bluuebunny/crossref_metadata_2025_split huggingface dataset:
The driver role of JAK‐STAT signalling in cancer stemness capabilities leading to new therapeutic strategies for therapy‐ and castration‐resistant prostate cancer
Authors: Lo U‐Ging , Chen Yu‐An , Cen Junjie , Deng Su , Luo Junghang , Zhau Haiyen , Ho Lin , Lai Chih‐Ho , Mu Ping , Chung Leland W.K. , Hsieh Jer‐Tsong 
Published: July 2022

AbstractBackgroundLineage plasticity in prostate cancer (PCa) has emerged as an important mechanism leading to the onset of therapy‐ and castration‐resistant PCa (t‐CRPC), which is closely associated with cancer stem cell (CSC) activity. This study is to identify critical driver(s) with mechanism of action and explore new targeting strategy.MethodsVarious PCa cell lines with different genetic manipulations were subjected to in vitro prostasphere assay, cell viability assay and in vivo stemness potential. In addition, bioinformatic analyses such as Ingenuity pathway and Gene Set Enrichment Analysis were carried out to determine clinical relevance. The in vivo anti‐tumour activity of JAK or STAT1 inhibitors was examined in clinically relevant t‐CRPC model.ResultsWe demonstrated the role of interferon‐related signalling pathway in promoting PCa stemness, which correlated with significant elevation of interferon related DNA damage resistance signature genes in metastatic PCa. Inhibition of JAK‐STAT1 signalling suppresses the in vitro and in vivo CSC capabilities. Mechanistically, IFIT5, a unique downstream effector of JAK‐STAT1 pathway, can facilitate the acquisition of stemness properties in PCa by accelerating the turnover of specific microRNAs (such as miR‐128 and ‐101) that can target several CSC genes (such as BMI1, NANOG, and SOX2). Consistently, knocking down IFIT5 in t‐CRPC cell can significantly reduce in vitro prostasphere formation as well as decrease in vivo tumour initiating capability.ConclusionsThis study provides a critical role of STAT1‐IFIT5 in the acquisition of PCSC and highlights clinical translation of JAK or STAT1 inhibitors to prevent the outgrowth of t‐CRPC.
Glioblastoma‐educated mesenchymal stem‐like cells promote glioblastoma infiltration via extracellular matrix remodelling in the tumour microenvironment
Authors: Kim Seung‐Mo , Lim Eun‐Jung , Yoo Ki‐Chun , Zhao Yi , Kang Jae‐Hyeok , Lim Eun‐Ji , Shin Incheol , Kang Seok‐Gu , Lim Han Woong , Lee Su‐Jae 
Published: July 2022

AbstractBackgroundThe biological function of mesenchymal stem‐like cells (MSLCs), a type of stromal cells, in the regulation of the tumour microenvironment is unclear. Here, we investigated the molecular mechanisms underlying extracellular matrix (ECM) remodelling and crosstalk between MSLCs and glioblastomas (GBMs) in tumour progression.MethodsIn vitro and in vivo co‐culture systems were used to analyze ECM remodelling and GBM infiltration. In addition, clinical databases, samples from patients with GBM and a xenografted mouse model of GBM were used.ResultsPrevious studies have shown that the survival of patients with GBM from whom MSLCs could be isolated is substantially shorter than that of patients from whom MSLCs could not be isolated. Therefore, we determined the correlation between changes in ECM‐related gene expression in MSLC‐isolatable patients with that in MSLC non‐isolatable patients using gene set enrichment analysis (GSEA). We found that lysyl oxidase (LOX) and COL1A1 expressions increased in MSLCs via GBM‐derived clusters of differentiation 40 ligand (CD40L). Mechanistically, MSLCs are reprogrammed by the CD40L/CD40/NFκB2 signalling axis to build a tumour infiltrative microenvironment involving collagen crosslinking. Importantly, blocking of CD40L by a neutralizing antibody‐suppressed LOX expression and ECM remodelling, decreasing GBM infiltration in mouse xenograft models. Clinically, high expression of CD40L, clusters of differentiation 40 (CD40) and LOX correlated with poor survival in patients with glioma. This indicated that GBM‐educated MSLCs promote GBM infiltration via ECM remodelling in the tumour microenvironment.ConclusionOur findings provide mechanistic insights into the pro‐infiltrative tumour microenvironment produced by GBM‐educated MSLCs and highlight a potential therapeutic target that can be used for suppressing GBM infiltration.
Trappc1 deficiency impairs thymic epithelial cell development by breaking endoplasmic reticulum homeostasis
Authors: Dong Xue , Liang Zhanfeng , Zhang Jiayu , Zhang Qian , Xu Yanan , Zhang Zhaoqi , Zhang Lianfeng , Zhang Baojun , Zhao Yong 
Published: July 2022

