bluuebunny/crossref_metadata_2025 huggingface dataset:
Didática e a prática docente na escola básica em uma perspectiva crítica de educação
Authors: Araújo Osmar Hélio Alves
Published: September 2019

Este artigo visa discutir o papel da Didática e da prática docente na escola básica em uma perspectiva crítica de educação. Inicialmente, discutiremos a Pedagogia como ciência da/para a educação; a Didática em uma perspectiva crítica e o seu papel na formação dos professores. Em seguida, destacaremos a necessidade de práticas docentes pedagógicas que apontem para novos horizontes, novas possibilidades de abordagem do contexto social atual, novos modos de perceber/entender e intervir nessa mesma realidade. Por fim, argumentaremos a favor da articulação entre a Didática, a Pedagogia e as demais áreas das ciências que auxiliam o trabalho docente na escola básica, como um meio de assegurar uma educação inteiramente como chave transformadora da sociedade.
Método de formação política da escola nacional Florestan Fernandes do MST
Authors: Mariano Alessandro Santos , Lombardi José Claudinei
Published: September 2019

O objetivo deste artigo é refletir sobre o método de formação política  Escola Nacional Florestan Fernandes, uma escola coordenada pelo Movimento dos Trabalhadores Rurais Sem Terra e que tem como principal papel a formação de militantes de movimentos e organizações populares do Brasil e outros países. A ENFF assume a concepção marxista de construção e socialização do conhecimento (MARX, 1987) e a orientação pedagógica da Pedagogia Socialista (PISTRAK, 2009), da Educação Popular (FREIRE, 2005 e da Pedagogia do Movimento (CALDART, 2004). Essa perspectiva pedagógica referencia-se no trabalho como princípio educativo, como práxis que articula a prática com o estudo, em organicidade com a arte e a cultura. A ENFF adota uma perspectiva contra hegemônico, direcionando seu trabalho para a formação da consciência de classe, por meio da socialização de conhecimentos de filosofia, de história e economia de política, considerados necessários para a formação crítica de sujeitos sociais que atuam com vistas à transformação revolucionária da sociedade, superando o capitalismo e avançando em direção ao socialismo, entendendo este como uma fase de transição para o comunismo.
As políticas de autsreidade e as atuais reformas do estado brasileiro: respostas dadas à crise capitalista
Authors: Nomeriano Aline Soares , Silva Renalvo Cavalcante
Published: September 2019

As atuais políticas de austeridade adotadas por diversos países capitalistas têm rebatimento direto sobre as condições de vida e trabalho da classe trabalhadora. Tanto nos países centrais como na periferia, a exemplo do Brasil, são colocados na ordem do dia pacotes de ajuste fiscal e reformas estatais que visam retomar a taxa de lucro do capital em queda. Neste sentido, este trabalho trata-se de um estudo bibliográfico que pretende analisar a relação entre a crise capitalista e as políticas de austeridade sobre os trabalhadores no Brasil contemporâneo. Para tanto, o artigo teve como principal aporte teórico as contribuições de Marx (2013), Mészáros (2002), Netto; Braz (2011), entre outros.
Sexual dimorphisms in adult human neural, mesoderm‐derived, and neural crest‐derived stem cells
Authors: Greiner Johannes F.W. , Merten Madlen , Kaltschmidt Christian , Kaltschmidt Barbara
Published: September 2019

Sexual dimorphisms contribute, at least in part, to the severity and occurrence of a broad range of neurodegenerative, cardiovascular, and bone disorders. In addition to hormonal factors, increasing evidence suggests that stem cell‐intrinsic mechanisms account for sex‐specific differences in human physiology and pathology. Here, we discuss sex‐related intrinsic mechanisms in adult stem cell populations, namely mesoderm‐derived stem cells, neural stem cells (NSCs), and neural crest‐derived stem cells (NCSCs), and their implications for stem cell differentiation and regeneration. We particularly focus on sex‐specific differences in stem cell‐mediated bone regeneration, in neuronal development, and in NSC‐mediated neuroprotection. Moreover, we review our own recently published observations regarding the sex‐dependent role of NF‐κB‐p65 in neuroprotection of human NCSC‐derived neurons and sex differences in NCSC‐related disorders, so‐called neurocristopathies. These observations are in accordance with the increasing evidence pointing toward sex‐specific differences in neurocristopathies and degenerative diseases like Parkinson's disease or osteoporosis. All findings discussed here indicate that sex‐specific variability in stem cell biology may become a crucial parameter for the design of future treatment strategies.
Premature mitotic entry induced by ATR inhibition potentiates olaparib inhibition‐mediated genomic instability, inflammatory signaling, and cytotoxicity in BRCA2‐deficient cancer cells
Authors: Schoonen Pepijn M. , Kok Yannick P. , Wierenga Elles , Bakker Bjorn , Foijer Floris , Spierings Diana C. J. , van Vugt Marcel A. T. M.
Published: September 2019

