bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nrf2 signaling and autophagy are complementary in protecting lipopolysaccharide/d-galactosamine-induced acute liver injury by licochalcone A
Authors: Lv Hongming , Yang Huahong , Wang Zhongfeng , Feng Haihua , Deng Xuming , Cheng Genhong , Ci Xinxin 
Published: April 2019

AbstractLicochalcone A (Lico A), isolated from Xinjiang licorice Glycyrrhiza inflate, has been shown to have antioxidative potential via the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) activation, which is involved in the prevention of acetaminophen-induced hepatotoxicity. The purpose of the current study was to further explore the protective effect of Lico A against lipopolysaccharide/d-galactosamine (LPS/GalN)-induced acute liver injury (ALI) and its underlying molecular mechanisms. Our results found that treatment with Lico A significantly reduced in LPS/GalN-induced hepatotoxicity by lessening lethality, alleviating histopathological liver changes, decreasing the alanine transaminase, and aspartate aminotransferase levels, attenuating the secretion of inflammatory cytokines, and regulating oxidative markers. Furthermore, Lico A efficiently alleviated LPS-induced inflammatory response by inhibiting TLR4-MAPK and -NF-κB, as well as the Txnip-NLRP3 signaling pathway. Meanwhile, Lico A induced the activation of Nrf2 and QSTM1 (P62) signaling and promoted autophagy involved in AMP-activated protein kinase (AMPK)-the transcription factor EB (TFEB) signaling, which may contribute to its hepatoprotective activity. Additional mechanistic investigations to evaluate the dependence of the hepatoprotective role of Lico A on Nrf2 revealed that a lack of Nrf2 promoted Lico A-induced autophagy, which contributed to the hepatoprotective effect of Lico A in Nrf2−/− mice. In addition, cotreatment with autophagy inhibitor (3-methyladenine, 3-MA) alleviated but did not abrogate the hepatoprotective effect of Lico A, which may be attributed to its ability to activate Nrf2. Our study firstly suggests that Lico A has protective potential against LPS/GalN-induced hepatotoxicity, which may be strongly associated with activation of Nrf2 and autophagy.
Di-n-butyl phthalate epigenetically induces reproductive toxicity via the PTEN/AKT pathway
Authors: Li Ran , Xing Qian-wei , Wu Xiao-lu , Zhang Lei , Tang Min , Tang Jing-yuan , Wang Jing-zi , Han Peng , Wang Shang-qian , Wang Wei , Zhang Wei , Zhou Guo-ping , Qin Zhi-qiang 
Published: April 2019

AbstractDi-n-butyl phthalate (DBP) is a kind of ubiquitous chemical linked to hormonal disruptions that affects male reproductive system. However, the mechanism of DBP-induced germ cells toxicity remains unclear. Here, we demonstrate that DBP induces reduction of proliferation, increase of apoptosis and DNA damage dependent on the PTEN/AKT pathway. Mechanistically, DBP decreases PTEN promoter methylation and increases its transcriptional activity, leading to increased PTEN expression. Notably, DNMT3b is confirmed as a target of miR-29b and miR-29b-mediated status of PTEN methylation is involved in the effects of DBP treatment. Meanwhile, DBP decreases AKT pathway expression via increasing PTEN expression. In addition, the fact that DBP decreases the sperm number and the percentage of motile and progressive sperm is associated with downregulated AKT pathway and sperm flagellum-related genes. Collectively, these findings indicate that DBP induces aberrant PTEN demethylation, leading to inhibition of the AKT pathway, which contributes to the reproductive toxicity.
Asymmetric ephaptic inhibition between compartmentalized olfactory receptor neurons
Authors: Zhang Ye , Tsang Tin Ki , Bushong Eric A. , Chu Li-An , Chiang Ann-Shyn , Ellisman Mark H. , Reingruber Jürgen , Su Chih-Ying 
Published: April 2019

AbstractIn the Drosophila antenna, different subtypes of olfactory receptor neurons (ORNs) housed in the same sensory hair (sensillum) can inhibit each other non-synaptically. However, the mechanisms underlying this underexplored form of lateral inhibition remain unclear. Here we use recordings from pairs of sensilla impaled by the same tungsten electrode to demonstrate that direct electrical (“ephaptic”) interactions mediate lateral inhibition between ORNs. Intriguingly, within individual sensilla, we find that ephaptic lateral inhibition is asymmetric such that one ORN exerts greater influence onto its neighbor. Serial block-face scanning electron microscopy of genetically identified ORNs and circuit modeling indicate that asymmetric lateral inhibition reflects a surprisingly simple mechanism: the physically larger ORN in a pair corresponds to the dominant neuron in ephaptic interactions. Thus, morphometric differences between compartmentalized ORNs account for highly specialized inhibitory interactions that govern information processing at the earliest stages of olfactory coding.
Exceptional hydrogen storage achieved by screening nearly half a million metal-organic frameworks
Authors: Ahmed Alauddin , Seth Saona , Purewal Justin , Wong-Foy Antek G. , Veenstra Mike , Matzger Adam J. , Siegel Donald J. 
Published: April 2019

