Molecular determinants of drug-specific sensitivity for epidermal growth factor receptor (EGFR) exon 19 and 20 mutants in non-small cell lung cancer.

We hypothesized that aberrations activating epidermal growth factor receptor (EGFR) via dimerization would be more sensitive to anti-dimerization agents (e.g., cetuximab). EGFR exon 19 abnormalities (L747_A750del; deletes amino acids LREA) respond to reversible EGFR kinase inhibitors (TKIs). Exon 20 in-frame insertions and/or duplications (codons 767 to 774) and T790M mutations are clinically resistant to reversible/some irreversible TKIs. Their impact on protein function/therapeutic actionability are not fully elucidated.In our study, the index patient with non-small cell lung cancer (NSCLC) harbored EGFR D770_P772del_insKG (exon 20). A twenty patient trial (NSCLC cohort) (cetuximab-based regimen) included two participants with EGFR TKI-resistant mutations ((i) exon 20 D770>GY; and (ii) exon 19 LREA plus exon 20 T790M mutations). Structural modeling predicted that EGFR exon 20 anomalies (D770_P772del_insKG and D770>GY), but not T790M mutations, stabilize the active dimer configuration by increasing the interaction between the kinase domains, hence sensitizing to an agent preventing dimerization. Consistent with predictions, the two patients harboring D770_P772del_insKG and D770>GY, respectively, responded to an EGFR antibody (cetuximab)-based regimen; the T790M-bearing patient showed no response to cetuximab combined with erlotinib. In silico modeling merits investigation of its ability to optimize therapeutic selection based on structural/functional implications of different aberrations within the same gene

Model reduction in computational homogenization for transient heat conduction

International audienceThis paper presents a computationally efficient homogenization method for transient heat conduction problems. The notion of relaxed separation of scales is introduced and the homogenization framework is derived. Under the assumptions of linearity and relaxed separation of scales, the microscopic solution is decomposed into a steady-state and a transient part. Static condensation is performed to obtain the global basis for the steady-state response and an eigenvalue problem is solved to obtain a global basis for the transient response. The macroscopic quantities are then extracted by averaging and expressed in terms of the coefficients of the reduced basis. Proof-of-principle simulations are conducted with materials exhibiting high contrast material properties. The proposed homogenization method is compared with the conventional steady-state homogenization and transient computational homogenization methods. Within its applicability limits, the proposed homogenization method is able to accurately capture the microscopic thermal inertial effects with significant computational efficiency

A multi-scale framework to predict damage initiation at martensite/ferrite interface

Martensite/ferrite (M/F) interface damage largely controls failure of dual-phase (DP) steels. In order to predict the failure and assess the ductility of DP steels, accurate models for the M/F interfacial zones are needed. Several M/F interface models have been proposed in the literature, which however do not incorporate the underlying microphysics. It has been recently suggested that (lath) martensite substructure boundary sliding dominates the M/F interface damage initiation and therefore should be taken into account. Considering the computationally infeasibility of direct numerical simulations of statistically representative DP steel microstructures, while explicitly resolving the interface microstructures and the sliding activity, a novel multi-scale approach is developed in this work. Two scales are considered: the DP steel mesostructure consisting of multiple lath martensite islands embedded in a ferrite matrix, and the microscopic M/F interfacial zone unit cell resolving the martensite substructure. Based on the emerging microscopic damage initiation pattern, an effective indicator for the M/F interface damage initiation is determined from the interface microstructural unit cell response, along with the effective sliding in this unit cell. Relating these two effective quantities for different interface microstructural configurations leads to an effective mesoscale model relating the interface damage indicator to the sliding activity of the martensite island in terms of the mesoscopic kinematics. This microphysics-based M/F interface damage indicator model, which could not be envisioned a-priori, is fully identified from a set of interfacial unit cell simulations, thus enabling the efficient prediction of interface damage initiation at the mesoscale. The capability of the developed effective model to predict the mesoscopic M/F interface damage initiation is demonstrated on an example of a realistic DP steel mesostructure

Revisiting the martensite/ferrite interface damage initiation mechanism:The key role of substructure boundary sliding

