On the strength of columns

The main object of these experiments was to determine how columns behave before collapse under axial loading. The original title of the research was "An investigation into the factors determining the strength of built-up steel struts". The title had to be amended as the testing machines necessitated the use of "model" sections.In mathematical investigations the columns considered are taken as ideal, and therefore materially different from actual columns. To some extent this difference could be attributed to the difference between theoretical assumed conditions of elasticity and those found in actual metals as manufactured. A more important cause of the difference is the varying nature of the end conditions employed. The results of the accurate researches of such men as Tetmajer, Hodgkinson, Christie and Howard, who brought with them not only ripe experience but careful and clear methods of experimenting are a testimony to the difficulty of reconciling theory and experiment.In the enthusiasm generated more than 150 years ago by the work of Euler, mathematical formulae were established with the purpose of making allowance for the imperfections existing in a practical column. So far a 3 the author is aware the subject has been treated only mathematically and no one has approached it experimentally, except to determine the effects of the direct eccentricity of loading. Despite the many minute mathematical investigations made, the comparative accuracy and even the validity of them is still doubtful. The a uthor’s discussions on the "Imperfection tests" show that the only variant of noteworthy consequence is the eccentricity of loading: the other imperfections, unless of a critical magnitude, having practically negligible effects on the ultimate strength of a column.Among the most notable features of the au t h o r ’s work could be considered the collective view of the stress-strain diagrams, thejintroduction of the virtual coefficients of elasticity, the definite divisions of the column graph, quantitative data about "permanent set", "imperfection tests" and the method for the adequate allowance in area due to rivet holes in a built-up piece.The bending formulae determined for long columns represent more accurately most of the experimental results. The yield range,- represented by a straight line law,- has not been definitely formulated. This is due to the fact that the exact values of the critical compressive and the tensile stress determining the range were not known with sufficient accuracy for the materials used by the earlier experimenters. No one, except Robertson, has carried out crushing tests with a view to determine the exact compressive stress-strain relations. It can be stated that the yield range will be represented by an equation of the formp = A + B - Cx2/k , where A - a constant depending on the material. B = a constant depending on the end conditions, C =a reducing factor depending on the end conditions.The behaviour of built-up columns has been the subject of world-wide discussion. The author’s views regarding the "non-homogeneous" action of the columns and the reduction in area for rivet holes are fully described in this Thesis.Though the present investigations embrace only a’”limited part of the vast field of experimental columns, the author feels that similar methods applied to full-sized sections will give results of value to the practical designer. A programme of column tests should include not only tension tests but also crushing tests with a view to determine the primary stress-strain relations. More "rivetreduction" experiments are needed to test the conclusions arrived at for the adequate allowance in area due to rivet holes

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Oral selinexor-dexamethasone for triple-class refractory multiple myeloma

BACKGROUND Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options. METHODS We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point. RESULTS A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients. CONCLUSIONS Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815. © 2019 Massachusetts Medical Society

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

No abstract available

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

non present