Nova Geminorum 1912 and the Origin of the Idea of Gravitational Lensing

Einstein's early calculations of gravitational lensing, contained in a scratch notebook and dated to the spring of 1912, are reexamined. A hitherto unknown letter by Einstein suggests that he entertained the idea of explaining the phenomenon of new stars by gravitational lensing in the fall of 1915 much more seriously than was previously assumed. A reexamination of the relevant calculations by Einstein shows that, indeed, at least some of them most likely date from early October 1915. But in support of earlier historical interpretation of Einstein's notes, it is argued that the appearance of Nova Geminorum 1912 (DN Gem) in March 1912 may, in fact, provide a relevant context and motivation for Einstein's lensing calculations on the occasion of his first meeting with Erwin Freundlich during a visit in Berlin in April 1912. We also comment on the significance of Einstein's consideration of gravitational lensing in the fall of 1915 for the reconstruction of Einstein's final steps in his path towards general relativity.Comment: 31 p

Evaluation of gene-based family-based methods to detect novel genes associated with familial late onset Alzheimer disease

AbstractGene-based tests to study the combined effect of rare variants towards a particular phenotype have been widely developed for case-control studies, but their evolution and adaptation for family-based studies, especially for complex incomplete families, has been slower. In this study, we have performed a practical examination of all the latest gene-based methods available for family-based study designs using both simulated and real datasets. We have examined the performance of several collapsing, variance-component and transmission disequilibrium tests across eight different software and twenty-two models utilizing a cohort of 285 families (N=1,235) with late-onset Alzheimer disease (LOAD). After a thorough examination of each of these tests, we propose a methodological approach to identify, with high confidence, genes associated with the studied phenotype with high confidence and we provide recommendations to select the best software and model for family-based gene-based analyses. Additionally, in our dataset, we identified PTK2B, a GWAS candidate gene for sporadic AD, along with six novel genes (CHRD, CLCN2, HDLBP, CPAMD8, NLRP9, MAS1L) as candidates genes for familial LOAD.</jats:p

Genome-wide survival analysis of age at onset of alcohol dependence in extended high-risk COGA families.

BackgroundThe age at onset of alcohol dependence (AD) is a critical moderator of genetic associations for alcohol dependence. The present study evaluated whether single nucleotide polymorphisms (SNPs) can influence the age at onset of AD in large high-risk families from the Collaborative Study on the Genetics of Alcoholism (COGA).MethodsGenomewide SNP genotyping was performed in 1788 regular drinkers from 118 large European American families densely affected with alcoholism. We used a genome-wide Cox proportional hazards regression model to test for association between age at onset of AD and SNPs.ResultsThis family-based analysis identified an intergenic SNP, rs2168784 on chromosome 3 that showed strong evidence of association (P=5×10(-9)) with age at onset of AD among regular drinkers. Carriers of the minor allele of rs2168784 had 1.5 times the hazard of AD onset as compared with those homozygous for the major allele. By the age of 20 years, nearly 30% of subjects homozygous for the minor allele were alcohol dependent while only 19% of those homozygous for the major allele were. We also identified intronic SNPs in the ADP-ribosylation factor like 15 (ARL15) gene on chromosome 5 (P=1.11×10(-8)) and the UTP20 small subunit (UTP20) gene on chromosome 12 (P=4.32×10(-8)) that were associated with age at onset of AD.ConclusionsThis extended family based genome-wide cox-proportional hazards analysis identified several loci that might be associated with age at onset of AD

Biomechanical Analysis of Stoop and Free-Style Squat Lifting and Lowering with a Generic Back-Support Exoskeleton Model

Musculoskeletal disorders (MSDs) induced by industrial manual handling tasks are a major issue for workers and companies. As flexible ergonomic solutions, occupational exoskeletons can decrease critically high body stress in situations of awkward postures and motions. Biomechanical models with detailed anthropometrics and motions help us to acquire a comprehension of person- and application-specifics by considering the intended and unintended effects, which is crucial for effective implementation. In the present model-based analysis, a generic back-support exoskeleton model was introduced and applied to the motion data of one male subject performing symmetric and asymmetric dynamic manual handling tasks. Different support modes were implemented with this model, including support profiles typical of passive and active systems and an unconstrained optimal support mode used for reference to compare and quantify their biomechanical effects. The conducted simulations indicate that there is a high potential to decrease the peak compression forces in L4/L5 during the investigated heavy loaded tasks for all motion sequences and exoskeleton support modes (mean reduction of 13.3% without the optimal support mode). In particular, asymmetric motions (mean reduction of 14.7%) can be relieved more than symmetric ones (mean reduction of 11.9%) by the exoskeleton support modes without the optimal assistance. The analysis of metabolic energy consumption indicates a high dependency on lifting techniques for the effectiveness of the exoskeleton support. While the exoskeleton support substantially reduces the metabolic cost for the free-squat motions, a slightly higher energy consumption was found for the symmetric stoop motion technique with the active and optimal support mode

Four-year update of the EXIST-2 study

Objectives We examined the long-term effects of everolimus in patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Methods Following favorable results from the double- blind core phase of EXIST-2 (NCT00790400), patients were allowed to receive open-label everolimus (extension phase). Patients initially randomly assigned to everolimus continued on the same dose; those who were receiving placebo crossed over to everolimus 10 mg/day. Dose modifications were based on tolerability. The primary end point was angiomyolipoma response rate, defined as a ≥50% reduction from baseline in the sum volume of target renal angiomyolipomas in the absence of new target angiomyolipomas, kidney volume increase of >20% from nadir, and angiomyolipoma-related bleeding grade ≥2. The key secondary end point was safety. Results Of the 112 patients who received ≥1 dose of everolimus, 58% (95% CI, 48.3% to 67.3%) achieved angiomyolipoma response. Almost all patients (97%) experienced reduction in renal lesion volumes at some point during the study period. Median duration of everolimus exposure was 46.9 months. Sixteen (14.3%) patients experienced angiomyolipoma progression at some point in the study. No angiomyolipoma-related bleeding or nephrectomies were reported. One patient on everolimus underwent embolization for worsening right flank pain. Subependymal giant cell astrocytoma lesion response was achieved in 48% of patients and skin lesion response in 68% of patients. The most common adverse events suspected to be treatment-related were stomatitis (42%), hypercholesterolemia (30.4%), acne (25.9%), aphthous stomatitis and nasopharyngitis (each 21.4%). Ten (8.9%) patients withdrew because of an adverse event. Renal function remained stable, and the frequency of emergent adverse events generally decreased over time. Conclusions Everolimus treatment remained safe and effective over approximately 4 years. The overall risk/benefit assessment supports the use of everolimus as a viable treatment option for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Trial registration ClinicalTrials.gov NCT0079040