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Anti‐cancer peptides (ACPs) represent a promising potential for cancer treatment, although their mechanisms need to be further elucidated to improve their application in cancer therapy. Lycosin‐I, a linear amphipathic peptide isolated from the venom of Lycosa singorensis, shows significant anticancer potential. Herein, it is found that Lycosin‐I, which can self‐assemble into a nanosphere structure, has a multimodal mechanism of action involving lipid binding for the selective and effective treatment of leukemia. Mechanistically, Lycosin‐I selectively binds to the K562 cell membrane, likely due to its preferential interaction with negatively charged phosphatidylserine, and rapidly triggers membrane lysis, particularly at high concentrations. In addition, Lycosin‐I induces apoptosis, cell cycle arrest in the G1 phase and ferroptosis in K562 cells by suppressing the PI3K‐AKT‐mTOR signaling pathway and activating cell autophagy at low concentrations. Furthermore, intraperitoneal injection of Lycosin‐I inhibits tumor growth of K562 cells in a nude mouse xenograft model without causing side effects. Collectively, the multimodal effect of Lycosin‐I can provide new insights into the mechanism of ACPs, and Lycosin‐I, which is characterized by high potency and specificity, can be a promising lead for the development of anti‐leukemia drugs. [ABSTRACT FROM AUTHOR]

Background: Chronic inflammation contributes to the progression of isoproterenol (ISO)‐induced heart failure (HF). Caspase‐associated recruitment domain (CARD) families are crucial proteins for initiation of inflammation in innate immunity. Nonetheless, the relevance of CARDs in ISO‐driven cardiac remodelling is little explored. Methods: This study utilized Card9−/− mice and reconstituted C57BL/6 mice with either Card9−/− or Otud1−/− marrow‐derived cells. Mechanistic studies were conducted in primary macrophages, cardiomyocytes, fibroblasts and HEK‐293T cells. Results: Here, we demonstrated that CARD9 was substantially upregulated in murine hearts infused with ISO. Either whole‐body CARD9 knockout or myeloid‐specific CARD9 deletion inhibited ISO‐driven murine cardiac inflammation, remodelling and dysfunction. CARD9 deficiency in macrophages prevented ISO‐induced inflammation and alleviated remodelling changes in cardiomyocytes and fibroblasts. Mechanistically, we found that ISO enhances the activity of CARD9 by upregulating ovarian tumour deubiquitinase 1 (OTUD1) in macrophages. We further demonstrated that OTUD1 directly binds to the CARD9 and then removes the K33‐linked ubiquitin from CARD9 to promote the assembly of the CARD9‐BCL10‐MALT1 (CBM) complex, without affecting CARD9 stability. The ISO‐activated CBM complex results in NF‐κB activation and macrophage‐based inflammatory gene overproduction, which then enhances cardiomyocyte hypertrophy and fibroblast fibrosis, respectively. Myeloid‐specific OTUD1 deletion also attenuated ISO‐induced murine cardiac inflammation and remodelling. Conclusions: These results suggested that the OTUD1‐CARD9 axis is a new pro‐inflammatory signal in ISO‐challenged macrophages and targeting this axis has a protective effect against ISO‐induced HF. Key points: Macrophage CARD9 was elevated in heart tissues of mice under chronic ISO administration.Either whole‐body CARD9 knockout or myeloid‐specific CARD9 deficiency protected mice from ISO‐induced inflammatory heart remodeling.ISO promoted the assembly of CBM complex and then activated NF‐κB signaling in macrophages through OTUD1‐mediated deubiquitinating modification.OTUD1 deletion in myeloid cells protected hearts from ISO‐induced injuries in mice. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DCM) represents a common pathological state brought about by diabetes mellitus (DM). Patchouli alcohol (PatA) is known for its diverse advantageous effects, notably its anti-inflammatory properties and protective role against metabolic disorders. Despite this, the influence of PatA on DCM remains relatively unexplored. To explore the effect of PatA on diabetes-induced cardiac injury and dysfunction in mice, streptozotocin (STZ) was used to mimic type 1 diabetes in mice. Serological markers and echocardiography show that PatA treatment protects the heart against cardiomyopathy by controlling myocardial fibrosis but not by reducing hyperglycemia in diabetic mice. Discovery Studio 2017 software was used to perform reverse target screening of PatA, and we found that JAK2 may be a potential target of PatA. RNA-seq analysis of heart tissues revealed that PatA activity in the myocardium was primarily associated with the inflammatory fibrosis through the Janus tyrosine kinase 2 (JAK2)/signal transducer and activator of the transcription 3 (STAT3) pathway. In vitro, we also found that PatA alleviates high glucose (HG) + palmitic acid (PA)-induced fibrotic and inflammatory responses via inhibiting the JAK2/STAT3 signaling pathway in H9C2 cells. Our findings illustrate that PatA mitigates the effects of HG + PA- or STZ-induced cardiomyopathy by acting on the JAK2/STAT3 signaling pathway. These insights indicate that PatA could potentially serve as a therapeutic agent for DCM treatment. [ABSTRACT FROM AUTHOR]

