bluuebunny/crossref_metadata_2025_split huggingface dataset:
An experimentally validated approach to calculate the blood-brain barrier permeability of small molecules
Authors: Wang Yukun , Gallagher Erin , Jorgensen Christian , Troendle Evan P. , Hu Dan , Searson Peter C. , Ulmschneider Martin. B. 
Published: April 2019

AbstractDrug development for the treatment of central nervous system (CNS) diseases is extremely challenging, in large part due to the difficulty in crossing the blood-brain barrier (BBB). Here we develop and experimentally validate a newin silicomethod to predict quantitatively the BBB permeability for small-molecule drugs. We show accurate prediction of solute permeabilities at physiological temperature using high-temperature unbiased atomic detail molecular dynamics simulations of spontaneous drug diffusion across BBB bilayers. These simulations provide atomic detail insights into the transport mechanisms, as well as converged kinetics and thermodynamics. The method is validated computationally against physiological temperature simulations for fast-diffusing compounds, as well as experimentally by direct determination of the compound permeabilities using a transwell assay as anin vitroBBB model. The overall agreement of the predicted values with both direct simulations at physiological temperatures and experimental data is excellent. This new tool has the potential to replace current semi-empiricalin silicoscreening andin vitropermeability measurements in CNS drug discovery.
Estrogen receptor beta enhances chemotherapy response of GBM cells by down regulating DNA damage response pathways
Authors: Zhou Mei , Sareddy Gangadhara R. , Li Mengxing , Liu Jinyou , Luo Yiliao , Venkata Prabhakar Pitta , Viswanadhapalli Suryavathi , Tekmal Rajeshwar R. , Brenner Andrew , Vadlamudi Ratna K. 
Published: April 2019

AbstractGlioblastoma (GBM) is the most commonly diagnosed brain tumor that exhibit high mortality rate and chemotherapy resistance is a major clinical problem. Recent studies suggest that estrogen receptor beta (ERβ), may function as a tumor suppressor in GBM. However, the mechanism(s) by which ERβ contributes to GBM suppression and chemotherapy response remains unknown. We examined the role of ERβ in the DNA damage response of GBM cells, and tested whether ERβ sensitizes GBM cells to chemotherapy. Cell viability and survival assays using multiple epitope tagged ERβ expressing established and primary GBM cells demonstrated that ERβ sensitizes GBM cells to DNA damaging agents including temozolomide (TMZ). RNA-seq studies using ERβ overexpression models revealed downregulation of number of genes involved in DNA recombination and repair, ATM signaling and cell cycle check point control. Gene set enrichment analysis (GSEA) suggested that ERβ–modulated genes were correlated negatively with homologous recombination, mismatch repair and G2M checkpoint genes. Further, RT-qPCR analysis revealed that chemotherapy induced activation of cell cycle arrest and apoptosis genes were attenuated in ERβKO cells. Additionally, ERβ overexpressing cells had a higher number of γH2AX foci following TMZ treatment. Mechanistic studies showed that ERβ plays an important role in homologous recombination (HR) mediated repair and ERβ reduced expression and activation of ATM upon DNA damage. More importantly, GBM cells expressing ERβ had increased survival when compared to control GBM cells in orthotopic GBM models. ERβ overexpression further enhanced the survival of mice to TMZ therapy in both TMZ sensitive and TMZ resistant GBM models. Additionally, IHC analysis revealed that ERβ tumors had increased expression of γH2AX and cleaved caspase-3. Using ERβ-overexpression and ERβ-KO GBM model cells, we have provided the evidence that ERβ is required for optimal chemotherapy induced DNA damage response and apoptosis in GBM cells.
Social Network Position Moderates the Relationship between Late-life Depressive Symptoms and Memory Differently in Men and Women
Authors: Kim Hairin , Kwak Seyul , Kim Junsol , Youm Yoosik , Chey Jeanyung 
Published: April 2019

