Early-stage design program for axial-force structures

Thesis (S.B. in Art and Design)--Massachusetts Institute of Technology, Dept. of Architecture, 2011.Cataloged from PDF version of thesis.Includes bibliographical references (p. 64).Structures that carry most of their load through the axial forces of tension or compression are more materially efficient than standard structures. However, they are not as straightforward to design since the forces in the structure depend on shape. The traditional method of form finding for such axial force structures is to create physical hanging models. These models are slow to produce and difficult to measure. Few digital design aids exist for designing axial force structures, and those that do tend to be for optimization or analysis, not necessarily for early stage design. In addition, they tend to lack desired functionality for a design program, and also tend focus on creating forms without considering engineering functionality. Since form and forces are so intertwined in axial-force structures, consideration of both in the early stages of design is desirable and is not fully addressed by existing programs. This thesis presents a new early stage design program, ForceDesigner, which improves the functionality of earlier programs and facilitates design by both architects and engineers. It builds on earlier design programs that use the particle spring system for creating digital hanging models, implementing the system in Processing and Java. The result is a program with a number of novel functions that allows designers interested in both form and forces to more quickly and easily create an unlimited number of efficient structures.by Alexander D. W. Jordan.S.B.in Art and Desig

Radiographic cortical thickness parameters as predictors of rotational alignment in proximal tibial shaft fractures: a cadaveric study

AIM The treatment of tibial fractures with an intramedullary nail is an established procedure. However, torsional control remains challenging using intraoperatively diagnostic tools. Radiographic tools such as the Cortical Step Sign (CSS) and the Diameter Difference Sign (DDS) may serve as tools for diagnosing a relevant malrotation. The aim of this study was to investigate the effect of torsional malalignment on CSS and DDS parameters and to construct a prognostic model to detect malalignment. METHODS A proximal tibial shaft fracture was set in human tibiae. Torsion was set stepwise from 0° to 30° in external and internal torsion. Images were obtained with a C-arm and transferred to a PC for measuring the medical cortical thickness (MCT), lateral cortical thickness (LCT), tibial diameter (TD) in AP and the anterior cortical thickness (ACT) as well as the posterior cortical thickness (PCT) and the transverse diameter (TD) of the proximal and the distal main fragment. RESULTS There were significant differences between the various degrees of torsion for each of the absolute values of the examined variables. The parameters with the highest correlation were TD, LCT and ACT. A model combining ACT, LCT, PCT and TD lateral was most suitable model in identifying torsional malalignment. The best prediction of clinically relevant torsional malalignment, namely 15°, was obtained with the TD and the ACT. CONCLUSION This study shows that the CSS and DDS are useful tools for the intraoperative detection of torsional malalignment in proximal tibial shaft fractures and should be used to prevent maltorsion

Dynamic antagonism between key repressive pathways maintains the placental epigenome

DNA and Histone 3 Lysine 27 methylation typically function as repressive modifications and operate within distinct genomic compartments. In mammals, the majority of the genome is kept in a DNA methylated state, whereas the Polycomb repressive complexes regulate the unmethylated CpG-rich promoters of developmental genes. In contrast to this general framework, the extra-embryonic lineages display non-canonical, globally intermediate DNA methylation levels, including disruption of local Polycomb domains. Here, to better understand this unusual landscape’s molecular properties, we genetically and chemically perturbed major epigenetic pathways in mouse trophoblast stem cells. We find that the extra-embryonic epigenome reflects ongoing and dynamic de novo methyltransferase recruitment, which is continuously antagonized by Polycomb to maintain intermediate, locally disordered methylation. Despite its disorganized molecular appearance, our data point to a highly controlled equilibrium between counteracting repressors within extra-embryonic cells, one that can seemingly persist indefinitely without bistable features typically seen for embryonic forms of epigenetic regulation

