bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Piezo1 attenuates demyelination in the central nervous system
Authors: Velasco‐Estevez María , Gadalla Kamal K. E. , Liñan‐Barba Núria , Cobb Stuart , Dev Kumlesh K. , Sheridan Graham K. 
Published: October 2019

AbstractPiezo1 is a mechanosensitive ion channel that facilitates the translation of extracellular mechanical cues to intracellular molecular signaling cascades through a process termed, mechanotransduction. In the central nervous system (CNS), mechanically gated ion channels are important regulators of neurodevelopmental processes such as axon guidance, neural stem cell differentiation, and myelination of axons by oligodendrocytes. Here, we present evidence that pharmacologically mediated overactivation of Piezo1 channels negatively regulates CNS myelination. Moreover, we found that the peptide GsMTx4, an antagonist of mechanosensitive cation channels such as Piezo1, is neuroprotective and prevents chemically induced demyelination. In contrast, the positive modulator of Piezo1 channel opening, Yoda‐1, induces demyelination and neuronal damage. Using an ex vivo murine‐derived organotypic cerebellar slice culture model, we demonstrate that GsMTx4 attenuates demyelination induced by the cytotoxic lipid, psychosine. Importantly, we confirmed the potential therapeutic effects of GsMTx4 peptide in vivo by co‐administering it with lysophosphatidylcholine (LPC), via stereotactic injection, into the cerebral cortex of adult mice. GsMTx4 prevented both demyelination and neuronal damage usually caused by the intracortical injection of LPC in vivo; a well‐characterized model of focal demyelination. GsMTx4 also attenuated both LPC‐induced astrocyte toxicity and microglial reactivity within the lesion core. Overall, our data suggest that pharmacological activation of Piezo1 channels induces demyelination and that inhibition of mechanosensitive channels, using GsMTx4, may alleviate the secondary progressive neurodegeneration often present in the latter stages of demyelinating diseases.
The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins
Authors: Deora Vandana , Lee John D. , Albornoz Eduardo A. , McAlary Luke , Jagaraj Cyril J. , Robertson Avril A. B. , Atkin Julie D. , Cooper Matthew A. , Schroder Kate , Yerbury Justin J. , Gordon Richard , Woodruff Trent M. 
Published: October 2019

AbstractMicroglial NLRP3 inflammasome activation is emerging as a key contributor to neuroinflammation during neurodegeneration. Pathogenic protein aggregates such as β‐amyloid and α‐synuclein trigger microglial NLRP3 activation, leading to caspase‐1 activation and IL‐1β secretion. Both caspase‐1 and IL‐1β contribute to disease progression in the mouse SOD1G93A model of amyotrophic lateral sclerosis (ALS), suggesting a role for microglial NLRP3. Prior studies, however, suggested SOD1G93A mice microglia do not express NLRP3, and SOD1G93A protein generated IL‐1β in microglia independent to NLRP3. Here, we demonstrate using Nlrp3‐GFP gene knock‐in mice that microglia express NLRP3 in SOD1G93A mice. We show that both aggregated and soluble SOD1G93A activates inflammasome in primary mouse microglia leading caspase‐1 and IL‐1β cleavage, ASC speck formation, and the secretion of IL‐1β in a dose‐ and time‐dependent manner. Importantly, SOD1G93A was unable to induce IL‐1β secretion from microglia deficient for Nlrp3, or pretreated with the specific NLRP3 inhibitor MCC950, confirming NLRP3 as the key inflammasome complex mediating SOD1‐induced microglial IL‐1β secretion. Microglial NLRP3 upregulation was also observed in the TDP‐43Q331K ALS mouse model, and TDP‐43 wild‐type and mutant proteins could also activate microglial inflammasomes in a NLRP3‐dependent manner. Mechanistically, we identified the generation of reactive oxygen species and ATP as key events required for SOD1G93A‐mediated NLRP3 activation. Taken together, our data demonstrate that ALS microglia express NLRP3, and that pathological ALS proteins activate the microglial NLRP3 inflammasome. NLRP3 inhibition may therefore be a potential therapeutic approach to arrest microglial neuroinflammation and ALS disease progression.
Short‐term plasticity following motor sequence learning revealed by diffusion magnetic resonance imaging
Authors: Tavor Ido , Botvinik‐Nezer Rotem , Bernstein‐Eliav Michal , Tsarfaty Galia , Assaf Yaniv 
Published: October 2019

