Proliferation to Apoptosis Tumor Cell Ratio as a Biomarker to Improve Clinical Management of Pre-Malignant and Symptomatic Plasma Cell Neoplasms

Proliferation and apoptosis of neoplastic cells are prognostic biomarkers in plasma cell neoplasms (PCNs). The prognostic capacity of proliferation to apoptosis ratio (Ratio-PA) in the era of immunomodulatory treatments is re-evaluated in 316 gammopathy of undetermined significance (MGUS), 57 smoldering multiple myeloma (SMM), and 266 multiple myeloma (MM) patients. Ratio-PA of 0.77 ± 0.12, 1.94 ± 0.52, and 11.2 ± 0.7 (p < 0.0001) were observed in MGUS, SMM, and MM patients. Ten-year overall survival (10y-OS) rates for patients with low/high Ratio-PA were 93.5%/77.3% p < 0.0001) for MGUS, 82.5%/64.7% (p < 0.05) for SMM, and 62.3%/47.0% (p < 0.05) for MM. For patients with low, intermediate, and high risk, 10y-OS for low/high Ratio-PA were 95.5%/72.9% (p < 0.0001), 74.2%/50.4% (p < 0.0001), and 35.3%/20.0% (p = 0.836), respectively. Ratio-PA was an independent prognostic factor for OS (HR = 2.119, p < 0.0001, Harrell-C-statistic = 0.7440 ± 0.0194) when co-analyzed with sex, age, and standard risk. In patients with Ratio-PA^high, only first-line therapy with VRd/VTd, but not PAD/VCD, coupled with ASCT was associated with high 10y-OS (82.7%). Tumor cell Ratio-PA estimated at diagnosis offers a prognostic biomarker that complements standard risk stratification and helps to guide the clinical management of pre-malignant and symptomatic PCNs. Every effort should be made to provide first-line therapies including VTd or VRd associated with ASCT to patients with Ratio-PA^high at higher risk of progression and death.     

Combination of computational prescreening and experimental library construction can accelerate enzyme optimization by directed evolution

Chiral compounds can be produced efficiently by using biocatalysts. However, wild-type enzymes often do not meet the requirements of a production process, making optimization by rational design or directed evolution necessary. Here, we studied the lipase-catalyzed hydrolysis of the model substrate 1-(2-naphthyl)ethyl acetate both theoretically and experimentally. We found that a computational equivalent of alanine scanning mutagenesis based on QM/MM methodology can be applied to identify amino acid positions important for the activity of the enzyme. The theoretical results are consistent with concomitant experimental work using complete saturation mutagenesis and high-throughput screening of the target biocatalyst, a lipase from Bacillus subtilis. Both QM/MM-based calculations and molecular biology experiments identify histidine 76 as a residue that strongly affects the catalytic activity. The experiments demonstrate its important influence on enantioselectivity.     

A QM/MM study of the catalytic mechanism of aspartate ammonia lyase

Aspartate ammonia lyase (Asp) is one of three types of ammonia lyases specific for aspartate or its derivatives as substrates, which catalyzes the reversible reaction of l-aspartate to yield fumarate and ammonia. In this paper, the catalytic mechanism of Asp has been studied by using combined quantum-mechanical/molecular-mechanical (QM/MM) approach. The calculation results indicate that the overall reaction only contains two elementary steps. The first step is the abstraction of C_β proton of l-aspartate by Ser318, which is calculated to be rate limiting. The second step is the cleavage of C_αN bond of l-aspartate to form fumarate and ammonia. Ser318 functions as the catalytic base, whereas His188 is a dispensable residue, but its protonation state can influence the active site structure and the existing form of leaving amino group, thereby influences the activity of the enzyme, which can well explain the pH dependence of enzymatic activity. Mutation of His188 to Ala only changes the active site structure and slightly elongates the distance of C_β proton of substrate with Ser318, causing the enzyme to remain significant but reduced activity.     

基于移动MM云开发平台的《基础维语》app的设计与开发

MM云开发平台是移动公司推出的手机应用制作平台,利用这个平台可以方便快捷地开发出很多手机应用程序.《基础维语》作为新疆大学生的一门选修课,被许多同学所喜欢,利用MM云开发平台的音乐制作模版,可以开发出很优秀《基础维语》移动学习app,经初步应用,取得很好的效果.     

基于YL-158G装置中电气集成与控制系统的关键技术

以高职组全国职业技能大赛"现代电气控制系统安装与调试"竞赛项目中YL-158G为载体,根据近年技能大赛的竞赛内容、评分标准,文章重点分析了西门子PLC应用技术、西门子变频器MM440、组态控制技术等关键技术     

QM/MM investigation of the reaction rates of substrates of 2,3-dimethylmalate lyase: A catabolic protein isolated from Aspergillus niger

Aspergillus niger is an industrially important microorganism used in the production of citric acid. It is a common cause of food spoilage and represents a health issue for patients with compromised immune systems. Recent studies on Aspergillus niger have revealed details on the isocitrate lyase (ICL) superfamily and its role in catabolism, including (2R, 3S)-dimethylmalate lyase (DMML). Members of this and related lyase super families are of considerable interest as potential treatments for bacterial and fungal infections, including Tuberculosis. In our efforts to better understand this class of protein, we investigate the catalytic mechanism of DMML, studying five different substrates and two different active site metals configurations using molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. We show that the predicted barriers to reaction for the substrates show good agreement with the experimental k_cat values. This results help to confirm the validity of the proposed mechanism and open up the possibility of developing novel mechanism based inhibitors specifically for this target.     

