bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting Merkel Cell Carcinoma by Engineered T Cells Specific to T-Antigens of Merkel Cell Polyomavirus
Authors: Gavvovidis Ioannis , Leisegang Matthias , Willimsky Gerald , Miller Natalie , Nghiem Paul , Blankenstein Thomas
Published: April 2018

Purpose: The causative agent of most cases of Merkel cell carcinoma (MCC) has been identified as the Merkel cell polyomavirus (MCV). MCV-encoded T antigens (Tag) are essential not only for virus-mediated tumorigenesis but also for maintaining MCC cell lines in vitro. MCV Tags are thus an appealing target for viral oncoprotein-directed T-cell therapy for MCC. With this study, we aimed to isolate and characterize Tag-specific T-cell receptors (TCR) for potential use in gene therapy clinical trials.

Experimental Design: T-cell responses against MCV Tag epitopes were investigated by immunizing transgenic mice that express a diverse human TCR repertoire restricted to HLA-A2. Human lymphocytes genetically engineered to express Tag-specific TCRs were tested for specific reactivity against MCC cell lines. The therapeutic potential of Tag-specific TCR gene therapy was tested in a syngeneic cancer model.

Results: We identified naturally processed epitopes of MCV Tags and isolated Tag-specific TCRs. T cells expressing these TCRs were activated by HLA-A2–positive cells loaded with cognate peptide or cells that stably expressed MCV Tags. We showed cytotoxic potential of T cells engineered to express these TCRs in vitro and demonstrated regression of established tumors in a mouse model upon TCR gene therapy.

Conclusions: Our findings demonstrate that MCC cells can be targeted by MCV Tag-specific TCRs. Although recent findings suggest that approximately half of MCC patients benefit from PD-1 pathway blockade, additional patients may benefit if their endogenous T-cell response can be augmented by infusion of transgenic MCV-specific T cells such as those described here. Clin Cancer Res; 24(15); 3644–55. ©2018 AACR.
Crosstalk Between Apoptosis and Autophagy Is Regulated by the Arginylated BiP/Beclin-1/p62 Complex
Authors: Song Xinxin , Lee Dae-Hee , Dilly Ashok-Kumar , Lee Young-Sun , Choudry Haroon Asif , Kwon Yong Tae , Bartlett David L. , Lee Yong J.
Published: April 2018

Emerging evidence demonstrates that autophagy and apoptosis are interconnected and their interplay greatly affects cell death. However, the key regulators in this crosstalk remain elusive. Therefore, the role of N-terminal arginylated BiP (R-BiP)/Beclin-1/p62 complex was examined in the crosstalk between apoptosis and autophagy during combination chemotherapy with mitomycin C and bortezomib using immunoblot, immunoprecipitation, and cellular imaging assays in wild-type (WT) and genetically engineered colorectal cancer cells. In addition, the tumoricidal efficacy of the combinatorial treatment in a nude mouse tumor xenograft model of colorectal cancer was assessed. Bortezomib combined with mitomycin C synergistically induced cytotoxicity and apoptosis rather than autophagy. Mechanistically, this combination inactivated Akt and subsequently induced Beclin-1 (BECN1) dephosphorylation at Ser 234/295. Dephosphorylation of Beclin-1 resulted in increased cleavage of Beclin-1 and disruption of the R-BiP/Beclin-1/p62 complex, which led to switching autophagy to the synergistic induction of apoptosis. Importantly, the combination significantly suppressed LS174T intraperitoneal xenograft tumor growth, induced Akt inactivation and Beclin-1 cleavage, and decreased autophagy in vivo. Moreover, the tumoricidal efficacy of the combinatorial treatment was less effective, in vitro and in vivo, in HCT116 tumors harboring a Beclin-1 caspase 8 cleavage site mutant knock-in.

Implications: This study uncovers that the R-BiP/Beclin-1/p62 complex has an important role in the crosstalk between apoptosis and autophagy. The results also propose how mono-drug resistance can be overcome using potent combinations to improve anticancer therapy. Mol Cancer Res; 16(7); 1077–91. ©2018 AACR.
Recognition of Recurrent Protein Expression Patterns in Pediatric Acute Myeloid Leukemia Identified New Therapeutic Targets
Authors: Hoff Fieke W. , Hu Chenyue W. , Qiu Yihua , Ligeralde Andrew , Yoo Suk-Young , Mahmud Hasan , de Bont Eveline S.J.M. , Qutub Amina A. , Horton Terzah M. , Kornblau Steven M.
Published: April 2018

Heterogeneity in the genetic landscape of pediatric acute myeloid leukemia (AML) makes personalized medicine challenging. As genetic events are mediated by the expression and function of proteins, recognition of recurrent protein patterns could enable classification of pediatric AML patients and could reveal crucial protein dependencies. This could help to rationally select combinations of therapeutic targets. To determine whether protein expression levels could be clustered into functionally relevant groups, custom reverse-phase protein arrays were performed on pediatric AML (n = 95) and CD34+ normal bone marrow (n = 10) clinical specimens using 194 validated antibodies. To analyze proteins in the context of other proteins, all proteins were assembled into 31 protein functional groups (PFG). For each PFG, an optimal number of protein clusters was defined that represented distinct transition states. Block clustering analysis revealed strong correlations between various protein clusters and identified the existence of 12 protein constellations stratifying patients into 8 protein signatures. Signatures were correlated with therapeutic outcome, as well as certain laboratory and demographic characteristics. Comparison of acute lymphoblastic leukemia specimens from the same array and AML pediatric patient specimens demonstrated disease-specific signatures, but also identified the existence of shared constellations, suggesting joint protein deregulation between the diseases.