Nonlinear QCD Evolution: Saturation without Unitarization

We consider the perturbative description of saturation based on the nonlinear QCD evolution equation of Balitsky and Kovchegov (BK). Although the nonlinear corrections lead to saturation of the scattering amplitude locally in impact parameter space, we show that they do not unitarize the total cross section. The total cross section for the scattering of a strongly interacting probe on a hadronic target is found to grow exponentially with rapidity. The origin of this violation of unitarity is the presence of long range Coulomb fields away from the saturation region. The growth of these fields with rapidity is not tempered by the nonlinearity of the BK equation.Comment: 4 pages, RevTe

Acetylation of C/EBP alpha inhibits its granulopoietic function

CCAAT/enhancer-binding protein alpha (C/EBP alpha) is an essential transcription factor for myeloid lineage commitment. Here we demonstrate that acetylation of C/EBP alpha at lysine residues K298 and K302, mediated at least in part by general control non-derepressible 5 (GCN5), impairs C/EBP alpha DNA-binding ability and modulates C/EBP alpha transcriptional activity. Acetylated C/EBP alpha is enriched in human myeloid leukaemia cell lines and acute myeloid leukaemia (AML) samples, and downregulated upon granulocyte-colony stimulating factor (G-CSF)-mediated granulocytic differentiation of 32Dcl3 cells. C/EBP alpha mutants that mimic acetylation failed to induce granulocytic differentiation in C/EBP alpha-dependent assays, in both cell lines and in primary hematopoietic cells. Our data uncover GCN5 as a negative regulator of C/EBP alpha and demonstrate the importance of C/EBP alpha acetylation in myeloid differentiation

Collaborative nowcasting of COVID-19 hospitalization incidences in Germany

Real-time surveillance is a crucial element in the response to infectious disease outbreaks. However, the interpretation of incidence data is often hampered by delays occurring at various stages of data gathering and reporting. As a result, recent values are biased downward, which obscures current trends. Statistical nowcasting techniques can be employed to correct these biases, allowing for accurate characterization of recent developments and thus enhancing situational awareness. In this paper, we present a preregistered real-time assessment of eight nowcasting approaches, applied by independent research teams to German 7-day hospitalization incidences during the COVID-19 pandemic. This indicator played an important role in the management of the outbreak in Germany and was linked to levels of non-pharmaceutical interventions via certain thresholds. Due to its definition, in which hospitalization counts are aggregated by the date of case report rather than admission, German hospitalization incidences are particularly affected by delays and can take several weeks or months to fully stabilize. For this study, all methods were applied from 22 November 2021 to 29 April 2022, with probabilistic nowcasts produced each day for the current and 28 preceding days. Nowcasts at the national, state, and age-group levels were collected in the form of quantiles in a public repository and displayed in a dashboard. Moreover, a mean and a median ensemble nowcast were generated. We find that overall, the compared methods were able to remove a large part of the biases introduced by delays. Most participating teams underestimated the importance of very long delays, though, resulting in nowcasts with a slight downward bias. The accompanying prediction intervals were also too narrow for almost all methods. Averaged over all nowcast horizons, the best performance was achieved by a model using case incidences as a covariate and taking into account longer delays than the other approaches. For the most recent days, which are often considered the most relevant in practice, a mean ensemble of the submitted nowcasts performed best. We conclude by providing some lessons learned on the definition of nowcasting targets and practical challenges

Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus

BACKGROUND: Diabetic nephropathy is a serious complication of diabetes mellitus and is associated with considerable morbidity and high mortality. There is increasing evidence to suggest that dysregulation of the epigenome is involved in diabetic nephropathy. We assessed whether epigenetic modification of DNA methylation is associated with diabetic nephropathy in a case-control study of 192 Irish patients with type 1 diabetes mellitus (T1D). Cases had T1D and nephropathy whereas controls had T1D but no evidence of renal disease. METHODS: We performed DNA methylation profiling in bisulphite converted DNA from cases and controls using the recently developed Illumina Infinium(R) HumanMethylation27 BeadChip, that enables the direct investigation of 27,578 individual cytosines at CpG loci throughout the genome, which are focused on the promoter regions of 14,495 genes. RESULTS: Singular Value Decomposition (SVD) analysis indicated that significant components of DNA methylation variation correlated with patient age, time to onset of diabetic nephropathy, and sex. Adjusting for confounding factors using multivariate Cox-regression analyses, and with a false discovery rate (FDR) of 0.05, we observed 19 CpG sites that demonstrated correlations with time to development of diabetic nephropathy. Of note, this included one CpG site located 18 bp upstream of the transcription start site of UNC13B, a gene in which the first intronic SNP rs13293564 has recently been reported to be associated with diabetic nephropathy. CONCLUSION: This high throughput platform was able to successfully interrogate the methylation state of individual cytosines and identified 19 prospective CpG sites associated with risk of diabetic nephropathy. These differences in DNA methylation are worthy of further follow-up in replication studies using larger cohorts of diabetic patients with and without nephropathy

