bluuebunny/crossref_metadata_2025_split huggingface dataset:
Major depression and enhanced molecular senescence abnormalities in young and middle-aged adults
Authors: Diniz Breno S. , Reynolds III Charles F. , Sibille Etienne , Bot Mariska , Penninx Brenda W. J. H 
Published: August 2019

AbstractRecent evidence suggests a significant overlap in biological changes between major depression and aging across the lifespan. We aim to evaluate the impact of a major depressive episode on the Senescence-Associated Secretory Phenotype (SASP) index, a dynamic secretory molecular pattern indicative of cellular senescence. We also tested the potential moderators of the association between major depression and the SASP index. We included 1165 young and middle-aged adults (527 with a current major depressive episode (cMDE) and 638 with no lifetime history of depression) from a community-based cohort from the Netherlands. We calculated the SASP index based on a previously developed composite index involving 19 biomarkers. cMDE had higher SASP index values (t(1163) = 2.93, p = 0.003) compared to controls in the univariate analysis. After controlling for sociodemographic and somatic health covariates, there was no significant association between cMDE and SASP index (F(1,1158) = 1.09, p = 0.29). Those with the most severe depressive episodes had significantly higher SASP indices compared to those with mild-to-moderate cMDE and controls (F(2,1162) = 6.73, p = 0.001). We found a significant interaction between cMDE and overweight (F(1,1164) = 5.1, p = 0.028): those with comorbid cMDE and overweight had the highest SASP index. Our study demonstrated a complex interaction between cMDE and medical morbidity, especially overweight, on the SASP index, suggesting that their coexistence aggravate age-related biological processes. Moreover, higher SASP index can be a biomarker for more severe depressive episodes.
Two pedigrees with arrhythmogenic right ventricular cardiomyopathy linked with R49H and F531C mutation in DSG2
Authors: Chen Xuepin , Peng Hui , Zheng Chenqing , Zhang Hongmei , Yan Chao , Ma Huihui , Dai Xiafei , Li Xiaoping 
Published: August 2019

AbstractArrhythmogenic right ventricular cardiomyopathy (ARVC) presents as the progressive fibrofatty replacement of the cardiomyocytes particularly in the right ventricular wall. Here, we report two cases with ARVC. In family A, the proband carries a Desmoglein2 (DSG2) gene complex heterozygous mutation NM_001943.4:c.146G>A/p.(Arg49His)and NM_001943.3:c.1592T>G/p.(Phe531Cys). In family B, the proband carries a homozygous mutation NM_001943.3:c.1592T>G/p.(Phe531Cys).
Bell’s theorem for temporal order
Authors: Zych Magdalena , Costa Fabio , Pikovski Igor , Brukner Časlav 
Published: August 2019

AbstractTime has a fundamentally different character in quantum mechanics and in general relativity. In quantum theory events unfold in a fixed order while in general relativity temporal order is influenced by the distribution of matter. When matter requires a quantum description, temporal order is expected to become non-classical—a scenario beyond the scope of current theories. Here we provide a direct description of such a scenario. We consider a thought experiment with a massive body in a spatial superposition and show how it leads to entanglement of temporal orders between time-like events. This entanglement enables accomplishing a task, violation of a Bell inequality, that is impossible under local classical temporal order; it means that temporal order cannot be described by any pre-defined local variables. A classical notion of a causal structure is therefore untenable in any framework compatible with the basic principles of quantum mechanics and classical general relativity.
Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model
Authors: Spangenberg Elizabeth , Severson Paul L. , Hohsfield Lindsay A. , Crapser Joshua , Zhang Jiazhong , Burton Elizabeth A. , Zhang Ying , Spevak Wayne , Lin Jack , Phan Nicole Y. , Habets Gaston , Rymar Andrey , Tsang Garson , Walters Jason , Nespi Marika , Singh Parmveer , Broome Stephanie , Ibrahim Prabha , Zhang Chao , Bollag Gideon , West Brian L. , Green Kim N. 
Published: August 2019

