bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Platelets in Myocardial Infarction, Ischemic Heart Disease, Cerebrovascular Disease, Thromboembolic Disorders and Acute Idiopathic Pericarditis
Authors: Zahavi J
Published: July 2018

Initial white thrombus formation, has been attributed to platelet interaction with damaged vessel wall at sites of vascular injury or atherosclerotic plaques in the process of platelet aggregation (PA) and adhesion. Enhancement of PA seems to be an important factor in the development of thrombosis in the coronary and cerebral blood vessels and in embolization of platelet microthrombi to the microcirculation of the vessels. This latter event in turn might lead to serious or fatal arrhythmias or to paroxysms of cerebral ischemia.

We have found enhanced PA in 66 patients with acute myocardial infarction (MI) and ischemic heart disease (IHD) which was specifically indicated by 4 distinct abnormalities: a) increased rate and extent of aggregation to 11,1 μM of adenosine diphosphate (ADP). b) Increased platelet responsiveness to 1,11 μM of ADP. c) Spontaneous aggregation which appeared in 95% of the patients compared to less than 5% of controls, d) Prolonged aggregation time indicated by parameter τ, τ = -[dt/dln(T–T ∞ ≤)], In addition, enhanced and occasionally more pronounced PA on the day of discharge from hospital, has been recently observed. The abnormal platelet behaviour was also detected in 10 thromboembolic disorder (TED), 28 acute cerebrovascular accident (CVA) and 24 acute infectious disease (AI) patients. It was, however, more pronounced in MI compared to TED and CVA patients. In AI the curves returned to normal some time after their subsidence, but remained abnormal for up to 2 years in IHD patients. In 10 patients with acute benign idiopathic pericarditis, which were included in the AI patients, PA proved to be a rehable indicator of the course of the disease and its treatment. Early reduction of corticosteroid dosage in the patients, was followed by increased abnormalities in the PA curves.

The enhanced PA in these patients is most probably an indicator of a thrombogenic state and seems to be an important contributory factor in the pathogenesis of coronary and cerebrovascular diseases. Preliminary reports of anti-aggregating drugs, wether beneficial or adverse, in these vascular disorders are controversial and further research is needed.
The Effect of Insulin Treatment on the Balance between Tissue Plasminogen Activator and Plasminogen Activator Inhibitor-1 in Type 2 Diabetic Patients
Authors: Vukovich Thomas , Proidl Sylvia , Knöbl Paul , Teufelsbauer Harald , Schnack Christoph , Schernthaner Guntram
Published: July 2018

Beside hypercoagulation and hyperactivated platelets disturbances of the fibrinolytic system towards hypofibrinolysis have been reported to be associated with both glycemic and lipidemic derangement in diabetic patients. In the present prospective follow-up study the effect of 16 weeks insulin treatment and glycemic regulation on plasma levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1), the main regulators of fibrinolysis, was investigated in 19 type-2 diabetic patients with secondary failure to sulphonylureas. A similar glycemic regulation was obtained in a control group of 10 type 2 diabetic patients with sufficient metabolic response to strict dietary treatment and continuation of sulphonylurea treatment. Compared to 27 healthy subjects levels of tPA and PAI-1 were not significantly increased in type 2 diabetic patients before metabolic intervention. Although a hypofibrinolytic state due to an increase of PAI-1 levels was previously reported in obese hyperinsulinemic patients, no effect of insulin treatment on both tPA- and PAI-1 levels was observed in the present study including patients with only slightly increased body mass index (median 26.0 kg/m2). By correlation analysis PAI-1 levels were significantly related to serum cholesterol (R = 0.52) and glycemic control (glucose R = 0.41) in the whole group of diabetic patients at entry and in both subgroups after 16 weeks of treatment (insulin group: cholesterol R = 0.46, HbA1c R = 0.51; sulphonylurea group: cholesterol R = 0.59, HbA1c R = 0.58). In healthy subjects tPA and PAI-1 was correlated to serum insulin (R = 0.54, R = 0.56) and triglycerides (R = 0.46, R = 0.40). In conclusion, our results indicate that insulin treatment associated with metabolic improvement has no adverse effect to fibrinolysis in type 2 diabetic patients.
A Comparison of Methods for the Measurement of Activated Factor VII
Authors: Kitchen S , Malia R G , Preston F E
Published: July 2018

A number of different methods are available for the measurement of factor VIIa. Almost all of these employ ratios of two different measurements of factor VII. In order to determine which is the most sensitive to activated factor VII we have compared currently available methods in the following groups: two patients with haemophilia A following treatment with activated recombinant factor VII (rVII a); 6 normal plasmas during cold promoted activation of factor VII; normal individuals (n = 23); and patients with unequivocal disseminated intravascular coagulation (DIC, n = 19). Factor VII was measured in an amidolytic assay (VII: Amid) and an antigen assay (VII:Ag). Clotting activity was measured using rabbit (VII:C Rab), human (VII:C Hum) and bovine (VII:C Bov) thromboplastin.

