Simultaneous targeting of TNF and Ang2 with a novel bispecific antibody enhances efficacy in an in vivo model of arthritis

Despite the clinical success of anti-tumor necrosis factor (TNF) therapies in the treatment of inflammatory conditions such as rheumatoid arthritis, Crohn disease and psoriasis, full control of the diseases only occurs in a subset of patients and there is a need for new therapeutics with improved efficacy against broader patient populations. One possible approach is to combine biological therapeutics, but both the cost of the therapeutics and the potential for additional toxicities needs to be considered. In addition to the various mediators of immune and inflammatory pathways, angiogenesis is reported to contribute substantially to the overall pathogenesis of inflammatory diseases. The combination of an anti-angiogenic agent with anti-TNF into one molecule could be more efficacious without the risk of severe immunosuppression. To evaluate this approach with our Zybody technology, we generated bispecific antibodies that contain an Ang2 targeting peptide genetically fused to the anti-TNF antibody adalimumab (Humira®). The bispecific molecules retain the binding and functional characteristics of the anti-TNF antibody, but with additional activity that neutralizes Ang2. In a TNF transgenic mouse model of arthritis, the bispecific anti-TNF-Ang2 molecules showed a dose-dependent reduction in both clinical symptoms and histological scores that were significantly better than that achieved by adalimumab alone.     

Changes in nitrogen and phosphorus cycling suggest a transition to phosphorus limitation with the stand development of larch plantations

Plant and Soil - The changes of nutrient limitation status for tree growth across a plantation chronosequence have great implications for plantation management. The underlying mechanisms for such a...     

Nitrogen deposition promotes phosphorus uptake of plants in a semi-arid temperate grassland

Plant and Soil - Nitrogen (N) deposition greatly influences ecosystem processes through the alteration of plant nutrition; however, there is limited understanding about the effects of phosphorus...     

BIPES,a cost-effective high-throughput method for assessing microbial diversity

Pyrosequencing of 16S rRNA (16S) variable tags has become the most popular method for assessing microbial diversity, but the method remains costly for the evaluation of large numbers of environmental samples with high sequencing depths. We developed a barcoded Illumina paired-end (PE) sequencing (BIPES) method that sequences each 16S V6 tag from both ends on the Illumina HiSeq 2000, and the PE reads are then overlapped to obtain the V6 tag. The average accuracy of Illumina single-end (SE) reads was only 97.9%, which decreased from ∼99.9% at the start of the read to less than 85% at the end of the read; nevertheless, overlapping of the PE reads significantly increased the sequencing accuracy to 99.65% by verifying the 3′ end of each SE in which the sequencing quality was degraded. After the removal of tags with two or more mismatches within the medial 40–70 bases of the reads and of tags with any primer errors, the overall base sequencing accuracy of the BIPES reads was further increased to 99.93%. The BIPES reads reflected the amounts of the various tags in the initial template, but long tags and high GC tags were underestimated. The BIPES method yields 20–50 times more 16S V6 tags than does pyrosequencing in a single-flow cell run, and each of the BIPES reads costs less than 1/40 of a pyrosequencing read. As a laborsaving and cost-effective method, BIPES can be routinely used to analyze the microbial ecology of both environmental and human microbiomes.     

Temporal dynamics of activated sludge bacterial communities in two diversity variant full-scale sewage treatment plants

Bacterial community in activated sludge (AS) is diverse and highly dynamic. Little is known about the mechanism shaping bacterial community composition and dynamics of AS and no study had quantitatively compared the contribution of abiotic environmental factors and biotic associations to the temporal dynamics of AS microbial communities with significantly different diversity. In this study, two full-scale sewage treatment plants (STPs) with distinct operational parameters and influent composition were sampled biweekly over 1 year to reveal the correlating factors to whole and sub-groups of AS bacterial community diversity and dynamics. The results show that the bacterial communities of the two STPs were entirely different and correlated with the influent composition and operating configurations. Bacterial associations represented by cohesion metrics and the environmental factor temperature were the primary correlated factors to the temporal bacterial community dynamics within each STP. The STP with high diversity and evenness could treat influent with higher suspended solid and a shorter sludge retention time, and was less correlated with environmental factors, implying the importance of diversity for AS system.

     

N limitation increases along a temperate forest succession: evidences from leaf stoichiometry and nutrient resorption

温带森林演替加剧了氮限制：来自叶片化学计量和养分重吸收的证据 森林生产力和碳汇功能在很大程度上取决于土壤氮和磷的有效性。然而,迄今为止,养分限制随森林演替的时间变化仍存在争议。叶片化学计量和养分重吸收是预测植物生长养分限制的重要指标。基于此,本研究测定了温带森林4个演替阶段所有木本植物叶片和凋落叶中氮和磷的含量,并分析了演替过程中非生物因子和生物因子如何影响叶片化学计量和养分重吸收。研究结果表明,在个体尺度上,叶片氮磷含量在演替末期显著增加,而叶片氮磷比无显著变化;氮的重吸收效率随演替显著增加,然而磷的重吸收效率先增加后减少;氮重吸收效率与磷重吸收效率的比值仅在演替末期显著增加。此外,植物氮素循环对土壤养分的响应比磷素循环更弱。在群落尺度上,叶片氮磷含量随森林演替呈现先降低后升高的趋势,主要受香农-维纳多样性指数和物种丰富度的影响;叶片氮磷比随演替而显著变化,主要由胸径的群落加权平均值决定;氮的重吸收效率增加,主要受物种丰富度和胸径的影响,而磷的重吸收效率相对稳定。因此,氮重吸收效率与磷重吸收效率的比值显著增加,表明随着温带森林演替,氮限制加剧。这些结果可能反映了较高生物多样性群落中物种间对有限资源的激烈竞争,强调了生物因子在驱动森林生态系统养分循环中的重要性,为中国温带和北方森林可持续经营的施肥管理提供了参考。     

