Actuation of single downstream nodes in growth factor network steers immune cell migration

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Structure of the Human TELO2-TTI1-TTI2 Complex

Phosphatidylinositol 3-kinase-related protein kinases (PIKKs) play critical roles in various metabolic pathways related to cell proliferation and survival. The TELO2-TTI1-TTI2 (TTT) complex has been proposed to recognize newly synthesized PIKKs and to deliver them to the R2TP complex (RUVBL1-RUVBL2-RPAP3-PIH1D1) and the heat shock protein 90 chaperone, thereby supporting their folding and assembly. Here, we determined the cryo-EM structure of the TTT complex at an average resolution of 4.2 Å. We describe the full-length structures of TTI1 and TELO2, and a partial structure of TTI2. All three proteins form elongated helical repeat structures. TTI1 provides a platform on which TELO2 and TTI2 bind to its central region and C-terminal end, respectively. The TELO2 C-terminal domain (CTD) is required for the interaction with TTI1 and recruitment of Ataxia-telangiectasia mutated (ATM). The N- and C-terminal segments of TTI1 recognize the FRAP-ATM-TRRAP (FAT) domain and the N-terminal HEAT repeats of ATM, respectively. The TELO2 CTD and TTI1 N- and C-terminal segments are required for cell survival in response to ionizing radiation.     

典型矿区植被覆盖度时空分布特征及影响因素

植被状况可以直接或间接地反映采煤对生态环境的影响。以长河井工煤矿、离柳井工煤矿、平朔露天煤矿3个典型矿区为研究区域。以Landsat数据为数据源，基于地形调节植被指数的像元二分模型提取植被覆盖度；采用趋势分析、线性回归斜率、稳定性分析方法，分析了3个典型矿区2001-2016年植被覆盖度的时空变化特征；运用"以时间换空间"的方法，采用相关分析方法对植被覆盖度变化的自然影响因素进行了分析。结果表明：（1）近16年3个典型矿区植被覆盖度呈增加趋势，长河、离柳、平朔矿区的增长速率分别为0.09%/10 a、0.10%/10 a、0.08%/10 a（P > 0.05）。（2）空间上，长河、离柳、平朔矿区植被覆盖度变化不明显比例分别占到66.63%，59.90%，62.25%，呈增加趋势的比例仅分别占28.14%、32.55%、27.81%，而呈减少趋势的比例分别占到5.23%、7.55%、9.94%。长河矿区明显改善的区域位于自然植被和耕作区的北部和东北部，离柳矿区明显改善的区域位于以低植被覆盖度为主的北部，平朔矿区明显改善的区域位于复垦的中西部。（3）不区分植被类型时，3个矿区的植被覆盖度变化与高程、高程与温度的交互作用表现出显著相关性（P < 0.01），与各自然因素的相关性总体表现为长河 > 离柳 > 平朔矿区；区分植被类型时，草地与坡度的相关性不显著（P > 0.05），与降雨量、高程存在显著正相关（P < 0.05）；灌木林与温度相关性不显著，与高程和降雨量的交互作用存在显著正相关；旱地与高程、高程与温度的交互作用存在显著相关性；疏林地与坡向、降雨量与坡向坡度的交互作用均没有表现出相关性；有林地与高程降雨量的交互作用表现出显著正相关性。探讨不同植被类型对自然因素的响应，可为矿区植被结构的选择，矿区复垦提供参考依据。     

Focus: Addiction: Relapse Prevention and the Five Rules of Recovery

There are four main ideas in relapse prevention. First, relapse is a gradual process with distinct stages. The goal of treatment is to help individuals recognize the early stages, in which the chances of success are greatest. Second, recovery is a process of personal growth with developmental milestones. Each stage of recovery has its own risks of relapse. Third, the main tools of relapse prevention are cognitive therapy and mind-body relaxation, which are used to develop healthy coping skills. Fourth, most relapses can be explained in terms of a few basic rules. Educating clients in these rules can help them focus on what is important: 1) change your life (recovery involves creating a new life where it is easier to not use); 2) be completely honest; 3) ask for help; 4) practice self-care; and 5) don’t bend the rules.     

Prodrug oncrasin-266 improves the stability,pharmacokinetics, and safety of NSC-743380

Through synthetic lethality screening of isogenic cell lines with and without the oncogenic KRAS gene and through lead compound optimization, we recently developed a novel anticancer agent designated NSC-743380 (oncrasin-72) that has promising in vitro and in vivo anticancer activity in a subset of cancer cell lines, including KRAS-mutant cancer cells. However, NSC-743380 tends to form dimers, which dramatically reduces its anticancer activity. To improve the physicochemical properties of NSC-743380, we synthesized a prodrug of NSC-743380, designated oncrasin-266, by modifying NSC-743380 with cyclohexylacetic acid and evaluated its in vitro and in vivo properties. Oncrasin-266 spontaneously hydrolyzed in phosphate-buffered saline in a time-dependent manner and was more stable than NSC-743380 in powder or stock solutions. In vivo administration of oncrasin-266 in mice led to the release of NSC-743380 which improved the pharmacokinetics of NSC-743380. Tissue distribution analysis revealed that oncrasin-266 was deposited in liver, whereas released NSC-743380 was detected in liver, lung, kidney, and subcutaneous tumor. Oncrasin-266 was better tolerated in mice at a higher dose level treatment (150–300 mg/kg, ip) than the parent agent was, suggesting that the prodrug reduced the acute toxicity of the parent agent. Our results demonstrated that the prodrug strategy could improve the stability, pharmacokinetic properties, and safety of NSC-743380.     