Of the clotting assays the most sensitive to the presence of factor VIIa was that which utilised bovine thromboplastin. Amidolytic and immunological measurements were unaffected by the activity state of factor VII. The ratios VII:C Rab/VII: Ag and VII:C Rab/VII:Amid were insensitive to activated factor VII. The ratios most sensitive to the presence of factor VII a were VII:C Bov/VII: Amid and VII: C Bov/VII:Ag. The ratios VII:C Bov/VII:C Rab and VII:C Bov/VII:C Hum are less sensitive but have the advantage for epidemiological studies of narrower reference ranges.
Tissue Plasminogen Activator Release in Chronic Venous Hypertension due to Heart Failure
Authors: Keber Irena , Keber Dušan , Stegnar Mojca , Vene Nina
Published: July 2018

In order to study the effects of chronic venous hypertension due to heart failure on blood fibrinolytic activity, tissue plasminogen activator (t-PA) antigen, plasminogen activator inhibitor 1 (PAI-1) antigen, t-PA activity and PAI activity were measured before and after venous occlusion of the arm for 20 min in 15 patients with right-sided heart failure, 15 patients with left-sided heart failure, and 30 control healthy subjects. Central venous pressure, measured by observing the jugular veins, was above 15 cm of the blood column in all patients with right-sided heart failure, and normal (below 8 cm) in all patients with left-sided heart failure and control subjects. There was no difference in the basal concentrations of t-PA (11.0, 10.2 and 10.8 ng/ml; all values medians) and PAI-1 antigens and their activities between right and left-sided heart failure and the control subjects. After the occlusion, t-PA antigen increased significantly less in right-sided heart failure (28.6 ng/ml) than in left-sided heart failure and the control subjects (54.5 and 45.9 ng/ml, respectively). It was concluded that the poor increase in fibrinolytic activity that had already been reported in patients with heart failure, was due to low t-PA release during occlusion and not to a high basal PAI level. It was limited to the patients with right-sided heart failure and was probably the consequence of chronic systemic venous hypertension.
Mass Contents of Inositol 1,4,5-Trisphosphate and 1,2-Diacylglycerol in Human Platelets Stimulated with a Thromboxane Analogue and Thrombin
Authors: Suganuma A , Nakashima S , Okano Y , Nozawa Y
Published: July 2018

Mass contents of inositol 1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol (DG) were measured in U46619-stimulated human platelets. 1 µM of U46619 induced maximum responses in aggregation, 5-hydroxytryptamine (5HT) secretion and increase in intracellular free Ca2+ concentration ([Ca2+]i). Aggregation was almost comparable to that induced by maximal dose (1 U/ml) of thrombin, while 5HT release was almost half. The initial [Ca2+]i peak in response to U46619 was about half of thrombin stimulation. Production of IP3 and DG was, however, less than one tenth of that seen in thrombin stimulation. The profile (time course and concentration-dependency) of IP3 formation did not correlate with that of [Ca2+]i, suggesting that U46619 stimulates IPs-dependent and -independent Ca2+ mobilization. DG production was small but sustained for more than 5 min. These findings support the recent hypothesis that aggregation is regulated by a delayed accumulation of DG. The low level of 5HT secretion could be explained by the low production of second messengers, IP3 and DG.
On the Significance of Different Aequorin Loading Techniques on Intracellular Aequorin Discharge, Baseline Calcium, Platelet Aggregation and Aequorin-Indicated Ca2+-Transients
Authors: Malmgren R , Grunfelt S , Joseph Rajiv
Published: July 2018

The study compares the decay of intracellular luminescence activity (L
max), the levels of basal [Ca2+]i in resting platelets, and agonist-induced peak [Ca2+]i-signals in platelets loaded with aequorin using the EGTA-, DMSO- and hypoosmotic shock treatment (HOST)-techniques. The highest load of intracellular aequorin with almost unchanged luminescence activity during 4 h was achieved with HOST. L
max decreased linearly in EGTA- and HOST-platelets, but the decay rate and the levels of basal [Ca2+]i were significantly lower in HOST-platelets. Platelet aggregation and aequorin-indicated [Ca2+]i-rise induced by thrombin and collagen were similar in EGTA- and HOST-platelets. In HOST-platelets, ADP-induced platelet aggregation was always accompanied by aequorin-signals, while at a similar time point, aequorin-signals were absent in 3 of 5 cases in EGTA-platelets. The initial aequorin loading was highest in DMSO-platelets, but L
max described an exponential decay, which was most pronounced when DMSO-platelets were maintained in Ca2+-free buffer (R
2 = 0.86). Agonist-induced platelet aggregation was significantly reduced in DMSO-platelets: thrombin-stimulation was accompanied by a significantly lower and delayed [Ca2+]i-rise and no aequorin-signal was obtained in response to ADP in 3 of 5 cases. The study shows that in addition of being a rapid loading-technique, the criteria of high intracellular aequorin load with low luminescence consumption, low basal [Ca2+]i and completely preserved platelet functions are most convincingly met by the HOST-method.
The Procoagulant Response of Cytomegalovirus Infected Endothelial Cells
Authors: van Dam-Mieras M C E , Muller A D , van Hinsbergh V W M , Mullers W J H A , Bomans P H H , Bruggeman C A
Published: July 2018

The report describes the effect of an in vitro infection of human umbilical vein endothelial cells with human Cytomegalovirus (CMV). The parameters studied are cellular procoagulant activity, secretion of plasminogen activator inhibitor (PAI-1) and urokinase-type plasminogen activator (u-PA), activation and internalization of factor X and Merocyanine 540 staining.