AbstractMany risk genes for the development of Alzheimer’s disease (AD) are exclusively or highly expressed in myeloid cells. Microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival. We designed and synthesized a highly selective brain-penetrant CSF1R inhibitor (PLX5622) allowing for extended and specific microglial elimination, preceding and during pathology development. We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia. Instead, Aβ deposits in cortical blood vessels reminiscent of cerebral amyloid angiopathy. Altered gene expression in the 5xFAD hippocampus is also reversed by the absence of microglia. Transcriptional analyses of the residual plaque-forming microglia show they exhibit a disease-associated microglia profile. Collectively, we describe the structure, formulation, and efficacy of PLX5622, which allows for sustained microglial depletion and identify roles of microglia in initiating plaque pathogenesis.
Genotoxic stress-triggered β-catenin/JDP2/PRMT5 complex facilitates reestablishing glutathione homeostasis
Authors: Cao Lixue , Wu Geyan , Zhu Jinrong , Tan Zhanyao , Shi Dongni , Wu Xingui , Tang Miaoling , Li Ziwen , Hu Yameng , Zhang Shuxia , Yu Ruyuan , Mo Shuang , Wu Jueheng , Song Erwei , Li Mengfeng , Song Libing , Li Jun 
Published: August 2019

AbstractThe mechanisms underlying how cells subjected to genotoxic stress reestablish reduction-oxidation (redox) homeostasis to scavenge genotoxic stress-induced reactive oxygen species (ROS), which maintains the physiological function of cellular processes and cell survival, remain unclear. Herein, we report that, via a TCF-independent mechanism, genotoxic stress induces the enrichment of β-catenin in chromatin, where it forms a complex with ATM phosphorylated-JDP2 and PRMT5. This elicits histone H3R2me1/H3R2me2s-induced transcriptional activation by the recruitment of the WDR5/MLL methyltransferase complexes and concomitant H3K4 methylation at the promoters of multiple genes in GSH-metabolic cascade. Treatment with OICR-9429, a small-molecule antagonist of the WDR5-MLL interaction, inhibits the β-catenin/JDP2/PRMT5 complex-reestablished GSH metabolism, leading to a lethal increase in the already-elevated levels of ROS in the genotoxic-agent treated cancer cells. Therefore, our results unveil a plausible role for β-catenin in reestablishing redox homeostasis upon genotoxic stress and shed light on the mechanisms of inducible chemotherapy resistance in cancer.
Tumor-targeted silencing of the peptide transporter TAP induces potent antitumor immunity
Authors: Garrido Greta , Schrand Brett , Rabasa Ailem , Levay Agata , D’Eramo Francesca , Berezhnoy Alexey , Modi Shrey , Gefen Tal , Marijt Koen , Doorduijn Elien , Dudeja Vikas , van Hall Thorbald , Gilboa Eli 
Published: August 2019

AbstractNeoantigen burden is a major determinant of tumor immunogenicity, underscored by recent clinical experience with checkpoint blockade therapy. Yet the majority of patients do not express, or express too few, neoantigens, and hence are less responsive to immune therapy. Here we describe an approach whereby a common set of new antigens are induced in tumor cells in situ by transient downregulation of the transporter associated with antigen processing (TAP). Administration of TAP siRNA conjugated to a broad-range tumor-targeting nucleolin aptamer inhibited tumor growth in multiple tumor models without measurable toxicity, was comparatively effective to vaccination against prototypic mutation-generated neoantigens, potentiated the antitumor effect of PD-1 antibody or Flt3 ligand, and induced the presentation of a TAP-independent peptide in human tumor cells. Treatment with the chemically-synthesized nucleolin aptamer-TAP siRNA conjugate represents a broadly-applicable approach to increase the antigenicity of tumor lesions and thereby enhance the effectiveness of immune potentiating therapies.
Outcomes from deep brain stimulation targeting subthalamic nucleus and caudal zona incerta for Parkinson’s disease
Authors: Mostofi Abteen , Evans Julian M. , Partington-Smith Lucy , Yu Kenny , Chen Cliff , Silverdale Monty A. 
Published: August 2019