TYPHOON PROCESS AND ITS IMPACT ON THE SURFACE CIRCULATION IN THE NORTHERN SOUTH CHINA SEA

A severe typhoon Utor,occurring between July 3 and 8,2001,brought heavy rainfall,strong wind and storm surge.Utor was responsible for tremendous destruction and economic losses in Philippines,Taiwan and Guangdong.An air-sea model system (MM5 and Princeton Ocean Model(POM))was built to simulate meteorological dynamics and ocean circulation in the South China Sea(SCS).In the POM the output of MM5 was used as the input data.With an increased number of vertical levels,a high-resolution planetary boundary layer scheme and updated landuse/vegetation data,the accuracy of computing wind,temperature and other meteorological fields are improved in near surface and upper levels in MM5 simulations.The simulated trajectory and wind speed of Utor are close to the observed results.The simulated distribution of rainfall is accorded well with measured data in the Pearl River Delta(PRD)area.At different meteorological stations in Hong Kong,the wind,temperature and sea surface pressure are well simulated.The simulated ocean surface current and surface temperature fields have an obvious rightward-biased response to the typhoon Utor,and the maximum velocity and the lowest temperature region appear in the 30 km of the right side of the typhoon track.The typhoon Utor could make the water 50m under the surface ocean unwell to surface and the ocean surface temperature decrease by about 2°C.     

Mapping evapotranspiration using MODIS and MM5 Four-Dimensional Data Assimilation

Evapotranspiration (ET), the sum of evaporation from soil and transpiration from vegetation, is of vital importance in the hydrologic cycle and must be taken into consideration in assessments of the water resources of any region. The MODerate resolution Imaging Spectroradiometer (MODIS) sensor offers a promising opportunity for estimating daily ET with a 1 km spatial resolution, but is hampered by frequent cloud contamination or data gaps from other factors. In this study, 1) a stand-alone ET model was applied and tested during clear or partial cloudy sky conditions using MODIS-based inputs of land surface and atmospheric data and 2) meteorological simulations by using Four-Dimensional Data Assimilation (FDDA) system between MODIS and the 5th Generation Meso-scale Meteorological Model (MM5) was used in cloudy conditions to facilitate continuous daily ET estimates. The MODIS ET algorithm modified from Mu et al. (2007) is based on the Penman-Monteith equation and was applied to predict ET at flux measurement sites. This algorithm considers both the effects of surface energy partitioning processes and environmental constraints on ET. We devised gap-filling approaches for MODIS aerosol and albedo data that were identified as bottlenecks to determine retrieval rates of insolation and ET. MODIS-derived input variables (i.e., meteorological variables and radiation components) for estimating ET showed a good agreement with flux tower observations at each site. The retrieval rate of MODIS ET doubled at four flux measurement sites after gap-filling with negligible compensation was undertaken for accuracy. In spite of the high accuracy of MODIS-derived input variables, MODIS ET showed meaningful errors at the four flux measurement sites. These errors were mainly associated with errors in the estimated canopy conductance. During clear sky conditions, MODIS was used to calculate ET, while the MODIS-MM5 FDDA system provided input variables for the calculation of ET under cloudy sky conditions. The performance of the MODIS-MM5 FDDA system was evaluated by comparing ET based on MODIS, which showed a good agreement with the MODIS ET for various land cover types. Our results indicate that MODIS can be applied to monitor the land surface energy budget and ET with reasonable accuracy and that MODIS-MM5 FDDA has the potential to provide reasonable input data of ET estimation under cloudy conditions.     

DFT与OFF相结合的RDX分子设计

RDX是环三甲撑三硝胺的简称,又名黑索金.是军民领域常用的高能炸药.生成焓是炸药的基本热力学性质,是其含能高低的标志,从理论上计算分子结构并预测其生成焓对含能材料的分子设计和品优炸药的筛选具有重要意义.在众多计算方法中,DFT采用大型基组计算目标分子的全电子,结果精确,可信度高,缺点是需时长,耗费计算资源;基于半经验法的从头算法是对Hartree-Fock方程的近似求解,耗费机时少,但结果可信度低;分子力场(OFF)基于牛顿经典力学,以原子间的相互作用势函数(或称力场)来描述分子内和分子间的作用力,计算速度非常快,可计算大分子或高分子材料的物理性质,但在计算分子结构方面效果不太理想.本文用密度泛函理论(DFT)与开放力场(OFF)相结合的方法,计算高能炸药--黑索金(RDX)的分子结构和气相生成焓,在保证计算精度的同时节约了时间.在构象搜索阶段,分别采用分子力学(MM)和分子动力学(MD)方法,实现对目标分子的结构驰豫和模拟退火,在分子的几何结构优化阶段,则采用DFT GGA-BLYP法.分析优化RDX分子的键长与键角表明,RDX分子结构的计算结果与实验测定基本吻合.设计反应路径,并利用DFT GGA-BLYP计算出RDX的气相生焓为188.604 kJ/mol,与实验测定值191.444 kJ/mol接近.     

区域生长辅助的地图配准在室内定位中的应用

地图匹配（ MM）算法通过粒子滤波（ PF）利用室内地图信息来抑制基于惯性传感器的室内定位系统的误差累计。利用区域生长（ RG）算法结合当前步长和方向信息在地图上找到合理的落脚范围,并以此来判断粒子的有效性。这种方法能有效改善地图配准算法的实用性和计算复杂度。提出一种改进的零速度（ ZV）检测算法能准确提取步伐信息,间接提升了零速度更新（ ZUPT）算法和地图配准算法的精度。实验结果表明：该算法的定位误差小于1.0%,定位精度比单纯的航位推算（ DR）算法平均提高了5.97%。