The infection does not result in an increase in PAI-1 and u-PA secretion, but it brings about a procoagulant response, which is relatively rapid compared to the tissue factor mediated response induced by inflammatory mediators. The time course and the coagulation factor dependency suggest a facilitated interaction of coagulation factors on the surface of infected cells. Chromogenic activity measurements after the addition of purified factor X and electron microscopic examination of the cells after addition of colloidal gold-factor X conjugates both point to an internalization of factor X and/or Xa after interaction with the endothelial cell surface. Merocyanine 540 staining suggests that CMV infection leads to membrane pertubations.
Genetic Variation in the Syntaxin-Binding Protein STXBP5 in Type 1 von Willebrand Disease Patients
Authors: Lind-Halldén Christina , Manderstedt Eric , Carlberg Daniel , Lethagen Stefan , Halldén Christer
Published: July 2018

von Willebrand factor (VWF) levels in healthy individuals and in patients with type 1 von Willebrand disease (VWD) are influenced by genetic variation in several genes, for example, VWF, ABO and STXBP5. Here, we comprehensively screen for STXBP5 variants and investigate their association with type 1 VWD in Swedish patients and controls. The coding region of the STXBP5 gene was re-sequenced in 107 type 1 VWD patients and the detected variants were genotyped in the type 1 VWD population and a Swedish control population (464 individuals). The functional effects of missense alleles were predicted in silico and the pattern of genetic variation in STXBP5 was analysed. Re-sequencing of 107 type 1 VWD patients identified three missense and three synonymous variants in the coding sequence of STXBP5. The low-frequency missense variants rs144099092 (0.005) and rs148830578 (0.029) were predicted to be damaging, but were not accumulated in patients. No other rare candidate mutations were detected. STXBP5 showed a high level of linkage disequilibrium and a low overall nucleotide diversity of π = 3.2 × 10−4 indicating intolerance to variants affecting protein function. Three previously type 1 VWD-associated single nucleotide polymorphisms were located on one haplotype that showed an increased frequency in patients versus controls. No differences in messenger ribonucleic acid abundance among haplotypes could be found using Genotype-Tissue Expression project data. In conclusion, a haplotype containing the STXBP5 Asn436Ser (rs1039084) mutation is associated with type 1 VWD and no rare STXBP5 mutations contribute to type 1 VWD in the Swedish population.
Urinuntersuchung – Schritt für Schritt
Authors: Kimmel Martin , Biegger Dagmar , Alscher Mark
Published: July 2018

The examination of the urine is the oldest and a very basic technique for every nephrologist. It helps to detect, diagnose and classify diseases of the kidneys and the urinary tract. Proteinuria is an important sign of kidney disease and an own factor in the pathophysiology of renal progression. Acanthocytes in the urine (> 5 %) have a high specifity (98 – 100 %) for diagnosing a glomerular hematuria.
Real Kummer quartics and their Heisenberg invariance
Authors: Krasnov V. A.
Published: July 2018

We consider two classifications of real Kummer quartics. They use the Heisenberg invariance of Kummer quartics. The first divides the whole variety of real Kummer quartics into four classes according to the Heisenberg-invariance type and then subdivides each class into subclasses to obtain a deformation classification. This subdivision into subclasses is performed by means of the topological classification of the real parts of real Kummer quartics. The second classification deals with the set of real Kummer quartics with a fixed Heisenberg group. Such a set consists of a continuous part and a discrete part. We describe the deformation classes of the continuous part and describe its discrete part.
Change in the rocky reef fish fauna of the iconic Poor Knights Islands Marine Reserve in north-eastern New Zealand over 4 decades
Authors: Schiel David R. , Ayling Tony , Kingsford Michael J. , Battershill Christopher N. , Choat J. Howard , Andrew Neil L. , Clements Kendall D. , Ayling Avril L. , Leum Linda L. , Poynter Mark , Jones Geoffrey P.
Published: July 2018

Marine reserves exhibit increases in targeted fish species, but long-term effects on biodiversity are poorly understood. Factors other than reserve status may affect decadal changes, including environmental change. We examined the fish fauna at the iconic Poor Knights Islands over 4 decades (1974–2016) before and after implementation of a no-take marine reserve in 1998. We document a substantial increase in commercially and recreationally targeted Chrysophrys auratus, which was virtually absent before 1994 but by 2016 had reached up to 11 fish per 500m2 (220 per hectare). There were also large changes to the fish community, including the decline of subtropical and coastal wrasses, some species with no change and others that increased significantly. Many declines occurred >20 years before the arrival of abundant C. auratus, suggesting the changes do not represent a trophic cascade. Furthermore, this normally benthic-feeding fish has adopted a mid-water foraging behaviour targeting planktivorous fish. The increase in C. auratus appears to be linked both to reserve status and catch regulations in the wider region. Overall, the data point to long-term environmental fluctuations from the late 1970s having a negative effect on the abundance of more than half the reef fish species at these islands.
Evaluation of the heavy metals threat to the Yanbu shoreline, Red Sea, Saudi Arabia
Authors: Alharbi Omar M. L. , Khattab Rafat A. , Ali Imran , Binnaser Yaser S. , Aqeel Adnan
Published: July 2018