Martensite/ferrite (M/F) interface damage plays a critical role in controlling failure of dual-phase (DP) steels and is commonly understood to originate from the large phase contrast between martensite and ferrite. This however conflicts with a few, recent observations, showing that considerable M/F interface damage initiation is often accompanied by apparent martensite island plasticity and weak M/F strain partitioning. In fact, martensite has a complex hierarchical structure which induces a strongly heterogeneous and orientation-dependent plastic response. Depending on the local stress state, (lath) martensite is presumed to be hard to deform based on common understanding. However, when favourably oriented, substructure boundary sliding can be triggered at a resolved shear stress which is comparable to that of ferrite. Moreover, careful measurements of the M/F interface structure indicate the occurrence of sharp martensite wedges protruding into the ferrite and clear steps in correspondence with lath boundaries, constituting a jagged M/F interfacial morphology that may have a large effect on the M/F interface behaviour. By taking into account the substructure and morphology features, which are usually overlooked in the literature, this contribution re-examines the M/F interface damage initiation mechanism. A systematic study is performed, which accounts for different loading conditions, phase contrasts, residual stresses/strains resulting from the preceding martensitic phase transformation, as well as the possible M/F interfacial morphologies. Crystal plasticity simulations are conducted to include inter-lath retained austenite (RA) films enabling the substructure boundary sliding. The results show that the substructure boundary sliding, which is the most favourable plastic deformation mode of lath martensite, can trigger M/F interface damage and hence control the failure behaviour of DP steels. The present finding may change the way in which M/F interface damage initiation is understood as a critical failure mechanism in DP steels

pH control for enhanced reductive bioremediation of chlorinated solvent source zones

Enhanced reductive dehalogenation is an attractive treatment technology for in situ remediation of chlorinated solvent DNAPL source areas. Reductive dehalogenation is an acid-forming process with hydrochloric acid and also organic acids from fermentation of the electron donors typically building up in the source zone during remediation. This can lead to groundwater acidification thereby inhibiting the activity of dehalogenating microorganisms. Where the soils’ natural buffering capacity is likely to be exceeded, the addition of an external source of alkalinity is needed to ensure sustained dehalogenation. To assist in the design of bioremediation systems, an abiotic geochemical model was developed to provide insight into the processes influencing the groundwater acidity as dehalogenation proceeds, and to predict the amount of bicarbonate required to maintain the pH at a suitable level for dehalogenating bacteria (i.e., > 6.5). The model accounts for the amount of chlorinated solvent degraded, site water chemistry, electron donor, alternative terminal electron- accepting processes, gas release and soil mineralogy. While calcite and iron oxides were shown to be the key minerals influencing the soil’s buffering capacity, for the extensive dehalogenation likely to occur in a DNAPL source zone, significant bicarbonate addition may be necessary even in soils that are naturally well buffered. Results indicated that the bicarbonate requirement strongly depends on the electron donor used and availability of competing electron acceptors (e.g., sulfate, iron(III)). Based on understanding gained from this model, a simplified model was developed for calculating a preliminary design estimate of the bicarbonate addition required to control the pH for user- specified operating conditions

Сорбция радионуклидов 137Cs, 85Sr и 60Co из модельных растворов жидких радиоактивных отходов низкой активности модифицированными горючими сланцами

The results of the study of cesium, strontium, cobalt radionuclides sorption from model solutions simulating liquid radioactive waste on promising sorbents based on thermally modified oil shale are presented. The dependency of texture parameters obtained from the results of nitrogen adsorption-desorption on the treatment method of oil shale and their relationship to sorption parameters such as distribution coefficient and removal efficiency was discussed. Understanding how pore characteristics affect the sorption activity of such complex systems as sorbents is important for the creation of radionuclide sorption materials with improved characteristics. The efficiency of sorption of cesium, strontium and cobalt radionuclides was rather high for sorbent samples: the distribution coefficient was about 103–104 ml/g with a removal efficiency of more than 66 %. The most effective sorbent was obtained from oil shale with a heating rate of 5 deg/min without subsequent steam treatment, which is recommended to be used for low-active radioactive waste treatment.Представлены результаты исследования сорбции радионуклидов цезия, стронция и кобальта перспективными сорбентами на основе термически модифицированных горючих сланцев из растворов, моделирующих жидкие радиоактивные отходы. На основании результатов низкотемпературной адсорбции–десорбции азота установлена зависимость текстурных параметров исследуемых сорбентов от метода обработки горючего сланца, а также описана зависимость эффективности сорбции (по величинам сорбции и коэффициента распределения) радионуклидов от текстурных параметров сорбентов. Понимание того, каким образом характеристики пор оказывают влияние на сорбционную активность таких сложных систем, как сорбенты, важно для создания высокоэффективных сорбционных материалов с усовершенствованными характеристиками. Установлено, что материалы на основе модифицированного горючего сланца сорбируют радионуклиды цезия, стронция, кобальта с высокой эффективностью: коэффициенты распределения каждого радионуклида составляют 103–104 мл/г при степени извлечения более 66 %. Наибольшую эффективность проявляет сорбент, полученный из горючего сланца при нагреве со скоростью 5 град/ мин без последующей обработки паром. Данный сорбент рекомендован к применению для очистки жидких радиоактивных отходов низкой активности от радионуклидов цезия, стронция, кобальта

