Mitophagy and Mitochondrial Quality Control Mechanisms in the Heart

Abstract

Purpose of Review

Mitochondrial homeostasis and quality control are essential to maintenance of cardiac function and a disruption of this pathway can lead to deleterious cardiac consequences.

Recent Findings

Mitochondrial quality control has been described as a major homeostatic mechanism in the cell. Recent studies highlighted that an impairment of mitochondrial quality control in different cell or mouse models is linked to cardiac dysfunction. Moreover, some conditions as aging, genetic mutations, or obesity have been associated with mitochondrial quality control alteration leading to an accumulation of damaged mitochondria responsible for increased production of reactive oxygen species, metabolic inflexibility, and inflammation, all of which can have sustained effects on cardiac cell function and even cell death.

Summary

In this review, we describe the major mechanisms of mitochondrial quality control, the factors that can impair mitochondrial quality control, and the consequences of disrupted mitochondrial quality control.

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Heterogeneity of Fibroblasts and Myofibroblasts in Pulmonary Fibrosis

Abstract

Purpose of Review

Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease of unknown etiopathogenesis with mean survival of 3–5 years and limited therapeutics. IPF is characterized by a loss of alveolar type II epithelial cells and aberrant activation of stromal cells, leading to a considerable effort to characterize the origin and activation mechanisms of fibroblasts and myofibroblasts in IPF lungs. In this review, the origin and contribution of fibroblast and myofibroblasts in lung fibrosis will be summarized.

Recent Findings

Lineage tracing experiments suggested that interstitial lung fibroblasts and lipofibroblasts, pericytes, and mesothelial cells differentiate into myofibroblasts. However, epithelial- and bone marrow-derived cells may give rise to collagen expressing cells but may not contribute to the pool of myofibroblasts.

Summary

There is great heterogeneity in fibroblasts and myofibroblasts in fibrotic lungs. Further, there is evidence for the expansion of pericyte-derived myofibroblasts and loss of lipofibroblasts and lipofibroblast-derived myofibroblasts in IPF.

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IJMS, Vol. 18, Pages 929: Molecular Ghrelin System in the Pancreatic Acinar Cells: The Role of the Polypeptide, Caerulein and Sensory Nerves

Ghrelin (GHRL) is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Experimental studies showed that GHRL protects the stomach and pancreas against acute damage, but the effect of GHRL on pancreatic acinar cells was still undetermined. Aim: To investigate the effect of GHRL and caerulein on the functional ghrelin system in pancreatic acinar cells taking into account the role of sensory nerves (SN). Methods: Experiments were carried out on isolated pancreatic acinar cells and AR42J cells. Before acinar cells isolation, GHRL was administered intraperitoneally at a dose of 50 µg/kg to rats with intact SN or with capsaicin deactivation of SN (CDSN). After isolation, pancreatic acinar cells were incubated in caerulein-free or caerulein containing solution. AR42J cells were incubated under basal conditions and stimulated with caerulein, GHRL or a combination of the above. Results: Incubation of isolated acinar cells with caerulein inhibited GHS-R and GHRL expression at the level of mRNA and protein in those cells. Either in rats with intact SN or with CDSN, administration of GHRL before isolation of acinar cells increased expression of GHRL and GHS-R in those cells and reversed the caerulein-induced reduction in expression of those parameters. Similar upregulation of GHS-R and GHRL was observed after administration of GHRL in AR42J cells. Conclusions: GHRL stimulates its own expression and expression of its receptor in isolated pancreatic acinar cells and AR42J cells on the positive feedback pathway. This mechanism seems to participate in the pancreatoprotective effect of GHRL in the course of acute pancreatitis.

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#ELCC17 latest: men in need of more frequent lung screening than women @myESMO https://t.co/0bilAYllQG

#ELCC17 latest: men in need of more frequent lung screening than women @myESMO https://t.co/0bilAYllQG

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Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type-Specific Differences

Endemic Burkitt lymphoma (eBL) is the most common pediatric cancer in malaria-endemic equatorial Africa and nearly always contains Epstein–Barr virus (EBV), unlike sporadic Burkitt lymphoma (sBL) that occurs with a lower incidence in developed countries. Given these differences and the variable clinical presentation and outcomes, we sought to further understand pathogenesis by investigating transcriptomes using RNA sequencing (RNAseq) from multiple primary eBL tumors compared with sBL tumors. Within eBL tumors, minimal expression differences were found based on: anatomical presentation site, in-hospital survival rates, and EBV genome type, suggesting that eBL tumors are homogeneous without marked subtypes. The outstanding difference detected using surrogate variable analysis was the significantly decreased expression of key genes in the immunoproteasome complex (PSMB9/β1i, PSMB10/β2i, PSMB8/β5i, and PSME2/PA28β) in eBL tumors carrying type 2 EBV compared with type 1 EBV. Second, in comparison with previously published pediatric sBL specimens, the majority of the expression and pathway differences was related to the PTEN/PI3K/mTOR signaling pathway and was correlated most strongly with EBV status rather than geographic designation. Third, common mutations were observed significantly less frequently in eBL tumors harboring EBV type 1, with mutation frequencies similar between tumors with EBV type 2 and without EBV. In addition to the previously reported genes, a set of new genes mutated in BL, including TFAP4, MSH6, PRRC2C, BCL7A, FOXO1, PLCG2, PRKDC, RAD50, and RPRD2, were identified. Overall, these data establish that EBV, particularly EBV type 1, supports BL oncogenesis, alleviating the need for certain driver mutations in the human genome.

Implications: Genomic and mutational analyses of Burkitt lymphoma tumors identify key differences based on viral content and clinical outcomes suggesting new avenues for the development of prognostic molecular biomarkers and therapeutic interventions. Mol Cancer Res; 15(5); 563–76. ©2017 AACR.

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Dysregulated GPCR Signaling and Therapeutic Options in Uveal Melanoma

Uveal melanoma is the most common primary intraocular malignant tumor in adults and arises from the transformation of melanocytes in the uveal tract. Even after treatment of the primary tumor, up to 50% of patients succumb to metastatic disease. The liver is the predominant organ of metastasis. There is an important need to provide effective treatment options for advanced stage uveal melanoma. To provide the preclinical basis for new treatments, it is important to understand the molecular underpinnings of the disease. Recent genomic studies have shown that mutations within components of G protein–coupled receptor (GPCR) signaling are early events associated with approximately 98% of uveal melanomas.

Implications: This review discusses the alterations in GPCR signaling components (GNAQ and GNA11), dysregulated GPCR signaling cascades, and viable targeted therapies with the intent to provide insight into new therapeutic strategies in uveal melanoma. Mol Cancer Res; 15(5); 501–6. ©2017 AACR.

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Constitutive Phosphorylation of STAT3 by the CK2-BLNK-CD5 Complex

In chronic lymphocytic leukemia (CLL), STAT3 is constitutively phosphorylated on serine 727 and plays a role in the pathobiology of CLL. However, what induces constitutive phosphorylation of STAT3 is currently unknown. Mass spectrometry was used to identify casein kinase 2 (CK2), a serine/threonine kinase that coimmunoprecipitated with serine phosphorylated STAT3 (pSTAT3). Furthermore, activated CK2 incubated with recombinant STAT3 induced phosphorylation of STAT3 on serine 727. Although STAT3 and CK2 are present in normal B- and T cells, STAT3 is not constitutively phosphorylated in these cells. Further study found that CD5 and BLNK coexpressed in CLL, but not in normal B- or T cells, are required for STAT3 phosphorylation. To elucidate the relationship of CD5 and BLNK to CK2 and STAT3, STAT3 was immunoprecipitated from CLL cells, and CK2, CD5, and BLNK were detected in the immunoprecipitate. Conversely, STAT3, CD5, and BLNK were in the immunoprecipitate of CLL cells immunoprecipitated with CK2 antibodies. Furthermore, siRNA knockdown of CD5 or BLNK, or treatment with CD5-neutralizing antibodies significantly reduced the levels of serine pSTAT3 in CLL cells. Finally, confocal microscopy determined that CD5 is cell membrane bound, and fractionation studies revealed that the CK2/CD5/BLNK/STAT3 complex remains in the cytoplasm, whereas serine pSTAT3 is shuttled to the nucleus.

Implications: These data show that the cellular proteins CK2, CD5, and BLNK are required for constitutive phosphorylation of STAT3 in CLL. Whether this protein complex phosphorylates other proteins or inhibiting its activity would have clinical benefit in patients has yet to be determined. Mol Cancer Res; 15(5); 610–8. ©2017 AACR.

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Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression

IDH1 mutations occur in the majority of low-grade gliomas and lead to the production of the oncometabolite, D-2-hydroxyglutarate (D-2HG). To understand the effects of tumor-associated mutant IDH1 (IDH1-R132H) on both the neural stem cell (NSC) population and brain tumorigenesis, genetically faithful cell lines and mouse model systems were generated. Here, it is reported that mouse NSCs expressing Idh1-R132H displayed reduced proliferation due to p53-mediated cell-cycle arrest as well as a decreased ability to undergo neuronal differentiation. In vivo, Idh1-R132H expression reduced proliferation of cells within the germinal zone of the subventricular zone (SVZ). The NSCs within this area were dispersed and disorganized in mutant animals, suggesting that Idh1-R132H perturbed the NSCs and the microenvironment from which gliomas arise. In addition, tumor-bearing animals expressing mutant Idh1 displayed a prolonged survival and also overexpressed Olig2, features consistent with IDH1-mutated human gliomas. These data indicate that mutant Idh1 disrupts the NSC microenvironment and the candidate cell-of-origin for glioma; thus, altering the progression of tumorigenesis. In addition, this study provides a mutant Idh1 brain tumor model that genetically recapitulates human disease, laying the foundation for future investigations on mutant IDH1-mediated brain tumorigenesis and targeted therapy.

Implications: Through the use of a conditional mutant mouse model that confers a less aggressive tumor phenotype, this study reveals that mutant Idh1 impacts the candidate cell-of-origin for gliomas. Mol Cancer Res; 15(5); 507–20. ©2017 AACR.

