Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeting the Oncogenic MUC1-C Protein Inhibits Mutant EGFR-Mediated Signaling and Survival in Non–Small Cell Lung Cancer Cells

Purpose: Non–small cell lung cancers (NSCLC) that express EGF receptor with activating mutations frequently develop resistance to EGFR kinase inhibitors. The mucin 1 (MUC1) heterodimeric protein is aberrantly overexpressed in NSCLC cells and confers a poor prognosis; however, the functional involvement of MUC1 in mutant EGFR signaling is not known. Experimental Design: Targeting the oncogenic MUC1 C-terminal subunit (MUC1-C) in NSCLC cells harboring mutant EGFR was studied for effects on signaling, growth, clonogenic survival, and tumorigenicity. Results: Stable silencing of MUC1-C in H1975/EGFR(L858R/T790M) cells resulted in downregulation of AKT signaling and inhibition of growth, colony formation, and tumorigenicity. Similar findings were obtained when MUC1-C was silenced in gefitinib-resistant PC9GR cells expressing EGFR(delE746_A750/T790M). The results further show that expression of a MUC1-C(CQC→AQA) mutant, which blocks MUC1-C homodimerization, suppresses EGFR(T790M), AKT and MEK→ERK activation, colony formation, and tumorigenicity. In concert with these results, treatment of H1975 and PC9GR cells with GO-203, a cell-penetrating peptide that blocks MUC1-C homodimerization, resulted in inhibition of EGFR, AKT, and MEK→ERK signaling and in loss of survival. Combination studies of GO-203 and afatinib, an irreversible inhibitor of EGFR, further demonstrate that these agents are synergistic in inhibiting growth of NSCLC cells harboring the activating EGFR(T790M) or EGFR(delE746-A750) mutants. Conclusions: These findings indicate that targeting MUC1-C inhibits mutant EGFR signaling and survival, and thus represents a potential approach alone and in combination for the treatment of NSCLCs resistant to EGFR kinase inhibitors. Clin Cancer Res; 20(21); 5423–34. ©2014 AACR.
Early growth response-1 worsens ventilator-induced lung injury by up-regulating prostanoid synthesis.

RATIONALE Ventilator-induced lung injury (VILI) is common and serious and may be mediated in part by prostanoids. We have demonstrated increased expression of the early growth response-1 (Egr1) gene by injurious ventilation, but whether-or how-such up-regulation contributes to injury is unknown. OBJECTIVES We sought to define the role of Egr1 in the pathogenesis of VILI. METHODS An in vivo murine model of VILI was used, and Egr1(+/+) (wild-type) and Egr1(-/-) mice were studied; the effects of prostaglandin E receptor subtype 1 (EP1) inhibition were assessed. MEASUREMENTS AND MAIN RESULTS Injurious ventilation caused lung injury in wild-type mice, but less so in Egr1(-/-) mice. The injury was associated with expression of EGR1 protein, which was localized to type II cells and macrophages and was concentrated in nuclear extracts. There was a concomitant increase in expression of phosphorylated p44/p42 mitogen-activated protein kinases. The prostaglandin E synthase (mPGES-1) gene has multiple EGR1 binding sites on its promoter, and induction of mPGES-1 mRNA (as well as the prostanoid product, PGE2) by injurious ventilation was highly dependent on the presence of the Egr1 gene. PGE2 mediates many lung effects via EP1 receptors, and EP1 blockade (with ONO-8713) lessened lung injury. CONCLUSIONS This is the first demonstration of a mechanism whereby expression of a novel gene (Egr1) can contribute to VILI via a prostanoid-mediated pathway.
Unleashing floret fertility in wheat through the mutation of a homeobox gene

