900 research outputs found
Fishing for small molecules to treat diabetes, from a beta cell perspective
No full textMaintenance of glucose homeostasis necessitates a precise control of insulin secretion. Pancreatic β cells sense fluctuation of blood glucose and secret insulin in response. However, functional β cell mass is decreased in diabetes. Here, to recover functional β cell mass, we use zebrafish as a model to perform in vivo drug discovery.In paper I, to discover drugs that could expand β cell mass through proliferation, we performed an in vivo screen in zebrafish based on a luminescence ubiquitination-based cell cycle indicator (LUCCI), identified a small molecule called HG-9-91-01, an inhibitor of salt-inducible kinases (SIKs), as a mitogen of mouse and human β cells. Mechanistic studies found HG-9-91-01 induced a transient upregulation of ATF6-dependent unfolded protein response (UPR), which together with other downstream effectors including CRTC1, CRTC2, mTOR and IRE1 led to a mitogenic response in β cells.In paper II, to discover drugs that could increase β cell mass from other origins, we performed in vivo screening in zebrafish for stimulators that convert glucagon-expressing ⍺ cells, somatostatin-expressing ẟ cells, and elastase-expressing acinar cells to β cells. 4 hits were identified in the screens and shown to promote β cell regeneration as well as reduce glucose in zebrafish with β cell ablation. However, only one hit called A-674563 induced a modest increase in reprogramming of ⍺ cells to β cells in lineage tracing experiments, whereas the other hits failed to promote reprogramming. Spontaneous conversion of ⍺- or ẟ- cells to β cells was rare, and no conversion of acinar cells to β cells was observed during β cell regeneration. Together, reprogramming of other pancreatic cells to β cells is rare and difficult to stimulate by small molecules in zebrafish.In paper III, a small molecule called Adjudin, identified in paper II, was discovered to promote β cell function in zebrafish. In translational studies using in vitro cultured mouse islets, we found that Adjudin promoted functional maturation of isolated islets from postnatal day 0 (P0) mice, as they gained capability of glucose responsive insulin secretion; Adjudin also improved recovery of islets from a type 2 diabetic mouse model. Moreover, Adjudin stimulated hepatic glucose uptake, an effect we further found largely independent of insulin in zebrafish and validated in primary human hepatocyte (PHH) formed spheroids with insulin resistance. Next, we examined Adjudin in a type 2 diabetic mouse model (db/db mice), observed improved glucose homeostasis in the mice that received Adjudin treatment. Together, Adjudin may serve as a potential therapeutic drug for diabetes.To summarize, using in vivo drug screening in zebrafish, we identified small molecules that could either expand β cell mass or promote β cell function, such findings may pave the way for future research and development of a novel treatment for diabetes.List of scientific papersI. In vivo screen identifies a SIK inhibitor that induces β cell proliferation through a transient UPR. Jérémie Charbord, Lipeng Ren*, Rohit B. Sharma*, Anna Johansson, Rasmus Ågren, Lianhe Chu, Dominika Tworus, Nadja Schulz, Pierre Charbord, Andrew F. Stewart, Peng Wang, Laura C. Alonso & Olov Andersson. Nature metabolism. 2021 May; 3(5):682-700. *These authors had equal contribution to the work. https://doi.org/10.1038/s42255-021-00391-x II. In vivo screening for small molecules promoting cellular reprogramming to insulin-producing β-cells. Lipeng Ren*, Jérémie Charbord*, Lianhe Chu, Nicole Schmitner, Jiarui Mi, Ka-Cheuk Liu, Dominika Tworus, Olov Andersson. *These authors had equal contribution to the work. [Manuscript]III. Adjudin improves beta cell maturation, hepatic glucose uptake and glucose homeostasis. Lipeng Ren, Jérémie Charbord, Lianhe Chu, Aurino M Kemas, Maria Bertuzzi, Jiarui Mi, Chen Xing, Volker M Lauschke, Olov Andersson. Diabetologia. 2023 Oct. https://doi.org/10.1007/s00125-023-06020-4 </p
MgO-modified biochar increases phosphate retention and rice yields in saline-alkaline soil
No full textFertilization effects on microbial community composition and aggregate formation in saline‐alkaline soil
No full textC−S‐Selective Stille‐Coupling Enables Stereodefined Alkene Synthesis
No full textA palladium‐catalyzed highly C‒S‐selective Stille cross‐coupling between aryl thianthrenium salts and tri‐ or tetrasubstituted alkenyl stannanes is described. Herein, critical challenges including site‐ and chemoselectivity control are well addressed through C‒H thianthrenation and C‒S alkenylation, thereby providing an expedient access to stereodefined tri‐ and tetrasubstituted alkenes in a stereoretentive fashion. Indeed, the palladium‐catalyzed Stille‐alkenylation of poly(pseudo)halogenated arenes displays privileged capability to differentiate C‒S over C‒I, C‒Br, C‒Cl bonds, as well as oxygen‐based triflates (C‒OTf), tosylates (C‒OTs), carbamates and sulfamates under mild reaction conditions. Sequential and multiple cross‐couplings via selective C‒X functionalization should be widely applicable for increasing functional molecular complexity. Modular installation of stereospecific alkene motifs into pharmaceuticals illustrated the synthetic application of the present protocol in drug discovery