AbstractThymic epithelial cells (TECs) are important for T cell development and immune tolerance establishment. Although comprehensive molecular regulation of TEC development has been studied, the role of transport protein particle complexes (Trappcs) in TECs is not clear. Using TEC‐specific homozygous or heterozygous Trappc1 deleted mice model, we find that Trappc1 deficiency cause severe thymus atrophy with decreased cell number and blocked maturation of TECs. Mice with a TEC‐specific Trappc1 deletion show poor thymic T cell output and have a greater percentage of activated/memory T cells, suffered from spontaneous autoimmune disorders. Our RNA‐seq and molecular studies indicated that the decreased endoplasmic reticulum (ER) and Golgi apparatus, enhanced unfolded protein response (UPR) and subsequent Atf4‐CHOP‐mediated apoptosis, and reactive oxygen species (ROS)‐mediated ferroptosis coordinately contributed to the reduction of Trappc1‐deleted TECs. Additionally, reduced Aire+ mTECs accompanied by the decreased expression of Irf4, Irf8, and Tbx21 in Trappc1 deficiency mTECs, may further coordinately block the tissue‐restricted antigen expression. In this study, we reveal that Trappc1 plays an indispensable role in TEC development and maturation and provide evidence for the importance of inter‐organelle traffic and ER homeostasis in TEC development.
Timing differences between HFOs and interictal epileptiform discharges generated in vitro by different mechanisms in rat hippocampal slices: A novel approach
Authors: Kalogeropoulos Konstantinos , Kleidonas Dimitrios , Psarropoulou Caterina 
Published: July 2022

AbstractObjectiveTo investigate the effect of generating mechanism on the relationship between interictal‐like epileptiform discharges (IEDs) and the underlying High Frequency Oscillations (HFOs; Ripples, R, and Fast Ripples, FR).MethodsSynchronous spontaneous IEDs were recorded from the CA1 area of hippocampal slices from adult rats, perfused by Mg2+‐free ACSF (n = 41slices/14 animals) or 4‐aminopyridine (50 μM, n = 37slices/16 animals); IED filtering revealed Rs and FRs and several metrics were calculated and compared (amplitude, duration, relative onset, time lag, % overlap, peak frequency, peak power, FR/R).ResultsLonger IEDs and higher 1st Population Spike (PS) amplitude in Mg2+‐free ACSF (vs 4‐AP; P < .001, P < .001) correlated with longer duration and higher amplitude Rs (P < .0001, P = .001) and longer duration FRs (P < .001). In both media, Rs and FRs appeared before IED onset with Rs preceding FRs; R‐ and FR‐IED lag (P = .008, P = .01) as well as R‐FR lag (P = .04) were significantly longer in Mg2+‐free ACSF vs in 4‐AP. R peak frequency and power were higher in Mg2+‐free ACSF, while no such differences were observed in FRs. Inter‐model differences were mostly reflected in Rs, not FRs, suggesting that mechanisms unique to R generation are more active in Mg2+‐free ACSF vs in 4‐AP. FRs appeared to contribute equally to IEDs irrespective of generating mechanism.SignificanceSeveral of the metrics used, particularly those regarding the timing between HFOs and IEDs, appear to correlate with the synchronizing mechanism and we propose that they may be useful when investigating antiepileptic substance effects on neuronal network activity.
Psychiatric adverse events in three phase III trials of eslicarbazepine acetate for focal seizures
Authors: Altalib Hamada , Grinnell Todd , Cantu David , Ikedo Fábio , Vieira Mariana , Zhang Yi , Blum David 
Published: July 2022