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Tumor-induced Stromal STAT1 Accelerates Breast Cancer via Deregulating Tissue Homeostasis

The tumor microenvironment (TME), the dynamic tissue space in which the tumor exists, plays a significant role in tumor initiation, and is a key contributor in cancer progression; however, little is known about tumor-induced changes in the adjacent tissue stroma. Herein, tumor-induced changes in the TME were explored at the morphologic and molecular level to further understand cancer progression. Tumor-adjacent mammary glands (TAG) displayed altered branching morphology, expansion of myofibroblasts, and increased mammosphere formation, broadly suggesting a tumor-induced field effect. FACS analysis of TAGs demonstrated an increased number of Lin^–CD24⁺/CD49⁺ enriched mammary gland stem cells (MaSC), suggesting deregulated tissue homeostasis in TAGs. Comparative transcriptome analysis of TAGs and contralateral control glands coupled with meta-analysis on differentially expressed genes with two breast cancer stromal patient microarray datasets identified shared upregulation of STAT1. Knockdown of STAT1 in cancer-associated fibroblast (CAF) cocultured with human breast cancer cells altered cancer cell proliferation, indicating a role for STAT1 as a stromal contributor of tumorigenesis. Furthermore, depletion of STAT1 in CAFs significantly reduced periductal reactive fibrosis and delayed early breast cancer progression in vivo. Finally, cotreatment with fludarabine, a FDA-approved STAT1 activation inhibitor and DNA synthesis inhibitor, in combination with doxorubicin, showed enhanced therapeutic efficacy in treating mouse mammary gland tumors. Taken together, these results demonstrate that stromal STAT1 expression promotes tumor progression and is a potential therapeutic target for breast cancer.

Implications: Tumors induce stromal STAT1-dependent cytokine secretion that promotes tumor cell proliferation and can be targeted using clinically-approved inhibitors of STAT1. Mol Cancer Res; 15(5); 585–97. ©2017 AACR.

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Exploiting AR-Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155

Androgen receptor (AR) signaling is fundamental to prostate cancer and is the dominant therapeutic target in metastatic disease. However, stringent androgen deprivation therapy regimens decrease quality of life and have been largely unsuccessful in curtailing mortality. Recent clinical and preclinical studies have taken advantage of the dichotomous ability of AR signaling to elicit growth-suppressive and differentiating effects by administering hyperphysiologic levels of testosterone. In this study, high-throughput drug screening identified a potent synergy between high-androgen therapy and YM155, a transcriptional inhibitor of survivin (BIRC5). This interaction was mediated by the direct transcriptional upregulation of the YM155 transporter SLC35F2 by the AR. Androgen-mediated YM155-induced cell death was completely blocked by the overexpression of multidrug resistance transporter ABCB1. SLC35F2 expression was significantly correlated with intratumor androgen levels in four distinct patient-derived xenograft models, and with AR activity score in a large gene expression dataset of castration-resistant metastases. A subset of tumors had significantly elevated SLC35F2 expression and, therefore, may identify patients who are highly responsive to YM155 treatment.

Implications: The combination of androgen therapy with YM155 represents a novel drug synergy, and SLC35F2 may serve as a clinical biomarker of response to YM155. Mol Cancer Res; 15(5); 521–31. ©2017 AACR.

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Highlights of This Issue

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Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma

Promoter methylation status of O-6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, is a critical biomarker in glioblastoma (GBM), as treatment decisions and clinical trial inclusion rely on its accurate assessment. However, interpretation of results is complicated by poor interassay reproducibility as well as a weak correlation between methylation status and expression levels of MGMT. This study systematically investigates the influence of tumor purity on tissue subjected to MGMT analysis. A quantitative, allele-specific real-time PCR (qAS-PCR) assay was developed to determine genotype and mutant allele frequency of telomerase promoter (pTERT) mutations as a direct measure of tumor purity. We studied tumor purity, pTERT mutation by Sanger sequencing, MGMT methylation by pyrosequencing, IDH1 mutation status, and clinical parameters in a cohort of high-grade gliomas (n = 97). The qAS-PCR reliably predicted pTERT genotype and tumor purity compared with independent methods. Tumor purity positively and significantly correlated with the extent of methylation in MGMT methylated GBMs. Extent of MGMT methylation differed significantly with respect to pTERT mutation hotspot (C228T vs. C250T). Interestingly, frontal lobe tumors showed greater tumor purity than those in other locations. Above all, tumor purity was identified as an independent prognostic factor in GBM. In conclusion, we determined mutual associations of tumor purity with MGMT methylation and pTERT mutations and found that the extent of MGMT methylation reflects tumor purity. In turn, tumor purity is prognostic in IDH1 wild-type GBM.

Implications: Tumor purity is an independent prognostic marker in glioblastoma and is associated with the extent of MGMT methylation. Mol Cancer Res; 15(5); 532–40. ©2017 AACR.

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Novel Assay to Detect RNA Polymerase I Activity In Vivo

This report develops an analytically validated chromogenic in situ hybridization (CISH) assay using branched DNA signal amplification (RNAscope) for detecting the expression of the 5' external transcribed spacer (ETS) of the 45S ribosomal (r) RNA precursor in formalin-fixed and paraffin-embedded (FFPE) human tissues. 5'ETS/45S CISH was performed on standard clinical specimens and tissue microarrays (TMA) from untreated prostate carcinomas, high-grade prostatic intraepithelial neoplasia (PIN), and matched benign prostatic tissues. Signals were quantified using image analysis software. The 5'ETS rRNA signal was restricted to the nucleolus. The signal was markedly attenuated in cell lines and in prostate tissue slices after pharmacologic inhibition of RNA polymerase I (Pol I) using BMH-21 or actinomycin D, and by RNAi depletion of Pol I, demonstrating validity as a measure of Pol I activity. Clinical human prostate FFPE tissue sections and TMAs showed a marked increase in the signal in the presumptive precursor lesion (high-grade PIN) and invasive adenocarcinoma lesions (P = 0.0001 and P = 0.0001, respectively) compared with non-neoplastic luminal epithelium. The increase in 5'ETS rRNA signal was present throughout all Gleason scores and pathologic stages at radical prostatectomy, with no marked difference among these. This precursor rRNA assay has potential utility for detection of increased rRNA production in various tumor types and as a novel companion diagnostic for clinical trials involving Pol I inhibition.

Implications: Increased rRNA production, a possible therapeutic target for multiple cancers, can be detected with a new, validated assay that also serves as a pharmacodynamic marker for Pol I inhibitors. Mol Cancer Res; 15(5); 577–84. ©2017 AACR.

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Distinctive Histogenesis and Immunological Microenvironment Based on Transcriptional Profiles of Follicular Dendritic Cell Sarcomas

Follicular dendritic cell (FDC) sarcomas are rare mesenchymal tumors with variable clinical, morphologic, and phenotypic characteristics. Transcriptome analysis was performed on multiple FDC sarcomas and compared with other mesenchymal tumors, microdissected Castleman FDCs, and normal fibroblasts. Using unsupervised analysis, FDC sarcomas clustered with microdissected FDCs, distinct from other mesenchymal tumors and fibroblasts. The specific endowment of FDC-related gene expression programs in FDC sarcomas emerged by applying a gene signature of differentially expressed genes (n = 1,289) between microdissected FDCs and fibroblasts. Supervised analysis comparing FDC sarcomas with microdissected FDCs and other mesenchymal tumors identified 370 and 2,927 differentially expressed transcripts, respectively, and on the basis of pathway enrichment analysis ascribed to signal transduction, chromatin organization, and extracellular matrix organization programs. As the transcriptome of FDC sarcomas retained similarity with FDCs, the immune landscape of FDC sarcoma was investigated by applying the CIBERSORT algorithm to FDC sarcomas and non-FDC mesenchymal tumors and demonstrated that FDC sarcomas were enriched in T follicular helper (T_FH) and T regulatory (T_REG) cell populations, as confirmed in situ by immunohistochemistry. The enrichment in specific T-cell subsets prompted investigating the mRNA expression of the inhibitory immune receptor PD-1 and its ligands PD-L1 and PD-L2, which were found to be significantly upregulated in FDC sarcomas as compared with other mesenchymal tumors, a finding also confirmed in situ. Here, it is demonstrated for the first time the transcriptional relationship of FDC sarcomas with nonmalignant FDCs and their distinction from other mesenchymal tumors.

Implications: The current study provides evidence of a peculiar immune microenvironment associated with FDC sarcomas that may have clinical utility. Mol Cancer Res; 15(5); 541–52. ©2017 AACR.

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Combined TRAF6 Targeting and Proteasome Blockade Has Anti-myeloma and Anti-Bone Resorptive Effects

TNF receptor–associated factor 6 (TRAF6) has been implicated in polyubiquitin-mediated IL1R/TLR signaling through activation of IB kinase (IKK) to regulate the NF-B and JNK signaling pathways. Here, TRAF6 protein was determined to be overexpressed in bone marrow mononuclear cells (BMMC) from patients with multiple myeloma. TRAF6 expression in BMMCs from patients with progressive disease is significantly elevated as compared with individuals in complete remission, with monoclonal gammopathy of undetermined significance, or healthy subjects. Furthermore, TRAF6 dominant–negative (TRAF6dn) peptides were constructed which specifically reduced TRAF6 signaling and activation of IKK. TRAF6 not only reduced cellular growth but also increased the apoptosis of multiple myeloma tumor cells in a concentration-dependent fashion. Because TRAF6 activates IKK through polyubiquitination, independent of its proteasome activity, a TRAF6dn peptide was combined with the proteasome inhibitors bortezomib or carfilzomib to treat multiple myeloma. Importantly, targeting of TRAF6 in the presence of proteasome inhibition enhanced anti–multiple myeloma effects and also decreased TLR/TRAF6/NF-B–related signaling. Finally, TRAF6dn dose dependently inhibited osteoclast cell formation from CD14⁺ monocytes, induced with RANKL and mCSF, and markedly reduced bone resorption in dentin pits. In all, these data demonstrate that blocking TRAF6 signaling has anti–multiple myeloma effects and reduces bone loss.

Implications: The ability to target TRAF6 signaling and associated pathways in multiple myeloma suggests a promising new therapeutic approach. Mol Cancer Res; 15(5); 598–609. ©2017 AACR.

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Genome-Wide Analysis Identifies MEN1 and MAX Mutations and a Neuroendocrine-Like Molecular Heterogeneity in Quadruple WT GIST

Quadruple wild-type (WT) gastrointestinal stromal tumor (GIST) is a genomic subgroup lacking KIT/PDGFRA/RAS pathway mutations, with an intact succinate dehydrogenase (SDH) complex. The aim of this work is to perform a wide comprehensive genomic study on quadruple WT GIST to improve the characterization of these patients. We selected 14 clinical cases of quadruple WT GIST, of which nine cases showed sufficient DNA quality for whole exome sequencing (WES). NF1 alterations were identified directly by WES. Gene expression from whole transcriptome sequencing (WTS) and miRNA profiling were performed using fresh-frozen, quadruple WT GIST tissue specimens and compared with SDH and KIT/PDGFRA-mutant GIST. WES identified an average of 18 somatic mutations per sample. The most relevant somatic oncogenic mutations identified were in TP53, MEN1, MAX, FGF1R, CHD4, and CTDNN2. No somatic alterations in NF1 were identified in the analyzed cohort. A total of 247 mRNA transcripts and 66 miRNAs were differentially expressed specifically in quadruple WT GIST. Overexpression of specific molecular markers (COL22A1 and CALCRL) and genes involved in neural and neuroendocrine lineage (ASCL1, Family B GPCRs) were detected and further supported by predicted miRNA target analysis. Quadruple WT GIST show a specific genetic signature that deviates significantly from that of KIT/PDGFRA-mutant and SDH-mutant GIST. Mutations in MEN1 and MAX genes, a neural-committed phenotype and upregulation of the master neuroendocrine regulator ASCL1, support a genetic similarity with neuroendocrine tumors, with whom they also share the great variability in oncogenic driver genes.