AbstractFew hydrogen adsorbents balance high usable volumetric and gravimetric capacities. Although metal-organic frameworks (MOFs) have recently demonstrated progress in closing this gap, the large number of MOFs has hindered the identification of optimal materials. Here, a systematic assessment of published databases of real and hypothetical MOFs is presented. Nearly 500,000 compounds were screened computationally, and the most promising were assessed experimentally. Three MOFs with capacities surpassing that of IRMOF-20, the record-holder for balanced hydrogen capacity, are demonstrated: SNU-70, UMCM-9, and PCN-610/NU-100. Analysis of trends reveals the existence of a volumetric ceiling at ∼40 g H2 L−1. Surpassing this ceiling is proposed as a new capacity target for hydrogen adsorbents. Counter to earlier studies of total hydrogen uptake in MOFs, usable capacities in the highest-capacity materials are negatively correlated with density and volumetric surface area. Instead, capacity is maximized by increasing gravimetric surface area and porosity. This suggests that property/performance trends for total capacities may not translate to usable capacities.
Phenotypes associated with genes encoding drug targets are predictive of clinical trial side effects
Authors: Nguyen Phuong A. , Born David A. , Deaton Aimee M. , Nioi Paul , Ward Lucas D. 
Published: April 2019

AbstractOnly a small fraction of early drug programs progress to the market, due to safety and efficacy failures, despite extensive efforts to predict safety. Characterizing the effect of natural variation in the genes encoding drug targets should present a powerful approach to predict side effects arising from drugging particular proteins. In this retrospective analysis, we report a correlation between the organ systems affected by genetic variation in drug targets and the organ systems in which side effects are observed. Across 1819 drugs and 21 phenotype categories analyzed, drug side effects are more likely to occur in organ systems where there is genetic evidence of a link between the drug target and a phenotype involving that organ system, compared to when there is no such genetic evidence (30.0 vs 19.2%; OR = 1.80). This result suggests that human genetic data should be used to predict safety issues associated with drug targets.
A fungal substrate mimicking molecule suppresses plant immunity via an inter-kingdom conserved motif
Authors: Misas Villamil Johana C. , Mueller André N. , Demir Fatih , Meyer Ute , Ökmen Bilal , Schulze Hüynck Jan , Breuer Marlen , Dauben Helen , Win Joe , Huesgen Pitter F. , Doehlemann Gunther 
Published: April 2019

AbstractUstilago maydis is a biotrophic fungus causing corn smut disease in maize. The secreted effector protein Pit2 is an inhibitor of papain-like cysteine proteases (PLCPs) essential for virulence. Pit2 inhibitory function relies on a conserved 14 amino acids motif (PID14). Here we show that synthetic PID14 peptides act more efficiently as PLCP inhibitors than the full-length Pit2 effector. Mass spectrometry shows processing of Pit2 by maize PLCPs, which releases an inhibitory core motif from the PID14 sequence. Mutational analysis demonstrates that two conserved residues are essential for Pit2 function. We propose that the Pit2 effector functions as a substrate mimicking molecule: Pit2 is a suitable substrate for apoplastic PLCPs and its processing releases the embedded inhibitor peptide, which in turn blocks PLCPs to modulate host immunity. Remarkably, the PID14 core motif is present in several plant associated fungi and bacteria, indicating the existence of a conserved microbial inhibitor of proteases (cMIP).
Genetic studies of accelerometer-based sleep measures yield new insights into human sleep behaviour
Authors: Jones Samuel E. , van Hees Vincent T. , Mazzotti Diego R. , Marques-Vidal Pedro , Sabia Séverine , van der Spek Ashley , Dashti Hassan S. , Engmann Jorgen , Kocevska Desana , Tyrrell Jessica , Beaumont Robin N. , Hillsdon Melvyn , Ruth Katherine S. , Tuke Marcus A. , Yaghootkar Hanieh , Sharp Seth A. , Ji Yingjie , Harrison Jamie W. , Freathy Rachel M. , Murray Anna , Luik Annemarie I. , Amin Najaf , Lane Jacqueline M. , Saxena Richa , Rutter Martin K. , Tiemeier Henning , Kutalik Zoltán , Kumari Meena , Frayling Timothy M. , Weedon Michael N. , Gehrman Philip R. , Wood Andrew R. 
Published: April 2019