Implication: Recognition of altered proteins in particular signatures suggests rational combinations of targets that could facilitate stratified targeted therapy. Mol Cancer Res; 16(8); 1275–86. ©2018 AACR.

See related article by Hoff et al., p. 1263
Tetrahydrocurcumin Provides Neuroprotection in Experimental Traumatic Brain Injury and the Nrf2 Signaling Pathway as a Potential Mechanism
Authors: Wei Guan , Chen Bingji , Lin Qingjiang , Li Yasong , Luo Liangqin , He Hefan , Fu Huangde
Published: April 2018

The protective effect of tetrahydrocurcumin (THC) after experimental traumatic brain injury (TBI) has been demonstrated, as demonstrated by the inhibition of oxidative stress, mitochondrial dysfunction, and apoptosis. However, the mechanisms underlying this effect are still not well understood. This study was to investigate the neuroprotective effects of THC, and its potential mechanisms, in a rat model of TBI. To this end, rats were divided into 4 groups: the sham group, the TBI group, the TBI + vehicle (V) group, and the TBI + THC group. THC or V was administered via intraperitoneal injection to rats in the TBI + V and TBI + THC groups 30 min after TBI. After euthanasia (24 h after TBI), neurological scores, brain water content, and neuronal cell death in the cerebral cortex were recorded. Brain samples were collected after neurological scoring for further analysis. THC treatment alleviated brain edema, attenuated TBI-induced neuronal cell apoptosis, and improved neurobehavioral function. In addition, NFE2-related factor 2 (Nrf2) expression was upregulated following TBI. These results suggest that THC improves neurological outcome after TBI, possibly by activating the Nrf2 signaling pathway.
Management of Subfoveal Perfluorocarbon Liquid: A Review
Authors: Liu Wu , Gao Meng , Liang Xida
Published: April 2018

Perfluorocarbon liquid (PFCL) has been widely used in vitreoretinal surgeries, especially in retinal detachment treatment. A prominent complication of intraoperative PFCL application is inadvertent subretinal PFCL retention. Subfoveal PFCL, even in small amounts, receives much attention due to its potential side effect on the macular structure and function. Whether to observe with follow-up or to deal with surgery is often an intractable problem in the management of subfoveal PFCL. Safety and necessity are the 2 key issues in considering surgical treatment, that is, can we avoid surgically induced macular injury and will surgery be beneficial for the recovery of vision? Herein, the authors review sub­foveal PFCL retention with its risk factors, morphological manifestations, pathological studies, clinical natural consequences, and different surgical methods with their outcomes. Analysis of the existing literature shows that visual acuity improved significantly after subfoveal PFCL removal or displacement and was positively correlated with visual acuity before the operation.
The Role of Proteasome Inhibitor MG132 in 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis in NC/Nga Mice
Authors: Ohkusu-Tsukada Kozo , Ito Daiki , Takahashi Kimimasa
Published: April 2018

Background: Although immunosuppressants for therapy of atopic dermatitis (AD) are still being sought, proteasome inhibitors are also potential candidates for the treatment of AD. Proteasome inhibitors exert various effects by blocking proteasomal degradation and help regulate processes such as apoptosis induction via caspase-9, cell cycle progression via cyclins, NF-κB inactivation via IκB, and downregulation of antigen cross-presentation. The cells targeted by proteasome inhibitors are therefore activated cells undergoing proliferation or differentiation, and antigen-presenting cells carrying out protein degradation. Objectives: This study investigated the therapeutic effects and side effects of a proteasome inhibitor, MG132, on the treatment of AD. Methods: AD-like disease in NC/Nga mice housed under specific pathogen-free conditions was induced by repeated application of 2,4-dinitrofluorobenzene (DNFB). Disease progression was evaluated by inflammation score, histopathology, and serum IgE level, and the effects of systemic MG132 administration were investigated. The percentages and absolute numbers for each population of Th1, Th2, and Th17 cells in the axillary lymph nodes were analyzed by flow cytometry. Results: DNFB application increased the expression of a unique major histocompatibility complex class I mutant molecule D/Ldm7 in dendritic cells (DCs), and increased Th1 and Th17 cells in NC/Nga mice. In vivo MG132 administration to NC/Nga mice with DNFB-induced dermatitis reduced Th17 cells but maintained the level of Th1 cells, resulting in the alleviation of dermatitis lesions by decreasing both serum IgE hyperproduction and mast cell migration. To understand the mechanisms maintaining Th1 cell levels following in vivo MG132-administration, we focused on the role of proteasomes regulating D/Ldm7 expression. Interestingly, 20S proteasome activity was higher in NC/Nga DCs than in BALB/c DCs. In vitro MG132 administration partially increased D/Ldm7 expression in a dose-dependent manner during DC maturation, and induced IFN-γ production from autoreactive CD8+ T cells but not from CD4+ T cells following coculturing with D/Ldm7-upregulated DCs. Conclusion: Although MG132 administration temporarily alleviated AD pathogenesis in NC/Nga mice, prolonged MG132 treatment may result in immunopathogenesis leading to chronic AD due to its side effect of maintaining Th1 levels via autoreactive CD8+ T cells.
CLIC1 Promotes the Progression of Gastric Cancer by Regulating the MAPK/AKT Pathways
Authors: Li Bo-pei , Mao Yuan-tian , Wang Zhen , Chen Ye-yang , Wang Ye , Zhai Chong-yu , Shi Bo , Liu Si-yu , Liu Jin-lu , Chen Jun-qiang
Published: April 2018