The coastline of Yanbu was studied for sediment contamination at nine locations (north and south Yanbu) using inductively coupled plasma mass spectrometry. The metal ions detected were copper, nickel, zinc, cadmium, chromium and lead, with concentrations of 1.35–73.0, 1.73–94.62, 5.88–241.10, 0.05–1.81, 4.81–201.01 and 0.08–23.33µgg–1 respectively. The standard deviation observed ranged from±0.5 to±0.53 for the analysis. The CVs ranged from 0.938 to 1.0, indicating the interdependence of the metal ions. Risk assessment indices (geo-accumulation, potential ecological risk and potential toxicity risk response) revealed that Site 9 was moderately polluted with copper, chromium and zinc and was severally polluted with cadmium. Cadmium was the highest accumulated metal, whereas lead was the least accumulated. The results indicated Site 9 had higher levels of heavy metals than sediments taken from the northern Yanbu sector. The southern site was polluted due to its proximity to the Yanbu industrial complex and sewage discharge point. Comparing the results of the present study with those of other national and international studies revealed comparable results, except at Site 9, where the concentrations of the metal ions were higher. Management strategies are suggested for the study area, which can also be used in other areas to avoid permanent threats to marine ecology.
Diffusion samples as a high-throughput screening method for alloy development
Authors: Ratschbacher Karin , Klotz Ulrich E. , Eisenbart Miriam
Published: July 2018

Diffusion couples of copper alloys are presented as screening tool for high-throughput alloy development. It allows estimating the precipitation hardening potential in multicomponent alloys of a vast number of compositions within one sample. The components were diffusion welded and annealed to form compositional gradients which were characterised through a grid of energy dispersive X-ray spectroscopy measurements. After splitting the different sample parts underwent different tempering treatments. Thereafter micro hardness grids matching the spectroscopy data were recorded and displayed in contour plots as a function of alloy composition that instantly show composition areas with hardening potential. A critical assessment of the reliability of the method is provided and checked for cu-Al/mn-Sn-ti systems against literature data.

This paper is part of a Thematic Issue on Copper and its Alloys.
Identification and characterization of a rhamnosyltransferase involved in rutin biosynthesis in Fagopyrum esculentum (common buckwheat)
Authors: Koja Eiki , Ohata Soichiro , Maruyama Yoshinori , Suzuki Hideyuki , Shimosaka Makoto , Taguchi Goro
Published: July 2018

Rutin, a 3-rutinosyl quercetin, is a representative flavonoid distributed in many plant species, and is highlighted for its therapeutic potential. In this study, we purified uridine diphosphate-rhamnose: quercetin 3-O-glucoside 6″-O-rhamnosyltransferase and isolated the corresponding cDNA (FeF3G6″RhaT) from seedlings of common buckwheat (Fagopyrum esculentum). The recombinant FeF3G6″RhaT enzyme expressed in Escherichia coli exhibited 6″-O-rhamnosylation activity against flavonol 3-O-glucoside and flavonol 3-O-galactoside as substrates, but showed only faint activity against flavonoid 7-O-glucosides. Tobacco cells expressing FeF3G6″RhaT converted the administered quercetin into rutin, suggesting that FeF3G6″RhaT can function as a rhamnosyltransferase in planta. Quantitative PCR analysis on several organs of common buckwheat revealed that accumulation of FeF3G6″RhaT began during the early developmental stages of rutin-accumulating organs, such as flowers, leaves, and cotyledons. These results suggest that FeF3G6″RhaT is involved in rutin biosynthesis in common buckwheat.
Serum Potassium and Cardiovascular Events in Heart Failure With Preserved Left Ventricular Ejection Fraction Patients
Authors: Nishihara Taiki , Tokitsu Takanori , Sueta Daisuke , Takae Masafumi , Oike Fumi , Fujisue Koichiro , Usuku Hiroki , Takashio Seiji , Hanatani Shinsuke , Kanazawa Hisanori , Arima Yuichiro , Sakamoto Kenji , Izumiya Yasuhiro , Yamabe Hiroshige , Kaikita Koichi , Yamamoto Eiichiro , Tsujita Kenichi
Published: July 2018

BACKGROUND

Although serum potassium (sK) levels are closely associated with the prognosis of chronic heart failure patients, the clinical significance of sK levels in cardiovascular outcomes of heart failure with preserved ejection fraction (HFpEF) patients is not fully understood.

METHODS

This study was a retrospective, single-center, observational study. We enrolled 506 consecutive HFpEF patients admitted to Kumamoto University Hospital and divided them into four groups according to the quartiles of the sK levels at discharge (Q1: sK < 4.1 mEq/l, Q2: 4.1 ≤ sK < 4.4 mEq/l, Q3: 4.4 ≤ sK < 4.7 mEq/l, and Q4: sK ≥ 4.7 mEq/l).

RESULTS

No significant differences were observed in the use of all drugs (loop diuretics, mineralocorticoid receptor antagonists, renin-angiotensin-aldosterone system inhibitors, calcium channel blockers, β-blockers, and statins) among the four groups. Hemoglobin, the estimated glomerular filtration rate, and pulse wave velocity levels were lower, and the serum sodium levels were higher in the Q4 group compared with those in the Q2 group. Kaplan–Meier analysis revealed significantly higher probabilities of both cardiovascular and HF-related events in the Q1, Q3, and Q4 groups than those in the Q2 group. Multivariate Cox proportional hazard analysis revealed that the Q1, Q3, and Q4 groups had significantly and independently higher probabilities of cardiovascular events compared with those in the Q2 group, indicating a J-shaped association between sK levels and cardiovascular events.

