Varieties of Top Incomes?

Focusing on the advanced political economies, this article critically reviews the recent scholarship on the evolution of top incomes over the past few decades. The existing literature shows that the determination of top incomes is complex, multifaceted and bound up with factors associated with both politics and economics. Technological change and globalization are vital sources of change in contemporary capitalism, but the continued diversity in top income shares across the advanced capitalist world suggests that these forces alone cannot account for the empirical patterns. Instead, there is compelling evidence that power and politics, including government policy, trade union and left party strength, institutions and financialization, all play a pivotal role in regulating distributive outcomes. It is argued that future research will require a plurality of methodological approaches in order to clarify the complex causal process that drives top-end income concentration

The preclinical pharmacology of the high affinity anti-IL-6R Nanobody (R) ALX-0061 supports its clinical development in rheumatoid arthritis

Introduction: The pleiotropic cytokine interleukin-6 (IL-6) plays an important role in the pathogenesis of different diseases, including rheumatoid arthritis (RA). ALX-0061 is a bispecific Nanobody (R) with a high affinity and potency for IL-6 receptor (IL-6R), combined with an extended half-life by targeting human serum albumin. We describe here the relevant aspects of its in vitro and in vivo pharmacology. Methods: ALX-0061 is composed of an affinity-matured IL-6R-targeting domain fused to an albumin-binding domain representing a minimized two-domain structure. A panel of different in vitro assays was used to characterize the biological activities of ALX-0061. The pharmacological properties of ALX-0061 were examined in cynomolgus monkeys, using plasma levels of total soluble (s)IL-6R as pharmacodynamic marker. Therapeutic effect was evaluated in a human IL-6-induced acute phase response model in the same species, and in a collagen-induced arthritis (CIA) model in rhesus monkeys, using tocilizumab as positive control. Results: ALX-0061 was designed to confer the desired pharmacological properties. A 200-fold increase of target affinity was obtained through affinity maturation of the parental domain. The high affinity for sIL-6R (0.19 pM) translated to a concentration-dependent and complete neutralization of sIL-6R in vitro. In cynomolgus monkeys, ALX-0061 showed a dose-dependent and complete inhibition of hIL-6-induced inflammatory parameters, including plasma levels of C-reactive protein (CRP), fibrinogen and platelets. An apparent plasma half-life of 6.6 days was observed after a single intravenous administration of 10 mg/kg ALX-0061 in cynomolgus monkeys, similar to the estimated expected half-life of serum albumin. ALX-0061 and tocilizumab demonstrated a marked decrease in serum CRP levels in a non-human primate CIA model. Clinical effect was confirmed in animals with active drug exposure throughout the study duration. Conclusions: ALX-0061 represents a minimized bispecific biotherapeutic of 26 kDa, nearly six times smaller than monoclonal antibodies. High in vitro affinity and potency was demonstrated. Albumin binding as a half-life extension technology resulted in describable and expected pharmacokinetics. Strong IL-6R engagement was shown to translate to in vivo effect in non-human primates, demonstrated via biomarker deregulation as well as clinical effect. Presented results on preclinical pharmacological properties of ALX-0061 are supportive of clinical development in RA

Versican-A Critical Extracellular Matrix Regulator of Immunity and Inflammation.

The extracellular matrix (ECM) proteoglycan, versican increases along with other ECM versican binding molecules such as hyaluronan, tumor necrosis factor stimulated gene-6 (TSG-6), and inter alpha trypsin inhibitor (IαI) during inflammation in a number of different diseases such as cardiovascular and lung disease, autoimmune diseases, and several different cancers. These interactions form stable scaffolds which can act as "landing strips" for inflammatory cells as they invade tissue from the circulation. The increase in versican is often coincident with the invasion of leukocytes early in the inflammatory process. Versican interacts with inflammatory cells either indirectly via hyaluronan or directly via receptors such as CD44, P-selectin glycoprotein ligand-1 (PSGL-1), and toll-like receptors (TLRs) present on the surface of immune and non-immune cells. These interactions activate signaling pathways that promote the synthesis and secretion of inflammatory cytokines such as TNFα, IL-6, and NFκB. Versican also influences inflammation by interacting with a variety of growth factors and cytokines involved in regulating inflammation thereby influencing their bioavailability and bioactivity. Versican is produced by multiple cell types involved in the inflammatory process. Conditional total knockout of versican in a mouse model of lung inflammation demonstrated significant reduction in leukocyte invasion into the lung and reduced inflammatory cytokine expression. While versican produced by stromal cells tends to be pro-inflammatory, versican expressed by myeloid cells can create anti-inflammatory and immunosuppressive microenvironments. Inflammation in the tumor microenvironment often contains elevated levels of versican. Perturbing the accumulation of versican in tumors can inhibit inflammation and tumor progression in some cancers. Thus versican, as a component of the ECM impacts immunity and inflammation through regulating immune cell trafficking and activation. Versican is emerging as a potential target in the control of inflammation in a number of different diseases