Poly(ADP‐ribose) polymerase (PARP) inhibitors are selectively cytotoxic in cancer cells with defects in homologous recombination (HR) (e.g., due to BRCA1/2 mutations). However, not all HR‐deficient tumors efficiently respond to PARP inhibition and often acquire resistance. It is therefore important to uncover how PARP inhibitors induce cytotoxicity and develop combination strategies to potentiate PARP inhibitor efficacy in HR‐deficient tumors. In this study, we found that forced mitotic entry upon ATR inhibition potentiates cytotoxic effects of PARP inhibition using olaparib in BRCA2‐depleted and Brca2 knockout cancer cell line models. Single DNA fiber analysis showed that ATR inhibition does not exacerbate replication fork degradation. Instead, we find ATR inhibitors accelerate mitotic entry, resulting in the formation of chromatin bridges and lagging chromosomes. Furthermore, using genome‐wide single‐cell sequencing, we show that ATR inhibition enhances genomic instability of olaparib‐treated BRCA2‐depleted cells. Inhibition of CDK1 to delay mitotic entry mitigated mitotic aberrancies and genomic instability upon ATR inhibition, underscoring the role of ATR in coordinating proper cell cycle timing in situations of DNA damage. Additionally, we show that olaparib treatment leads to increased numbers of micronuclei, which is accompanied by a cGAS/STING‐associated inflammatory response in BRCA2‐deficient cells. ATR inhibition further increased the numbers of cGAS‐positive micronuclei and the extent of cytokine production in olaparib‐treated BRCA2‐deficient cancer cells. Altogether, we show that ATR inhibition induces premature mitotic entry and mediates synergistic cytotoxicity with PARP inhibition in HR‐deficient cancer cells, which involves enhanced genomic instability and inflammatory signaling.
Prospective detection of mutations in cerebrospinal fluid, pleural effusion, and ascites of advanced cancer patients to guide treatment decisions
Authors: Villatoro Sergio , Mayo‐de‐las‐Casas Clara , Jordana‐Ariza Núria , Viteri‐Ramírez Santiago , Garzón‐Ibañez Mónica , Moya‐Horno Irene , García‐Peláez Beatriz , González‐Cao María , Malapelle Umberto , Balada‐Bel Ariadna , Martínez‐Bueno Alejandro , Campos Raquel , Reguart Noemí , Majem Margarita , Blanco Remei , Blasco Ana , Catalán María J. , González Xavier , Troncone Giancarlo , Karachaliou Niki , Rosell Rafael , Molina‐Vila Miguel A.
Published: September 2019

Many advanced cases of cancer show central nervous system, pleural, or peritoneal involvement. In this study, we prospectively analyzed if cerebrospinal fluid (CSF), pleural effusion (PE), and/or ascites (ASC) can be used to detect driver mutations and guide treatment decisions. We collected 42 CSF, PE, and ASC samples from advanced non‐small‐cell lung cancer and melanoma patients. Cell‐free DNA (cfDNA) was purified and driver mutations analyzed and quantified by PNA‐Q‐PCR or next‐generation sequencing. All 42 fluid samples were evaluable; clinically relevant mutations were detected in 41 (97.6%). Twenty‐three fluids had paired blood samples, 22 were mutation positive in fluid but only 14 in blood, and the abundance of the mutant alleles was significantly higher in fluids. Of the 34 fluids obtained at progression to different therapies, EGFR resistance mutations were detected in nine and ALK acquired mutations in two. The results of testing of CSF, PE, and ASC were used to guide treatment decisions, such as initiation of osimertinib treatment or selection of specific ALK tyrosine–kinase inhibitors. In conclusion, fluids close to metastatic sites are superior to blood for the detection of relevant mutations and can offer valuable clinical information, particularly in patients progressing to targeted therapies.
T‐cell depleted HLA‐haploidentical HSCT in a child with neuromyelitis optica
Authors: Ceglie Giulia , Papetti Laura , Figà Talamanca Lorenzo , Lucarelli Barbarella , Algeri Mattia , Gaspari Stefania , Li Pira Giuseppina , Colafati Giovanna‐Stefania , Montanari Mauro , Valeriani Massimiliano , Locatelli Franco , Merli Pietro
Published: September 2019

Neuromyelitis optica is an immune‐mediated disease characterized by a relapsing course, resulting in progressive disability. In children, given the long life expectancy, a disease‐modifying treatment could be particularly desirable. Unfortunately, the currently available treatment strategies with this potential are scarce. Very limited data are available about the use of allogeneic hematopoietic stem cell transplantation (HSCT) for autoimmune neurological diseases. In this report, we present a pediatric case successfully treated with allogeneic HSCT from an HLA‐haploidentical donor, after ex vivo TCR/CD19‐depletion of the graft. To the best of our knowledge, this is the first case of a pediatric patient to benefit from such a treatment.
Achieving Both High Voltage and High Capacity in Aqueous Zinc‐Ion Battery for Record High Energy Density
Authors: Ma Longtao , Li Na , Long Changbai , Dong Binbin , Fang Daliang , Liu Zhuoxin , Zhao Yuwei , Li Xinliang , Fan Jun , Chen Shimou , Zhang Suojiang , Zhi Chunyi
Published: September 2019

In this work, a high‐voltage output and long‐lifespan zinc/vanadium oxide bronze battery using a Co0.247V2O5⋅0.944H2O nanobelt is developed. The high crystal architecture could enable fast and reversible Zn2+ intercalation/deintercalation at highly operational voltages. The developed battery exhibits a high voltage of 1.7 V and delivers a high capacity of 432 mAh g−1 at 0.1 A g−1. The capacity at voltages above 1.0 V reaches 227 mAh g−1, which is 52.54% of the total capacity and higher than the values of all previously reported Zn/vanadium oxide batteries. Further study reveals that, compared with the pristine vanadium oxide bronze, the absorption energy for Zn2+ increases from 1.85 to 2.24 eV by cobalt ion intercalation. Furthermore, it also shows a high rate capability (163 mAh g−1 even at 10 A g−1) and extraordinary lifespan over 7500 cycles, with a capacity retention of 90.26%. These performances far exceed those for all reported zinc/vanadium oxide bronze batteries. Subsequently, a nondrying and antifreezing tough flexible battery with a high energy density of 432 Wh kg−1 at 0.1 A g−1 is constructed, and it reveals excellent drying and freezing tolerance. This research represents a substantial advancement in vanadium materials for various battery applications, achieving both a high discharge voltage and high capacity.
Robotics in the Gut
Authors: Min Jihong , Yang Yiran , Wu Zhiguang , Gao Wei
Published: September 2019

