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1.
J Agric Food Chem ; 72(35): 19286-19294, 2024 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-39039661

RESUMEN

UDP-N-acetylglucosamine pyrophosphorylase (UAP) catalyzes the last step in the hexosamine biosynthesis pathway to directly produce UDP-N-acetylglucosamine (UDP-GlcNAc). Because UAPs play important physiological and pathological roles in organisms, they are considered potential targets for drug and pesticide development. However, the lack of efficient and selective inhibitors is a bottleneck that must be overcome. This study reports the first crystal structure of the insect UAP from Spodoptera frugiperda (SfUAP) in complex with UDP-GlcNAc. SfUAP has two insect-specific structural characteristics in the active pocket, namely, a free Cys (Cys334) and a Mg2+ binding site, which differentiate it from human UAP (HsAGX1) and fungal UAP (AfUAP) in terms of substrate and inhibitor binding. N-(4-Nitrophenyl)maleimide (pNPMI) and myricetin are discovered as potent covalent and noncovalent inhibitors of SfUAP, respectively. Moreover, myricetin can significantly reduce the level of cellular O-GlcNAcylation by inhibiting both UAP and O-GlcNAc transferase. These findings provide novel insights into the development of UAP-based drugs and pesticides.


Asunto(s)
Inhibidores Enzimáticos , Hexosaminas , Proteínas de Insectos , Spodoptera , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Proteínas de Insectos/metabolismo , Proteínas de Insectos/química , Proteínas de Insectos/genética , Proteínas de Insectos/antagonistas & inhibidores , Hexosaminas/química , Hexosaminas/metabolismo , Hexosaminas/biosíntesis , Nucleotidiltransferasas/química , Nucleotidiltransferasas/metabolismo , Nucleotidiltransferasas/antagonistas & inhibidores , Nucleotidiltransferasas/genética , Vías Biosintéticas , Sitios de Unión
2.
Proc Natl Acad Sci U S A ; 121(24): e2318124121, 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38830100

RESUMEN

There is much excitement about the opportunity to harness the power of large language models (LLMs) when building problem-solving assistants. However, the standard methodology of evaluating LLMs relies on static pairs of inputs and outputs; this is insufficient for making an informed decision about which LLMs are best to use in an interactive setting, and how that varies by setting. Static assessment therefore limits how we understand language model capabilities. We introduce CheckMate, an adaptable prototype platform for humans to interact with and evaluate LLMs. We conduct a study with CheckMate to evaluate three language models (InstructGPT, ChatGPT, and GPT-4) as assistants in proving undergraduate-level mathematics, with a mixed cohort of participants from undergraduate students to professors of mathematics. We release the resulting interaction and rating dataset, MathConverse. By analyzing MathConverse, we derive a taxonomy of human query behaviors and uncover that despite a generally positive correlation, there are notable instances of divergence between correctness and perceived helpfulness in LLM generations, among other findings. Further, we garner a more granular understanding of GPT-4 mathematical problem-solving through a series of case studies, contributed by experienced mathematicians. We conclude with actionable takeaways for ML practitioners and mathematicians: models that communicate uncertainty, respond well to user corrections, and can provide a concise rationale for their recommendations, may constitute better assistants. Humans should inspect LLM output carefully given their current shortcomings and potential for surprising fallibility.


Asunto(s)
Lenguaje , Matemática , Solución de Problemas , Humanos , Solución de Problemas/fisiología , Estudiantes/psicología
3.
Sci Data ; 10(1): 895, 2023 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-38092796

RESUMEN

Small-scale motion detection using non-invasive remote sensing techniques has recently garnered significant interest in the field of speech recognition. Our dataset paper aims to facilitate the enhancement and restoration of speech information from diverse data sources for speakers. In this paper, we introduce a novel multimodal dataset based on Radio Frequency, visual, text, audio, laser and lip landmark information, also called RVTALL. Specifically, the dataset consists of 7.5 GHz Channel Impulse Response (CIR) data from ultra-wideband (UWB) radars, 77 GHz frequency modulated continuous wave (FMCW) data from millimeter wave (mmWave) radar, visual and audio information, lip landmarks and laser data, offering a unique multimodal approach to speech recognition research. Meanwhile, a depth camera is adopted to record the landmarks of the subject's lip and voice. Approximately 400 minutes of annotated speech profiles are provided, which are collected from 20 participants speaking 5 vowels, 15 words, and 16 sentences. The dataset has been validated and has potential for the investigation of lip reading and multimodal speech recognition.