AbstractObjectiveEslicarbazepine acetate (ESL) is a once‐daily (QD), oral anti‐seizure medication for the treatment of focal (partial‐onset) seizures. Here, we evaluate risk factors for the development of psychiatric treatment‐emergent adverse events (TEAEs) in clinical trials of adjunctive ESL in adults with focal seizures.MethodsThis post‐hoc analysis evaluated data pooled from three Phase III, randomized, double‐blind, placebo‐controlled trials (BIA‐2093‐301, ‐302, ‐304). After an 8‐week baseline period, patients were randomized equally to receive placebo, ESL 400 mg (not reported here), 800 mg, or 1200 mg QD (up to 2‐week titration; 12‐week maintenance; optional open‐label extension [OLE]). Incidences of psychiatric TEAEs were evaluated according to three separate criteria: medical history of psychiatric disorders (yes/no); baseline use of psychotropic drugs (yes/no); Montgomery–Åsberg Depression Rating Scale (MADRS) score at baseline (0–6: normal; 7–19: mild depression; 20–34: moderate depression).ResultsThe analysis populations comprised 1251 patients for the controlled study period and 1137 patients for the 1‐year OLE. Psychiatric TEAE incidence was similar between patients taking ESL and placebo in the controlled and OLE study periods and was not related to ESL dose. Psychiatric TEAEs generally occurred more frequently in patients with a medical history of psychiatric disorders, using psychotropic drugs, or with depressive symptoms than in those without a history, not using psychotropic drugs, or with no depressive symptoms. Depression and anxiety were the most frequently reported psychiatric TEAEs.SignificanceOverall, in clinical trials of ESL in adults with focal seizures, incidences of psychiatric events were not statistically different between patients taking ESL and placebo, were not related to ESL dose, and generally occurred more frequently in patients with baseline psychiatric symptoms or a history of psychiatric disorders. Long‐term exposure to ESL was not associated with a marked increase in the incidence of psychiatric TEAEs.
Epidemiology and disease burden of tuberous sclerosis complex in France: A population‐based study based on national health insurance data
Authors: Fagnani Francis , Laurendeau Caroline , de Zelicourt Marie , Marshall Jade 
Published: July 2022

AbstractObjectiveTuberous sclerosis complex (TSC) is a rare multisystem disorder, often associated with epilepsy. This retrospective study aimed to identify patients with TSC, including those with epilepsy, from a French healthcare claims database, and to report incidence, prevalence, and healthcare costs and resource utilization.MethodsThe anonymized French health insurance database (SNDS) covers almost the entire French population. Patients with TSC were identified as having ≥1 International Classification of Diseases, Tenth Revision (ICD‐10) diagnosis code Q85.1 or a long‐term disease (LTD) registration over the inclusion period (2006–2017). Patients with an ICD‐10 epilepsy code or who were dispensed ≥1 antiseizure medication (ASM) in the same year or after their TSC diagnosis were identified as having TSC with epilepsy. Newly diagnosed patients over the inclusion period constituted the incident cohort. Healthcare costs (patients with recorded costs only), healthcare resource use, and ASM dispensation are reported for patients with 2018 data.ResultsIn 2018, 3139 prevalent patients with TSC were identified (crude prevalence, 4.69 per 100 000); the incident cohort comprised 2988 patients (crude incidence, 0.44 per 100 000). Among patients with TSC, 67% (2101/3139) had epilepsy (mean [standard deviation, SD] age: 28.8 [18.8] years; male: 48%). Among patients with epilepsy, total mean (SD) annual healthcare costs were €11 413 (27 620) per capita (outpatient, 63%; inpatient, 37%), 46% were hospitalized during 2018 (mean [SD]: 1.8 [10.9] acute care visits per patient), and 65% visited a hospital specialist. Among patients with epilepsy, medication (mean [SD]: €4518 [12 102] per capita) was the greatest contributor (63%) to outpatient costs, and in 2018, 74% were dispensed ≥1 different ASM and 9% were dispensed ≥4 ASMs.SignificanceTSC with epilepsy was associated with substantial healthcare costs and resource utilization, particularly outpatient and medication costs. Many patients with TSC with epilepsy were prescribed multiple ASMs, suggesting refractory epilepsy.
Relevance of oxygen carrier properties on the design of a chemical looping combustion unit with gaseous fuels
Authors: Abad Alberto , Gayán Pilar , García‐Labiano Francisco , de Diego Luis F. , Izquierdo María T. , Mendiara Teresa , Adánez Juan 
Published: July 2022