Since the advent of ingestible temperature sensors and capsule endoscopes, rapid advances in electronics, robotics, nanotechnology, and material sciences have opened the door for the development of novel medical ingestible robots. The untethered robots provide direct, non‐invasive access to the entire gastrointestinal (GI) tract. Furthermore, the tissues, gases, and fluids of the gastrointestinal lumen contain a multitude of biomarkers indicative of gut diseases and health. Ingestible medical robots equipped with advanced imaging and sensing techniques can enable the diagnosis and monitoring of diseases, while providing a better pathophysiological understanding of gastrointestinal disorders. In addition, various robotic actuation mechanisms in the macro‐ and microscale can realize enhanced drug delivery and surgical interventions for the treatment of diseases. In this paper, an overview of recent advances in ingestible robots toward imaging, sensing, drug delivery, and surgical applications in the GI tract is provided. Key challenges and strategies for the development of novel ingestible robots and future directions of ingestible robots toward precision medicine are also discussed.
An Event‐based Approach to Measurement: Facilitating Observational Measurement in Highly Variable Clinical Settings
Authors: Fernandez Rosemarie , Rosenman Elizabeth D. , Brolliar Sarah , Chipman Anne K. , Kalynych Colleen , Vrablik Marie C. , Keebler Joseph R. , Lazzara Elizabeth H.
Published: September 2019

Background

Translational research in medical education requires the ability to rigorously measure learner performance in actual clinical settings; however, current measurement systems cannot accommodate the variability inherent in many patient care  environments. This is especially problematic in emergency medicine, where patients represent a wide spectrum of severity for a single clinical presentation. Our objective is to describe and implement EBAM, an event‐based approach to measurement that can be applied to actual emergency medicine clinical events.

Methods

We used a four‐step event‐based approach to create an emergency department trauma resuscitation patient care measure. We applied the measure to a database of 360 actual trauma resuscitations recorded in a Level I trauma center using trained raters. A subset (n = 50) of videos was independently rated in duplicate to determine inter‐rater reliability. Descriptive analyses were performed to describe characteristics of resuscitation events and Cohen's kappa was used to calculate reliability.

Results

The methodology created a metric containing both universal items that are applied to all trauma resuscitation events and conditional items that only apply in certain situations. For clinical trauma events, injury severity scores ranged from 1 to 75 with a mean (±SD) of 21 (±15) and included both blunt (254/360; 74%) and penetrating (86/360; 25%) traumatic injuries, demonstrating the diverse nature of the clinical encounters. The mean (±SD) Cohen's kappa for patient care items was 0.7 (±0.3).

Conclusion

We present an event‐based approach to performance assessment that may address a major gap in translational education research. Our work centered on assessment of patient care behaviors during trauma resuscitation. More work is needed to evaluate this approach across a diverse array of clinical events.
Copper‐Mediated Cascade Trifunctionalization of N‐Propargylamides
Authors: Wei Wen‐Ting , Ying Wei‐Wei , Meng Xiao‐Xiao , Song Si‐Zhe , Li Qiang
Published: September 2019

The trifunctionalization of alkynes accompanied by intramolecular migration is one of the most powerful tools for rapid enhancing of molecular complexity in synthetic chemistry. Despite significant achievements have been made in the presence of noble metals (such as Au‐, Rh‐, Pd‐, etc.), employment of copper is still underrepresented. Furthermore, 1,1‐diiodoalkenes is the core structure of varieties natural products and pharmaceuticals, as well as valuable intermediates for futher manipulations. Herein we report a general and step‐economic protocol for the synthesis of 1,1‐diiodoalkenes via copper‐mediated cascade trifunctionalization of N‐propargylamides with halogen sources and tert‐butyl nitrite (TBN). This three‐component trifunctionalization method enables one‐step formation of six new chemical bonds in a high chemo‐ and regioselective manner. Moreover, the synthesized products have also been selected for evaluation of antitumor activities. One compound was found to display the best potent inhibitory activities against A549, SMMC‐7721 and T‐24 cells with IC50 values of 9.16, 23.83 and 18.13 μmol L−1.
Three‐Dimensional Graphene‐Foam‐Supported Hierarchical Nickel Iron Phosphide Nanosheet Arrays as Efficient and Stable Bifunctional Electrocatalysts for Overall Water Splitting
Authors: Jian Xue , Li Shuo , Liu Jinzhe , Zhou Chencheng , Guo Shouzhi , Zhang Peilin , Yang Yun , Chen Luyang
Published: September 2019

The development of stable non‐noble metal‐based electrocatalysts with high performance for overall water splitting is critical in the field of renewable energy. Herein, we combined nickel iron phosphide (NiFe‐P) nanosheets with three‐dimensional porous graphene foam (3DGF) as a substrate to design a bifunctional electrocatalyst NiFe‐P@3DGF with excellent catalytic activity towards oxygen and hydrogen evolution reactions (OER and HER, respectively) under alkaline conditions. At a current density of 10 mA cm−2, the overpotentials for the OER and HER are less than 189 and 131 mV, respectively, and the stabilities exceed 50 h. Furthermore, this bifunctional catalyst also exhibits excellent water‐splitting capability with a cell voltage of 1.57 V at 10 mA cm−2. The special structure of the 3DGF substrate with its large surface area, high conductivity, and robust skeleton, as well as the unique core–shell structure of NiFe (oxy)hydroxides/phosphide formed throughout the reaction promote the high activity of the electrocatalyst. Therefore, this work provides a new perspective to exploit the efficient bifunctional electrocatalyst using porous 3DGF as the substrate.
Utilization of Banana Stem Juice as a Feedstock Material for Bioethanol Production
Authors: Gupta Geetika , Baranwal Manoj , Saxena Sanjai , Reddy Mondem Sudhakara
Published: September 2019

