bluuebunny/crossref_metadata_2025_split huggingface dataset:
Robotics in the Gut
Authors: Min Jihong , Yang Yiran , Wu Zhiguang , Gao Wei 
Published: September 2019

AbstractSince 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

ABSTRACTBackgroundTranslational 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.MethodsWe 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.ResultsThe 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).ConclusionWe 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

AbstractThe 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

AbstractThe 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

AbstractBananas 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.
Two‐Phase Flow Modeling of Direct Methanol Fuel Cell Anode Compartment
Authors: Kablou Y. , Matida E. , Cruickshank C. 
Published: September 2019

AbstractA 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

AbstractIntroductionTo 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.DiscussionThe 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.ConclusionsA 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).