Influence of the Selected Physical Modifier on the Dynamical Behavior of the Polymer Composites Used in the Aviation Industry

In this research, an analysis of polymer composite with the matrix of L285-cured hardener H286 and six reinforcement layers of carbon fabric GG 280 T was provided. It involved a comparison of the dynamical behavior responses for three cases of composite structures in the context of the presence of the mass share modifier. The samples with the addition of a physical modifier with varying mass percentages were investigated by being subjected to dynamic tests with specific parameters, i.e., constant excitation amplitude and vibration frequency in the vicinity of the base resonance zone. The analysis allowed for indicating the relationship between the composition of the prepared composites and their dynamic response via stiffness characteristics. In addition, the investigation resulted in determining the range of harmful dynamical operating conditions, which may contribute to damage to the composite structures.     

Magnetic Properties and the Electronic Structure of the Gd0.4Tb0.6Co2 Compound

We report on the comprehensive experimental and theoretical studies of magnetic and electronic structural properties of the Gd_0.4Tb_0.6Co₂ compound crystallization in the cubic Laves phase (C15). We present new results and compare them to those reported earlier. The magnetic study was completed with electronic structure investigations. Based on magnetic isotherms, magnetic entropy change (ΔS_M) was determined for many values of the magnetic field change (Δμ₀H), which varied from 0.1 to 7 T. In each case, the ΔS_M had a maximum around room temperature. The analysis of Arrott plots supplemented by a study of temperature dependency of Landau coefficients revealed that the compound undergoes a magnetic phase transition of the second type. From the M(T) dependency, the exchange integrals between rare-earth R-R (J_RR), R-Co (J_RCo), and Co-Co (J_CoCo) atoms were evaluated within the mean-field theory approach. The electronic structure was determined using the X-ray photoelectron spectroscopy (XPS) method as well as by calculations using the density functional theory (DFT) based Full Potential Linearized Augmented Plane Waves (FP-LAPW) method. The comparison of results of ab initio calculations with the experimental data indicates that near T_C the XPS spectrum collects excitations of electrons from Co3d states with different values of exchange splitting. The values of the magnetic moment on Co atoms determined from magnetic measurements, estimated from the XPS spectra, and results from ab initio calculations are quantitatively consistent.     

Volumetric growth of the lungs in human fetuses: an anatomical,hydrostatic and statistical study

Purpose

The prenatal assessment of lung volume is becoming increasingly important in determining survival in both preterm infants and newborns affected by pulmonary hypoplasia. This study aimed to examine the lung volumes in the human fetus at varying gestational ages.

Materials and methods

Using anatomical, hydrostatic (water displacement according to Archimedes’ patent) and statistical methods (one-way ANOVA test for paired data and post-hoc Bonferroni test, Kolmogorov–Smirnov test, Levene’s test, Student’s t test, regression analysis), volumes of the right and left lungs were measured in 67 human fetuses of both sexes (35 males, 32 females) aged 16–25 weeks, derived from spontaneous abortions and stillbirths.

Results

No male–female differences concerning the right and left pulmonary volumes were found. The mean volume of the right lung increased from 1.43 ± 0.25 to 8.45 ± 2.66 cm³, according to the cubic function y = –1.592 + 0.0007 × age³ ± 0.851 (R ² = 0.84). The volumetric growth of the left lung, from 1.24 ± 0.22 to 6.78 ± 3.03 cm³, followed the cubic model y = –1.110 + 0.0005 × age³ ± 0.794 (R ² = 0.78). The total pulmonary volume increased from 2.67 ± 0.47 to 15.22 ± 5.58 cm³, in accordance with the cubic model y = –2.729 + 0.0012 × age³ ± 1.598 (R ² = 0.83). The mean volumes of the right and left lungs accounted for 54.9 ± 2.0 and 45.1 ± 2.0 %, respectively, of the total lung volume.

Conclusions

No sex differences are found between the lung volumes in the fetus. The growth of fetal lung volume follows a three-degree polynomial function. Throughout the analyzed period the two lungs grow proportionately to each other, with the volumetric predominance of the right lung. The lung volumes in the fetus are of great relevance in the evaluation of the normal pulmonary growth and the diagnosis of pulmonary hypoplasia.     

Whole exome sequencing unravels disease‐causing genes in consanguineous families in Qatar

Whole exome sequencing (WES) has greatly facilitated the identification of causal mutations for diverse human genetic disorders. We applied WES as a molecular diagnostic tool to identify disease‐causing genes in consanguineous families in Qatar. Seventeen consanguineous families with diverse disorders were recruited. Initial mutation screening of known genes related to the clinical diagnoses did not reveal the causative mutations. Using WES approach, we identified the definitive disease‐causing mutations in four families: (i) a novel nonsense homozygous (c.1034C>G) in PHKG2 causing glycogen storage disease type 9C (GSD9C) in a male with initial diagnosis of GSD3; (ii) a novel homozygous 1‐bp deletion (c.915del) in NSUN2 in a male proband with Noonan‐like syndrome; (iii) a homozygous SNV (c.1598C>G) in exon 11 of IDUA causing Hurler syndrome in a female proband with unknown clinical diagnosis; (iv) a de novo known splicing mutation (c.1645+1G>A) in PHEX in a female proband with initial diagnosis of autosomal recessive hypophosphatemic rickets. Applying WES as a diagnostic tool led to the unambiguous identification of disease‐causing mutations in phenotypically complex disorders or correction of the initial clinical diagnosis in ?25% of our cases.     