Implications: This study provides novel insights into the biology of quadruple WT GIST that potentially resembles neuroendocrine tumors and should promote the development of specific therapeutic approaches. Mol Cancer Res; 15(5); 553–62. ©2017 AACR.

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A Transcriptional Program for Detecting TGF{beta}-Induced EMT in Cancer

Most cancer deaths are due to metastasis, and epithelial-to-mesenchymal transition (EMT) plays a central role in driving cancer cell metastasis. EMT is induced by different stimuli, leading to different signaling patterns and therapeutic responses. TGFβ is one of the best-studied drivers of EMT, and many drugs are available to target this signaling pathway. A comprehensive bioinformatics approach was employed to derive a signature for TGFβ-induced EMT which can be used to score TGFβ-driven EMT in cells and clinical specimens. Considering this signature in pan-cancer cell and tumor datasets, a number of cell lines (including basal B breast cancer and cancers of the central nervous system) show evidence for TGFβ-driven EMT and carry a low mutational burden across the TGFβ signaling pathway. Furthermore, significant variation is observed in the response of high scoring cell lines to some common cancer drugs. Finally, this signature was applied to pan-cancer data from The Cancer Genome Atlas to identify tumor types with evidence of TGFβ-induced EMT. Tumor types with high scores showed significantly lower survival rates than those with low scores and also carry a lower mutational burden in the TGFβ pathway. The current transcriptomic signature demonstrates reproducible results across independent cell line and cancer datasets and identifies samples with strong mesenchymal phenotypes likely to be driven by TGFβ.

Implications: The TGFβ-induced EMT signature may be useful to identify patients with mesenchymal-like tumors who could benefit from targeted therapeutics to inhibit promesenchymal TGFβ signaling and disrupt the metastatic cascade. Mol Cancer Res; 15(5); 619–31. ©2017 AACR.

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A coaxial slot antenna with frequency of 433 MHz for microwave ablation therapies: design, simulation, and experimental research

Abstract

Investigation of the structures and properties of antennas is important in the design of microwave ablation (MWA) system. In this study, we studied the performance of the novel tri- and single-slot antennas with frequency of 433 MHz in ex vivo conditions. The dielectric properties of liver tissue under different thermal coagulation levels were explored, which was beneficial to evaluate ablation condition of tissue and simulate temperature field. Then, the performances of the antennas were analyzed by using numerical method based on finite element method (FEM). It indicated that the present antennas with frequency of 433 MHz could produce a gourd-shaped MWA area with a longer length. Compared to antenna with frequency of 2450 MHz, the designed single-slot antenna could obtain the larger MWA area. In addition, the multiple-point ablations and a larger MWA area could be achieved simultaneously by using the present tri-slot antenna. This study has a potential for the innovative design of MWA antenna for treatment of liver tumor with a large range and a long length.

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Refined multiscale fuzzy entropy based on standard deviation for biomedical signal analysis

Abstract

Multiscale entropy (MSE) has been a prevalent algorithm to quantify the complexity of biomedical time series. Recent developments in the field have tried to alleviate the problem of undefined MSE values for short signals. Moreover, there has been a recent interest in using other statistical moments than the mean, i.e., variance, in the coarse-graining step of the MSE. Building on these trends, here we introduce the so-called refined composite multiscale fuzzy entropy based on the standard deviation (RCMFE_σ) and mean (RCMFE_μ) to quantify the dynamical properties of spread and mean, respectively, over multiple time scales. We demonstrate the dependency of the RCMFE_σ and RCMFE_μ, in comparison with other multiscale approaches, on several straightforward signal processing concepts using a set of synthetic signals. The results evidenced that the RCMFE_σ and RCMFE_μ values are more stable and reliable than the classical multiscale entropy ones. We also inspect the ability of using the standard deviation as well as the mean in the coarse-graining process using magnetoencephalograms in Alzheimer's disease and publicly available electroencephalograms recorded from focal and non-focal areas in epilepsy. Our results indicated that when the RCMFE_μ cannot distinguish different types of dynamics of a particular time series at some scale factors, the RCMFE_σ may do so, and vice versa. The results showed that RCMFE_σ-based features lead to higher classification accuracies in comparison with the RCMFE_μ-based ones. We also made freely available all the Matlab codes used in this study at http://ift.tt/2qnmEHM.

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Malaria

Malaria: An infectious disease caused by protozoan parasites from the Plasmodium family that can be transmitted by the bite of the Anopheles mosquito or by a contaminated needle or transfusion. Falciparum malaria is the most deadly type.

The symptoms of malaria include cycles of chills, fever, sweats, muscle aches and headache that recur every few days. There can also be vomiting, diarrhea, coughing, and yellowing (jaundice) of the skin and eyes. Persons with severe falciparum malaria can develop bleeding problems, shock, kidney and liver failure, central nervous system problems, coma, and die. Travelers to areas with malaria are advised to take medications to prevent infection if exposed. The treatment of malaria is with oral or intravenous medications, including chloroquine, mefloquine (Larium), or atovaquone/proguanil (Malarone).

Malaria transmission occurs primarily between dusk and dawn because of the nocturnal feeding habits of Anopheles mosquitoes. One should therefore take protective measures to reduce contact with mosquitoes, especially during these hours. These measures include remaining in well-screened areas, using mosquito nets, and wearing clothes that cover most of the body.

Additionally, one should have insect repellent for use on exposed skin. The most effective repellent against a wide range of vectors is DEET (N,N-diethylmetatoluamide), an ingredient in many commercially available insect repellents. The actual concentration of DEET varies widely among repellents. DEET formulations as high as 50% are recommended for both adults and children > 2 months of age.

Travelers not staying in well-screened or air-conditioned rooms are advised to use a pyrethroid-containing flying-insect spray in living and sleeping areas during the evening and nighttime hours. They should sleep under insecticide-treated bed nets. Bed nets are more effective if they are treated with permethrin or deltamethrin insecticide; bed nets may be purchased that have already been treated with insecticide.

Among the many names for malaria are ague, jungle fever, marsh or swamp fever, and paludism.

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
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A systematic review and network meta-analysis of immunotherapy and targeted therapy for advanced melanoma

Abstract

Immune and BRAF-targeted therapies have changed the therapeutic scenario of advanced melanoma, turning the clinical decision-making a challenging task. This Bayesian network meta-analysis assesses the role of immunotherapies and targeted therapies for advanced melanoma. We retrieved randomized controlled trials testing immune, BRAF- or MEK-targeted therapies for advanced melanoma from electronic databases. A Bayesian network model compared therapies using hazard ratio (HR) for overall survival (OS), progression-free survival (PFS), and odds ratio (OR) for response rate (RR), along with 95% credible intervals (95% CrI), and probabilities of drugs outperforming others. We assessed the impact of PD-L1 expression on immunotherapy efficacy. Sixteen studies evaluating eight therapies in 6849 patients were analyzed. For OS, BRAF-MEK combination and PD-1 single agent ranked similarly and outperformed all other treatments. For PFS, BRAF-MEK combination surpassed all other options, including CTLA-4-PD-1 dual blockade hazard ratio (HR: 0.56; 95% CrI: 0.33–0.97; probability better 96.2%), whereas BRAF single agent ranked close to CTLA-4-PD-1 blockade. For RR, BRAF-MEK combination was superior to all treatments including CTLA-4-PD-1 (OR: 2.78; 1.18–6.30; probability better 97.1%). No OS data were available for CTLA-4-PD-1 blockade at the time of systematic review, although PFS and RR results suggested that this combination could also bring meaningful benefit. PD-L1 expression, as presently defined, failed to inform patient selection to PD-1-based immunotherapy. BRAF-MEK combination seemed an optimal therapy for BRAF-mutated patients, whereas PD-1 inhibitors seemed optimal for BRAF wild-type patients. Longer follow-up is needed to ascertain the role of CTLA-4-PD-1 blockade. Immunotherapy biomarkers remain as an unmet need.

This Bayesian meta-analysis compared immunotherapy and BRAF-MEK-targeted therapy in more than 6000 melanoma patients. Double BRAF-MEK therapy ranked highest in terms of survival and response followed by single agent PD-1 and BRAF inhibitors. Those results should better inform patient selection.

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Groundwater depletion and climate change: future prospects of crop production in the Central High Plains Aquifer

Abstract

Crop production in the Central High Plains is at an all-time high due to increased demand for biofuels, food, and animal products. Despite the need to produce more food by mid-century to meet expected population growth, under current management and genetics, crop production is likely to plateau or decline in the Central High Plains due to groundwater withdrawal at rates that greatly exceed recharge to the aquifer. The Central High Plains has experienced a consistent decline in groundwater storage due to groundwater withdrawal for irrigation greatly exceeding natural recharge. In this heavily irrigated region, water is essential to maintain yields and economic stability. Here, we evaluate how current trends in irrigation demand may impact groundwater depletion and quantify the impacts of these changes on crop yield and production through to 2099 using the well-established System Approach to Land Use Sustainability (SALUS) crop model. The results show that status quo groundwater management will likely reduce irrigated corn acreage by ~60% and wheat acreage by ~50%. This widespread forced shift to dryland farming, coupled with the likely effects of climate change, will contribute to overall changes in crop production. Taking into account both changes in yield and available irrigated acreage, corn production would decrease by approximately 60%, while production of wheat would remain fairly steady with a slight increase of about 2%.

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The mitochondrial outer membrane protein mitoNEET is a redox enzyme catalyzing electron transfer from FMNH2 to oxygen or ubiquinone [Metabolism]

Increasing evidence suggests that mitoNEET, a target of the type II diabetes drug pioglitazone, is a key regulator of energy metabolism in mitochondria. MitoNEET is anchored to the mitochondrial outer membrane via its N-terminal alpha-helix domain, and hosts a redox-active [2Fe-2S] cluster in its C-terminal cytosolic region. The mechanism by which mitoNEET regulates energy metabolism in mitochondria, however, is not fully understood. Previous studies have shown that mitoNEET specifically interacts with the reduced flavin mononucleotide (FMNH2) and that FMNH2 can quickly reduce the mitoNEET [2Fe-2S] clusters. Here, we report that the reduced mitoNEET [2Fe-2S] clusters can be readily oxidized by oxygen. In the presence of FMN, NADH, and flavin reductase which reduces FMN to FMNH2 using NADH as the electron donor, mitoNEET mediates oxidation of NADH with a concomitant reduction of oxygen. Ubiquinone-2, an analog of ubiquinone-10, can also oxidize the reduced mitoNEET [2Fe-2S] clusters under anaerobic or aerobic conditions. Compared with oxygen, ubiquinone-2 appears to be more efficient in oxidizing the mitoNEET [2Fe-2S] clusters, suggesting that ubiquinone could be an intrinsic electron acceptor of the reduced mitoNEET [2Fe-2S] clusters in mitochondria. Pioglitazone or its analog NL-1 appears to inhibit the electron transfer activity of mitoNEET by forming a unique complex with mitoNEET and FMNH2. The results suggest that mitoNEET is a redox enzyme that may promote oxidation of NADH to facilitate enhanced glycolysis in cytosol, and that pioglitazone may regulate energy metabolism in mitochondria by inhibiting the electron transfer activity of mitoNEET.

