bluuebunny/crossref_metadata_2025 huggingface dataset:
Providing Accountability in Heterogeneous Systems-on-Chip
Authors: Kalayappan Rajshekar , Sarangi Smruti R.
Published: September 2018

When modern systems-on-chip (SoCs), containing designs from different organizations, miscompute or underperform in the field, discerning the responsible component is a non-trivial task. A perfectly accountable system is one in which the on-chip component at fault is always unambiguously detected. The achievement of
accountability
can be greatly aided by the collection of runtime information that captures the events in the system that led to the error. Such information collection must be fair and impartial to all parties. In this article, we prove that logging messages communicated between components from different organizations is sufficient to provide accountability, provided the logs are authentic. We then construct a solution based on this premise, with an on-chip trusted auditing system to authenticate the logs. We present a thorough design of the auditing system, and demonstrate that its performance overhead is a mere 0.49%, and its area overhead is a mere 0.194% (in a heterogeneous 48 core, 400
mm
2
chip). We also demonstrate the viability of this solution using three representative bugs found in popular commercial SoCs.
Energy-Efficient Real-Time Scheduling of DAG Tasks
Authors: Bhuiyan Ashikahmed , Guo Zhishan , Saifullah Abusayeed , Guan Nan , Xiong Haoyi
Published: September 2018

This work studies energy-aware real-time scheduling of a set of sporadic Directed Acyclic Graph (DAG) tasks with implicit deadlines. While meeting all real-time constraints, we try to identify the best task allocation and execution pattern such that the average power consumption of the whole platform is minimized. To our knowledge, this is the first work that addresses the power consumption issue in scheduling multiple DAG tasks on multi-cores and allows intra-task processor sharing. First, we adapt the decomposition-based framework for federated scheduling and propose an energy-sub-optimal scheduler. Then, we derive an approximation algorithm to identify processors to be merged together for further improvements in energy-efficiency. The effectiveness of the proposed approach is evaluated both theoretically via approximation ratio bounds and also experimentally through simulation study. Experimental results on randomly generated workloads show that our algorithms achieve an energy saving of 60% to 68% compared to existing DAG task schedulers.
Packet Aggregation Real-Time Scheduling for Large-Scale WIA-PA Industrial Wireless Sensor Networks
Authors: Jin Xi , Guan Nan , Xia Changqing , Wang Jintao , Zeng Peng
Published: September 2018

The IEC standard WIA-PA is a communication protocol for industrial wireless sensor networks. Its special features, including a hierarchical topology, hybrid centralized-distributed management and packet aggregation make it suitable for large-scale industrial wireless sensor networks. Industrial systems place large real-time requirements on wireless sensor networks. However, the WIA-PA standard does not specify the transmission methods, which are vital to the real-time performance of wireless networks, and little work has been done to address this problem.

In this article, we propose a real-time aggregation scheduling method for WIA-PA networks. First, to satisfy the real-time constraints on dataflows, we propose a method that combines the real-time theory with the classical bin-packing method to aggregate original packets into the minimum number of aggregated packets. The simulation results indicate that our method outperforms the traditional bin-packing method, aggregating up to 35% fewer packets, and improves the real-time performance by up to 10%. Second, to make it possible to solve the scheduling problem of WIA-PA networks using the classical scheduling algorithms, we transform the ragged time slots of WIA-PA networks to a universal model. In the simulation, a large number of WIA-PA networks are randomly generated to evaluate the performances of several real-time scheduling algorithms. By comparing the results, we obtain that the earliest deadline first real-time scheduling algorithm is the preferred method for WIA-PA networks.
Divergent Biological Response to Neoadjuvant Chemotherapy in Muscle-invasive Bladder Cancer
Authors: Seiler Roland , Gibb Ewan A. , Wang Natalie Q. , Oo Htoo Zarni , Lam Hung-Ming , van Kessel Kim E. , Voskuilen Charlotte S. , Winters Brian , Erho Nicholas , Takhar Mandeep M. , Douglas James , Vakar-Lopez Funda , Crabb Simon J. , van Rhijn Bas W.G. , Fransen van de Putte Elisabeth E. , Zwarthoff Ellen C. , Thalmann George N. , Davicioni Elai , Boormans Joost L. , Dall'Era Marc , van der Heijden Michiel S. , Wright Jonathan L. , Black Peter C.
Published: September 2018

Purpose:

After cisplatin-based neoadjuvant chemotherapy (NAC), 60% of patients with muscle-invasive bladder cancer (MIBC) still have residual invasive disease at radical cystectomy. The NAC-induced biological alterations in these cisplatin-resistant tumors remain largely unstudied.

Experimental Design:

Radical cystectomy samples were available for gene expression analysis from 133 patients with residual invasive disease after cisplatin-based NAC, of whom 116 had matched pre-NAC samples. Unsupervised consensus clustering (CC) was performed and the consensus clusters were investigated for their biological and clinical characteristics. Hematoxylin & Eosin and IHC on tissue microarrays were used to confirm tissue sampling and gene expression analysis.

Results:

Established molecular subtyping models proved to be inconsistent in their classification of the post-NAC samples. Unsupervised CC revealed four distinct consensus clusters. The CC1-Basal and CC2-Luminal subtypes expressed genes consistent with a basal and a luminal phenotype, respectively, and were similar to the corresponding established pretreatment molecular subtypes. The CC3-Immune subtype had the highest immune activity, including T-cell infiltration and checkpoint molecule expression, but lacked both basal and luminal markers. The CC4-Scar–like subtype expressed genes associated with wound healing/scarring, although the proportion of tumor cell content in this subtype did not differ from the other subtypes. Patients with CC4-Scar–like tumors had the most favorable prognosis.