AbstractBoth subthalamic nucleus (STN) and caudal zona incerta (cZI) have been implicated as the optimal locus for deep brain stimulation (DBS) in Parkinson’s disease (PD). We present a retrospective clinico-anatomical analysis of outcomes from DBS targeting both STN and cZI. Forty patients underwent bilateral DBS using an image-verified implantable guide tube/stylette technique. Contacts on the same quadripolar lead were placed in both STN and cZI. After pulse generator programming, contacts yielding the best clinical effect were selected for chronic stimulation. OFF-medication unified PD rating scale (UPDRS) part III scores pre-operatively and ON-stimulation at 1–2 year follow up were compared. Active contacts at follow-up were anatomically localised from peri-operative imaging. Overall, mean UPDRS part III score improvement was 55 ± 9% (95% confidence interval), with improvement in subscores for rigidity (59 ± 13%), bradykinesia (58 ± 13%), tremor (71 ± 24%) and axial features (36 ± 19%). Active contacts were distributed in the following locations: (1) within posterior/dorsal STN (50%); (2) dorsal to STN (24%); (3) in cZI (21%); and (4) lateral to STN (5%). When contacts were grouped by location, no significant differences between groups were seen in baseline or post-operative improvement in contralateral UPDRS part III subscores. We conclude that when both STN and cZI are targeted, active contacts are distributed most commonly within and immediately dorsal to STN. In a subgroup of cases, cZI contacts were selected for chronic stimulation in preference. Dual targeting of STN and cZI is feasible and may provide extra benefit compared with conventional STN DBS is some patients.
Systematic identification and characterization of Aedes aegypti long noncoding RNAs (lncRNAs)
Authors: Azlan Azali , Obeidat Sattam M. , Yunus Muhammad Amir , Azzam Ghows 
Published: August 2019

AbstractLong noncoding RNAs (lncRNAs) play diverse roles in biological processes. Aedes aegypti (Ae. aegypti), a blood-sucking mosquito, is the principal vector responsible for replication and transmission of arboviruses including dengue, Zika, and Chikungunya virus. Systematic identification and developmental characterisation of Ae. aegypti lncRNAs are still limited. We performed genome-wide identification of lncRNAs, followed by developmental profiling of lncRNA in Ae. aegypti. We identified a total of 4,689 novel lncRNA transcripts, of which 2,064, 2,076, and 549 were intergenic, intronic, and antisense respectively. Ae. aegypti lncRNAs share many characteristics with other species including low expression, low GC content, short in length, and low conservation. Besides, the expression of Ae. aegypti lncRNAs tend to be correlated with neighbouring and antisense protein-coding genes. A subset of lncRNAs shows evidence of maternal inheritance; hence, suggesting potential role of lncRNAs in early-stage embryos. Additionally, lncRNAs show higher tendency to be expressed in developmental and temporal specific manner. The results from this study provide foundation for future investigation on the function of Ae. aegypti lncRNAs.
Divalent cations can control a switch-like behavior in heterotypic and homotypic RNA coacervates
Authors: Onuchic Paulo L. , Milin Anthony N. , Alshareedah Ibraheem , Deniz Ashok A. , Banerjee Priya R. 
Published: August 2019

AbstractLiquid-liquid phase separation (LLPS) of RNA-protein complexes plays a major role in the cellular function of membraneless organelles (MLOs). MLOs are sensitive to changes in cellular conditions, such as fluctuations in cytoplasmic ion concentrations. To investigate the effect of these changes on MLOs, we studied the influence of divalent cations on the physical and chemical properties of RNA coacervates. Using a model system comprised of an arginine-rich peptide and RNA, we predicted and observed that variations in signaling cations exert interaction-dependent effects on RNA LLPS. Changing the ionic environment has opposing effects on the propensity for heterotypic peptide-RNA and homotypic RNA LLPS, which results in a switch between coacervate types. Furthermore, divalent ion variations continuously tune the microenvironments and fluid properties of heterotypic and homotypic droplets. Our results may provide a general mechanism for modulating the biochemical environment of RNA coacervates in a cellular context.
Randomized clinical trial: the effect of probiotic Bacillus coagulans Unique IS2 vs. placebo on the symptoms management of irritable bowel syndrome in adults
Authors: Madempudi Ratna Sudha , Ahire Jayesh J. , Neelamraju Jayanthi , Tripathi Anirudh , Nanal Satyavrat 
Published: August 2019