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Ets Homologous Factor (EHF) has Critical Roles in Epithelial Dysfunction in Airway Disease [Gene Regulation]

The airway epithelium forms a barrier between the internal and external environments. Epithelial dysfunction is critical in the pathology of many respiratory diseases including cystic fibrosis (CF). Ets homologous factor (EHF) is a key member of the transcription factor (TF) network that regulates gene expression in the airway epithelium in response to endogenous and exogenous stimuli. EHF, which has altered expression in inflammatory states, maps to the 5 ′ end of an intergenic region on Chr11p13 that was implicated as a modifier of CF airway disease. Here we determine the functions of EHF in primary human bronchial epithelial (HBE) cells and relevant airway cell lines. Using EHF chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) and RNA-seq after EHF depletion, we show that EHF targets in HBE cells are enriched for genes involved in inflammation and wound repair. Furthermore, changes in gene expression impact cell phenotype, since EHF depletion alters epithelial secretion of a neutrophil chemokine and slows wound closure in HBE cells. EHF activates expression of the SAM pointed domain-containing ETS transcription factor (SPDEF), which contributes to goblet cell hyperplasia. Our data reveal a critical role for EHF in regulating epithelial function in lung disease.

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Msh homeobox 1 (Msx1)- and Msx2-overexpressing bone marrow-derived mesenchymal stem cells resemble blastema cells and enhance regeneration in mice [Gene Regulation]

Amputation of the proximal region in mammals is not followed by regeneration because blastema cells (BCs) and expression of regenerative genes such as Msh homeobox (Msx) genes are absent in this animal group. The lack of BCs and positional information in other cells are therefore the main obstacle to therapeutic approaches for limb regeneration. Hence, this study aimed to create blastema− like cells (BlCs) by overexpressing Msx1 and Msx2 genes in mouse bone marrow− derived mesenchymal stem cells (mBMSCs) to regenerate a proximally amputated digit tip. We transduced mBMSCs with Msx1 and Msx2 genes and compared osteogenic activity and expression levels of several Msx-regulated genes (Bmp4, Fgf8, and keratin 14 (K14)) in BlCs groups including MSX1, MSX 2, and MSX1/2 (in a 1:1 ratio) with those in mBMSCs and BCs in vitro and in vivo following injection into the amputation site. We found that Msx gene overexpression increased expression of specific blastemal markers and enhanced proliferation rate and osteogenesis of BlCs compared with mBMSCs and BCs via activation of Fgf8 and Bmp4. Histological analyses indicated full regrowth of digit tips in the Msx-overexpressing groups, particularly in MSX1/2, through endochondral ossification 6 weeks post-injection. In contrast, mBMSCs and BCs formed abnormal bone and nail. Full digit tip was regenerated only in the MSX1/2 group and was related to boosted Bmp4, Fgf8, and K14 gene expression and to limb-patterning properties resulting from Msx1 and Msx2 overexpression. We propose that Msx-transduced cells that can regenerate epithelial and mesenchymal tissues may potentially be utilized in limb regeneration.

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A Bacteroidetes locus dedicated to fungal 1,6-{beta}-glucan degradation: unique substrate conformation drives specificity of the key endo-1,6-{beta}-glucanase [Enzymology]

Glycans are major nutrients available to the human gut microbiota (HGM). The Bacteroides are generalist glycan degraders and this function is mediated largely by polysaccharide utilization loci (PULs). The genomes of several Bacteroides species contain a PUL, PUL1,6-beta;-glucan, that was predicted to target mixed linked plant 1,3;1,4-beta-glucans. To test this hypothesis we characterized the proteins encoded by this locus in Bacteroides thetaiotaomicron, a member of the HGM. We show here that PUL1,6-β-glucan does not orchestrate the degradation of a plant polysaccharide but targets a fungal cell wall glycan, 1,6-beta-glucan, which is a growth substrate for the bacterium. The locus is upregulated by 1,6-beta-glucan, and encodes two enzymes, a surface endo-1,6-beta-glucanase, BT3312, and a periplasmic beta-glucosidase that targets primarily 1,6-beta-glucans. The non-catalytic proteins encoded by PUL1,6-beta-glucan target 1,6-beta-glucans and comprise a surface glycan binding protein and a SusD homologue that delivers glycans to the outer membrane transporter. We identified the central role of the endo-1,6-beta-glucanase in 1,6-beta-glucan depolymerization by deleting bt3312, which prevented the growth of B. thetaiotaomicron on 1,6-beta-glucan. The crystal structure of BT3312 in complex with β-glucosyl-1,6-deoxynojirimycin, revealed a TIM barrel catalytic domain that contains a deep substrate binding cleft tailored to accommodate the hook-like structure adopted by 1,6-beta-glucan. Specificity is driven by the complementarity of the enzyme active site cleft and the conformation of the substrate. We also noted that PUL1,6-beta-glucan is syntenic to many PULs from other Bacteroidetes suggesting that utilization of yeast and fungal cell wall 1,6-beta-glucans is a widespread adaptation within the human microbiota.

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Mechanism of Ubiquitin Chain Synthesis Employed by a HECT Ubiquitin Ligase [Protein Synthesis and Degradation]

Homologous to E6AP Carboxyl Terminus (HECT) ubiquitin (Ub) ligases (E3s) are a large class of enzymes that bind to their substrates and catalyze ubiquitination through the formation of a Ub thioester intermediate. The mechanisms by which these E3s assemble polyubiquitin chains on their substrates remain poorly defined. We report here that the Nedd4 family HECT E3, WWP1, assembles substrate-linked Ub chains containing K63, K48, and K11 linkages (K63 > K48 > K11). Our results demonstrate that WWP1 catalyzes the formation of Ub chains through a sequential addi-tion mechanism, in which Ub monomers are trans-ferred in a successive fashion to the substrate, and that ubiquitination by WWP1 requires the pres-ence of a low-affinity, noncovalent Ub-binding site within the HECT domain. Unexpectedly, we find that the formation of Ub chains by WWP1 occurs in two distinct phases. In the first phase, chains are synthesized in a unidirectional manner and linked exclusively through K63 of Ub. In the second phase, chains are elongated in a multidirec-tional fashion characterized by the formation of mixed Ub linkages and branched structures. Our results provide new insight into the mechanism of Ub chain formation employed by Nedd4 family HECT E3s and suggest a framework for under-standing how this family of E3s generates Ub sig-nals that function in proteasome-independent and proteasome-dependent pathways.

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Deficiency in the manganese efflux transporter SLC30A10 induces severe hypothyroidism in mice [Metabolism]

Manganese (Mn) is an essential metal that becomes toxic at elevated levels. Loss-of-function mutations in SLC30A10, a cell surface-localized Mn efflux transporter, cause a heritable Mn metabolism disorder resulting in elevated Mn levels and parkinsonian-like movement deficits. The underlying disease mechanisms are unclear; therefore, treatment is challenging. To understand the consequences of loss of SLC30A10 function at the organism level, we generated Slc30a10 knockout mice. During early development, knockouts were indistinguishable from controls. Surprisingly, however, after weaning and compared with controls, knockout mice failed to gain weight, were smaller, and died prematurely (by ~6-8 weeks of age). At 6 weeks, Mn levels in the brain, blood, and liver of the knockouts were ~20-60-fold higher than controls. Unexpectedly, histological analyses revealed that the brain and liver of the knockouts were largely unaffected, but that their thyroid exhibited extensive alterations. As hypothyroidism leads to growth defects and premature death in mice, we assayed for changes in thyroid and pituitary hormones. At 6 weeks and compared with controls, the knockouts had markedly reduced thyroxine levels (~50-80%) and profoundly increased thyroid stimulating hormone levels (~800-1000-fold), indicating that Slc30a10 knockout mice develop hypothyroidism. Importantly, a low Mn diet produced lower tissue Mn levels in the knockouts and rescued the phenotype, suggesting that Mn toxicity was the underlying cause. Our unanticipated discovery highlights the importance of determining the role of thyroid dysfunction in the onset and progression of Mn-induced disease and identifies Slc30a10 knockout mice as a new model for studying thyroid biology.

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Sirtuin 2 mutations in human cancers impair its function in genome maintenance [Cell Biology]

Sirtuin 2 (SIRT2) is a sirtuin family deacetylase, which maintains genome integrity and prevents tumorigenesis. While Sirt2 deficiency in mice leads to tumorigenesis, the functional significance of somatic SIRT2 mutations in human tumors is unclear. Using structural insight combined with bioinformatic and functional analyses, we show that naturally occurring cancer-associated SIRT2 mutations at evolutionarily conserved sites disrupt its deacetylation of DNA-damage response proteins by impairing SIRT2 catalytic activity or protein levels but not its localization or binding with substrate. We observed that these SIRT2 mutant proteins fail to restore the replication stress sensitivity, impairment in recovery from replication stress, and impairment in ATR-interacting protein (ATRIP) foci accumulation of SIRT2 deficiency. Moreover, the SIRT2 mutant proteins failed to rescue the spontaneous induction of DNA damage and micronuclei of SIRT2 deficiency in cancer cells. Our findings support a model for SIRT2′s tumor-suppressive function in which somatic mutations in SIRT2 contribute to genomic instability by impairing its deacetylase activity or diminishing its protein levels in the DNA-damage response. In conclusion, our work provides a mechanistic basis for understanding the biological and clinical significance of SIRT2 mutations in genome maintenance and tumor suppression.

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Metallic Twin Grain Boundaries Embedded in MoSe2 Monolayers Grown by Molecular Beam Epitaxy

ACS Nano

DOI: 10.1021/acsnano.7b02172

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Chemical Interaction-Guided, Metal-Free Growth of Large-Area Hexagonal Boron Nitride on Silicon-Based Substrates

ACS Nano

DOI: 10.1021/acsnano.7b01666

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Listening to your heartbeat helps you read other people’s minds

People who are more aware of their heartbeats are better at perceiving the emotions of others, suggesting training might help some autism symptoms

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Listening to your heartbeat helps you read other people’s minds

People who are more aware of their heartbeats are better at perceiving the emotions of others, suggesting training might help some autism symptoms

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The “80 Joule Criterion” reconsidered today

Reviewing the literature for injury to man caused by bullets or fragments reveals that the 80 Joule injury criterion is referenced in nearly every technical report [8,5,6] or textbook [7]. The 80 Joule (precisely 78.453J) or 58 ft-lb criterion as named today was derived from the 8 mkg value first mentioned 1896 by the Prussian artillery lieutenant general Heinrich Wilhelm Rohne in his textbook [1] “Schießlehre für Infanterie unter besonderer Berücksichtigung des Gewehr 88 und der Schießvorschrift für die Infanterie“.