CONCLUSIONS

sK levels at discharge could provide important prognostic information in regard to HFpEF. Further evaluation in a larger number of patients might be needed.

Clinical Trials Registration

UMIN-CTR (http://www.umin.ac.jp/ctr/).

Identifier

UMIN000029600.

Public Access Information

Opt-out materials are available at the website: http://www.kumadai-junnai.com/home/wp-content/uploads/houkatsu.pdf.
iS-CellR: a user-friendly tool for analyzing and visualizing single-cell RNA sequencing data
Authors: Patel Mitulkumar V
Published: July 2018

Interactive platform for single-cell RNA-sequencing (iS-CellR) is a web-based Shiny application that is designed to provide user-friendly, comprehensive analysis of single-cell RNA sequencing data. iS-CellR has the capability to run on any modern web browser and provides an accessible graphical user interface that enables the user to perform complex single-cell RNA-sequencing analysis without requiring programming skills.

Availability and implementation

iS-CellR is open source and available through GitHub at https://github.com/immcore/iS-CellR. iS-CellR is implemented in Docker and can be launched on any operating system with Docker installed.

Supplementary information

Supplementary data are available at Bioinformatics online.
SATurn: a modular bioinformatics framework for the design of robust maintainable web-based and standalone applications
Authors: Damerell David R , Strain-Damerell Claire , Garsot Sefa , Joyce Stephen P , Barrett Paul , Marsden Brian D
Published: July 2018

SATurn is a modular, open-source, bioinformatics platform designed to specifically address the problems of maintenance and longevity commonly associated with the development of simple tools funded by academic research grants. Applications developed in SATurn can be deployed as web-based tools, standalone applications or hybrid tools which have the benefits of both. Within the Structural Genomics Consortium we have utilized SATurn to create a bioinformatics portal which routinely supports a diverse group of scientists including those interested in structural biology, cloning, glycobiology and chemical biology.

Availability and implementation

https://github.com/ddamerell53/SATurn

Supplementary information

Supplementary data are available at Bioinformatics online.
MetaboRank: network-based recommendation system to interpret and enrich metabolomics results
Authors: Frainay Clément , Aros Sandrine , Chazalviel Maxime , Garcia Thomas , Vinson Florence , Weiss Nicolas , Colsch Benoit , Sedel Frédéric , Thabut Dominique , Junot Christophe , Jourdan Fabien
Published: July 2018

Motivation

Metabolomics has shown great potential to improve the understanding of complex diseases, potentially leading to therapeutic target identification. However, no single analytical method allows monitoring all metabolites in a sample, resulting in incomplete metabolic fingerprints. This incompleteness constitutes a stumbling block to interpretation, raising the need for methods that can enrich those fingerprints. We propose MetaboRank, a new solution inspired by social network recommendation systems for the identification of metabolites potentially related to a metabolic fingerprint.

Results

MetaboRank method had been used to enrich metabolomics data obtained on cerebrospinal fluid samples from patients suffering from hepatic encephalopathy (HE). MetaboRank successfully recommended metabolites not present in the original fingerprint. The quality of recommendations was evaluated by using literature automatic search, in order to check that recommended metabolites could be related to the disease. Complementary mass spectrometry experiments and raw data analysis were performed to confirm these suggestions. In particular, MetaboRank recommended the overlooked α-ketoglutaramate as a metabolite which should be added to the metabolic fingerprint of HE, thus suggesting that metabolic fingerprints enhancement can provide new insight on complex diseases.

Availability and implementation

Method is implemented in the MetExplore server and is available at www.metexplore.fr. A tutorial is available at https://metexplore.toulouse.inra.fr/com/tutorials/MetaboRank/2017-MetaboRank.pdf.

Supplementary information

Supplementary data are available at Bioinformatics online.
A Bayesian approach to Mendelian randomization with multiple pleiotropic variants
Authors: Berzuini Carlo , Guo Hui , Burgess Stephen , Bernardinelli Luisa
Published: July 2018

We propose a Bayesian approach to Mendelian randomization (MR), where instruments are allowed to exert pleiotropic (i.e. not mediated by the exposure) effects on the outcome. By having these effects represented in the model by unknown parameters, and by imposing a shrinkage prior distribution that assumes an unspecified subset of the effects to be zero, we obtain a proper posterior distribution for the causal effect of interest. This posterior can be sampled via Markov chain Monte Carlo methods of inference to obtain point and interval estimates. The model priors require a minimal input from the user. We explore the performance of our method by means of a simulation experiment. Our results show that the method is reasonably robust to the presence of directional pleiotropy and moderate correlation between the instruments. One section of the article elaborates the model to deal with two exposures, and illustrates the possibility of using MR to estimate direct and indirect effects in this situation. A main objective of the article is to create a basis for developments in MR that exploit the potential offered by a Bayesian approach to the problem, in relation with the possibility of incorporating external information in the prior, handling multiple sources of uncertainty, and flexibly elaborating the basic model.
The Mitochondrial Contribution to Animal Performance, Adaptation, and Life-History Variation
Authors: Hood Wendy R , Austad Steven N , Bize Pierre , Jimenez Ana Gabriela , Montooth Kristi L , Schulte Patricia M , Scott Graham R , Sokolova Inna , Treberg Jason R , Salin Karine
Published: July 2018

