bluuebunny/crossref_metadata_2025_split huggingface dataset:
Emerging roles of allosteric modulators in the regulation of protein‐protein interactions (PPIs): A new paradigm for PPI drug discovery
Authors: Ni Duan , Lu Shaoyong , Zhang Jian 
Published: April 2019

AbstractProtein‐protein interactions (PPIs) are closely implicated in various types of cellular activities and are thus pivotal to health and disease states. Given their fundamental roles in a wide range of biological processes, the modulation of PPIs has enormous potential in drug discovery. However, owing to the general properties of large, flat, and featureless interfaces of PPIs, previous attempts have demonstrated that the generation of therapeutic agents targeting PPI interfaces is challenging, rendering them almost “undruggable” for decades. To date, rapid progress in chemical and structural biology techniques has promoted the exploitation of allostery as a novel approach in drug discovery. By attaching to allosteric sites that are topologically and spatially distinct from PPI interfaces, allosteric modulators can achieve improved physiochemical properties. Thus, allosteric modulators may represent an alternative strategy to target intractable PPIs and have attracted intense pharmaceutical interest. In this review, we first briefly introduce the characteristics of PPIs and then present different approaches for investigating PPIs, as well as the latest methods for modulating PPIs. Importantly, we comprehensively review the recent progress in the development of allosteric modulators to inhibit or stabilize PPIs. Finally, we conclude with future perspectives on the discovery of allosteric PPI modulators, especially the application of computational methods to aid in allosteric PPI drug discovery.
Identifying and characterizing treatment‐resistant schizophrenia in observational database studies
Authors: Jönsson Linus , Simonsen Jacob , Brain Cecilia , Kymes Steven , Watson Louise 
Published: April 2019

AbstractObjectivesTreatment‐resistant schizophrenia (TRS) is clinically defined as failure to respond to two antipsychotics of adequate dose and duration. An algorithm (registry TRS) was developed, for identifying patients with TRS in claim datasets from Sweden and the United States.MethodsSchizophrenia (SZ) patients aged ≥13 years were identified in both datasets and matched to controls. Patients were identified as having TRS by use of the registry TRS or ≥1 prescription for clozapine or use of other published criteria. The algorithm was compared for sensitivity, and patients with and without TRS were compared for psychiatric and hospital burden and Global Assessment of Functioning (GAF) scores. TRS prevalence was not assessed due to lack of clinically validated data to test the specificity of the algorithm.ResultsSwedish registry TRS patients ≤45 years at first SZ diagnosis had significantly lower GAF scores and earlier disease onset than non‐TRS patients. SZ patients with higher psychiatric comorbidity and hospital burden were more likely identified as TRS by all algorithms. The registry algorithm was significantly more sensitive to multiple inpatient stays and all psychiatric comorbidities at identifying TRS.ConclusionThe registry algorithm appeared more sensitive at identifying patients with TRS, who had greater psychiatric and hospital burden.
Seasonal and pharmaceutical‐induced changes in selenoprotein glutathione peroxidase 4 activity in the reproductive dynamics of the soil biosentinel Podarcis sicula (Chordata: Reptilia)
Authors: Guerriero Giulia , Parisi Costantino , Abdel‐Gawad Fagr Kh. , Hentati Olfa , D'Errico Gerardino 
Published: April 2019

AbstractThere is rising concern for the interaction of environmental contaminants with brain transcriptome and the potential effect on reproductive processes. The present study sought to determine selenoprotein glutathione peroxidase 4 (gpx4) transcriptional activity in the brain and testis of the soil biosentinel, Podarcis sicula, through the main phases of the reproductive cycle and whether pharmaceuticals exert an endocrine disruption. Based on gpx4 cloned amminoacids sequence (GenBank AEX09236.1.), we used a bioinformatic approach to assess the structural role. Specifically, we detected seasonally the reactive oxygen species (ROS) level using electron spin resonance spectroscopy and gpx4 transcriptional activity using quantitative real‐time polymerase chain reaction. In addition, the impact of pharmaceuticals was assessed after 21‐days of treatment with ICI 182,780 and human chorionic gonadotropin administration in mating and winter stasis, respectively. Bioinformatic data shows the gpx4 proteic activity and a phylogenetic profile. ROS contents in lizard brain are significantly less than in testis and display higher levels after treatments. Brain gpx4 expression gives statistically significant seasonal differences, opposite trends in testis and altered expression in both tissues, with evidence of testis morphological and DNA disruption. Taken together, these results provide direct evidence that gpx4 in P. sicula plays a seasonal regulatory role and may be a reliable biomarker for reproductive health toxicity screening.
Task‐based assessment of a convolutional neural network for segmenting breast lesions for radiomic analysis
Authors: Spuhler Karl D. , Ding Jie , Liu Chunling , Sun Junqi , Serrano‐Sosa Mario , Moriarty Meghan , Huang Chuan 
Published: April 2019

