Evaluating the microbial experience influence on anti-tumor immune response

Despite the steady increase of hygienic standards, the CDC continues to report an increase of immune-mediated diseases such as allergies and asthma. Human avoidance of microbial exposure and subsequently less experienced immune systems may be the cause for this increase. We investigated if increased microbial exposure results in increased immunity to cancer (B16 melanoma) by measuring activated lymphocytes between two groups of C57Bl/6 mice: specific pathogen free (SPF) mice (which had little microbial exposure) and cohoused (COH) mice (which were exposed to numerous microbes). Previous research shows that the CoH mouse model mimics a human adult’s immune system, while the SPF mouse model mimics that of a human infant’s. Activated lymphocyte levels were quantified with weekly bleeds using antibody staining flow cytometry. Anti-tumor response was evaluated through multiple harvests in which blood, lymph nodes, spleens, and tumors were collected and analyzed with flow cytometry. CoH mice were expected to have heightened levels of activated lymphocytes and an anti-tumor response superior to the SPF mice. The CoH mice did gain microbial experience and showed in a higher quantity of activated CD8+ T cells. Preliminary results suggest that this may have resulted in an increased anti-tumor response and slowed cancer proliferation

Antibioticagebruik deels afhankelijk van bedrijfsvoering

Het antibioticagebruik op bedrijven varieert in hoge mate. De verschillen blijken deels afhankelijk van de bedrijfsvoering. De melkveehouder met een wat groter quotum, lager celgetal en hogere gezondheidsstatus gebruikt meer. Dit is in feite de ‘succesvolle’ veehouder. Dit lijkt dus de groep om op te focussen

Advances in enhanced sampling along adaptive paths of collective variables

Study of complex activated molecular transitions by molecular dynamics (MD) simulation can be a daunting task, especially when little knowledge is available on the reaction coordinate describing the mechanism of the process. Here, we assess the path-metadynamics enhanced sampling approach in combination with force field and ab initio [density functional theory (DFT)] MD simulations of conformational and chemical transitions that require three or more collective variables (CVs) to describe the processes. We show that the method efficiently localizes the average transition path of each process and simultaneously obtains the free energy profile along the path. The new multiple-walker implementation greatly speeds-up the calculation, with an almost trivial scaling of the number of parallel replicas. Increasing the dimensionality by expanding the set of CVs leads to a less than linear increase in the computational cost, as shown by applying the method to a conformational change in increasingly longer polyproline peptides. Combined with DFT-MD to model acid (de-)protonation in explicit water solvent, the transition path and associated free energy profile were obtained in less than 100 ps of simulation. A final application to hydrogen fuel production catalyzed by a hydrogenase enzyme showcases the unique mechanistic insight and chemical understanding that can be obtained from the average transition path. Published by AIP Publishing

On the origin of the extremely different solubilities of polyethers in water

The solubilities of polyethers are surprisingly counter-intuitive. The best-known example is the difference between polyethylene glycol ([–CH2–CH2–O–]n) which is infinitely soluble, and polyoxymethylene ([–CH2–O–]n) which is completely insoluble in water, exactly the opposite of what one expects from the C/O ratios of these molecules. Similar anomalies exist for oligomeric and cyclic polyethers. To solve this apparent mystery, we use femtosecond vibrational and GHz dielectric spectroscopy with complementary ab initio calculations and molecular dynamics simulations. We find that the dynamics of water molecules solvating polyethers is fundamentally different depending on their C/O composition. The ab initio calculations and simulations show that this is not because of steric effects (as is commonly believed), but because the partial charge on the O atoms depends on the number of C atoms by which they are separated. Our results thus show that inductive effects can have a major impact on aqueous solubilities

Complex pattern of genetic structuring in the Atlantic salmon (Salmo salar L.) of the River Foyle system in northwest Ireland: disentangling the evolutionary signal from population stochasticity

Little is known about the microevolutionary processes shaping within river population genetic structure of aquatic organisms characterized by high levels of homing and spawning site fidelity. Using a microsatellite panel, we observed complex and highly significant levels of intrariver population genetic substructure and Isolation-by-Distance, in the Atlantic salmon stock of a large river system. Two evolutionary models have been considered explaining mechanisms promoting genetic substructuring in Atlantic salmon, the member-vagrant and metapopulation models. We show that both models can be simultaneously used to explain patterns and levels of population structuring within the Foyle system. We show that anthropogenic factors have had a large influence on contemporary population structure observed. In an analytical development, we found that the frequently used estimator of genetic differentiation, FST, routinely underestimated genetic differentiation by a factor three to four compared to the equivalent statistic Jost's Dest (Jost 2008). These statistics also showed a near-perfect correlation. Despite ongoing discussions regarding the usefulness of “adjusted”FST statistics, we argue that these could be useful to identify and quantify qualitative differences between populations, which are important from management and conservation perspectives as an indicator of existence of biologically significant variation among tributary populations or a warning of critical environmental damage

Temporal relationship between instantaneous pressure gradients and peak‐to‐peak systolic ejection gradient in congenital aortic stenosis

ObjectiveWe sought to identify a time during cardiac ejection when the instantaneous pressure gradient (IPG) correlated best, and near unity, with peak‐to‐peak systolic ejection gradient (PPSG) in patients with congenital aortic stenosis. Noninvasive echocardiographic measurement of IPG has limited correlation with cardiac catheterization measured PPSG across the spectrum of disease severity of congenital aortic stenosis. A major contributor is the observation that these measures are inherently different with a variable relationship dependent on the degree of stenosis.DesignHemodynamic data from cardiac catheterizations utilizing simultaneous pressure measurements from the left ventricle (LV) and ascending aorta (AAo) in patients with congenital valvar aortic stenosis was retrospectively reviewed over the past 5 years. The cardiac cycle was standardized for all patients using the percentage of total LV ejection time (ET). Instantaneous gradient at 5% intervals of ET were compared to PPSG using linear regression and Bland‐Altman analysis.ResultsA total of 22 patients underwent catheterization at a median age of 13.7 years (interquartile range [IQR] 10.3‐18.0) and median weight of 51.1 kg (IQR 34.2‐71.6). The PPSG was 46.5 ± 12.6 mm Hg (mean ± SD) and correlated suboptimally with the maximum and mean IPG. The midsystolic IPG (occurring at 50% of ET) had the strongest correlation with the PPSG (PPSG = 0.97(IPG50%)–1.12, R2 = 0.88), while the IPG at 55% of ET was closest to unity (PPSG = 0.997(IPG55%)–1.17, R2 = 0.87).ConclusionsThe commonly measured maximum and mean IPG are suboptimal estimates of the PPSG in congenital aortic stenosis. Using catheter‐based data, IPG at 50%–55% of ejection correlates well with PPSG. This may allow for a more accurate estimation of PPSG via noninvasive assessment of IPG.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140042/1/chd12514.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/140042/2/chd12514_am.pd