bluuebunny/crossref_metadata_2025_split huggingface dataset:
Super-resolution localization photoacoustic microscopy using intrinsic red blood cells as contrast absorbers
Authors: Kim Jongbeom , Kim Jin Young , Jeon Seungwan , BAIK Jin Woo , Cho Seong Hee , Kim Chulhong 
Published: November 2019

AbstractPhotoacoustic microscopy (PAM) has become a premier microscopy tool that can provide the anatomical, functional, and molecular information of animals and humans in vivo. However, conventional PAM systems suffer from limited temporal and/or spatial resolution. Here, we present a fast PAM system and an agent-free localization method based on a stable and commercial galvanometer scanner with a custom-made scanning mirror (L-PAM-GS). This novel hardware implementation enhances the temporal resolution significantly while maintaining a high signal-to-noise ratio (SNR). These improvements allow us to photoacoustically and noninvasively observe the microvasculatures of small animals and humans in vivo. Furthermore, the functional hemodynamics, namely, the blood flow rate in the microvasculature, is successfully monitored and quantified in vivo. More importantly, thanks to the high SNR and fast B-mode rate (500 Hz), by localizing photoacoustic signals from captured red blood cells without any contrast agent, unresolved microvessels are clearly distinguished, and the spatial resolution is improved by a factor of 2.5 in vivo. L-PAM-GS has great potential in various fields, such as neurology, oncology, and pathology.
Identification of novel common variants associated with chronic pain using conditional false discovery rate analysis with major depressive disorder and assessment of pleiotropic effects of LRFN5
Authors: Johnston Keira J. A. , Adams Mark J. , Nicholl Barbara I. , Ward Joey , Strawbridge Rona J. , McIntosh Andrew M. , Smith Daniel J. , Bailey Mark E. S. 
Published: November 2019

AbstractChronic pain is a complex trait that is moderately heritable and genetically, as well as phenotypically, correlated with major depressive disorder (MDD). Use of the conditional false discovery rate (cFDR) approach, which leverages pleiotropy identified from existing GWAS outputs, has been successful in discovering novel associated variants in related phenotypes. Here, genome-wide association study outputs for both von Korff chronic pain grade and for MDD were used to identify variants meeting a cFDR threshold for each outcome phenotype separately, as well as a conjunctional cFDR (ccFDR) threshold for both phenotypes together. Using a moderately conservative threshold, we identified a total of 11 novel single nucleotide polymorphisms (SNPs), six of which were associated with chronic pain grade and nine of which were associated with MDD. Four SNPs on chromosome 14 were associated with both chronic pain grade and MDD. SNPs associated only with chronic pain grade were located withinSLC16A7on chromosome 12. SNPs associated only with MDD were located either in a gene-dense region on chromosome 1 harbouringLINC01360,LRRIQ3, FPGTandFPGT-TNNI3K, or within/close toLRFN5on chromosome 14. The SNPs associated with both outcomes were also located withinLRFN5. Several of the SNPs on chromosomes 1 and 14 were identified as being associated with expression levels of nearby genes in the brain and central nervous system. Overall, using the cFDR approach, we identified several novel genetic loci associated with chronic pain and we describe likely pleiotropic effects of a recently identified MDD locus on chronic pain.
The association between antibodies to neurotropic pathogens and bipolar disorder
Authors: Snijders Gijsje J. L. J. , van Mierlo Hans C. , Boks Marco P. , Begemann Marieke J. H. , Sutterland Arjen L. , Litjens Manja , Ophoff Roel A. , Kahn René S. , de Witte Lot D. 
Published: November 2019