Conclusions:

This study expands our knowledge on MIBC not responding to cisplatin by suggesting molecular subtypes to understand the biology of these tumors. Although these molecular subtypes imply consequences for adjuvant treatments, this ultimately needs to be tested in clinical trials.
Sorafenib and Carfilzomib Synergistically Inhibit the Proliferation, Survival, and Metastasis of Hepatocellular Carcinoma
Authors: Jiang Chao , Xu Rui , Li Xiao-Xing , Zhou Yu-Feng , Xu Xiao-Yi , Yang Yang , Wang Hui-Yun , Zheng X.F. Steven
Published: September 2018

Hepatocellular carcinoma (HCC) is one of the most common and deadly human cancers. The 5-year survival rate is very low. Unfortunately, there are few efficacious therapeutic options. Until recently, Sorafenib has been the only available systemic drug for advanced HCC. However, it has very limited survival benefits, and new therapies are urgently needed. In this study, we investigated the anti-HCC activity of carfilzomib, a second-generation, irreversible proteasome inhibitor, as a single agent and in combination with sorafenib. In vitro, we found that carfilzomib has moderate anticancer activity toward liver cancer cells, but strongly enhances the ability of sorafenib to suppress HCC cell growth, proliferation, migration, invasion, and survival. Remarkably, the drug combination exhibits even more potent antitumor activity when tested in animal tumor models. Mechanistically, the combined treatment activates caspase-dependent and endoplasmic reticulum stress/CHOP-mediated apoptotic pathways, and suppresses epithelial–mesenchymal transition. In conclusion, our results demonstrate that the combination of carfilzomib and sorafenib has synergistic antitumor activities against HCC, providing a potential therapeutic strategy to improve the mortality and morbidity of HCC patients.
The Aged Microenvironment Influences the Tumorigenic Potential of Malignant Prostate Epithelial Cells
Authors: Bianchi-Frias Daniella , Damodarasamy Mamatha , Hernandez Susana A. , Gil da Costa Rui M. , Vakar-Lopez Funda , Coleman Ilsa M. , Reed May J. , Nelson Peter S.
Published: September 2018

The incidence of prostate cancer is directly linked to age, but age-associated changes that facilitate prostate cancer development and progression are poorly understood. This study investigated age-related changes in the prostate microenvironment for their influence on prostate cancer behavior. Prostate cancer cells implanted orthotopically into the prostate demonstrated accelerated tumor growth in aged compared with young mice. Metastatic lesions following intravenous injection were also more numerous in aged mice. Tumors from young and aged mice showed no significant differences concerning their proliferation index, apoptosis, or angiogenesis. However, analysis of tumor-infiltrating immune cells by IHC and RNA sequencing (RNA-seq) revealed elevated numbers of macrophages in prostates from aged mice, which are quickly polarized towards a phenotype resembling protumorigenic tumor-associated macrophages upon tumor cell engraftment. Older patients with prostate cancer (>60 years old) in The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) dataset displayed higher expression of macrophage markers (CD163 and VSIG4) which associated with higher rates of biochemical relapse. Remodeling of the collagenous extracellular matrix (ECM) was associated with prostate cancer growth and invasion in the aged microenvironment. Moreover, the collagen matrix extracted from aged mice enhanced the invasiveness and proliferation of prostate cancer cells in vitro. Together, these results demonstrate that the aged prostatic microenvironment can regulate the growth and metastasis of malignant prostate cells, highlighting the role of resident macrophages and their polarization towards a protumorigenic phenotype, along with remodeling of the ECM.

Implications:

These findings demonstrate the importance of age-associated tumor microenvironment alterations in regulating key aspects of prostate cancer progression.
Immunohistochemical and Molecular Analyses Focusing on Mesenchymal Cells in Papillary Thyroid Carcinoma with Desmoid-Type Fibromatosis
Authors: Takada Nami , Mussazhanova Zhanna , Hirokawa Mitsuyoshi , Nakashima Masahiro , Miyauchi Akira
Published: September 2018

Objective: This study was designed to evaluate the prevalence of CTNNB1 (β-catenin) mutations in cases of papillary thyroid carcinoma with desmoid-type fibromatosis (PTC-DTF) expressing aberrant nuclear and cytoplasmic immunoreactivity for β-catenin. Methods: Eight cases of PTC-DTF were available for this study. Immunohistochemistry for β-catenin and BRAFV600E was performed. CTNNB1 and BRAFV600E mutations were also evaluated by direct sequencing. Results: For β-catenin, although we could demonstrate aberrant nuclear and cytoplasmic immunoreactivity in DTF components in all cases, suggesting activated Wnt signaling, direct sequencing revealed a missense mutation, c.121A>G (p.T41A), in exon 3 in only one case, and no mutations in exons 3, 4, and 5 in the other cases. In the BRAFV600E analyses, immunohistochemistry revealed positive staining in the carcinoma cells but not DTF components of all cases. These findings were subsequently validated by direct sequencing. Conclusion: This study suggests the significance of the BRAFV600E mutation and activation of Wnt signaling pathway in the carcinoma cells and DTF components, respectively. We believe that the CTNNB1 mutations are not the major factor behind β-catenin translocation indicating Wnt pathway activation. Further study is required to evaluate whether molecular abnormalities other than the CTNNB1 mutation cause activation of Wnt signaling in DTF components of PTC-DTF.
Differential Expression of Cancer-Associated Fibroblast-Related Proteins in Ductal Carcinoma in situ According to Molecular Subtype and Stromal Histology
Authors: Lee Ji Hee  , Kim Hye Min , Koo Ja Seung
Published: September 2018