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An autopsy case of fatal acute peritonitis complicated by illegal acupuncture therapy

Acupuncture is a key component of traditional Chinese medicine involving inserting thin needles into the body at acupuncture points. Recently, the use of acupuncture has increased in Eastern and Western countries, which is commonly used for pain relief [1]. It is generally accepted as a safe intervention when practiced by well educated and appropriately trained practitioner using clean technique and disposable single-use needles. Most reported adverse effects are minor without serious events. We experienced a rare autopsy case, who died from fatal acute peritonitis after receiving acupuncture by an illegal practitioner.

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A biased opinion: Demonstration of cognitive bias on a fingerprint matching task through knowledge of DNA test results

Fingerprint analysis has been used for over a century as a means of comparing a suspect and a perpetrator within a police investigation. A ‘match’ or ‘identification’ decision means that the suspect may remain a ‘person of interest’ in a case. In contrast, a ‘no-match’ or ‘exclusion’ decision means that an innocent party may be cleared of charges or released from custody. Finally an ‘inconclusive’ decision means that the analyst does not have sufficient information to draw a definitive conclusion, and any charge or conviction would need to rest on alternative evidence.

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Post-autopsy computed tomography. Pros and cons in a firearm death

Many studies have focused on the importance of post-mortem computed tomography (PMCT) prior to or in substitution of standard forensic autopsies in case of firearm death. However, due to the fact that PMCT is not routinely performed in all countries, in cases of death abroad it can happen that a CT scan is performed only after a first autopsy.A case of post-mortem re-examination, including the external examination and a post-autopsy computed tomography (PACT), of a gunshot victim of homicide in a foreign country is presented, and the pros and cons of imaging in post-autopsy setting are discussed.

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Differentiation of Lead-Free and Lead-Based Primers using Post-Fire Priming Cup Residue

When a weapon is discharged a plume of residue originating from the ammunition settles on the shooter, the victim, and that which is in the vicinity during the shooting. This residue, more commonly referred to as gunshot residue (GSR), is traditionally identified based on the presence of lead (Pb), barium (Ba), and antimony (Sb). It is often used in criminal cases as a method of identifying a shooter or estimating a shooting distance, which may assist in the discrimination between hypotheses (i.e.

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High-Speed Video Analysis of Forward and Backward Spattered Blood Droplets

Working for project No. 06-S-02 for the Midwest Forensics Resource Center (MFRC), T.L. Laber, B.P. Epstein, and M.C. Taylor took a series of over 500 high-speed videos of common bloodletting mechanisms [2]. The set of videos include blood spatter formation due to a gunshot, blood spatter due to a blunt object such as a hammer, or blood drop formation from a single droplet and are located on the MFRC website [1]. In literature, the videos have been referred to before [3–5], and are routinely used in bloodstain pattern analysis (BPA) presentation and training classes.

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A Step toward High-Energy Silicon-Based Thin Film Lithium Ion Batteries

ACS Nano

DOI: 10.1021/acsnano.7b00922

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Growth of Quasi-Free-Standing Single-Layer Blue Phosphorus on Tellurium Monolayer Functionalized Au(111)

ACS Nano

DOI: 10.1021/acsnano.7b01575

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Octopus-Inspired Assembly of Nanosucker Arrays for Dry/Wet Adhesion

ACS Nano

DOI: 10.1021/acsnano.7b00809

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Canonical JAK-STAT signaling is pivotal for long-term depression at adult hippocampal temporoammonic-CA1 synapses [Research]

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway is involved in numerous cellular processes and it is implicated in neurodegenerative disorders, like Alzheimer disease. Recent studies identified a crucial role for this pathway in activity-dependent long-term depression (LTD) at hippocampal Schaffer collateral (SC)-CA1 synapses. However, it is unclear if JAK-STAT signaling also regulates excitatory synaptic function at the anatomically distinct temporoammonic (TA) input to CA1 neurons. Here we demonstrate that LTD at adult TA-CA1 synapses involves JAK-STAT signaling, but unlike SC-CA1 synapses, requires rapid gene transcription. TA-CA1 LTD requires NMDA receptor activation and is independent of PI3K or ERK signaling. JAK-STAT signaling was critical for TA-CA1 LTD as inhibition of JAK or STAT blocked LTD induction and prevented NMDA-induced AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor internalization in hippocampal neurons. Moreover, an increase in phosphorylated JAK2 and STAT3 accompanied chemical induction of LTD and AMPA receptor internalization. STAT3-driven gene transcription was required for LTD as inhibition of STAT3-DNA binding, nuclear export, and gene transcription all prevented LTD induction. These data indicate an essential role for canonical JAK-STAT signaling in activity-dependent LTD at TA-CA1 synapses and provide valuable insight into the role of the TA input in hippocampal synaptic plasticity.—McGregor, G., Irving, A. J., Harvey, J. Canonical JAK-STAT signaling is pivotal for long-term depression at adult hippocampal temporoammonic-CA1 synapses.

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Inhibition of inflammasome activation improves lung acute injury induced by carrageenan in a mouse model of pleurisy [Research]

The inflammasome NLRP3 is a molecular pathway activated by a wide range of cellular insults to elicit innate immune defenses through the activation of caspase-1 and the maturation of proinflammatory cytokines, such as IL-1β and IL-18. The expression of NRLP3 is abnormally elevated in numerous human inflammatory diseases, including pulmonary diseases. An injection of carrageenan (CAR) into the pleural cavity triggered an acute inflammatory response, leading to tissue damage, inflammatory exudates, leukocyte infiltration, and increased myeloperoxidase activity. The aim of this study was to assess the effect of the inflammasome blocking agents BAY 11-7082 (30 mg/kg, i.p.) and Brilliant Blue G (BBG) (45.5 mg/kg, i.p.) in a mouse model of CAR-induced pleurisy. Treatment with BAY 11-7082 or BBG 1 h after CAR injection attenuated pulmonary membrane thickening and polymorphonuclear leukocyte infiltration, reduced NF-B translocation in the nucleus, and inhibited the assembly of the NRLP3/ASC/caspase-1 complex. Treatment with BAY 11-7082 or BBG also down-regulated iNOS, nitrotyrosine, and poly-ADP-ribosyl polymerase expression and inhibited CAR-induced apoptosis. Our results demonstrate that treatment with inflammasome-blocking agents can significantly reduce the development of acute CAR-induced lung injury.—Fusco, R. Gugliandolo, E., Biundo, F., Campolo, M., Di Paola, R., Cuzzocrea, S. Inhibition of inflammasome activation improves lung acute injury induced by carrageenan in a mouse model of pleurisy.

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Different expression levels of DLK1 inversely modulate the oncogenic potential of human MDA-MB-231 breast cancer cells through inhibition of NOTCH1 signaling [Research]

NOTCH receptors participate in cancer cell proliferation and survival. Accumulated evidence indicates that, depending on the cellular context, these receptors can function as oncogenes or as tumor-suppressor genes. The epidermal growth factor–like protein delta-like homolog (DLK)1 acts as a NOTCH inhibitor and is involved in the regulation of normal and tumoral growth. In this work, we focused on the role of DLK1 in the control of breast cancer cell growth, a tumor type in which NOTCH receptors have been shown to play both opposite roles. We found that human DLK1 inhibits NOTCH signaling in MDA-MB-231 breast cancer cells. The proliferation rate and invasion capabilities of these cells depended on the level of NOTCH activation and signaling, as regulated by DLK1. High levels of DLK1 expression led to a significant decrease in NOTCH signaling, which was associated with a decrease in breast cancer cell proliferation and invasion. On the contrary, lower levels of NOTCH inhibition, caused by lower levels of DLK1 overexpression, led to enhanced in vitro MDA-MB-231 cell invasion, and to both in vitro and in vivo increased cell proliferation. The data presented in this work suggest that a fine regulation of NOTCH signaling plays an important role in the control of breast cancer cell proliferation and invasion.—Nueda, M.-L., Naranjo, A.-I., Baladrón V., Laborda, J. Different expression levels of DLK1 inversely modulate the oncogenic potential of human MDA-MB-231 breast cancer cells through inhibition of NOTCH1 signaling.

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PGLP-1, a novel long-acting dual-function GLP-1 analog, ameliorates streptozotocin-induced hyperglycemia and inhibits body weight loss [Research]

It is well known that glucagon-like peptide 1 (GLP-1) has antidiabetic action. It has 2 distinct functions, an insulinotropic effect dependent on GLP-1 receptor (GLP-1R) and an insulinomimetic effect independent of GLP-1R. However, use of GLP-1 in vivo is limited by its short half-life. Therefore, our lab designed PGLP-1, a novel 2-function candidate peptide as a potential substitute. Using a streptozotocin-induced hyperglycemic mouse model, we demonstrated in vitro and in vivo that PGLP-1 had insulinotropic actions dependent on GLP-1R and insulinomimetic functions independent of GLP-1R. PGLP-1 treatment increased islet β-cell mass, plasma insulin, and C-peptide levels and Ki-67-immunoreactive β-cell numbers, verifying that PGLP-1 can work as a short GLP-1R agonist, similar to commercially available exendin-4. Additionally, PGLP-1 improved insulin sensitivity, inhibited gluconeogenesis by increasing expression of AMPK and receptor subfamily 0, group B, member 2 (SHP), and inhibited body weight loss by inhibiting β-oxidation, suggesting that PGLP-1 had insulinomimetic action. Taken together, these data indicated that PGLP-1, as a dual-function peptide, improved glycemic control and inhibited body weight loss, suggesting it could be useful for type 1 diabetes mellitus patients as an adjunctive therapy to insulin.—Gao, H., Zhao, Q., Song, Z., Yang, Z., Wu, Y., Tang, S., Alahdal, M., Zhang, Y., Jin, L. PGLP-1, a novel long-acting dual-function GLP-1 analog, ameliorates streptozotocin-induced hyperglycemia and inhibits body weight loss.

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Men need more frequent lung cancer screening than women

Men need more frequent lung cancer screening than women, according to research presented at the European Lung Cancer Conference (ELCC). The US Preventive Services Task Force recommends annual screening for lung cancer with low dose computed tomography...