The reliability of replications: a study in computational reproductions

This study investigates researcher variability in computational reproduction, an activity for which it is least expected. Eighty-five independent teams attempted numerical replication of results from an original study of policy preferences and immigration. Reproduction teams were randomly grouped into a ‘transparent group’ receiving original study and code or ‘opaque group’ receiving only a method and results description and no code. The transparent group mostly verified original results (95.7% same sign and p-value cutoff), while the opaque group had less success (89.3%). Second-decimal place exact numerical reproductions were less common (76.9 and 48.1%). Qualitative investigation of the workflows revealed many causes of error, including mistakes and procedural variations. When curating mistakes, we still find that only the transparent group was reliably successful. Our findings imply a need for transparency, but also more. Institutional checks and less subjective difficulty for researchers ‘doing reproduction’ would help, implying a need for better training. We also urge increased awareness of complexity in the research process and in ‘push button’ replications

Evidence-based guidelines for supportive care of patients with Ebola virus disease.

The 2013-16 Ebola virus disease outbreak in west Africa was associated with unprecedented challenges in the provision of care to patients with Ebola virus disease, including absence of pre-existing isolation and treatment facilities, patients' reluctance to present for medical care, and limitations in the provision of supportive medical care. Case fatality rates in west Africa were initially greater than 70%, but decreased with improvements in supportive care. To inform optimal care in a future outbreak of Ebola virus disease, we employed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to develop evidence-based guidelines for the delivery of supportive care to patients admitted to Ebola treatment units. Key recommendations include administration of oral and, as necessary, intravenous hydration; systematic monitoring of vital signs and volume status; availability of key biochemical testing; adequate staffing ratios; and availability of analgesics, including opioids, for pain relief

The Crowdsourced Replication Initiative: Investigating Immigration and Social Policy Preferences. Executive Report.

In an era of mass migration, social scientists, populist parties and social movements raise concerns over the future of immigration-destination societies. What impacts does this have on policy and social solidarity? Comparative cross-national research, relying mostly on secondary data, has findings in different directions. There is a threat of selective model reporting and lack of replicability. The heterogeneity of countries obscures attempts to clearly define data-generating models. P-hacking and HARKing lurk among standard research practices in this area.This project employs crowdsourcing to address these issues. It draws on replication, deliberation, meta-analysis and harnessing the power of many minds at once. The Crowdsourced Replication Initiative carries two main goals, (a) to better investigate the linkage between immigration and social policy preferences across countries, and (b) to develop crowdsourcing as a social science method. The Executive Report provides short reviews of the area of social policy preferences and immigration, and the methods and impetus behind crowdsourcing plus a description of the entire project. Three main areas of findings will appear in three papers, that are registered as PAPs or in process

The Helicobacter pylori Genome Project : insights into H. pylori population structure from analysis of a worldwide collection of complete genomes

Helicobacter pylori, a dominant member of the gastric microbiota, shares co-evolutionary history with humans. This has led to the development of genetically distinct H. pylori subpopulations associated with the geographic origin of the host and with differential gastric disease risk. Here, we provide insights into H. pylori population structure as a part of the Helicobacter pylori Genome Project (HpGP), a multi-disciplinary initiative aimed at elucidating H. pylori pathogenesis and identifying new therapeutic targets. We collected 1011 well-characterized clinical strains from 50 countries and generated high-quality genome sequences. We analysed core genome diversity and population structure of the HpGP dataset and 255 worldwide reference genomes to outline the ancestral contribution to Eurasian, African, and American populations. We found evidence of substantial contribution of population hpNorthAsia and subpopulation hspUral in Northern European H. pylori. The genomes of H. pylori isolated from northern and southern Indigenous Americans differed in that bacteria isolated in northern Indigenous communities were more similar to North Asian H. pylori while the southern had higher relatedness to hpEastAsia. Notably, we also found a highly clonal yet geographically dispersed North American subpopulation, which is negative for the cag pathogenicity island, and present in 7% of sequenced US genomes. We expect the HpGP dataset and the corresponding strains to become a major asset for H. pylori genomics