Objective: The purpose of this study is to investigate the expression of cancer-associated fibroblast (CAF)-related proteins and their implication in ductal carcinoma in situ (DCIS). Methods: We constructed a tissue microarray of 223 cases of DCIS and examined immunohistochemical staining for the 7 CAF-related proteins. We classified DCIS into luminal type, human epidermal growth factor receptor-2 (HER-2) type, and triple negative breast cancer (TNBC) according to the immunohistochemical results for estrogen receptor, progesterone receptor, and HER-2. We also classified DCIS into desmoplastic, normal-like, and inflammatory type according to stromal histology. Results: There were significant differences in the expression of S100A4, podoplanin, prolyl 4-hydroxylase subunit alpha 3, NG2, and PDGFRα in stromal cells of DCIS when classified according to molecular subtype. The expression rate of all CAF-related proteins in stromal cells was higher in the HER-2 type and TNBC than in the luminal type (p < 0.001). When classified according to stromal subtype, there were significant differences in the expression of all CAF-related proteins in stromal cells, with the inflammatory stromal type showing higher expression of CAF-related proteins than other stromal types. Conclusion: The expression of CAF-related proteins in stromal cells of DCIS varies according to molecular subtype and stromal type.
Comparative Analysis of Biological and Functional Properties of Bone Marrow Mesenchymal Stromal Cells Expanded in Media with Different Platelet Lysate Content
Authors: Skific Marijana , Golemovic Mirna , Crkvenac-Gornik Kristina , Vrhovac Radovan , Golubic Cepulic Branka
Published: September 2018

Due to their ability to induce immunological tolerance in the recipient, mesenchymal stromal cells (MSCs) have been utilized in the treatment of various hematological and immune- and inflammation-mediated diseases. The clinical application of MSCs implies prior in vitro expansion that usually includes the use of fetal bovine serum (FBS). The present study evaluated the effect of different platelet lysate (PL) media content on the biological properties of MSCs. MSCs were isolated from the bone marrow of 13 healthy individuals and subsequently expanded in three different culture conditions (10% PL, 5% PL, 10% FBS) during 4 passages. The cells cultured in different conditions had comparable immunophenotype, clonogenic potential, and differentiation capacity. However, MSC growth was significantly enhanced in the presence of PL. Cultures supplemented with 10% PL had a higher number of cumulative population doublings in all passages when compared to the 5% PL condition (p < 0.03). Such a difference was also observed when 10% PL and 10% FBS conditions were compared (p < 0.005). A statistically significant difference in population doubling time was determined only between the 10% PL and 10% FBS conditions (p < 0.005). Furthermore, MSCs cultured in 10% PL were able to cause a 66.9% reduction of mitogen-induced lymphocyte proliferation. Three chromosome aberrations were detected in PL conditions. Since two changes occurred in the same do nor, it is possible they were donor dependent rather than caused by the culture condition. These findings demonstrate that a 10% PL condition enables a higher yield of MSCs within a shorter time without altering MSC properties, and should be favored over the 5% PL condition.
Anatomy Revisited: Hemodialysis Catheter Malposition into the Chest
Authors: Xie Pan , Peng Kanfu , Zhang Keqin , Zhao Hongwen , Sheng Yuxiu , Tao Min , Yuan Qian , Ronco Claudio
Published: September 2018

In most situations, central catheters are implanted in the right jugular vein as initial access for hemodialysis. However, after repeated punctures, the proximal vessels become stenosed and thrombosed and misplacement is likely to occur. Correct catheter position in the vein can be easily ascertained with X-ray or cross-sectional CT imaging. In this report, we describe the case of a 77-year-old patient on chronic hemodialysis via catheter due to arteriovenous fistula dysfunction. We placed a cuffed-tunneled hemodialysis catheter in the left internal jugular vein. Malpositioning of the catheter led to perforation of the great veins and migration of the catheter tip into the chest. It is important to be aware of the risk of potential incorrect positioning of dialysis catheters. Due to the stenosis and fragility of the vessel wall, perforation may occur. In cases of doubt, correct placement of large-bore catheters via the internal jugular vein should be verified by means of appropriate imaging before hemodialysis is performed.
The in Vitro Effect of Polyvinylpyrrolidone and Citrate Coated Silver Nanoparticles on Erythrocytic Oxidative Damage and Eryptosis
Authors: Ferdous Zannatul , Beegam Sumaya , Tariq Saeed , Ali Badreldin H , Nemmar Abderrahim
Published: September 2018

