4,870 research outputs found
Tumor cell nuclei soften during transendothelial migration
During cancer metastasis, tumor cells undergo significant deformation in order to traverse through endothelial cell junctions in the walls of blood vessels. As cells pass through narrow gaps, smaller than the nuclear diameter, the spatial configuration of chromatin must change along with the distribution of nuclear enzymes. Nuclear stiffness is an important determinant of the ability of cells to undergo transendothelial migration, yet no studies have been conducted to assess whether tumor cell cytoskeletal or nuclear stiffness changes during this critical process in order to facilitate passage. To address this question, we employed two non-contact methods, Brillouin confocal microscopy (BCM) and confocal reflectance quantitative phase microscopy (QPM), to track the changes in mechanical properties of live, transmigrating tumor cells in an in vitro collagen gel platform. Using these two imaging modalities to study transmigrating MDA-MB-231, A549, and A375 cells, we found that both the cells and their nuclei soften upon extravasation and that the nuclear membranes remain soft for at least 24 h. These new data suggest that tumor cells adjust their mechanical properties in order to facilitate extravasation
The macro-economic effects of health co-benefits associated with climate change mitigation strategies
The UK government has specific targets for greenhouse gas (GHG) emission reduction to
lower the risk of dangerous climate change. Strategies to reduce GHG emissions are
sometimes perceived as expensive and difficult to implement but previous work has
demonstrated significant potential health co-benefits from ‘Active Travel and low carbon
driving’, ‘Housing Insulation/Ventilation’, and ‘Healthy Diet’ scenarios which may be
attractive to policymakers. Here a Computable General Equilibrium model is used to assess
the financial effects of such health co-benefits on the wider economy including changes in
labour force, social security payments and healthcare costs averted. Results suggest that for
all scenarios the financial impacts of the health co-benefits will be positive and increased
active travel in particular is likely to make a substantial contribution, largely due to health
care costs averted.
Strategies to reduce GHG emissions and improve health are likely to result in substantial and
increasing positive contributions to the economy which may offset some potential economic
costs and thereby be seen more favourably in times of economic austerity
Exploring the Use of Cost-Benefit Analysis to Compare Pharmaceutical Treatments for Menorrhagia
Background: The extra-welfarist theoretical framework tends to focus on health-related quality of life, whilst the welfarist framework captures a wider notion of well-being. EQ-5D and SF-6D are commonly used to value outcomes in chronic conditions with episodic symptoms, such as heavy menstrual bleeding (clinically termed menorrhagia). Because of their narrow-health focus and the condition’s periodic nature these measures may be unsuitable. A viable alternative measure is willingness to pay (WTP) from the welfarist framework. Objective: We explore the use of WTP in a preliminary cost-benefit analysis comparing pharmaceutical treatments for menorrhagia.
Methods: A cost-benefit analysis was carried out based on an outcome of WTP. The analysis is based in the UK primary care setting over a 24-month time period, with a partial societal perspective. Ninety-nine women completed a WTP exercise from the ex-ante (pre-treatment/condition) perspective. Maximum average WTP values were elicited for two pharmaceutical treatments, levonorgestrel-releasing intrauterine system (LNG-IUS) and oral treatment. Cost data were offset against WTP and the net present value derived for treatment. Qualitative information explaining the WTP values was also collected.
Results: Oral treatment was indicated to be the most cost-beneficial intervention costing £107 less than LNG-IUS and generating £7 more benefits. The mean incremental net present value for oral treatment compared with LNG-IUS was £113. The use of the WTP approach was acceptable as very few protests and non-responses were observed. Conclusion: The preliminary cost-benefit analysis results recommend oral treatment as the first-line treatment for menorrhagia. The WTP approach is a feasible alternative to the conventional EQ-5D/SF-6D approaches and offers advantages by capturing benefits beyond health, which is particularly relevant in menorrhagia
Myocardial Viability Imaging using Manganese-Enhanced MRI in the First Hours after Myocardial Infarction
Early measurements of tissue viability after myocardial infarction (MI) are essential for accurate diagnosis and treatment planning but are challenging to obtain. Here, manganese, a calcium analogue and clinically approved magnetic resonance imaging (MRI) contrast agent, is used as an imaging biomarker of myocardial viability in the first hours after experimental MI. Safe Mn dosing is confirmed by measuring in vitro beating rates, calcium transients, and action potentials in cardiomyocytes, and in vivo heart rates and cardiac contractility in mice. Quantitative T1 mapping-manganese-enhanced MRI (MEMRI) reveals elevated and increasing Mn uptake in viable myocardium remote from the infarct, suggesting MEMRI offers a quantitative biomarker of cardiac inotropy. MEMRI evaluation of infarct size at 1 h, 1 and 14 days after MI quantifies myocardial viability earlier than the current gold-standard technique, late-gadolinium-enhanced MRI. These data, coupled with the re-emergence of clinical Mn -based contrast agents open the possibility of using MEMRI for direct evaluation of myocardial viability early after ischemic onset in patients
Current quark mass dependence of nucleon magnetic moments and radii
A calculation of the current-quark-mass-dependence of nucleon static
electromagnetic properties is necessary in order to use observational data as a
means to place constraints on the variation of Nature's fundamental parameters.