PurposeRadiomics allows for powerful data‐mining and feature extraction techniques to guide clinical decision making. Image segmentation is a necessary step in such pipelines and different techniques can significantly affect results. We demonstrate that a convolutional neural network (CNN) segmentation method performs comparably to expert manual segmentations in an established radiomics pipeline.MethodsUsing the manual regions of interest (ROIs) of an expert radiologist (R1), a CNN was trained to segment breast lesions from dynamic contrast‐enhanced MRI (DCE‐MRI). Following network training, we segmented lesions for the testing set of a previously established radiomics pipeline for predicting lymph node metastases using DCE‐MRI of breast cancer. Prediction accuracy of CNN segmentations relative to manual segmentations by R1 from the original study, a resident (R2), and another expert radiologist (R3) were determined. We then retrained the CNN and radiomics model using R3’s manual segmentations to determine the effects of different expert observers on end‐to‐end prediction.ResultsUsing R1’s ROIs, the CNN achieved a mean Dice coefficient of 0.71 ± 0.16 in the testing set. When input to our previously published radiomics pipeline, these CNN segmentations achieved comparable prediction performance to R1’s manual ROIs, and superior performance to those of the other radiologists. Similar results were seen when training the CNN and radiomics model using R3’s ROIs.ConclusionA CNN architecture is able to provide DCE‐MRI breast lesion segmentations which are suitable for input to our radiomics model. Moreover, the previously established radiomics model and CNN can be accurately trained end‐to‐end using ground truth data provided by distinct experts.
Nonfragile reliable control for positive switched systems with actuator faults and saturation
Authors: Li Miao , Zhang Junfeng , Jia Xianglei , Yang Haoyue 
Published: April 2019

SummaryThis paper presents a nonfragile reliable control approach to positive switched systems with actuator faults and saturation. In order to guarantee the reliability of the controller, the controller gain matrix is chosen as the sum of a normal gain matrix and a gain perturbation matrix. A nonfragile reliable control is first proposed for the considered systems using a gain matrix decomposition technique. Then, the presented nonfragile control design approach is developed for the systems with exogenous disturbances. An approach to compute the normal gain matrix and the gain perturbation matrix is also provided. Under the obtained controller, the resulting closed‐loop systems are positive and L1‐gain stable. Meanwhile, all the states will stay inside a cone. All presented conditions are described via linear programming. Finally, two examples are provided to verify the effectiveness of the theory findings.
Novel ultrafiltration membranes with the least fouling properties for the treatment of veterinary antibiotics in the pharmaceutical wastewater
Authors: Bojaran Majid , Akbari Ahmad , Yunessnia lehi Arash 
Published: April 2019

Dendrimers have received more attention in all fields of research these days. In the present study, polyamidoamine (PAMAM) dendrimers were synthesized on the acrylic ultrafiltration membranes to minimize fouling as an important deficiency in the separation process. The antifouling activity of these dendrimers with different generations (G0‐3) was tested to restrict three macrolides (tylvalosin, tylosin, and tulathromycin) and two pleuromutilins (tiamulin and valnemulin) as veterinary antibiotic drugs with amine groups and positive charges at pH = 7 of the membrane surface. These compounds are risky for human consumption. Due to having several amine functional groups and branches, PAMAM dendrimers can be a great coating agent for antifouling. G3 PAMAM dendrimer‐coated membranes had the best performance (water flux: 130.7 L/m2·h, rejection of tulathromycin: 91.4%, flux recovery ratio: 86.3%). The function of this ultrafiltration process depended on pore size and also charge surface. A significant reduction for irreversible and reversible fouling was observed for this new ultrafiltration membrane (Fir: 14.5%, Fre: 21.9%). This observation was confirmed by the power law model. Three 5‐hour cycle ultrafiltration processes were carried out for veterinary antibiotic wastewater that showed 3.18% loss of initial water flux (for the third cycle), final cleaning efficiency of 96.82%, and tylvalosin rejection of 94.1%.
A pilot evaluation of the social validity of a bullying bystander program adapted for high school students
Authors: Doumas Diana M. , Midgett Aida , Watts April D. 
Published: April 2019