Epilogue — Demography and anthropology

As a conclusion, this paper reviews briefly the content of the volume. The wealth of demographic data has not been adequately exploited in anthropology; this is why this publication is valuable in showing attempts to apply demographic data in a variety of anthropological problems. This symposium has explored many interesting points which we recall here. Yet it has also opened up a whole range of further questions on the material presented as well as in this broad field. Several directions of research could be developed, for instance, testing among human populations, over long periods, the ecological thoughts of ecosystems evolving as a cascade of instabilities, rather than a succession of equilibrium states. Let us also recall the pervasive nature of demographic facts in topics such as the energy cycle or the genetic structure and evolution of human populations.     

Relative growth rate correlates negatively with pathogen resistance in radish: the role of plant chemistry

Plant growth rate has frequently been associated with herbivore defence: a large investment in quantitative defence compounds occurs at the expense of growth. We tested whether such a relationship also holds for growth rate and pathogen resistance. For 15 radish (Raphanus sativus L.) cultivars, we determined the potential growth rate and the resistance to fungal wilt disease caused by Fusarium oxysporum. We subsequently aimed to explain a putative negative relationship between growth rate and resistance based on plant chemical composition. Both growth rate and resistance level varied greatly among cultivars. Moreover, there was a strong negative correlation between growth rate and resistance, i.e. there are costs associated with a high resistance level. Roots of slow-growing, resistant cultivars have a higher biomass density. Using pyrolysis mass spectrometry. we part1y explained variation in both growth rate and resistance in terms of the same change in chemical composition. Leaves of slow-growing, resistant cultivars contained more cell wall material. Surprisingly, roots of slow-growing, highly resistant cultivars contained significantly less cell wall material, and more cytoplasmic elements (proteins). We speculate that this higher protein concentration is related to high construction and turn-over costs and high metabolic activity. The latter in turn is thought to be responsible for a rapid and adequate resistance reaction, in which phenols may be involved.     

The different effects of PEG 6000 and NaCI on leaf development are associated with differential inhibition of root water transport

The inhibitory effects of PEG on whole-plant growth can exceed the effects of other osmolytes such as NaCI, and this has been ascribed to toxic contaminants, or to reduced oxygen availability in PEG solutions. We investigated another possibility, namely that PEG has an additional inhibitory effect on root water transport which in turn affects leaf development. The effects on first-leaf growth of applications of PEG 6000 or isoosmotic NaCI to the roots were determined using hydroponically grown maize (Zea mays L.) seedlings. Leaf growth rates were inhibited within minutes of PEG application to the roots and remained inhibited for days. The inhibitory effects on growth of NaCI, and also of KCl and mannitol, were much smaller. The comparative effects of NaCI and PEG on root water transport were determined by assaying pressurized flow through excised roots. PEG induced a 7-fold greater inhibition of flow through live roots than NaCI. Killing of the roots by heat treatment, to reduce cell membrane resistances to solute penetration, nearly doubled the flow rate for roots in NaCI, but not for roots in PEG. We suggest that the greater viscosity of PEG solutions, as compared with NaCI, may be a primary factor contributing to the additional inhibition of water flow through live and killed roots. PEG did not have additional effects on leaf turgor but had a 3 times greater inhibitory effect than NaCI on the irreversible extensibility of the leaves and induced 16 times more leaf accumulation of the growth inhibitory stress hormone abscisic acid (ABA). We conclude that greater inhibition of root water transport by PEG 6000, as compared with NaCI, leads to additional reductions in extensibility, additional ABA accumulation, and a greater inhibition of leaf growth.     

Divergent growth of Norway spruce on Babia Góra Mountain in the western Carpathians

Growth divergence – i.e. the expression of divergent growth trends of neighboring trees – has certain implications for dendrochronological research, for instance in the context of climate reconstructions but also in terms of estimating net ecosystem productivity. Thus, understanding the underlying mechanisms is essential to extend our fundamental dendroecological knowledge. In this context, the Picea genus plays an important role since several of its species were reported to exhibit growth divergence. Here, we investigate a well sampled Norway spruce (Picea abies (L.) Karst) data set for growth divergence comprising ring-width and Blue Intensity measurements from seven sites on Babia Góra Mountain, at the border between Poland and Slovakia. By means of Principal Component Gradient Analysis, inter-series correlations, and climate growth relationships, we are able to show that I) Norway spruce on Babia Góra expressed growth divergence since the 1970s, II) the definition of groups increased the strength of population signals and the stability of climate-growth relationships, and III) Blue Intensity appeared as a more robust proxy for environmental conditions. We discuss soil heterogeneity, genetics, and air pollution as possible underlying mechanisms, thereby indicating further research avenues to obtain a better understanding of growth divergence.