AbstractLate-life depression has been considered to be associated with memory deficits and hippocampal volume reduction. Considering that not all depression patients undergo the same amount of cognitive impairment or regional brain volume loss, moderating factors such as complex mental activity and social activity have been examined to assess whether these factors attenuate the detrimental impact of depressive symptoms on cognitive function and regional brain volume. However, the premise that a cognitively stimulating experience may modify the association between depressive symptoms and memory or hippocampal volume has not been investigated using social network data, which would reflect individuals’ concrete characteristic of everyday social activity. In a social network, a brokerage position which connects two otherwise unconnected others demands mental and physical efforts. Using complete social network data in an entire village in South Korea, we examined whether opportunities for brokerage in social networks alter the negative association between depressive symptoms and episodic memory function or hippocampal volume in older adults. Initially, 125 participants were included in the analysis involving episodic memory function. Then, of which 65 participants completed the MRI scan, and were included in the subsequent analysis containing the hippocampal volume. Furthermore, we investigated the gender-specific effect of brokerage based on the previously reported gender difference in the effect of social networks. We found a gender-specific moderating effect of brokerage. For men, a large opportunity for brokerage weakened the negative association between depressive symptoms and memory performance and left hippocampal volume. In contrast, women showed that a large opportunity for brokerage was not beneficial for assuaging the impact of depressive symptoms on memory performance and hippocampal volume. In women, the opportunity for brokerage was positively associated with the detrimental impact of depressive symptoms on memory performance and hippocampal volume. Our findings suggest that occupying a bridging position in a social network may minimize the impact of depressive symptoms on memory function and hippocampal volume among older men, whereas the opposite holds true for older women.
Bedrock-alluvial streams with knickpoint and plunge pool that migrate upstream with permanent form
Authors: Zhang Li , Iwasaki Toshiki , Li Tiejian , Fu Xudong , Wang Guangqian , Parker Gary 
Published: April 2019

AbstractPurely alluvial rivers cannot sustain knickpoints along their long profiles, as they would be obliterated by diffusional morphodynamics. Bedrock streams with a partial alluvial cover, however, form and sustain slope breaks over long periods of time. Here we consider the case of an initial profile of a bedrock-alluvial stream with a sharp slope break, or knickpoint, from high to low midway. We show that if the initial flow is sufficiently Froude-supercritical in the upstream reach and Froude-subcritical in the downstream reach, a three-tiered structure can evolve at the slope break: a hydraulic jump at the water surface; a scour hole in the alluvium above the bedrock, and a plunge pool carved into bedrock. Once the profile adjusts to balance uplift, it can migrate upstream without changing form.
The in vitro host cell immune response to bovine-adapted Staphylococcus aureus varies according to bacterial lineage
Authors: Murphy Mark P. , Niedziela Dagmara A. , Leonard Finola C. , Keane Orla M. 
Published: April 2019

AbstractMastitis is the most economically important disease affecting dairy cattle worldwide. Staphylococcus aureus is a highly prevalent cause of mastitis, causing infections ranging from sub-clinical to gangrenous. However, the interaction between the genotype of the infecting strain of S. aureus and the host response remains largely uncharacterised. To better understand the variation in presentation and outcomes of S. aureus-mediated bovine mastitis, we studied the interaction of a panel of mastitis isolates from several prominent bovine-associated lineages with bovine mammary epithelial cells (bMEC) and neutrophils. Significant differences in immune gene expression by infected primary or immortalised bMEC, or their elaboration of neutrophil chemoattractants, were observed and were dependent on the lineage of the infecting strain. Differences were also apparent in the invasiveness of S. aureus strains and their ability to survive killing by neutrophils. Our results demonstrate that a range of immune responses occur, suggesting the importance of S. aureus strain in dictating mastitis disease course. S. aureus lineages may therefore have adopted differing strategies for exploitation of the intramammary niche. Consequently, improved diagnosis of infecting lineage may enable better prognosis for S. aureus mastitis and reduce morbidity and economic loss.
p27/Kip1 functions as a tumor suppressor and oncoprotein in osteosarcoma
Authors: Currier Arthur W. , Kolb E. A. , Gorlick Richard G. , Roth Michael E. , Gopalakrishnan Vidya , Sampson Valerie B. 
Published: April 2019