Animals display tremendous variation in their rates of growth, reproductive output, and longevity. While the physiological and molecular mechanisms that underlie this variation remain poorly understood, the performance of the mitochondrion has emerged as a key player. Mitochondria not only impact the performance of eukaryotes via their capacity to produce ATP, but they also play a role in producing heat and reactive oxygen species and function as a major signaling hub for the cell. The papers included in this special issue emerged from a symposium titled “Inside the Black Box: The Mitochondrial Basis of Life-history Variation and Animal Performance.” Based on studies of diverse animal taxa, three distinct themes emerged from these papers. (1) When linking mitochondrial function to components of fitness, it is crucial that mitochondrial assays are performed in conditions as close as the intracellular conditions experienced by the mitochondria in vivo. (2) Functional plasticity allows mitochondria to retain their performance, as well as that of their host, over a range of exogenous conditions, and selection on mitochondrial and nuclear-derived proteins can optimize the match between the environment and the bioenergetic capacity of the mitochondrion. Finally, (3) studies of wild and wild-derived animals suggest that mitochondria play a central role in animal performance and life history strategy. Taken as a whole, we hope that these papers will foster discussion and inspire new hypotheses and innovations that will further our understanding of the mitochondrial processes that underlie variation in life history traits and animal performance.
5 Update to Chapter 9: Multiple Parties and Multiple Claims
Authors: Trevor C Hartley
Published: July 2018

This section of the noter-up to Civil Jurisdiction and Judgments in Europe: The Brussels I Regulation, the Lugano Convention, and the Hague Choice of Court Convention by Trevor Hartley discusses multiple parties and multiple claims. These include multiple defendants under Brussels 2012, Article 8(1).
10 Update to Chapter 18: Brussels and Lugano: Grounds for Refusal of Recognition and Enforcement of Judgments
Authors: Trevor C Hartley
Published: July 2018

This section of the noter-up to Civil Jurisdiction and Judgments in Europe: The Brussels I Regulation, the Lugano Convention, and the Hague Choice of Court Convention by Trevor Hartley discusses grounds for refusal of recognition and enforcement of judgments. These include issues relating to jurisdiction of the court of origin
11 Update to Chapter 21: Concurrent Proceedings
Authors: Trevor C Hartley
Published: July 2018

This section of the noter-up to Civil Jurisdiction and Judgments in Europe: The Brussels I Regulation, the Lugano Convention, and the Hague Choice of Court Convention by Trevor Hartley discusses concurrent proceedings. These include when a court is regarded as seised under Lugano 2007 and Brussels 2012.
Challenges to Arbitrators, Counsel, and Experts
Authors: Commission Jeffery , Moloo Rahim
Published: July 2018

This chapter discusses challenges to arbitrators in International Centre for Settlement of Investment Disputes (ICSID) and ICSID Additional-Facility arbitrations, challenges to arbitrators in UNCITRAL arbitrations, and challenges to counsel and experts in ICSID and UNCITRAL arbitrations. Disqualification proposals have become a routine procedural mechanism used by both claimants and respondents in ICSID and UNCITRAL investment arbitrations. During the period 1982–2017, parties filed 121 disqualification proposals in ICSID proceedings. These included not only original arbitration proceedings, but also post-award proceedings, such as rectification, interpretation and annulment proceedings. In addition to arbitrators, disqualification proposals now target counsel, party-appointed experts, and tribunal-appointed experts. The chapter examines the relevant articles and rules that apply when challenges are against ICSID arbitrators, the timeliness of challenge application, the potential waiver of the right to seek disqualification, and arbitrator resignations in response to disqualification proposals. It also considers the procedure for adjudicating challenges to arbitrators in UNCITRAL arbitrations.
Non-Disputing Party Participation and Transparency
Authors: Commission Jeffery , Moloo Rahim
Published: July 2018

This chapter examines the issue of transparency in treaty-based investment arbitration by focusing on the participation of third parties or non-disputing parties in disputes. More specifically, it considers the procedural issues that transparency mechanisms in bilateral-investment treaties and free-trade agreements, as well as in recently revised arbitral rules, create for arbitral tribunals and those appearing before them. After discussing non-disputing party practice in investment arbitrations, the chapter explains the practice of non-disputing state parties in UNCITRAL and International Centre for Settlement of Investment Disputes (ICSID) arbitrations. It also analyses transparency mechanisms beyond the participation of non-disputing parties in investment arbitrations from the written procedure through to the oral procedure, culminating in a tribunal's decisions and award.
Other Procedures
Authors: Commission Jeffery , Moloo Rahim
Published: July 2018