4.
ACS Nano ; 17(20): 20643-20653, 2023 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-37796635

RESUMEN

Here, by introducing polystyrenesulfonate (PSS) as a multifunctional bridging molecule to synchronously coordinate the interaction between the precursor and the structure-directing agent, we developed a mesoporous conductive polymer of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) featuring adjustable size in the range of 105-1836 nm, open nanochannels, large specific surface area (105.5 m2 g-1), and high electrical conductivity (172.9 S cm-1). Moreover, a large-area ultrathin PEDOT:PSS thin film with well-defined mesopores can also be obtained by controllable growth on various functional interfaces. As an example, we demonstrated that the iodine-loaded mesoporous PEDOT:PSS nanospheres can serve as a promising cathode for aqueous zinc-iodine batteries with high specific capacity (241 mAh g-1), excellent rate performance, and superlong 20,000 cycle life. In-depth theoretical calculations and systematic experimental results together reveal that the exposed sulfur- and oxygen-containing functional groups hold strong interactions with iodine species, resulting in effectively anchoring iodine species and inhibiting the shuttling of polyiodide intermediates, thus ensuring the long-term stability of the batteries. This work introduces a member to the family of mesoporous materials as well as porous polymers with versatile applications.

5.
J Am Chem Soc ; 145(40): 22158-22167, 2023 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-37779473

RESUMEN

Li-SOCl2 batteries possess ultrahigh energy densities and superior safety features at a wide range of operating temperatures. However, the Li-SOCl2 battery system suffers from poor reversibility due to the sluggish kinetics of SOCl2 reduction during discharging and the oxidation of the insulating discharge products during charging. To achieve a high-power rechargeable Li-SOCl2 battery, herein we introduce the molecular catalyst I2 into the electrolyte to tailor the charging and discharging reaction pathways. The as-assembled rechargeable cell exhibits superior power density, sustaining an ultrahigh current density of 100 mA cm-2 during discharging and delivering a reversible capacity of 1 mAh cm-2 for 200 cycles at a current density of 2 mA cm-2 and 6 mAh cm-2 for 50 cycles at a current density of 5 mA cm-2. Our results reveal the molecular catalyst-mediated reaction mechanisms that fundamentally alter the rate-determining steps of discharging and charging in Li-SOCl2 batteries and highlight the viability of transforming a primary high-energy battery into a high-power rechargeable system, which has great potential to meet the ever-increasing demand of energy-storage systems.

6.
Nat Commun ; 14(1): 5235, 2023 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-37640714

RESUMEN

Stable cathodes with multiple redox-active centres affording a high energy density, fast redox kinetics and a long life are continuous pursuits for aqueous zinc-organic batteries. Here, we achieve a high-performance zinc-organic battery by tuning the electron delocalization within a designed fully conjugated two-dimensional hydrogen-bonded organic framework as a cathode material. Notably, the intermolecular hydrogen bonds endow this framework with a transverse two-dimensional extended stacking network and structural stability, whereas the multiple C = O and C = N electroactive centres cooperatively trigger multielectron redox chemistry with super delocalization, thereby sharply boosting the redox potential, intrinsic electronic conductivity and redox kinetics. Further mechanistic investigations reveal that the fully conjugated molecular configuration enables reversible Zn2+/H+ synergistic storage accompanied by 10-electron transfer. Benefitting from the above synergistic effects, the elaborately tailored organic cathode delivers a reversible capacity of 498.6 mAh g-1 at 0.2 A g-1, good cyclability and a high energy density (355 Wh kg-1).

