Input–output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data

The ErbB signaling pathways, which regulate diverse physiological responses such as cell survival, proliferation and motility, have been subjected to extensive molecular analysis. Nonetheless, it remains poorly understood how different ligands induce different responses and how this is affected by oncogenic mutations. To quantify signal flow through ErbB‐activated pathways we have constructed, trained and analyzed a mass action model of immediate‐early signaling involving ErbB1–4 receptors (EGFR, HER2/Neu2, ErbB3 and ErbB4), and the MAPK and PI3K/Akt cascades. We find that parameter sensitivity is strongly dependent on the feature (e.g. ERK or Akt activation) or condition (e.g. EGF or heregulin stimulation) under examination and that this context dependence is informative with respect to mechanisms of signal propagation. Modeling predicts log‐linear amplification so that significant ERK and Akt activation is observed at ligand concentrations far below the K_d for receptor binding. However, MAPK and Akt modules isolated from the ErbB model continue to exhibit switch‐like responses. Thus, key system‐wide features of ErbB signaling arise from nonlinear interaction among signaling elements, the properties of which appear quite different in context and in isolation.     

Further investigation on the lateral and transversal proton currents at the thylakoid membrane level by hydrogen-deuterium exchange

Energetically-coupled processes (electron flow, proton uptake and correlated pH gradient) were investigated on envelope-free chloroplasts of lettuce suspended in ¹H₂O or ²H₂O media. Study of the light-intensity and temperature dependencies of these phenomena led to the following observations: 1. At neutral pH, ²H₂O diminishes the transmembrane H⁺ gradient in strong light (chain Photosystem II + Photosystem I) but not in low light; the total H⁺ uptake is increased at all light intensities: the buffering capacity of the inner compartment is increased in heavy water, possibly through enhancement of interactions between membranous titrable groups and the aqueous phase. 2. ²H₂O does not affect the photochemical events of the redox chain, whatever the electron pathway (PSII, PSI or PSII + PSI): only thermal steps are inhibited. The diminution of the apparent quantum yield, sometimes observed, may be ascribed to the dual site of action of the artificial redox carrier (ferricyanide) then used. 3. ²H₂O does not modify the activation energy of the limiting step of the electron flow (PSII + PSI) in uncoupled (44 vs. 47 kJ · mol^?1) or — but less clearly — in coupled, i.e., ‘basal’, state (55 vs. 59 kJ · mol^?1). ²H₂O does not either change the temperature of the phase transition of the membrane (17°C) for the uncoupled flow. However, a low-temperature transition, observed only for the coupled chain, is slightly increased by ²H₂O; this thermal transition is attributed to the freezing of some bound water near the plastoquinone pool. 4. Δp²H is smaller than Δp¹H at all temperatures (PSII + PSI chain). ΔpH is quasi-constant from 0°C to 10°C, then decreases when temperature rises. ²H₂O does not change the activation energy of the dark passive H⁺ efflux, which is almost twice that of the coupled electron flow. The phase transition at low temperature suggests that the proton efflux occurs via two parallel pathways, one temperature-dependent and the other temperature-independent. Except for the increase of the internal buffering capacity, the effects of ²H₂O on the membrane conformation seem limited, as shown by the unchanged activation energies of the electron flow and of the H⁺ leakage. The null activation energy observed at low temperature emphasizes the role of the bound water in these processes; however, the different effects of ²H₂O on the transition temperatures indicate that this bound water has different properties when associated with the translocation sites or with the H⁺ leakage ones. This ‘microcompartmentation’ of the membranes is consistent with the concept of lateral pH heterogeneity we have previously suggested (de Kouchkovsky, Y., and Haraux, F. (1981) Biochem. Biophys. Res. Commun. 99, 205–212). The theoretical computations and the experimental results suggest that in the steady state, the internal pH would be several tenths of a ‘unit’ lower near the plastoquinones than near the H⁺ efflux sites (coupling factors); this difference would be increased when ²H₊ replaces ¹H⁺, owing to the lower mobility of the deuteron. It is concluded that local, and not average, pH (and ΔpH) should be considered for the understanding of the energy transduction processes.     