AbstractChemical looping combustion (CLC) is a novel technology for the combustion of fuels with inherent CO2 capture. CLC is based on the transference of oxygen from air to fuel by means of an oxygen carrier which is based on a metal oxide. CuO/Al2O3 (14 wt.% CuO) and Fe2O3/Al2O3 (20 wt.% Fe2O3) particles have been used in several CLC units with different results when methane combustion was evaluated. In order to shed light on the main processes affecting methane conversion in CLC, a mathematical model for a dual circulating fluidized bed (DCFB) system was developed to simulate the behavior of CuO/Al2O3 and Fe2O3/Al2O3 in a CLC unit. The model consists of the coupling of individual fuel and air reactor models to simulate steady state of the CLC unit. Individual models consider both the fluid dynamics of the fluidized beds at the high velocity regime and the corresponding kinetics of oxygen carrier reactions, that is, reduction in the fuel reactor and oxidation in the air reactor. The model was validated using results obtained in a 120 kWth CLC unit with CuO/Al2O3 and Fe2O3/Al2O3 particles. The validated model was used to simulate the performance of these materials in the 10 MWth CLC unit. Desing parameters of the fuel and air reactors as well as the suitable particle size of the oxygen carriers were determined in order to achieve the complete combustion of natural gas in the CLC unit as a function of the oxygen carrier properties. © 2022 The Authors. Greenhouse Gases: Science and Technology published by Society of Chemical Industry and John Wiley & Sons Ltd.
Adsorptive capture of CO2 by amine‐impregnated activated carbon, pumice, and zeolite 4A
Authors: Ozturk Bahtiyar , Demiral Seyda , Ozen Hulya Aykac 
Published: July 2022

AbstractThis study provides comparative information about CO2 capture of raw and amine‐impregnated micro‐, meso‐, and macroporous support materials. Zeolite 4A (4A), activated carbon (AC), and pumice (P) were used as micro‐, meso‐, and macroporous support materials, respectively, and monoethanolamine (MEA) and diethanolamine (DEA) were used as the immobilized liquid. Adsorption of CO2 from CO2‐N2 mixtures (3–28%, v/v) was performed in a constant volume‐variable pressure cell at 293 ± 2 K, and desorption of saturated sorbents was carried out at 373 ± 2 K. The textural properties of the porous supports have been seen to play an important role in amine loading into the pores and the mass transport of CO2 into/from the amine‐loaded pores. Among the porous supports, despite its lower surface area, pumice with a macroporous backbone helped immobilization of a large amount of amine and facilitated the CO2 sorption and desorption. Amine loading increased the CO2 capture efficiencies of activated carbon, pumice, and zeolite 4A as 13.4, 19.1, and 5.4 times for MEA and 6.2, 8.8, and 4.1 times for DEA, respectively. It was found that the CO2 release rates from MEA‐ and DEA‐impregnated 4A, AC, and P were 0.215, 0.475, and 0.556 mg CO2·g sorbent–1·min–1 and 0.242, 0.580, and 0.670 mg CO2·g sorbent–1·min–1, respectively, at 373 ± 2 K and 1 kPa. The CO2 sorption capacities of the MEA‐impregnated support materials from the cyclic operation were affected negatively more than the DEA‐impregnated ones and this effect increased from the microporous support material to the macroporous. © 2022 Society of Chemical Industry and John Wiley & Sons, Ltd.
Computational macroscopic lifetime imaging and concentration unmixing of autofluorescence
Authors: Ochoa Marien , Smith Jason T. , Gao Shan , Intes Xavier 
Published: July 2022