Background/Aims: Silver nanoparticles (AgNPs) are increasingly used as antimicrobial agents and drug carriers in various biomedical fields. AgNPs can encounter erythrocytes either directly following intravenous injection, or indirectly via translocation from the site of administration. However, information regarding the pathophysiological effects and possible mechanism of action of AgNPs on the erythrocytes are still inadequately studied. Thus, the aim of our study was to investigate the mechanism underlying the effect of coating and concentration of AgNPs on mouse erythrocytes in vitro. Methods: We studied the interaction of polyvinylpyrrolidone (PVP) and citrate (CT) coated AgNPs (10 nm) at various concentrations (2.5, 10, 40 µg/ml) with mouse erythrocytes in vitro using various techniques including transmission electron microscopy (TEM), hemolysis, and colorimetric measurement of markers of oxidative stress comprising malondialdehyde (MDA), reduced glutathione (GSH), and catalase (CAT). Intracellular calcium (Ca2+) was determined using Fura 2AM fluorescence. Annexin V was quantified using ELISA and the caspase 3 was determined both flurometrically and by western blot technique. Results: Following incubation of the erythrocytes with AgNPs, both PVP- and CT- AgNPs induced significant and dose - dependent increase in hemolysis. TEM revealed that both PVP- and CT- AgNPs were taken up by erythrocytes. The erythrocyte susceptibility to lipid peroxidation measured by MDA was significantly increased in both PVP-and CT- AgNPs. The concentration of GSH and CAT activity were significantly decreased by both types of AgNPs. Additionally, PVP- and CT- AgNPs significantly increased intracellular Ca2+ in a dose -dependent manner. Likewise, the concentration of the cellular protein annexin V was significantly and dose - dependently enhanced by both types of AgNPs. Furthermore, PVP- and CT- AgNPs induced significant increase in calpain activity in incubated erythrocytes. Conclusion: We conclude that both PVP- and CT- AgNPs causes hemolysis, and are taken up by erythrocytes. Moreover, we demonstrated that AgNPs induces oxidative stress and eryptosis. These findings provide evidence for the potential pathophysiological effect of PVP-and CT- AgNPs on erythrocyte physiology.
A Bayesian Network Meta-Analysis Comparing the Efficacies of Eleven Novel Therapies with the Common Salvage Regimen for Relapsed or Refractory Acute Myeloid Leukemia
Authors: Huang Juan  , Gui Chunxue , Zhang Lei , Che Feifei , Wang Chunsen
Published: September 2018

Background/Aims: Acute myeloid leukemia (AML) is a relapsed and refractory hematological malignancy with a lower morbidity but higher mortality. In addition to hematopoietic stem cell transplantation, chemotherapy is used as the front-line treatment. However, the diversity of available agents and the inconsistency of outcomes of relevant trials render treatment decision-making tough. Network meta-analysis (NMA) is an efficient statistical framework that makes a comprehensive comparison and provides a valuable clinical reference. Methods: All the potential trials were retrieved from the medical database and screened according to the inclusion and exclusion criteria. The main characteristics of each trial as well as the primary outcomes, including complete remission (CR), overall response rate (ORR), overall survival (OS), and event-free survival (EFS), were extracted. In addition, the network graph was plotted to illustrate the connections among the trials involved. Comparison results in the network were exhibited in a forest plot. Furthermore, the surface under the cumulative ranking curve (SUCRA) was introduced to rank the treatments for each endpoint. Results: A total of 11 trials were selected from 1,625 identifications. No significant difference in the common treatment was observed for the endpoints CR and ORR. In terms of OS, CPX-351 (HR: 0.77, 95% CrI: 0.63, 0.94) and HiDAC plus MK-8776 (HR: 0.80, 95% CrI: 0.68, 0.93) showed a superiority over the common salvage regimen in the short term, while HiDAC plus MK-8776 (HR: 0.80, 95% CrI: 0.70, 0.93) and Ara-C plus vosaroxin (HR: 0.86, 95% CrI: 0.74, 0.99) outperformed the common salvage regimen for the 3-year OS. In addition, clofarabine plus Ara-C (HR: 0.61, 95% CrI: 0.53, 0.69) and CPX-351 (HR: 0.71, 95% CrI: 0.60, 0.83) were confirmed to be efficacious in enhancing the rate of EFS. Conclusion: Referring to the network outcome and SUCRA value, clofarabine plus Ara-C (CR: 79.05%, ORR: 80.02%) and Ara-C plus vosaroxin (CR: 75.42%, ORR: 73.43%) were potentially the top two choices for both CR and ORR. CPX-351 (1-year OS: 91.36%), HiDAC plus MK-8776 (3-year OS: 94.23%) and clofarabine plus Ara-C (1-year EFS: 97.34%) yielded the highest probabilities to be the optimal choices for 1-year OS, 3-year OS and 1-year EFS, respectively.
Exercise-Stress Echocardiography and Effort Intolerance in Asymptomatic/Minimally Symptomatic Patients With Degenerative Mitral Regurgitation Combined Invasive–Noninvasive Hemodynamic Monitoring
Authors: Utsunomiya Hiroto , Hidaka Takayuki , Susawa Hitoshi , Izumi Kanako , Harada Yu , Kinoshita Mirai , Itakura Kiho , Masada Kenji , Kihara Yasuki
Published: September 2018

Background

Effort intolerance, measured objectively by reduced peak oxygen consumption (V

o
2

), has been considered as an important prognosticator in degenerative mitral regurgitation (MR). However, its mechanism is unknown.