AbstractExposure to neurotropic pathogens has been hypothesized to be a risk factor for the development of bipolar disorder (BD). However, evidence so far is inconsistent. We, therefore, analyzed the seroprevalence and titer levels of IgG antibodies against several herpesviruses and Toxoplasma gondii (T. gondii) in plasma of 760 patients with a bipolar disorder, 144 first-degree matched relatives and 132 controls of the Dutch Bipolar (DB) Cohort using ELISA. In addition, we performed a literature-based meta-analysis on the seroprevalence of IgG antibodies against these pathogens (n = 14). Our results in the DB Cohort and subsequent meta-analysis (n = 2364 BD patients, n = 5101 controls) show no association between exposure to herpesviruses and bipolar disorder (HSV-1 [adjusted OR 0.842, 95% CI 0.567–1.230], HSV-2 [adjusted OR 0.877, 95% CI 0.437–1.761], CMV [adjusted OR 0.884 95% CI 0.603–1.295], EBV [adjusted OR 0.968 95% CI 0.658–1.423]). In the DB Cohort, we did not find an association between bipolar disorder and T. gondii titer or seroprevalence either [adjusted OR 1.018, 95% CI 0.672–1.542]. The overall OR was not significant for T. gondii [OR: 1.4, 95% CI 0.95–1.90, p = 0.09), but subgroup analyses in age groups below 40 years showed a significantly increased seroprevalence of T. gondii IgGs in BD [OR: 1.8 (95% CI 1.10–2.89, p = 0.021]. Our meta-analysis indicates that T. gondii exposure may be a risk factor for BD in certain subpopulations.
Down-regulation of TUFM impairs host cell interaction and virulence by Paracoccidioides brasiliensis
Authors: Marcos Caroline Maria , Tamer Gabrielle , de Oliveira Haroldo Cesar , Assato Patricia Akemi , Scorzoni Liliana , Santos Claudia Tavares , de Lacorte Singulani Junya , de Fátima da Silva Julhiany , de Almeida Rodrigo , de Paula e Silva Ana Carolina Alves , da Silva Rosangela Aparecida Moraes , de Andrade Cleverton Roberto , Tamayo Diana Patricia , Lopez Angela Maria , Barbosa Natália Moreira , Zanelli Cleslei Fernando , Hernandez- Ruiz Orville , McEwen Juan G. , Mendes-Giannini Maria José Soares , Fusco-Almeida Ana Marisa 
Published: November 2019

AbstractThe genus Paracoccidioides consist of dimorphic fungi geographically limited to the subtropical regions of Latin America, which are responsible for causing deep systemic mycosis in humans. However, the molecular mechanisms by which Paracoccidioides spp. causes the disease remain poorly understood. Paracoccidioides spp. harbor genes that encode proteins involved in host cell interaction and mitochondrial function, which together are required for pathogenicity and mediate virulence. Previously, we identified TufM (previously known as EF-Tu) in Paracoccidioides brasiliensis (PbTufM) and suggested that it may be involved in the pathogenicity of this fungus. In this study, we examined the effects of downregulating PbTUFM using a silenced strain with a 55% reduction in PbTUFM expression obtained by antisense-RNA (aRNA) technology. Silencing PbTUFM yielded phenotypic differences, such as altered translation elongation, respiratory defects, increased sensitivity of yeast cells to reactive oxygen stress, survival after macrophage phagocytosis, and reduced interaction with pneumocytes. These results were associated with reduced virulence in Galleria mellonella and murine infection models, emphasizing the importance of PbTufM in the full virulence of P. brasiliensis and its potential as a target for antifungal agents against paracoccidioidomycosis.
Non-genomic effects of the Pregnane X Receptor negatively regulate platelet functions, thrombosis and haemostasis
Authors: Flora Gagan D. , Sahli Khaled A. , Sasikumar Parvathy , Holbrook Lisa-Marie , Stainer Alexander R. , AlOuda Sarah K. , Crescente Marilena , Sage Tanya , Unsworth Amanda J. , Gibbins Jonathan M. 
Published: November 2019

AbstractThe pregnane X receptor (PXR) is a nuclear receptor (NR), involved in the detoxification of xenobiotic compounds. Recently, its presence was reported in the human vasculature and its ligands were proposed to exhibit anti-atherosclerotic effects. Since platelets contribute towards the development of atherosclerosis and possess numerous NRs, we investigated the expression of PXR in platelets along with the ability of its ligands to modulate platelet activation. The expression of PXR in human platelets was confirmed using immunoprecipitation analysis. Treatment with PXR ligands was found to inhibit platelet functions stimulated by a range of agonists, with platelet aggregation, granule secretion, adhesion and spreading on fibrinogen all attenuated along with a reduction in thrombus formation (bothin vitroandin vivo). The effects of PXR ligands were observed in a species-specific manner, and the human-specific ligand, SR12813, was observed to attenuate thrombus formationin vivoin humanised PXR transgenic mice. PXR ligand-mediated inhibition of platelet function was found to be associated with the inhibition of Src-family kinases (SFKs). This study identifies acute, non-genomic regulatory effects of PXR ligands on platelet function and thrombus formation. In combination with the emerging anti-atherosclerotic properties of PXR ligands, these anti-thrombotic effects may provide additional cardio-protective benefits.
FlySilico: Flux balance modeling of Drosophila larval growth and resource allocation
Authors: Schönborn Jürgen Wilhelm , Jehrke Lisa , Mettler-Altmann Tabea , Beller Mathias 
Published: November 2019