Significance Grain number is a key determinant of cereal grain yield, but its underlying genetic basis in wheat remains undefined. This study demonstrates a direct association between increased floret fertility, higher grain number per spike, and higher plot yields of field-grown wheat. The GNI1 gene, encoding an HD-Zip I transcription factor, was identified as responsible for increased floret fertility. The WT allele acts specifically during rachilla development, with its product serving to lower grain yield potential; in contrast, the reduced-function variant increased both floret and grain number. GNI1 evolved through gene duplication in the Triticeae, and its mutations have been under parallel selection in both wheat and barley over the course of domestication. Floret fertility is a key determinant of the number of grains per inflorescence in cereals. During the evolution of wheat (Triticum sp.), floret fertility has increased, such that current bread wheat (Triticum aestivum) cultivars set three to five grains per spikelet. However, little is known regarding the genetic basis of floret fertility. The locus Grain Number Increase 1 (GNI1) is shown here to be an important contributor to floret fertility. GNI1 evolved in the Triticeae through gene duplication. The gene, which encodes a homeodomain leucine zipper class I (HD-Zip I) transcription factor, was expressed most abundantly in the most apical floret primordia and in parts of the rachilla, suggesting that it acts to inhibit rachilla growth and development. The level of GNI1 expression has decreased over the course of wheat evolution under domestication, leading to the production of spikes bearing more fertile florets and setting more grains per spikelet. Genetic analysis has revealed that the reduced-function allele GNI-A1 contributes to the increased number of fertile florets per spikelet. The RNAi-based knockdown of GNI1 led to an increase in the number of both fertile florets and grains in hexaploid wheat. Mutants carrying an impaired GNI-A1 allele out-yielded WT allele carriers under field conditions. The data show that gene duplication generated evolutionary novelty affecting floret fertility while mutations favoring increased grain production have been under selection during wheat evolution under domestication.
Mesenchymal Stem Cell Therapy in Submandibular Salivary Gland Allotransplantation: Experimental Study.

BACKGROUND Allotransplantation of submandibular salivary glands (SMGs) could be an alternative treatment option for severe keratoconjunctivitis sicca in non-candidates for autologous submandibular salivary gland transplantation. This study was conducted to evaluate the effect of allogeneic mesenchymal stem cell (MSC) therapy on the survival of allotransplanted SMGs. METHODS Thirty-six SMG allotransplantations (n = 6 per group) were performed in New Zealand white (NZW) rabbits and randomly divided into the following groups: Allograft control (Allo-Ctrl), low dose FK506 (FK506-L), high dose FK506 (FK506-H), allogeneic MSCs, MSCs+FK506-L, and MSCs+FK506-H. Rabbits were closely observed for two weeks. Gland viability and rejection were assessed by monitoring interleukin-2 (IL-2) levels by enzyme-linked immunosorbent assay (ELISA), sialoscintigraphy, M3-muscarinic acetylcholine receptor (M3 receptor) expression, histological evaluation, and apoptosis assay. RESULTS Intraoperatively, all glands showed patency and saliva flow except one gland. Sialoscintigraphy revealed significantly higher saliva production within the MSC-treated glands. Histologically, MSC-treated glands showed higher glandular tissue preservation and less acini atrophy. MSCs+FK506-H group revealed significantly lower apoptosis percentage. The highest survival was observed in the MSCs+FK506-H, followed by the FK506-H and MSCs+FK506-L, and lastly less in the FK506-L and MSCs groups. CONCLUSIONS Concurrent administration of MSCs with FK506-H (0.16 mg/kg) resulted in higher survival rate with greater glandular tissue preservation and salivary secretion. MSCs with FK506-L (0.08 mg/kg) could be an alternative to FK506-H (0.16 mg) in salivary gland allotransplantation.
The significant others: Global search for direct kinase substrates using chemical approaches

Protein kinases function as key signaling hubs in the intricate network of biochemical signaling processes in the living cell. More than two‐thirds of the human proteome is estimated to be phosphorylated at ~960,000 phosphosites, which makes it challenging to identify the direct contribution of any desired kinase in generating this phosphoproteome. In this review, we discuss some of the methods that have been developed over the years for global identification of kinase substrates. The methods are essentially categorized into two classes, namely, (i) direct tagging of kinase substrates and (ii) indirect phosphoproteomics‐based approaches. We discuss the advantages and limitations entailed to each of the method introduced, with a special emphasis on the analog‐sensitive (as) kinase approach method. © 2019 IUBMB Life, 71(6):721–737, 2019
Physical Properties of High Entropy Alloys