Prolonged stimulation of β-adrenergic receptor (β-AR) can lead to sympathetic overactivity that causes pathologic cardiac hypertrophy and fibrosis, ultimately resulting in heart failure. Recent studies suggest that abnormal protein ubiquitylation may contribute to the pathogenesis of cardiac hypertrophy and remodeling. In this study, we demonstrated that deficiency of a deubiquitinase, Josephin domain-containing protein 2 (JOSD2), ameliorated isoprenaline (ISO)- and myocardial infarction (MI)-induced cardiac hypertrophy, fibrosis, and dysfunction both in vitro and in vivo. Conversely, JOSD2 overexpression aggravated ISO-induced cardiac pathology. Through comprehensive mass spectrometry analysis, we identified that JOSD2 interacts with Calcium–calmodulin-dependent protein kinase II (CaMKIIδ). JOSD2 directly hydrolyzes the K63-linked polyubiquitin chains on CaMKIIδ, thereby increasing the phosphorylation of CaMKIIδ and resulting in calcium mishandling, hypertrophy, and fibrosis in cardiomyocytes. In vivo experiments showed that the cardiac remodeling induced by JOSD2 overexpression could be reversed by the CaMKIIδ inhibitor KN-93. In conclusion, our study highlights the role of JOSD2 in mediating ISO-induced cardiac remodeling through the regulation of CaMKIIδ ubiquitination, and suggests its potential as a therapeutic target for combating the disease. Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary. All have been checked [ABSTRACT FROM AUTHOR]

Macrophage activation has been shown to play an essential role in renal fibrosis and dysfunction in hypertensive chronic kidney disease. Dectin-1 is a pattern recognition receptor that is also involved in chronic noninfectious diseases through immune activation. However, the role of Dectin-1 in Ang II-induced renal failure is still unknown. In this study, we found that Dectin-1 expression on CD68 + macrophages was significantly elevated in the kidney after Ang II infusion. We assessed the effect of Dectin-1 on hypertensive renal injury using Dectin-1-deficient mice infused by Angiotensin II (Ang II) at 1000 ng/kg/min for 4 weeks. Ang II-induced renal dysfunction, interstitial fibrosis, and immune activation were significantly attenuated in Dectin-1-deficient mice. A Dectin-1 neutralizing antibody and Syk inhibitor (R406) were used to examine the effect and mechanism of Dectin-1/Syk signaling axle on cytokine secretion and renal fibrosis in culturing cells. Blocking Dectin-1 or inhibiting Syk significantly reduced the expression and secretion of chemokines in RAW264.7 macrophages. The in vitro data showed that the increase in TGF-β1 in macrophages enhanced the binding of P65 and its target promotor via the Ang II-induced Dectin-1/Syk pathway. Secreted TGF-β1 caused renal fibrosis in kidney cells through Smad3 activation. Thus, macrophage Dectin-1 may be involved in the activation of neutrophil migration and TGF-β1 secretion, thereby promoting kidney fibrosis and dysfunction. [ABSTRACT FROM AUTHOR]

Background and Purpose: The NLR family pyrin domain‐containing 3 (NLRP3) inflammasome is activated in many inflammatory conditions. So far, no low MW compounds inhibiting NLRP3 have entered clinical use. Identification of naturally occurring NLRP3 inhibitors may be beneficial to the design and development of compounds targeting NLRP3. Alantolactone is a phytochemical from a traditional Chinese medicinal plant with anti‐inflammatory activity, but its precise target remains unclear. Experimental Approach: A bank of phytochemicals was screened for inhibitors of NLRP3‐driven production of IL‐1β in cultures of bone‐marrow‐derived macrophages from female C57BL/6 mice. Models of gouty arthritis and acute lung injury in male C57BL/6J mice were used to determine the in vivo effects of the most potent compound. Key Results: Among the 150 compounds screened in vitro, alantolactone exhibited the highest inhibitory activity against LPS + ATP‐induced production of IL‐1β in macrophages, suppressing IL‐1β secretion, caspase‐1 activation and pyroptosis. Alantolactone directly bound to the NACHT domain of NLRP3 to inhibit activation and assembly of NLRP3 inflammasomes. Molecular simulation analysis suggested that Arg335 in NLRP3 was a critical residue for alantolactone binding, leading to suppression of NLRP3–NEK7 interaction. In vivo studies confirmed significant alleviation by alantolactone of two NLRP3‐driven inflammatory conditions, acute lung injury and gouty arthritis. Conclusion and Implications: The phytochemical alantolactone inhibited activity of NLRP3 inflammasomes by directly targeting the NACHT domain of NLRP3. Alantolactone shows great potential in the treatment of NLRP3‐driven diseases and could lead to the development of novel NLRP3 inhibitors. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic inflammatory disease with high morbidity and mortality rates worldwide. Doublecortin‐like kinase 1 (DCLK1), a microtubule‐associated protein kinase, is involved in neurogenesis and human cancers. However, the role of DCLK1 in atherosclerosis remains undefined. In this study, we identified upregulated DCLK1 in macrophages in atherosclerotic lesions of ApoE−/− mice fed an HFD and determined that macrophage‐specific DCLK1 deletion attenuates atherosclerosis by reducing inflammation in mice. Mechanistically, RNA sequencing analysis indicated that DCLK1 mediates oxLDL‐induced inflammation via NF‐κB signaling pathway in primary macrophages. Coimmunoprecipitation followed by LC–MS/MS analysis identified IKKβ as a binding protein of DCLK1. We confirmed that DCLK1 directly interacts with IKKβ and phosphorylates IKKβ at S177/181, thereby facilitating subsequent NF‐κB activation and inflammatory gene expression in macrophages. Finally, a pharmacological inhibitor of DCLK1 prevents atherosclerotic progression and inflammation both in vitro and in vivo. Our findings demonstrated that macrophage DCLK1 promotes inflammatory atherosclerosis by binding to IKKβ and activating IKKβ/NF‐κB. This study reports DCLK1 as a new IKKβ regulator in inflammation and a potential therapeutic target for inflammatory atherosclerosis. Syopsis: Macrophage DCLK1 promotes inflammatory atherosclerosis by directly binding to IKKβ and activating IKKβ/NF‐κB signal. DCLK1 is a new regulator of IKKβ and a potential therapeutic target for atherosclerosis. Macrophage‐specific deletion or pharmacological inhibition of DCLK1 attenuates inflammatory atherosclerosis in mice.Blockage of DCLK1 alleviates oxLDL‐induced inflammation by inhibiting NF‐κB activation in macrophages.DCLK1 directly binds to IKKβ to induce IKKβ phosphorylation at S177/181, resulting in NF‐κB activation. [ABSTRACT FROM AUTHOR]

