Estimation of survival distributions of treatment policies in two-stage randomization designs in clinical trials

Some clinical trials follow a design where patients are randomized to a primary therapy at entry followed by another randomization to maintenance therapy contingent upon disease remission. Ideally, analysis would allow different treatment policies, i.e., combinations of primary and maintenance therapy if specified up-front, to be compared. Standard practice is to conduct separate analyses for the primary and follow-up treatments, which does not address this issue directly. We propose consistent estimators for the survival distribution and mean restricted survival time for each treatment policy in such two-stage studies and derive large-sample properties. The methods are demonstrated on a leukemia clinical trial data set and through simulation.     

维持性血液透析患者孤独状况与社会支持的关系研究

目的:调查维持性血液透析(MHD)患者的孤独状况,并探讨其与社会支持的关系。方法:采用问卷调查的方式对145例2018年1月至2019年6月期间来我院就诊的MHD患者(实验组)和同期150例健康状况良好正常人(对照组)进行调查,内容包括一般资料调查表、孤独量表(UCLA)、社会支持评定量表(SSRS),单因素Logistic回归模型筛选出造成孤独状况的危险因素,再采用非条件多因素Logistic回归模型计算危险因素与疾病的相关性。结果:实验组UCLA得分为(65.12±12.38)分,明显高于对照组的(25.38±5.57)分(P0.05),实验组SSRS量表中客观支持、主观支持、支持利用度以及总分分别为(14.86±1.89)分、(13.12±2.13)分、(10.88±1.56)分、(35.21±11.82)分,均低于对照组的(18.78±3.23)分、(20.95±3.06)分、(15.61±2.28)分、(50.98±15.24)分(P0.05)。多因素非条件Logistic回归显示MHD患者孤独状态的危险因素依次是客观支持、主观支持、支持利用度、透析年限及年龄(OR=5.246、4.568、4.315、4.172、2.342,均P0.05)。结论:MHD患者处于较为严重的孤独状态,社会支持是造成患者孤独状况的首要危险因素,良好的社会支持可以改善MHD患者的孤独状况。     

益生菌对维持性血液透析慢性肾脏病患者肠道菌群失调的影响

目的 探究益生菌对维持性血液透析慢性肾脏病患者肠道菌群失调的影响,为此类患者的治疗提供参考。 方法 选取2017年4月到2019年4月我院收治的78例维持性血液透析慢性肾病患者,按照随机数字法分为观察组和对照组各39例。对照组患者给予常规治疗,观察组患者给予常规治疗联合益生菌。检测两组患者肠道菌群变化,同时检测血清炎性因子(IL6、TNFα、CRP)、肠道屏障功能(D乳酸、内毒素)及肾功能指标[肌酐(serum creatinine,Scr)、尿素氮(blood urea nitrogen,BUN)]水平。 结果 治疗后两组患者Scr、BUN水平均下降(均P0.05)。治疗后两组患者肠道双歧杆菌、乳杆菌数量均增加,大肠埃希菌、肠球菌数量均下降,且观察组患者改善情况优于对照组,差异有统计学意义(t=4.226、9.634、6.157、2.739,P结论 益生菌对维持性血液透析慢性肾脏病患者肠道菌群失衡、肠道屏障功能和微炎症状态均具有改善作用,可为该类患者临床治疗提供一定参考。     

Solid-state fermentation-supported enhanced production of α-galactosidase by a deoxyglucose-resistant mutant of <Emphasis Type="Italic">Aspergillus niger</Emphasis> and thermostabilization of the production process

The aim of the present investigation was to comparatively evaluate the behaviour of A. niger and its derepressed mutant in production of α-galactosidase in submerged (SmF) and solid state fermentation (SSF) using basal Vogel’s medium or corn steep liquor as nitrogen source and observe the response of latter source under both cultural techniques under different temperature regimes, and determine if SSF can be exploited in a wide range of temperature expected to vary in this fermentation system. All studies were performed in both systems under pre-optimized cultural conditions. Higher melting temperature and negative values of entropy of activation in SSF indicated that the genetic system of both organisms was thermodynamically resistant in the presence of corn steep liquor but sensitive to inactivation in the presence of Vogel’s nitrogen sources in submerged fermentation. This was reflected as the organisms demanded higher magnitudes of energy for product formation in the presence of ammonium salts. Studies on influence of corn steep liquor revealed that it had stabilizing effect too in both fermentation systems but the mutant strain was more stable in both fermentation systems. Because of these properties, the mutant organism may be exploited for bulk production of α-galactosidase in SSF under condition where temperature may fluctuate during fermentation.     