7.
Nat Protoc ; 18(8): 2459-2484, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37460631

RESUMEN

Conducting polymers with conjugated backbones have been widely used in electrochemical energy storage, catalysts, gas sensors and biomedical devices. In particular, two-dimensional (2D) mesoporous conducting polymers combine the advantages of mesoporous structure and 2D nanosheet morphology with the inherent properties of conducting polymers, thus exhibiting improved electrochemical performance. Despite the use of bottom-up self-assembly approaches for the fabrication of a variety of mesoporous materials over the past decades, the synchronous control of the dimensionalities and mesoporous architectures for conducting polymer nanomaterials remains a challenge. Here, we detail a simple, general and robust route for the preparation of a series of 2D mesoporous conducting polymer nanosheets with adjustable pore size (5-20 nm) and thickness (13-45 nm) and controllable morphology and composition via solution-based self-assembly. The synthesis conditions and preparation procedures are detailed to ensure the reproducibility of the experiments. We describe the fabrication of over ten high-quality 2D-ordered mesoporous conducting polymers and sandwich-structured hybrids, with tunable thickness, porosity and large specific surface area, which can serve as potential candidates for high-performance electrode materials used in supercapacitors and alkali metal ion batteries, and so on. The preparation time of the 2D-ordered mesoporous conducting polymer is usually no more than 12 h. The subsequent supercapacitor testing takes ~24 h and the Na ion battery testing takes ~72 h. The procedure is suitable for users with expertise in physics, chemistry, materials and other related disciplines.


Asunto(s)
Nanoestructuras , Polímeros , Polímeros/química , Reproducibilidad de los Resultados , Nanoestructuras/química , Porosidad , Catálisis
8.
Adv Sci (Weinh) ; 10(19): e2301918, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37098637

RESUMEN

Despite the impressive progress in mesoporous materials over past decades, for those precursors having no well-matched interactions with soft templates, there are still obstacles to be guided for mesoporous structure via soft-template strategies. Here, a polyoxometalate-assisted co-assembly route is proposed for controllable construction of superstructured mesoporous materials by introducing polyoxometalates as bifunctional bridge units, which weakens the self-nucleation tendency of the precursor through coordination interactions and simultaneously connects the template through the induced dipole-dipole interaction. By this strategy, a series of meso-structured polymers, featuring highly open radial mesopores and dendritic pore walls composed of continuous interwoven nanosheets can be facilely obtained. Further carbonization gave rise to nitrogen-doped hierarchical mesoporous carbon decorated uniformly with ultrafine γ-Mo2 N nanoparticles. Density functional theory proves that nitrogen-doped carbon and γ-Mo2 N can strongly adsorb polyiodide ions, which effectively alleviate polyiodide dissolving in organic electrolytes. Thereby, as the cathode materials for sodium-iodine batteries, the I2 -loaded carbonaceous composite shows a high specific capacity (235 mA h g-1 at 0.5 A g-1 ), excellent rate performance, and cycle stability. This work will open a new venue for controllable synthesis of new hierarchical mesoporous functional materials, and thus promote their applications toward diverse fields.

9.
J Agric Food Chem ; 71(4): 1845-1851, 2023 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-36655791

RESUMEN

Camptothecin (CPT) is a prominent molecule in natural product research because of its application prospects in medicine and agriculture. In this study, CPT and its derivatives were discovered to be competitive inhibitors of group II and group h insect chitinases, both of which are key components of insect chitinolytic systems. CPT and 7-ethyl-10-hydroxycamptothecin (SN-38) inhibited group II chitinase from Ostrinia furnacalis (OfChtII) with Ki values of 5.1 and 2.0 µM, respectively. Results from tryptophan fluorescence spectroscopy, molecular docking analysis, and molecular dynamics simulations revealed that both CPT and SN-38 inhibit OfChtII-C1 by interacting with solvent-exposed tryptophan residues in a substrate-binding cleft. CPT exhibited high insecticidal activity toward the orthopteran pest Locusta migratoria, possibly because of the midgut metabolism of CPT, with only moderate activities toward lepidopteran pests. Even though SN-38 exhibited much lower insecticidal activities than CPT, it still showed higher inhibitory activity toward chitinase. This study reports a new molecular target of CPT and provides insights into molecular design of CPT-based insecticides against different kinds of pests.