Background/Aims: Chloride intracellular channel 1 (CLIC1), which is a member of the chloride channel protein family, is associated with various human tumors. Recent studies have shown that CLIC1 is involved in the occurrence and development of gastric cancer (GC). However, the exact mechanism remains unclear in GC. Methods: Effects of CLIC1 on the progression of GC in vivo and in vitro and the potential underlying mechanisms have been investigated by analysing 54 patients with GC, as well as human gastric cell lines SGC-7901 and MGC-803, utilizing proteomics, RT-PCR, Western blotting, flow cytometry, Cell invasion and migration assays and xenograft tumor models. Results: Our study shows that CLIC1 knockdown by targeted-siRNA markedly inhibits GC cell invasion and migration and induces apoptosis in vitro. In total, 54 differentially expressed proteins were identified in GC cells SGC-7901 after CLIC1 silencing by isobaric tags for relative isotope labeled and absolute quantitation (iTRAQ) technology, including integrin α1 (ITGα1) and ITGα3. The expression levels of ITGα3, ITGαv, ITGβ1 and Bcl-2 mRNA and protein were decreased significantly in GC cells after CLIC1 knockdown; ITGα1 and Fas were upregulated, but the level of survivin was not significantly different. GC growth and metabolism were decreased in vivo after CLIC1 silencing, but apoptosis was markedly increased. Further study showed that the expression levels of ITGα3, ITGαv and ITGβ1, as well as AKT-phosphorylation, ERK-phosphorylation and p38-phosphorylation, were reduced in vivo after CLIC1 knockdown, while ITGα1 was upregulated. Conclusions: We speculate that CLIC1 may play an important role in the progression of GC, and its mechanism may be related to the regulation of integrin family proteins, which leads to the sequential regulation of the PI3K/AKT, MAPK/ERK and MAPK/p38 pathways.
Atorvastatin Attenuates Myocardial Hypertrophy in Spontaneously Hypertensive Rats via the C/EBPβ/PGC-1α/UCP3 Pathway
Authors: Chen Yintao , Chang Ye , Zhang Naijin , Guo Xiaofan , Sun Guozhe , Sun Yingxian
Published: April 2018

Background/Aims: Many clinical and experimental studies have shown that treatment with statins could prevent myocardial hypertrophy and remodeling induced by hypertension and myocardial infarction. But the molecular mechanism was not clear. We aimed to investigate the beneficial effects of atorvastatin on hypertension-induced myocardial hypertrophy and remodeling in spontaneously hypertensive rats (SHR) with the hope of revealing other potential mechanisms or target pathways to interpret the pleiotropic effects of atorvastatin on myocardial hypertrophy. Methods: The male and age-matched animals were randomly divided into three groups: control group (8 WKY), SHR (8 rats) and intervention group (8 SHR). The SHR in intervention group were administered by oral gavage with atorvastatin (suspension in distilled water, 10 mg/Kg once a day) for 6 weeks, and the other two groups were administered by gavage with equal quantity distilled water. Blood pressure of rats was measured every weeks using a standard tail cuff sphygmomanometer. Left ventricular (LV) dimensions were measured from short-axis views of LV under M-mode tracings using Doppler echocardiograph. Cardiomyocyte apoptosis was assessed by the TUNEL assay. The protein expression of C/EBPβ, PGC-1α and UCP3 were detected by immunohistochemistry or Western blot analysis. Results: At the age of 16 weeks, the mean arterial pressure of rats in three groups were 103.6±6.1, 151.8±12.5 and 159.1±6.2 mmHg respectively, and there wasn’t statistically significant difference between the SHR and intervention groups. Staining with Masson’s trichrome demonstrated that the increased interstitial fibrosis of LV and ventricular remodeling in the SHR group were attenuated by atorvastatin treatment. Echocardiography examination exhibited that SHR with atorvastatin treatment showed an LV wall thickness that was obviously lower than that of water-treated SHR. In hypertrophic myocardium, accompanied by increasing C/EBPβ expression and the percentage of TUNEL-positive cells, the expression of Bcl-2/Bax ratio, PGC-1α and UCP3 were reduced, all of which could be abrogated by treatment with atorvastatin for 6 weeks. Conclusion: This study further confirmed that atorvastatin could attenuate myocardial hypertrophy and remodeling in SHR by inhibiting apoptosis and reversing changes in mitochondrial metabolism. The C/EBPβ/PGC-1α/UCP3 signaling pathway might also be important for elucidating the beneficial pleiotropic effects of atorvastatin on myocardial hypertrophy.
Tagging Functional Polymorphism in 3’ Untranslated Region of Methylene Tetrahydrofolate Reductase and Risk of Ischemic Stroke
Authors: Shi Jiajia , He Wei , Wang Yu , Hua Jiajia
Published: April 2018