The majority of studies on high-entropy alloys are focused on their phase, microstructure, and mechanical properties. However, the physical properties of these materials are also encouraging. This paper provides a brief overview of the physical properties of high-entropy alloys. Emphasis is laid on magnetic, electrical, and thermal properties.
Single-molecule excitation–emission spectroscopy

Significance The most popular methods of single-molecule detection are based on fixed-wavelength excitation of individual molecules combined with dispersed detection of emission. While these methods are well established, they mainly provide information on the excited-state environment of the fluorophore. Here, we introduce an approach capable of simultaneously acquiring the full information, involving both ground- and excited states, by recording a 2D excitation versus emission map for single molecules by use of a birefringent interferometer. We interpret the results in terms of optical lineshape theory. The presented approach is easily implementable and applicable to a wide range of scientific problems, ranging from spectroscopy of supramolecular biological complexes to materials science. Single-molecule spectroscopy (SMS) provides a detailed view of individual emitter properties and local environments without having to resort to ensemble averaging. While the last several decades have seen substantial refinement of SMS techniques, recording excitation spectra of single emitters still poses a significant challenge. Here we address this problem by demonstrating simultaneous collection of fluorescence emission and excitation spectra using a compact common-path interferometer and broadband excitation, which is implemented as an extension of a standard SMS microscope. We demonstrate the technique by simultaneously collecting room-temperature excitation and emission spectra of individual terrylene diimide molecules and donor–acceptor dyads embedded in polystyrene. We analyze the resulting spectral parameters in terms of optical lineshape theory to obtain detailed information on the interactions of the emitters with their nanoscopic environment. This analysis finally reveals that environmental fluctuations between the donor and acceptor in the dyads are not correlated.
A WRKY transcription factor PbrWRKY53 from Pyrus betulaefolia is involved in drought tolerance and AsA accumulation

Summary WRKY comprises a large family of transcription factors in plants, but most WRKY members are still poorly understood. In this study, we report the identification and functional characterization of PbrWRKY53 isolated from Pyrus betulaefolia. PbrWRKY53 was greatly up‐regulated by drought and abscisic acid, but slightly induced by salt and cold. Subcellar localization analyses showed that PbrWRKY53 was located in the nucleus. Ectopic expression of PbrWRKY53 in tobacco and Pyrus ussuriensis conferred enhanced tolerance to drought stress. The transgenic plants exhibited better water status, less reactive oxygen species generation and higher levels of antioxidant enzyme activities and metabolites than the wild type. In addition, overexpression of PbrWRKY53 in transgenic tobacco resulted in enhanced expression level of PbrNCED1, and led to the increase in larger amount of vitamin C accumulation in comparison to WT. Knock‐down of PbrWRKY53 in P. ussuriensis down‐regulated PbrNCED1 abundance, accompanied by compromised drought tolerance. Yeast one‐hybrid assay, EMSA and transient expression analysis demonstrated that PbrWRKY53 could bind to the W‐box element in the promoter region of PbrNCED1. Taken together, these results demonstrated that PbrWRKY53 plays a positive role in drought tolerance, which might be, at least in part, promoting production of vitamin C via regulating PbrNCED1 expression.
Mutation in a flexible linker modulates binding affinity for modular complexes

Tandem beta zippers are modular complexes formed between repeated linear motifs and tandemly arrayed domains of partner proteins in which β‐strands form upon binding. Studies of such complexes, formed by LIM domain proteins and linear motifs in their intrinsically disordered partners, revealed spacer regions between the linear motifs that are relatively flexible but may affect the overall orientation of the binding modules. We demonstrate that mutation of a solvent exposed side chain in the spacer region of an LHX4–ISL2 complex has no significant effect on the structure of the complex, but decreases binding affinity, apparently by increasing flexibility of the linker.
A HGF/cMET Autocrine Loop Is Operative in Multiple Myeloma Bone Marrow Endothelial Cells and May Represent a Novel Therapeutic Target