Bananas are widely cultivated in tropical and subtropical countries and about 220 tons of biomass waste is produced per hectare of banana plantation. Banana pseudostem contains nearly 90% of moisture and about 4–5 m3 sap is generated from one ton of dried stem with high chemical oxygen demand(COD) and biological oxygen demand (BOD). The feasibility of using banana sap as a feedstock to produce ethanol is evaluated in this study. Banana sap is obtained by crushing the pseudostems and concentrated ten times and supplementing with other industrial byproducts such as corn steep liquor(CSL), spent wash (SW), and yeast extract (YE) for ethanol production. Acid and alkali hydrolyzes are performed to enhance the sugar levels of the sap before fermentation. Two different strains of Saccharomyces cerevisiae (MTCC170 and MTCC180) are used for fermentation. In general, supplementation of banana sap with industrial byproducts significantly enhanced the ethanol production. The maximum ethanol production (2.5 g −1) is observed with concentrated banana sap supplemented with 25% SW (v/v) with MTCC170, which is 16‐fold higher than banana sap alone. Theethanol content is also higher in alkali‐hydrolyzed banana sap supplemented with 25% SW compared to control. These results suggest that banana sap can be used as a renewable source to produce ethanol by supplementing with other industrial byproducts.
Controlling Apparent Coordinated Solvent Number in the Perovskite Intermediate Phase Film for Developing Large‐Area Perovskite Solar Modules
Authors: Lou Lingyun , Liu Tongfa , Xiao Junyan , Xiao Shuang , Long Xia , Zheng Shizhao , Yang Shihe
Published: September 2019

Uniform and pinhole‐free organic lead halide perovskite films in a large area are of paramount importance for achieving high power conversion efficiencies (PCEs) of perovskite solar modules (PSMs). To obtain such high‐quality perovskite films in a large area, one commonly needs to prepare a perovskite intermediate phase, in which coordinated solvent number (CSN) seems to be a key parameter. However, the CSN is difficult to measure and control. To understand the relationship between the CSN and perovskite film quality, in situ evolution of the intermediate phase is investigated. The CSN in the intermediate phase film is measured by the high‐accuracy balance. Uniform and pinhole‐free perovskite films are reproducibly formed by tuning the CSN in the intermediate phase film with a mixed antisolvent of ethyl acetate (EA) and toluene (Tol) blended with a 1:1 volume ratio. A hole conductor–free PSM (10 × 10 cm2) thus fabricates and, based on printable carbon electrode, achieves a PCE of 10.2% in 52 cm2 active area. This effective method provides a promising direction for developing high‐quality and large‐area perovskite films for photovoltaic and other optoelectronic applications.
Two‐Phase Flow Modeling of Direct Methanol Fuel Cell Anode Compartment
Authors: Kablou Y. , Matida E. , Cruickshank C.
Published: September 2019

A quasi two‐dimensional numerical model was developed to predict the two‐phase flow behavior within the anode compartment of direct methanol fuel cells (DMFCs). Different void fraction correlations were employed to examine and estimate the pressure drop, flowrate and methanol concentration variations across the fuel channels. By comparing the modeling results with experimental data, it was discovered that the calculated pressure drop values were highly dependent on the type of void fraction correlation utilized. The best experimental agreement was achieved when using the “separated” flow modeling approach with a void fraction correlation that accounted for surface tension and capillary effects. The “homogenous” flow modeling methodology on the other hand, was found to be inadequate and in all cases, underestimated the two‐phase pressure drop. The model demonstrated that the acceleration and gravitational pressure losses had the lowest and highest impact on the overall two‐phase pressure drop, respectively. The frictional pressure loss effects only started to appear at higher fuel flowrates and at elevated operating current densities. It was also revealed that increasing the cell's operating current density while maintaining the fuel flowrate, would significantly increase the overall two‐phase pressure drop with negligible impact on the net methanol concentration across the anode compartment.
Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3
Authors: Fang Jing , Ji Yan‐Xiao , Zhang Peng , Cheng Lin , Chen Yue , Chen Jun , Su Yanfang , Cheng Xu , Zhang Yan , Li Tianyu , Zhu Xuehai , Zhang Xiao‐Jing , Wei Xiang
Published: September 2019

Background and Aims

Although knowledge regarding the pathogenesis of nonalcoholic fatty liver disease (NAFLD) has profoundly grown in recent decades, the internal restrictive mechanisms remain largely unknown. We have recently reported that the transcription repressor interferon regulatory factor‐2 binding protein 2 (IRF2BP2) is enriched in cardiomyocytes and inhibits pathological cardiac hypertrophy in mice. Notably, IRF2BP2 is abundantly expressed in hepatocytes and dramatically down‐regulated in steatotic livers, whereas the role of IRF2BP2 in NAFLD is unknown.

Approach and Results

Herein, using gain‐of‐function and loss‐of‐function approaches in mice, we demonstrated that while hepatocyte‐specific Irf2bp2 knockout exacerbated high‐fat diet–induced hepatic steatosis, insulin resistance and inflammation, hepatic Irf2bp2 overexpression protected mice from these metabolic disorders. Moreover, the inhibitory role of IRF2BP2 on hepatosteatosis is conserved in a human hepatic cell line in vitro. Combinational analysis of digital gene expression and chromatin immunoprecipitation sequencing identified activating transcription factor 3 (ATF3) to be negatively regulated by IRF2BP2 in NAFLD. Chromatin immunoprecipitation and luciferase assay substantiated the fact that IRF2BP2 is a bona fide transcription repressor of ATF3 gene expression via binding to its promoter region. Functional studies revealed that ATF3 knockdown significantly relieved IRF2BP2 knockout‐exaggerated hepatosteatosis in vitro.

Conclusion

IRF2BP2 is an integrative restrainer in controlling hepatic steatosis, insulin resistance, and inflammation in NAFLD through transcriptionally repressing ATF3 gene expression.
γδ T Cells Promote Steatohepatitis by Orchestrating Innate and Adaptive Immune Programming
Authors: Torres‐Hernandez Alejandro , Wang Wei , Nikiforov Yuri , Tejada Karla , Torres Luisana , Kalabin Aleksandr , Adam Salma , Wu Jingjing , Lu Lu , Chen Ruonan , Lemmer Aaron , Camargo Jimmy , Hundeyin Mautin , Diskin Brian , Aykut Berk , Kurz Emma , Kochen Rossi Juan A. , Khan Mohammed , Liria Miguel , Sanchez Gustavo , Wu Nan , Su Wenyu , Adams Steven , Haq Muhammad Israr Ul , Farooq Mohammad Saad , Vasudevaraja Varshini , Leinwand Joshua , Miller George
Published: September 2019

Background and Aims

The recruitment and activation of inflammatory cells in the liver delineates the transition from hepatic steatosis to steatohepatitis (SH).