Understanding the molecular mechanisms of pathological vascular remodeling is important for treating cardiovascular diseases and complications. Recent studies have highlighted a role of deubiquitinases in vascular pathophysiology. Here, we investigate the role of a deubiquitinase, OTUD1, in angiotensin II (Ang II)‐induced vascular remodeling. We detect upregulated OTUD1 in the vascular endothelium of Ang II‐challenged mice and show that OTUD1 deletion attenuates vascular remodeling, collagen deposition, and EndMT. Conversely, OTUD1 overexpression aggravates these pathological changes both in vivo and in vitro. Mechanistically, SMAD3 is identified as a substrate of OTUD1 using co‐immunoprecipitation followed by LC–MS/MS. We find that OTUD1 stabilizes SMAD3 and facilitates SMAD3/SMAD4 complex formation and subsequent nuclear translocation through both K48‐ and K63‐linked deubiquitination. OTUD1‐mediated SMAD3 activation regulates transcription of genes involved in vascular EndMT and remodeling in HUVECs. Finally, SMAD3 inhibition reverses OTUD1‐promoted vascular remodeling. Our findings demonstrate that endothelial OTUD1 promotes Ang II‐induced vascular remodeling by deubiquitinating SMAD3. We identify SMAD3 as a target of OTUD1 and propose OTUD1 as a potential therapeutic target for diseases related to vascular remodeling. Synopsis: OTUD1 stabilizes SMAD3 and facilitates its activation by K48‐ and K63‐linked deubiquitination to regulate vascular EndMT and remodeling in mouse endothelial cells. OTUD1 deletion attenuates vascular remodeling, collagen deposition, and EndMT in angiotensin II‐challenged mice.OTUD1 stabilizes SMAD3 and facilitates its activation by K48‐ and K63‐linked deubiquitination.Endothelial OTUD1‐mediated SMAD3 activation regulates transcription of genes involved in vascular EndMT and remodeling. [ABSTRACT FROM AUTHOR]

Obesity‐induced cardiomyopathy (OIC) is an increasingly serious global disease caused by obesity. Chronic inflammation greatly contributes to the pathogenesis of OIC. This study aimed to explore the role and mechanism of tabersonine (Tab), a natural alkaloid with antiinflammatory activity, in the treatment of OIC. High fat diet (HFD)‐induced obese mice were administered with Tab. The results showed that Tab significantly inhibit inflammation, myocardial fibrosis, and hypertrophy to prevent heart dysfunction, without the alteration of body weight and hyperlipidemia, in HFD‐induced obese mice. H9c2 cells and primary cardiomyocytes stimulated by palmitic acid (PA) were used to explore the molecular mechanism and target of Tab. We examined the effect of Tab on key proteins involved in HFD/PA‐induced inflammatory signaling pathway and found that Tab significantly inhibits TAK1 phosphorylation in cardiomyocytes. We further detected the direct interaction between Tab and TAK1 at the cellular, animal, and molecular levels. We found that Tab directly binds to TAK1 to inhibit TAK1 phosphorylation, which then blocks TAK1‐TAB2 interaction and then NF‐κB pro‐inflammatory pathway in cultured cardiomyocytes. Our results indicate that Tab is a potential agent for the treatment of OIC, and TAK1 is an effective therapeutic target for this disease. [ABSTRACT FROM AUTHOR]

Chronic inflammation plays an important role in hypertensive heart failure. Suppressing angiotensin II (Ang II)‐induced cardiac inflammation may contribute to the treatment of hypertension‐associated heart failure. Sclareol, a natural product initially isolated from the leaves and flowers of Salvia sclarea, possesses antiinflammatory and immune‐regulation activity in various systems. However, its effect on Ang II‐induced cardiac remodeling remains unknown. In this study, we have explored the potential effects of sclareol on Ang II‐induced heart failure. In vivo experiments were conducted in mice with Ang II‐pump infusion for 28 days. Sclareol administration at 5 mg·kg−1·d−1 significantly reduced the expression of myocardial injury markers. Sclareol also exerts protective effects against Ang II‐induced cardiac dysfunction in mice which is associated with alleviated cardiac inflammation and fibrosis. Transcriptome analysis revealed that inhibition of the Ang II‐activated mitogen‐activated protein kinase (MAPK) pathway contributed to the protective effect of sclareol. Sclareol inhibits Ang II‐activated MAPKs pathway to reduce inflammatory response in mouse hearts and cultured cardiomyocytes. Blockage of MAPKs in cardiomyocytes abolished the antiinflammatory effects of sclareol. In conclusion, we show that sclareol protects hearts against Ang II‐induced injuries through inhibiting MAPK‐mediated inflammation, indicating the potential use of sclareol in the prevention of hypertensive heart failure. [ABSTRACT FROM AUTHOR]

