PCA-based lung motion model

Organ motion induced by respiration may cause clinically significant targeting errors and greatly degrade the effectiveness of conformal radiotherapy. It is therefore crucial to be able to model respiratory motion accurately. A recently proposed lung motion model based on principal component analysis (PCA) has been shown to be promising on a few patients. However, there is still a need to understand the underlying reason why it works. In this paper, we present a much deeper and detailed analysis of the PCA-based lung motion model. We provide the theoretical justification of the effectiveness of PCA in modeling lung motion. We also prove that under certain conditions, the PCA motion model is equivalent to 5D motion model, which is based on physiology and anatomy of the lung. The modeling power of PCA model was tested on clinical data and the average 3D error was found to be below 1 mm.Comment: 4 pages, 1 figure. submitted to International Conference on the use of Computers in Radiation Therapy 201

Mars analysis correction data assimilation: a multi-annual reanalysis of atmospheric observations for the red planet

Ever-increasing numbers of atmospheric observations from orbiting spacecraft, and increasingly sophisticated numerical atmospheric models, have recently permitted data assimilation techniques to be applied to planets beyond the Earth. Mars is the first extra-terrestrial planet for which reanalyses of the atmospheric state are now available. The Thermal Emission Spectrometer (TES) on board NASA’s Mars Global Surveyor (MGS) has produced an extensive atmospheric data set during its scientific mapping phase between 1999 and 2004. Nadir thermal profiles for the atmosphere below about 40 km altitude, and total dust and water ice opacities, have been retrieved from TES spectra, covering almost three complete Martian seasonal cycles (each seasonal cycle on Mars corresponds to 668.6 mean solar days, and the Martian mean solar day is about 24 hours and 40 minutes). Note that dust on Mars plays a key role in the weather and climate, mainly through its strong absorption of short wave radiation with a short radiative relaxation timescale of 1-2 days. Assimilating dust opacities correctly is, therefore, particularly important for atmospheric data assimilation on the Red Planet. TES retrieved observations have been analysed by assimilation into a Mars general circulation model (MGCM), making use of a sequential procedure known as the Analysis Correction scheme, a form of successive corrections method which has proved simple and robust under Martian conditions, even during the less-than-ideal MGS aerobraking period. The MGCM used at the University of Oxford and at The Open University consists of a spectral dynamical solver and a tracer transport scheme developed in the UK. Its package of state-of-the-art physical parameterization routines is shared with the LMD-MarsGCM, developed by the Laboratoire de Météorologie Dynamique in Paris (France). One limitation of TES is that relatively few limb profiles are available, compared to nadir soundings. Our MGS/TES reanalysis, therefore, does not include observations of temperature above about 40 km altitude, nor 3D information on dust opacity (the vertical distribution of dust opacity is prescribed assuming a well mixed dust layer with a rapid transition to a clear upper atmosphere at a height which depends on latitude and season. In September 2006 NASA’s Mars Reconnaissance Orbiter (MRO) started its mapping phase. The Mars Climate Sounder (MCS) on board MRO is a radiometer with eight mid- and far-infrared channels and one visible channel, which takes measurements in limb and off-nadir geometries. Retrieved vertical profiles of temperature, dust and water ice opacities from MCS observations can now be assimilated using the same scheme we used for TES, with the advantage of the extension in altitude (thermal profiles can extend to above 80 km altitude, although errors become larger at greater altitudes), the increased vertical resolution (~ 5km compared to > 10km for TES nadir retrievals), and the direct information on the vertical distribution of dust and water ice. Overall, the application of our data assimilation scheme to retrieved observations from TES and MCS spans almost six complete Martian seasonal cycles. This represents a multi-annual climatology for Mars, which has the advantage of being a complete, dynamically-balanced, four-dimensional best-fit to observations for all the atmospheric variables, including those for which no direct measurements are available (e.g. wind and surface pressure) and with regions of no observations filled-in in a physically-consistent way. The reanalysis represents, therefore, a unique opportunity to study the inter-annual variability of the Martian weather and climate with respect to all its components, such as the dust cycle, the water cycle, the CO2 cycle, the atmospheric tides and other prominent waves, such as high latitude baroclinic waves. In this contribution we present the first results of a complete assimilation of both datasets, using a consistent model and data assimilation scheme, and highlight the challenges of combining TES and MCS data assimilation to produce a multi-annual climatology. Particular attention will be devoted to the inter-annual variability of the atmospheric thermal field in response to dust storm activity. We will also provide an insight into the dynamics, looking in particular at the high latitude winds, waves and polar vortices. Our data assimilation products are freely available to the community for both science- and engineering-oriented purposes. The British Atmospheric Data Centre (BADC, http://badc.nerc.ac.uk) hosts our datasets, which, for the time being, are limited to the MGS/TES reanalysis. People may contact the corresponding author in order to register their interest and be updated about the status of the project. New versions of the MGS/TES reanalysis as well as the MRO/MCS reanalysis will be made available through the BADC in future. Interested people can download the current TES reanalysis dataset by registering at the BADC and searching for the MACDA (“Mars Analysis Correction Data Assimilation”) project. The direct link to the project is provided by the following URL: http://badc.nerc.ac.uk/view/badc.nerc.ac.uk__ATOM__DE_095e8da2-cf02-11e0-8b7a-00e08147026