A Poincare' covariant Faddeev equation, which describes baryons as composites
of confined-quarks and -nonpointlike-diquarks, is used to calculate this
dependence The results indicate that, like observables dependent on the
nucleons' magnetic moments, quantities sensitive to their magnetic and charge
radii, such as the energy levels and transition frequencies in Hydrogen and
Deuterium, might also provide a tool with which to place limits on the allowed
variation in Nature's constants.Comment: 23 pages, 2 figures, 4 tables, 4 appendice
Psychiatry during the Nazi era: ethical lessons for the modern professional
For the first time in history, psychiatrists during the Nazi era sought to systematically exterminate their patients. However, little has been published from this dark period analyzing what may be learned for clinical and research psychiatry. At each stage in the murderous process lay a series of unethical and heinous practices, with many psychiatrists demonstrating a profound commitment to the atrocities, playing central, pivotal roles critical to the success of Nazi policy. Several misconceptions led to this misconduct, including allowing philosophical constructs to define clinical practice, focusing exclusively on preventative medicine, allowing political pressures to influence practice, blurring the roles of clinicians and researchers, and falsely believing that good science and good ethics always co-exist. Psychiatry during this period provides a most horrifying example of how science may be perverted by external forces. It thus becomes crucial to include the Nazi era psychiatry experience in ethics training as an example of proper practice gone awry
Correlated dynamics in egocentric communication networks
We investigate the communication sequences of millions of people through two
different channels and analyze the fine grained temporal structure of
correlated event trains induced by single individuals. By focusing on
correlations between the heterogeneous dynamics and the topology of egocentric
networks we find that the bursty trains usually evolve for pairs of individuals
rather than for the ego and his/her several neighbors thus burstiness is a
property of the links rather than of the nodes. We compare the directional
balance of calls and short messages within bursty trains to the average on the
actual link and show that for the trains of voice calls the imbalance is
significantly enhanced, while for short messages the balance within the trains
increases. These effects can be partly traced back to the technological
constrains (for short messages) and partly to the human behavioral features
(voice calls). We define a model that is able to reproduce the empirical
results and may help us to understand better the mechanisms driving technology
mediated human communication dynamics.Comment: 7 pages, 6 figure
Analytic study of properties of holographic p-wave superconductors
In this paper, we analytically investigate the properties of p-wave
holographic superconductors in -Schwarzschild background by two
approaches, one based on the Sturm-Liouville eigenvalue problem and the other
based on the matching of the solutions to the field equations near the horizon
and near the asymptotic region. The relation between the critical
temperature and the charge density has been obtained and the dependence of the
expectation value of the condensation operator on the temperature has been
found. Our results are in very good agreement with the existing numerical
results. The critical exponent of the condensation also comes out to be 1/2
which is the universal value in the mean field theory.Comment: Latex, To appear in JHE
Assessment of a novel, capsid-modified adenovirus with an improved vascular gene transfer profile
<p>Background: Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Gene therapy may provide a successful approach to improve the clinical outcome of these conditions, but would benefit from the development of more efficient vectors for vascular gene delivery. The aim of this study was to assess whether a novel genetically engineered Adenovirus could be utilised to produce enhanced levels of vascular gene expression.</p>
<p>Methods: Vascular transduction capacity was assessed in primary human saphenous vein smooth muscle and endothelial cells using vectors expressing the LacZ reporter gene. The therapeutic capacity of the vectors was compared by measuring smooth muscle cell metabolic activity and migration following infection with vectors that over-express the candidate therapeutic gene tissue inhibitor of matrix metalloproteinase-3 (TIMP-3).</p>
<p>Results: Compared to Adenovirus serotype 5 (Ad5), the novel vector Ad5T*F35++ demonstrated improved binding and transduction of human vascular cells. Ad5T*F35++ mediated expression of TIMP-3 reduced smooth muscle cell metabolic activity and migration in vitro. We also demonstrated that in human serum samples pre-existing neutralising antibodies to Ad5T*F35++ were less prevalent than Ad5 neutralising antibodies.</p>
<p>Conclusions: We have developed a novel vector with improved vascular transduction and improved resistance to human serum neutralisation. This may provide a novel vector platform for human vascular gene transfer.</p>
Alteration of Sequence Specificity of the Type IIS Restriction Endonuclease BtsI
The Type IIS restriction endonuclease BtsI recognizes and digests at GCAGTG(2/0). It comprises two subunits: BtsIA and BtsIB. The BtsIB subunit contains the recognition domain, one catalytic domain for bottom strand nicking and part of the catalytic domain for the top strand nicking. BtsIA has the rest of the catalytic domain that is responsible for the DNA top strand nicking. BtsIA alone has no activity unless it mixes with BtsIB to reconstitute the BtsI activity. During characterization of the enzyme, we identified a BtsIB mutant R119A found to have a different digestion pattern from the wild type BtsI. After characterization, we found that BtsIB(R119A) is a novel restriction enzyme with a previously unreported recognition sequence CAGTG(2/0), which is named as BtsI-1. Compared with wild type BtsI, BtsI-1 showed different relative activities in NEB restriction enzyme reaction buffers NEB1, NEB2, NEB3 and NEB4 and less star activity. Similar to the wild type BtsIB subunit, the BtsI-1 B subunit alone can act as a bottom nicking enzyme recognizing CAGTG(-/0). This is the first successful case of a specificity change among this restriction endonuclease type
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