Diabetes manifests as chronic inflammation and leads to the development diabetic cardiomyopathy (DCM). Targeting key proteins in inflammatory signaling may provide new therapy for DCM. In this study, the authors explore the pharmacological effects and mechanisms of Schisandrin B (Sch B), a natural compound with anti‐inflammatory activity against DCM. It is shown that Sch B prevents high‐level glucose (HG)‐induced hypertrophic and fibrotic responses in cultured cardiomyocytes. RNA sequencing and inflammatory qPCR microarray show that Sch B mainly affects myeloid differentiation primary response 88 (MyD88)‐dependent inflammatory gene expression in HG‐challenged cardiomyocytes. Further studies indicate that Sch B directly binds to and inhibits MyD88 activation, but does not alter MyD88‐independent Toll‐like receptor signaling in vivo and in vitro. Inhibiting or silencing MyD88 is associated with reduced levels of HG‐induced inflammatory cytokines and myocardial injuries in vitro. Treatment of type 1 and type 2 diabetic mice with Sch B protects heart function, reduces myocardial injuries, and decreases secretion of inflammatory cytokines. Cardiomyocyte‐specific MyD88 knockout also protects mice against cardiac inflammation and injury in type 1 diabetic mice. In conclusion, these studies show that cardiomyocyte MyD88 plays an apathogenetic role in DCM and Sch B specifically targets MyD88 to reduce inflammatory DCM. [ABSTRACT FROM AUTHOR]

This letter studies a vertical federated edge learning (FEEL) system for collaborative objects/human motion recognition by exploiting the distributed integrated sensing and communication (ISAC). In this system, distributed edge devices first send wireless signals to sense targeted objects/human, and then exchange intermediate computed vectors (instead of raw sensing data) for collaborative recognition while preserving data privacy. To boost the spectrum and hardware utilization efficiency for FEEL, we exploit ISAC for both target sensing and data exchange, by employing dedicated frequency-modulated continuous-wave (FMCW) signals at each edge device. Under this setup, we propose a vertical FEEL scheme for realizing the recognition based on the collected multi-view wireless sensing data. In this scheme, each edge device owns an individual local L-model to transform its sensing data into an intermediate vector with relatively low dimensions, which is then transmitted to a coordinating edge device for final output via a common downstream S-model. By considering a human motion recognition task, experimental results show that our vertical FEEL based approach achieves recognition accuracy up to 98% with an improvement up to 8% compared to the benchmarks, including on-device training and horizontal FEEL. [ABSTRACT FROM AUTHOR]

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Background: Non‐alcoholic fatty liver disease (NAFLD) is the most predominant form of liver diseases worldwide. Recent evidence shows that myeloid differentiation factor 2 (MD2), a protein in innate immunity and inflammation, regulates liver injury in models of NAFLD. Here, we investigated a new mechanism by which MD2 participates in the pathogenesis of experimental NAFLD. Methods: Wild‐type, Md2−/− and bone marrow reconstitution mice fed with high‐fat diet (HFD) were used to identify the role of hepatocyte MD2 in NAFLD. Transcriptomic RNA‐seq and pathway enrich analysis were performed to explore the potential mechanisms of MD2. In vitro, primary hepatocytes and macrophages were cultured for mechanistic studies. Results: Transcriptome analysis and bone marrow reconstitution studies showed that hepatocyte MD2 may participate in regulating lipid metabolism in models with NAFLD. We then discovered that Md2 deficiency in mice prevents HFD‐mediated suppression of AMP‐activated protein kinase (AMPK). This preservation of AMPK in Md2‐deficient mice was associated with normalized sterol regulatory element binding protein 1 (SREBP1) transcriptional program and a lack of lipid accumulation in both hepatocytes and liver. We then showed that hepatocyte MD2 links HFD to AMPK/SREBP1 through TANK binding kinase 1 (TBK1). In addition, MD2‐increased inflammatory factor from macrophages induces hepatic TBK1 activation and AMPK suppression. Conclusion: Hepatocyte MD2 plays a pathogenic role in NAFLD through TBK1‐AMPK/SREBP1 and lipid metabolism pathway. These studies provide new insight into a non‐inflammatory function of MD2 and evidence for the important role of MD2 in NALFD. [ABSTRACT FROM AUTHOR]

Constrained reinforcement learning (CRL), also termed as safe reinforcement learning, is a promising technique enabling the deployment of RL agent in real-world systems. In this paper, we propose a successive convex approximation based off-policy optimization (SCAOPO) algorithm to solve the general CRL problem, which is formulated as a constrained Markov decision process (CMDP) in context of the average cost. The SCAOPO is based on solving a sequence of convex objective/feasibility optimization problems obtained by replacing the objective and constraint functions in the original problem with convex surrogate functions. The proposed SCAOPO enables reuse of experiences from previous updates, thereby significantly reducing implementation cost when deployed in real-world engineering systems that need to online learn the environment. In spite of the time-varying state distribution and the stochastic bias incurred by off-policy learning, the SCAOPO with a feasible initial point can still provably converge to a Karush-Kuhn-Tucker (KKT) point of the original problem almost surely. [ABSTRACT FROM AUTHOR]