This chapter examines other procedures in investment arbitration proceedings, with particular emphasis on how International Centre for Settlement of Investment Disputes (ICSID) and UNCITRAL tribunals have addressed them in practice. ICSID has schematically set out what it describes as ‘the steps in the process’ in an ICSID arbitration using a flow chart. However, this flow chart is not able to anticipate with much certainty the potential impact of certain other procedures. The chapter first explains the determination of the legal place or seat of arbitration in non-ICSID Convention arbitrations before discussing the practice of early dismissal mechanisms, specifically, ICSID Rule 41(5) objections for manifest lack of legal merit. It then considers the question of site visits conducted by tribunals in ICSID and UNCITRAL arbitrations, the practice of tribunal-appointed experts, and requests for reconsideration. It also outlines the features of multi-party arbitration, including the procedures and issues associated with mass claims.
Statements or Submissions on Costs
Authors: Commission Jeffery , Moloo Rahim
Published: July 2018

This chapter considers the duration and costs of investment arbitrations as well as the procedural mechanics of cost submissions or statements of costs. It first examines the timing, format, and content of cost submissions and statements of costs before discussing the relevant arbitral rules that govern such submissions in International Centre for Settlement of Investment Disputes (ICSID) Convention and ICSID Additional-Facility arbitration proceedings, along with the average amount of such costs. It then explains the UNCITRAL Arbitration Rules on costs submissions, taking into account the average amount of those costs, and the duration of arbitration proceedings. It also analyses how arbitral tribunals have allocated costs in ICSID and UNCITRAL proceedings and highlights the factors deemed relevant by tribunals in those decisions.
Introduction
Authors: Haldemann Frank , Unger Thomas
Published: July 2018

This book provides a systematic in-depth study of the Principles, which were conceived and designed ‘as a guideline to assist States in developing effective measures for combating impunity’. The document contains 38 Principles, analyzed in the present book in the context of a host of complex theoretical and practical issues currently discussed in the arena of human rights and beyond. This introduction orients readers towards the basic issues, situating the Principles in their wider historical and political context and elucidating their conceptual and normative nature. It also clarifies the role, limitations and opportunities of the Principles in addressing current challenges, especially with respect to ‘transitional’ societies emerging from prolonged periods of armed conflict or oppression.
The Inalienable Right to the Truth
Authors: Groome Dermot
Published: July 2018

Principle 2 is concerned with the inalienable right to truth, a right that arises from the right to know and obliges governments to establish mechanisms to facilitate the revelation of the truth about serious violations of human rights. The right to truth has been explicitly incorporated into several international instruments and, in 2010, became expressly guaranteed in the International Convention for the Protection of All Persons from Enforced Disappearance (ICPPED). In practice, the right to truth is realized through laws enabling requests for state-held information; archives; truth commissions; national and international courts; and human rights commissions. After providing a contextual and historical overview of Principle 2, this chapter describes its normative (legal/ethical) foundation, focusing on how its interpretation is influenced by international law and how it relates to notions of transitional justice. It also analyzes the applications of the Principle in practice.
The Victims’ Right to Know
Authors: Groome Dermot
Published: July 2018

Principle 4 deals with the victims’ right to know, which is most often exercised in conjunction with Principle 2, the right to truth. This principle not only guarantees families to know the ultimate fate of relatives but also requires a full and fair exposition of what happened, including the existence of human rights violations. The right to know was first articulated in Article 32 of Additional Protocol I to the Geneva Conventions and has evolved as a principle of customary international humanitarian law. Principle 4 recognizes the basic human need for families to know the fate of missing loved ones and is best understood as a right extending humanitarian protection to families of the missing. This chapter first provides a contextual and historical background on Principle 4 before discussing its theoretical framework and the ways in which the right to know is exercised in practice.
Guarantees of Independence, Impartiality, and Competence
Authors: Nuzov Ilya , Freeman Mark
Published: July 2018

Principle 7 deals with guarantees of three separate but interrelated aspects of commissions of inquiry: independence, impartiality and competence. This principle emphasizes the need for guarantees of independence, impartiality and competence in two different realms: the process leading to a commission’s establishment, and the commission’s ultimate terms of reference. As such, the scope of Principle 7 overlaps with Principle 6, which deals with the establishment of truth commissions, and Principle 8, which deals with the mandates of commissions of inquiry. This chapter first provides a contextual and historical background on Principle 7 before discussing its theoretical framework and the ways in which the values espoused in Principle 7 are exercised by states in practice.
Publicizing the Commission’s Reports
Authors: Harwood Catherine , Stahn Carsten
Published: July 2018

Principle 13 deals with the publication of the commission’s reports. The principle of publicity is a key component of the United Nations’ Updated Impunity Principles. Through full publication and wide dissemination of a report, the right to the truth is realized. An authoritative account of violations might also promote accountability and reconciliation. A final report should be widely accessible, taking into consideration cultural and technological contexts. However, commissions may receive information confidentially and exclude some information from reports for security reasons and to avoid interference with witnesses and commissioners. This chapter first provides a contextual and historical background on Principle 13 before discussing its theoretical framework and how commissions have adopted confidentiality measures to protect witnesses and victims.
Measures for Facilitating Access to Archives
Authors: Cadelo Valentina , Peterson Trudy Huskamp
Published: July 2018