Methods and Results

In 25 asymptomatic/minimally symptomatic patients with grade III+ or greater degenerative MR undergoing semisupine invasive exercise testing, Doppler estimates and invasive measurement of systolic (SPAP) and mean pulmonary artery pressure (MPAP) and cardiac output (CO) were simultaneously obtained. Echocardiographic estimates of SPAP, MPAP, and CO correlated well with invasive measurement at peak exercise (bias, SPAP, −0.7±7.4 mm Hg; MPAP, 1.2±6.3 mm Hg; CO, 0.2±2.5 L/min). Heart rate reserve (β, 3.997; 95% CI, 2.704–5.290 per 41.5% increase;
P
<0.001), MPAP/CO slope (β, −3.846; 95% CI, −5.926 to −1.766 per 4.85 mm Hg/L per minute increase;
P
=0.001), and tricuspid annular plane systolic excursion/SPAP slope (β, 4.094; 95% CI, 2.252–5.936 per 0.22 mm/mm Hg increase;
P
=0.003) were associated with peak V

o
2

even after adjustment for increase in MR vena contracta during exercise and peak SPAP. The MPAP/CO slope of 4.13 had a sensitivity and a specificity for predicting effort intolerance (%predicted peak V

o
2

<70%) of 57% and 91%, respectively, whereas the tricuspid annular plane systolic excursion/SPAP slope of 0.25 had a respective sensitivity and specificity of 86% and 82%.

Conclusions

The agreement between echocardiographic and invasive measures of pulmonary artery pressures and CO during exercise is acceptable. In patients with degenerative MR, effort intolerance is predominantly because of chronotropic incompetence, abnormal pulmonary vascular reserve, and limited right ventricular contractile reserve and not simply because of exercise-induced MR or pulmonary hypertension.
Atrial Dysfunction in Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Zghaib Tarek , Bourfiss Mimount , van der Heijden Jeroen F. , Loh Peter , Hauer Richard N. , Tandri Harikrishna , Calkins Hugh , Nazarian Saman , te Riele Anneline S.J.M. , Zimmerman Stefan L. , Velthuis Birgitta K.
Published: September 2018

Background:

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy that is predominantly known to affect the ventricles. Evidence for atrial involvement remains limited. Therefore, we aimed to characterize atrial involvement in ARVC using functional cardiac magnetic resonance, define the extent of atrial size and function variation attributable to ventricular variables, and identify cardiac magnetic resonance–based predictors of atrial arrhythmias (AA) in ARVC.

Methods and Results:

We analyzed cine cardiac magnetic resonance images of 66 definite ARVC patients without a history of AA or severe heart failure and 24 healthy controls. Using tissue tracking, we evaluated phasic biatrial volumes, ejection fractions (EFs), peak longitudinal strain, and strain rates (SRs). The primary outcome was the occurrence of AA during 6.8 years [3.0–10.8 years] of follow-up. Compared with controls, ARVC patients had higher biatrial volumes, reduced right atrial (RA) conduit function (passive EF [RAEF
passive
] and peak early-diastolic SR), reduced RA and left atrial (LA) reservoir function (peak systolic SR), and reduced RA and LA pump function (peak late-diastolic SR;
P
<0.05). Using multivariable analysis, predictors of increased risk of AA during follow-up were higher atrial volumes (RAV
min
and LAV
min
), decreased LA reservoir function (total LAEF and LA peak longitudinal strain), and decreased RA conduit function (passive RAEF and RA early-diastolic SR).

Conclusions:

Compared with controls, patients with ARVC were found to have enlarged atria with decreased function on functional cardiac magnetic resonance examination. RA and LA parameters predict incident AA after adjusting for clinical and ventricular characteristics which suggests atrial involvement in ARVC.
Emerging Roles of Vascular Endothelium in Metabolic Homeostasis
Authors: Pi Xinchun , Xie Liang , Patterson Cam
Published: September 2018

Our understanding of the role of the vascular endothelium has evolved over the past 2 decades, with the recognition that it is a dynamically regulated organ and that it plays a nodal role in a variety of physiological and pathological processes. Endothelial cells (ECs) are not only a barrier between the circulation and peripheral tissues, but also actively regulate vascular tone, blood flow, and platelet function. Dysregulation of ECs contributes to pathological conditions such as vascular inflammation, atherosclerosis, hypertension, cardiomyopathy, retinopathy, neuropathy, and cancer. The close anatomic relationship between vascular endothelium and highly vascularized metabolic organs/tissues suggests that the crosstalk between ECs and these organs is vital for both vascular and metabolic homeostasis. Numerous reports support that hyperlipidemia, hyperglycemia, and other metabolic stresses result in endothelial dysfunction and vascular complications. However, how ECs may regulate metabolic homeostasis remains poorly understood. Emerging data suggest that the vascular endothelium plays an unexpected role in the regulation of metabolic homeostasis and that endothelial dysregulation directly contributes to the development of metabolic disorders. Here, we review recent studies about the pivotal role of ECs in glucose and lipid homeostasis. In particular, we introduce the concept that the endothelium adjusts its barrier function to control the transendothelial transport of fatty acids, lipoproteins, LPLs (lipoprotein lipases), glucose, and insulin. In addition, we summarize reports that ECs communicate with metabolic cells through EC-secreted factors and we discuss how endothelial dysregulation contributes directly to the development of obesity, insulin resistance, dyslipidemia, diabetes mellitus, cognitive defects, and fatty liver disease.
Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis
Authors: Soppert Josefin , Kraemer Sandra , Beckers Christian , Averdunk Luisa , Möllmann Julia , Denecke Bernd , Goetzenich Andreas , Marx Gernot , Bernhagen Jürgen , Stoppe Christian
Published: September 2018

Background

Although macrophage migration inhibitory factor (
MIF
) has been demonstrated to mediate cardioprotection in ischemia/reperfusion injury and antagonize fibrotic effects through its receptor,
CD
74, the function of the soluble
CD
74 receptor ectodomain (
sCD
74) and its interaction with circulating
MIF
have not been explored in cardiac disease.