AbstractCurrent noninvasive methods to detect structural plasticity in humans are mainly used to study long‐term changes. Diffusion magnetic resonance imaging (MRI) was recently proposed as a novel approach to reveal gray matter changes following spatial navigation learning and object‐location memory tasks. In the present work, we used diffusion MRI to investigate the short‐term neuroplasticity that accompanies motor sequence learning. Following a 45‐min training session in which participants learned to accurately play a short sequence on a piano keyboard, changes in diffusion properties were revealed mainly in motor system regions such as the premotor cortex and cerebellum. In a second learning session taking place immediately afterward, feedback was given on the timing of key pressing instead of accuracy, while participants continued to learn. This second session induced a different plasticity pattern, demonstrating the dynamic nature of learning‐induced plasticity, formerly thought to require months of training in order to be detectable. These results provide us with an important reminder that the brain is an extremely dynamic structure. Furthermore, diffusion MRI offers a novel measure to follow tissue plasticity particularly over short timescales, allowing new insights into the dynamics of structural brain plasticity.
Cost‐Effectiveness of Noninvasive Screening for Alcohol‐Related Liver Fibrosis
Authors: Asphaug Lars , Thiele Maja , Krag Aleksander , Melberg Hans Olav ,   on behalf of the GALAXY Consortium
Published: October 2019

Background and Aims
Alcohol‐related liver disease is often undetected until irreversible late‐stage decompensated disease manifests. Consequently, there is an unmet need for effective and economically reasonable pathways to screen for advanced alcohol‐related fibrosis.

Approach and Results
We used real‐world data from a large biopsy‐controlled study of excessive drinkers recruited from primary and secondary care, to evaluate the cost‐effectiveness of four primary care initiated strategies: (1) routine liver function tests with follow‐up ultrasonography for test‐positives, (2) the enhanced liver fibrosis (ELF) test with hospital liver stiffness measurement (LSM) for positives, (3) a three‐tier strategy using the Forns Index to control before strategy 2, and (4) direct referral of all to LSM. We used linked decision trees and Markov models to evaluate outcomes short term (cost‐per‐accurate diagnosis) and long term (quality‐adjusted life‐years [QALYs]). For low‐prevalence populations, ELF with LSM follow‐up was most cost‐effective, both short term (accuracy 96%, $196 per patient) and long term (incremental cost‐effectiveness ratio [ICER] $5,387‐$8,430/QALY), depending on whether diagnostic testing had lasting or temporary effects on abstinence rates. Adding Forns Index decreased costs to $72 per patient and accuracy to 95%. The strategy resulted in fewer QALYs due to more false negatives but an ICER of $3,012, making this strategy suited for areas with restricted access to ELF and transient elastography or lower willingness‐to‐pay. For high‐prevalence populations, direct referral to LSM was highly cost‐effective (accuracy 93%, $297 per patient), with ICERs between $490 and $1,037/QALY.

Conclusions
Noninvasive screening for advanced alcohol‐related fibrosis is a cost‐effective intervention when different referral pathways are used according to the prevalence of advanced fibrosis. Patients in the primary health care sector should be tested with the ELF test followed by LSM if the test was positive, whereas direct referral to LSM is highly cost‐effective in high‐prevalence cohorts.
Molecular expression profiles of morphologically defined hippocampal neuron types: Empirical evidence and relational inferences
Authors: White Charise M. , Rees Christopher L. , Wheeler Diek W. , Hamilton David J. , Ascoli Giorgio A. 
Published: October 2019

AbstractGene and protein expressions are key determinants of cellular function. Neurons are the building blocks of brain circuits, yet the relationship between their molecular identity and the spatial distribution of their dendritic inputs and axonal outputs remains incompletely understood. The open‐source knowledge base Hippocampome.org amasses such transcriptomic data from the scientific literature for morphologically defined neuron types in the rodent hippocampal formation: dentate gyrus, CA3, CA2, CA1, subiculum, and entorhinal cortex. Positive, negative, or mixed expression reports were initially obtained from published articles directly connecting molecular evidence to neurons with known axonal and dendritic patterns across hippocampal layers. Here, we supplement this information by collating, formalizing, and leveraging relational expression inferences that link a gene or protein expression or lack thereof to that of another molecule or to an anatomical location. With these additional interpretations, we freely release online a comprehensive human‐ and machine‐readable molecular profile for more than 100 neuron types in Hippocampome.org. Analysis of these data ascertains the ability to distinguish unequivocally most neuron types in each of the major subdivisions of the hippocampus based on currently known biochemical markers. Moreover, grouping neuron types by expression similarity reveals eight superfamilies characterized by a few defining molecules.
Changes in event‐based streamflow magnitude and timing after suburban development with infiltration‐based stormwater management
Authors: Hopkins Kristina G. , Bhaskar Aditi S. , Woznicki Sean A. , Fanelli Rosemary M. 
Published: October 2019