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A Collection-Distribution Center Location and Allocation Optimization Model in Closed-Loop Supply Chain for Chinese Beer Industry

Recycling waste products is an environmental-friendly activity that can result in manufacturing cost saving and economic efficiency improving. In the beer industry, recycling bottles can reduce manufacturing cost and the industry’s carbon footprint. This paper presents a model for a collection-distribution center location and allocation problem in a closed-loop supply chain for the beer industry under a fuzzy random environment, in which the objectives are to minimize total costs and transportation pollution. Both random and fuzzy uncertainties, for which return rate and disposal rate are considered fuzzy random variables, are jointly handled in this paper to ensure a more practical problem solution. A heuristic algorithm based on priority-based global-local-neighbor particle swarm optimization (pb-glnPSO) is applied to ensure reliable solutions for this NP-hard problem. A beer company case study is given to illustrate the application of the proposed model and to demonstrate the priority-based global-local-neighbor particle swarm optimization.

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Lectin pathway effector enzyme mannan-binding lectin-associated serine protease-2 can activate native complement C3 in absence of C4 and/or C2 [Research]

All 3 activation pathways of complement—the classic pathway (CP), the alternative pathway, and the lectin pathway (LP)— converge into a common central event: the cleavage and activation of the abundant third complement component, C3, via formation of C3-activating enzymes (C3 convertases). The fourth complement component, C4, and the second component, C2, are indispensable constituents of the C3 convertase complex, C4bC2a, which is formed by both the CP and the LP. Whereas in the absence of C4, CP can no longer activate C3, LP retains a residual but physiologically critical capacity to convert native C3 into its activation fragments, C3a and C3b. This residual C4 and/or C2 bypass route is dependent on LP-specific mannan-binding lectin-associated serine protease-2. By using various serum sources with defined complement deficiencies, we demonstrate that, under physiologic conditions LP-specific C4 and/or C2 bypass activation of C3 is mediated by direct cleavage of native C3 by mannan-binding lectin-associated serine protease-2 bound to LP-activation complexes captured on ligand-coated surfaces.—Yaseen, S., Demopulos, G., Dudler, T., Yabuki, M., Wood, C. L., Cummings, W. J., Tjoelker, L. W., Fujita, T., Sacks, S., Garred, P., Andrew, P., Sim, R. B., Lachmann, P. J., Wallis, R., Lynch, N., Schwaeble, W. J. Lectin pathway effector enzyme mannan-binding lectin-associated serine protease-2 can activate native complement C3 in absence of C4 and/or C2.

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Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance [Research]

Although chemotherapy is designed to eradicate tumor cells, it also has significant effects on normal tissues. The platinum-induced fatty acid 16:4(n-3) (hexadeca-4,7,10,13-tetraenoic acid) induces systemic resistance to a broad range of DNA-damaging chemotherapeutics. We show that 16:4(n-3) exerts its effect by activating splenic F4/80⁺/CD11b^low macrophages, which results in production of chemoprotective lysophosphatidylcholines (LPCs). Pharmacologic studies, together with analysis of expression patterns, identified GPR120 on F4/80⁺/CD11b^low macrophages as the relevant receptor for 16:4(n-3). Studies that used splenocytes from GPR120-deficient mice have confirmed this conclusion. Activation of the 16:4(n-3)-GPR120 axis led to enhanced cPLA₂ activity in these splenic macrophages and secretion of the resistance-inducing lipid mediator, lysophosphatidylcholine(24:1). These studies identify a novel and unexpected function for GPR120 and suggest that antagonists of this receptor might be effective agents to limit development of chemotherapy resistance.—Houthuijzen, J. M., Oosterom, I., Hudson, B. D., Hirasawa, A., Daenen, L. G. M., McLean, C. M., Hansen, S. V. F., van Jaarsveld, M. T. M., Peeper, D. S., Jafari Sadatmand, S., Roodhart, J. M. L., van de Lest, C. H. A., Ulven, T., Ishihara, K., Milligan, G., Voest, E. E. Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance.

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Erratum [Erratum]

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Hexokinase II-derived cell-penetrating peptide targets mitochondria and triggers apoptosis in cancer cells [Research]

Overexpression of mitochondria-bound hexokinase II (HKII) in cancer cells plays an important role in their metabolic reprogramming and protects them against apoptosis, thereby facilitating their growth and proliferation. Here, we show that covalently coupling a peptide corresponding to the mitochondrial membrane–binding N-terminal 15 aa of HKII (pHK) to a short, penetration-accelerating sequence (PAS) enhances the cellular uptake, mitochondrial localization, and cytotoxicity of the peptide in HeLa cells. Further analysis revealed that pHK-PAS depolarized mitochondrial membrane potential, inhibited mitochondrial respiration and glycolysis, and depleted intracellular ATP levels. The effects of pHK-PAS were correlated with dissociation of endogenous full-length HKII from mitochondria and release of cytochrome c. Of significance, pHK-PAS treatment of noncancerous HEK293 cells resulted in substantially lower cytotoxicity. Thus, pHK-PAS effectively disrupted the mitochondria-HKII association in cancer cells, which led to mitochondrial dysfunction and, finally, apoptosis. Our results demonstrate the potential of the pHK-PAS cell-penetrating peptide as a novel therapeutic strategy in cancer.—Woldetsadik, A. D., Vogel, M. C., Rabeh, W. M., Magzoub, M. Hexokinase II–derived cell-penetrating peptide targets mitochondria and triggers apoptosis in cancer cells.

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Role of HSP60 (HSPD1) in diabetes-induced renal tubular dysfunction: regulation of intracellular protein aggregation, ATP production, and oxidative stress [Research]

Because underlying mechanisms of diabetic nephropathy/tubulopathy remained poorly understood, we aimed to define a key protein involving in hyperglycemia-induced renal tubular dysfunction. All altered renal proteins identified from previous large-scale proteome studies were subjected to global protein network analysis, which revealed heat shock protein 60 (HSP60, also known as HSPD1) as the central node of protein–protein interactions. Functional validation was performed using small interfering RNA (siRNA) to knock down HSP60 (siHSP60). At 48 h after exposure to high glucose (HG) (25 mM), Madin-Darby canine kidney (MDCK) renal tubular cells transfected with controlled siRNA (siControl) had significantly increased level of HSP60 compared to normal glucose (NG) (5.5 mM), whereas siHSP60-transfected cells showed a dramatically decreased HSP60 level. siHSP60 modestly increased intracellular protein aggregates in both NG and HG conditions. Luciferin–luciferase assay showed that HG modestly increased intracellular ATP, and siHSP60 further enhanced such an increase. OxyBlot assay showed significantly increased level of oxidized proteins in HG-treated siControl-transfected cells, whereas siHSP60 caused marked increase of oxidized proteins under the NG condition. However, the siHSP60-induced accumulation of oxidized proteins was abolished by HG. In summary, our data demonstrated that HSP60 plays roles in regulation of intracellular protein aggregation, ATP production, and oxidative stress in renal tubular cells. Its involvement in HG-induced tubular cell dysfunction was most likely via regulation of intracellular ATP production.—Aluksanasuwan, S., Sueksakit, K., Fong-ngern, K., Thongboonkerd, V. Role of HSP60 (HSPD1) in diabetes-induced renal tubular dysfunction: regulation of intracellular protein aggregation, ATP production, and oxidative stress.

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Gcn5 determines the fate of Drosophila germline stem cells through degradation of Cyclin A [Research]

The fluctuating CDK-CYCLIN complex plays a general role in cell-cycle control. Many types of stem cells use unique features of the cell cycle to facilitate asymmetric division. However, the manner in which these features are established remains poorly understood. The cell cycle of Drosophila female germline stem cells (GSCs) is characterized by short G₁ and very long G₂ phases, making it an excellent model for the study of cell cycle control in stem cell fate determination. Using a Drosophila female GSC model, we found Gcn5, the first discovered histone acetyltransferase, to maintain germline stem cells in Drosophila ovaries. Results showed that Gcn5 is dispensable for the transcriptional silencing of bam, but interacts with Cyclin A to facilitate proper turnover in GSCs. Results also showed that Gcn5 promotes Cyclin A ubiquitination, which is dependent on its acetylating activity. Finally, results showed that knockdown of Cyclin A rescued the GSC-loss phenotype caused by lack of Gcn5. Collectively, these findings support the conclusion that Gcn5 acts through acetylation to facilitate Cyclin A ubiquitination and proper turnover, thereby determining the fate of GSCs.—Liu, T., Wang, Q., Li, W., Mao, F., Yue, S., Liu, S., Liu, X., Xiao, S., Xia, L. Gcn5 determines the fate of Drosophila germline stem cells through degradation of Cyclin A.

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Activation of the hypoxia-inducible factor 1{alpha} promotes myogenesis through the noncanonical Wnt pathway, leading to hypertrophic myotubes [Research]

Regeneration of skeletal muscle is a complex process that requires the activation of quiescent adult stem cells, called satellite cells, which are resident in hypoxic niches in the tissue. Hypoxia has been recognized as a key factor to maintain stem cells in an undifferentiated state. Herein we report that hypoxia plays a fundamental role also in activating myogenesis. In particular, we found that the activation of the hypoxia-inducible factor (HIF)-1α under hypoxia, in murine skeletal myoblasts, leads to activation of MyoD through the noncanonical Wnt/β-catenin pathway. Moreover, chemical inhibition of HIF-1α activity significantly reduces differentiation, thus confirming its crucial role in the process. Furthermore, hypoxia-preconditioned myoblasts, once induced to differentiate under normoxic conditions, tend to form hypertrophic myotubes. These results support the notion that hypoxia plays a pivotal role in activating the regeneration process by directly inducing myogenesis through HIF-1α. Although preliminary, these findings may suggest new perspective for novel therapeutic targets in the treatment of several muscle diseases.—Cirillo, F., Resmini, G., Ghiroldi, A., Piccoli, M., Bergante, S., Tettamanti, G., Anastasia, L. Activation of the hypoxia-inducible factor 1α promotes myogenesis through the noncanonical Wnt pathway, leading to hypertrophic myotubes.

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Maresin 1 improves insulin sensitivity and attenuates adipose tissue inflammation in ob/ob and diet-induced obese mice [Research]

The beneficial actions of n-3 fatty acids on obesity-induced insulin resistance and inflammation have been related to the synthesis of specialized proresolving lipid mediators (SPMs) like resolvins. The aim of this study was to evaluate the ability of one of these SPMs, maresin 1 (MaR1), to reverse adipose tissue inflammation and/or insulin resistance in two models of obesity: diet-induced obese (DIO) mice and genetic (ob/ob) obese mice. In DIO mice, MaR1 (2 μg/kg; 10 d) reduced F4/80-positive cells and expression of the proinflammatory M1 macrophage phenotype marker Cd11c in white adipose tissue (WAT). Moreover, MaR1 decreased Mcp-1, Tnf-α, and Il-1β expression, upregulated adiponectin and Glut-4, and increased Akt phosphorylation in WAT. MaR1 administration (2 μg/kg; 20 d) to ob/ob mice did not modify macrophage recruitment but increased the M2 macrophage markers Cd163 and Il-10. MaR1 reduced Mcp-1, Tnf-α, Il-1β, and Dpp-4 and increased adiponectin gene expression in WAT. MaR1 treatment also improved the insulin tolerance test of ob/ob mice and increased Akt and AMPK phosphorylation in WAT. These data suggest that treatment with MaR1 can counteract the dysfunctional inflamed WAT and could be useful to improve insulin sensitivity in murine models of obesity.—Martínez-Fernández, L., González-Muniesa, P., Laiglesia, L. M., Sáinz, N., Prieto-Hontoria, P. L., Escoté, X., Odriozola, L., Corrales, F. J., Arbones-Mainar, J. M., Martínez, J. A., Moreno-Aliaga, M. J. Maresin 1 improves insulin sensitivity and attenuates adipose tissue inflammation in ob/ob and diet-induced obese mice.