Asunto(s)
Quitinasas , Insecticidas , Irinotecán , Insecticidas/farmacología , Insecticidas/química , Simulación del Acoplamiento Molecular , Quitinasas/genética , Quitinasas/farmacología , Triptófano
10.
Br J Anaesth ; 130(2): 191-201, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36088134

RESUMEN

BACKGROUND: Early exposure to general anaesthetics for multiple surgeries or procedures might negatively affect brain development. Recent studies indicate the importance of microbiota in the development of stress-related behaviours. We determined whether repeated anaesthesia and surgery in early life cause gut microbiota dysbiosis and anxiety-like behaviours in rats. METHODS: Sprague Dawley rats received skin incisions under sevoflurane 2.3 vol% three times during the first week of life. After 4 weeks, gut microbiota, anxiety-related behaviours, hippocampal serotonergic activity, and plasma stress hormones were tested. Subsequently, we explored the effect of faecal microbiota transplantation from multiple anaesthesia/surgery exposed rats after administration of a cocktail of antibiotics on anxiety-related behaviours. RESULTS: Anxiety-like behaviours were observed in rats with repeated anaesthesia/surgery exposures: In the OF test, multiple anaesthesia/surgery exposures induced a decrease in the time spent in the centre compared to the Control group (P<0.05, t=3.05, df=16, Cohen's d=1.44, effect size=0.58). In the EPM test, rats in Multiple AS group travelled less (P<0.05, t=5.09, df=16, Cohen's d=2.40, effective size=0.77) and spent less time (P<0.05, t=3.58, df=16, Cohen's d=1.69, effect size=0.65) in the open arms when compared to the Control group. Repeated exposure caused severe gut microbiota dysbiosis, with exaggerated stress response (P<0.01, t=4.048, df=16, Cohen's d=-1.91, effect size=-0.69), a significant increase in the hippocampal concentration of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) (P<0.05; for 5-HT: t=3.33, df=18, Cohen's d=-1.49, effect size=-0.60; for 5-HIAA: t=3.12, df=18, Cohen's d=-1.40, effect size=-0.57), and changes in gene expression of serotonergic receptors later in life (for Htr1a: P<0.001, t=4.49, df=16, Cohen's d=2.24, effect size=0.75; for Htr2c: P<0.01, t=3.72, df=16, Cohen's d=1.86, effect size=0.68; for Htr6: P<0.001, t=7.76, df=16, Cohen's d=3.88, effect size=0.89). Faecal microbiota transplantation led to similar anxiety-like behaviours and changes in the levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. CONCLUSIONS: Gut microbiota dysbiosis caused by early repeated exposure to anaesthesia and surgery affects long-term anxiety emotion behaviours in rats.


Asunto(s)
Anestesia , Microbioma Gastrointestinal , Ratas , Animales , Serotonina/metabolismo , Ácido Hidroxiindolacético , Ratas Sprague-Dawley , Disbiosis/inducido químicamente , Ansiedad/etiología
11.
J Agric Food Chem ; 70(35): 10762-10770, 2022 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-36000580

RESUMEN

The low efficiency of RNA interference (RNAi) in insects via the oral administration of double-stranded RNA (dsRNA) is a considerable obstacle preventing its application in insect pest control. The instability of dsRNA and insufficient dsRNA uptake are known to limit the RNAi efficiency. To overcome these limitations, the block copolymer poly(ethylene glycol)-polylysine(thiol) [PEG-PLys(SH)] was designed in this study to form well-defined, core-shell nanoparticles to protect dsRNA from premature degradation and to facilitate its movement through various physiological barriers. The developed material had excellent structural stability and dsRNA-protecting capacity, thereby enabling the prolonged survival of dsRNA in the digestive tract for endocytosis into the midgut cells of the migratory locust, Locusta migratoria. After encapsulation of a dsLmCHS2 payload (a midgut gene), a 60% down-regulation of LmCHS2, accompanied with observations of amorphous and discontinuous linings of the peritrophic matrix and abnormal phenotypes, was observed. In addition, the elaborated nanoscale dsRNA condensates appeared to readily extravasate through the narrow fenestrations in the linings of midgut epithelial cells into the hemolymph and be distributed throughout the body. After encapsulation of a dsLmCHS1 payload (a cuticle gene), a distinctive lethal phenotype with molting failure was observed as a result of a 50% down-regulation in LmCHS1. The persistent leaf adherence of these dsRNA constructs was also capable of resisting continuous rinsing. Therefore, these dsRNA constructs represent a robust type of RNAi pesticide, which has potential as a versatile pesticide against a variety of molecular targets for the control of destructive insects and insects resistant to conventional pesticides.