Methods and Results

Cardiac fibroblasts were isolated from hearts of neonatal mice and differentiated into myofibroblasts. Co‐treatment with recombinant
MIF
and
sCD
74 induced cell death (
P
<0.001), which was mediated by receptor‐interacting serine/threonine‐protein kinase (
RIP)
1/
RIP
3‐dependent necroptosis (
P
=0.0376). This effect was specific for cardiac fibroblasts and did not affect cardiomyocytes. Gene expression analyses using microarray and
RT
‐
qPCR
technology revealed a 4‐fold upregulation of several interferon‐induced genes upon co‐treatment of myofibroblasts with
sCD
74 and
MIF
(Ifi44:
P
=0.011; Irg1:
P
=0.022; Clec4e:
P
=0.011). Furthermore, Western blot analysis confirmed the role of
sCD
74 as a modulator of
MIF
signaling by diminishing
MIF
‐mediated protein kinase B (
AKT)
activation (
P
=0.0197) and triggering p38 activation (
P
=0.0641). We obtained evidence that
sCD
74 inhibits
MIF
‐mediated survival pathway through the C‐X‐C chemokine receptor 4/
AKT
axis, enabling the induction of
CD
74‐dependent necroptotic processes in cardiac myofibroblasts. Preliminary clinical data revealed a lowered
sCD
74/
MIF
ratio in heart failure patients (17.47±10.09 versus 1.413±0.6244).

Conclusions

These findings suggest that treatment of cardiac myofibroblasts with
sCD
74 and
MIF
induces necroptosis, offering new insights into the mechanism of myofibroblast depletion during scar maturation. Preliminary clinical data provided first evidence about a clinical relevance of the
sCD
74/
MIF
axis in heart failure, suggesting that these proteins may be a promising target to modulate cardiac remodeling and disease progression in heart failure.
Multilateral Investment Court: The Gap Between the EU and China
Authors: Ning Hongling , Qi Tong
Published: September 2018

The EU has now shifted from ad hoc investment arbitration to an envisaged Multilateral Investment Court. Its essential character is expected to be a two-instance standing court system, together with a random allocation of cases. This judicialized court system could address China’s preference of correctness as to ISDS system to some extent, subject to the competence of judges, while at the same time it raises new problems and new concerns. Firstly, would the envisaged standing court, in the context of enhancing the regulatory powers of states, still be qualified as a neutral forum to strike the appropriate balance between the protection of investors’ right and preservation of states’ regulatory powers? Secondly, would the judicialized court system be effective and flexible enough to suit the current nature of ISDS? Thirdly, would the envisaged two-tier court system be put into efficient operation so as not to become a de facto bar to access of justice? In fact, a judicialized system has its pros and cons, and thus its successful establishment and operation would be subject to more detailed rules.
Onosma zagrica (Boraginaceae), a new species from Iran
Authors: DEHSHIRI MOHAMMAD MEHDI
Published: September 2018

A new species of Onosma sect. Onosma L. (Boraginaceae), O. zagrica Dehshiri, is described and illustrated from the western part of Iran from Khargushan Mountain near the Khorramabad city (Lorestan Province). The new species differs from Onosma kilouyensis Boiss. & Hausskn. in being a smaller plant, 1.4–3 × 0.25–0.7 cm, narrowly elliptic or linear-lanceolate cauline leaf, longer pedicels, yellow or at first cream, then blue corolla, and smaller nutlet. The IUCN threat category of O. zagrica is determined as “CR (Critically Endangered)”.
A revision of the Afrotropical species of Pachylophus Loew (Diptera: Chloropidae) and some related Ovoviviparous genera
Authors: DEEMING JOHN C.
Published: September 2018

In Pachylophus all described Afrotropical species are treated and P. aristalis, ismayi, nigeriensis, tschirnhausi, mirabilis, lacteibasis and stuckenbergi are described as new species. Pachylophus tellinii Bezzi is placed in synonymy. In Phyladelphus the type species thalhammeri and the single described Afrotropical species, P. geminus, are treated and P. woodi and P. maraisi are described as new species. The genus Sabeurina is erected to accommodate Eurina minuta Loew and a new Afrotropical species S. occidentalis. Some taxonomic notes are given on the Afrotropical species currently included in Platycephala. The immature stages and biological notes concerning the treated genera are described and discussed in the contexts of ovoviviparity and classification. Keys are provided for the identification of all the Afrotropical species known in each of the genera treated.
First record of the genus Phanerotomella (Hymenoptera: Braconidae) from Baltic amber with the description of a new species
Authors: KITTEL REBECCA N.
Published: September 2018

A new but exinct chelonine wasp species, Phanerotomella brevivena Kittel sp. nov. (Braconidae: Cheloninae) of the modern genus Phanerotomella is described from Baltic amber. This new species differs from all other extant Phanerotomella species by having the fore wing vein SR-1 only partially sclerotised. This is the first fossil record of the genus in amber.
Morphology and molecular phylogeny of Macrobrachium suphanense sp. nov. (Decapoda: Palaemonidae) from Thailand
Authors: SAENGPHAN NUKUL , PANIJPAN BHINYO , SENAPIN SAENGCHAN , LAOSINCHAI PARAMES , RUENWONGSA PINTIP , SUKSOMNIT AUAREE , PHIWSAIYA KORNSUNEE
Published: September 2018