AbstractSleep is an essential human function but its regulation is poorly understood. Using accelerometer data from 85,670 UK Biobank participants, we perform a genome-wide association study of 8 derived sleep traits representing sleep quality, quantity and timing, and validate our findings in 5,819 individuals. We identify 47 genetic associations at P < 5 × 10−8, of which 20 reach a stricter threshold of P < 8 × 10−10. These include 26 novel associations with measures of sleep quality and 10 with nocturnal sleep duration. The majority of identified variants associate with a single sleep trait, except for variants previously associated with restless legs syndrome. For sleep duration we identify a missense variant (p.Tyr727Cys) in PDE11A as the likely causal variant. As a group, sleep quality loci are enriched for serotonin processing genes. Although accelerometer-derived measures of sleep are imperfect and may be affected by restless legs syndrome, these findings provide new biological insights into sleep compared to previous efforts based on self-report sleep measures.
Improved measures for evolutionary conservation that exploit taxonomy distances
Authors: Malhis Nawar , Jones Steven J. M. , Gsponer Jörg 
Published: April 2019

AbstractSelective pressures on protein-coding regions that provide fitness advantages can lead to the regions' fixation and conservation in genome duplications and speciation events. Consequently, conservation analyses relying on sequence similarities are exploited by a myriad of applications across all biosciences to identify functionally important protein regions. While very potent, existing conservation measures based on multiple sequence alignments are so pervasive that improvements to solutions of many problems have become incremental. We introduce a new framework for evolutionary conservation with measures that exploit taxonomy distances across species. Results show that our taxonomy-based framework comfortably outperforms existing conservation measures in identifying deleterious variants observed in the human population, including variants located in non-abundant sequence domains such as intrinsically disordered regions. The predictive power of our approach emphasizes that the phenotypic effects of sequence variants can be taxonomy-level specific and thus, conservation needs to be interpreted accordingly.
Microphase separation of a miscible binary liquid mixture under confinement at the nanoscale
Authors: Essafri Ilham , Morineau Denis , Ghoufi Aziz 
Published: April 2019

AbstractRecent experimental works suggested that the confinement into a cylindrical nanopore induced the microphase separation of a binary liquid, despite the miscible character of its bulk counterpart. A core–shell organization was evidenced such that one of the liquids was strongly anchored to the solid surface whereas the other was confined at the center of the pore. At the same time, a study based on atomistic simulations suggested a strong heterogeneity and the absence of a separation. In this work, by refining the solid–liquid interactions to qualitatively reproduce the experimental adsorption isotherms of both single liquids, the microphase separation and the core–shell structure are captured. By tuning the surface chemistry of the nanopore to mimic hydrophilic and hydrophobic confinement, we show that it is possible to control the structural characteristics of the core–shell structure.The molecular origin of the microphase separation is then ascribed to the strong hydrogen bonds and a commensurate arrangement between the confining material and both liquids.
Systematic review (protocol) of clinical effectiveness and models of care of low-resource pulmonary rehabilitation
Authors: Habib GM Monsur , Rabinovich Roberto , Divgi Kalyani , Ahmed Salahuddin , Saha Samir Kumar , Singh Sally , Uddin Aftab , Pinnock Hilary 
Published: April 2019

AbstractMore than half of the people with chronic respiratory diseases (CRDs) live in low- and middle-income countries (LMICs). The increasing disability, reduced productivity, associated anxiety and depression from CRDs result in social isolation and economic hardship for patients and their families. Pulmonary rehabilitation (PR) is a guideline-recommended multidisciplinary and multifaceted intervention that improves the physical and psychological condition of people with CRD. However, PR services are underprovided and uptake is poor in LMICs, especially in low-resourced setting. We aim to systematically assess the effectiveness, applicable components and mode of delivery of PR. We will search MEDLINE, EMBASE, CABI, AMED and CENTRAL from January 1990 using a PICOS search strategy (Population: adults with CRD (including chronic obstructive pulmonary disease, post-tuberculosis, remodelled asthma); Intervention: PR; Comparator: usual care; Outcomes: functional exercise capacity and Health-Related Quality-of-Life; Setting: low-resource settings). Two reviewers will independently screen titles/abstracts and full texts for eligibility and extract data from included papers. We will use the Cochrane Risk-of-Bias tool, rating the quality of evidence using GRADE. We will use narrative synthesis to answer our three objectives: What is the effectiveness of PR in low-resource settings? What components are used in effective studies? What models of service delivery are used? This systematic review will inform the potential impact and practical models of low-resource PR for the betterment of patients with CRDs to improve their substantial health-care burden and address poor quality of life.
Association of Circulating YKL-40 Levels and CHI3L1 Variants with the Risk of Spinal Deformity Progression in Adolescent Idiopathic Scoliosis
Authors: Nada Dina , Julien Cédric , Rompré Pierre H. , Akoume Marie-Yvonne , Gorman Kristen F. , Samuels Mark E. , Levy Emile , Kost Jason , Li Dawei , Moreau Alain 
Published: April 2019