AbstractOrganisms depend on a highly connected and regulated network of biochemical reactions fueling life sustaining and growth promoting functions. While details of this metabolic network are well established, knowledge of the superordinate regulatory design principles is limited. Here, we investigated by iterative wet lab and modeling experiments the resource allocation process during the larval development of Drosophila melanogaster. We chose this system, as survival of the animals depends on the successful allocation of their available resources to the conflicting processes of growth and storage metabolite deposition. First, we generated “FlySilico”, a curated metabolic network of Drosophila, and performed time-resolved growth and metabolite measurements with larvae raised on a holidic diet. Subsequently, we performed flux balance analysis simulations and tested the predictive power of our model by simulating the impact of diet alterations on growth and metabolism. Our predictions correctly identified the essential amino acids as growth limiting factor, and metabolic flux differences in agreement with our experimental data. Thus, we present a framework to study important questions of resource allocation in a multicellular organism including process priorization and optimality principles.
Identification of cell context-dependent YAP-associated proteins reveals β1 and β4 integrin mediate YAP translocation independently of cell spreading
Authors: Lee Joanna Y. , Dominguez Antonia A. , Nam Sungmin , Stowers Ryan S. , Qi Lei. S , Chaudhuri Ovijit 
Published: November 2019

AbstractYes-associated protein (YAP) is a transcriptional regulator and mechanotransducer, relaying extracellular matrix (ECM) stiffness into proliferative gene expression in 2D culture. Previous studies show that YAP activation is dependent on F-actin stress fiber mediated nuclear pore opening, however the protein mediators of YAP translocation remain unclear. Here, we show that YAP co-localizes with F-actin during activating conditions, such as sparse plating and culturing on stiff 2D substrates. To identify proteins mediating YAP translocation, we performed co-immunoprecipitation followed by mass spectrometry (co-IP/MS) for proteins that differentially associated with YAP under activating conditions. Interestingly, YAP preferentially associates with β1 integrin under activating conditions, and β4 integrin under inactivating conditions. In activating conditions, CRISPR/Cas9 knockout (KO) of β1 integrin (ΔITGB1) resulted in decreased cell area, which correlated with decreased YAP nuclear localization. ΔITGB1 did not significantly affect the slope of the correlation between YAP nuclear localization with area, but did decrease overall nuclear YAP independently of cell spreading. In contrast, β4 integrin KO (ΔITGB4) cells showed no change in cell area and similarly decreased nuclear YAP. These results reveal proteins that differentially associate with YAP during activation, which may aid in regulating YAP nuclear translocation.
Freezing of gaze during action preparation under threat imminence
Authors: Rösler Lara , Gamer Matthias 
Published: November 2019

AbstractWhen confronted with threatening stimuli, animals typically respond with freezing behavior characterized by reduced movement and heart rate deceleration. Freezing-like responses during threat anticipation have also been observed in humans and are associated with anxiety. Recent evidence yet suggests that freezing does not necessarily reflect helpless immobility but can also aid the preparation of a threat escape. To investigate which further behavioral responses human freezing encompasses, we presented 50 young adults (10 male) with aversive stimuli that could sometimes be avoided while measuring gaze, cardiovascular and electrodermal activity. In trials in which the threat could be escaped, participants displayed reduced heart rate, increased electrodermal activity and reduced visual exploration. Furthermore, heart rate deceleration and restricted visual exploration predicted the speed of flight responses. These results provide evidence for freezing behavior in measures of visual exploration and suggest that such responding is adaptive in preparing the subsequent escape of approaching threats.
Analysis of free chlorine in aqueous solution at very low concentration with lateral flow tests
Authors: Schwenke K. Uta , Spiehl Dieter , Krauße Marcel , Riedler Laura , Ruppenthal Anna , Villforth Klaus , Meckel Tobias , Biesalski Markus , Rupprecht Daniel , Schwall Gerhard 
Published: November 2019

