Regional Human Rights Regimes: A Comparison and Appraisal

For Americans at least, active concern for human rights on the international plane is demonstrated perhaps most conspicuously in the promotion and protection of human rights through the United Nations and its allied agencies--apart, that is, from the promotion and protection of human rights through United States foreign policy and the work of such nongovernmental organizations as Amnesty International. Supplementing this globally-oriented human rights activity, however, are international human rights regimes operating regionally in Western Europe, the Americas, Africa and the Middle East. Concededly, Asia is not yet represented, and only the first three of the represented regions have gone so far as to create enforcement mechanisms within the framework of a human rights charter, as evidenced by the European Convention for the Protection of Human Rights and Fundamental Freedoms and the European Social Charter, the American Convention on Human Rights and the Banjul (African) Charter on Human and Peoples\u27 Rights. The Permanent Arab Commission on Human Rights, founded by the Council of the League of Arab States in September 1968 but since then understandably preoccupied by the rights of Palestinian Arabs in and to the Israeli-occupied territories, has yet to bring a proposed Arab Convention on Human Rights to successful conclusion, and so far has tended to function more in terms of the promotion than the protection of human rights. Nevertheless, the regional development of human rights norms, institutions and procedures is likely to grow. Already an important dynamic of international human rights law and policy, it is, in any event, here to stay

2022 Update for the Differences Between Thermodynamic Temperature and ITS-90 Below 335 K

In 2011, a working group of the Consultative Committee for Thermometry published their best estimates of the differences between the thermodynamic temperature T and its approximation (T-90), the temperature according to the International Temperature Scale of 1990, ITS-90. These consensus estimates, in combination with measurements made in accordance with ITS-90, are an important alternative to primary thermometry for those requiring accurate measurements of thermodynamic temperature. Since 2011, there has been a change in the definition of the kelvin and significant improvements in primary thermometry. This paper updates the (T - T-90) estimates by combining and analyzing the data used for the 2011 estimates and data from more recent primary thermometry. The results of the analysis are presented as a 12th-order polynomial representing the updated consensus values for the differences and a sixth-order polynomial for their uncertainty estimates. (C) 2022 Author(s)

Increased Expression of Cytotoxic T-Lymphocyte-Associated Protein 4 by T Cells, Induced by B7 in Sera, Reduces Adaptive Immunity in Patients With Acute Liver Failure.

BACKGROUND & AIMS: Patients with acute liver failure (ALF) have defects in innate immune responses to microbes (immune paresis) and are susceptible to sepsis. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), which interacts with the membrane receptor B7 (also called CD80 and CD86), is a negative regulator of T-cell activation. We collected T cells from patients with ALF and investigated whether inhibitory signals down-regulate adaptive immune responses in patients with ALF. METHODS: We collected peripheral blood mononuclear cells from patients with ALF and controls from September 2013 through September 2015 (45 patients with ALF, 20 patients with acute-on-chronic liver failure, 15 patients with cirrhosis with no evidence of acute decompensation, 20 patients with septic shock but no cirrhosis or liver disease, and 20 healthy individuals). Circulating CD4+ T cells were isolated and analyzed by flow cytometry. CD4+ T cells were incubated with antigen, or agonist to CD3 and dendritic cells, with or without antibody against CTLA4; T-cell proliferation and protein expression were quantified. We measured levels of soluble B7 molecules in supernatants of isolated primary hepatocytes, hepatic sinusoidal endothelial cells, and biliary epithelial cells from healthy or diseased liver tissues. We also measured levels of soluble B7 serum samples from patients and controls, and mice with acetaminophen-induced liver injury using enzyme-linked immunosorbent assays. RESULTS: Peripheral blood samples from patients with ALF had a higher proportion of CD4+ CTLA4+ T cells than controls; patients with infections had the highest proportions. CD4+ T cells from patients with ALF had a reduced proliferative response to antigen or CD3 stimulation compared to cells from controls; incubation of CD4+ T cells from patients with ALF with an antibody against CTLA4 increased their proliferative response to antigen and to CD3 stimulation, to the same levels as cells from controls. CD4+ T cells from controls up-regulated expression of CTLA4 after 24-48 hours culture with sera from patients with ALF; these sera were found to have increased concentrations of soluble B7 compared to sera from controls. Necrotic human primary hepatocytes exposed to acetaminophen, but not hepatic sinusoidal endothelial cells and biliary epithelial cells from patients with ALF, secreted high levels of soluble B7. Sera from mice with acetaminophen-induced liver injury contained high levels of soluble B7 compared to sera from mice without liver injury. Plasma exchange reduced circulating levels of soluble B7 in patients with ALF and expression of CTLA4 on T cells. CONCLUSIONS: Peripheral CD4+ T cells from patients with ALF have increased expression of CTLA4 compared to individuals without ALF; these cells have a reduced response to antigen and CD3 stimulation. We found sera of patients with ALF and from mice with liver injury to have high concentrations of soluble B7, which up-regulates CTLA4 expression by T cells and reduces their response to antigen. Plasma exchange reduces levels of B7 in sera from patients with ALF and might be used to restore antimicrobial responses to patients