AbstractSingle‐pixel computational imaging can leverage highly sensitive detectors that concurrently acquire data across spectral and temporal domains. For molecular imaging, such methodology enables to collect rich intensity and lifetime multiplexed fluorescence datasets. Herein we report on the application of a single‐pixel structured light‐based platform for macroscopic imaging of tissue autofluorescence. The super‐continuum visible excitation and hyperspectral single‐pixel detection allow for parallel characterization of autofluorescence intensity and lifetime. Furthermore, we exploit a deep learning based data processing pipeline, to perform autofluorescence unmixing while yielding the autofluorophores' concentrations. The full scheme (setup and processing) is validated in silico and in vitro with clinically relevant autofluorophores flavin adenine dinucleotide, riboflavin, and protoporphyrin. The presented results demonstrate the potential of the methodology for macroscopically quantifying the intensity and lifetime of autofluorophores, with higher specificity for cases of mixed emissions, which are ubiquitous in autofluorescence and multiplexed in vivo imaging.
Acute stress induces an aberrant increase of presynaptic release of glutamate and cellular activation in the hippocampus of BDNFVal/Met mice
Authors: Musazzi Laura , Tornese Paolo , Sala Nathalie , Lee Francis S. , Popoli Maurizio , Ieraci Alessandro 
Published: July 2022

AbstractStressful life events are considered major risk factors for the development of several psychiatric disorders, though people differentially cope with stress. The reasons for this are still largely unknown but could be accounted for by individual genetic variants, previous life events, or the kind of stressors. The human brain‐derived neurotrophic factor (BDNF) Val66Met variant, which was found to impair intracellular trafficking and activity‐dependent secretion of BDNF, has been associated with increased susceptibility to develop several neuropsychiatric disorders, although there is still some controversial evidence. On the other hand, acute stress has been consistently demonstrated to promote the release of glutamate in cortico‐limbic regions and altered glutamatergic transmission has been reported in psychiatric disorders. However, it is not known if the BDNF Val66Met single‐nucleotide polymorphism (SNP) affects the stress‐induced presynaptic glutamate release. In this study, we exposed adult male BDNFVal/Val and BDNFVal/Met knock‐in mice to 30 min of acute restraint stress. Plasma corticosterone levels, glutamate release, protein, and gene expression in the hippocampus were analyzed immediately after the end of the stress session. Acute restraint stress similarly increased plasma corticosterone levels and nuclear glucocorticoid receptor levels and phosphorylation in both BDNFVal/Val and BDNFVal/Met mice. However, acute restraint stress induced higher increases in hippocampal presynaptic release of glutamate, phosphorylation of cAMP‐response element binding protein (CREB), and levels of the immediate early gene c‐fos of BDNFVal/Met compared to BFNFVal/Val mice. Moreover, acute restraint stress selectively increased phosphorylation levels of synapsin I at Ser9 and at Ser603 in BDNFVal/Val and BDNFVal/Met mice, respectively. In conclusion, we report here that the BDNF Val66Met SNP knock‐in mice display an altered response to acute restraint stress in terms of hippocampal glutamate release, CREB phosphorylation, and neuronal activation, compared to wild‐type animals. Taken together, these results could partially explain the enhanced vulnerability to stressful events of Met carriers reported in both preclinical and clinical studies.
Influence of sphingomyelin metabolism during epithelial–mesenchymal transition associated with aging in the renal papilla
Authors: Brandán Yamila Romina , Favale Nicolás Octavio , Pescio Lucila Gisele , Santacreu Bruno Jaime , Guaytima Edith del Valle , Sterin‐Speziale Norma B. , Márquez María Gabriela 
Published: July 2022