Background/Aims: The association between genetic polymorphisms in the exon or untranslated region of the methylenetetrahydrofolate reductase gene (MTHFR) and the risk of human ischemic stroke (IS) has been well-documented. In this study, we focused on a polymorphism previously screened by high-throughput analysis and on its potential function in patients with IS Methods: This hospital-based case-control study was conducted in 400 patients and 400 healthy volunteers. Genotyping was conducted using TaqMan probes. Potential interactions were predicted by multiple bioinformatics analysis. Relative expression levels of MTHFR were detected confirmed by dual-luciferase assay. Results: The MTHFR polymorphism rs142884651 was significantly associated with a decreased risk of IS compared with the wild-type GA genotype (P = 0.02) and AA genotype (P = 0.001). According to bioinformatics analysis and luciferase assay, this polymorphism could attenuate the binding of let-7f and miR-196a (P = 0.021 and 0.019, respectively) leading to the accumulation of MTHFR and degradation of serum homocysteine, and resulting in a better IS outcome. Conclusion: This study demonstrated that the MTHFR rs142884651 polymorphism is associated with a decreased risk of IS and may act as a biomarker of short-term outcome in patients with IS.
Long Intergenic Noncoding RNA 00152 Promotes Glioma Cell Proliferation and Invasion by Interacting with MiR-16
Authors: Chen Xin , Li Deheng , Gao Yang , Tang Wei , IW Lao , Cao Yiqun , Hao Bin
Published: April 2018

Background/Aims: Long noncoding RNAs (lncRNAs) are a novel class of protein-noncoding transcripts that are aberrantly expressed in multiple diseases including cancers. LINC00152 has been identified as an oncogene involved in many kinds of cancer; however, its expression pattern and function in human glioma remain unclear. Methods: Quantitative real-time polymerase chain reaction was carried out to measure LINC00152 expression in human glioma cell lines and tissues. CCK-8 and EdU assays were performed to assess cell proliferation, and scratch assays and Transwell assays were used to assess cell migration and invasion, respectively. Luciferase reporter assays were carried out to determine the interaction between miR-16 and LINC00152. In vivo experiments were conducted to assess tumor formation. Results: LINC00152 was found to be significantly upregulated in human glioma cell lines and clinical samples. Knockdown of LINC00152 suppressed glioma cell proliferation, migration, and invasion in vitro. In vivo assays in nude mice confirmed that LINC00152 knockdown inhibits tumor growth. Furthermore, mechanistic investigation showed that LINC00152 binds to miR-16 in a sequence-specific manner and suppresses its expression. miR-16 inhibition strongly attenuated LINC00152 knockdown–mediated suppressive effects on proliferation, migration, and invasion. Moreover, LINC00152 induced BMI1 expression by sponging miR-16; this effect further promoted glioma cell proliferation and invasion. Conclusion: We regard LINC00152 as an oncogenic lncRNA promoting glioma cell proliferation and invasion and as a potential target for human glioma treatment.
Characterization and Analysis of Whole Transcriptome of Giant Panda Spleens: Implying Critical Roles of Long Non-Coding RNAs in Immunity
Authors: Peng Rui , Liu Yuliang , Cai Zhigang , Shen Fujun , Chen Jiasong , Hou Rong , Zou Fangdong
Published: April 2018

Background/Aims: Giant pandas, an endangered species, are a powerful symbol of species conservation. Giant pandas may suffer from a variety of diseases. Owing to their highly specialized diet of bamboo, giant pandas are thought to have a relatively weak ability to resist diseases. The spleen is the largest organ in the lymphatic system. However, there is little known about giant panda spleen at a molecular level. Thus, clarifying the regulatory mechanisms of spleen could help us further understand the immune system of the giant panda as well as its conservation. Methods: The two giant panda spleens were from two male individuals, one newborn and one an adult, in a non-pathological condition. The whole transcriptomes of mRNA, lncRNA, miRNA, and circRNA in the two spleens were sequenced using the Illumina HiSeq platform. EBseq and IDEG6 were used to observe the differentially expressed genes (DEGs) between these two spleens. Gene Ontology and KEGG analyses were used to annotate the function of DEGs. Furthermore, networks between non-coding RNAs and protein-coding genes were constructed to investigate the relationship between non-coding RNAs and immune-associated genes. Results: By comparative analysis of the whole transcriptomes of these two spleens, we found that one of the major roles of lncRNAs could be involved in the regulation of immune responses of giant panda spleens. In addition, our results also revealed that microRNAs and circRNAs may have evolved to regulate a large set of biological processes of giant panda spleens, and circRNAs may function as miRNA sponges. Conclusion: To our knowledge, this is the first report of lncRNAs and circRNAs in giant panda, which could be a useful resource for further giant panda research. Our study reveals the potential functional roles of miRNAs, lncRNAs, and circRNAs in giant panda spleen.
Cinobufagin Induces Apoptosis in Osteosarcoma Cells Via the Mitochondria-Mediated Apoptotic Pathway
Authors: Dai Guo , Zheng Di , Guo Weichun , Yang Jian , Cheng An-yuan
Published: April 2018