湖北省植被分类的研究 Ⅰ.自然植被

本文论述了湖北植被分类的原则、依据,植被分类的单位和命名,并拟订了5级分类系统,以植被型、群系、群丛作为主要分类单位。根据多年来全省野外调查资料分析,湖北植被划分为8个植被型组、13个植被型、66个群系组、152个群系、10个群丛。     

Monoaminhaltige Strukturen im Zentralnervensystem der Trichoptera (Insecta) Teil II

Zusammenfassung Mit Hilfe der fluoreszenzmikroskopischen Methode nach Falck und Hillarp wurden die monoaminhaltigen Strukturen im Zentralnervensystem einiger Trichopteren untersucht (vgl. Klemm, 1968). Im Protocerebrum können vier Gruppen von katecholamin-haltigen Zellkörpern unterschieden werden. Eine weitere unregelmäßig darstellbare Gruppe von globulösen Perikarya liegt im Lobus opticus. Fluoreszierende Varikositäten durchsetzen locker das Cerebralganglion und sind in folgenden Neuropilstrukturen konzentriert: Medulla, Lobula, Corpus centrale, Nodulus, Corpus ventrale, - und -Lobus und Lobus communis. Letzterer verbindet den - und den -Lobus mit dem nicht fluoreszierenden Pedunculus. In der Lamina, in der accessorischen Medulla, in der Pons cerebralis, im Tuberculum opticum, im Tractus olfactorio-globularis, im Pedunculus, im Stielglomerulus und in den Globulizellen ließen sich keine Katecholamine nachweisen. Zwischen dem monoaminhaltigen Lobus communis und dem nicht fluoreszierenden Pedunculus besteht eine scharfe Grenze. Fluoreszierende variköse Fasern und einzelne fluoreszierende Perikarya befinden sich im Deuto- und Tritocerebrum. Zwei fluoreszierende Bahnen können im Cerebralganglion unterschieden werden: 1. Stratum caudale, 2. Tractus ventralis. Letzterer beginnt mit seiner Pars anterior und posterior im dorsalen fluoreszierenden Neuropil des Protocerebrum. Die beiden Teile laufen frontal und caudal um den Zentralkörper herum und vereinigen sich unterhalb des Zentralkörpers in der Pars communis. Von hier aus zieht der paarige Tractus ventralis bis in das Tritocerebrum. Die Frage einer Homologisierung dieser Bahnen wird diskutiert.Ähnlich wie im Ganglion suboesophageale sind in den drei thorakalen und fünf separaten abdominalen Ganglien zwei Paar fluoreszierender Zellkörper vorhanden, in denen Dopamin mikrospektrofluorimetrisch festgestellt werden konnte. Ein Paar dieser Zellen liegt caudoventral, das andere dorso-median bis dorso-caudal. Ihre Zellfortsätze und Abzweigungen werden beschrieben. In einzelnen Fällen konnte noch ein zweites dorsales Paar fluoreszierender Perikarya sichtbar gemacht werden. Das letzte Ganglion der Bauchkette setzt sich aus zwei bis drei Gangliomeren zusammen. Die Anzahl ihrer fluoreszierenden Perikarya ist reduziert. Das Neuropil der Ganglien im Bauchmark ist von monoaminhaltigen Fasern durchsetzt, wobei sich in der dorsalen Hälfte mehr fluoreszierendes Neuropil befindet als in der ventralen. Lateral in den Ganglien sind die monoaminhaltigen varikösen Fasern vorwiegend dorsoventrad angeordnet. Im medianen Teil laufen sie in Längsrichtung, verzweigen sich und setzen sich in die Konnektive fort und verbinden die katecholaminhaltigen Neuropilbereiche der einzelnen Ganglien miteinander.

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Monoamine-containing structures in the central nervous system in Trichoptera (Insecta). Part II