Chinese herbal formula JiaWeiSiNiSan (JWSNS) has been widely used to prevent stress-induced neuropsychiatric ailments in clinics and proven to have therapeutic anti-stress effects on rats. However, the mechanism remains unclear. Based on the proteomics of cerebrospinal fluid (CSF), this study explores the possible mechanism and target proteins of JiaWeiSiNiSan raising stress resilience and preventing stress damage. A 6-week Chronic Unpredictable Mild Stress (CUMS) model was applied on adult Wistar male rats to observe the effects of JWSNS on improving mental stress resilience. Tandem Mass Tag (TMT) proteomics and bioinformatics analysis were used to screen and analyze differentially expressed proteins (DEPs) in CSF. Parallel Reaction Monitoring (PRM) was used to validate target DEPs. Significantly decreased sucrose preference, locomotion activity level and accuracy of T-maze, as well as increased immobility time, were observed in CUMS rats compared to CON rats while JWSNS improved above depression-like behaviours. The quantitative proteomics and bioinformatics analysis showed that JWSNS decreased the expression of Rps4x, HSP90AA1, Rps12, Uba1, Rsp14, Tuba1b in CUMS rats CSF (p < 0.05, FDR < 0.5). Immunofluorescence results showed that the number of BrdU/DCX positive cells (p < 0.01) and the relative number of neurons (p < 0.01) in the hippocampus dentate gyrus (DG) of the JSWNS group significantly increased, compared with the CUMS group. JWSNS could increase mental stress resilience and prevent stress damage by regulating proteins in CSF. This study provides a scientific basis for further study on Chinese formulas preventing mental illness. [ABSTRACT FROM AUTHOR]

Intramuscular fat (IMF) and subcutaneous fat (SCF) are important traits affecting the economics of the pork industry, in which less SCF and more IMF content is desirable. However, the mechanisms that regulate IMF and SCF content are not clear yet. In this study, we demonstrate that KLF3 (Krüppel‐like factor 3) was negatively correlated with IMF content in the longissimus dorsi muscle of Erhualian pigs. In addition, the expression level of KLF3 was significantly higher in IMF than SCF. Overexpression and knockdown experiments revealed that KLF3 could suppress adipocyte differentiation in vitro by downregulating adipogenic markers, including PPARG, C/EBPA, and FABP4. Luciferase activity analysis proved that miR‐32‐5p was able to suppress KLF3. Notably, miR‐32‐5p level was negatively correlated to KLF3 mRNA level in both IMF and SCF tissues. The same relationship was proved in samples with different IMF content. Further studies showed that miR‐32‐5p could promote adipocyte differentiation via inhibiting KLF3. Our results suggest that the miR‐32‐5p‐KLF3 pathway is involved in the regulation of differential fat deposition of IMF and SCF tissues. [ABSTRACT FROM AUTHOR]

Purpose: The aims of this study are to conduct a systematic review of public–private partnership (PPP) studies published from 2009 to 2019, to compare the results with Ke et al. (2009) who reviewed the PPP literature published from 1998 to 2008, and to trace the evolution of the PPP knowledge in the past two decades. This study also presents the possible directions that the PPP research may go towards in the future, arguably. Design/methodology/approach: This study carried out a top journal-based search to identify the quality PPP articles published from 2009 to 2019. A total of 12 top-tier construction journals were systematically searched in the database of web of science (WOS), from which 279 PPP articles were identified for review. Findings: The number of the identified articles, the titles of the journals, institutions, the most cited papers, and prevalent research methods were analyzed and compared. The existing PPP studies in construction journals were classified into seven streams. Through analysis of the PPP research status and gaps, five future research directions were revealed. Originality/value: This study contributes to the current body of knowledge by revealing the research trend of PPP from 2009 to 2019. It presents the change of PPP development trend in the past decade through comparison with Ke et al. (2009). It also reveals the major research streams and points out the directions that the PPP research may go towards in the future. Moreover, this study is helpful to the practice as well. It can enhance the practitioners' understanding of the PPP development in the past decade. In addition, it identified the research institutions contributing the most in the area of PPP, which may serve as valuable reference for practitioners to locate the best institutions for consultancy or collaboration. [ABSTRACT FROM AUTHOR]

We propose a novel randomized channel sparsifying hybrid precoding (RCSHP) design to reduce the signaling overhead of channel estimation and the hardware cost and power consumption at the base station (BS), in order to fully harvest benefits of frequency division duplex (FDD) massive multiple-input multiple-output (MIMO) systems. RCSHP allows time-sharing among multiple analog precoders, each serving a compatible user group. The analog precoder is adapted to the channel statistics to properly sparsify the channel for the associated user group, such that the resulting effective channel (product of channel and analog precoder) not only has enough spatial degrees of freedom (DoF) to serve this group of users, but also can be accurately estimated under the limited pilot budget. The digital precoder is adapted to the effective channel based on the duality theory to facilitate the power allocation and exploit the spatial multiplexing gain. We formulate the joint optimization of the time-sharing factors and the associated sets of analog precoders and power allocations as a general utility optimization problem, which considers the impact of effective channel estimation error on the system performance. Then we propose an efficient stochastic successive convex approximation algorithm to provably obtain Karush-Kuhn-Tucker (KKT) points of this problem. [ABSTRACT FROM AUTHOR]