AbstractThe p27/kip1 (p27) tumor suppressor inhibits cyclin/cyclin-dependent kinase (CDK) complexes and halts cell cycle progression. p27 further regulates invasion and migration in cancer cells, suggesting p27 also functions as an oncoprotein. Using a human osteosarcoma tissue microarray we identified high expression of cytoplasmic p27 in metastatic tumors. We demonstrated a positive correlation between mRNA and protein expression of p27 and expression of key metastatic markers, vimentin, snail-2, β-catenin and stathmin-1 (STMN1) in patient tumors. Our results show that T198 phosphorylation of p27 controls the interaction between p27 and STMN1 that regulates microtubule stabilization and the invasion and migration of osteosarcoma cells. We found that anti-tumoral activity of gemcitabine and the Wee1 kinase inhibitor AZD1775 in osteosarcoma cells, was dependent on drug sequencing that relied on p27 stabilization. Gemcitabine activated caspase-3 and synergized with AZD1775 through caspase-mediated cleavage of p27, that dissociated from STMN1 and effectively induced apoptosis. Further, blockage of nuclear export of p27 by inhibition of Exportin-1 (XPO1) promoted growth arrest, demonstrating that the biological effects of agents relied on the expression and localization of p27. Together, these data provide a rationale for combining chemotherapy with agents that promote p27 tumor suppressor activity for the treatment of osteosarcoma.
Maf deficiency in T cells dysregulates Treg - TH17 balance leading to spontaneous colitis
Authors: Imbratta Claire , Leblond Marine M. , Bouzourène Hanifa , Speiser Daniel E. , Velin Dominique , Verdeil Grégory 
Published: April 2019

AbstractThe maintenance of homeostasis in the gut is a major challenge for the immune system. Here we demonstrate that the transcription factor MAF plays a central role in T cells for the prevention of gastro-intestinal inflammation. Conditional knock out mice lackingMafin all T cells developed spontaneous late-onset colitis, correlating with a decrease of FOXP3+RORγt+T cells proportion, dampened IL-10 production in the colon and an increase of inflammatory TH17 cells. Strikingly, FOXP3+specific conditional knock out mice for MAF did not develop colitis and demonstrated normal levels of IL-10 in their colon, despite the incapacity of regulatory T cells lacking MAF to suppress colon inflammation inRag1−/−mice transferred with naïve CD4+T cells. We showed that one of the cellular sources of IL-10 in the colon of these mice are TH17 cells. Thus, MAF is critically involved in the maintenance of the gut homeostasis by regulating the balance between Tregand TH17 cells either at the level of their differentiation or through the modulation of their functions.
Complete assembly of the Leishmania donovani (HU3 strain) genome and transcriptome annotation
Authors: Camacho Esther , González-de la Fuente Sandra , Rastrojo Alberto , Peiró-Pastor Ramón , Solana Jose Carlos , Tabera Laura , Gamarro Francisco , Carrasco-Ramiro Fernando , Requena Jose M. , Aguado Begoña 
Published: April 2019

AbstractLeishmania donovani is a unicellular parasite that causes visceral leishmaniasis, a fatal disease in humans. In this study, a complete assembly of the genome of L. donovani is provided. Apart from being the first published genome of this strain (HU3), this constitutes the best assembly for an L. donovani genome attained to date. The use of a combination of sequencing platforms enabled to assemble, without any sequence gap, the 36 chromosomes for this species. Additionally, based on this assembly and using RNA-seq reads derived from poly-A + RNA, the transcriptome for this species, not yet available, was delineated. Alternative SL addition sites and heterogeneity in the poly-A addition sites were commonly observed for most of the genes. After a complete annotation of the transcriptome, 2,410 novel transcripts were defined. Additionally, the relative expression for all transcripts present in the promastigote stage was determined. Events of cis-splicing have been documented to occur during the maturation of the transcripts derived from genes LDHU3_07.0430 and LDHU3_29.3990. The complete genome assembly and the availability of the gene models (including annotation of untranslated regions) are important pieces to understand how differential gene expression occurs in this pathogen, and to decipher phenotypic peculiarities like tissue tropism, clinical disease, and drug susceptibility.
Probing prothrombin structure by limited proteolysis
Authors: Acquasaliente Laura , Pelc Leslie A. , Di Cera Enrico 
Published: April 2019

