Apparatus for histological validation of in vivo and ex vivo magnetic resonance imaging of the human prostate

This article describes apparatus to aid histological validation of magnetic resonance imaging studies of the human prostate. The apparatus includes a 3D-printed patientspecific mold that facilitates aligned in vivo and ex vivo imaging, in situ tissue fixation, and tissue sectioning with minimal organ deformation. The mold and a dedicated container include MRI-visible landmarks to enable consistent tissue positioning and minimize image registration complexity. The inclusion of high spatial resolution ex vivo imaging aids in registration of in vivo MRI and histopathology data

The biomechanics of amnion rupture: an X-ray diffraction study

Pre-term birth is the leading cause of perinatal and neonatal mortality, 40% of which are attributed to the pre-term premature rupture of amnion. Rupture of amnion is thought to be associated with a corresponding decrease in the extracellular collagen content and/or increase in collagenase activity. However, there is very little information concerning the detailed organisation of fibrillar collagen in amnion and how this might influence rupture. Here we identify a loss of lattice like arrangement in collagen organisation from areas near to the rupture site, and present a 9% increase in fibril spacing and a 50% decrease in fibrillar organisation using quantitative measurements gained by transmission electron microscopy and the novel application of synchrotron X-ray diffraction. These data provide an accurate insight into the biomechanical process of amnion rupture and highlight X-ray diffraction as a new and powerful tool in our understanding of this process

The Virtues of Thisness Presentism

Presentists believe that only present things exist. But opponents insist this view has unacceptable implications: if only present things exist, we can’t express singular propositions about the past, since the obvious propositional constituents don’t exist, nor can we account for temporal passage, or the openness of the future. According to such opponents, and in spite of the apparent ‘common sense’ status of the view, presentism should be rejected on the basis of these unacceptable implications. In this paper, I present and defend a version of presentism (‘Thisness Presentism’) that avoids the unacceptable implications. The basic strategy I employ is familiar—I postulate presently existing entities to serve as surrogates (or ‘proxies’) for non-present entities—but some of the details of my proposal are more novel, and their application to these problems is certainly novel. One overarching thesis of this paper is that Thisness Presentism is preferable to other versions of presentism since it solves important problems facing standard iterations of the view. And I assume that this is a good positive reason in favour of the underlying thisness ontology

Culling-Induced Changes in Badger (Meles meles) Behaviour, Social Organisation and the Epidemiology of Bovine Tuberculosis

In the UK, attempts since the 1970s to control the incidence of bovine tuberculosis (bTB) in cattle by culling a wildlife host, the European badger (Meles meles), have produced equivocal results. Culling-induced social perturbation of badger populations may lead to unexpected outcomes. We test predictions from the ‘perturbation hypothesis’, determining the impact of culling operations on badger populations, movement of surviving individuals and the influence on the epidemiology of bTB in badgers using data dervied from two study areas within the UK Government's Randomised Badger Culling Trial (RBCT). Culling operations did not remove all individuals from setts, with between 34–43% of badgers removed from targeted social groups. After culling, bTB prevalence increased in badger social groups neighbouring removals, particularly amongst cubs. Seventy individual adult badgers were fitted with radio-collars, yielding 8,311 locational fixes from both sites between November 2001 and December 2003. Home range areas of animals surviving within removed groups increased by 43.5% in response to culling. Overlap between summer ranges of individuals from Neighbouring social groups in the treatment population increased by 73.3% in response to culling. The movement rate of individuals between social groups was low, but increased after culling, in Removed and Neighbouring social groups. Increased bTB prevalence in Neighbouring groups was associated with badger movements both into and out of these groups, although none of the moving individuals themselves tested positive for bTB. Significant increases in both the frequency of individual badger movements between groups and the emergence of bTB were observed in response to culling. However, no direct evidence was found to link the two phenomena. We hypothesise that the social disruption caused by culling may not only increase direct contact and thus disease transmission between surviving badgers, but may also increase social stress within the surviving population, causing immunosuppression and enhancing the expression of disease

A low upper mass limit for the central black hole in the late-type galaxy NGC 4414