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Differential expression of human {gamma}-tubulin isotypes during neuronal development and oxidative stress points to a {gamma}-tubulin-2 prosurvival function [Research]

-Tubulins are highly conserved members of the tubulin superfamily essential for microtubule nucleation. Humans possess 2 -tubulin genes. It is thought that -tubulin-1 represents a ubiquitous isotype, whereas -tubulin-2 is found predominantly in the brain, where it may be endowed with divergent functions beyond microtubule nucleation. The molecular basis of the purported functional differences between -tubulins is unknown. We report discrimination of human -tubulins according to their electrophoretic and immunochemical properties. In vitro mutagenesis revealed that the differences in electrophoretic mobility originate in the C-terminal regions of the -tubulins. Using epitope mapping, we discovered mouse monoclonal antibodies that can discriminate between human -tubulin isotypes. Real time quantitative RT-PCR and 2-dimensional-PAGE showed that -tubulin-1 is the dominant isotype in fetal neurons. Although -tubulin-2 accumulates in the adult brain, -tubulin-1 remains the major isotype in various brain regions. Localization of -tubulin-1 in mature neurons was confirmed by immunohistochemistry and immunofluorescence microscopy on clinical samples and tissue microarrays. Differentiation of SH-SY5Y human neuroblastoma cells by all-trans retinoic acid, or oxidative stress induced by mitochondrial inhibitors, resulted in upregulation of -tubulin-2, whereas the expression of -tubulin-1 was unchanged. Fractionation experiments and immunoelectron microscopy revealed an association of -tubulins with mitochondrial membranes. These data indicate that in the face of predominant -tubulin-1 expression, the accumulation of -tubulin-2 in mature neurons and neuroblastoma cells during oxidative stress may denote a prosurvival role of -tubulin-2 in neurons.—Dráberová, E., Sulimenko, V., Vinopal, S., Sulimenko, T., Sládková, V., D'Agostino, L., Sobol, M., Hozák, P., Křen, L., Katsetos, C. D., Dráber, P. Differential expression of human -tubulin isotypes during neuronal development and oxidative stress points to -tubulin-2 prosurvival function.

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A maternal Western diet during gestation and lactation modifies offsprings microbiota activity, blood lipid levels, cognitive responses, and hippocampal neurogenesis in Yucatan pigs [Research]

A suboptimal early nutritional environment (i.e., excess of energy, sugar, and fat intake) can increase susceptibility to diseases and neurocognitive disorders. The purpose of this study was to investigate in nonobese Yucatan minipigs (Sus scrofa) the impact of maternal diet [standard diet (SD) vs. Western diet (WD)] during gestation and 25 d of lactation on milk composition, blood metabolism, and microbiota activity of sows (n = 17) and their piglets (n = 65), and on spatial cognition (n = 51), hippocampal plasticity (n = 17), and food preferences/motivation (n = 51) in the progeny. Milk dry matter and lipid content, as well as plasma total cholesterol and free fatty acid (FFA) concentrations (P < 0.05) were higher in WD than in SD sows. Microbiota activity decreased in both WD sows and 100-d-old piglets (P < 0.05 or P < 0.10, depending on short-chain FAs [SCFAs]). At weaning [postnatal day (PND) 25], WD piglets had increased blood triglyceride and FFA levels (P < 0.01). Both SD and WD piglets consumed more of a known SD than an unknown high-fat and -sucrose (HFS) diet (P < 0.0001), but were quicker to obtain HFS rewards compared with SD rewards (P < 0.01). WD piglets had higher working memory (P = 0.015) and reference memory (P < 0.001) scores, which may reflect better cognitive abilities in the task context and a higher motivation for the food rewards. WD piglets had a smaller hippocampal granular cell layer (P = 0.03) and decreased neurogenesis (P < 0.005), but increased cell proliferation (P < 0.001). A maternal WD during gestation and lactation, even in the absence of obesity, has significant consequences for piglets’ blood lipid levels, microbiota activity, gut–brain axis, and neurocognitive abilities after weaning.—Val-Laillet, D., Besson, M., Guérin, S., Coquery, N., Randuineau, G., Kanzari, A., Quesnel, H., Bonhomme, N., Bolhuis, J. E., Kemp, B., Blat, S., Le Huërou-Luron, I., Clouard, C. A maternal Western diet during gestation and lactation modifies offspring’s microbiota activity, blood lipid levels, cognitive responses, and hippocampal neurogenesis in Yucatan pigs.

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Altered methylation of specific DNA loci in the liver of Bhmt-null mice results in repression of Iqgap2 and F2rl2 and is associated with development of preneoplastic foci [Research]

Folate B₁₂–dependent remethylation of homocysteine is important, but less is understood about the importance of the alternative betaine-dependent methylation pathway—catalyzed by betaine-homocysteine methyltransferase (BHMT)—for establishing and maintaining adequate DNA methylation across the genome. We studied C57Bl/6J Bhmt (betaine-homocysteine methyltransferase)-null mice at age 4, 12, 24, and 52 wk (N = 8) and observed elevation of S-adenosylhomocysteine concentrations and development of preneoplastic foci in the liver (increased placental glutathione S-transferase and cytokeratin 8-18 activity; starting at 12 wk). At 4 wk, we identified 63 differentially methylated CpGs (DMCs; false discovery rate < 5%) proximal to 81 genes (across 14 chromosomes), of which 18 were differentially expressed. Of these DMCs, 52% were located in one 15.5-Mb locus on chromosome 13, which encompassed the Bhmt gene and defined a potentially sensitive region with mostly decreased methylation. Analyzing Hybrid Mouse Diversity Panel data, which consisted of 100 inbred strains of mice, we identified 97 DMCs that were affected by Bhmt genetic variation in the same region, with 7 overlapping those found in Bhmt-null mice (P < 0.001). At all time points, we found a hypomethylated region mapping to Iqgap2 (IQ motif-containing GTPase activating protein 2) and F2rl2 (proteinase-activated receptor-3), 2 genes that were also silenced and underexpressed, respectively.—Lupu, D. S., Orozco, L. D., Wang, Y., Cullen, J. M., Pellegrini, M., Zeisel, S. H. Altered methylation of specific DNA loci in the liver of Bhmt-null mice results in repression of Iqgap2 and F2rl2 and is associated with development of preneoplastic foci.

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RNA editing enzyme ADAR2 is a mediator of neuropathic pain after peripheral nerve injury [Research]

Transcriptional and post-translational regulations are important in peripheral nerve injury–induced neuropathic pain, but little is known about the role of post-transcriptional modification. Our objective was to determine the possible effect of adenosine deaminase acting on RNA (ADAR) enzymes, which catalyze post-transcriptional RNA editing, in tactile allodynia, a hallmark of neuropathic pain. Seven days after L5 spinal nerve transection (SNT) in adult mice, we found an increase in ADAR2 expression and a decrease in ADAR3 expression in the injured, but not in the uninjured, dorsal root ganglions (DRGs). These changes were accompanied by elevated levels of editing at the D site of the serotonin (5-hydroxytryptamine) 2C receptor (5-HT_2CR), at the I/V site of coatomer protein complex subunit α (COPA), and at the R/G site of AMPA receptor subunit GluA2 in the injured DRG. Compared to Adar2^+/+/Gria2^R/R littermate controls, Adar2^–/–/Gria2^R/R mice completely lacked the increased editing of 5-HT_2CR, COPA, and GluA2 transcripts in the injured DRG and showed attenuated tactile allodynia after SNT. Furthermore, the antidepressant fluoxetine inhibited neuropathic allodynia after injury and reduced the COPA I/V site editing in the injured DRG. These findings suggest that ADAR2 is a mediator of injury-induced tactile allodynia and thus a potential therapeutic target for the treatment of neuropathic pain.—Uchida, H., Matsumura, S., Okada, S., Suzuki, T., Minami, T., Ito, S. RNA editing enzyme ADAR2 is a mediator of neuropathic pain after peripheral nerve injury.

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Lipoxin A4 stimulates endothelial miR-126-5p expression and its transfer via microvesicles [Research]

The proresolution lipid mediator lipoxin (LX)A₄ bestows protective bioactions on endothelial cells. We examined the impact of LXA₄ on transcellular endothelial signaling via microRNA (miR)-containing microvesicles. We report LXA₄ inhibition of MV release by TNF-α-treated HUVECs, associated with the down-regulation of 18 miR in endothelial microvesicles (EMVs) and the up-regulation of miR-126-5p, both in HUVECs and in EMVs. LXA₄ up-regulated miR-126-5p by ~5-fold in HUVECs and promoted a release of microvesicles (LXA₄-EMVs) that enhanced miR-126-5p by ~7-fold in recipient HUVECs. In these cells, LXA₄-EMVs abrogated the up-regulation of VCAM-1, induced in recipient HUVECs by EMVs released by untreated or TNF-α-treated HUVECs. LXA₄-EMVs also reduced by ~40% the expression of SPRED1, which we validated as an miR-126-5p target, whereas they stimulated monolayer repair in an in vitro wound assay. This effect was lost when the EMVs were depleted of miR-126-5p. These results provide evidence that changes in miR expression and microvesicle packaging and transfer represent a mechanism of action of LXA₄, which may be relevant in vascular biology and inflammation.—Codagnone, M., Recchiuti, A., Lanuti, P., Pierdomenico, A. M., Cianci, E., Patruno, S., Mari, V. C., Simiele, F., Di Tomo, P., Pandolfi, A., Romano, M. Lipoxin A₄ stimulates endothelial miR-126-5p expression and its transfer via microvesicles.