Approach and Results

We found that in SH, γδT cells are recruited to the liver by C‐C chemokine receptor (CCR) 2, CCR5, and nucleotide‐binding oligomerization domain‐containing protein 2 signaling and are skewed toward an interleukin (IL)‐17A+ phenotype in an inducible costimulator (ICOS)/ICOS ligand–dependent manner. γδT cells exhibit a distinct Vγ4+, PD1+, Ly6C+CD44+ phenotype in SH. Moreover, γδT cells up‐regulate both CD1d, which is necessary for lipid‐based antigens presentation, and the free fatty acid receptor, CD36. γδT cells are stimulated to express IL‐17A by palmitic acid and CD1d ligation. Deletion, depletion, and targeted interruption of γδT cell recruitment protects against diet‐induced SH and accelerates disease resolution.

Conclusions

We demonstrate that hepatic γδT cells exacerbate SH, independent of IL‐17 expression, by mitigating conventional CD4+ T‐cell expansion and modulating their inflammatory program by CD1d‐dependent vascular endothelial growth factor expression.
Hepatocyte ELOVL Fatty Acid Elongase 6 Determines Ceramide Acyl‐Chain Length and Hepatic Insulin Sensitivity in Mice
Authors: Matsuzaka Takashi , Kuba Motoko , Koyasu Saori , Yamamoto Yuta , Motomura Kaori , Arulmozhiraja Sundaram , Ohno Hiroshi , Sharma Rahul , Shimura Takuya , Okajima Yuka , Han Song‐iee , Aita Yuichi , Mizunoe Yuhei , Osaki Yoshinori , Iwasaki Hitoshi , Yatoh Shigeru , Suzuki Hiroaki , Sone Hirohito , Takeuchi Yoshinori , Yahagi Naoya , Miyamoto Takafumi , Sekiya Motohiro , Nakagawa Yoshimi , Ema Masatsugu , Takahashi Satoru , Tokiwa Hiroaki , Shimano Hitoshi
Published: September 2019

Background and Aims

Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. ELOVL fatty acid elongase 6 (Elovl6) is responsible for converting C16 saturated and monounsaturated fatty acids (FAs) into C18 species. We have previously shown that Elovl6 contributes to obesity‐induced insulin resistance by modifying hepatic C16/C18‐related FA composition.

Approach and Results

To define the precise molecular mechanism by which hepatic Elovl6 affects energy homeostasis and metabolic disease, we generated liver‐specific Elovl6 knockout (LKO) mice. Unexpectedly, LKO mice were not protected from high‐fat diet–induced insulin resistance. Instead, LKO mice exhibited higher insulin sensitivity than controls when consuming a high‐sucrose diet (HSD), which induces lipogenesis. Hepatic patatin‐like phospholipase domain‐containing protein 3 (Pnpla3) expression was down‐regulated in LKO mice, and adenoviral Pnpla3 restoration reversed the enhancement in insulin sensitivity in HSD‐fed LKO mice. Lipidomic analyses showed that the hepatic ceramide(d18:1/18:0) content was lower in LKO mice, which may explain the effect on insulin sensitivity. Ceramide(d18:1/18:0) enhances protein phosphatase 2A (PP2A) activity by interfering with the binding of PP2A to inhibitor 2 of PP2A, leading to Akt dephosphorylation. Its production involves the formation of an Elovl6–ceramide synthase 4 (CerS4) complex in the endoplasmic reticulum and a Pnpla3–CerS4 complex on lipid droplets. Consistent with this, liver‐specific Elovl6 deletion in ob/ob mice reduced both hepatic ceramide(d18:1/18:0) and PP2A activity and ameliorated insulin resistance.

Conclusions

Our study demonstrates the key role of hepatic Elovl6 in the regulation of the acyl‐chain composition of ceramide and that C18:0‐ceramide is a potent regulator of hepatic insulin signaling linked to Pnpla3‐mediated NAFLD.
Hypoxia‐Inducible Factor‐2α Reprograms Liver Macrophages to Protect Against Acute Liver Injury Through the Production of Interleukin‐6
Authors: Gao Rachel Y. , Wang Meng , Liu Qihui , Feng Dechun , Wen Yankai , Xia Yang , Colgan Sean P. , Eltzschig Holger K. , Ju Cynthia
Published: September 2019

Background and Aims

Acetaminophen (APAP) overdose represents the most frequent cause of acute liver failure, resulting in death or liver transplantation in more than one third of patients in the United States. The effectiveness of the only antidote, N‐acetylcysteine, declines rapidly after APAP ingestion, long before patients are admitted to the clinic with symptoms of severe liver injury. The direct hepatotoxicity of APAP triggers a cascade of innate immune responses that may exacerbate or limit the progression of tissue damage. A better understanding of this complex mechanism will help uncover targets for therapeutic interventions.

Approach and Results

We observed that APAP challenge caused stabilization of hypoxia‐inducible factors (HIFs) in the liver and hepatic macrophages (MΦs), particularly HIF‐2α. Genetic deletion of the HIF‐2α gene in myeloid cells (HIF‐2αmye/−) markedly exacerbated APAP‐induced liver injury (AILI) without affecting APAP bioactivation and detoxification. In contrast, hepatic and serum levels of the hepatoprotective cytokine interleukin 6 (IL‐6), its downstream signal transducer and transcription factor 3 activation in hepatocytes, as well as hepatic MΦ IL‐6 expression were markedly reduced in HIF‐2αmye/− mice compared to wild‐type mice post‐APAP challenge. In vitro experiments revealed that hypoxia induced IL‐6 production in hepatic MΦs and that such induction was abolished in HIF‐2α‐deleted hepatic MΦs. Restoration of IL‐6 by administration of exogenous IL‐6 ameliorated AILI in HIF‐2αmye/− mice. Finally, IL‐6‐mediated hepatoprotection against AILI was abolished in hepatocyte‐specific IL‐6 receptor knockout mice.