Asunto(s)
Locusta migratoria , Plaguicidas , Animales , Hemolinfa , Proteínas de Insectos/genética , Proteínas de Insectos/metabolismo , Insectos/metabolismo , Locusta migratoria/genética , Locusta migratoria/metabolismo , Plaguicidas/metabolismo , Interferencia de ARN , ARN Bicatenario/genética , ARN Bicatenario/metabolismo
12.
Sci Data ; 9(1): 474, 2022 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-35922418

RESUMEN

This paper presents a comprehensive dataset intended to evaluate passive Human Activity Recognition (HAR) and localization techniques with measurements obtained from synchronized Radio-Frequency (RF) devices and vision-based sensors. The dataset consists of RF data including Channel State Information (CSI) extracted from a WiFi Network Interface Card (NIC), Passive WiFi Radar (PWR) built upon a Software Defined Radio (SDR) platform, and Ultra-Wideband (UWB) signals acquired via commercial off-the-shelf hardware. It also consists of vision/Infra-red based data acquired from Kinect sensors. Approximately 8 hours of annotated measurements are provided, which are collected across two rooms from 6 participants performing 6 daily activities. This dataset can be exploited to advance WiFi and vision-based HAR, for example, using pattern recognition, skeletal representation, deep learning algorithms or other novel approaches to accurately recognize human activities. Furthermore, it can potentially be used to passively track a human in an indoor environment. Such datasets are key tools required for the development of new algorithms and methods in the context of smart homes, elderly care, and surveillance applications.

14.
Macromol Rapid Commun ; 43(14): e2100897, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35182088

RESUMEN

Conjugated polymers possess better electron conductivity due to large π-electron conjugated configuration endowing them significant scientific and technological interest. However, the obvious deficiency of active-site underutilization impairs their electrochemical performance. Therefore, designing and engineering π-conjugated polymers with rich redox functional groups and mesoporous architectures could offer new opportunities for them in these emerging applications and further expand their application scopes. Herein, a series of 1,3,5-tris(4-aminophenyl) benzene (TAPB)-based π-conjugated mesoporous polymers (π-CMPs) are constructed by one-pot emulsion-induced interface assembly strategy. Furthermore, co-induced in situ polymerization on 2D interfaces by emulsion and micelles is explored, which delivers sandwiched 2D mesoporous π-CMPs-coated graphene oxides (GO@mPTAPB). Benefiting from specific redox-active functional groups, excellent electron conductivity and a 2D mesoporous conjugated framework, GO@mPTAPB exhibits high capability of accommodating Li+ anions (up to 382 mAh g-1 at 0.2 A g-1 ) and outstanding electrochemical stability (87.6% capacity retention after 1000 cycles). The ex situ Raman and impedance spectra are further applied to reveal the high reversibility of GO@mPTAPB. This work will greatly promote the development of advanced π-CMPs-based organic anodes toward energy storage devices.