Hyperglycemia activates toll-like receptor 4 (TLR4) to induce inflammation in diabetic cardiomyopathy (DCM). However, the mechanisms of TLR4 activation remain unclear. Here we examine the role of myeloid differentiation 2 (MD2), a co-receptor of TLR4, in high glucose (HG)- and diabetes-induced inflammatory cardiomyopathy. We show increased MD2 in heart tissues of diabetic mice and serum of human diabetic subjects. MD2 deficiency in mice inhibits TLR4 pathway activation, which correlates with reduced myocardial remodeling and improved cardiac function. Mechanistically, we show that HG induces extracellular advanced glycation end products (AGEs), which bind directly to MD2, leading to formation of AGEs-MD2-TLR4 complex and initiation of pro-inflammatory pathways. We further detect elevated AGE-MD2 complexes in heart tissues and serum of diabetic mice and human subjects with DCM. In summary, we uncover a new mechanism of HG-induced inflammatory responses and myocardial injury, in which AGE products directly bind MD2 to drive inflammatory DCM. The mechanisms underlying cardiac inflammation in diabetic cardiomyopathy are incompletely understood. Here the authors show that advanced glycation end products bind to the TLR4 co-receptor MD2 initiating pro-inflammatory pathways. [ABSTRACT FROM AUTHOR]

The prostaglandin-endoperoxide synthase-2 (PTGS2) plays essential roles in diverse pathological process. Although recent studies implied that PTGS2 was closely related with chemoresistance, the precise roles and the underlying mechanisms of PTGS2 in the developing process of chemoresistance in non-small cell lung cancer (NSCLC) remained elusive. In the present study, we revealed a novel molecular mechanism of PTGS2 implicated in the chemoresistance of NSCLC and proposed a model for the positive feedback regulation of PTGS2 in the process of developing resistance phenotype in NSCLC cells. Our results demonstrated that cisplatin induced PTGS2 expression through the ROS-ERK1/2-NF-κB signaling axis. The prostaglandin E2 (PGE2) derived from PTGS2 catalyzation further strengthened PTGS2 expression via the PGE2-EPs-ERK1/2 positive feedback loop, which induced multidrug resistance of NSCLC cells through up-regulation of BCL2 expression and the subsequent attenuation of cell apoptosis. Consistently, high levels of both PTGS2 and BCL2 were closely associated with poor survival in NSCLC patients. Inhibition of PTGS2 significantly reversed the chemoresistance in the resistant NSCLC in vitro and in vivo. Our results suggested that PTGS2 might be employed as an adjunctive therapeutic target for improving the response to the therapeutic agents in a subset of resistant NSCLC. [ABSTRACT FROM AUTHOR]

Previous studies suggest that specific binding to the complex consisting of fibroblast growth factor receptor‐1 (FGFR1) and the coreceptor beta‐Klotho (KLB) is the premise for human FGF19 and FGF21 activating the downstream signaling cascades, and regulating the metabolic homeostasis. However, it was found that human FGF21 loses its ability to bind to FGFR1–KLB after iodination with Na125I and chloramine T, whereas human FGF19 retained its affinity for FGFR1–KLB even after iodination. The molecular mechanisms underlying these differences remained elusive. In this study, we first demonstrated that an intramolecular disulfide bond was formed between cysteine‐102 and cysteine‐121 in FGF21, implying that the oxidation of the cysteine to cysteic acid, which may interfere with the active conformation of FGF21, did not occur during the iodination procedures, and thus ruled out the possibility of the two conserved cysteine residues mediating the loss of FGF21 binding affinity to FGFR1–KLB upon iodination. Site‐directed mutagenesis and molecular modeling were further applied to determine the residue(s) responsible for the loss of FGFR1–KLB affinity. The results showed that mutation of a single tyrosine‐207, but not the other five tyrosine residues in FGF21, to a phenylalanine retained the FGFR1–KLB affinity of FGF21 even after iodination, whereas replacing the corresponding phenylalanine residue with tyrosine in FGF19 did not alter its binding affinity to FGFR1–KLB, but decreased the receptor binding ability of the iodinated protein, suggesting that tyrosine‐207 is the crucial amino acid responsible for the loss of specifying FGFR1–KLB affinity of the iodinated FGF21. Human fibroblast growth factor‐21 (FGF21) but not FGF19 lost its ability to bind to FGF receptor‐1 and coreceptor beta‐Klotho (FGFR1–KLB) after iodination with Na125I and chloramine T. Our results suggesting that tyrosine‐207 in FGF21 is the crucial amino acid responsible for the loss of specifying FGFR1–KLB affinity of the iodinated FGF21. [ABSTRACT FROM AUTHOR]

