher Education Commission Pakistan under the International Research Support Initiative Program

Structure-Activity Relationship Study Enables the Discovery of a Novel Berberine Analogue as RXRα Activator to Inhibit Colon Cancer

黄连素是从黄连、黄柏等传统中药中提取的单体化合物，常用于治疗痢疾及其它消化道感染。近年来，黄连素的抗心律失常、调控能量代谢、降血糖血脂和抗癌等多重功效使其成为一个“明星”中药单体化合物。尽管黄连素具有很好的安全性，但其抗癌作用在临床应用上仍具有许多局限性，包括抗癌活性低、溶解度和生物利用度低等。然而，由于黄连素的分子靶点不清楚，以往对黄连素的改造比较盲目和随机，并未取得较好的进展。胡天惠团队与张延东团队紧密合作、优势互补，针对黄连素与RXR的结合模式，运用结构生物学方法和全合成相结合，设计合成了多种黄连素衍生物，并开展了构效关系分析。发现黄连素衍生物B-12在结合并激活RXR、抗肠癌活性、溶解度和生物利用度方面均明显优于黄连素，且保留了黄连素的肿瘤选择性和低毒副作用，具有很好的临床转化前景。该研究也为结构生物学指导黄连素衍生物药物设计提供了理论基础。本论文的通讯作者为医学院占艳艳副教授、张延东教授和胡天惠教授。医学院博士生徐贝贝和化学化工学院博士生江训金为共同第一作者。We reported recently that berberine, a traditional oriental medicine to treat gastroenteritis, binds and activates Retinoid X receptor α (RXRα) to suppress the growth of colon cancer cells. Here, we extended our studies based on the binding mode of berberine with RXRα by design, synthesis and biological evaluation of a focused library of 15 novel berberine analogues. Among them, 3,9-dimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium chloride (B-12) was identified as the optimal RXRα activator. More efficiently than berberine, B-12 bound and altered the conformation of RXRα/LBD, thereby suppressing Wnt/β-catenin pathway and colon cancer cell growth via RXRα mediation. In addition, B-12 not only preserved berberine’s tumor selectivity but also greatly improved its bioavailability. Remarkably, in mice, B-12 did not show obvious side effects including hypertriglyceridemia as other RXRα agonists, or induce hepatorenal toxicity. Together, our study describes an approach for the rational design of berberine-derived RXRα activators as novel effective antineoplastic agents for colon cancer.This work was supported by the National Natural Science Foundation of China (31770860, 21772164, 81572589, 81602560 and 21572187), and the Natural Science Foundation of Fujian Province (2018R1036-2, 2017J06020, 2019R1001-4, and 2019R1001-5). 项目得到了国家自然科学基金委促进海峡两岸科技合作联合基金重点项目、面上项目和福建省自然科学基金的支持

ULK1 phosphorylates Exo70 to suppress breast cancer metastasis

乳腺癌是威胁女性生命健康的“头号杀手”，而远处转移是乳腺癌患者死亡的主要原因。因此，了解乳腺癌如何发动侵袭和转移，对于有效治疗乳腺癌、延长病人生存期具有重要意义。本研究中，该团队发现ULK1通过结合并磷酸化胞泌蛋白复合体关键亚基Exo70来抑制乳腺癌转移。ULK1对Exo70上Ser47，Ser59和Ser89位点的磷酸化，严重地削弱了Exo70的自身寡聚化和与其它胞外分泌复合体亚基的结合，进而减少了细胞运动伪足形成以及基质金属蛋白酶的分泌，从而抑制乳腺癌细胞的迁移和侵袭。该论文首次揭示了胞外分泌复合体重要成员Exo70在乳腺癌中受到ULK1和ERK1/2的双重磷酸化调控，从而使得乳腺癌细胞可以根据外环境来决定潜伏还是发动侵袭转移，为乳腺癌的治疗提供了新的理论基础。 本论文的通讯作者为占艳艳副教授、郭巍教授和胡天惠教授。医学院博士生毛丽媛、占艳艳副教授、吴斌博士和医学院博士生于强为共同第一作者。【Abstract】Increased expression of protein kinase ULK1 was reported to negatively correlate with breast cancer metastasis. Here we report that ULK1 suppresses the migration and invasion of human breast cancer cells. The suppressive effect is mediated through direct phosphorylation of Exo70, a key component of the exocyst complex. ULK1 phosphorylation inhibits Exo70 homo-oligomerization as well as its assembly to the exocyst complex, which are needed for cell protrusion formation and matrix metalloproteinases secretion during cell invasion. Reversely, upon growth factor stimulation, Exo70 is phosphorylated by ERK1/2, which in turn suppresses its phosphorylation by ULK1. Together, our study identifies Exo70 as a substrate of ULK1 that inhibits cancer metastasis, and demonstrates that two counteractive regulatory mechanisms are well orchestrated during tumor cell invasion.This work was supported by the grants from the National Natural Science Foundation of China (81572589, U1405228, 81472568, and 31770860), the Natural Science Foundation of Fujian grant (2017J06020, 2018J01400, 2017R1036-4, 2017R1036-6, 2016R1034-1, and 2016R1034-4), and the Xiamen Science and Technology grant (3502Z20159013) to Y.-y.Z. and T.H., and National Institute of Health R01 GM111128 to W.G.该论文的研究成果是在国家自然科学基金和福建省基金的资助下，与美国宾夕法尼亚大学和清华大学共同协作完成的

Matrine Reverses the Warburg Effect and Suppresses Colon Cancer Cell Growth via Negatively Regulating HIF-1α.