Conclusions

The data demonstrate that APAP treatment leads to HIF‐2α stabilization in hepatic MΦs and that HIF‐2α subsequently reprograms hepatic MΦs to produce the hepatoprotective cytokine IL‐6, thereby ameliorating AILI.
Immunomodulatory Mechanism of Acyclic Nucleoside Phosphates in Treatment of Hepatitis B Virus Infection
Authors: Murata Kazumoto , Tsukuda Senko , Suizu Futoshi , Kimura Akihiro , Sugiyama Masaya , Watashi Koichi , Noguchi Masayuki , Mizokami Masashi
Published: September 2019

Background and Aims

Current treatment with nucleos(t)ide analogs (NUCs) safely controls the replication of hepatitis B virus (HBV) and improves prognosis in patients with HBV. However, the inability to completely clear HBV is problematic, and novel therapies are desired. It has been believed that all NUCs have similar functions to inhibit HBV reverse transcriptase. However, our recent findings that only acyclic nucleoside phosphonates (ANPs; adefovir dipivoxil and tenofovir disoproxil fumarate) had an additional effect of inducing interferon (IFN)‐λ3 in the gastrointestinal tract suggests that ANPs are not only distinct from nucleoside analogs (lamivudine and entecavir) in their structures but also in their functions. Because enteric lipopolysaccharide (LPS) can cross the intestine and affect peripheral blood mononuclear cells (PBMCs), we hypothesized that orally administered ANPs could have further additional effects to modulate LPS‐mediated cytokine profile in PBMCs.

Approach and Results

This study showed that pretreatment of PBMCs, from either healthy volunteers or patients with HBV, with ANPs inhibited LPS‐mediated interleukin (IL)‐10 production, which reciprocally induced IL‐12p70 and tumor necrosis factor‐α production in a dose‐dependent manner. Furthermore, the combination of IFN‐α and ANPs synergistically enhanced LPS‐mediated IL‐12p70 production in PBMCs. Mechanistic analyses revealed that cellular metabolites of ANPs directly bound the Akt protein, inhibiting its translocation to the plasma membrane, thereby impairing Akt phosphorylation. Therefore, pretreatment of PBMCs with ANPs impairs LPS‐mediated IL‐10 production.

Conclusions

Among NUCs, only ANPs have an additional pharmacological effect modulating LPS‐mediated cytokine production, which is expected to produce favorable immune responses toward HBV elimination. This additional immunomodulation by ANPs in PBMCs, as well as IFN‐λ3 induction in the gastrointestinal tract, provides insights into HBV treatment.
Inclusion of pregnant women in antiretroviral drug research: what is needed to move forwards?
Authors: Fairlie Lee , Waitt Catriona , Lockman Shahin , Moorhouse Michelle , Abrams Elaine J. , Clayden Polly , Boffito Marta , Khoo Saye , Rees Helen , Cournil Amandine , Venter Willem Francois , Serenata Celicia , Chersich Matthew
Published: September 2019

Introduction

To adequately ascertain drug safety and efficacy, drug trials need to include participants from all groups likely to receive the medication following approval. Pregnant women, however, are mostly excluded from trials, and women participating are often required to use highly effective contraception and taken off study product (even off study) if they conceive. There is little commercial incentive for including pregnant women in clinical trials, even when preclinical animal and human pharmacokinetic and safety data appear reassuring. With this conservative approach, large numbers of pregnant women are exposed to drug postlicensing with little known about drug safety and efficacy, and little done to systematically monitor outcomes of pregnancy exposure.

Discussion

The article focuses on antiretrovirals for treating and preventing HIV, and presents potential approaches which could extend to other therapeutic areas, to obtaining adequate and timely data to inform use of these drugs in this population. Most importantly the pregnancy risk profile of investigational agents can be systematically stratified from low to high risk, based on guidelines from regulatory bodies. This stratification can determine the progress through preclinical work with animals and non‐pregnant women to opportunistic studies among women who become pregnant on a clinical trial or within routine clinical treatment. Stratification can include pregnant women in clinical trials, concurrent with Phase II/III trials in non‐pregnant adults, and ultimately to postmarketing surveillance for outcomes in pregnant women and their infants. Each step can be enabled by clear criteria from international and local regulatory bodies on progression through study phases, standardized protocols for collecting relevant data, collaborative data sharing, pregnancy outcomes surveillance systems supported by committed funding for these endeavours.

Conclusions

A formalized step‐wise approach to including pregnant women in antiretroviral drug research should become the new norm. Systematic implementation of this approach would yield more timely and higher quality pregnancy dosing, safety and efficacy data. Through more vigorous action, regulatory bodies could responsibly overcome reluctance to include pregnant women in drug trials. Funders, researchers and programme implementers need to be galvanized to progressively include pregnant women in research – the use of newer, more effective drugs in women is at stake (349).
Integration of an Addiction Team in a Liver Transplantation Center
Authors: Donnadieu‐Rigole Hélène , Jaubert Laura , Ursic‐Bedoya José , Hanslik Bertrand , Mura Thibault , Gamon Lucie , Faure Stéphanie , Navarro Francis , Perney Pascal , Herrero Astrid , Pageaux Georges‐Philippe
Published: September 2019

