A novel Golgi mannosidase inhibitor: Molecular design,synthesis, enzyme inhibition,and inhibition of spheroid formation

Effective chemotherapy for solid cancers is challenging due to a limitation in permeation that prevents anticancer drugs from reaching the center of the tumor, therefore unable to limit cancer cell growth. To circumvent this issue, we planned to apply the drugs directly at the center by first collapsing the outer structure. For this, we focused on cell–cell communication (CCC) between N-glycans and proteins at the tumor cell surface. Mature N-glycans establish CCC; however, CCC is hindered when numerous immature N-glycans are present at the cell surface. Inhibition of Golgi mannosidases (GMs) results in the transport of immature N-glycans to the cell surface. This can be employed to disrupt CCC. Here, we describe the molecular design and synthesis of an improved GM inhibitor with a non-sugar mimic scaffold that was screened from a compound library. The synthesized compounds were tested for enzyme inhibition ability and inhibition of spheroid formation using cell-based methods. Most of the compounds designed and synthesized exhibited GM inhibition at the cellular level. Of those, AR524 had higher inhibitory activity than a known GM inhibitor, kifunensine. Moreover, AR524 inhibited spheroid formation of human malignant cells at low concentration (10 µM), based on the disruption of CCC by GM inhibition.     

Individualistic responses of forest herb traits to environmental change

• Intraspecific trait variation (ITV; i.e. variability in mean and/or distribution of plant attribute values within species) can occur in response to multiple drivers. Environmental change and land‐use legacies could directly alter trait values within species but could also affect them indirectly through changes in vegetation cover. Increasing variability in environmental conditions could lead to more ITV, but responses might differ among species. Disentangling these drivers on ITV is necessary to accurately predict plant community responses to global change.
• We planted herb communities into forest soils with and without a recent history of agriculture. Soils were collected across temperate European regions, while the 15 selected herb species had different colonizing abilities and affinities to forest habitat. These mesocosms (384) were exposed to two‐level full‐factorial treatments of warming, nitrogen addition and illumination. We measured plant height and specific leaf area (SLA).
• For the majority of species, mean plant height increased as vegetation cover increased in response to light addition, warming and agricultural legacy. The coefficient of variation (CV) for height was larger in fast‐colonizing species. Mean SLA for vernal species increased with warming, while light addition generally decreased mean SLA for shade‐tolerant species. Interactions between treatments were not important predictors.
• Environmental change treatments influenced ITV, either via increasing vegetation cover or by affecting trait values directly. Species’ ITV was individualistic, i.e. species responded to different single resource and condition manipulations that benefited their growth in the short term. These individual responses could be important for altered community organization after a prolonged period.

     

基于物候特征的盐渍化信息数据挖掘研究

盐渍化是影响植被和作物长势的重要因素,精确反演盐渍化的时空分布信息至关重要。基于MOD13A1-NDVI数据反演生长季开始日期(SOS)、生长季结束日期(EOS)、生长季长度(LEN)等物候参数和计算出能高精度反演盐渍化空间分布的多种植被指数、盐分指数、地形指数、干旱指数等参数后作为BP-ANN人工神经网络的输入因子来反演盐渍化信息,同时按照植被类型和地貌类型进行分区来反演盐渍化信息,以探讨盐渍化受植被和地貌类型的影响。主要结论如下:(1)盐渍化的形成受多种因素的影响,与物候参数大多呈非线性关系,不能单纯的以某拟合公式来进行表达,需要借助人工神经网络超强的非线性拟合能力来反演盐渍化信息。(2)通过深入挖掘植被物候信息,在融入物候参数后的反演精度显著提高。可决系数R2从0.68(非物候参数)增加到0.79(包括物候参数),但是需要加入地形、影像数据和土壤水分等方面的信息来更加精确的反演盐渍化信息。生物累积量指标LSI(Large seasonal integral)和SSI(Small seasonal integral)能够很好的表征盐渍化的信息。(3)划分植被类型后的盐渍化提取精度进一步提高,可决系数R~2达到了0.88。(4)以地貌特征作为类型分区后,反演结果的R~2达到了0.85,精度较高,比以植被类型作为分区的精度略小。高程较低区域的盐渍化现象普遍较重,盐渍化程度受到地形和地貌因素的影响显著。(5)农用地区域多为非盐渍化和轻度盐渍化地,稀疏植被区多为重盐渍化地。研究区的非盐渍化和轻盐渍化地、中盐渍化地和重度盐渍化地比例分别为53.42%,13.71%,32.87%。以上的研究结果提出了一种融合物候信息和非物候参数来反演盐渍化信息的方法,进行深入的协同植被物候监测盐渍化信息方面的数据挖掘,在融入了物候参数后,盐渍化的预测精度显著提高。     

A comparison of direct and indirect methods for measuring leaf and surface areas of individual bushes

Indirect estimates of leaf area from measurements with three commercially available instruments (DEMON, LAI-2000 and Sunfleck Ceptometer) were compared with directly measured areas of individual Retama sphaerocarpa bushes. The three indirect methods gave good estimates of the total surface area of individual bushes. For the DEMON, the method of log-linear averaging of transmitted radiation gave estimates closer to directly measured surface area than the method of averaging transmission linearly. For the LAI-2000, estimated surface area index multiplied by canopy projected area gave the best agreement with directly measured values. For measurements with the Sunfleck Ceptometer, values of surface area estimated from the transmission of photosynthetic quantum flux density, without correcting for diffuse radiation, gave the best agreement with directly measured values. Surface areas estimated by the three instruments were not significantly different from directly measured total (leaf + branch + stem) surface areas. Leaf surface area could be calculated from estimated total surface area minus directly measured branch surface area. Measured branch surface area was linearly related to canopy projected area.     