15.
Surg Endosc ; 35(1): 174-181, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-31993823

RESUMEN

BACKGROUND: The traditional open or laparoscopic segmentectomy of liver segment 7 (S7) requires exposing and controlling the root of the right hepatic vein(RHV)after full mobilization and lifting up of the right liver before liver transection. This approach violates the "no-touch" principle for malignant tumors, and makes laparoscopic resection technically challenging. So reports on isolated totally laparoscopic anatomic S7 segmentectomy have rarely been reported. This study describes our experience in laparoscopic anatomic S7 segmentectomy using in situ split along the right intersectoral and intersegmental planes of the liver. To our knowledge, this is the first description of this novel approach. METHODS: From September 2017 to May 2019, patients who underwent laparoscopic anatomic S7 segmentectomy for hepatocellular carcinoma at the HPB Surgery Department, Sun Yat-Sen Memorial Hospital entered into this retrospective study. This in situ split approach was designed using main vessels as the plane markers of right intersectoral and intersegmental planes, along which liver transection was carried out. There was no need to mobilize the right liver and control the root of RHV. RESULTS: There were 9 women and 15 men. The average diameter of the tumors on preoperative CT/MR was 3.4 cm (range 2-6 cm). All the procedures were successfully carried out laparoscopically. There was no perioperative death. The average operative time was 216.5 min (range 180-310 min). The average blood loss was 320 ml (range 120-620 ml). Pathological study showed all the operations to be R0 resections. CONCLUSION: Laparoscopic anatomic S7 segmentectomy using the in situ split approach resulted in R0 liver resection in all our patients with primary liver cancer. The operation was technically feasible and it provided a better view and increased maneuverability in the cramped operative space compared with the traditional open/laparoscopic approach. The approach also better complies with the "no-touch" principle for malignant tumors. Its long-term oncological outcomes require further studies.


Asunto(s)
Carcinoma Hepatocelular/cirugía , Hepatectomía/métodos , Laparoscopía/métodos , Neoplasias Hepáticas/cirugía , Adulto , Anciano , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/patología , Femenino , Venas Hepáticas/cirugía , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Tempo Operativo , Estudios Retrospectivos
16.
ACS Nano ; 14(11): 16046-16056, 2020 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-33147943

RESUMEN

Metal sulfides have attracted tremendous research interest for developing high-performance electrodes for potassium-ion batteries (PIBs) for their high theoretical capacities. Nevertheless, the practical application of metal sulfides in PIBs is still unaddressed due to their intrinsic shortcomings of low conductivity and severe volume changes during the potassiation/depotassiation process. Herein, robust Fe7S8/C hybrid nanocages reinforced by defect-rich MoS2 nanosheets (Fe7S8/C@d-MoS2) were designed, which possess abundant multichannel and active sites for potassium-ion transportation and storage. Kinetic analysis and theoretical calculation verify that the introduction of defect-rich MoS2 nanosheets dramatically promotes the potassium-ion diffusion coefficient. The ex-situ measurements revealed the potassium-ion storage mechanism in the Fe7S8/C@d-MoS2 composite. Benefitting from the tailored structural design, the Fe7S8/C@d-MoS2 hybrid nanocages show high reversible capacity, exceptional rate property, and superior cyclability.

17.
Am J Transl Res ; 12(7): 3842-3857, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32774739

RESUMEN

Laryngeal carcinoma is one of the common malignancies of head and neck. However, the pathogenesis of laryngeal cancer has been not completely clear. To identify the effects of hypoxia on the invasion, metastasis, and metabolism of laryngeal carcinoma, iTRAQ-labeling-with-LC-MS/MS analysis was performed to identify differentially expressed proteins of the SCC10A cells under hypoxia and normoxia, while metabolites were examined by metabolic profiling. 155 proteins and 180 metabolites were identified and the PCK2 protein was selected for validation by Western Blotting. Immunohistochemistry (IHC) was performed to analyze the expression of PCK2 in formalin-fixed paraffin-embedded (FFPE) tissue sections, including laryngeal squamous cell carcinoma tissues from various stages. Collectively, we report that down-regulation of PCK2 inhibits the invasion, migration, and proliferation of laryngeal cancer under hypoxia and down-regulation of PCK2 may be used as a new strategy for laryngeal cancer therapy.