AbstractProthrombin, or coagulation factor II, is a multidomain zymogen precursor of thrombin that undergoes an allosteric equilibrium between two alternative conformations, open and closed, that react differently with the physiological activator prothrombinase. Specifically, the dominant closed form promotes cleavage at R320 and initiates activation along the meizothrombin pathway, whilst the open form promotes cleavage at R271 and initiates activation along the alternative prethrombin-2 pathway. Here we report how key structural features of prothrombin can be monitored by limited proteolysis with chymotrypsin that attacks W468 in the flexible autolysis loop of the protease domain in the open but not the closed form. Perturbation of prothrombin by selective removal of its constituent Gla domain, kringles and linkers reveals their long-range communication and supports a scenario where stabilization of the open form switches the pathway of activation from meizothrombin to prethrombin-2. We also identify R296 in the A chain of the protease domain as a critical link between the allosteric open-closed equilibrium and exposure of the sites of cleavage at R271 and R320. These findings reveal important new details on the molecular basis of prothrombin function.
Brevibacterium from Austrian hard cheese harbor a putative histamine catabolism pathway and a plasmid for adaptation to the cheese environment
Authors: Anast Justin M. , Dzieciol Monika , Schultz Dylan L. , Wagner Martin , Mann Evelyne , Schmitz-Esser Stephan 
Published: April 2019

AbstractThe genus Brevibacterium harbors many members important for cheese ripening. We performed real-time quantitative PCR (qPCR) to determine the abundance of Brevibacterium on rinds of Vorarlberger Bergkäse, an Austrian artisanal washed-rind hard cheese, over 160 days of ripening. Our results show that Brevibacterium are abundant on Vorarlberger Bergkäse rinds throughout the ripening time. To elucidate the impact of Brevibacterium on cheese production, we analysed the genomes of three cheese rind isolates, L261, S111, and S22. L261 belongs to Brevibacterium aurantiacum, whereas S111 and S22 represent novel species within the genus Brevibacterium based on 16S rRNA gene similarity and average nucleotide identity. Our comparative genomic analysis showed that important cheese ripening enzymes are conserved among the genus Brevibacterium. Strain S22 harbors a 22 kb circular plasmid which encodes putative iron and hydroxymethylpyrimidine/thiamine transporters. Histamine formation in fermented foods can cause histamine intoxication. We revealed the presence of a putative metabolic pathway for histamine degradation. Growth experiments showed that the three Brevibacterium strains can utilize histamine as the sole carbon source. The capability to utilize histamine, possibly encoded by the putative histamine degradation pathway, highlights the importance of Brevibacterium as key cheese ripening cultures beyond their contribution to cheese flavor production.
High-frequency dynamics of evanescently-coupled nanowire lasers
Authors: Adams M. J. , Jevtics D. , Strain M. J. , Henning I. D. , Hurtado A. 
Published: April 2019

AbstractWe analyse the dynamics and conditions for stability in an array of two laterally-coupled nanowire lasers in terms of their separation, difference in resonant frequencies and pumping rate under conditions of weak coupling. We find that the regions of stability are very small and are found close to zero frequency offset between the lasers. Outside these regions various forms of instability including periodic oscillation, chaos and complex dynamics are predicted. Importantly, the analysis of the frequency of periodic oscillations for realistic laser separations and pumping yields values of order 100 GHz thus underlining the significant potential of nanowire laser arrays for ultra-high frequency on-chip systems with very low foot-print and energy requirements.
Different Circulating Trace Amine Profiles in De Novo and Treated Parkinson’s Disease Patients
Authors: D’Andrea Giovanni , Pizzolato Gilberto , Gucciardi Antonina , Stocchero Matteo , Giordano Giuseppe , Baraldi Eugenio , Leon Alberta 
Published: April 2019