AbstractAlthough school‐based programs are effective at decreasing bullying, the majority of studies have been conducted with elementary and middle school students. We conducted a pilot study using a randomized controlled design investigating the social validity of a brief, bullying bystander program adapted to be age‐appropriate for high school students (N = 65). Results indicated that high school students in the intervention group perceived the program to be acceptable and relevant and reported greater increases in knowledge ( = 0.27) and confidence to intervene ( = 0.27) in bullying situations compared to students in the control group. Despite being trained in the use of four intervention strategies, students reported using two of the strategies infrequently. Additionally, we found a significant difference between the intervention and control group for only one strategy (Φ = −0.44). This study provides partial support for the social validity of the adapted program. Implications for implementing the program at the high school level are discussed.
Activation of cGMP/PKG/p65 signaling associated with PDE5‐Is downregulates CCL5 secretion by CD8+ T cells in benign prostatic hyperplasia
Authors: Jin Song , Xiang Peng , Liu Jie , Yang Yang , Hu Shuai , Sheng Jindong , He Qun , Yu Wei , Han Wenke , Jin Jie , Peng Jing 
Published: April 2019

AbstractBackgroundBenign prostatic hyperplasia (BPH) is the most common urological disease in elderly men, but the underlying pathophysiological mechanisms are complex and not fully understood. Phosphodiesterase type 5 inhibitors (PDE5‐Is) used to treat BPH could upregulate the cyclic guanosine monophosphate (cGMP)‐dependent protein kinase G (PKG) signaling, which was shown to blunt inflammation in the prostate. Our previous findings indicate that CD8+ T cells promote the proliferation of BPH epithelial cells (BECs) in low androgen conditions through secretion of CCL5; however, the role of the cGMP/PKG pathway in the process is unclear.MethodsParaffin‐embedded tissues were used for expression quantity of CD8+ T cells, CCL5, cyclin D1, and PDE5 protein by immunohistology in prostate specimens which were/were not treated with finasteride 5 mg daily for at least 6 months before surgery. BPH‐1 cells were cocultured with or without CD8
+ T cells or PDE5‐Is in low androgen conditions for 4 days. The conditioned media, BPH‐1 cells, and CD8
+ T cells were harvested for the subsequent experiments. The quantitative polymerase chain reaction was used for assaying the level of messenger RNA expression of CCL5. CCL5 in the conditioned media was detected by the enzyme‐linked immunosorbent assay. The effect of PDE5‐Is on cocultured BPH‐1/CD8
+ T‐cell proliferation was detected by the cell counting kit‐8. A high‐fat diet (HFD)‐induced prostatic hyperplasia rat model was used to investigate the effect of cGMP/PKG activation in CD8
+ T cells in vivo.ResultsCD8+ T‐cell infiltration into human BPH tissues was positively correlated with the expression of CCL5, cyclin D1, and PDE5, whereas in an HFD‐induced prostatic hyperplasia rat model, the activation of the cGMP/PKG signaling by a PDE5‐I could suppress the CD8
+ T‐cell infiltration and the CCL5 and cyclin D1 expression. Furthermore, the activation of the cGMP/PKG pathway inhibited CCL5 secretion by CD8
+ T cells by downregulating nuclear factor‐κB p65 phosphorylation, which reduced the growth of BPH‐1 through CCL5/STAT5/CCND1 signaling.ConclusionsOur results indicate that the upregulation of the cGMP/PKG/p65 signaling reduces CCL5 secretion in CD8
+ T cells, which in turn decreases the proliferation of BECs in low androgen conditions, suggesting that the combination of 5α reductase inhibitors lowering androgen levels and PDE5‐Is may be a novel, more effective treatment for BPH patients.
Protein kinase D1 induces G1‐phase cell‐cycle arrest independent of Checkpoint kinases by phosphorylating Cell Division Cycle Phosphatase 25
Authors: Nickkholgh Bita , Sittadjody Sivanandane , Ordonez Karina , Rothberg Michael Bryan , Balaji K. C. 
Published: April 2019