AbstractGreen stormwater infrastructure implementation in urban watersheds has outpaced our understanding of practice effectiveness on streamflow response to precipitation events. Long‐term monitoring of experimental suburban watersheds in Clarksburg, Maryland, USA, provided an opportunity to examine changes in event‐based streamflow metrics in two treatment watersheds that transitioned from agriculture to suburban development with a high density of infiltration‐focused stormwater control measures (SCMs). Urban Treatment 1 has predominantly single family detached housing with 33% impervious cover and 126 SCMs. Urban Treatment 2 has a mix of single family detached and attached housing with 44% impervious cover and 219 SCMs. Differences in streamflow‐event magnitude and timing were assessed using a before‐after‐control‐reference‐impact design to compare urban treatment watersheds with a forested control and an urban control with detention‐focused SCMs. Streamflow and precipitation events were identified from 14 years of sub‐daily monitoring data with an automated approach to characterize peak streamflow, runoff yield, runoff ratio, streamflow duration, time to peak, rise rate, and precipitation depth for each event. Results indicated that streamflow magnitude and timing were altered by urbanization in the urban treatment watersheds, even with SCMs treating 100% of the impervious area. The largest hydrologic changes were observed in streamflow magnitude metrics, with greater hydrologic change in Urban Treatment 2 compared with Urban Treatment 1. Although streamflow changes were observed in both urban treatment watersheds, SCMs were able to mitigate peak flows and runoff volumes compared with the urban control. The urban control had similar impervious cover to Urban Treatment 2, but Urban Treatment 2 had more than twice the precipitation depth needed to initiate a flow response and lower median peak flow and runoff yield for events less than 20 mm. Differences in impervious cover between the Urban Treatment watersheds appeared to be a large driver of differences in streamflow response, rather than SCM density. Overall, use of infiltration‐focused SCMs implemented at a watershed‐scale did provide enhanced attenuation of peak flow and runoff volumes compared to centralized‐detention SCMs.
FTIR spectra signatures reveal different cellular effects of EGFR inhibitors on nonsmall cell lung cancer cells
Authors: Tabtimmai Lueacha , Srisook Pimonwan , Kuaprasert Buabarn , Thumanu Kanjana , Choowongkomon Kiattawee 
Published: October 2019

AbstractATP‐analogue inhibitors, Gefitinib (Iressa) and Erlotinib (Tarceva) had been approved for advanced and metastatic nonsmall cell lung cancer (NSCLC) cells against tyrosine kinase domain of epidermal growth factor receptor (EGFR). Many techniques have been developed to better understand the drug mechanism which is multistep, time‐consuming and expensive. Herein, we performed Fourier‐transform infrared (FTIR) microscopy for evaluating the biochemical change on NSCLC (A549) cells after treatment. At levels that produced equivalent effects, Gefitinib dramatically induced cell apoptosis via impaired mitochondrial transmembrane potential. Whereas, Erlotinib had a slight effect on A549. Principal component analysis was performed to distinguish the effect of EGFR inhibitors on A549. FTIR spectra regions were divided into three regions: lipids (3000‐2800 cm−1), proteins (1700‐1500 cm−1) and carbohydrates and nuclei acids (1200‐1000 cm−1). Biochemical changes can be evaluated by these spectral regions. This work may be a novel concept for utilizing FTIR spectroscopy for high‐throughput discriminative effects of a drug or compound and its derivatives on cells.
Aberrant expression of a five‐microRNA signature in breast carcinoma as a promising biomarker for diagnosis
Authors: Bitaraf Amirreza , Babashah Sadegh , Garshasbi Masoud 
Published: October 2019