AbstractThe therapeutic effects of B. coagulans Unique IS2 have been well established in children with irritable bowel syndrome (IBS), but its efficacy in adults remain under reported. Thus, in this study the efficacy of B. coagulans Unique IS2 in the management of IBS symptoms in adults was investigated. Patients (n = 153) fulfilling Rome III criteria were provided placebo capsules for a 2 weeks run-in period. Only patients satisfying compliance criteria (n = 136) were randomized (double blind) to receive either B. coagulans Unique IS2 (2 billion CFU) or placebo capsules daily for 8 weeks. Reduction of abdominal discomfort/pain intensity and increase in complete spontaneous bowel movements were analyzed as primary end points. Other clinical symptoms of IBS and serum cytokines were also evaluated. B. coagulans Unique IS2 showed significant improvement in primary and secondary endpoints, as compared to placebo. Haematology of both the arms remained normal. No significant changes in pro- (IL-6, IL-12, TNF-α, INF- γ) and anti-inflammatory cytokine (IL-10) levels were detected at the end of B. coagulans treatment (8 weeks) as compared to placebo. B. coagulans was well tolerated with no severe adverse events to report. Overall, the results demonstrate that B. coagulans Unique IS2 is efficacious in the management of IBS symptoms in adults (18–60 years).
Cross comparison and prognostic assessment of breast cancer multigene signatures in a large population-based contemporary clinical series
Authors: Vallon-Christersson Johan , Häkkinen Jari , Hegardt Cecilia , Saal Lao H. , Larsson Christer , Ehinger Anna , Lindman Henrik , Olofsson Helena , Sjöblom Tobias , Wärnberg Fredrik , Ryden Lisa , Loman Niklas , Malmberg Martin , Borg Åke , Staaf Johan 
Published: August 2019

AbstractMultigene expression signatures provide a molecular subdivision of early breast cancer associated with patient outcome. A gap remains in the validation of such signatures in clinical treatment groups of patients within population-based cohorts of unselected primary breast cancer representing contemporary disease stages and current treatments. A cohort of 3520 resectable breast cancers with RNA sequencing data included in the population-based SCAN-B initiative (ClinicalTrials.gov ID NCT02306096) were selected from a healthcare background population of 8587 patients diagnosed within the years 2010–2015. RNA profiles were classified according to 19 reported gene signatures including both gene expression subtypes (e.g. PAM50, IC10, CIT) and risk predictors (e.g. Oncotype DX, 70-gene, ROR). Classifications were analyzed in nine adjuvant clinical assessment groups: TNBC-ACT (adjuvant chemotherapy, n = 239), TNBC-untreated (n = 82), HER2+/ER− with anti-HER2+ ACT treatment (n = 110), HER2+/ER+ with anti-HER2 + ACT + endocrine treatment (n = 239), ER+/HER2−/LN− with endocrine treatment (n = 1113), ER+/HER2−/LN− with endocrine + ACT treatment (n = 243), ER+/HER2−/LN+ with endocrine treatment (n = 423), ER+/HER2−/LN+ with endocrine + ACT treatment (n = 433), and ER+/HER2−/LN− untreated (n = 200). Gene signature classification (e.g., proportion low-, high-risk) was generally well aligned with stratification based on current immunohistochemistry-based clinical practice. Most signatures did not provide any further risk stratification in TNBC and HER2+/ER– disease. Risk classifier agreement (low-, medium/intermediate-, high-risk groups) in ER+ assessment groups was on average 50–60% with occasional pair-wise comparisons having <30% agreement. Disregarding the intermediate-risk groups, the exact agreement between low- and high-risk groups was on average ~80–95%, for risk prediction signatures across all assessment groups. Outcome analyses were restricted to assessment groups of TNBC-ACT and endocrine treated ER+/HER2−/LN− and ER+/HER2−/LN+ cases. For ER+/HER2− disease, gene signatures appear to contribute additional prognostic value even at a relatively short follow-up time. Less apparent prognostic value was observed in the other groups for the tested signatures. The current study supports the usage of gene expression signatures in specific clinical treatment groups within population-based breast cancer. It also stresses the need of further development to reach higher consensus in individual patient classifications, especially for intermediate-risk patients, and the targeting of patients where current gene signatures and prognostic variables provide little support in clinical decision-making.
Bone sarcoma patient-derived xenografts are faithful and stable preclinical models for molecular and therapeutic investigations
Authors: Nanni Patrizia , Landuzzi Lorena , Manara Maria Cristina , Righi Alberto , Nicoletti Giordano , Cristalli Camilla , Pasello Michela , Parra Alessandro , Carrabotta Marianna , Ferracin Manuela , Palladini Arianna , Ianzano Marianna L. , Giusti Veronica , Ruzzi Francesca , Magnani Mauro , Donati Davide Maria , Picci Piero , Lollini Pier-Luigi , Scotlandi Katia 
Published: August 2019