CD1a autoreactive T cells recognize natural skin oils that function as headless antigens

CD1a autoreactive T cells are common in human blood and skin, but the search for natural autoantigens has been confounded by background T cell responses to CD1 proteins and self lipids. After capturing CD1a-lipid complexes, we gently eluted ligands, while preserving unliganded CD1a for testing lipids from tissues. CD1a released hundreds of ligands of two types. Inhibitory ligands were ubiquitous membrane lipids with polar headgroups, whereas stimulatory compounds were apolar oils. CD1a autoantigens naturally accumulate in epidermis and sebum, where they were identified as squalene and skin waxes. T cell activation by skin oils suggests that headless mini-antigens nest within CD1a and displace non-antigenic resident lipids with large head groups. Oily autoantigens naturally coat the skin's surface, pointing to a new mechanism of barrier immunity

Key stages in mammary gland development: The mammary end bud as a motile organ

In the rodent, epithelial end buds define the tips of elongating mammary ducts. These highly motile structures undergo repeated dichotomous branching as they aggressively advance through fatty stroma and, turning to avoid other ducts, they finally cease growth leaving behind the open, tree-like framework on which secretory alveoli develop during pregnancy. This review identifies the motility of end buds as a unique developmental marker that represents the successful integration of systemic and local mammotrophic influences, and covers relevant advances in ductal growth regulation, extracellular matrix (ECM) remodeling, and cell adhesion in the inner end bud. An unexpected growth-promoting synergy between insulin-like growth factor-1 and progesterone, in which ducts elongate without forming new end buds, is described as well as evidence strongly supporting self-inhibition of ductal elongation by end-bud-secreted transforming growth factor-β acting on stromal targets. The influence of the matrix metalloproteinase ECM-remodeling enzymes, notably matrix metalloproteinase-2, on end bud growth is discussed in the broader context of enzymes that regulate the polysaccharide-rich glycosaminoglycan elements of the ECM. Finally, a critical, motility-enabling role for the cellular architecture of the end bud is identified and the contribution of cadherins, the netrin/neogenin system, and ErbB2 to the structure and motility of end buds is discussed

Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes.

A considerable body of research indicates that mammary gland branching morphogenesis is dependent, in part, on the extracellular matrix (ECM), ECM-receptors, such as integrins and other ECM receptors, and ECM-degrading enzymes, including matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). There is some evidence that these ECM cues affect one or more of the following processes: cell survival, polarity, proliferation, differentiation, adhesion, and migration. Both three-dimensional culture models and genetic manipulations of the mouse mammary gland have been used to study the signaling pathways that affect these processes. However, the precise mechanisms of ECM-directed mammary morphogenesis are not well understood. Mammary morphogenesis involves epithelial 'invasion' of adipose tissue, a process akin to invasion by breast cancer cells, although the former is a highly regulated developmental process. How these morphogenic pathways are integrated in the normal gland and how they become dysregulated and subverted in the progression of breast cancer also remain largely unanswered questions

Response and Acquired Resistance to Everolimus in Anaplastic Thyroid Cancer

Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is effective in treating tumors harboring alterations in the mTOR pathway. Mechanisms of resistance to everolimus remain undefined. Resistance developed in a patient with metastatic anaplastic thyroid carcinoma after an extraordinary 18-month response. Whole-exome sequencing of pretreatment and drug-resistant tumors revealed a nonsense mutation in TSC2, a negative regulator of mTOR, suggesting a mechanism for exquisite sensitivity to everolimus. The resistant tumor also harbored a mutation in MTOR that confers resistance to allosteric mTOR inhibition. The mutation remains sensitive to mTOR kinase inhibitors