Up to 50% of liver transplantation (LT) recipients with known or clandestine alcohol‐use disorder (AUD) before surgery return to alcohol use after LT. However, only severe alcohol relapse, which varies in frequency from 11% to 26% of patients, has an impact on longterm survival and significantly decreases survival rates after 10 years. Therefore, it is crucial to identify patients with the highest risk of severe relapse in order to arrange specific, standardized monitoring by an addiction team before and after LT. The aims of this study were to describe the effects of combined management of AUD on the rate of severe alcohol relapse and to determine the risk factors before LT that predict severe relapse. Patients transplanted between January 2008 and December 2014 who had met with the LT team’s addiction specialist were included in the study. Patients who exhibited alcohol‐related relapse risk factors received specific addiction follow‐up. A total of 235 patients were enrolled in the study. Most of them were men (79%), and the mean age at the time of the LT was 55.7 years. Severe relapse occurred in only 9% of the transplant recipients. Alcohol‐related factors of severe relapse were a pretransplant abstinence of 6 months and family, legal, or professional consequences of alcohol consumption, whereas the nonalcohol‐related factors were being single and being eligible for a disability pension. In conclusion, the integration of an addiction team in a LT center may be beneficial. The addiction specialist can identify patients at risk of severe relapse in the pretransplantation period and hence arrange for specific follow‐up.
Simultaneous optimization of crusher and phase cycling schemes for magnetic resonance spectroscopy: an extension of dephasing optimization through coherence order pathway selection
Authors: Landheer Karl , Juchem Christoph
Published: September 2019

Purpose

To extend the dephasing optimization through coherence order pathway selection (DOTCOPS) algorithm, originally designed solely for gradient crusher schemes, to include tailored phase cycling schemes for arbitrary pulse sequences and arbitrary number of coupled spins.

Theory and Methods

The effects all possible nested and cogwheel phase cycling schemes have on the coherence order pathways for an arbitrary experiment are considered. The DOTCOPS algorithm uses a cost function to maximally eliminate unwanted coherence pathways, with schemes preferentially eliminating unwanted coherence pathways that are less affected by the crusher scheme. Efficacy was demonstrated experimentally in 2 separate MR spectroscopy (MRS) sequences: semi–localized adiabatic selective refocusing (sLASER) and MEscher‐GArwood sLASER both with phantom and in vivo experiments.

Results

For all sequences investigated, cogwheel was found to theoretically outperform typical nested phase cycling schemes. The chosen cogwheel phase cycling schemes through DOTCOPS were found to outperform a typical 2‐step phase cycling scheme in both phantom and in vivo experiments. Both crusher schemes and phase cycling schemes with 8, 16, or 32 steps are presented for 6 of the most common advanced MRS sequences.

Conclusion

The DOTCOPS algorithm has been extended to provide optimal crusher and phase cycling schemes considered in tandem. DOTCOPS can be applied to any pulse sequence of interest for any number of coupled spins. DOTCOPS is now able to alleviate the long‐standing issue of designing effective crusher and phase cycling schemes for complex MRS modern sequences and, as a result, is expected to improve the data quality of virtually all applications.
Diagnostic algorithm for ameloblastic carcinoma
Authors: Kase Yutaro , Kasamatsu Atsushi , Saito Tomoaki , Koike Kazuyuki , Iyoda Manabu , Nakashima Dai , Endo‐Sakamoto Yosuke , Sunohara Masataka , Shiiba Masashi , Uzawa Katsuhiro , Tanzawa Hideki
Published: September 2019

Ameloblastic carcinoma (AC) is an odontogenic malignant tumor which combines the histological features of ameloblastoma and cytologic atypia. The key point of the diagnosis and clinical characteristics of AC have not been well defined, as it is a rare type of tumor. Hence, in this study, we present’ for better clarity the diagnostic flowchart for AC, ameloblastoma, and metastasizing ameloblastoma.
SoyCSN: Soybean context‐specific network analysis and prediction based on tissue‐specific transcriptome data
Authors: Wang Juexin , Hossain Md Shakhawat , Lyu Zhen , Schmutz Jeremy , Stacey Gary , Xu Dong , Joshi Trupti
Published: September 2019

The Soybean Gene Atlas project provides a comprehensive map for understanding gene expression patterns in major soybean tissues from flower, root, leaf, nodule, seed, and shoot and stem. The RNA‐Seq data generated in the project serve as a valuable resource for discovering tissue‐specific transcriptome behavior of soybean genes in different tissues. We developed a computational pipeline for Soybean context‐specific network (SoyCSN) inference with a suite of prediction tools to analyze, annotate, retrieve, and visualize soybean context‐specific networks at both transcriptome and interactome levels. BicMix and Cross‐Conditions Cluster Detection algorithms were applied to detect modules based on co‐expression relationships across all the tissues. Soybean context‐specific interactomes were predicted by combining soybean tissue gene expression and protein–protein interaction data. Functional analyses of these predicted networks provide insights into soybean tissue specificities. For example, under symbiotic, nitrogen‐fixing conditions, the constructed soybean leaf network highlights the connection between the photosynthesis function and rhizobium–legume symbiosis. SoyCSN data and all its results are publicly available via an interactive web service within the Soybean Knowledge Base (SoyKB) at http://soykb.org/SoyCSN. SoyCSN provides a useful web‐based access for exploring context specificities systematically in gene regulatory mechanisms and gene relationships for soybean researchers and molecular breeders.
Structure–function study of a novel inhibitor of the casein kinase 1 family inArabidopsis thaliana
Authors: Saito Ami N. , Matsuo Hiromi , Kuwata Keiko , Ono Azusa , Kinoshita Toshinori , Yamaguchi Junichiro , Nakamichi Norihito
Published: September 2019