A bipartite structural organization defines the SERINC family of HIV-1 restriction factors

The human integral membrane protein SERINC5 potently restricts HIV-1 infectivity and sensitizes the virus to antibody-mediated neutralization. Here, using cryo-EM, we determine the structures of human SERINC5 and its orthologue from Drosophila melanogaster at subnanometer and near-atomic resolution, respectively. The structures reveal a novel fold comprised of ten transmembrane helices organized into two subdomains and bisected by a long diagonal helix. A lipid binding groove and clusters of conserved residues highlight potential functional sites. A structure-based mutagenesis scan identified surface-exposed regions and the interface between the subdomains of SERINC5 as critical for HIV-1-restriction activity. The same regions are also important for viral sensitization to neutralizing antibodies, directly linking the antiviral activity of SERINC5 with remodeling of the HIV-1 envelope glycoprotein

Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family

Definition of a Structured Training Curriculum for Robot-assisted Radical Cystectomy with Intracorporeal Ileal Conduit in Male Patients: A Delphi Consensus Study Led by the ERUS Educational Board

Robot-assisted radical cystectomy (RARC) continues to expand, and several surgeons start training for this complex procedure. This calls for the development of a structured training program, with the aim to improve patient safety during RARC learning curve. A modified Delphi consensus process was started to develop the curriculum structure. An online survey based on the available evidence was delivered to a panel of 28 experts in the field of RARC, selected according to surgical and research experience, and expertise in running training courses. Consensus was defined as ≥80% agreement between the responders. Overall, 96.4% experts completed the survey. The structure of the RARC curriculum was defined as follows: (1) theoretical training; (2) preclinical simulation-based training: 5-d simulation-based activity, using models with increasing complexity (ie, virtual reality, and dry- and wet-laboratory exercises), and nontechnical skills training session; (3) clinical training: modular console activity of at least 6 mo at the host center (a RARC case was divided into 11 steps and steps of similar complexity were grouped into five modules); and (4) final evaluation: blind review of a video-recorded RARC case. This structured training pathway will guide a starting surgeon from the first steps of RARC toward independent completion of a full procedure. Clinical implementation is urgently needed

MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure.

OBJECTIVE: Acute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation with massive infiltration of myeloid cells in necrotic areas. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown. Here, we aimed to investigate the impact of Mer tyrosine kinase (MerTK) during ALF and also examine how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response. DESIGN: Flow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotype, functional/transcriptomic profile and tissue topography of MerTK+ monocytes/macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer-/-) mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice. RESULTS: We demonstrate a significant expansion of resolution-like MerTK+HLA-DRhigh cells in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCIIhigh macrophages during the resolution phase in ALF, APAP-treated Mer-/- mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells and increased number of neutrophils. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DRhigh phenotype which promotes neutrophil apoptosis and their subsequent clearance. CONCLUSIONS: We identify a hepatoprotective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Energetic synchrony throughout the non-breeding season in common guillemots from four colonies

The non‐breeding season presents significant energetic challenges to birds that breed in temperate or polar regions, with clear implications for population dynamics. In seabirds, the environmental conditions at non‐breeding sites drive food availability and the energetic cost of regulatory processes, resulting in variation in diet, behaviour and energetics; however, very few studies have attempted to understand if and how these aspects vary between populations. We investigated whether non‐breeding location influenced diet, behaviour and energetics in the common guillemot Uria aalge. We studied guillemots from four UK breeding colonies, two located on the west coast of Scotland and two on the east. We quantified non‐breeding distribution, foraging behaviour and activity budgets of 39 individuals from July to March, using geolocation–immersion loggers and time‐depth recorders, and used feather stable isotope signatures to infer diet during the post‐breeding moult. We calculated energy expenditure and investigated whether the peak (an indicator of the potential vulnerability to marine threats) varied between colonies. Individuals were spatially segregated according to the coastline they breed on, with west coast guillemots distributed off the west coast of the UK and east coast guillemots distributed off the east coast. Diet and behaviour were more similar in guillemots that shared a breeding coastline than those that did not, as west coast guillemots foraged at a lower trophic level, spent less time diving and engaged in more pelagic foraging than east coast guillemots. However, energy expenditure was remarkably similar between colonies, peaking during late February/early March, indicating that, during our study period, there was high synchrony between colonies in the timing of potential vulnerability to marine threats. Therefore, any anthropogenic changes that result in decreased food availability or increased energy expenditure during late winter may have greater impacts on energy balance, with consequences for population dynamics.</jats:p

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13