AbstractEarly diagnosis of Parkinson’s disease (PD) remains a challenge to date. New evidence highlights the potential clinical value of circulating trace amines (TAs) in early-stage PD and their involvement in disease progression. A new ultra performance chromatography mass spectrometry (UPLC-MS/MS) method was developed to quantify plasmatic TAs, and the catecholamines and indolamines pertaining to the same biochemical pathways. Three groups of subjects were recruited: 21de novo, drug untreated, PD patients, 27 in treatment PD patients and 10 healthy subjects as controls. Multivariate and univariate data analyses were applied to reveal metabolic changes among the groups in attempt to discover new putative markers for early PD detection and disease progression. Different circulating levels of tyrosine (p = 0.002), tyramine (p < 0.001), synephrine (p = 0.015), norepinephrine (p = 0.012), metanephrine (p = 0.001), β-phenylethylamine (p = 0.001) and serotonin (p = 0.006) were found among the three groups. While tyramine behaves as a putative biomarker for early-stage PD (AUC = 0.90) tyramine, norepinephrine, and tyrosine appear to act as biomarkers of disease progression (AUC > 0.75). The findings of this pilot cross-sectional study suggest that biochemical anomalies of the aminergic and indolic neurotransmitters occur in PD patients. Compounds within the TAs family may constitute putative markers for early stage detection and progression of PD.
Inheritance and fitness costs of resistance to Bacillus thuringiensis toxin Cry2Ad in laboratory strains of the diamondback moth, Plutella xylostella (L.)
Authors: Liao Jinying , Xue Yiqun , Xiao Guangjing , Xie Miao , Huang Shuting , You Shijun , Wyckhuys Kris A. G. , You Minsheng 
Published: April 2019

AbstractThe diamondback moth, Plutella xylostella (Lepidoptera: Plutellidae), is one of the main pests of Brassica crops worldwide. Management of P. xylostella is particularly challenging, as different field populations have readily acquired resistance to a wide range of insecticides, including Bacillus thuringiensis (Bt) toxins. In this study, a novel strain of P. xyllostela (Fuzhou-R2Ad) with 120-fold resistance to Bt Cry2Ad was selected in the laboratory, after screening for 66 generations from the susceptible strain Fuzhou-S. In the absence of Bt Cry2Ad toxin, the Fuzhou-R2Ad had significantly lower fitness as compared to the susceptible strain, which might be related to induced genetic changes to Bt toxins. We used several models to measure the dominance levels of insecticide resistance among different strains and found an incompletely recessive inheritance pattern of the Fuzhou-R2Ad resistance, which might be controlled by multiple genes. This study constitutes the first report of laboratory-acquired resistance to Cry2Ad toxin in P. xylostella. Our work presents further insights into the mechanism of Bt resistance and has immediate implications for the integrated pest management of P. xylostella globally.
Precision and informational limits in inelastic optical spectroscopy
Authors: Török Peter , Foreman Matthew R. 
Published: April 2019

AbstractUsing Fisher information and the Cramér-Rao lower bound, we analyse fundamental precision limits in the determination of spectral parameters in inelastic optical scattering. General analytic formulae are derived which account for the instrument response functions of the dispersive element and relay optics found in practical Raman and Brillouin spectrometers. Limiting cases of dispersion and diffraction limited spectrometers, corresponding to measurement of Lorentzian and Voigt lineshapes respectively, are discussed in detail allowing optimal configurations to be identified. Effects of defocus, spherical aberration, detector pixelation and a finite detector size are also considered.
Quantum Effects In Imaging Nano-Structures Using Photon-Induced Near-Field Electron Microscopy
Authors: Etman Naglaa , Said Afaf M. A. , Atia Khaled S. R. , Sultan Reem , Hameed Mohamed Farhat O. , Amin Muhamed , Obayya S. S. A. 
Published: April 2019

AbstractIn this paper, we introduce the quantum mechanical approach as a more physically-realistic model to accurately quantify the electron-photon interaction in Photon-induced near-field electron microscopy (PINEM). Further, we compare the maximum coupling speed between the electrons and the photons in the quantum and classical regime. For a nanosphere of radius 2.13 nm, full quantum calculations show that the maximum coupling between photon and electron occurs at a slower speed than classical calculations report. In addition, a significant reduction in PINEM field intensity is observed for the full quantum model. Furthermore, we discuss the size limitation for particles imaged using the PIMEN technique and the role of the background material in improving the PINEM intensity. We further report a significant reduction in PINEM intensity in nearly touching plasmonic particles (0.3 nm gap) due to tunneling effect.