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Reduced mitochondrial activity in colonocytes facilitates AMPK{alpha}2-dependent inflammation [Research]

Intestinal inflammation is associated with low levels of mucosal ATP, highlighting the importance of mitochondrial function associated with ATP production in the pathophysiology of the disease. In the inflamed colon of humans and mice, we found decreased levels of mitochondrial complex cytochrome c oxidase I/IV and lower ATP levels. Thus, we generated colonic ⁰ cells with reduced mitochondrial function linked to ATP production by selective depletion of mitochondrial DNA. In these cells, RNA sequencing revealed a substantial number of differentially expressed transcripts, among which 240 belonged to inflammatory pathways activated in human inflamed colon and TNF-α-treated cells (false discovery rate < 0.05). TNF-α treatment of colonic ⁰ cells augmented IL-8 expression by 9-fold (P < 0.01) via NF-B compared to TNF-α-treated control. Moreover, reduced mitochondrial function facilitated TNF-α-mediated NF-B luciferase promoter activity as a result of lowered inhibitory IBα (nuclear factor of light polypeptide gene enhancer in B-cell inhibitor, α), leading to elevated NF-B. In cells with reduced mitochondrial function, TNF-α facilitated AMPKα2 activation by 8-fold (P < 0.01), which was involved in NF-B-dependent IL-8 expression. Last, in human and mouse colon, anti-TNF-α treatment restored reduced mitochondria-dependent inflammation. We propose that selective targeting of this novel mechanism provides new treatment opportunities for intestinal inflammation.—Heller, S., Penrose, H. M., Cable, C., Biswas, D., Nakhoul, H., Baddoo, M., Flemington, E., Crawford, S. E., Savkovic, S. D. Reduced mitochondrial activity in colonocytes facilitates AMPKα2-dependent inflammation.

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Roles of 5-lipoxygenase and cyclooxygenase-2 in the biosynthesis of hemiketals E2 and D2 by activated human leukocytes [Research]

The 2 hemiketal (HK) eicosanoids HKD₂ and HKE₂ are the major products of the biosynthetic crossover of the 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) pathways. HKs result from the rearrangement of a di-endoperoxide intermediate formed in the COX-2-dependent oxygenation of 5S-hydroxyeicosatetraenoic acid (5S-HETE). We analyzed HK biosynthesis in human leukocytes stimulated ex vivo and defined the biosynthetic roles of 5-LOX and COX-2, using inhibitors and incubations with exogenous substrates. Activation of leukocytes with LPS followed by treatment with the calcium ionophore A23187 resulted in the formation of PGE₂, 5-HETE, and LTB₄ as the principal metabolites of COX-2 and 5-LOX, respectively. The formation of HKD₂ and HKE₂ was highest after 15 min LPS treatment, and at that time, levels were similar to PGE₂, but less than 5-HETE and LTB₄. The time course of HK formation paralleled that of 5-HETE and LTB₄, implying the availability of the 5S-HETE substrate as a limiting factor in biosynthesis rather than expression levels of COX-2. Specific inhibitors of COX-2 and 5-LOX decreased formation of HKD₂ and HKE₂. Platelets did not form HKs from exogenous 5S-HETE, implying that COX-1 is not involved. HKs are early products during an inflammatory event and require cells that express 5-LOX and COX-2 for their biosynthesis.—Giménez-Bastida, J. A., Shibata, T., Uchida, K., Schneider, C. Roles of 5-lipoxygenase and cyclooxygenase-2 in the biosynthesis of hemiketals E₂ and D₂ by activated human leukocytes.

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Critical role of the cAMP-PKA pathway in hyperglycemia-induced epigenetic activation of fibrogenic program in the kidney [Research]

Hyperglycemia is a major pathogenic factor that promotes diabetic nephropathy, but the underlying mechanism remains incompletely understood. Here, we show that high glucose induced cAMP response element-binding protein (CREB)-binding protein (CBP)–mediated H3K9/14 hyperacetylation in approximately 5000 gene promoters in glomerular mesangial cells, including those of Tgfb1, Tgfb3, and Ctgf, the major profibrotic factors that are known to drive diabetic renal fibrogenesis. In these promoters, H3K9/14 hyperacetylation was closely associated with NF-B or CREB motifs. Chromatin immunoprecipitation assays confirmed that hyperglycemia promoted phospho-p65 or phospho-CREB and CBP bindings and RNA polymerase II recruitment to these promoters in mesangial cells as well as in glomeruli that were purified from type I and type II diabetic mice. Under hyperglycemia, cAMP production and PKA activity were markedly increased as a result of glucose transporter 1–mediated glucose influx that drives glucose metabolism and ATP production, which led to increased phosphorylation of p65 and CREB. Inhibition of adenylyl cyclase or PKA activity blocked p65 and CREB phosphorylation, CBP recruitment, and histone acetylation in these promoters. Collectively, these data demonstrate that the cAMP-PKA pathway plays a key role in epigenetic regulation of key profibrotic factors in diabetes.—Deb, D. K., Bao, R., Li, Y. C. Critical role of the cAMP-PKA pathway in hyperglycemia-induced epigenetic activation of fibrogenic program in the kidney.

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Combination therapy with liposomal neuroprotectants and tissue plasminogen activator for treatment of ischemic stroke [Research]

For ischemic stroke treatment, extension of the therapeutic time window (TTW) of thrombolytic therapy with tissue plasminogen activator (tPA) and amelioration of secondary ischemia/reperfusion (I/R) injury are most desirable. Our previous studies have indicated that liposomal delivery of neuroprotectants into an ischemic region is effective for stroke treatment. In the present study, for solving the above problems in the clinical setting, the usefulness of combination therapy with tPA and liposomal fasudil (fasudil-Lip) was investigated in ischemic stroke model rats with photochemically induced thrombosis, with clots that were dissolved by tPA. Treatment with tPA 3 h after occlusion markedly increased blood–brain barrier permeability and activated matrix metalloproteinase (MMP)-2 and -9, which are involved in cerebral hemorrhage. However, an intravenous administration of fasudil-Lip before tPA markedly suppressed the increase in permeability and the MMP activation stemming from tPA. The combination treatment showed significantly larger neuroprotective effects, even in the case of delayed tPA administration compared with each treatment alone or the tPA/fasudil-treated group. These findings suggest that treatment with fasudil-Lip before tPA could decrease the risk of tPA-derived cerebral hemorrhage and extend the TTW of tPA and that the combination therapy could be a useful therapeutic option for ischemic stroke.—Fukuta, T., Asai, T., Yanagida, Y., Namba, M., Koide, H., Shimizu, K., Oku, N. Combination therapy with liposomal neuroprotectants and tissue plasminogen activator for treatment of ischemic stroke.

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Down-regulated miR-26a promotes proliferation, migration, and invasion via negative regulation of MTDH in esophageal squamous cell carcinoma [Research]

Numerous studies have reported that the role played by miR-26a in cancer is controversial, but whether miR-26a regulates metadherin (MTDH) expression in esophageal squamous cell carcinoma (ESCC) is unclear. We performed this study to investigate the clinical relevance of miR-26a expression in ESCC. miR-26a was detected by using the in situ hybridization method. To functionally analyze the role of miR-26a in ESCC cell lines in vitro, KYSE-450 and Eca109 cells were employed, whose endogenous miR-26a was artificially down- or up-regulated, respectively, by using lentiviral-based transfection. There was significant association between miR-26a expression and clinical stage (P = 0.049), lymph node metastasis (P = 0.023), tumor volume (P = 0.003), and poor overall prognosis (P = 0.026). miR-26a was able to suppress proliferation and migration of ESCC cells in vitro. Moreover, we have confirmed that miR-26a can negatively regulate MTDH in ESCC cells by using luciferase reporter assay. In addition, to investigate the role miR-26a plays in cell proliferation, we nude mice were xenografted with ESCC cells whose miR-26a was stably down- and up-regulated. Together, our results show that miR-26a is capable of suppressing the proliferation and migration of ESCC cells via negative regulation of MTDH. Moreover, miR-26a expression was clinically relevant in cancer progression and poor prognosis, which supports the idea that miR-26a acts as a tumor suppressor in ESCC.—Yang, C., Zheng, S., Liu, T., Liu, Q., Dai, F., Zhou, J., Chen, Y., Sheyhidin, I., Lu, X. Down-regulated miR-26a promotes proliferation, migration, and invasion via negative regulation of MTDH in esophageal squamous cell carcinoma.

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Viruses comprise an extensive pool of mobile genetic elements in eukaryote cell cultures and human clinical samples [Research]

Viruses shape a diversity of ecosystems by modulating their microbial, eukaryotic, or plant host metabolism. The complexity of virus–host interaction networks is progressively fathomed by novel metagenomic approaches. By using a novel metagenomic method, we explored the virome in mammalian cell cultures and clinical samples to identify an extensive pool of mobile genetic elements in all of these ecosystems. Despite aseptic treatment, cell cultures harbored extensive and diverse phage populations with a high abundance of as yet unknown and uncharacterized viruses (viral dark matter). Unknown phages also predominated in the oropharynx and urine of healthy individuals and patients infected with cytomegalovirus despite demonstration of active cytomegalovirus replication. The novelty of viral sequences correlated primarily with the individual evaluated, whereas relative abundance of encoded protein functions was associated with the ecologic niches probed. Together, these observations demonstrate the extensive presence of viral dark matter in human and artificial ecosystems.—Thannesberger, J., Hellinger, H.-J., Klymiuk, I., Kastner, M.-T., Rieder, F. J. J., Schneider, M., Fister, S., Lion, T., Kosulin, K., Laengle, J., Bergmann, M., Rattei, T., Steininger, C. Viruses comprise an extensive pool of mobile genetic elements in eukaryote cell cultures and human clinical samples.

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Soluble CD14 acts as a DAMP in human macrophages: origin and involvement in inflammatory cytokine/chemokine production [Research]

The innate immune system is able to detect bacterial LPS through the pattern recognition receptor CD14, which delivers LPS to various TLR signaling complexes that subsequently induce intracellular proinflammatory signaling cascades. In a previous study, we showed the overproduction of the soluble form of CD14 (sCD14) by macrophages from patients with cystic fibrosis (CF). CF is an autosomal recessive disorder that is caused by mutations in the gene that encodes the CFTR protein and is characterized by persistent inflammation. Macrophages play a significant role in the initial stages of this disease due to their inability to act as suppressor cells, leading to chronic inflammation in CF. In this work, we investigated the origin of sCD14 by human macrophages and studied the effect of sCD14 on the production of inflammatory cytokine/chemokine. Our data indicate that sCD14 stimulate proinflammatory cytokine/chemokine production in a manner that is independent of LPS but dependent on the TLR-4/CD14 membrane complex, NF-B, and the inflammasome. Therefore, sCD14, overproduced by CF macrophages, originates primarily from the endocytosis/exocytosis process and should be considered to be a danger-associated molecular pattern. This elucidation of the origin and inflammation-induced mechanisms associated with sCD14 contributes to our understanding of maintained tissue inflammation.—Lévêque, M., Simonin-Le Jeune, K., Jouneau, S., Moulis, S., Desrues, B., Belleguic, C., Brinchault, G., Le Trionnaire, S., Gangneux, J.-P., Dimanche-Boitrel, M.-T., Martin-Chouly, C. Soluble CD14 acts as a DAMP in human macrophages: origin and involvement in inflammatory cytokine/chemokine production.

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