Proteomics Applications in Neuroanatomy : a search for new regional markers in the mammalian brain

Many studies have been undertaken to acquire full knowledge on the cortical parcellation of the mammalian brain in distinct areas. These functional and anatomical entities are interconnected in a highly-specific manner and enable complex behavior, adjusted to the environment and habitat of the species. Various types of techniques have attempted to reveal the areal parcellation. The different methods used failed however in reaching a consensus about cortical organization due to differences in measurement method, the characteristic they focused on, and the lack of transferability of results to other species. These drawbacks were assumed to be get round by mapping the mammalian cortex with molecular areal marker distribution. The present research study introduces protein expression profiling as a novel approach in neuroanatomical studies. Gene expression profiling has been applied extensively in the past, but we moved the focus to the actual active molecules in all cellular processes and pathways, the proteins. The proteomics technique of 2-D DIGE, combined with mass spectrometry, was applied as screening method for new areal markers, with subsequent validation of their applicability with immunocytochemistry at the protein level and in situ hybridization at the mRNA level. Comparison of the protein content of three visual areas (17, 18 and 19) with 2-D DIGE located fifteen differentially expressed spots. Subsequent mass spectrometry identified ten proteins in these spots, from which we selected the low molecular weight subunit of neurofilament or NFL as potential areal marker. Indeed, we were able to prove a correlation between differential expression levels of NFL to differential laminar distribution patterns in all three visual areas. Immunocytochemistry revealed area-specific NFL protein distribution in the cat visual cortex with differences in staining intensity, cell and fiber density, type and organization. The boundaries between areas 17, 18 and 19 were set, with the 17/18 border as a transitional border-zone rather than a clear or clear-cut border. To assess the value of NFL as areal marker in the visual cortex of other mammalian species we performed immunocytochemistry on rat, mouse and macaque monkey tissue sections. In all three mammalian species, NFL protein distribution allowed setting boundaries between primary and secondary areas and subareas. This first part of the study delivered ‘proof of principle’; 2-D DIGE is adequate to screen for neurochemical differences between cortical areas that are mirrored by area-specific distribution patterns as detectable by immunocytochemistry. Since NFL was proven a valuable, new marker in the mouse visual cortex, we performed immunocytochemistry on coronal sections along the rostro-caudal axis to visualize this protein’s distribution throughout the entire mouse brain. Indeed, NFL protein displayed area-specific expression patterns throughout the entire forebrain. Cortical boundaries were set based on differences in laminar distribution patterns of neuronal cells and fibers. These borders were classified in three types (clear-cut, clear and transitional). When grouping corresponding area-specific patterns, this classification was clearly related to the functionality of cortical systems. We identified characteristic NFL protein outlines in the paleocortex, including the anterior cingulate, the insular and the retrosplenial cortex, the motor cortex and the sensory cortex. Immunoreactivity for NFL grants complementary information on the areal parcellation of the mouse brain, for which until this day exists no consensus brain map. NFL protein distribution opens new perspectives to study position and size of different cortical systems in less understood mammalian species. Next, we investigated if the area-specific expression pattern of the NFL protein could be correlated to an area-specific distribution pattern of the NFL mRNA. Neurons which translate NFL were located by means of in situ hybridization histochemistry as a fast and reliable screening method. Indeed, NFL mRNA appeared in the mouse cortex in an area-specific manner, what allowed cortical delineation. Not all boundaries between abutting regions were perfectly clear, but this presents no drawback on the advantages of in situ hybridization. In the final chapter of the results sections, proteome profiling was performed on two primary sensory areas of the mouse brain. 23 spots were located as differential, and were mass spectrometrically identified as 26 different proteins. The potential areal markers identified differed quite from the earlier identified candidates in the cat visual cortex. CKB and CRMP2 were selected and validated by means of in situ hybridization. While CKB mRNA allowed clear delination of mouse cortical areas, CRMP2 mainly visualized subcortical regions. To conclude, protein expression profiling and thus new areal markers deliver additional information in a fast, reliable and reproducible manner in relation to remaining issues in neuroanatomical research on smaller mammals, but also on complex species, like primates and humans.status: publishe