JCB903697 Supplemental Material - Supplemental material for Selective intra-arterial brain cooling improves long-term outcomes in a non-human primate model of embolic stroke: Efficacy depending on reperfusion status
No full textSupplemental material, JCB903697 Supplemental Material for Selective intra-arterial brain cooling improves long-term outcomes in a non-human primate model of embolic stroke: Efficacy depending on reperfusion status by Di Wu, Jian Chen, Mohammed Hussain, Longfei Wu, Jingfei Shi, Chuanjie Wu, Yanhui Ma, Mo Zhang, Qi Yang, Yongjuan Fu, Yunxia Duan, Cui Ma, Feng Yan, Zixin Zhu, Xiaoduo He, Tianqi Yao, Ming Song, Xinglong Zhi, Chunxiu Wang, Lipeng Cai, Chuanhui Li, Shengli Li, Yongbiao Zhang, Yuchuan Ding and Xunming Ji in Journal of Cerebral Blood Flow & Metabolism</p
Structural and optoelectronic properties of selenium-doped silicon formed using picosecond pulsed laser mixing
No full textOptimization of porous carbon structure through high-temperature pyrolysis for enhanced electrochemical performance of supercapacitors
No full textHerein, phosphoric acid activation followed by high-temperature pyrolysis is employed to synthesize high-performance porous carbon materials using sustainable biomass (almond shells) as the precursor. The almond shell-derived porous carbon materials exhibited a large specific surface area (1164/1395 m²/g) and high pore volume (1.39/1.40 cm³/g). After high-temperature pyrolysis at 1000°C, the biomass-derived porous carbon material AC600(1000) exhibited a larger average pore size with a hierarchical pore structure (micropores-mesopores). AC600(1000) also possessed more graphite domain structures, defects, and abundant surface oxygen-containing functional groups. In a symmetric cell configuration with 6 M KOH electrolyte, the optimized AC600(1000) operates stably over a wide voltage range (0-1.5 V), demonstrating a high specific capacitance of 142.15 F/g at 0.5 A/g. It also exhibites excellent rate performance, retaining a high specific capacitance of 106.38 F/g even at 20 A/g (74.83% capacitance retention), while the unoptimized AC600 achieved only 45.66 F/g (35.48% capacitance retention). Furthermore, it preserved 88.4% of its initial capacitance after 20,000 cycles at a current density of 5 A/g (almost 100% coulombic efficiency). This study shows proper synthetic routes that can boost significantly the performance of biomass derived carbons for supercapacitors, providing insights into structure-electrochemistry correlation. Thus, a sustainable and scalable production of carbon materials from biomass for energy storage applications is presented, which could promote the use of these materials on an industrial scale.Funding from Ministerio de Ciencia Innovacion y Universidades (MCIU), Agencia Estatal de Investigacion (AEI) and the European Regional Development Fund (FEDER) (Grant PID2021–128390OB-I00, TED2021–130205B-C21, and PLEC2022–009328) are gratefully acknowledged. ICN2 is funded by the CERCA programme/Generalitat de Catalunya and supported by the Severo Ochoa Centres of Excellence programme, Grant CEX2021–001214-S, funded by MCIN/AEI/ 10.13039.501100011033. This work has been carried out within the framework of doctoral program (PhD) of Material Science at Universitat Autonoma de Barcelona (UAB) (Lipeng WANG). L.P. Wang also acknowledges his scholarship (No. 202206420015) under China Scholarship Council. L.N. Bengoa thanks the support provided by Horizon Europe programme through a Marie Curie Postdoctoral Fellowship (Grant 101062498-POMZAB). Authors want to thank ICN2 and ICMAB core facilities.With funding from the Spanish government through the "Severo Ochoa Centre of Excelence" accreditation (CEX2021–001214-S)Peer reviewe
The Lightweight Design of a Dump Truck Frame based on Dynamic Responses
No full textThis paper develops a new scheme for the
lightweight design of heavy dump truck frames based on the
characteristics of dynamic responses. The dynamic response
is predicted using a finite element (FE) model which is
verified by an experimental mode analysis. The FE model is
then used to investigate the characteristics of dynamic
responses and frame weight changes with respect to the
mass changes of each frame component for selecting
significant components. An optimization is finally developed
for the lightweight design under constrains that maintain
required dynamic responses and static strength. The
optimization results show that the weight of frame can be
reduced by 8%, showing that the scheme is an effective way
to achieve automotive lightweight design
Abstract 4631: Enhanced glycolysis promotes function of tumor associated macrophages in mouse breast cancer model
No full textAbstract