Evidence for clinical,genetic and biochemical variability in spinal muscular atrophy with progressive myoclonic epilepsy

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA‐PME) is a recently delineated, autosomal recessive condition caused by rare mutations in the N‐acylsphingosine amidohydrolase 1 (acid ceramidase) ASAH1 gene. It is characterized by motor neuron disease followed by progressive myoclonic seizures and eventual death due to respiratory insufficiency. Here we report an adolescent female who presented with atonic and absence seizures and myoclonic jerks and was later diagnosed as having myoclonic‐absence seizures. An extensive genetic and metabolic work‐up was unable to arrive at a molecular diagnosis. Whole exome sequencing (WES) identified two rare, deleterious mutations in the ASAH1 gene: c.850G>T;p.Gly284X and c.456A>C;p.Lys152Asn. These mutations were confirmed by Sanger sequencing in the patient and her parents. Functional studies in cultured fibroblasts showed that acid ceramidase was reduced in both overall amount and enzymatic activity. Ceramide level was doubled in the patient's fibroblasts as compared to control cells. The results of the WES and the functional studies prompted an electromyography (EMG) study that showed evidence of motor neuron disease despite only mild proximal muscle weakness. These findings expand the phenotypic spectrum of SMA‐PME caused by novel mutations in ASAH1 and highlight the clinical utility of WES for rare, intractable forms of epilepsy.     

B‐cell modulation of dendritic‐cell function: Signals from the far side

An appropriate immune response against a specific pathogen requires finely orchestrated interactions between the various cell populations within the immune system. At the same time, immunological tolerance to self must be maintained. DCs play an essential role in achieving these dual requisites. They coordinate adaptive immunity by integrating signals directly emanating from both infectious agents and cells of the immune system. Many such signals, especially those from innate cells and T cells, have been extensively characterized. In contrast, little is known about how B cells modulate function of DCs. B cells produce a variety of cytokines, including IL‐10 and IL‐6, which are known to influence DC function. In addition, Igs constitute the major secretory products of terminally differentiated B cells (plasma cells). DCs express various types of receptors for binding Ig, such as Fc receptors and C‐type lectin receptors. In accordance, Igs can regulate DC function depending on the receptors engaged. Here, we review the emerging immunomodulatory role of cytokines and Ig secreted by B cells. We discuss the evidence for how these B‐cell‐derived factors may shape the adaptive immune response by directly acting on DCs.     

Tissue Repair and Fibrosis

Background

Because antileukotrienes may inhibit inflammation, it is plausible that montelukast administered for a long time could suppress skin wheal and flare reaction, and thus, it should be discarded prior to the tests. This study assessed the effect of long-lasting treatment with montelukast alone or in combination with antihistamines on wheal and flare in skin pricks tests (SPT) in patients sensitized to perennial allergens.

Methods

We conducted a 32-week, double-blind, placebo-controlled, cross-over and randomized trial that implicated two arms: arm A, 20 patients received levocetirizine, montelukast with or without levocetirizine or placebo; arm B, 20 patients received desloratadine, montelukast with or without desloratadine or placebo. All treatment periods lasted 6 weeks and were separated by 2-week washouts. At baseline and on the last day of each treatment period, SPT were performed in all participants.

Results

Both levocetirizine and desloratadine in monotherapy, or in combination with montelukast, were effective in reducing wheal and flare in SPT. Monotherapy with montelukast did not change the size of the wheal for either histamine or for house dust mites, in either arm of the study, but significantly reduced the size of flare for histamine in arm A. Addition of montelukast to antihistamine did not exceed efficacy of monotherapy with antihistamine in both arms of the study.

Conclusions

Since the size of wheal determines the results of SPT, montelukast, even taken for a long time, does not have to be discarded prior to the tests.     