AbstractThe cellular and molecular mechanisms underlying spinal deformity progression in adolescent idiopathic scoliosis (AIS) remain poorly understood. In this study, 804 French-Canadian patients and 278 age- and sex-matched controls were enrolled and genotyped for 12 single nucleotide polymorphisms (SNPs) in the chitinase 3-like 1 (CHI3L1) gene or its promoter. The plasma YKL-40 levels were determined by ELISA. We showed that elevation of circulating YKL-40 levels was correlated with a reduction of spinal deformity progression risk. We further identified significant associations of multiple CHI3L1 SNPs and their haplotypes with plasma YKL-40 levels and scoliosis severity as a function of their classification in a specific endophenotype. In the endophenotype FG3 group, we found that patients harboring the haplotype G-G-A-G-G-A (rs880633|rs1538372|rs4950881|rs10399805|rs6691378|rs946261), which presented in 48% of the cases, showed a positive correlation with the plasma YKL-40 levels (P = 7.6 × 10−6 and coefficient = 36). Conversely, the haplotype A-A-G-G-G-G, which presented in 15% of the analyzed subjects, showed a strong negative association with the plasma YKL-40 levels (P = 2 × 10−9 and coefficient = −9.56). We found that this haplotype showed the strongest association with AIS patients in endophenotype FG2 (P = 9.9 × 10−6 and coefficient = −13.53), who more often develop severe scoliosis compared to those classified in the other two endophenotypes. Of note, it showed stronger association in females (P = 1.6 × 10−7 and coefficient = −10.08) than males (P = 0.0021 and coefficient = −9.01). At the functional level, we showed that YKL-40 treatments rescued Gi-coupled receptor signalling dysfunction occurring in primary AIS osteoblasts. Collectively, our findings reveal a novel role for YKL-40 in AIS pathogenesis and a new molecular mechanism interfering with spinal deformity progression.
Mucosal and systemic SIV-specific cytotoxic CD4+ T cell hierarchy in protection following intranasal/intramuscular recombinant pox-viral vaccination of pigtail macaques
Authors: Khanna Mayank , Jackson Ronald J. , Alcantara Sheilajen , Amarasena Thakshila H. , Li Zheyi , Kelleher Anthony D. , Kent Stephen J. , Ranasinghe Charani 
Published: April 2019

AbstractA HIV vaccine that provides mucosal immunity is urgently needed. We evaluated an intranasal recombinant Fowlpox virus (rFPV) priming vaccine followed by intramuscular Modified Vaccinia Ankara (rMVA) booster vaccine, both expressing SIV antigens. The vaccination generated mucosal and systemic SIV-specific CD4+ T cell mediated immunity and was associated with partial protection against high-dose intrarectal SIVmac251 challenge in outbred pigtail macaques. Three of 12 vaccinees were completely protected and these animals elicited sustained Gag-specific poly-functional, cytotoxic mucosal CD4+ T cells, complemented by systemic poly-functional CD4+ and CD8+ T cell immunity. Humoral immune responses, albeit absent in completely protected macaques, were associated with partial control of viremia in animals with relatively weaker mucosal/systemic T cell responses. Co-expression of an IL-4R antagonist by the rFPV vaccine further enhanced the breadth and cytotoxicity/poly-functionality of mucosal vaccine-specific CD4+ T cells. Moreover, a single FPV-gag/pol/env prime was able to induce rapid anamnestic gp140 antibody response upon SIV encounter. Collectively, our data indicated that nasal vaccination was effective at inducing robust cervico-vaginal and rectal immunity, although cytotoxic CD4+ T cell mediated mucosal and systemic immunity correlated strongly with ‘complete protection’, the different degrees of protection observed was multi-factorial.
Mapping Bromodomains in breast cancer and association with clinical outcome
Authors: Pérez-Pena Javier , Páez Raquel , Nieto-Jiménez Cristina , Sánchez Verónica Corrales , Galan-Moya Eva M. , Pandiella Atanasio , Győrffy Balázs , Ocana Alberto 
Published: April 2019