Summary The distribution of monoamine-containing structures in the central nervous system of Trichoptera has been investigated with the histochemical fluorescence method of Falck and Hillarp (cf. also Klemm, 1968). In the protocerebrum, four groups of catecholamine containing perikarya can be distinguished. Another group of irregularly appearing cell bodies is situated in the optical lobe. Fluorescent varicosities occur scattered throughout the cerebral ganglion, being concentrated in the following neuropile areas: In the medulla, the lobula, the corpus centrale, the noduli, the corpora ventralia, and the - and -lobes, as well as in the lobus communis where the - and -lobes join the non-fluorescent pedunculus. In the lamina, the accessory medulla, the pons cerebralis, the tuberculum opticum, the tractus olfactorio-globularis, the pedunculus including its glomerular region, and the globuli-cells, no catecholamines are detectable. There is a sharp borderline between the monoamine-containing lobus communis and the non-fluorescent pedunculus. Fluorescent varicose fibres and single fluorescent perikarya occur in the Deuto- and Tritocerebrum. Two fluorescent tracts can be distinguished in the cerebral ganglion: 1. Stratum caudale. 2. Tractus ventralis. The pars anterior and pars posterior of the tractus ventralis begin in the dorsal fluorescent neuropile of the cerebral ganglion and join underneath the central body into their pars communis. From this, it can be traced as tractus ventralis into the tritocerebrum. The possible homologies of these tracts are discussed. Similar to the ganglion suboesophageale, the three thoracal and the five separate abdominal ganglia contain two paires of fluorescent cell bodies. Microspectrofluorometrically a content of dopamine in these cells could be established. One pair lies caudoventrally. The two other cell bodies are situated dorso-medially to dorso-caudally; their position varies notably, especially in the abdominal ganglia. The cell process and its arborisations are described. Occasionally a second dorsal cellpair could be observed. The last ganglion of the abdominal chain is composed of at least two gangliomeres with a reduced number of fluorescent perikarya. The neuropile of the thoracal- and abdominal ganglia is penetrated by monoamine-containing fibres, with a predominance in the dorsal half. In the ganglia, the fluorescent varicose fibres are mainly oriented dorso-ventrally in the lateral part and longitudinally in the medial part, where they branch and continue into the connectives. In this way, the catecholamine-containing neuropiles of adjacent ganglia are connected to each other.

Die vorliegende Arbeit wurde unterstützt durch The Swedish Medical Research Council (No. B70-14X-56-06 und B70-14X-05).     

Recent Technologies for Genetic Code Expansion and their Implications on Synthetic Biology Applications

Genetic code expansion (GCE) enables the site-specific incorporation of non-canonical amino acids as novel building blocks for the investigation and manipulation of proteins. The advancement of genetic code expansion has been benefited from the development of synthetic biology, while genetic code expansion also helps to create more synthetic biology tools. In this review, we summarize recent advances in genetic code expansion brought by synthetic biology progresses, including engineering of the translation machinery, genome-wide codon reassignment, and the biosynthesis of non-canonical amino acids. We highlight the emerging application of this technology in construction of new synthetic biology parts, circuits, chassis, and products.     

Environmental lead reduces the resilience of bald eagle populations

Bald eagles (Haliaeetus leucocephalus) are considered a recovery success in the United States after rebounding from near extirpation due to widespread use of the insecticide dichlorodiphenyltrichloroethane (DDT) in the twentieth century. Although abundances of bald eagles have increased since DDT was banned, other contaminants have remained in the environment with unknown influence on eagle population trends. Ingestion of spent lead (Pb) ammunition, the source of Pb most available to eagles and other scavengers in the United States, is known to kill individual eagles, but the influence of the contaminant on overall population dynamics remains unclear, resulting in longstanding controversy over the continued legality of the use of Pb in terrestrial hunting ammunition. We hypothesized that mortalities from the ingestion of Pb reduced the long-term growth rate and resiliency of bald eagles in the northeast United States over the last 3 decades. We used Holling's definition of resilience (the ability of a system to absorb changes of state variables, driving variables, and parameters and still persist) to quantify how reduction in survival from Pb-associated mortalities reduced the likelihood of population persistence. We used a population matrix model and necropsy records gathered between 1990 and 2018 from a 7-state area to compare population dynamics under current versus hypothetical Pb-reduced and Pb-free scenarios. Despite a robust increase in eagle abundances in the northeast United States over that period, we estimated that deaths arising from ingestion of Pb was associated with a 4.2% (females) and 6.3% (males) reduction in the asymptotic long-term growth rate (lambda). Comparison between real (current) and counterfactual (Pb-reduced and Pb-free) population dynamics indicated that the deaths from acute Pb poisoning were additive because the mortality events were associated with marked reduction in annual survival performance of hatchlings and reproductive females. These shifts in survival performance were further associated with a reduction in resilience for hatchling (95.4%) and breeding (81.6%) female eagles. Counterintuitively, the current conditions produced an increase in resilience (68.9%) for immature and non-breeding female eagles over hypothetical Pb-free conditions, suggesting that the population of eagles in the northeast United States reorganized (in a population dynamics sense) to ensure population expansion despite additive mortalities associated with Pb. This study can be used by state and federal wildlife managers or non-governmental organizations to inform policy surrounding the use of lead ammunition or to educate hunters on the population-scale effects of their ammunition choices.     