We focus on a dual-functional multi-input-multi-output (MIMO) radar-communication (RadCom) system, where a single transmitter with multiple antennas communicates with downlink cellular users and detects radar targets simultaneously. Several design criteria are considered for minimizing the downlink multiuser interference. First, we consider both omnidirectional and directional beampattern design problems, where the closed-form globally optimal solutions are obtained. Based on the derived waveforms, we further consider weighted optimizations targeting a flexible tradeoff between radar and communications performance and introduce low-complexity algorithms. Moreover, to address the more practical constant modulus waveform design problem, we propose a branch-and-bound algorithm that obtains a globally optimal solution, and derive its worst-case complexity as function of the maximum iteration number. Finally, we assess the effectiveness of the proposed waveform design approaches via numerical results. [ABSTRACT FROM AUTHOR]

In this paper, we study the energy efficiency (EE) of a downlink multicell massive distributed antenna system (DAS) in the presence of pilot contamination (PC), where the antennas are clustered on the remote radio heads (RRHs). We employ a practical power consumption model by considering the transmit power, the circuit power, and the backhaul power, in contrast to most of the existing works which focus on colocated antenna systems (CASs), where the backhaul power is negligible. For a given average user rate, we consider the problem of maximizing the EE with respect to the number of antennas of each RRH $n$, the number of RRHs $M$, and the number of users $K$ and study the impact of system parameters on the optimal $n$, $M$, and $K$. Specifically, by applying random matrix theory, we derive the closed-form expressions of the optimal $n$ and find the solution of the optimal $M$ and $K$ under a simplified channel model with maximum ratio transmission. From the results, we find that, to achieve the optimal EE, a large number of antennas is needed for a given user rate and PC. As the number of users increases, EE can be improved further by having more RRHs and antennas. Moreover, if the backhauling power is not large, a massive DAS can be more energy efficient than a massive CAS. These insights provide a useful guide to the practical deployment of massive DASs. [ABSTRACT FROM PUBLISHER]

In this paper, we analyze the spectral efficiency of multicell massive multiple-input–multiple-output (MIMO) systems with downlink training and a new pilot contamination precoding (PCP) scheme. First, we analyze the spectral efficiency of the beamforming training (BT) scheme with maximum-ratio transmission (MRT) precoding. Then, we derive an approximate closed-form expression of the spectral efficiency to find the optimal lengths of uplink and downlink pilots. Simulation results show that the achieved spectral efficiency can be improved due to channel estimation at the user side, but in comparison with a single-cell scenario, the spectral efficiency per cell in multicell scenario degrades because of pilot contamination. We focus on the practical case where the number of base station (BS) antennas is large but still finite and propose the BT and PCP (BT-PCP) transmission scheme to mitigate the pilot contamination with limited cooperation between BSs. We confirm the effectiveness of the proposed BT-PCP scheme with simulation, and we show that the proposed BT-PCP scheme achieves higher spectral efficiency than the conventional PCP method and that the performance gap from the perfect channel state information (CSI) scenario without pilot contamination is small. [ABSTRACT FROM AUTHOR]

This letter proposes a new modified energy detector for random signals in Gaussian noise. This new detector, whose decision variable is the weighted sum of the signal amplitude and its square, has a simple structure similar to the conventional energy detector. We propose a parameter optimization method to find the proper weighting factor by maximizing the error exponent of the misdetection probability based on large deviation theory. We also apply this method to optimize the power operation $p$ of another modified energy detector recently proposed by Chen. Numerical results show that, with the parameters obtained by the proposed method, both modified detectors achieve performance almost as well as the optimal detector. [ABSTRACT FROM PUBLISHER]

Metal-organic frameworks (MOFs) have potentially useful applications and an intriguing variety of architectures and topologies. Two homochiral coordination polymers have been synthesized by the hydrothermal method, namely poly[(μ- N-benzyl-L-phenylalaninato-κ4 O, O′: O, N)(μ-formato-κ2 O: O′)zinc(II)], [Zn(C16H16NO2)(HCOO)] n, (1), and poly[(μ- N-benzyl-L-leucinato-κ4 O, O′: O, N)(μ-formato-κ2 O: O′)zinc(II)], [Zn(C13H18NO2)(HCOO)] n, (2), and studied by single-crystal X-ray diffraction, elemental analyses, IR spectroscopy and fluorescence spectroscopy. Compounds (1) and (2) each have a two-dimensional layer structure, with the benzyl or isobutyl groups of the ligands directed towards the interlayer interface. Photoluminescence investigations show that both (1) and (2) display a strong emission in the blue region. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 23 (FGF23) is a bone-derived endocrine regulator of phosphate homeostasis and has been considered as a potential therapeutic target for hypophosphatemic disorders. Herein, we isolated a novel FGF23-binding peptide by screening a phage display library with FGF23, the minimal epitope of FGF23 binding to the binary fibroblast growth factor receptor (FGFR)-Klotho complex. The corresponding peptide (referred to as 23-b6) showed high homology to the immunoglobulin-like (Ig-like) domain III (D3) of FGFR1c, the predominant receptor mediating the phosphaturic activity of FGF23. The 23-b6 peptide and panning target FGF23 carried opposite charges and shared similar hydrophilic profiles. Functional analysis indicated that synthetic 23-b6 peptide exhibited antagonistic effect on the inhibition of phosphate uptake by FGF23 in opossum kidney cells (OK cells). The mechanisms of 23-b6 peptide impairing the bioactivity of FGF23 involved blockade of the activation of Erk cascade and up-regulation of NaPi-2a and NaPi-2c expression in OK cells. Our results demonstrate that the 23-b6 peptide is a potent FGF23 antagonist with increased effect on phosphate uptake in kidney cells and might have therapeutic potentials in hypophosphatemic disorders characterized by an abnormally high level of FGF23. [ABSTRACT FROM AUTHOR]