Background/Aims: Osteosarcoma is a common primary malignant bone tumor that mainly occurs in childhood and adolescence. Despite developments in the diagnosis and treatment of osteosarcoma, the prognosis is still very poor. Cinobufagin is an active component in the anti-tumor Chinese medicine called “Chan Su”, and we previously revealed that cinobufagin induced apoptosis and reduced the viability of osteosarcoma cells; however, the underlying mechanism remains to be elucidated. Herein, the present study was undertaken to illuminate the molecular mechanism of cinobufagin-induced apoptosis of osteosarcoma cell. Methods: U2OS and 143B cells were treated with different concentrations of cinobufagin. Cell viability, colony formation ability and morphological changes were assessed by a CCK-8 assay, a clonogenic assay and light microscopy, respectively. Cell apoptosis was detected by Hoechst 33258 and Annexin V-FITC/PI staining. Reactive oxygen species (ROS) and mitochondrial membrane potential (ΔΨm) were determined by flow cytometry. Glutathione (GSH) levels were detected by a GSH and GSSG assay kit. The levels of apoptosis-related proteins were determined by western blotting, and 143B cells were introduced to establish a xenograft tumor model. The effect of cinobufagin on osteosarcoma was further investigated in vivo. Results: Our results showed that cinobufagin significantly reduced the viability of U2OS and 143B cells in vitro in a dose-and time-dependent manner. In addition, cinobufagin-induced apoptosis in U2OS and 143B cells was concentration-dependent. Moreover, we found that cinobufagin treatment increased the level of intracellular ROS, decreased ΔΨm, reduced GSH and inhibited GSH reductase (GR). The effects of cinobufagin on cell proliferation, apoptosis, ROS generation and ΔΨm loss were dramatically reversed when the cells were pretreated with the thiol-antioxidants NAC or GSH. Moreover, cinobufagin treatment increased the expression of the pro-apoptotic protein Bax and decreased the expression of the anti-apoptitic protein Bcl-2, thus altering the ratio of Bax to Bcl-2. Furthermore, Cinobufagin treatment caused cytochrome c release from the mitochondria to cytoplasm, thus increasing the protein levels of cleaved-caspase family members to induce apoptosis. Ac-DEVD-CHO or Z-LEHD-FMK significantly reduced cinobufagin-induced apoptosis. Finally, a subcutaneous xenograft animal study verified that cinobufagin also significantly suppressed osteosarcoma growth in vivo. Conclusions: Our present data demonstrated that cinobufagin triggered cell apoptosis in osteosarcoma cells via the intrinsic mitochondria-dependent apoptosis pathway by the accumulation of ROS and the loss of ΔΨm. In an in vivo subcutaneous xenograft model, cinobufagin exhibited excellent tumor inhibitory effects. These results suggest that cinobufagin might potentially be further developed as an anti-tumor candidate for treating osteosarcoma patients in the clinic.
Heme Oxygenase-1 in Macrophages Drives Septic Cardiac Dysfunction via Suppressing Lysosomal Degradation of Inducible Nitric Oxide Synthase
Authors: Jia Liangliang , Wang Yaping , Wang Yidong , Ma Yuankun , Shen Jian , Fu Zurong , Wu Yue , Su Sheng’an , Zhang Yuhao , Cai Zhejun , Wang Jian’an , Xiang Meixiang
Published: April 2018

Rationale:

To date, our understanding of the role of HO-1 (heme oxygenase-1) in inflammatory diseases has mostly been limited to its catalytic function and the potential for its heme-related catabolic products to suppress inflammation and oxidative stress. Whether and how HO-1 in macrophages plays a role in the development of septic cardiac dysfunction has never been explored.

Objective:

Here, we investigated the role of macrophage-derived HO-1 in septic cardiac dysfunction.

Methods and Results:

Intraperitoneal injection of lipopolysaccharide significantly activated HO-1 expression in cardiac infiltrated macrophages. Surprisingly, we found that myeloid conditional HO-1 deletion in mice evoked resistance to lipopolysaccharide-triggered septic cardiac dysfunction and lethality in vivo, which was accompanied by reduced cardiomyocyte apoptosis in the septic hearts and decreased peroxynitrite production and iNOS (inducible NO synthase) in the cardiac infiltrated macrophages, whereas proinflammatory cytokine production and macrophage infiltration were unaltered. We further demonstrated that HO-1 suppression abolished the lipopolysaccharide-induced iNOS protein rather than mRNA expression in macrophages. Moreover, we confirmed that the inhibition of HO-1 promoted iNOS degradation through a lysosomal rather than proteasomal pathway in macrophages. Suppression of the lysosomal degradation of iNOS by bafilomycin A1 drove septic cardiac dysfunction in myeloid HO-1–deficient mice. Mechanistically, we demonstrated that HO-1 interacted with iNOS at the flavin mononucleotide domain, which further prevented iNOS conjugation with LC3 (light chain 3) and subsequent lysosomal degradation in macrophages. These effects were independent of HO-1’s catabolic products: ferrous ion, carbon monoxide, and bilirubin.

Conclusions:

Our results indicate that HO-1 in macrophages drives septic cardiac dysfunction. The mechanistic insights provide potential therapeutic targets to treat septic cardiac dysfunction.
Rearrangement of the Protein Phosphatase 1 Interactome During Heart Failure Progression
Authors: Chiang David Y. , Alsina Katherina M. , Corradini Eleonora , Fitzpatrick Martin , Ni Li , Lahiri Satadru K. , Reynolds Julia O. , Pan Xiaolu , Scott Larry , Heck Albert J.R. , Wehrens Xander H.T.
Published: April 2018

Background:

Heart failure (HF) is a complex disease with a rising prevalence despite advances in treatment. Protein phosphatase 1 (PP1) has long been implicated in HF pathogenesis, but its exact role is both unclear and controversial. Most previous studies measured only the PP1 catalytic subunit (PP1c) without investigating its diverse set of interactors, which confer localization and substrate specificity to the holoenzyme. In this study, we define the PP1 interactome in cardiac tissue and test the hypothesis that this interactome becomes rearranged during HF progression at the level of specific PP1c interactors.