AbstractProtein Kinase D1 (PrKD1) functions as a tumor and metastasis suppressor in several human cancers by influencing cell‐cycle progression. However, the exact mechanism of cell‐cycle regulation by PrKD1 is unclear. Overexpression and ectopic expression of PrKD1 induces G1 arrest in cancer cell lines. Because checkpoint kinases (CHEKs) are known to play a role in progression through the G1 phase, we downregulated CHEK1, which did not overcome the G1 arrest induced by PrKD1. Using in vitro phosphorylation and Western blot assays, we showed that PrKD1 phosphorylates all CDC25 isoforms (known substrates of CHEK kinases), independent from CHEK kinases, suggesting that direct phosphorylation of CDC25 by PrKD1 may be an alternate mechanism of G1 arrest. The study has identified a molecular mechanism for the influence of PrKD1 in cell‐cycle progression.
Benzimidazole‐Substituted Indolo[3,2‐b]carbazoles: Acid‐Responsive Probes
Authors: Kadam Vinay S. , Bhatt Prachi A. , Karmakar Himadri S. , Zade Sanjio S. , Patel Arun L. 
Published: April 2019

AbstractBenzimidazole substituted indolo[3,2‐b]carbazole derivatives (5 and 6) were synthesized by formylation of N,N′‐dioctylindolo[3,2‐b]carbazole followed by reaction with o‐phenyelene diamine. The structures of these two compounds were characterized by high resolution mass‐spectrometry (HRMS) and NMR (1H and 13C) spectroscopy. Their photophysical and electrochemical properties were studied by absorption and emission spectroscopy and cyclic voltammetry. Compounds 5 and 6 showed sensitivity towards acid in solution as well as in the solid state. Density functional theory (DFT) studies showed that compound 5 is more planar compared to 6. Frontier molecular orbitals (FMO) analysis suggested that photoinduced electron transfer (PET) from indolo[3,2‐b]carbazole moiety (fluorophore) to the protonated benzimidazole unit results in quenching.
A Kinetic Study of the Intramolecular Nitroaldol (Henry) Reaction Giving 2‐Nitroindan‐1‐ols
Authors: Horáková Eva , Valtr Jakub , Dostálová Kamila , Drabina Pavel , Váňa Jiří , Růžička Aleš , Hanusek Jiří 
Published: April 2019

AbstractAn intramolecular base‐catalyzed nitroaldol reaction of three newly prepared 2‐(2‐nitroalkyl)benzaldehydes (1a‐c) giving corresponding 2‐nitroindan‐1‐ols (2a‐c) was studied in water and five non‐aqueous solvents. Whilst for the parent 2‐(2‐nitroethyl)benzaldehyde (1a) the reaction takes place in two kinetically discernible steps – deprotonation and cyclization, for 2‐(2‐nitropropyl)‐ and 2‐(2‐nitro‐2‐phenylethyl)benzaldehydes 1b and 1c general base‐catalyzed formation of a reactive carbanion is rate‐limitting. An unusually high Brønsted coefficient (βB=1.12 ± 0.03) was found for 1b indicating smaller imbalance of the transition state whose structure therefore resembles a nitronate. Cyclization products 2a‐c prefer relative trans‐configuration in ratios from 55:45 to 83:17 depending on the solvent. Mutual interconversion of the cis‐/trans‐diastereoisomers occurs either via nitronate species 2a– or via a reverse ring opening/ring closing pathway through the nitronate species 1b– and 1c–. The mechanism was also supported by quantum calculations.
Unveiling the Interfacial Effects for Enhanced Hydrogen Evolution Reaction on MoS2/WTe2 Hybrid Structures
Authors: Zhou Yu , Pondick Joshua V. , Silva Jose Luis , Woods John M. , Hynek David J. , Matthews Grace , Shen Xin , Feng Qingliang , Liu Wen , Lu Zhixing , Liang Zhixiu , Brena Barbara , Cai Zhao , Wu Min , Jiao Liying , Hu Shu , Wang Hailiang , Araujo Carlos Moyses , Cha Judy J. 
Published: April 2019

AbstractUsing the MoS2‐WTe2 heterostructure as a model system combined with electrochemical microreactors and density function theory calculations, it is shown that heterostructured contacts enhance the hydrogen evolution reaction (HER) activity of monolayer MoS2. Two possible mechanisms are suggested to explain this enhancement: efficient charge injection through large‐area heterojunctions between MoS2 and WTe2 and effective screening of mirror charges due to the semimetallic nature of WTe2. The dielectric screening effect is proven minor, probed by measuring the HER activity of monolayer MoS2 on various support substrates with dielectric constants ranging from 4 to 300. Thus, the enhanced HER is attributed to the increased charge injection into MoS2 through large‐area heterojunctions. Based on this understanding, a MoS2/WTe2 hybrid catalyst is fabricated with an HER overpotential of −140 mV at 10 mA cm−2, a Tafel slope of 40 mV dec−1, and long stability. These results demonstrate the importance of interfacial design in transition metal dichalcogenide HER catalysts. The microreactor platform presents an unambiguous approach to probe interfacial effects in various electrocatalytic reactions.
Scalable Nanoshaping of Hierarchical Metallic Patterns with Multiplex Laser Shock Imprinting Using Soft Optical Disks
Authors: Jin Shengyu , Zhou Zhiguang , Sakr Enas Said Attia , Motlag Maithilee , Huang Xinyu , Tong Lei , Bermel Peter , Ye Lei , Cheng Gary J. 
Published: April 2019