高效棉酚降解枯草芽孢杆菌M-4菌株的常压室温等离子体诱变及发酵工艺优化

【背景】棉粕中游离棉酚的存在制约了棉粕作为饲料蛋白源的利用,棉酚的微生物降解问题成为研究热点。本实验室前期发现枯草芽孢杆菌(Bacillus subtilis) M-4菌株具有较强的降解棉酚能力,而且已经应用于棉粕脱毒工业。【目的】进一步提高枯草芽孢杆菌M-4菌株降解棉粕中棉酚的能力,扩大棉粕在养殖业的应用领域。【方法】采用常压室温等离子体诱变(atmospheric and room temperature plasma,ARTP)技术对菌株M-4进行诱变,以液体培养条件下的棉酚降解率为初筛指标,筛选获得正向突变株。以棉粕固体发酵条件下的棉酚降解率为复筛指标,测定初筛获得的正向突变株实际降解棉粕中游离棉酚的能力。以棉酚残存量和棉酚降解率为检测指标,采用单因素试验优化固体条件下棉粕发酵条件,获得突变株发酵棉粕的最适工艺参数。【结果】初筛获得正向突变株19株。复筛得到一株高效的突变株MY-4-17,在棉粕固体发酵条件下其棉酚降解率高达97.15%,比菌株M-4的棉酚降解率提高了2.55%。经过5次传代培养,突变株MY-4-17的遗传稳定性良好。突变株MY-4-17发酵棉粕的最适工艺参数为...     

The effects of electromyography-assisted modelling in estimating musculotendon forces during gait in children with cerebral palsy

Neuro-musculoskeletal modelling can provide insight into the aberrant muscle function during walking in those suffering cerebral palsy (CP). However, such modelling employs optimization to estimate muscle activation that may not account for disturbed motor control and muscle weakness in CP. This study evaluated different forms of neuro-musculoskeletal model personalization and optimization to estimate musculotendon forces during gait of nine children with CP (GMFCS I-II) and nine typically developing (TD) children. Data collection included 3D-kinematics, ground reaction forces, and electromyography (EMG) of eight lower limb muscles. Four different optimization methods estimated muscle activation and musculotendon forces of a scaled-generic musculoskeletal model for each child walking, i.e. (i) static optimization that minimized summed-excitation squared; (ii) static optimization with maximum isometric muscle forces scaled to body mass; (iii) an EMG-assisted approach using optimization to minimize summed-excitation squared while reducing tracking errors of experimental EMG-linear envelopes and joint moments; and (iv) EMG-assisted with musculotendon model parameters first personalized by calibration. Both static optimization approaches showed a relatively low model performance compared to EMG envelopes. EMG-assisted approaches performed much better, especially in CP, with only a minor mismatch in joint moments. Calibration did not affect model performance significantly, however it did affect musculotendon forces, especially in CP. A model more consistent with experimental measures is more likely to yield more physiologically representative results. Therefore, this study highlights the importance of calibrated EMG-assisted modelling when estimating musculotendon forces in TD children and even more so in children with CP.     

A new vitrification device that absorbs excess vitrification solution adaptable to a closed system for the cryopreservation of mouse embryos

Several closed vitrification devices that avoid contact with liquid nitrogen have been reported. Recently, based on the Kitasato Vitrification System (KVS), we developed the Closed-KVS, which is a closed vitrification device. The KVS is an open vitrification device that can absorb excess vitrification solution. In this study, we performed two experiments to evaluate the efficacy of the Closed-KVS as a vitrification device for the cryopreservation of mouse embryos at the blastocyst and two-cell stage. In the first experiment, the blastocysts were vitrified using either the Closed-KVS or the KVS (control device). The survival, re-expansion, and hatching rates were not significantly different between embryos vitrified using the Closed-KVS and those vitrified using the KVS. In the second experiment, we evaluated the embryonic development of the two-cell stage embryos vitrified using the Closed-KVS. There were no significant differences in the survival, blastocyst formation, or hatching rates between vitrified or non-vitrified embryos. Additionally, we evaluated the cooling and warming rates of these devices using a numerical simulation method. The cooling rates of the Closed-KVS were similar regardless of whether the outer cap was pre-cooled and were lower than those of the KVS. However, the warming rates of the Closed-KVS (irrespective of cap pre-cooling) were the same as those of the KVS (612,000 °C/min). In summary, the Closed-KVS is a novel closed vitrification device for the cryopreservation of mouse embryos at the blastocyst and two-cell stage.     

Quantifying nutrient inputs by gulls to a fluctuating lake,aided by movement ecology methods

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