Principle 15 requires States to adopt measures that facilitate access to archives for victims, persons implicated in human rights violations, and individuals undertaking historical research. Access to records/archives means making them available for consultation as a result both of legal authorization and the existence of finding aids. Authorizing access to archives, particularly those of governments, is a political act. After providing a contextual and historical background on Principle 15, this chapter discusses its theoretical framework as well as its implementation, focusing on how international and national courts have taken a variety of positions on access. While the theoretical and best practice framework for access to archives exists, the chapter argues that implementation of Principle 15 is far from satisfactory. It also highlights important challenges that persist due to the reluctance of states to provide access to information, often linked to national security concerns.
Jurisdiction of International and Internationalized Criminal Tribunals
Authors: Schabas William A
Published: July 2018

Principle 20 is concerned with the jurisdiction of international and internationalized criminal tribunals regarding the prosecution of war crimes and other atrocities. The word ‘impunity’, defined at the beginning of the United Nations Updated Set of Principles, implies punishment or some similar sanction. It inexorably directs us towards judicial activity of criminal courts or the lack of it. The first sentence of Principle 20 is addressed to the national justice system, while the second sentence focuses on the international and internationalized criminal tribunals and their relationship to national courts. The final sentence of Principle 20 requires States to ‘fully satisfy their legal obligations’ with respect to international and internationalized criminal tribunals. This chapter first provides a contextual and historical background on Principle 20 before discussing its theoretical framework and how it has been observed in practice.
Restrictions on the Right of Asylum
Authors: Harvey Colin
Published: July 2018

Principle 25 deals with restrictions on the right of asylum. In the global struggle against impunity, Principle 25 takes account of the concern that the institution of asylum might be used to evade criminal justice and accountability. Its goal is to ensure that there are no ‘safe havens’ for war criminals and those who have committed crimes against humanity. The primary focus is on denial of status to make sure that the institution of asylum is not used to avoid facing the responsibility to challenge and combat impunity. This chapter first provides a contextual and historical background on Principle 25 before discussing its theoretical framework and how the exclusion clauses of refugee law have been applied in practice.
Restrictions on Extradition/Non Bis in Idem
Authors: Roth Robert
Published: July 2018

Principle 26 deals with restrictions on extradition and the principle non bis in idem. More specifically, it addresses obstacles to extradition and double jeopardy (ne bis in idem), two issues that both place restrictions rather than prohibitions on the exercise of criminal jurisdiction than interdictions to assert jurisdiction. The principle ne bis in idem and extradition law have evolved from a ‘State-oriented’ approach into an ‘individual-oriented approach’. Principle 26 highlights a series of controversial issues, including the denial of extradition to countries enforcing the death penalty to the so-called ‘shield trials’, and tries to strike a balance between the fight against impunity and the enhancement of individual rights for persons facing trials, even for ‘serious crimes under international law’. This chapter first provides a contextual and historical background on Principle 26 before discussing its theoretical framework and how the Principle has been applied in practice.
Restrictions on the Jurisdiction of Military Courts
Authors: Aoláin Fionnuala Ní
Published: July 2018

Principle 29 deals with restrictions on the jurisdiction of military courts. Under this Principle, the adjudication of human rights violations by military courts is explicitly excluded, and ordinary domestic courts are mandated as the only appropriate venue of judicial oversight. Nevertheless, military courts remain functionally important for the routine and uncontroversial deployment of military law consistent with international law. The chapter first provides a contextual and historical background on Principle 29 before discussing its theoretical framework and how military courts are used in various countries such as Ireland and Turkey. Issues arising when civilians find themselves within the jurisdiction of military courts are also examined, along with the difficulties of ensuring fair trials in military courts. This chapter shows that military courts, while certainly serving important functions within the military forces of states, remain subject to human rights and humanitarian law compliance.
Reform of Laws and Institutions Contributing to Impunity
Authors: Duthie Roger , Mayer-Rieckh Alexander
Published: July 2018

Principle 38 calls for the repeal or abolition of laws and institutions that contribute to impunity for human rights violations. It considers habeas corpus as a fundamental and non-derogable individual right, and calls for the enactment of ‘legislative measures necessary to ensure protection of human rights and to safeguard democratic institutions and processes’, along with a ‘comprehensive review of legislation and administrative regulations’. This chapter first provides a contextual and historical background on Principle 38 before discussing its theoretical framework and practice. It shows how this Principle has evolved from an initial narrower focus only on emergency legislation and courts in preparatory reports and prior versions to a broader focus on legislative and institutional reform to combat impunity. It also cites examples of legislative reform in countries such as Morocco, Guatemala, Northern Ireland, Sierra Leone, and Uganda, particularly where truth commission recommendations have addressed the matter.
The Law of Assignment
Authors: Smith Marcus , Leslie Nico
Published: July 2018

This book is the leading text on the law relating to intangible property or choses in action. Its clear and approachable structure covers all forms of intangible property (debts, rights under contract, securities, intellectual property, leases, rights/causes of action, and equitable rights), considering the nature of intangible property, how it comes into being, and how it is transferred or assigned. The first part of the book analyses the general principles regarding intangibles and their transfer, and the second examines the practical considerations relating to particular types of intangibles, securities, insurance contracts, leases, and intellectual property under the law. This new edition includes new chapters on powers of attorney and factoring, areas particularly important to legal practice. Other significant developments include the expansion of the chapter on leases to include leasing of chattels, and more material on securities, especially regarding the operation of settlement systems.