Purpose: The aim of this study was to investigate the angiogenic role of the hepatocyte growth factor (HGF)/cMET pathway and its inhibition in bone marrow endothelial cells (EC) from patients with multiple myeloma versus from patients with monoclonal gammopathy of undetermined significance (MGUS) or benign anemia (control group). Experimental Design: The HGF/cMET pathway was evaluated in ECs from patients with multiple myeloma (multiple myeloma ECs) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies, or on refractory phase to these drugs; in ECs from patients with MGUS (MGECs); and in those patients from the control group. The effects of a selective cMET tyrosine kinase inhibitor (SU11274) on multiple myeloma ECs' angiogenic activities were studied in vitro and in vivo. Results: Multiple myeloma ECs express more HGF, cMET, and activated cMET (phospho (p)-cMET) at both RNA and protein levels versus MGECs and control ECs. Multiple myeloma ECs are able to maintain the HGF/cMET pathway activation in absence of external stimulation, whereas treatment with anti-HGF and anti-cMET neutralizing antibodies (Ab) is able to inhibit cMET activation. The cMET pathway regulates several multiple myeloma EC activities, including chemotaxis, motility, adhesion, spreading, and whole angiogenesis. Its inhibition by SU11274 impairs these activities in a statistically significant fashion when combined with bortezomib or lenalidomide, both in vitro and in vivo. Conclusions: An autocrine HGF/cMET loop sustains multiple myeloma angiogenesis and represents an appealing new target to potentiate the antiangiogenic management of patients with multiple myeloma. Clin Cancer Res; 20(22); 5796–807. ©2014 AACR.
Umbilical Cord Serum Ferritin Concentration is Inversely Associated with Umbilical Cord Hemoglobin in Neonates Born to Adolescents Carrying Singletons and Women Carrying Multiples.

BACKGROUND It has been proposed that the fetus prioritizes iron for hemoglobin production over delivery to tissues. However, few studies have evaluated the interrelations between hemoglobin and multiple iron status biomarkers in umbilical cord blood. A full understanding is needed of how these parameters influence each other within cord blood to fully interpret iron and hematologic status at birth. OBJECTIVES We evaluated the determinants of neonatal hemoglobin and assessed the interrelations between hemoglobin, serum iron status indicators, and serum iron regulatory hormones in healthy neonates. METHODS This was an observational study that assessed umbilical cord hemoglobin (Hb), serum ferritin (SF), erythropoietin (EPO), soluble transferrin receptor (sTfR), serum iron, hepcidin, vitamin B-12, folate, IL-6, and CRP measured in 234 neonates born to adolescents or to women carrying multiples. Correlations between these indicators were evaluated and mediation models consistent with the observed significant determinants of cord Hb concentrations were developed. RESULTS A highly significant inverse association was found between cord SF and Hb concentrations that was not attributable to neonatal or maternal inflammation (as measured by IL-6 and CRP). The inverse association was present in the combined cohort, as well as in the adolescent and multiples cohorts independently. Mediation analyses found that EPO and hepcidin had significant indirect effects on cord Hb, associations that are explicable by mediation through SF and sTfR. CONCLUSION In contrast to observations made in older infants, a highly significant inverse association between Hb and SF, as well positive associations between Hb and both sTfR and EPO, were observed in umbilical cord blood from neonates born to adolescents or women carrying multiples. These findings, combined with review of the published literature, indicate a need for analysis of the relations between multiple parameters to assess iron and hematologic status at birth. These clinical trials were registered at clinicaltrials.gov as NCT01582802 (https://clinicaltrials.gov/ct2/show/NCT01582802) and NCT01019902 (https://clinicaltrials.gov/ct2/show/NCT01019902).
Chemical profile of Lippia thymoides, evaluation of the acetylcholinesterase inhibitory activity of its essential oil, and molecular docking and molecular dynamics simulations