Methods:

Mice were subjected to transverse aortic constriction and grouped on the basis of ejection fraction into sham, hypertrophy, moderate HF (ejection fraction, 30%–40%), and severe HF (ejection fraction <30%). Cardiac lysates were subjected to affinity purification with anti-PP1c antibodies followed by high-resolution mass spectrometry. PP1 regulatory subunit 7 (Ppp1r7) was knocked down in mouse cardiomyocytes and HeLa cells with adeno-associated virus serotype 9 and siRNA, respectively. Calcium imaging was performed on isolated ventricular myocytes.

Results:

Seventy-one and 98 PP1c interactors were quantified from mouse cardiac and HeLa lysates, respectively, including many novel interactors and protein complexes. This represents the largest reproducible PP1 interactome data set ever captured from any tissue, including both primary and secondary/tertiary interactors. Nine PP1c interactors with changes in their binding to PP1c were strongly associated with HF progression, including 2 known (Ppp1r7 and Ppp1r18) and 7 novel interactors. Within the entire cardiac PP1 interactome, Ppp1r7 had the highest binding to PP1c. Cardiac-specific knockdown in mice led to cardiac dysfunction and disruption of calcium release from the sarcoplasmic reticulum.

Conclusions:

PP1 is best studied at the level of its interactome, which undergoes significant rearrangement during HF progression. The 9 key interactors that are associated with HF progression may represent potential targets in HF therapy. In particular, Ppp1r7 may play a central role in regulating the PP1 interactome by acting as a competitive molecular “sponge” of PP1c.
Genetic and Environmental Contributions to the Covariation Between Cardiometabolic Traits
Authors: Chen Xu , Kuja‐Halkola Ralf , Chang Zheng , Karlsson Robert , Hägg Sara , Svensson Per , Pedersen Nancy L. , Magnusson Patrik K. E.
Published: April 2018

Background

The variation and covariation for many cardiometabolic traits have been decomposed into genetic and environmental fractions, by using twin or single‐nucleotide polymorphism (
SNP
) models. However, differences in population, age, sex, and other factors hamper the comparison between twin‐ and
SNP
‐based estimates.

Methods and Results

Twenty‐four cardiometabolic traits and 700,000 genotyped
SNP
s were available in the study base of 10 682 twins from TwinGene cohort. For the 27 highly correlated pairs (absolute phenotypic correlation coefficient ≥0.40), twin‐based bivariate structural equation models were performed in 3870 complete twin pairs, and
SNP
‐based bivariate genomic relatedness matrix restricted maximum likelihood methods were performed in 5779 unrelated individuals. In twin models, the model including additive genetic variance and unique/nonshared environmental variance was the best‐fitted model for 7 pairs (5 of them were between blood pressure traits); the model including additive genetic variance, common/shared environmental variance, and unique/nonshared environmental variance components was best fitted for 4 pairs, but estimates of shared environment were close to zero; and the model including additive genetic variance, dominant genetic variance, and unique/nonshared environmental variance was best fitted for 16 pairs, in which significant dominant genetic effects were identified for 13 pairs (including all 9 obesity‐related pairs). However,
SNP
models did not identify significant estimates of dominant genetic effects for any pairs. In the paired
t
test, twin‐ and
SNP
‐based estimates of additive genetic correlation were not significantly different (both were 0.67 on average), whereas the nonshared environmental correlations from these 2 models differed slightly from each other (on average, twin‐based estimate=0.64 and SNP‐based estimate=0.68).

Conclusions

Beside additive genetic effects and nonshared environment, nonadditive genetic effects (dominance) also contribute to the covariation between certain cardiometabolic traits (especially for obesity‐related pairs); contributions from the shared environment seem to be weak for their covariation in TwinGene samples.
Planning Complexity Registers as a Cost in Metacontrol
Authors: Kool Wouter , Gershman Samuel J. , Cushman Fiery A.
Published: April 2018

Decision-making algorithms face a basic tradeoff between accuracy and effort (i.e., computational demands). It is widely agreed that humans can choose between multiple decision-making processes that embody different solutions to this tradeoff: Some are computationally cheap but inaccurate, whereas others are computationally expensive but accurate. Recent progress in understanding this tradeoff has been catalyzed by formalizing it in terms of model-free (i.e., habitual) versus model-based (i.e., planning) approaches to reinforcement learning. Intuitively, if two tasks offer the same rewards for accuracy but one of them is much more demanding, we might expect people to rely on habit more in the difficult task: Devoting significant computation to achieve slight marginal accuracy gains would not be “worth it.” We test and verify this prediction in a sequential reinforcement learning task. Because our paradigm is amenable to formal analysis, it contributes to the development of a computational model of how people balance the costs and benefits of different decision-making processes in a task-specific manner; in other words, how we decide when hard thinking is worth it.
Magnifying the View of the Hand Changes Its Cortical Representation. A Transcranial Magnetic Stimulation Study
Authors: Ambron Elisabetta , White Nicole , Faseyitan Olufunsho , Kessler Sudha K. , Medina Jared , Coslett H. Branch
Published: April 2018

