The Bibliothèque raisonnée Review of Volume 3 of the Treatise: Authorship, Text, and Translation

The review of volume 3 of Hume’s Treatise, a review that appeared in the Bibliothèque raisonnée in the spring of 1741, was the first published responseto Hume’s ethical theory. This review is also of interest because of questions that have arisen about its authorship and that of the earlier review of volume 1 of the Treatise in the same journal. In Part 1 of this paper we attribute to Pierre Des Maizeaux the notice of vols. 1 and 2 of the Treatise published in the spring 1739 issue of the Bibliothèque raisonnée. We then focus on the question of the authorship of the review of vol. 3. In Part 2 of our paper we provide a transcription of the French text of this review. Part 3 is a new English translation of the review. Part 4 provides comparisons between passages from the textof the Treatise, the French translations of these passages in the Bibliothèque raisonnée review, and our back-translations of these same passages. We alsoprovide brief comparisons between our translation of passages from this review and an earlier translation of these passages

StaTips Part VI: Bivariate correlation

A very common situation in medical research, including orthodontics, is when a researcher has to verify the association between 2variables, best referred to as bivariate correlation. Bivariate correlation is an analysis that measures the strength of relationship between twovariables through the calculation of different correlation coefficients. The most common correlation coefficients are: Pearson (r), Kendall(rho), Spearman (rho) and the point-biserial (rpb). The choice of the correct coefficient is based on the type of data to be analysed and, forsome of them, the existence of assumptions for using parametrical tests. Indications on how to choose the correct coefficient and abouttheir interpretation are provided

Validation of super-resolution 4Pi-microscopy, and its application to the study of intra-Golgi transport

Two problems have hampered the use of light microscopy for structural studies of cellular organelles for a long time: the limited spatial resolution, and the difficulty of obtaining true structural boundaries from complex intensity curves. The advent of modern super-resolution light-microscopy techniques and their combination with objective image segmentation now provide us with the means to bridge the gap between light and electron microscopy in cell biological applications. This study provides the first comparative correlative analysis of three-dimensional (3D) structures obtained by 4Pi-microscopy with those of transmission microscopy (TEM). The distribution within the cisternae of isolated Golgi stacks of the cargo protein PC3-pEGFP is here mapped in 3D by both 4Pi-microscopy and TEM for a detailed comparative analysis of their imaging capabilities. A high correlation was seen for these structures, demonstrating the particular accuracy of 4Pi-microscopy. Furthermore, for the first time, the transport of a cargo molecule (VSVG-pEGFP) through individual Golgi stacks (labelled by GalT-venusYFP) is visualized at the 4Pi-microscope super-resolution level. Following the procedures validated by the correlative analysis, the transport experiments show that: 1) VSVG-pEGFP rapidly enter/exit individual Golgi stack; 2) VSVG-pEGFP never fills the GalT-venusYFP compartment completely; and 3) the GalT-venusYFP compartment volume increases upon VSVG-pEGFP arrival. This morphological evidence supports some previous TEM-based observations of the intra-Golgi transport of VSVG-pEGFP and provides new insights towards a better understanding of protein transport across the Golgi stack. This study thus demonstrates the general applicability of super-resolution 4Pi-microscopy coupled with the zero-crossing-based segmentation technique for structural studies of sub-organelle protein distributions in living cells

StaTips Part IV: Selection, interpretation and reporting of the intraclass correlation coefficient

The intraclass correlation coefficient (ICC) is an index or repeatability that reflects both the degree of correlation and agreement between measurements. The ICC is widely used in orthodontic research for any continuous data set that satisfies assumptions for using the parametric methods. However, the ICC comprises a total of ten different variants not always recognized by researchers, which may give different outcomes. Here, a practical guide to choose the corrected variant of the ICC based on study design, and three different aspects (referred to as ‘model’, ‘type’ and ‘definition’) is provided. Finally, a full example of correct data interpretation and reporting is included

StaTips Part I: Choosing statistical test when dealing with differences

When dealing with statistical test hypothesis, one of the most common problems to deal with relates to the difference between or among groups, treatments or time points. Herein, a short guide is provided to chose the proper statistical test according to the nature of the data and study design