We present our mass estimate of the central black hole in the isolated spiral galaxy NGC 4414. Using natural guide star adaptive optics assisted observations with the Gemini Near-Infrared Integral Field Spectrometer (NIFS) and the natural seeing Gemini Multi-Object Spectrographs-North (GMOS), we derived two-dimensional stellar kinematic maps of NGC 4414 covering the central 1.5 arcsec and 10 arcsec, respectively, at a NIFS spatial resolution of 0.13 arcsec. The kinematic maps reveal a regular rotation pattern and a central velocity dispersion dip down to around 105 km s$^{-1}$. We constructed dynamical models using two different methods: Jeans anisotropic dynamical modeling and axisymmetric Schwarzschild modeling. Both modeling methods give consistent results, but we cannot constrain the lower mass limit and only measure an upper limit for the black hole mass of M$_{BH}$ = 1.56 × 10$^{6}$M⊙ (at 3σ level) which is at least 1σ below the recent M$_{BH}$−σe relations. Further tests with dark matter, mass-to-light ratio variation and different light models confirm that our results are not dominated by uncertainties. The derived upper limit mass is not only below the M$_{BH}$−σe relation, but is also five times lower than the lower limit black hole mass anticipated from the resolution limit of the sphere of influence. This proves that via high quality integral field data we are now able to push black hole measurements down to at least five times less than the resolution limit.The authors want to thank Tony Wong for providing the CO data of NGC 4414 and Remco Van den Bosch for fruitful discussions regarding the MGE model of NGC 4414. M.C. acknowledges support from a Royal Society University Research Fellowship. Based on observations obtained at the Gemini Observatory, which is operated by the Association of Universities for Research in Astronomy, Inc., under a cooperative agreement with the NSF on behalf of the Gemini partnership: the National Science Foundation (United States), the National Research Council (Canada), CONICYT (Chile), the Australian Research Council (Australia), Ministério da Ciência, Tecnologia e Inovação (Brazil) and Ministerio de Ciencia, Tecnología e Innovación Productiva (Argentina), under program GN-2007A-Q-45. Based on observations made with the NASA/ESA Hubble Space Telescope, obtained from the ESA Hubble Science Archive at the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS 5-26555. Funding for SDSS-III has been provided by the Alfred P. Sloan Foundation, the Participating Institutions, the National Science Foundation, and the U.S. Department of Energy Office of Science. The SDSS-III web site is http://www.sdss3.org/. SDSS-III is managed by the Astrophysical Research Consortium for the Participating Institutions of the SDSS-III Collaboration including the University of Arizona, the Brazilian Participation Group, Brookhaven National Laboratory, Carnegie Mellon University, University of Florida, the French Participation Group, the German Participation Group, Harvard University, the Instituto de Astrofisica de Canarias, the Michigan State/Notre Dame/JINA Participation Group, Johns Hopkins University, Lawrence Berkeley National Laboratory, Max Planck Institute for Astrophysics, Max Planck Institute for Extraterrestrial Physics, New Mexico State University, New York University, Ohio State University, Pennsylvania State University, University of Portsmouth, Princeton University, the Spanish Participation Group, University of Tokyo, University of Utah, Vanderbilt University, University of Virginia, University of Washington, and Yale University. This research made use of Montage. It is funded by the National Science Foundation under Grant Number ACI-1440620, and was previously funded by the National Aeronautics and Space Administration’s Earth Science Technology Office, Computation Technologies Project, under Cooperative Agreement Number NCC5-626 between NASA and the California Institute of Technology. This research has made use of the NASA/IPAC Extragalactic Database (NED) which is operated by the Jet Propulsion Laboratory, California Institute of Technology, under contract with the National Aeronautics and Space Administration. We acknowledge the usage of the HyperLeda database (http://leda.univ-lyon1.fr

Minimal stress shielding with a Mallory-Head titanium femoral stem with proximal porous coating in total hip arthroplasty

<p>Abstract</p> <p>Background</p> <p>As longevity of cementless femoral components enters the third decade, concerns arise with long-term effects of fixation mode on femoral bone morphology. We examined the long-term consequences on femoral remodeling following total hip arthroplasty with a porous plasma-sprayed tapered titanium stem.</p> <p>Methods</p> <p>Clinical data and radiographs were reviewed from a single center for 97 randomly selected cases implanted with the Mallory-Head Porous femoral component during primary total hip arthroplasty. Measurements were taken from preoperative and long-term follow-up radiographs averaging 14 years postoperative. Average changes in the proximal, middle and diaphyseal zones were determined.</p> <p>Results</p> <p>On anteroposterior radiographs, the proximal cortical thickness was unchanged medially and the lateral zone increased 1.3%. Middle cortical thickness increased 4.3% medially and 1.2% laterally. Distal cortical thickness increased 9.6% medially and 1.9% laterally. Using the anteroposterior radiographs, canal fill at 100 mm did not correlate with bony changes at any level (Spearman's rank correlation coefficient of -0.18, 0.05, and 0.00; p value = 0.09, 0.67, 0.97). On lateral radiographs, the proximal cortical thickness increased 1.5% medially and 0.98% laterally. Middle cortical thickness increased 2.4% medially and 1.3% laterally. Distal cortical thickness increased 3.5% medially and 2.1% laterally. From lateral radiographs, canal fill at 100 mm correlated with bony hypertrophy at the proximal, mid-level, and distal femur (Spearman's rank correlation coefficient of 0.85, 0.33, and 0.28, respectively; p value = 0.001, 0.016, and 0.01, respectively).</p> <p>Conclusion</p> <p>Stress shielding is minimized with the Mallory-Head titanium tapered femoral stem with circumferential proximal plasma-sprayed coating in well-fixed and well-functioning total hip arthroplasty. Additionally, the majority of femora demonstrated increased cortical thickness in all zones around the stem prosthesis. Level of Evidence: Therapeutic Level III.</p