18.
Liver Int ; 40(7): 1655-1669, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32329946

RESUMEN

BACKGROUND: EDP-305 is a novel and potent farnesoid X receptor (FXR) agonist, with no/minimal cross-reactivity to TGR5 or other nuclear receptors. Herein we report therapeutic efficacy of EDP-305, in direct comparison with the first-in-class FXR agonist obeticholic acid (OCA), in mouse models of liver disease. METHODS: EDP-305 (10 and 30 mg/kg/day) or OCA (30mg/kg/day) was tested in mouse models of pre-established biliary fibrosis (BALBc.Mdr2-/-, n = 9-12/group) and steatohepatitis induced by methionine/choline-deficient diet (MCD, n = 7-12/group). Effects on biliary epithelium were evaluated in vivo and in primary EpCAM + hepatic progenitor cell (HPC) cultures. RESULTS: In a BALBc.Mdr2-/- model, EDP-305 reduced serum transaminases by up to 53% and decreased portal pressure, compared to untreated controls. Periportal bridging fibrosis was suppressed by EDP-305 at both doses, with up to a 39% decrease in collagen deposition in high-dose EDP-305. In MCD-fed mice, EDP-305 treatment reduced serum ALT by 62% compared to controls, and profoundly inhibited perisinusoidal 'chicken wire' fibrosis, with over 80% reduction in collagen deposition. In both models, treatment with 30mg/kg OCA reduced serum transaminases up to 30%, but did not improve fibrosis. The limited impact on fibrosis was mediated by cholestasis-independent worsening of ductular reaction by OCA in both disease models; OCA but not EDP-305 at therapeutic doses promoted ductular proliferation in healthy mice and favoured differentiation of primary HPC towards cholangiocyte lineage in vitro. CONCLUSIONS: EDP-305 potently improved pre-established liver injury and hepatic fibrosis in murine biliary and metabolic models of liver disease, supporting the clinical evaluation of EDP-305 in fibrotic liver diseases including cholangiopathies and non-alcoholic steatohepatitis.


Asunto(s)
Ácido Quenodesoxicólico , Hígado , Animales , Ácido Quenodesoxicólico/farmacología , Fibrosis , Hígado/patología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Ratones , Ratones Endogámicos C57BL , Esteroides
19.
J Autom Reason ; 64(2): 331-360, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32063661

RESUMEN

In complex analysis, the winding number measures the number of times a path (counter-clockwise) winds around a point, while the Cauchy index can approximate how the path winds. We formalise this approximation in the Isabelle theorem prover, and provide a tactic to evaluate winding numbers through Cauchy indices. By further combining this approximation with the argument principle, we are able to make use of remainder sequences to effectively count the number of complex roots of a polynomial within some domains, such as a rectangular box and a half-plane.

20.
Nanomaterials (Basel) ; 9(9)2019 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-31484297

RESUMEN

Integrating a highly conductive carbon host and polar inorganic compounds has been widely reported to improve the electrochemical performances for promising low-cost lithium sulfur batteries. Herein, a MoS2/mesoporous carbon hollow sphere (MoS2/MCHS) structure has been proposed as an efficient sulfur cathode via a simple wet impregnation method and gas phase vulcanization method. Multi-fold structural merits have been demonstrated for the MoS2/MCHS structures. On one hand, the mesoporous carbon hollow sphere (MCHS) matrix, with abundant pore structures and high specific surface areas, could load a large amount of sulfur, improve the electronical conductivity of sulfur electrodes, and suppress the volume changes during the repeated sulfur conversion processes. On the other hand, ultrathin multi-layer MoS2 nanosheets are revealed to be uniformly distributed in the mesoporous carbon hollow spheres, enhancing the physical adsorption and chemical entrapment functionalities towards the soluble polysulfide species. Having benefited from these structural advantages, the sulfur-impregnated MoS2/MCHS cathode presents remarkably improved electrochemical performances in terms of lower voltage polarization, higher reversible capacity (1094.3 mAh g-1), higher rate capability (590.2 mAh g-1 at 2 C), and better cycling stability (556 mAh g-1 after 400 cycles at 2 C) compared to the sulfur-impregnated MCHS cathode. This work offers a novel delicate design strategy for functional materials to achieve high performance lithium sulfur batteries.

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