AbstractA specific family of proteins that participate in epigenetic regulation is the bromodomain (BRD) family of proteins. In this work, we aimed to explore the expression of the BRD family at a transcriptomic level in breast cancer, and its association with patient survival. mRNA level data from normal breast and tumor tissues were extracted from public datasets. Gene set enrichment analysis (GSEA) was performed to identify relevant biological functions. The KM Plotter Online tool was used to evaluate the relationship between the presence of different genes and patient clinical outcome. mRNA level data from HER2+ breast cancer patients sensible and resistant to trastuzumab were also evaluated. The BRD family was an enriched function. In HER2 positive tumors the combined analyses of BRD2, BAZ1A, TRIM33 and ZMYND8 showed a detrimental relapse free survival (RFS). Similarly, the combined analysis of BRD2, BAZ1A, PHIP, TRIM33, KMT2A, ASH1L, PBRM1, correlated with an extremely poor overall survival (OS). The prognosis was confirmed using an independent dataset from TCGA. Finally, no relation between expression of BRD genes and response to trastuzumab was observed in the HER2 population. Upregulation of some BRD genes is associated with detrimental outcome in HER2 positive tumors, regardless trastuzumab treatment.
Utility Of POC Xpert HIV-1 Tests For Detection-Quantification Of Complex HIV Recombinants Using Dried Blood Spots From Kinshasa, D. R. Congo
Authors: Rubio-Garrido Marina , Ndarabu Adolphe , Reina Gabriel , Barquín David , Fernández-Alonso Mirian , Carlos Silvia , Holguín África 
Published: April 2019

AbstractPoint-of-Care (POC) molecular assays improve HIV infant diagnosis and viral load (VL) quantification in resource-limited settings. We evaluated POC performance in Kinshasa (Democratic Republic of Congo), with high diversity of HIV-1 recombinants. In 2016, 160 dried blood samples (DBS) were collected from 85 children (60 HIV−, 18 HIV+, 7 HIV-exposed) and 75 HIV+ adults (65 treated, 10 naive) at Monkole Hospital (Kinshasa). We compared viraemia with Cepheid-POC-Xpert-HIV-1VL and the non-POC-COBAS®AmpliPrep/COBAS®TaqMan®HIV-1-Testv2 in all HIV+, carrying 72.4%/7.2% HIV-1 unique/complex recombinant forms (URF/CRF). HIV-1 infection was confirmed in 14 HIV+ children by Cepheid-POC-Xpert-HIV-1Qual and in 70 HIV+ adults by both Xpert-VL and Roche-VL, identifying 8 false HIV+ diagnosis performed in DRC (4 adults, 4 children). HIV-1 was detected in 95.2% and 97.6% of 84 HIV+ samples by Xpert-VL and Roche-VL, respectively. Most (92.9%) HIV+ children presented detectable viraemia by both VL assays and 74.3% or 72.8% of 70 HIV+ adults by Xpert or Roche, respectively. Both VL assays presented high correlation (R2 = 0.89), but showing clinical relevant ≥0.5 log VL differences in 15.4% of 78 cases with VL within quantification range by both assays. This is the first study confirming the utility of Xpert HIV-1 tests for detection-quantification of complex recombinants currently circulating in Kinshasa.
The paradoxes of the Late Hesperian Mars ocean
Authors: Turbet M. , Forget F. 
Published: April 2019

AbstractThe long-standing debate on the existence of ancient oceans on Mars has been recently revived by evidence for tsunami resurfacing events that date from the Late Hesperian geological era. It has been argued that these tsunami events originated from the impact of large meteorites on a deglaciated or nearly deglaciated ocean present in the northern hemisphere of Mars. Here we show that the presence of such a late ocean faces a paradox. If cold, the ocean should have been entirely frozen shortly after its formation, thus preventing the formation of tsunami events. If warm, the ice-free ocean should have produced fluvial erosion of Hesperian Mars terrains much more extensively than previously reported. To solve this apparent paradox, we suggest a list of possible tests and scenarios that could help to reconcile constraints from climate models with tsunami hypothesis. These scenarios could be tested in future dedicated studies.