Domain Altering SNPs in the Human Proteome and Their Impact on Signaling Pathways

Single nucleotide polymorphisms (SNPs) constitute an important mode of genetic variations observed in the human genome. A small fraction of SNPs, about four thousand out of the ten million, has been associated with genetic disorders and complex diseases. The present study focuses on SNPs that fall on protein domains, 3D structures that facilitate connectivity of proteins in cell signaling and metabolic pathways. We scanned the human proteome using the PROSITE web tool and identified proteins with SNP containing domains. We showed that SNPs that fall on protein domains are highly statistically enriched among SNPs linked to hereditary disorders and complex diseases. Proteins whose domains are dramatically altered by the presence of an SNP are even more likely to be present among proteins linked to hereditary disorders. Proteins with domain-altering SNPs comprise highly connected nodes in cellular pathways such as the focal adhesion, the axon guidance pathway and the autoimmune disease pathways. Statistical enrichment of domain/motif signatures in interacting protein pairs indicates extensive loss of connectivity of cell signaling pathways due to domain-altering SNPs, potentially leading to hereditary disorders

Evolutionary Epidemiology of Drug-Resistance in Space

The spread of drug-resistant parasites erodes the efficacy of therapeutic treatments against many infectious diseases and is a major threat of the 21st century. The evolution of drug-resistance depends, among other things, on how the treatments are administered at the population level. “Resistance management” consists of finding optimal treatment strategies that both reduce the consequence of an infection at the individual host level, and limit the spread of drug-resistance in the pathogen population. Several studies have focused on the effect of mixing different treatments, or of alternating them in time. Here, we analyze another strategy, where the use of the drug varies spatially: there are places where no one receives any treatment. We find that such a spatial heterogeneity can totally prevent the rise of drug-resistance, provided that the size of treated patches is below a critical threshold. The range of parasite dispersal, the relative costs and benefits of being drug-resistant compared to being drug-sensitive, and the duration of an infection with drug-resistant parasites are the main factors determining the value of this threshold. Our analysis thus provides some general guidance regarding the optimal spatial use of drugs to prevent or limit the evolution of drug-resistance

Identifying allosteric fluctuation transitions between different protein conformational states as applied to Cyclin Dependent Kinase 2

BACKGROUND: The mechanisms underlying protein function and associated conformational change are dominated by a series of local entropy fluctuations affecting the global structure yet are mediated by only a few key residues. Transitional Dynamic Analysis (TDA) is a new method to detect these changes in local protein flexibility between different conformations arising from, for example, ligand binding. Additionally, Positional Impact Vertex for Entropy Transfer (PIVET) uses TDA to identify important residue contact changes that have a large impact on global fluctuation. We demonstrate the utility of these methods for Cyclin-dependent kinase 2 (CDK2), a system with crystal structures of this protein in multiple functionally relevant conformations and experimental data revealing the importance of local fluctuation changes for protein function. RESULTS: TDA and PIVET successfully identified select residues that are responsible for conformation specific regional fluctuation in the activation cycle of Cyclin Dependent Kinase 2 (CDK2). The detected local changes in protein flexibility have been experimentally confirmed to be essential for the regulation and function of the kinase. The methodologies also highlighted possible errors in previous molecular dynamic simulations that need to be resolved in order to understand this key player in cell cycle regulation. Finally, the use of entropy compensation as a possible allosteric mechanism for protein function is reported for CDK2. CONCLUSION: The methodologies embodied in TDA and PIVET provide a quick approach to identify local fluctuation change important for protein function and residue contacts that contributes to these changes. Further, these approaches can be used to check for possible errors in protein dynamic simulations and have the potential to facilitate a better understanding of the contribution of entropy to protein allostery and function