AbstractThe renal collecting ducts (CD) are formed by a fully differentiated epithelium, and their tissue organization and function require the presence of mature cell adhesion structures. In certain circumstances, the cells can undergo de‐differentiation by a process called epithelial–mesenchymal transition (EMT), in which the cells lose their epithelial phenotype and acquire the characteristics of the mesenchymal cells, which includes loss of cell–cell adhesion. We have previously shown that in renal papillary CD cells, cell adhesion structures are located in sphingomyelin (SM)‐enriched plasma membrane microdomains and the inhibition of SM synthase 1 activity induced CD cells to undergo an EMT process. In the present study, we evaluated the influence of SM metabolism during the EMT of the cells that form the CD of the renal papilla during aging. To this end, primary cultures of renal papillary CD cells from young, middle‐, and aged‐rats were performed. By combining biochemical and immunofluorescence studies, we found experimental evidence that CD cells undergo an increase in spontaneous and reversible EMT during aging and that at least one of the reasons for this phenomenon is the decrease in SM content due to the combination of decreased SM synthase activity and an increase in SM degradation mediated by neutral sphingomyelinase. Age is a risk factor for many diseases, among which renal fibrosis is included. Our findings highlight the importance of sphingolipids and particularly SM as a modulator of the fate of CD cells and probably contribute to the development of treatments to avoid or reverse renal fibrosis during aging.
A novel role of helix‐loop‐helix transcriptional factor Bhlhe40 in osteoclast activation
Authors: Hirata Hirohito , Kamohara Asana , Murayama Masatoshi , Nishioka Kenichi , Honda Hiroaki , Urano Yasuteru , Soejima Hidenobu , Oki Shinya , Kukita Toshio , Kawano Shunsuke , Mawatari Masaaki , Kukita Akiko 
Published: July 2022

AbstractThe basic helix‐loop‐helix transcriptional factor, Bhlhe40 has been shown as a crucial regulator of immune response, tumorigenesis, and circadian rhythms. We identified Bhlhe40 as a possible regulator of osteoclast differentiation and function by shRNA library screening and found that Bhlhe40 was required for osteoclast activation. Bhlhe40 expression was induced in bone marrow macrophages (BMMs) by RANKL, whereas the expression of its homolog Bhlhe41 was decreased in osteoclastogenesis. μCT analysis of tibias revealed that Bhlhe40 knockout (KO) mice exhibited increased bone volume phenotype. Bone morphometric analysis showed that osteoclast number and bone resorption were decreased in Bhlhe40 KO mice, whereas significant differences in the osteoblast parameters were not seen between wild‐type (WT) and Bhlhe40 KO mice. In vitro culture of BMMs showed that Bhlhe40 deficiency did not cause difference in osteoclast formation. In contrast, bone resorption activity of Bhlhe40 KO osteoclasts was markedly reduced in comparison with that of WT osteoclasts. Analysis of potential target genes of Bhlhe40 using data‐mining platform ChIP‐Atlas (http://chip-atlas.org) revealed that predicted target genes of Bhlhe40 were related to proton transport and intracellular vesicle acidification. We then analyzed the expression of proton pump, the vacuolar (V)‐ATPases which are responsible for bone resorption. The expression of V‐ATPases V1c1 and V0a3 was suppressed in Bhlhe40 KO osteoclasts. In addition, Lysosensor yellow/blue DND 160 staining demonstrated that vesicular acidification was attenuated in vesicles of Bhlhe40 KO osteoclasts. Furthermore, analysis with pH‐sensitive fluorescent probe showed that proton secretion was markedly suppressed in Bhlhe40 KO osteoclasts compared to that in WT osteoclasts. Our findings suggest that Bhlhe40 plays a novel important role in the regulation of acid production in osteoclastic bone resorption.