DNA Induces Conformational Changes in a Recombinant Human Minichromosome Maintenance Complex

ATP-dependent DNA unwinding activity has been demonstrated for recombinant archaeal homohexameric minichromosome maintenance (MCM) complexes and their yeast heterohexameric counterparts, but in higher eukaryotes such as Drosophila, MCM-associated DNA helicase activity has been observed only in the context of a co-purified Cdc45-MCM-GINS complex. Here, we describe the production of the recombinant human MCM (hMCM) complex in Escherichia coli. This protein displays ATP hydrolysis activity and is capable of unwinding duplex DNA. Using single-particle asymmetric EM reconstruction, we demonstrate that recombinant hMCM forms a hexamer that undergoes a conformational change when bound to DNA. Recombinant hMCM produced without post-translational modifications is functional in vitro and provides an important tool for biochemical reconstitution of the human replicative helicase.     

Characterization of the Yeast Telomere Nucleoprotein Core: Rap1 BINDS INDEPENDENTLY TO EACH RECOGNITION SITE

At the core of Saccharomyces cerevisiae telomeres is an array of tandem telomeric DNA repeats bound site-specifically by multiple Rap1 molecules. There, Rap1 orchestrates the binding of additional telomere-associated proteins and negatively regulates both telomere fusion and length homeostasis. Using electron microscopy, viscosity, and light scattering measurements, we show that purified Rap1 is a monomer in solution that adopts a ringlike or C shape with a central cavity. Rap1 could orchestrate telomere function by binding multiple telomere array sites through either cooperative or independent mechanisms. To determine the mechanism, we analyze the distribution of Rap1 monomers on defined telomeric DNA arrays. This analysis clearly indicates that Rap1 binds independently to each nonoverlapping site in an array, regardless of the spacing between sites, the total number of sites, the affinity of the sites for Rap1, and over a large concentration range. Previous experiments have not clearly separated the effects of affinity from repeat spacing on telomere function. We clarify these results by testing in vivo the function of defined telomere arrays containing the same Rap1 binding site separated by spacings that were previously defined as low or high activity. We find that Rap1 binding affinity in vitro correlates with the ability of telomeric repeat arrays to regulate telomere length in vivo. We suggest that Rap1 binding to multiple sites in a telomere array does not, by itself, promote formation of a more energetically stabile complex.     

Report on non-temperature related variations in CO<Subscript>2</Subscript> efflux rates from young tree stems in the dormant season

Respiration rates are reported to increase exponentially with temperature. Respiration rates of woody tissues are commonly measured as CO₂ efflux rates () from that tissue. However, this paper describes clear variations in stem that were not related to temperature for the case of a young beech (Fagus sylvatica L.) and oak (Quercus robur L.) tree during the dormant season. The CO₂ concentration ([CO₂]) in the xylem of the beech tree showed similar temperature-independent variations. The trees were grown in a growth chamber in which radiation patterns and temperature were kept constant. was measured with an IRGA connected to cuvettes surrounding a stem segment. Xylem [CO₂] was measured in situ using a CO₂ microelectrode. Depressions in and [CO₂] occurred during the light period, despite equal temperatures in the light and dark period. Explanations found in literature for discrepancies in the exponential relationship between temperature and are the influence of (1) sap flow or (2) decreased cell water content. However, (1) the variations were observed in the dormant season, when no sap flow was observed yet, and (2) reduced cell water content was not likely to be apparent as differences in stem transpiration rates between the dark and light period were not significant. Hence, previously formulated theories failed to explain our results. This work therefore provides a new ground for discussion on other possible causes of daytime depressions in . One might be the refixation of respired CO₂ by corticular photosynthesis in the stem parts adjacent to the stem segment enclosed by the cuvette.     