Regulation of cytotoxic lymphocyte effector functions

Studies of patients with inborn errors of immunity provide an important opportunity to understand the human immune system in a natural context. The articles in this thesis are a compilation of such investigations. With our work, we aimed to identify the cause of primary hemophagocytic lymphohistiocytosis (HLH) in an unexplained pediatric patient (paper I), explore the modulation of SAMD9 and SAMD9L gain-of-function (GOF) mutants (paper II), and understand natural killer (NK) cell biology in the context of DEF6 deficiency (paper III). In paper I, we uncovered biallelic loss-of-function variants in RHOG in a 4-monthold patient presenting with HLH and displaying defective lymphocyte exocytosis. Deletion of RHOG in a human NK cell line abrogated exocytosis that could be rescued by constructs expressing wild type RHOG protein. Moreover, we found that MUNC13-4, associated with autosomal recessive familial HLH type 3, required RHOG interactions for recruitment to the plasma membrane during cytotoxic granule exocytosis. Thus, we demonstrated that RHOG is essential in cytotoxic granule exocytosis by human T and NK cells and proposed that biallelic loss-offunction mutations in RHOG are a novel cause for familial HLH. In paper II, we examined a variety of pathogenic SAMD9 and SAMD9L GOF variants associated with syndromes encompassing bone marrow failure, autoinflammation or selective loss of NK cells, B cells, and monocytes. We sought to understand whether viral host range factors, which are known to antagonize wild-type SAMD9 and SAMD9L proteins, could counteract the anti-proliferative and anti-translational activities of these pathogenic variants. SAMD9 or SAMD9L variants and viral factors were overexpressed in a cell line, followed by biochemical and functional analyses. Vaccinia virus K1 exhibited the highest inhibitory capacity but could not antagonize a truncated variant of SAMD9L that lacked the K1 binding site. The other factors (M062, C7 and KI) could interact with all the SAMD9 and SAMD9L mutants but displayed low capacity in antagonizing the anti-translational and anti-proliferative action of SAMD9/9L mutants. This study provided some novel insights into the structure and the regulation of SAMD9/9L proteins. Additionally, it showed that targeting pathogenic GOF SAMD9/L mutants via viral host range factors or, more broadly speaking, by protein-protein interaction is possible. Autosomal recessive mutations in DEF6 are associated with autoimmunity and severe herpes virus infections. While the latter is a hallmark of NK cell deficiencies, this cell type has not been thoroughly studied in DEF6-deficient patients. In paper III, we surveyed the role of DEF6 in NK cell development and function. We analyzed NK cell phenotypes in DEF6-deficient patients from two unrelated families and found a reduction in canonical CD56dimPLZF+ NK cells concomitant with the expansion of CMV-induced adaptive CD56dimPLZF– NK cells. Deletion of DEF6 in induced pluripotent stem cells gave rise to mature NK cells in an in vitro culture system. In primary human NK cells, deletion of DEF6 reduced cell viability, degranulation and IFN-γ production. We therefore postulate that impaired canonical NK cell survival and function may contribute to the viral susceptibility of DEF6 deficient individuals. To conclude, these studies have shed light on several cellular and molecular mechanisms behind IEI. These mechanisms enlarge our understanding of cytotoxic lymphocytes and of the immune system in general. Moreover, they have inspired us to pursue new directions and experimental approaches in our research

StaTips Part VIII: Confidence interval for the sample mean

When conducting research on a given type of patients, it is impossible to examine all the existing subjects of that type (population) to derive the true mean of the parameter of interest. More realistically, by the investigation of a small group of subjects (sample) from the whole population, researchers can estimate an interval into which the true mean of the population lies. In statistics, such interval is referred to as confidence interval (CI). The calculation of the CI from a sample mean is simple and gives important information, not only regarding the true mean of the population, but also on the statistical significance of the difference between groups being compared. For these reasons, the reporting of the CIs is preferred over the p value alone

StaTips Part II: Assessment of the repeatability of measurements for continuous data

Primary research requests the recording of data through measurements, such as linear and angular parameters in cephalometric, strength of adhesion, skeletal maturation stages and so on. In all of these cases, an analysis of the method error, i.e. repeatability of the measurements, is a fundamental part of the study. In this paper, the case of the continuous data set will be taken into consideration

Hiperparatiroidismo primario, secundario y terciario : actualización

Fil: Perinetti, H. A.. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Departamento de Medicina Quirúrgic