Characteristics of metabolic stability and the cell permeability of 2‐pyrimidinyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione with antidepressant‐ and anxiolytic‐like activities

A series of 2‐pyrimidinyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione has been synthesized in an attempt to discover a new class of psychotropic agents. Compounds were evaluated for their in vitro affinity for serotonin 5‐HT_1A, 5‐HT₇, and phosphodiesterases PDE4 and PDE10. The most potent compound 2‐pyrimidinyl‐1‐piperazinyl‐butyl‐imidazo[2,1‐f]purine‐2,4‐dione ( 4b ) behaved as strong and selective antagonist of 5‐HT_1A. Molecular modeling studies revealed differences in binding mode between compound 4b and buspirone, which might reflect variation of the ligands’ affinity and potency in the 5‐HT_1A receptor. Compound 4b in silico models demonstrated drug‐likeness properties and, contrary to buspirone, showed a metabolic stability in mouse liver microsomes system. Experimentally obtained value of apparent permeability coefficient P_app for 4b in parallel artificial permeability assay indicates the possibility of binding weakly to plasma proteins and high intestinal absorption fraction. Evaluation of the antidepressant‐ and anxiolytic‐like activities of 4b revealed both activities at the same dose of 1.25 mg/kg and seemed to be specific. The antidepressant and/or anxiolytic properties of 4b may be related to its first‐pass effect.     

Genetic modifiers of EGFR dependence in non-small cell lung cancer

Lung adenocarcinomas harboring activating mutations in the epidermal growth factor receptor (EGFR) represent a common molecular subset of non-small cell lung cancer (NSCLC) cases. EGFR mutations predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and thus represent a dependency in NSCLCs harboring these alterations, but the genetic basis of EGFR dependence is not fully understood. Here, we applied an unbiased, ORF-based screen to identify genetic modifiers of EGFR dependence in EGFR-mutant NSCLC cells. This approach identified 18 kinase and kinase-related genes whose overexpression can substitute for EGFR in EGFR-dependent PC9 cells, and these genes include seven of nine Src family kinase genes, FGFR1, FGFR2, ITK, NTRK1, NTRK2, MOS, MST1R, and RAF1. A subset of these genes can complement loss of EGFR activity across multiple EGFR-dependent models. Unbiased gene-expression profiling of cells overexpressing EGFR bypass genes, together with targeted validation studies, reveals EGFR-independent activation of the MEK-ERK and phosphoinositide 3-kinase (PI3K)-AKT pathways. Combined inhibition of PI3K-mTOR and MEK restores EGFR dependence in cells expressing each of the 18 EGFR bypass genes. Together, these data uncover a broad spectrum of kinases capable of overcoming dependence on EGFR and underscore their convergence on the PI3K-AKT and MEK-ERK signaling axes in sustaining EGFR-independent survival.The term “oncogene addiction” has been used to describe the phenomenon whereby tumor cells exhibit singular reliance on an oncogene or oncogenic pathway for their survival, despite the accumulation of multiple genetic lesions (1). In non-small cell lung cancer (NSCLC), this principle is perhaps best exemplified with the finding that epidermal growth factor receptor (EGFR) mutations predict response to EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, and thus represent a dependency in the subset of tumors harboring these alterations (2–6). However, though EGFR-mutant NSCLCs typically respond dramatically to EGFR TKIs, clinical responses are not universal, even within this genetically defined cohort, with the rate of objective response estimated to be ∼71% (5, 6). Furthermore, the overwhelming majority of patients who initially respond to EGFR inhibitors ultimately develop resistance to therapy (7). A deeper understanding of the genetic underpinnings of EGFR addiction, and how EGFR-mutant cells can overcome reliance on EGFR, may improve clinical outcomes.Here, we have applied an unbiased screening approach to identify genetic modifiers of EGFR dependence in NSCLC. Mounting evidence supports the existence of several genetic modifiers of EGFR dependence in EGFR-mutant NSCLC, which can reduce the degree to which these tumors rely on EGFR and thereby contribute to EGFR TKI resistance (8). Examples include amplification of the MET receptor tyrosine kinase (RTK) (9), activation of the NF-κB pathway (8), amplification of the HER2 (ERBB2) RTK (10), amplification of the CRKL gene (11), and activation of the AXL kinase (12). Notably, MET bypass can be reciprocally achieved via EGFR activation in MET-dependent cells (13), and analogous examples of reciprocal kinase switching have been reported in other kinase-driven cancer models (14, 15). These and other findings suggest that compensatory kinase switching may be a more general way in which oncogene-dependent cancers overcome reliance on their primary driver kinase (14, 16), but the full-range of kinases capable of mediating EGFR bypass has not been systematically studied.Recent advances in large-scale functional genetic libraries have made it possible to query a wide range of genetic perturbations for their ability to modulate specific cellular phenotypes in mammalian systems (17, 18). Using the model of EGFR-mutant, erlotinib-sensitive NSCLC cells, we have performed a systematic ORF-based screen to identify kinase and kinase-related genes whose overexpression can complement loss of EGFR activity in an EGFR-dependent context. Our findings indicate broad potential for EGFR substitution in the setting of EGFR dependence, with compensatory mechanisms commonly conferring EGFR-independent activation of the PI3K-AKT and MEK-ERK signaling pathways. Importantly, this approach has recovered known mechanisms of erlotinib resistance as well as identified novel mediators of EGFR bypass in EGFR-mutant NSCLC. These data support the idea that the EGFR-dependent state can be redundantly driven by diverse genetic inputs that commonly converge on shared downstream signaling nodes.