Whole-Genome Cartography of Estrogen Receptor α Binding Sites

Using a chromatin immunoprecipitation-paired end diTag cloning and sequencing strategy, we mapped estrogen receptor α (ERα) binding sites in MCF-7 breast cancer cells. We identified 1,234 high confidence binding clusters of which 94% are projected to be bona fide ERα binding regions. Only 5% of the mapped estrogen receptor binding sites are located within 5 kb upstream of the transcriptional start sites of adjacent genes, regions containing the proximal promoters, whereas vast majority of the sites are mapped to intronic or distal locations (>5 kb from 5′ and 3′ ends of adjacent transcript), suggesting transcriptional regulatory mechanisms over significant physical distances. Of all the identified sites, 71% harbored putative full estrogen response elements (EREs), 25% bore ERE half sites, and only 4% had no recognizable ERE sequences. Genes in the vicinity of ERα binding sites were enriched for regulation by estradiol in MCF-7 cells, and their expression profiles in patient samples segregate ERα-positive from ERα-negative breast tumors. The expression dynamics of the genes adjacent to ERα binding sites suggest a direct induction of gene expression through binding to ERE-like sequences, whereas transcriptional repression by ERα appears to be through indirect mechanisms. Our analysis also indicates a number of candidate transcription factor binding sites adjacent to occupied EREs at frequencies much greater than by chance, including the previously reported FOXA1 sites, and demonstrate the potential involvement of one such putative adjacent factor, Sp1, in the global regulation of ERα target genes. Unexpectedly, we found that only 22%–24% of the bona fide human ERα binding sites were overlapping conserved regions in whole genome vertebrate alignments, which suggest limited conservation of functional binding sites. Taken together, this genome-scale analysis suggests complex but definable rules governing ERα binding and gene regulation

Nucleocytoplasmic human O-GlcNAc transferase is sufficient for O-GlcNAcylation of mitochondrial proteins

O-linked N-acetylglucosamine modification (O-GlcNAcylation) is a nutrient-dependent protein post-translational modification (PTM), dynamically and reversibly driven by two enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) that catalyse the addition and the removal of the O-GlcNAc moieties to/from serine and threonine residues of target proteins respectively. Increasing evidence suggests involvement of O-GlcNAcylation in many biological processes, including transcription, signalling, neuronal development and mitochondrial function. The presence of a mitochondrial O-GlcNAc proteome and a mitochondrial OGT (mOGT) isoform has been reported. We explored the presence of mOGT in human cell lines and mouse tissues. Surprisingly, analysis of genomic sequences indicates that this isoform cannot be expressed in most of the species analysed, except some primates. In addition, we were not able to detect endogenous mOGT in a range of human cell lines. Knockdown experiments and Western blot analysis of all the predicted OGT isoforms suggested the expression of only a single OGT isoform. In agreement with this, we demonstrate that overexpression of the nucleocytoplasmic OGT (ncOGT) isoform leads to increased O-GlcNAcylation of mitochondrial proteins, suggesting that ncOGT is necessary and sufficient for the generation of the O-GlcNAc mitochondrial proteome

Key stages in mammary gland development: The cues that regulate ductal branching morphogenesis

Part of how the mammary gland fulfills its function of producing and delivering adequate amounts of milk is by forming an extensive tree-like network of branched ducts from a rudimentary epithelial bud. This process, termed branching morphogenesis, begins in fetal development, pauses after birth, resumes in response to estrogens at puberty, and is refined in response to cyclic ovarian stimulation once the margins of the mammary fat pad are met. Thus it is driven by systemic hormonal stimuli that elicit local paracrine interactions between the developing epithelial ducts and their adjacent embryonic mesenchyme or postnatal stroma. This local cellular cross-talk, in turn, orchestrates the tissue remodeling that ultimately produces a mature ductal tree. Although the precise mechanisms are still unclear, our understanding of branching in the mammary gland and elsewhere is rapidly improving. Moreover, many of these mechanisms are hijacked, bypassed, or corrupted during the development and progression of cancer. Thus a clearer understanding of the underlying endocrine and paracrine pathways that regulate mammary branching may shed light on how they contribute to cancer and how their ill effects might be overcome or entirely avoided

The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells

Regulatory T cells (Tregs) have a central role in maintaining immune homoeostasis through various mechanisms. Although the Forkhead transcription factor Foxp3 defines the Treg cell lineage and functions, the molecular mechanisms of Foxp3 induction and maintenance remain elusive. Here we show that Foxp3 is one of the direct targets of Nr4a2. Nr4a2 binds to regulatory regions of Foxp3, where it mediates permissive histone modifications. Ectopic expression of Nr4a2 imparts Treg-like suppressive activity to naïve CD4+ T cells by inducing Foxp3 and by repressing cytokine production, including interferon-γ and interleukin-2. Deletion of Nr4a2 in T cells attenuates induction of Tregs and causes aberrant induction of Th1, leading to the exacerbation of colitis. Nr4a2-deficeint Tregs are prone to lose Foxp3 expression and have attenuated suppressive ability both in vitro and in vivo. Thus, Nr4a2 has the ability to maintain T-cell homoeostasis by regulating induction, maintenance and suppressor functions of Tregs, and by repression of aberrant Th1 induction