AbstractTest strips are convenient tools for rapid, semi-quantitative analysis of a variety of parameters by dipping them for a few seconds in a sample solution followed by a simple colorimetric read-out. Their sensitivity is mainly determined by the reactivity of the test dyes on the reaction zone and is not sufficient for some applications. The detection limit of commercially available free chlorine test strips, for example, is at present not low enough to confirm the absence of this analyte as disinfectant in rinsing solutions after disinfection or to control required residual amounts of chlorine in drinking water. Therefore, we developed a user-friendly lateral flow test which is capable to detect very low amounts of free chlorine. The latter relies on a larger sample volume passing the reaction zone as compared to simple dip test strips. An amount of as low as 0.05 ppm chlorine can, however, only be detected if oxidation stable flow test substrates are used. The eventually developed flow test reaches a 10x higher sensitivity than a commercial dip test. The result is obtained within 4–5 min flow time, whereby no action is required by the user during this analysis time.
Structural basis for phospholipase A2-like toxin inhibition by the synthetic compound Varespladib (LY315920)
Authors: Salvador Guilherme H. M. , Gomes Antoniel A. S. , Bryan-Quirós Wendy , Fernández Julián , Lewin Matthew R. , Gutiérrez José María , Lomonte Bruno , Fontes Marcos R. M. 
Published: November 2019

AbstractThe World Health Organization recently listed snakebite envenoming as a Neglected Tropical Disease, proposing strategies to significantly reduce the global burden of this complex pathology by 2030. In this context, effective adjuvant treatments to complement conventional antivenom therapy based on inhibitory molecules for specific venom toxins have gained renewed interest. Varespladib (LY315920) is a synthetic molecule clinically tested to block inflammatory cascades of several diseases associated with elevated levels of secreted phospholipase A2 (sPLA2). Most recently, Varespladib was tested against several whole snake venoms and isolated PLA2 toxins, demonstrating potent inhibitory activity. Herein, we describe the first structural and functional study of the complex between Varespladib and a PLA2-like snake venom toxin (MjTX-II). In vitro and in vivo experiments showed this compound’s capacity to inhibit the cytotoxic and myotoxic effects of MjTX-II from the medically important South American snake, Bothrops moojeni. Crystallographic and bioinformatics analyses revealed interactions of Varespladib with two specific regions of the toxin, suggesting inhibition occurs by physical blockage of its allosteric activation, preventing the alignment of its functional sites and, consequently, impairing its ability to disrupt membranes. Furthermore, based on the analysis of several crystallographic structures, a distinction between toxin activators and inhibitors is proposed.
Abnormal Osteoblastic Response to Leptin in Patients with Adolescent Idiopathic Scoliosis
Authors: Man Gene Chi-Wai , Tam Elisa Man-Shan , Wong Yi Shun , Hung Vivian Wing-Ying , Hu Zongshan , Lam Tsz Ping , Liu Zhen , Cheung Wing Hoi , Ng Tzi Bun , Zhu Zezhang , Qiu Yong , Cheng Jack Chun-Yiu 
Published: November 2019

AbstractAdolescent idiopathic scoliosis (AIS) is a complex three-dimensional structural deformity of the spine with unknown etiology. Although leptin has been postulated as one of the etiologic factors in AIS, its effects on osteoblastic activity remain unknown. Herein, we conducted this study to investigate whether there are abnormal functional responses to leptin and abnormal expression of leptin receptor in AIS osteoblasts. In vitro assays were performed with osteoblasts isolated from 12 severe AIS girls and 6 non-AIS controls. The osteoblasts were exposed to different concentrations of leptin (0, 10, 100, 1000 ng/mL). The effects of leptin on cell proliferation, differentiation and mineralization were determined. Protein expressions of leptin receptor (LEP-R) under basal and osteogenic conditions were also evaluated by Western blot. Our results showed that leptin significantly stimulated osteoblasts from non-AIS subjects to proliferate, differentiate and mineralized. However, in the AIS group, the stimulatory effects of leptin on cell proliferation, differentiation, and mineralization were not observed. In addition, no statistically significant difference in the expression of leptin receptor under both basal and osteogenic conditions was found between AIS and control group. In conclusion, these findings might help to explain the low bone mass and deranged bone quality that is clinically associated with AIS girls.
Identification of novel blood biomarkers of treatment response in cystic fibrosis pulmonary exacerbations by label-free quantitative proteomics
Authors: Dong Kang , Moon Kyung-Mee , Chen Virginia , Ng Raymond , Foster Leonard J. , Tebbutt Scott J. , Quon Bradley S. 
Published: November 2019