AbstractBackgroundBreast cancer (BC) is the most common malignancy among females with dismal quality of life in patients. It has been proven that epigenetic factors, especially microRNAs, are involved in breast carcinogenesis and progression. This study aimed to assess the expression and clinical performances of a five‐microRNA signature (miR‐127‐3p, miR‐133a‐3p, miR‐155‐5p, miR‐199b‐5p, and miR‐342‐5p) in breast cancer and adjacent normal tissues to identify a potential biomarker for BC and investigate the relationship between their expression and clinicopathological features of BC patients as well.MethodsIn this case‐control investigation, we recruited 50 pairs of tumor and matched non‐tumor surgical specimens from patients diagnosed with BC. Expression levels of miR‐127‐3p, miR‐133a‐3p, miR‐155‐5p, miR‐199b‐5p, and miR‐342‐5p were measured in BC and adjacent normal tissues by RT‐qPCR.ResultsWe found that miR‐127‐3p, miR‐133a‐3p, miR‐199b‐5p, and miR‐342‐5p were significantly down‐regulated, while miR‐155‐5p was significantly up‐regulated in BC tumor tissues compared with the corresponding adjacent normal tissues. The decreased expression of miR‐127‐3p, miR‐133a‐3p, miR‐342‐5p, and up‐regulation of miR‐155‐5p showed a significant correlation with disease stage. We also found a significant down‐regulation of miR‐127‐3p, miR‐199b‐5p, and miR‐342‐5p compared in HER‐2‐negative patients. Our results indicated that miR‐155‐5p had a higher expression level in HER‐2‐positive patients. Receiver operating characteristic (ROC) curve analysis demonstrated that all these five microRNAs can serve as potential biomarkers to distinguish between tumor and non‐tumor breast tissue samples.ConclusionsThe present findings suggested that dysregulation of this five‐miRNA signature might be considered as a promising and functional biomarker for BC diagnosis.
Justice and rule of law failure in Haiti: A view from the Shanties
Authors: Marcelin Louis H. , Cela Toni 
Published: October 2019

AbstractSince 1995, significant investments have been made in justice reform initiatives in Haiti. The results, however, have been meager. Drawing upon data from a longitudinal study conducted in Cité Soleil between 2008 and 2011, this article illuminates the short‐sightedness of top‐down reforms that fail to meet the demands of the population, leaving them to fend for themselves. In the absence of a viable justice system Cité Soleil residents have resorted to alternative, and at times pathological, measures to exact some level of “justice”. In this article, we contend that an empirically grounded base of knowledge of the demand side of justice and the promotion of trust‐building strategies that engage the active participation of citizens in the country are necessary to enact and sustain justice and rule of law reform. Such an approach will create a venue to channel civil society's demands, build political will and facilitate coordination between stakeholders and Haitian society for self‐sustained rule of law institutions and long‐term peace building in Haiti.
HSP90 regulates osteosarcoma cell apoptosis by targeting the p53/TCF‐1‐mediated transcriptional network
Authors: Yang Jie , Li Yu‐Hang , He Ming‐Tang , Qiao Ju‐Feng , Sang Yuan , Cheang Lek Hang , Gomes Fernando Cardoso , Hu Yang , Li Zhen‐Yan , Liu Ning , Zhang Huan‐Tian , Zha Zhen‐Gang 
Published: October 2019

AbstractOsteosarcoma (OS) is the most common bone tumor that occurs predominantly in children and teenagers. Although many genes, such as p53 and Rb1, have been shown to be mutated, deregulation of the canonical Wnt/β‐catenin signaling pathway is frequently observed in OS. We recently demonstrated that heat shock protein 90 (HSP90) is involved in the regulation of runt‐related transcription factor 2 via the AKT/GSK‐3β/β‐catenin signaling pathway in OS. However, the precise role of T cell factors/lymphoid enhancer‐binding factor (TCFs/LEF) family members, which are the major binding complex of β‐catenin, in OS is poorly understood. In the present study, we first demonstrated that TCF‐1 is overexpressed in OS compared with other bone tumors. Knockdown of TCF‐1 significantly induced cell cycle arrest, severe DNA damage, and subsequent caspase‐3‐dependent apoptosis. Interestingly, coexpression of HSP90 and TCF‐1 was observed in OS, and mechanistically, we demonstrated that TCF‐1 expression is regulated by HSP90 either through a β‐catenin‐dependent mechanism or a direct degradation of the proteasome. We also found that overexpression of TCF‐1 partially abolishes the apoptosis induced by HSP90 inhibition. Furthermore, we provided evidence that p53, but not miR‐34a, plays a crucial role in the HSP90‐regulated TCF‐1 expression and subsequent apoptosis. Given the diverse combination regimens of HSP90 inhibition with some other treatments, we propose that the p53 status and the expression level of TCF‐1 should be taken into consideration to enhance the therapeutic efficacy of HSP90 inhibition.
LINC01342 promotes the progression of ovarian cancer by absorbing microRNA‐30c‐2‐3p to upregulate HIF3A
Authors: Zhang Chu , Liu Jie , Zhang Yang , Luo Chengyan , Zhu Tong , Zhang Rongrong , Yao Ruiqin 
Published: October 2019