The essential oils of the fresh and dry flowers, leaves, branches, and roots of Lippia thymoides were obtained by hydrodistillation and analyzed using gas chromatography (GC) and GC–mass spectrometry (MS). The acetylcholinesterase inhibitory activity of the essential oil of fresh leaves was investigated on silica gel plates. The interactions of the key compounds with acetylcholinesterase were simulated by molecular docking and molecular dynamics studies. In total, 75 compounds were identified, and oxygenated monoterpenes were the dominant components of all the plant parts, ranging from 19.48% to 84.99%. In the roots, the main compounds were saturated and unsaturated fatty acids, having contents varying from 39.5% to 32.17%, respectively. In the evaluation of the anticholinesterase activity, the essential oils (detection limit (DL) = 0.1 ng/spot) were found to be about ten times less active than that of physostigmine (DL = 0.01ng/spot), whereas thymol and thymol acetate presented DL values each of 0.01 ng/spot, equivalent to that of the positive control. Based on the docking and molecular dynamics studies, thymol and thymol acetate interact with the catalytic residues Ser203 and His447 of the active site of acetylcholinesterase. The binding free energies (ΔGbind) for these ligands were -18.49 and -26.88 kcal/mol, demonstrating that the ligands are able to interact with the protein and inhibit their catalytic activity.
A technique for isolating differences between files

A simple algorithm is described for isolating the differences between two files. One application is the comparing of two versions of a source program or other file in order to display all differences. The algorithm isolates differences in a way that corresponds closely to our intuitive notion of difference, is easy to implement, and is computationally efficient, with time linear in the file length. For most applications the algorithm isolates differences similar to those isolated by the longest common subsequence. Another application of this algorithm merges files containing independently generated changes into a single file. The algorithm can also be used to generate efficient encodings of a file in the form of the differences between itself and a given “datum” file, permitting reconstruction of the original file from the diference and datum files.
Stimulus-Response and Response-Effect Compatibility With Touchless Gestures and Moving Action Effects

Objective: To determine whether response-effect (R-E) compatibility or stimulus-response (S-R) compatibility is more critical for touchless gesture responses. Background: Content on displays can be moved in the same direction (S-R incompatible but R-E compatible) or opposite direction (S-R compatible but R-E incompatible) as the touchless gesture that produces the movement. Previous studies suggested that it is easier to produce a button-press response when it is R-E compatible (and S-R incompatible). However, whether this R-E compatibility effect also occurs for touchless gesture responses is unknown. Method: Experiments 1 and 2 employed an R-E compatibility manipulation in which participants made responses with an upward or downward touchless gesture that resulted in the display content moving in the same (compatible) or opposite (incompatible) direction. Experiment 3 employed an S-R compatibility manipulation in which the stimulus occurred at the upper or lower location on the screen. Results: Overall, only negligible influences of R-E compatibility on performing the touchless gestures were observed (in contrast to button-press responses), whereas S-R compatibility heavily affected the gestural responses. Conclusion: The R-E compatibility obtained in many previous studies with various types of responses appears not to hold for touchless gestures as responses. Application: The results suggest that in the design of touchless interfaces, unique factors may contribute to determining which mappings of gesture and display movements are preferred by users.
A Pilot Study to Investigate the Balance between Proteases and α1-Antitrypsin in Bronchoalveolar Lavage Fluid of Lung Transplant Recipients

The neutrophilic component in bronchiolitis obliterans syndrome (BOS, the main form of chronic lung rejection), plays a crucial role in the pathogenesis and maintenance of the disorder. Human Neutrophil Elastase (HNE), a serine protease responsible of elastin degradation whose action is counteracted by α1-antitrypsin (AAT), a serum inhibitor specific for this protease. This work aimed to investigate the relationship between HNE and AAT in bronchoalveolar lavage fluid (BALf) from stable lung transplant recipients and BOS patients to understand whether the imbalance between proteases and inhibitors is relevant to the development of BOS. To reach this goal a multidisciplinary procedure was applied which included: (i) the use of electrophoresis/western blotting coupled with liquid chromatography-mass spectrometric analysis; (ii) the functional evaluation of the residual antiprotease activity, and (iii) a neutrophil count. The results of these experiments demonstrated, for the first time, the presence of the complex between HNE and AAT in a number of BALf samples. The lack of this complex in a few specimens analyzed was investigated in relation to a patient’s lung inflammation. The neutrophil count and the determination of HNE and AAT activities allowed us to speculate that the presence of the complex correlated with the level of lung inflammation.