AbstractStandard therapy of osteosarcoma (OS) and Ewing sarcoma (EW) rests on cytotoxic regimes, which are largely unsuccessful in advanced patients. Preclinical models are needed to break this impasse. A panel of patient-derived xenografts (PDX) was established by implantation of fresh, surgically resected osteosarcoma (OS) and Ewing sarcoma (EW) in NSG mice. Engraftment was obtained in 22 of 61 OS (36%) and 7 of 29 EW (24%). The success rate in establishing primary cell cultures from OS was lower than the percentage of PDX engraftment in mice, whereas the reverse was observed for EW; the implementation of bothin vivoandin vitroseeding increased the proportion of patients yielding at least one workable model. The establishment ofin vitrocultures from PDX was highly efficient in both tumor types, reaching 100% for EW. Morphological and immunohistochemical (SATB2, P-glycoprotein 1, CD99, caveolin 1) studies and gene expression profiling showed a remarkable similarity between patient’s tumor and PDX, which was maintained over several passages in mice, whereas cell cultures displayed a lower correlation with human samples. Genes differentially expressed between OS original tumor and PDX mostly belonged to leuykocyte-specific pathways, as human infiltrate is gradually replaced by murine leukocytes during growth in mice. In EW, which contained scant infiltrates, no gene was differentially expressed between the original tumor and the PDX. A novel therapeutic combination of anti-CD99 diabody C7 and irinotecan was tested against two EW PDX; both drugs inhibited PDX growth, the addition of anti-CD99 was beneficial when chemotherapy alone was less effective. The panel of OS and EW PDX faithfully mirrored morphologic and genetic features of bone sarcomas, representing reliable models to test therapeutic approaches.
Magnetized suspended carbon nanotubes based nanofluid flow with bio-convection and entropy generation past a vertical cone
Authors: Ramzan Muhammad , Mohammad Mutaz , Howari Fares 
Published: August 2019

AbstractThe captivating attributes of carbon nanotubes (CNT) comprising chemical and mechanical steadiness, outstanding electrical and thermal conductivities, featherweight, and physiochemical consistency make them coveted materials in the manufacturing of electrochemical devices. Keeping in view such exciting features of carbon nanotubes, our objective in the present study is to examine the flow of aqueous based nanofluid comprising single and multi-wall carbon nanotubes (CNTs) past a vertical cone encapsulated in a permeable medium with convective heat and solutal stratification. The impacts of heat generation/absorption, gyrotactic-microorganism, thermal radiation, and Joule heating with chemical reaction are added features towards the novelty of the erected model. The coupled differential equations are attained from the partial differential equations by exercising the local similarity transformation technique. The set of conservation equations supported by the associated boundary conditions are worked out numerically by employing bvp4c MATLAB function. The sway of numerous appearing parameters in the analysis on the allied distributions is scrutinized and the fallouts are portrayed graphically. The physical quantities of interest including Skin friction coefficient, the rate of heat and mass transfers are assessed versus essential parameters and their outcomes are demonstrated in tabulated form. It is witnessed that the velocity of the fluid decreases for boosting values of the magnetic and suction parameters in case of both nanotubes. Moreover, the density of motile microorganism is decreased versus larger estimates of bio-convection constant. A notable highlight of the presented model is the endorsement of the results by matching them to an already published material in the literature. A venerable harmony in this regard is achieved.
A non-linear mathematical model using optical sensor to predict heart decellularization efficacy
Authors: Pereira Rayssa Helena Arruda , Prado Adilson Ribeiro , Caro Luiz Felipe Castello Del , Zanardo Tadeu Ériton Caliman , Alencar Airlane Pereira , Nogueira Breno Valentim 
Published: August 2019

AbstractOne of the main problems of the decellularization technique is the subjectivity of the final evaluation of its efficacy in individual organs. This problem can result in restricted cell repopulation reproducibility and worse responses to transplant tissues. Our proposal is to analyze the optical profiles produced by hearts during perfusion decellularization, as an additional method for evaluating the decellularization process of each individual organ. An apparatus comprised of a structured LED source and photo detector on an adjustable base was developed to capture the relationship between transmitted light during the perfusion of murine hearts, and residual DNA content. Voltage-time graphic records were used to identify a nonlinear mathematical model to discriminate between decellularizations with remaining DNA above (Incomplete Decellularization) and below (Complete Decellularization) the standardized limits. The results indicate that temporal optical evaluation of the process enables inefficient cell removal to be predicted in the initial stages, regardless of the apparent transparency of the organ. Our open system also creates new possibilities to add distinct photo detectors, such as for specific wavelengths, image acquisition, and physical-chemical evaluation of the scaffold, in order to collect different kinds of information, from dozens of studies. These data, when compiled and submitted to machine learning techniques, have the potential to initiate an exponential advance in tissue bioengineering research.