Changes in the perceived size of a body part using magnifying lenses influence tactile perception and pain. We investigated whether the visual magnification of one's hand also influences the motor system, as indexed by transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs). In Experiment 1, MEPs were measured while participants gazed at their hand with and without magnification of the hand. MEPs were significantly larger when participants gazed at a magnified image of their hand. In Experiment 2, we demonstrated that this effect is specific to the hand that is visually magnified. TMS of the left motor cortex did not induce an increase of MEPs when participants looked at their magnified left hand. Experiment 3 was performed to determine if magnification altered the topography of the cortical representation of the hand. To that end, a 3 × 5 grid centered on the cortical hot spot (cortical location at which a motor threshold is obtained with the lowest level of stimulation) was overlaid on the participant's MRI image, and all 15 sites in the grid were stimulated with and without magnification of the hand. We confirmed the increase in the MEPs at the hot spot with magnification and demonstrated that MEPs significantly increased with magnification at sites up to 16.5 mm from the cortical hot spot. In Experiment 4, we used paired-pulse TMS to measure short-interval intracortical inhibition and intracortical facilitation. Magnification was associated with an increase in short-interval intracortical inhibition. These experiments demonstrate that the visual magnification of one's hand induces changes in motor cortex excitability and generates a rapid remapping of the cortical representation of the hand that may, at least in part, be mediated by changes in short-interval intracortical inhibition.
The Neotropical mite genus Neopilizetes (Oribatida: Galumnidae): redescription of N. neotropicus, rediagnosis of the genus, and descriptions of four new species
Authors: AMORIM SAULO S. , NORTON ROY A. , OLIVEIRA ANIBAL R.
Published: April 2018

Neopilizetes is a genus of the oribatid mite family Galumnidae that was first characterized by having well-developed setae, a dorsosejugal suture, and raised striae on the prodorsum and notogaster. It was proposed to accommodate Pilizetes neotropicus Balogh & Mahunka 1978 from Brazil—the only supposed Pilizetes species known outside the Ethiopian Region—and it has remained monotypic. We found adults of N. neotropicus and four related species in soil–litter interface samples of a single cacao plantation in Ilhéus, Bahia, Brazil. Herein we: redescribe N. neotropicus; describe Neopilizetes thoracicus n. sp., Neopilizetes tigris n. sp., Neopilizetes triumnasus n. sp. and Neopilizetes unumnasus n. sp., and use this information to develop a new concept and expanded diagnosis of Neopilizetes. A key to the five species is provided, and we offer reasons for rejecting the classification of Neopilizetes as a subgenus of Pilizetes.
A Dynamically Consistent, Multivariable Ocean Climatology
Authors: Fukumori Ichiro , Heimbach Patrick , Ponte Rui M. , Wunsch Carl
Published: April 2018

A dynamically consistent 20-yr average ocean climatology based on monthly values during the years 1994–2013 has been produced from the most recent state estimate of the Estimating the Circulation and Climate of the Ocean (ECCO) project, globally, top to bottom. The estimate was produced from a least squares fit of a free-running ocean general circulation model to almost all available near-global data. Data coverage in space and time during this period is far more homogeneous than in any earlier interval and includes CTD, elephant seal, and Argo temperature and salinity profiles; sea ice coverage; full altimetric and gravity-field coverage; satellite sea surface temperatures; and the initializing meteorological coverage from the European Centre for Medium-Range Weather Forecasts (ECMWF) interim reanalysis (ERA-Interim). Dominant remaining data inhomogeneity arises from increasing coverage from the Argo profiles from about 2000 to the present. The state estimate exactly satisfies the primitive equations of the free-running Massachusetts Institute of Technology General Circulation Model (MITgcm) at all times and hence produces values satisfying the fundamental conservation laws of energy, freshwater, and so forth, permitting its use for climate change studies. Quantities such as calculated heat content depend upon all observations, not just temperature, for example, altimetric height and meteorological exchanges. Output files are publicly available in Network Common Data Form (netCDF) and MATLAB form and include hydrographic variables, three components of velocity, and pressure at all depths, as well as other variables, including inferred air–sea momentum and buoyancy fluxes, 3D mixing parameters, and sea ice cover.
Increased Frequency of Summer Extreme Heat Waves over Texas Area Tied to the Amplification of Pacific Zonal SST Gradient
Authors: Deng Kaiqiang , Ting Mingfang , Yang Song , Tan Yaheng
Published: April 2018

Summer extreme heat waves (EHWs) over the Texas area and their trend are investigated using observations and atmospheric general circulation model (AGCM) output. There is a positive linear trend in Texas EHW days for the period 1979–2015. While the interannual variability of the Texas EHWs is linked to ENSO conditions, the upward trend in Texas EHWs is found to be significantly associated with the tropical Pacific zonal SST gradient (PZSSTG). The amplification of PZSSTG leads to both enhanced convection in the western Pacific and suppressed convection in the central-eastern Pacific (i.e., La Niña–like pattern), both of which can induce anomalous anticyclones over the Texas area through two distinct planetary wave trains in the antecedent spring. As a result, anomalously sinking motions and divergent water vapor flux appear over the Texas area, which reduce precipitation and increase downward solar radiation, leading to dry and hot soil that favors the occurrence of Texas summer EHWs. In addition, all AGCMs using observed SSTs as boundary conditions were able to simulate the observed decreasing trend in Texas summer precipitation and the observed increasing trend in Texas summer surface air temperature. The observed relationships between winter PZSSTG and the following spring–summer Texas precipitation/temperature were also reproduced by these models, where the intensified PZSSTG tended to reduce the Texas precipitation while increasing the surface air temperature.
Influence of Intraseasonal–Interannual Oscillations on Tropical Cyclone Genesis in the Western North Pacific
Authors: Chen Jau-Ming , Wu Ching-Hsuan , Chung Pei-Hsuan , Sui Chung-Hsiung
Published: April 2018