AbstractLarge‐area patterning of metals in nanoscale has always been a challenge. Traditional microfabrication processes involve many high‐cost steps, including etching and high‐vacuum deposit, which limit the development of functional nanostructures, especially multiscale metallic patterns. Here, multiplex laser shock imprinting (MLSI) process is introduced to directly manufacture hierarchical micro/nanopatterns at a high strain rate on metallic surfaces using soft optical disks with 1D periodic trenches as molds. The unique metal/polymer layered structures in inexpensive soft optical disks make them strong candidates of molds for MLSI processes. The feasibility of MLSI on hard metals toward soft molds is studied using theoretical simulation. In addition, various types of hierarchical structures are fabricated via MLSI, and their optical reflectance can be modulated via a combination of depth (laser power density), width (types of molds), and angles (rotation between molds). The optical properties have been studied with surface plasmon polariton modes theory. This work opens a new way of manufacturing hierarchical micro/nanopatterns on metals, which is promising for future applications in fields of plasmonics and metasurfaces.
Directional Fano Resonance in an Individual GaAs Nanospheroid
Authors: Ma Churong , Yan Jiahao , Huang Yingcong , Yang Guowei 
Published: April 2019

AbstractFano resonance has been observed in a wide variety of nanophotonic structures such as photonic crystals, plasmonic structures, and metamaterials. It arises from the interference of discrete resonance states with broadband continuum states. As an emerging nanophotonic material, high‐index all‐dielectric nanomaterials provide a new platform to achieve Fano resonance by virtue of the simultaneous excited electric and magnetic resonances. However, to date, Fano resonance in the visible region has not been observed in individual high‐index all‐dielectric nanoparticles. Here, for the first time, the experimental observation of the directional Fano resonance is reported in an individual GaAs nanospheroid. The special geometry enables GaAs nanospheroids to generate spectrally overlapped electric and magnetic dipole resonances, which enhances their spectral coupling, giving rise to asymmetric‐shaped backward scattering spectrum. This directional Fano resonance can be tuned by the aspect ratio of nanospheroids as well as excitation polarization. In addition, efficient directional light scattering is realized at the total scattering peak of the GaAs nanospheroid. The forward‐to‐backward scattering ratio can be largely enhanced due to Fano dip in the backward scattering spectrum. These findings suggest that high‐index all‐dielectric nanospheroid is a promising candidate for directional sources and optical switches.
Oriented Polarization Tuning Broadband Absorption from Flexible Hierarchical ZnO Arrays Vertically Supported on Carbon Cloth
Authors: Wang Lei , Li Xiao , Li Qingqing , Yu Xuefeng , Zhao Yunhao , Zhang Jie , Wang Min , Che Renchao 
Published: April 2019

AbstractA novel strategy is used to design large‐scale polarized carbon‐based dielectric composites with sufficient interaction to electromagnetic waves. Highly uniform polar zinc oxide arrays are vertically grown on a flexible conductive carbon cloth substrate (CC@ZnO) via an in situ orientation growth process. Anion regulation is found to be a key factor to the morphology of hierarchical ZnO arrays including single‐rod, cluster and tetrapod‐shaped. As a typical dielectric loss hybrid composite, the electromagnetic parameters of the CC@ZnO system and charge density distribution in polarized ZnO rods confirm that the 3D intertwined carbon cloth is used as a conductive network to provide ballistic electron transportation. Moreover, the defect‐rich ZnO arrays are well in contact with the CC substrate, favoring interface polarization, multiscattering, as well as impedance matching. Surprisingly, the efficient absorption bandwidth of the CC@ZnO‐1 composite can reach 10.6 GHz, covering all X and Ku bands. The oriented ZnO possesses oxygen vacancies and exposure to a large amount of intrinsic polar surfaces, encouraging the polarization behavior under microwave frequency. Optimized CC@ZnO materials exhibit fast electron transportation, strong microwave energy dissipation, and superior wide absorption. The results suggest that the CC@ZnO composites have promising potential as flexible, tuning, and broadband microwave absorbers.