ДИСПЕРСНОСТЬ И МОРФОЛОГИЯ ГИДРОЗОЛЯ ДИОКСИДА ТИТАНА

Hydrous titanium dioxide has been obtained by hydrolysis of titanium tetrachloride in aqueous solution both with and without alcohol. Method of atomic force microscopy has been used in order to investigate morphology of air dried samples of  hydrous titanium dioxide. The paper shows  formation of conglomerates in case of hydrolysis without addition of isobutyl alcohol. According to turbidimetric data particle radius of hydrosol has varied in the suspension within the range of (135 ± 5) nm that is in good correlation with atomic force microscopy data. Гидратированный диоксид титана получен гидролизом тетрахлорида титана в водной среде как в присутствии спирта, так и без него. Методом атомно-силовой микроскопии изучена морфология высушенных на воздухе образцов гидратированного диоксида титана. Показано образование конгломератов в случае проведения гидролиза без добавления изобутилового спирта. По данным турбидиметрии, радиус частиц гидрозоля в суспензии изменялся в пределах (135 ± 5) нм, что находится в хорошей корреляции с данными атомно-силовой микроскопии

Meiosis in Mice without a Synaptonemal Complex

The synaptonemal complex (SC) promotes fusion of the homologous chromosomes (synapsis) and crossover recombination events during meiosis. The SC displays an extensive structural conservation between species; however, a few organisms lack SC and execute meiotic process in a SC-independent manner. To clarify the SC function in mammals, we have generated a mutant mouse strain (Sycp1−/−Sycp3−/−, here called SC-null) in which all known SC proteins have been displaced from meiotic chromosomes. While transmission electron microscopy failed to identify any remnants of the SC in SC-null spermatocytes, neither formation of the cohesion axes nor attachment of the chromosomes to the nuclear membrane was perturbed. Furthermore, the meiotic chromosomes in SC-null meiocytes achieved pre-synaptic pairing, underwent early homologous recombination events and sustained a residual crossover formation. In contrast, in SC-null meiocytes synapsis and MLH1-MLH3-dependent crossovers maturation were abolished, whereas the structural integrity of chromosomes was drastically impaired. The variable consequences that SC inactivation has on the meiotic process in different organisms, together with the absence of SC in some unrelated species, imply that the SC could have originated independently in different taxonomic groups

Perturbation-based stochastic multi-scale computational homogenization method for woven textile composites

In this paper, a stochastic homogenization method that couples the state-of-the-art computational multi-scale homogenization method with the stochastic finite element method, is proposed to predict the statistics of the effective elastic properties of textile composite materials. Uncertainties associated with the elastic properties of the constituents are considered. Accurately modeling the fabric reinforcement plays an important role in the prediction of the effective elastic properties of textile composites due to their complex structure. The p-version finite element method is adopted to refine the analysis. Performance of the proposed method is assessed by comparing the mean values and coefficients of variation for components of the effective elastic tensor obtained from the present method against corresponding results calculated by using Monte Carlo simulation method for a plain-weave textile composite. Results show that the proposed method has sufficient accuracy to capture the variability in effective elastic properties of the composite induced by the variation of the material properties of the constituents

A novel quantitative high-throughput screen identifies drugs that both activate SUMO conjugation via the inhibition of microRNAs 182 and 183 and facilitate neuroprotection in a model of oxygen and glucose deprivation

The conjugation/de-conjugation of Small Ubiquitin-like Modifier (SUMO) has been shown to be associated with a diverse set of physiologic/pathologic conditions. The clinical significance and ostensible therapeutic utility offered via the selective control of the global SUMOylation process has become readily apparent in ischemic pathophysiology. Herein, we describe the development of a novel quantitative high-throughput screening (qHTS) system designed to identify small molecules capable of increasing SUMOylation via the regulation/inhibition of members of the microRNA (miRNA)-182 family. This assay employs a SHSY5Y human neuroblastoma cell line stably transfected with a dual firefly-Renilla luciferase reporter system for identification of specific inhibitors of either miR-182 or miR-183. In this study, we have identified small molecules capable of inducing increased global conjugation of SUMO in both SHSY5Y cells and rat E18-derived primary cortical neurons. The protective effects of a number of the identified compounds were confirmed via an in vitro ischemic model (oxygen/glucose deprivation). Of note, this assay can be easily repurposed to allow high-throughput analyses of the potential drugability of other relevant miRNA(s) in ischemic pathobiology.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Intramural Research Program of the NINDS/NIH, an IRTA-OxCam Fellowship and by the Wellcome Trust [RRZA/057 and RG79423]