AbstractOvarian cancer (OC) is a highly prevalent gynecologic malignancy and its mortality is extremely high. Therefore, the development of novel therapeutic approaches for OC is of great significance. In this study, LINC01342 was upregulated in OC tissue in the GSE38666 microarray and in tumor tissue samples collected in our center. The silencing of LINC01342 suppressed the proliferative and metastatic capacities of A2780 and HO8910 cells. Subcellular distribution assays showed that LINC01342 was mainly enriched in the cytoplasm. Subsequently, the downregulation of microRNA‐30c‐2‐3p was proven to be the target of LINC01342. The silencing of microRNA‐30c‐2‐3p enhanced the clonality and migratory capacity of OC cells. Moreover, the silencing of microRNA‐30c‐2‐3p could reverse the inhibited migration and clonality in OC cells caused by LINC01342 knockdown. In addition, hypoxia‐inducible factor 3 subunit α (HIF3A) was proven to be the target gene of microRNA‐30c‐2‐3p, which was upregulated. HIF3A was negatively regulated by microRNA‐30c‐2‐3p but positively regulated by LINC01342 in OC cells. An RNA binding protein immunoprecipitation assay showed that microRNA‐30c‐2‐3p, LINC01342, and HIF3A could bind to argonaute RISC catalytic component 2. The overexpression of HIF3A reversed the inhibited migration and clonality in OC cells with LINC01342 knockdown. By analyzing the follow‐up data from the enrolled OC patients, the LINC01342 and HIF3A levels were negatively correlated with prognosis, while the microRNA‐30c‐2‐3p level was positively correlated with the same. In short, the upregulated LINC01342 in OC absorbs microRNA‐30c‐2‐3p to release HIF3A. Thus, upregulated HIF3A expression accelerates the progression of OC.
A Population Pharmacokinetic Model of Oral Docetaxel Coadministered With Ritonavir to Support Early Clinical Development
Authors: Yu Huixin , Janssen Julie M. , Sawicki Emilia , van Hasselt J. G. Coen , de Weger Vincent A. , Nuijen Bastiaan , Schellens Jan H. M. , Beijnen Jos H. , Huitema Alwin D. R. 
Published: October 2019

AbstractOral administration of docetaxel is an attractive alternative for conventional intravenous (IV) administration. The low bioavailability of docetaxel, however, hinders the application of oral docetaxel in the clinic. The aim of the current study was to develop a population pharmacokinetic (PK) model for docetaxel and ritonavir based on the phase 1 studies and to support drug development of this combination treatment. PK data were collected from 191 patients who received IV docetaxel and different oral docetaxel formulations (drinking solution, ModraDoc001 capsule, and ModraDoc006 tablet) coadministered with ritonavir. A PK model was first developed for ritonavir. Subsequently, a semiphysiological PK model was developed for docetaxel, which incorporated the inhibition of docetaxel metabolism by ritonavir. The uninhibited intrinsic clearance of docetaxel was estimated based on data on IV docetaxel as 1980 L/h (relative standard error, 11%). Ritonavir coadministration extensively inhibited the hepatic metabolism of docetaxel to 9.3%, which resulted in up to 12‐fold higher docetaxel plasma concentrations compared to oral docetaxel coadministered without ritonavir. In conclusion, a semiphysiological PK model for docetaxel and ritonavir was successfully developed. Coadministration of ritonavir resulted in increased plasma concentrations of docetaxel after administration of the oral formulations of ModraDoc. Furthermore, the oral ModraDoc formulations showed lower variability in plasma concentrations between and within patients compared to the drinking solution. Comparable exposure could be reached with the oral ModraDoc formulations compared to IV administration.