唐鱼仔鱼耳石的形态发育及日轮

观察了实验室人工繁殖饲养的唐鱼(Tanichthys albonubes)仔鱼耳石形态发育,研究了其生长轮的沉积规律。唐鱼仔鱼耳石长径与鱼体全长(TL)均呈线性相关,其关系式为:微耳石Dl=0.019 6TL-0.031 0(r=0.961 6,P<0.001,n=218),矢耳石Ds=0.027 6TL-0.043 7(r=0.924 0,P<0.001,n=219),星耳石Da=0.016 6TL-0.004 1(r=0.369 6,P<0.001,n=44)。仔鱼耳石上第一个轮纹在孵出后第2 d形成,生长轮数目与仔鱼日龄(D)呈线性相关,其斜率与1无显著差异,因此生长轮为日轮,其关系式为:微耳石LI=1.006D-1.700 1(r=0.994 2,P<0.001,n=205),矢耳石SI=0.953 8D-0.911 6(r=0.993 5,P<0.001,n=161)。生长过程中矢耳石形状变化较大,星耳石出现时间较晚,而微耳石形状稳定,日轮可读性较好,故更适合作为日轮研究的材料。     

流速对细鳞裂腹鱼游泳行为及能量消耗影响的研究

通过自制密封的鱼类游泳实验装置, 研究了流速对细鳞裂腹鱼游泳行为和能量消耗的影响。结果显示,细鳞裂腹鱼的摆尾频率随游泳速度的变化有明显的变化规律, 摆尾频率随着流速的增加而显著性的增加,而摆尾幅度有减小趋势, 差异性不显著。结果还表明, (26±1) ℃时, (10.60±0.54) cm 细鳞裂腹鱼的相对临界游泳速度为(11.5±0.5) BL/s, 绝对临界游泳速度为(110.28±2.02) cm/s。测定的相对临界流速较其他的鲤科鱼大,是对生存水流环境(流速0.5—1.5m/s)适应性的表现。这一结果表明鱼类的游泳能力是能够训练的。运动代谢率与相对流速的关系为, AMR = 93.08e(0.307v) + 314.33, R2= 0.994; 单位距离能耗与流速的指数关系为COT =28e (-1.03V) +6.05, R2= 0.998。流速达到8 BL/s 时, 裂腹鱼耗氧率开始下降, 从流速7 BL/s 时, (1245.57±90.97 )mg O2/(kg·h)最大, 下降到(978.78±189.38) mg O2/(kg·h)。1—7 BL/s 流速范围内, 裂腹鱼单位时间内的耗氧率随着游泳速度的增加而增加, 而且随着游泳速度的增加, 单位距离能耗(COT)逐渐减少, 最小能耗在6 倍体长流速, 0.68 m/s 时, 为(6.00±1.57) J/(kg·m), 其能量利用效率最大。       

不同流速下红鳍银鲫趋流行为与耗氧率的变化

在28℃水温下,使用特制的鱼类游泳行为和活动代谢同步测定装置对红鳍银鲫(Barbodes schwanenfeldi)幼鱼在0 m/s、0.1 m/s、0.3 m/s、0.5 m/s 4种流速条件下的趋流行为和耗氧率进行了同步测定和统计分析.结果表明: 红鳍银鲫在静水下的游泳活动表现出随机而无特定的方向性,当流速达到0.3 m/s以上时则呈现很强的趋流性.和静水对照组相比,三个流速实验组在各个时间段的趋流率、摆尾频率和耗氧率均显著上升,其中多数时间段以0.3 m/s流速组最大,0.5 m/s流速组次之.低流速组(0,0.1 m/s)三个指标在90 min内随时间变化不显著,而高流速组(0.3,0.5 m/s)随时间变化明显.红鳍银鲫在90 min各个时间段摆尾频率(Tail beat frequency)与趋流率(Rheotaxis frequency)均呈显著的线性相关,其回归关系式为:RF=a bTBF,a值在41.13-55.02、b值在8.0 7-11.42、R在0.69-0.95之间;摆尾频率和耗氧率(Oxygen consumption rate)同样呈 显著的线性相关,其回归关系式为:OCR=a bTBF,a值在77.38-137.42, b值在10.85-59.36,R在0.87-0.96之间.0.3 m/s流速下红鳍银鲫趋流率、摆尾频率和耗氧率24 h的变化规律为:实验开始时三个指标均随时间延长而逐渐增大,在3 h达到最大值,然后开始下降并长时间维持在一定水平上,其中耗氧率在最初3 h的增幅显著大于趋流率和摆尾频率,而随后回落的幅度却小于前两者.在较高流速下,红鳍银鲫幼鱼不能长期保持趋流状态和维持较高的代谢水平     

Synthesis and structure-activity relationship of a novel sulfone series of TNF-alpha converting enzyme inhibitors

Replacement of the amide functionality in IM491 (N-hydroxy-(5S,6S)-1-methyl-6-[[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl]5-piperidinecarboxamide) with a sulfonyl group led to a new series of alpha,beta-cyclic and beta,beta-cyclic gamma-sulfonyl hydroxamic acids, which were potent TNF-alpha converting enzyme (TACE) inhibitors. Among them, inhibitor 4b (N-hydroxy-(4S,5S)-1-methyl-5-[[4-(2-methyl-4-quinolinylmethoxy)phenyl]sulfonylmethyl]-4-pyrrolidinecarboxamide) exhibited IC50 values of < 1 nM and 180 nM in porcine TACE (pTACE) and cell assays, respectively, with excellent selectivity over MMP-1, -2, -9 and -13 and was orally bioavailable with an F value of 46% in mice.