A small freshwater prawn in Thailand has been found to be a new species and is named Macrobrachium suphanense (Decapoda: Palaemonidae). Fully grown male M. suphanense appeared very different from the most closely related male of M. sintangense: size smaller, second pereiopod smaller and less robust, rostrum form different and, in females, fewer eggs. Less closely related, fully grown M. dolatum has sharper distal cutting edge on fixed finger and M. hungi has longer rostrum than M. suphanense. DNA analyses put M. suphanense, M. sintangense and M. nipponense in the same clade with M. nipponense sister to the other two. Two more clades consist of M. dienbienphuense and M. niphanae on the one hand and M. lanchesteri and M. rosenbergii on the other. The relationship among the three clades is not clearly resolved.
Validation of the GPM Version-5 Surface Rainfall Products over Great Britain and Ireland
Authors: Watters Daniel , Battaglia Alessandro , Mroz Kamil , Tridon Frédéric
Published: September 2018

Instantaneous surface rain rate estimates from the Global Precipitation Measurement (GPM) mission’s Dual-Frequency Precipitation Radar (DPR) and combined DPR and multifrequency microwave imager (CMB) version-5 products are compared to those from the Met Office Radarnet 4 system’s Great Britain and Ireland (GBI) radar composite product. The spaceborne and ground-based rainfall products are collocated spatially and temporally and compared at 5- and 25-km resolutions over GBI during a 3-yr period (from May 2014 to April 2017). The comparison results are evaluated as a function of both the intensity and variability of precipitation within the DPR field of view and are stratified spatially and seasonally. CMB and DPR products underestimate rain rates with respect to the Radarnet product by 21% and 31%, respectively, when considering 25-km resolution data taken within 75 km of a ground-based radar. Large variability in the discrepancies between spaceborne and ground-based rain rate estimates is the result of limitations of both systems and random errors in the collocation of their measurements. The Radarnet retrieval is affected by issues with measuring the vertical extent of precipitation at far ranges, while the GPM system struggles in properly quantifying orographic precipitation. Part of the underestimation by the GPM products appears to be a consequence of an erroneous DPR clutter identification in the presence of low freezing levels. Both products are susceptible to seasonal variations in performance and decreases in precision with increased levels of heterogeneity within the instruments’ field of view.
A Numerical Study of Coastal-Trapped Waves in Jervis Bay, Australia
Authors: Liao Fanglou , Wang Xiao Hua
Published: September 2018

Coastal-trapped waves (CTWs) in Jervis Bay were investigated using a Jervis Bay Ocean Model (JBOM), based on the Princeton Ocean Model. Under the typical temperature stratification in Jervis Bay in summer, the first three modes of external CTWs can scatter into the bay. The wind stress inside Jervis Bay can generate CTWs, and the wind stress on the adjacent shelf can also generate CTWs in the bay by oscillations at the bay's opening, which are associated with temperature fluctuations there. The actual subinertial CTWs in Jervis Bay are a result of the interference of these CTWs. The amplitudes of the first three CTW modes were calculated from the observed sea level data. Three numerical experiments were designed to identify the major forcing for the observed subinertial temperature oscillations in Jervis Bay during an observational program in the summer of 1988/89. It was found that the local wind stress was the major contributor to the observed oscillations.
Teaching–learning resources and supports in the music classroom: Key aspects for the inclusion of visually impaired students
Authors: Pino Angela , Viladot Laia
Published: September 2018

Currently, there still exist barriers that prevent a satisfactory connection between music education and the visually impaired population. This is due to the teachers’ lack of preparation and their general ignorance of the functioning of the Braille music system, the materials, specialist support, and other tools needed for the inclusion of this type of students in the classroom. In order to familiarize the educational community with the resources and specialist support involved in inclusive music teaching, we conducted and analysed semi-structured interviews with the following persons: (1) the music specialists at the Organización Nacional de Ciegos Españoles Resource Centre (Spanish National Organization of the Blind); (2) a music teacher who had two visually impaired students in her classes; and (3) a blind student who studied music and had specialized in piano performance. The contributions made by this article consist of the categorization of the different teaching–learning resources involved in inclusion, information on how specialist support can be provided to facilitate these resources, and the relationships between resources and specialist support taking into account the point of view of teacher as the main figure responsible for inclusion in the music classroom.
Everyday austerity: Towards relational geographies of family, friendship and intimacy
Authors: Hall Sarah Marie
Published: September 2018

This paper advances ideas about relational geographies to explore ‘everyday austerity’. Whilst geographers have analysed the causes and aftermath of the recent financial crisis, the focus largely remains on problems within economic systems and urban governance, rather than austerity as lived experience. I outline how focusing on everyday relationships and relational spaces – family, friendship and intimate relations – provides exciting opportunities for thinking geographically about everyday life in austerity. Using examples of care and support and mundane mobilities, I demonstrate how a relational approach extends current understandings of how austerity cuts through, across and between spaces.
Paleoenvironmental changes during the last 3000 years in Lake Cari-Laufquen (Northern Patagonia, Argentina), inferred from ostracod paleoecology, petrophysical, sedimentological and geochemical data
Authors: Coviaga Corina , Cusminsky Gabriela , Pérez Alejandra Patricia , Schwalb Antje , Markgraf Vera , Ariztegui Daniel
Published: September 2018