Context: The insulin-like growth factor (IGF) and insulin receptors' (IR) axes play important roles in both breast cancer and diabetes mellitus. Aim: We tend to explore the expression characteristics of proteins in IGF/IR axis in breast cancer with type 2 diabetes mellitus (T2DM). Settings and Design: We conducted a case-control investigation of T2DM and non-diabetes (n = 40, 1:1) in breast cancer patients. Materials and Methods: Some important molecules of IGF/IR axis were detected in breast cancer tissues by immunohistochemical staining. The multivariable analyses of the relationship of clinicopathological characters with the significant molecules were also detected. Statistical Analysis Used: The results were statistically evaluated by Statistical Package for the Social Sciences (SPSS version 17.0) software. Chi-square test and logistic regression are used. Results: Higher expression of IGF 1 receptor (IGF1R) was found in breast cancers of patients with T2DM, compared those without diabetes (P = 0.044). Negative expression of human epidermal growth factor receptor 2 (Her2) was found to be associated with higher expression of IGF1R in the breast cancers of patients with T2DM. There were no differences found in the expression of proteins of IGF-1, IGF-2, IGF-binding protein 3 (IGFBP3), IR, insulin receptor substrate (IRS)-1, IRS-2 and mammalian target of rapamycin (mTOR) between T2DM group and non-diabetes group. Conclusion: Our study found that breast cancer with T2DM had a higher expression of IGF1R, and the higher IGF1R was associated with negative Her2 expression. [ABSTRACT FROM AUTHOR]

Purpose: The objectives of this study were to investigate the incidences of hepatitis B virus (HBV) reactivation and hepatitis in gastrointestinal cancer patients with positive hepatitis B surface antigen (HBsAg) after chemotherapy and assess the effect of antiviral therapy on preventing HBV reactivation and hepatitis. Methods: The medical records of gastric or colorectal cancer patients with positive HBsAg undergoing chemotherapy in West China Hospital were reviewed from January 2009 to August 2014. Results: One hundred and fifty-six patients were included. Seventy-six patients had no records of the baseline HBV DNA copy (bHDC) and received no antiviral therapy. Of 80 patients with known bHDCs, 39 patients received antiviral therapy. The incidence of HBV reactivation was 14.6 % in the non-antiviral group with known bHDCs ( n = 41), compared with 0 % in the antiviral group ( P = 0.039). Compared with 12.8 % in the antiviral group ( P = 0.034), 29.9 % of patients suffered from hepatitis in the total non-antiviral group ( n = 117). More patients with moderate/severe hepatitis were seen in the non-antiviral group ( P = 0.027). Non-antiviral therapy was the only risk factor for hepatitis in multivariate analysis (HR 3.195, 95 % CI 1.117-10.989; P = 0.043). Conclusions: HBV reactivation and hepatitis occurred in a significant proportion of gastrointestinal cancer patients with positive HBsAg who received chemotherapy. Antiviral therapy could reduce the incidences of HBV reactivation and hepatitis. [ABSTRACT FROM AUTHOR]

Massive multiple-input multiple-output (MIMO) systems and small cell networks are both regarded as promising candidates to meet the exponential growth of mobile data traffic for the next generation (5G) wireless communications. Hence, a new kind of multitier networks which combine massive MIMO macro cells with a secondary tier of small cells is proposed to resolve the contradiction of large network coverage and high data rate. In such multitier networks, it is inevitable to allocate nonorthogonal uplink pilot sequences to user equipment (UE) due to the large number of users. We propose a pilot reuse scheme by exploiting the unique architecture of this networks and analyse the special mixed channel state information (CSI) yielded by the pilot reuse scheme. Based on the mixed CSI, we formulate a downlink transmit beamforming problem of minimizing the total power consumption while satisfying the quality of service (QoS) requirements with outage constraints. After decomposing the original problem into simpler subproblems, we provide an efficient algorithm to combine these subproblems and solve them iteratively for generating the beamforming vectors. Monte Carlo simulations show that the average power consumption of the proposed pilot reuse scheme and its associated beamforming algorithm is close to that of the perfect CSI case. [ABSTRACT FROM AUTHOR]

Development of drug resistance is a challenging problem in cancer chemotherapy. It has been shown that basic fibroblast growth factor (bFGF) plays an important role in an epigenetic mechanism of drug resistance. We have isolated a bFGF binding peptide P7 with inhibitory activity against bFGF-induced proliferation of human gastric cancer cells by screening a phage display library. In this study, we found that P7 peptide also has efficacy of reversing bFGF-induced resistance to Adriamycin (ADM) in human gastric cancer cells. Further investigations with SGC-7901 cells revealed that inhibition of Akt activation triggered by bFGF, and reversal of bFGF-induced up-regulation of Bcl-2 and XIAP and down-regulation of Bax, contribute to P7 peptide counteracting the anti-apoptotic effect of bFGF, and further reversing bFGF-induced resistance to ADM. The results suggested that the bFGF-binding peptide may have therapeutic potential of drug resistance in gastric cancer. [ABSTRACT FROM AUTHOR]