不同耕作方式对陇中旱农区春小麦和豌豆根系空间分布及产量的影响

依托陇中旱农区长期的保护性耕作定位试验,对不同耕作方式下春小麦和豌豆根系空间分布特征及作物产量进行研究,以探索耕作措施影响作物产量的机制.结果表明: 随着生育期的推进,春小麦和豌豆的总根长、根表面积呈先增后减的趋势,开花期达到最大;春小麦根系苗期以0～10 cm最多,花期、成熟期10～30 cm最多;而豌豆根系苗期和成熟期均以0～10 cm最多,花期10～30 cm最多.免耕秸秆覆盖和免耕覆膜增加了根长和根表面积,春小麦和豌豆各生育时期的根长较传统耕作增加了35.9%～92.6%,根表面积增加了43.2%～162.4%.免耕秸秆覆盖和免耕覆膜优化了春小麦和豌豆根系分布,与传统耕作相比,增加了春小麦和豌豆苗期0～10 cm土层根长和根表面积分布比例,花期和成熟期深层次根系分布也显著增加,免耕秸秆覆盖在开花期30～80 cm土层根长和根表面积的分布比例分别比传统耕作提高了3.3%和9.7%.春小麦各生育期的总根长、根表面积与产量呈显著正相关,豌豆各生育期的总根长与豌豆产量呈极显著正相关.免耕秸秆覆盖和免耕覆膜较传统耕作春小麦和豌豆产量增加23.4%～38.7%,水分利用效率提高了13.7%～28.5%.在陇中旱农区,免耕秸秆覆盖和免耕覆膜可以增加作物根长和根表面积,优化了根系在土壤中的空间分布,增强作物根层吸收能力,从而提高作物产量和水分高效利用.     

Analysis of the binding loops configuration and surface adaptation of different crystallized single‐domain antibodies in response to various antigens

Monoclonal antibodies have revolutionized the biomedical field through their ubiquitous utilization in different diagnostics and therapeutic applications. Despite this widespread use, their large size and structural complexity have limited their versatility in specific applications. The antibody variable region that is responsible for binding antigen is embodied within domains that can be rescued individually as single‐domain antibody (sdAb) fragments. Because of the unique characteristics of sdAbs, such as low molecular weight, high physicochemical stability, and the ability to bind antigens inaccessible to conventional antibodies, they represent a viable alternative to full‐length antibodies. Consequently, 149 crystal structures of sdAbs, originating from human (VH), camelids (VHH), or sharks (VNAR), were retrieved from the Protein Data Bank, and their structures were compared. The 3 types of sdAbs displayed complementarity determining regions (CDRs) with different lengths and configurations. CDR3 of the VHH and VNAR domains were dominated by pleated and extended orientations, respectively. Although VNAR showed the smallest average molecular weight and molecular surface area compared with VHH and VH antibodies. However, the solvent accessible surface area measurements of the 3 tested sdAbs types were very similar. All the antihapten VHH antibodies showed pleated CDR3, which were sufficient to create a binding pocket to accommodate haptens (methotrexate and azo dyes) in terms of shape and electrostatic potential. The sdAbs that recognized lysozyme showed more diversity in their CDR3 orientation to enable them to recognize various topographies of lysozyme. Subsequently, the three sdAb classes were different in size and surface area and have shown distinguishable ability to optimize their CDR length and orientation to recognize different antigen classes.     

Acute effects of Amomum villosum Lour. fruit extract on postprandial glycemia and insulin secretion: A single-blind,placebo-controlled,crossover study in healthy subjects

BackgroundAmomum villosum Lour., (Zingiberaceae) an herbaceous plant in the ginger family, has been used to treat various diseases. In a single-blind, randomized, crossover study, we assessed the postprandial blood insulin and blood glucose responses in healthy subjects (n = 40) after the Amomum villosum water extract (AVE) (5 g/person) or a placebo (5 g/person) consumption.MethodsDuring each treatment course, the healthy subject consumed a regular late afternoon meal, followed by fasting for 12 h, and arrived at the clinical study center the next morning. Blood insulin and blood glucose levels were assessed at 0, 30, 60, 90, and 120 min after AVE consumption. Between each treatment, the subjects accomplished one week of a washout period.ResultsThe AVE intake demonstrated a significant (67.26%) decline in postprandial blood glucose AUC_{0–120 min} (incremental area under the curve from 0 to 120 min) versus the placebo (P = 0.011). Furthermore, AVE reduced postprandial blood insulin AUC_{0–120 min} by 59.95% compared to the placebo group (P < 0.003), supporting the blood glucose results.ConclusionThis study revealed that AVE consumption significantly reduced postprandial insulin and glucose levels in healthy individuals, due in part to inhibition of α-glucosidase, and glucose transport.