Tumor associated macrophages(TAMs) represent a major part of immune cells in tumor microenvironment(TME) and play crucial roles in promoting tumor progression by secreting cytokines or enzymes that could remodel TME or enhance envision or migration capabilities of tumor cells. Given their indispensable effect on tumor, the mechanisms underlying TAMs’ tumor-promoting phenotype and function remain unclear. Glucose metabolism in tumor cells has been intensively studied; however, the status of glucose metabolism of TAMs is still unclear. In this study, we aim to identify glucose metabolism status in TAMs, and explore how glucose metabolism regulates phenotype and function of TAMs. In the begining, we isolated TAMs from 4T1 mouse breast tumor, spleen macrophages from normal mouse as a control, and performed RNA sequencing to analyze the expression pattern in glucose metabolism related genes. The results from transcriptomics showed that TAM shown up regulation of glycolysis genes pattern. Then we analyzed and found that HK’s activity was increased while IDH’s activity was decreased in mouse breast cancer moel. Furthermore, In vitro, we found that up regulation of impotent glycolysis genes including HK2, PFK-L and LDHA in mouse peritoneal macrophages (CMPM) and mouse bone marrow derived macrophages (CMBMDM) conditionally cultured with 4T1 supernatants. Glucose consumption or production of lactate and ATP were also increased in CMPM or CMBMDM. Then we monitored lactate producing rate with seahorse energy metabolism detector, and found that either CMPM or CMBMDM produced lactate faster than that of control. Moreover, inhibition of LDHA activity by oxamate ( inhibitor) also decreased glucose consumption and lactate production. Importantly, the expression of Arg1 and CD206, positively correlated with glycolysis and function of TAMs. Finally, we search the underneath mechanism and found PI3K/AKT pathway was activated in CMPM or CMBMDM. In detail it was found that p-p85 and p-AKT was upregulated at 8 hour after 4T1 supernatants stimulation. Inhibition of PI3K/AKT pathway by LY294002 (PI3K inhibitor), notably inhibited the expression of glycolysis genes and markers of TAMs, which indicated that PI3K/AKT pathway maybe involved in glycolysis of TAMs. Together, we identified that TAMs adopted glycolysis as a major way to consume glucose and glycolysis was directly contributed to the phenotype and function of TAMs, which was regulated by PI3K/AKT signaling pathway.
Citation Format: Yan Liu, Wei Zhou, Wei Wang, Lipeng Bai, Huiwen He, Jian Guo, Yunping Luo. Enhanced glycolysis promotes function of tumor associated macrophages in mouse breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4631. doi:10.1158/1538-7445.AM2017-4631</jats:p
The Institution-based View of Internationalization of Emerging Market Enterprises (EMEs): Research of Chinese Firms’ Outward FDI Based on Case-studies of Wanda Group’s Internationalization Strategy
No full textThis research examines the internationalization activities of emerging market enterprises (EMEs). Through systematically and critically analysing and evaluating one leg of international business strategy tripod (resource-based view, industry-based view, institution-based view), namely institution-based view especially, and the three pillars of institution-based view as well as the influence of three types of institutional pressures in detail, the research enables us to know the drivers, motivations, strategies and challenges of outward FDI from emerging markets especially Chinese private EMEs.
Using the multiple cases study of Wanda’s M&A of AMC Entertainment, Sunseeker and Legendary Entertainment, we find that in terms of regulatory pillar of institution-based view, looking back through four main transitions and transformations in the development history of Wanda Group both domestically and internationally, we can find that Wanda’s every big decision and strategies was made under the influence and pressure of regulatory institutions and coercive isomorphism. Compared with SOEs, private EMEs face more challenges and difficulties in domestic environment therefore exploring overseas expansion to secure their assets and seek new opportunities such as Wanda. As for the normative pillar of institutions, Chairman Wang Jianlin’s personal vision and ambition to build a marvellous, desirable and respectable business empire plays the significant role in Wanda’s going global process. On behalf of private entrepreneurs, Wang’s “Chinese dream” to build an international Wanda and a centennial enterprise constantly drives him to expand in the global marketplace. In reference to the cultural-cognitive pillar of institutions and mimetic isomorphism, Wanda use international management team and local talents to decrease cultural-cognitive distance and seek for host-country legitimacy, which efficiently improve and promote Wanda’s internationalization and corporate governance. The flexible application of guanxi culture helps Wang Jianlin walk fast and far. But different from I hypothesized, the influence of mimetic isomorphism on Wanda’s international expansion is not significant since Wanda is the big giant in his industry and always gain first-mover advantage
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