Casein kinase 1 (CK1) is an evolutionarily conserved protein kinase family among eukaryotes. Studies in non‐plants have shown CK1‐dependent divergent biological processes, but the collective knowledge regarding the biological roles of plant CK1 lags far behind other members of the Eukarya. One reason for this is that plants have many more genes encoding CK1 than do animals. To accelerate our understanding of the plant CK1 family, a strong CK1 inhibitor that efficiently inhibits multiple members of the CK1 protein family in vivo (i.e.,in planta) is required. Here, we report a novel, specific, and effective CK1 inhibitor in Arabidopsis. Using circadian period‐lengthening activity as an estimation of the CK1 inhibitor effect in vivo, we performed a structure–activity relationship study of analogues of the CK1 inhibitor PHA767491 (1,5,6,7‐tetrahydro‐2‐(4‐pyridinyl)‐4H‐pyrrolo[3,2‐c]pyridin‐4‐one hydrochloride). A propargyl group at the pyrrole nitrogen atom (AMI‐212) or a bromine atom at the pyrrole C3 position (AMI‐23) had stronger CK1 inhibitory activity than PHA767491. A hybrid molecule of AMI‐212 and AMI‐23 (AMI‐331) was about 100‐fold more inhibitory than the parent molecule PHA767491. Affinity proteomics using an AMI‐331 probe showed that the targets of AMI‐331 inhibition are mostly CK1 kinases. As such, AMI‐331 is a potent and selective CK1 inhibitor that shows promise in the research of CK1 in plants.
Photocatalytic Degradation of Metronidazole Using D‐g‐C3N4‐Bi5O7I Composites Under Visible Light Irradiation: Degradation Product, and Mechanisms
Authors: Salimi Maryam , Esrafili Ali , Sobhi Hamid Reza , Behbahani Mohammad , Gholami Mitra , Farzadkia Mahdi , Jafari Ahmad Jonidi , Kalantary Roshanak Rezaei
Published: September 2019

Herein, the efficiency of a number of D‐g‐C3N4‐Bi5O7I composites for the photocatalytic degradation of metronidazole (MNZ) was investigated under visible‐light irradiation. Initially, the operating parameters, intermediate products and related mechanisms were thoroughly assessed. The photocatalytic performance of D‐g‐C3N4‐Bi5O7I composites containing 40 wt% D‐g‐C3N4 (D‐CNBi‐40) was almost 4.3 times more efficient than that of the D‐g‐C3N4. Then, the effects of pH and D‐CNBi‐40 dosage on the photocatalytic degradation of MNZ were also studied and the optimum values were set. The optimum photocatalytic efficiency were achieved at pH 10, and carrier dosage of 0.8 g L−1. In another development, it was revealed that the variations in the catalyst performance were negligible over at least four consecutive cyclic runs. The photocurrent response of D‐CNBi‐40 was 0.7μA.cm−1 under visible light irradiation, which was 1.5 and 2.18 times higher than that of Bi5O7I, and D‐g‐C3N4, respectively. The results regarding the radical quenching process demonstrated that •O2–, and h+ were the dominant active species in the degradation of MNZ, whilst •OH played no major role in the respective degredation. In addition, the products generated from the degredation of MNZ were identified by GC/MS. The utiliziation of D‐CNBi‐40 in various water matrices for the degradation of MNZ disclosed that it has a great potential for practical application. Finally, it is thought that this study could be a step forward toward establishing an effective and recycable photocatalytic system in wide variety of aquatic samples.
Cascade of Michael Addition/Retro‐Michael Reaction/Skeletal Rearrangement in the Synthesis of Arylmethylidene Derivatives of Imidazothiazolotriazines
Authors: Izmest'ev Alexei N. , Kim Nikita A. , Karnoukhova Valentina A. , Kolotyrkina Natalya G. , Kravchenko Angelina N. , Gazieva Galina A.
Published: September 2019

Chemo‐, regio‐ and diastereoselective approach to the synthesis of arylmethylideneimidazothiazolotriazines has been developed based on the Michael addition/retro‐Michael reaction and Michael addition/retro‐Michael reaction/skeletal rearrangement cascade processes in the reactions of imidazo[4,5‐e]thiazolo[3,2‐b][1,2,4]triazines with arylmethylidene derivatives of malononitrile.
Green Approach of Photoinitiated Polymerization Using Monomers Derived from Oleic Acid and Ionic Liquid
Authors: Sanay Berran , Strehmel Bernd , Strehmel Veronika
Published: September 2019

Bio‐based monomers synthesized from oleic acid mix and nonvolatile ionic liquid monomers were investigated by photo‐DSC using 2,4,6‐trimethylbenzoylphenyl phosphinate (Irgacure® TPO−L) or dibenzoyldiethylgermane (Ivocerin®) as photoinitiator. The results were compared with those obtained for commercial hexanediol‐1,6‐di(meth)acrylate. The ionic liquid monomers (N‐octyl‐N’‐vinylimidazolium bis(trifluoromethylsulfonyl)imide (NTf2) and N‐decyl‐N’‐vinylimidazolium NTf2) showed lower reactivity compared to the diacrylate and slightly higher reactivity than the methacrylates. The vinyl group bound at the imidazolium ring fully converted during photoinitiated polymerization as confirmed by 1H NMR analysis. Final conversion was higher for the imidazole‐functionalized methacrylate derived from fatty acid compared to both the hydroxy‐functionalized derivative and hexandiol‐1,6‐dimethacrylate although the maximum of the polymerization rate was lower for the bio‐based monomers indicating their lower reactivity.
The Practical Method to Synthesize Gold Nanoparticles Supported on Hydrotalcite and Application on Oxidation and Hydration Reactions
Authors: Yao Wei , Wu Qiang , Huang Ronghui , Zhang Yilin , Yang Yongchun , Zhang Liang , Wang Dawei
Published: September 2019

A gold nanoparticles‐supported hydrotalcite was developed and employed as a stable and efficient catalyst for the oxidation of styrene and hydration of alkynes. Preparation of the catalyst involves a reaction between and hydration reactions, but also excellent reusability in more than five cycles.AuPPh3Cl and hydrotalcite under mild conditions. The prepared catalyst exhibited not only outstanding catalytic activity for oxidation