Gauging NOTCH1 Activation in Cancer Using Immunohistochemistry

Fixed, paraffin-embedded (FPE) tissues are a potentially rich resource for studying the role of NOTCH1 in cancer and other pathologies, but tests that reliably detect activated NOTCH1 (NICD1) in FPE samples have been lacking. Here, we bridge this gap by developing an immunohistochemical (IHC) stain that detects a neoepitope created by the proteolytic cleavage event that activates NOTCH1. Following validation using xenografted cancers and normal tissues with known patterns of NOTCH1 activation, we applied this test to tumors linked to dysregulated Notch signaling by mutational studies. As expected, frequent NICD1 staining was observed in T lymphoblastic leukemia/lymphoma, a tumor in which activating NOTCH1 mutations are common. However, when IHC was used to gauge NOTCH1 activation in other human cancers, several unexpected findings emerged. Among B cell tumors, NICD1 staining was much more frequent in chronic lymphocytic leukemia than would be predicted based on the frequency of NOTCH1 mutations, while mantle cell lymphoma and diffuse large B cell lymphoma showed no evidence of NOTCH1 activation. NICD1 was also detected in 38% of peripheral T cell lymphomas. Of interest, NICD1 staining in chronic lymphocytic leukemia cells and in angioimmunoblastic lymphoma was consistently more pronounced in lymph nodes than in surrounding soft tissues, implicating factors in the nodal microenvironment in NOTCH1 activation in these diseases. Among carcinomas, diffuse strong NICD1 staining was observed in 3.8% of cases of triple negative breast cancer (3 of 78 tumors), but was absent from 151 non-small cell lung carcinomas and 147 ovarian carcinomas. Frequent staining of normal endothelium was also observed; in line with this observation, strong NICD1 staining was also seen in 77% of angiosarcomas. These findings complement insights from genomic sequencing studies and suggest that IHC staining is a valuable experimental tool that may be useful in selection of patients for clinical trials

Accumulation of mutations in antibody and CD8 T cell epitopes in a B cell depleted lymphoma patient with chronic SARS-CoV-2 infection

Antibodies against the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can drive adaptive evolution in immunocompromised patients with chronic infection. Here we longitudinally analyze SARS-CoV-2 sequences in a B cell-depleted, lymphoma patient with chronic, ultimately fatal infection, and identify three mutations in the spike protein that dampen convalescent plasma-mediated neutralization of SARS-CoV-2. Additionally, four mutations emerge in non-spike regions encoding three CD8 T cell epitopes, including one nucleoprotein epitope affected by two mutations. Recognition of each mutant peptide by CD8 T cells from convalescent donors is reduced compared to its ancestral peptide, with additive effects resulting from double mutations. Querying public SARS-CoV-2 sequences shows that these mutations have independently emerged as homoplasies in circulating lineages. Our data thus suggest that potential impacts of CD8 T cells on SARS-CoV-2 mutations, at least in those with humoral immunodeficiency, warrant further investigation to inform on vaccine design

Event shapes in e+e- annihilation and deep inelastic scattering

This article reviews the status of event-shape studies in e+e- annihilation and DIS. It includes discussions of perturbative calculations, of various approaches to modelling hadronisation and of comparisons to data.Comment: Invited topical review for J.Phys.G; 40 pages; revised version corrects some nomenclatur