The Warburg effect is a peculiar feature of cancer’s metabolism, which is an attractive therapeutic target that could aim tumor cells while sparing normal tissue. Matrine is an alkaloid extracted from the herb root of a traditional Chinese medicine, Sophora flavescens Ait. Matrine has been reported to have selective cytotoxicity toward cancer cells but with elusive mechanisms. Here, we reported that matrine was able to reverse the Warburg effect (inhibiting glucose uptake and lactate production) and suppress the growth of human colon cancer cells in vitro and in vivo . Mechanistically, we revealed that matrine significantly decreased the messenger RNA (mRNA) and protein expression of HIF-1α, a critical transcription factor in reprogramming cancer metabolism toward the Warburg effect. As a result, the expression levels of GLUT1, HK2, and LDHA, the downstream targets of HIF-1α in regulating glucose metabolism, were dramatically inhibited by matrine. Moreover, this inhibitory effect of matrine was significantly attenuated when HIF-1α was knocked down or exogenous overexpressed in colon cancer cells. Together, our results revealed that matrine inhibits colon cancer cell growth via suppression of HIF-1α expression and its downstream regulation of Warburg effect. Matrine could be further developed as an antitumor agent targeting the HIF-1α-mediated Warburg effect for colon cancer treatment

Mucosal-associated invariant T cells augment immunopathology and gastritis in chronic helicobacter pyloriInfection

Mucosal-associated invariant T (MAIT) cells produce inflammatory cytokines and cytotoxic granzymes in response to by-products of microbial riboflavin synthesis. Although MAIT cells are protective against some pathogens, we reasoned that they might contribute to pathology in chronic bacterial infection. We observed MAIT cells in proximity to Helicobacter pylori bacteria in human gastric tissue, and so, using MR1-tetramers, we examined whether MAIT cells contribute to chronic gastritis in a mouse H. pylori SS1 infection model. Following infection, MAIT cells accumulated to high numbers in the gastric mucosa of wild-type C57BL/6 mice, and this was even more pronounced in MAIT TCR transgenic mice or in C57BL/6 mice where MAIT cells were preprimed by Ag exposure or prior infection. Gastric MAIT cells possessed an effector memory Tc1/Tc17 phenotype, and were associated with accelerated gastritis characterized by augmented recruitment of neutrophils, macrophages, dendritic cells, eosinophils, and non-MAIT T cells and by marked gastric atrophy. Similarly treated MR1−/− mice, which lack MAIT cells, showed significantly less gastric pathology. Thus, we demonstrate the pathogenic potential of MAIT cells in Helicobacter-associated immunopathology, with implications for other chronic bacterial infections

MrkH, a Novel c-di-GMP-Dependent Transcriptional Activator, Controls Klebsiella pneumoniae Biofilm Formation by Regulating Type 3 Fimbriae Expression

Klebsiella pneumoniae causes significant morbidity and mortality worldwide, particularly amongst hospitalized individuals. The principle mechanism for pathogenesis in hospital environments involves the formation of biofilms, primarily on implanted medical devices. In this study, we constructed a transposon mutant library in a clinical isolate, K. pneumoniae AJ218, to identify the genes and pathways implicated in biofilm formation. Three mutants severely defective in biofilm formation contained insertions within the mrkABCDF genes encoding the main structural subunit and assembly machinery for type 3 fimbriae. Two other mutants carried insertions within the yfiN and mrkJ genes, which encode GGDEF domain- and EAL domain-containing c-di-GMP turnover enzymes, respectively. The remaining two isolates contained insertions that inactivated the mrkH and mrkI genes, which encode for novel proteins with a c-di-GMP-binding PilZ domain and a LuxR-type transcriptional regulator, respectively. Biochemical and functional assays indicated that the effects of these factors on biofilm formation accompany concomitant changes in type 3 fimbriae expression. We mapped the transcriptional start site of mrkA, demonstrated that MrkH directly activates transcription of the mrkA promoter and showed that MrkH binds strongly to the mrkA regulatory region only in the presence of c-di-GMP. Furthermore, a point mutation in the putative c-di-GMP-binding domain of MrkH completely abolished its function as a transcriptional activator. In vivo analysis of the yfiN and mrkJ genes strongly indicated their c-di-GMP-specific function as diguanylate cyclase and phosphodiesterase, respectively. In addition, in vitro assays showed that purified MrkJ protein has strong c-di-GMP phosphodiesterase activity. These results demonstrate for the first time that c-di-GMP can function as an effector to stimulate the activity of a transcriptional activator, and explain how type 3 fimbriae expression is coordinated with other gene expression programs in K. pneumoniae to promote biofilm formation to implanted medical devices