South American paleoreconstructions are of global interest because it is the only landmass extending from the tropics to the southern high latitudes and intersecting the entire southern westerly wind belt. In this context, endorheic environments, as Lake Cari-Laufquen Grande (LCLG; 41º35’S, 69º25’W) are excellent sites for paleoenvironmental studies, since they react rapidly to changes in the precipitation/evaporation ratio. In this study, the limnological conditions prevailing during the last 3000 years have been inferred based on a multiproxy analysis of the sedimentary sequence of LCLG (water depth 4 m, core length 505 cm). Today, this is one of the few lakes in Northern Patagonia, providing a unique paleoclimatic and paleoecological lacustrine record. The ostracod assemblages, along with sedimentological, petrophysical and geochemical data, show hydrological changes in Cari-Lauquen Grande basin during the studied period. Our results indicate the continuous presence of a saline to brackish lake. However, changes in ostracod assemblages and sedimentological features reveal variations in the relative salinity of the system. The lake paleosalinity was estimated based on ostracod salinity optima, using a calibration dataset of 29 species and 72 different environments. Intervals of high salinity (24–26 g L-1) were dominated by L. rionegroensis (morph.I) and organic-poor sediments. Periods of lower salinity (14–20 g L-1) favored the occurrence of oligo-mesohaline taxa, such as R. whatleyi, L. rionegroensis (morph.III), Cypridopsis sp., L. patagonica and I. ramirezi. The sediments further display higher values of both TOC and magnetic susceptibility. These salinity changes are interpreted as water level variations, associated in turn to cold-wet and warm-dry periods in northern Patagonia. Our results provide new insights into the late-Holocene environmental history of the region, characterized by a paucity of records. In addition, the ostracod paleoecology modeled using a WA approach allowed quantitative inferences of salinity changes, highlighting their potential in Quaternary paleoclimate research.
Exploring young people’s emotional well-being and resilience in educational contexts: A resilient space?
Authors: Cocking Chris , Sherriff Nigel , Aranda Kay , Zeeman Laetitia
Published: September 2018

The term ‘resilience’ is pervasive in narratives of young people’s emotional well-being. However, the meaning it has for those it describes is perhaps less well understood. Resilience was investigated as part of an engagement exercise into health improvement commissioning in educational contexts in the South East of England. One hundred and nine young people in total were involved, and this article reports data collected from two areas that were explored, comprising a sub-set of 58 participants: emotional well-being and resilience (n = 23) and the whole school approach (n = 35). It was apparent that while not all participants engaged with the term ‘resilience’ itself, they nevertheless often adopted creative individual and collective strategies to protect and enhance their emotional well-being. Furthermore, participants reported a sense of resilience that arose from a shared sense of adversity that helped strengthen collective support and solidarity, thus supporting previous work on emergent collective resilience. Theoretical and practical implications are discussed, along with a recommendation for more participatory research, so that young people can be more confident that their views are being considered within such exercises.
Lolland-Falster Health Study: Study protocol for a household-based prospective cohort study
Authors: Jepsen Randi , Egholm Cecilie Lindström , Brodersen John , Simonsen Erik , Grarup Jesper , Cyron Arne , Ellervik Christina , Rasmussen Knud
Published: September 2018

Introduction: Lolland-Falster consists of two islands in the southern part of Denmark where income is lower and life expectancy is shorter than in the general Danish population. It is a mixed rural-provincial area with approximately 100,000 inhabitants. The Lolland-Falster Health Study was initiated to gain knowledge on the determinants of health in this disadvantaged area. Methods: The study is a household-based prospective cohort study including people of all ages. The entire household of randomly selected inhabitants is allocated either to an invited group or to an uninvited, non-contacted control group. The data collection encompasses questionnaires, physical examination and biological samples, i.e. blood and urine for same-day analysis and biobank storage, and saliva and faeces also for biobank storage. The civil registration number links collected data for each individual, family and household, with information in Danish registers. The data collection started in February 2016 and is estimated to end by 2019 after the enrolment of 20,000 people. Analysis: A number of in-depth sub-studies are planned. Emphasis will be given to analysis of intra- and inter-family variations in health determinants, genetics, lifestyle and health status. Ethics: Region Zealand’s Ethical Committee on Health Research (SJ-421) and the Danish Data Protection Agency (REG-24-2015) approved the study. Trial registration: Clinicaltrials.gov (NCT02482896). Strength and limitations of this study: The strength of this study is that Lolland-Falster Health Study is a useful scientific resource for investigating cross-sectional difference and time trends within and between individuals, families and households. LOFUS adds diversity to the previously collected Danish population studies in urbanized areas. The limitation is that data collection is expensive. Conclusions: LOFUS will contribute to the knowledge on health in disadvantaged, rural-provincial areas.
Intensive care unit providers more quickly and accurately assess risk of multiple harms using an engineered safety display
Authors: Romig Mark , Carolan Howard , Ravitz Alan , Schell-Chaple Hildy , Yoon Edward , Dwyer Cindy , Thornton Kevin , Gropper Michael , Pronovost Peter J , Sapirstein Adam
Published: September 2018

Project Emerge took a systems engineering approach to reduce avoidable harm in the intensive care unit. We developed a socio-technology solution to aggregate and display information relevant to preventable patient harm. We compared providers’ efficiency and ability to assess and assimilate data associated with patient-safety practice compliance using the existing electronic health record to Emerge, and evaluated for speed, accuracy, and the number of mouse clicks required. When compared to the standard electronic health record, clinicians were faster (529 ± 210 s vs 1132 ± 344 s), required fewer mouse clicks (42.3 ± 15.3 vs 101.3 ± 33.9), and were more accurate (24.8 ± 2.7 of 28 correct vs 21.2 ± 2.9 of 28 correct) when using Emerge. All results were statistically significant at a p-value < 0.05 using Wilcoxon signed-rank test ( n = 18). Emerge has the potential to make clinicians more productive and patients safer by reducing the time and errors when obtaining information to reduce preventable harm.