AbstractPulmonary exacerbations (PEx) are clinically impactful events for individuals with CF. Unfortunately, many CF individuals with PEx fail to regain their baseline lung function despite treatment. The objective of this study was to use unbiased proteomic technology to identify novel blood protein biomarkers that change following intravenous (IV) antibiotic treatment and to explore if changes correlate with clinical response by the end of treatment. Blood samples from 25 PEx events derived from 22 unique CF adults were collected within 24 hours of hospital admission, day 5, day 10, and IV antibiotic completion. Three-hundred and forty-six blood proteins were evaluated with label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) quantitative proteomics and immunoassays. Forty-seven plasma proteins changed significantly following 5 days of IV antibiotic treatment (q-value ≤ 0.10). Early change in IGF2R from hospital admission to day 5 correlated with overall change in symptom score (CFRSD-CRISS) by the end of treatment (r = −0.48, p-value = 0.04). Several plasma proteins identified and quantified by label-free LC-MS/MS changed early following treatment with IV antibiotics and many of these proteins are involved in complement activation and inflammatory/immune-related pathways. Early change in IGF2R correlated with symptom response following IV antibiotic treatment and requires further validation as a predictive biomarker of symptom response.
Similar plasma lipidomic profile in people living with HIV treated with a darunavir-based or an integrase inhibitor-based antiretroviral therapy
Authors: Mena Alvaro , Clavero Elvira , Díaz-Díaz José Luis , Castro Angeles 
Published: November 2019

AbstractCardiovascular disease is an important cause of morbidity and mortality in people living with HIV (PLWH), who commonly experience lipid disturbances. The aim of this study was to determine whether the plasma lipidomic profile differs between PLWH receiving a darunavir-based ART and those receiving integrase inhibitor-based ART. This was a cross-sectional study of unselected patients for whom metabolomic analysis was performed using ultra-high-performance liquid chromatography coupled to mass spectrometry. Data for the two subgroups were compared by calculating the log2 of the fold change for each metabolite and then grouping these into the main lipid families. Sixty-two PLWH aged 49.3 ± 8.6 years (82% men) were included: 12 patients (19.4%) had hypertension, 8 (12.9%) had type 2 diabetes, 25 (41.0%) had dyslipidaemia and 9 (14.5%) were taking statins, without significant differences in all these variables between the two groups. Twenty-five (40.3%) received darunavir-based ART and 37 (59.7%) integrase inhibitor-based ART. Although the differences were not statistically significant, patients treated with darunavir-based ART had higher concentrations of total cholesterol (211 mg/dL vs 194 mg/dL), LDL-cholesterol (132 mg/dL vs 117 mg/dL) and triglycerides (155 mg/dL vs 122 mg/dL), and lower HDL-cholesterol concentration (50 mg/dL vs 52 mg/dL). The main lipid families and metabolites differed slightly between groups (log2-fold change; P-value): ceramides (−0.07; 0.49), phosphatidylinositols (−0.05; 0.63), diacylglycerols (0.10; 0.64), phosphatidylethanolamines (0.03; 0.78), triacylglycerols (0.27; 0.18) and lysophosphatidylethanolamines (0.03; 0.83). In the integrase inhibitor-based group, the use of tenofovir alafenamide fumarate significantly increases the majority of lipid fractions, when compared with tenofovir disoproxil fumarate. The lipidomic profile did not differ between PLWH treated with darunavir-based or integrase inhibitor-based ART. This was especially true for ceramides, which are involved in cardiovascular disease. Further studies are needed to study the impact of ART in lipidomic profile.