Influences of intraseasonal–interannual oscillations on tropical cyclone (TC) genesis are evaluated by productivity of TC genesis ( PTCG) from the developing (TC d) and nondeveloping (TC n) precursory tropical disturbances (PTDs). A PTD is identified by a cyclonic tropical disturbance with a strong-enough intensity, a large-enough maximum center, and a long-enough lifespan. The percentage value of PTDs evolving into TC d is defined as PTCG. The analysis is performed over the western North Pacific (WNP) basin during the 1990–2014 warm season (May–September). The climatological PTCG in the WNP basin is 0.35. Counted in a common period, mean numbers of PTDs in the favorable and unfavorable conditions of climate oscillations for TC genesis [such as equatorial Rossby waves (ERWs), the Madden–Julian oscillation (MJO), and El Niño–Southern Oscillation (ENSO)], all exhibit a stable value close to the climatological mean [~31 (100 days)−1]. However, PTCG increases (decreases) during the phases of positive-vorticity (negative-vorticity) ERWs, the active (inactive) MJO, and El Niño (La Niña) years. PTCG varies from 0.17 in the most unfavorable environment (La Niña, inactive MJO, and negative-vorticity ERW) to 0.56 in the most favorable environment (El Niño, active MJO, and positive-vorticity ERW). ERWs are most effective in modulating TC genesis, especially in the negative-vorticity phases. Overall, increased PTCG is facilitated with strong and elongated 850-hPa relative vorticity overlapping a cyclonic shear line pattern, while decreased PTCG is related to weak relative vorticity. Relative vorticity acts as the most important factor to modulate PTCG, when compared with vertical wind shear and 700-hPa relative humidity.
Warming is Driving Decreases in Snow Fractions While Runoff Efficiency Remains Mostly Unchanged in Snow-Covered Areas of the Western United States
Authors: McCabe Gregory J. , Wolock David M. , Valentin Melissa
Published: April 2018

Winter snowfall and accumulation is an important component of the surface water supply in the western United States. In these areas, increasing winter temperatures T associated with global warming can influence the amount of winter precipitation P that falls as snow S. In this study we examine long-term trends in the fraction of winter P that falls as S (Sfrac) for 175 hydrologic units (HUs) in snow-covered areas of the western United States for the period 1951–2014. Because S is a substantial contributor to runoff R across most of the western United States, we also examine long-term trends in water-year runoff efficiency [computed as water-year R/water-year P (Reff)] for the same 175 HUs. In that most S records are short in length, we use model-simulated S and R from a monthly water balance model. Results for Sfrac indicate long-term negative trends for most of the 175 HUs, with negative trends for 139 (~79%) of the HUs being statistically significant at a 95% confidence level (p = 0.05). Additionally, results indicate that the long-term negative trends in Sfrac have been largely driven by increases in T. In contrast, time series of Reff for the 175 HUs indicate a mix of positive and negative long-term trends, with few trends being statistically significant (at p = 0.05). Although there has been a notable shift in the timing of R to earlier in the year for most HUs, there have not been substantial decreases in water-year R for the 175 HUs.
Influence of a Great Plains Urban Environment on a Simulated Supercell
Authors: Reames Larissa J. , Stensrud David J.
Published: April 2018

The effect of urban areas on weakly forced precipitation systems has been studied extensively. However, interactions between urban areas and strongly forced convection, such as supercells, remain relatively unexamined. The present study uses simulations of a supercell to quantify the impacts of a large plains urban area on the evolution and strength of a supercell. An initial ensemble of simulations (CTRLE) of a supercell over homogeneous land use is performed using the WRF-ARW Model. Additionally, 108 simulations are conducted in which the land-use pattern of Dallas–Ft. Worth, Texas, is placed inside the model domain, with the city center shifted to be in or near the path of the supercell. Simulations with urban areas are compared to CTRLE, with the aid of hierarchical clustering analysis to form statistically similar groups of simulations. Clustering analyses identify groups of ensemble members with closely located urban areas that have similar patterns of 0–1-km updraft helicity and near-surface minimum temperature and maximum wind speeds. Comparison of these groups of ensemble members to CTRLE suggests the urban area has a significant impact on storm characteristics, particularly on low-level rotation and mesocyclone track. Simulations where the storm passes to the north of or directly over the city center late in its life cycle deviate most significantly from CTRLE. In these members, low-and midlevel mesocyclone strength increases, and the mesocyclone tracks farther south when compared to CTRLE.
The Effects of Social Connections on Evacuation Decision Making during Hurricane Irma
Authors: Collins Jennifer , Ersing Robin , Polen Amy , Saunders Michelle , Senkbeil Jason
Published: April 2018

This study investigates the influence of individuals’ social connections in their decision to either evacuate or not evacuate in the days preceding the landfall of Hurricane Irma. Using Hurricane Irma in September 2017 as a case study, a survey was conducted on two groups (those who evacuated and those who did not evacuate) to assess people’s social connections specifically examining three dimensions: dependability, density, and diversity. These variables, together with socioeconomic variables (e.g., race/ethnicity, age, education), were considered in order to better explain the influences on evacuation decision-making. To collect accurate ephemeral decision-making data from evacuees, the surveys were completed during the evacuation for those who evacuated and shortly after the passage of Hurricane Irma for those who did not evacuate. Through statistical analyses, it was concluded that density and diversity of people’s social networks played a significant role in the decision to evacuate or not, with evacuees having more dense and diverse relationships. On the other hand, the perceived dependability of a person’s social connections (i.e., their perceived access to resources and support) did not significantly impact the decision to evacuate for Hurricane Irma. This study has important implications for adding to the knowledge base on community-based sustainable disaster preparedness and resilience.