Drug Abuse in China: Past,Present and Future

Following British importation of opium to China in 1760s, the use and production of the drug in China increased dramatically. This situation was aggravated after the failure of Opium Wars that occurred between the United Kingdom and the Qing Empire in China with the aim of forcing China to import British Opium; this war made China open the door to a free flowing opium trade, with disastrous social and public health consequences. The subsequent rise of the new China created drug-free atmosphere by strict legislation and punishment, in which drug use greatly decreased. However, in the context of governmental reform and the open-door policies of the 1980s, drug abuse has re-emerged as a major public health problem. Today, drug abuse is highly linked to the spread of HIV/AIDS and to drug-related crimes in China. To combat the severe drug problem facing the nation, the Chinese government has adopted the Methadone Maintenance Treatment program, a multi-faceted therapeutic approach that aims to reduce the health and social problem induced by drug epidemics. In addition, traditional Chinese medicine, including herbal therapy and acupuncture, both found to be effective in the prevention of relapse and causes few side effects, making them useful for the treatment of opiate addiction. With continuous application of these therapies and managements that have been proved to be effective in harm reduction in the western countries, we believe that drug abuse and its related problems in China will be brought under control.     

Over-expression of GFP-FEZ1 causes generation of multi-lobulated nuclei mediated by microtubules in HEK293 cells

FEZ1 (Fasciculation and elongation protein zeta 1) is an ortholog of the Caenorhabditis elegans protein UNC-76, involved in neuronal development and axon outgrowth, in that worm. Mammalian FEZ1 has already been reported to cooperate with PKC-zeta in the differentiation and polarization of PC12 neuronal cells. Furthermore, FEZ1 is associated with kinesin 1 and JIP1 to form a cargo-complex responsible for microtubule based transport of mitochondria along axons. FEZ1 can also be classified as a hub protein, since it was reported to interact with over 40 different proteins in yeast two-hybrid screens, including at least nine nuclear proteins. Here, we transiently over-expressed GFP-FEZ1full in human HEK293 and HeLa cells in order to study the sub-cellular localization of GFP-FEZ1. We observed that over 40% of transiently transfected cells at 3 days post-transfection develop multi-lobulated nuclei, which are also called flower-like nuclei. We further demonstrated that GFP-FEZ1 localizes either to the cytoplasm or the nuclear fraction, and that the appearance of the flower-like nuclei depends on intact microtubule function. Finally, we show that FEZ1 co-localizes with both, α- and especially with γ-tubulin, which localizes as a centrosome like structure at the center of the multiple lobules. In summary, our data suggest that FEZ1 has an important centrosomal function and supply new mechanistic insights to the formation of flower-like nuclei, which are a phenotypical hallmark of human leukemia cells.     

A new role for the Endothelin-1/Endothelin-A receptor signaling during early neural crest specification

The neural crest is induced at the border of the neural plate in a multistep process by signals emanated from the epidermis, neural plate and mesoderm. In this work we show for the first time the existence of a neural crest maintenance step which is dependent on signals released from the mesoderm. We identified Endothelin-1 (Edn1) and its receptor (Ednra) as key players of this signal and we show that Edn1/Ednra signaling is required for maintenance of the neural crest by a dual mechanism of cell specification and cell survival. We show that: (i) Ednra is expressed in prospective neural crest; (ii) loss-of-function experiments with antisense morpholino or with specific chemical inhibitor suppress the expression of early neural crest markers; (iii) gain-of-function experiments expand the neural crest territory; (iv) epistatic experiments show that Ednra/Edn1 is downstream of the early neural crest gene Msx1 and upstream of the late genes Sox9 and Sox10; and (v) Edn1/Ednra signaling inhibits apoptosis and controls cell specification of the neural crest. Together, our results provide insight on a new role of Edn1/Ednra cell signaling pathway during early neural crest development.