Gene Expression Analysis Reveals Inhibition of Radiation-Induced TGFβ-Signaling by Hyperbaric Oxygen Therapy in Mouse Salivary Glands

A side effect of radiation therapy in the head and neck region is injury to surrounding healthy tissues such as irreversible impaired function of the salivary glands. Hyperbaric oxygen therapy (HBOT) is clinically used to treat radiation-induced damage but its mechanism of action is largely unknown. In this study, we investigated the molecular pathways that are affected by HBOT in mouse salivary glands two weeks after radiation therapy by microarray analysis. Interestingly, HBOT led to significant attenuation of the radiation-induced expression of a set of genes and upstream regulators that are involved in processes such as fibrosis and tissue regeneration. Our data suggest that the TGFβ-pathway, which is involved in radiation-induced fibrosis and chronic loss of function after radiation therapy, is affected by HBOT. On the longer term, HBOT reduced the expression of the fibrosis-associated factor α-smooth muscle actin in irradiated salivary glands. This study highlights the potential of HBOT to inhibit the TGFβ-pathway in irradiated salivary glands and to restrain consequential radiation induced tissue injury.     

A G1‐like state allows HIV‐1 to bypass SAMHD1 restriction in macrophages

An unresolved question is how HIV‐1 achieves efficient replication in terminally differentiated macrophages despite the restriction factor SAMHD1. We reveal inducible changes in expression of cell cycle‐associated proteins including MCM2 and cyclins A, E, D1/D3 in macrophages, without evidence for DNA synthesis or mitosis. These changes are induced by activation of the Raf/MEK/ERK kinase cascade, culminating in upregulation of CDK1 with subsequent SAMHD1 T592 phosphorylation and deactivation of its antiviral activity. HIV infection is limited to these G1‐like phase macrophages at the single‐cell level. Depletion of SAMHD1 in macrophages decouples the association between infection and expression of cell cycle‐associated proteins, with terminally differentiated macrophages becoming highly susceptible to HIV‐1. We observe both embryo‐derived and monocyte‐derived tissue‐resident macrophages in a G1‐like phase at frequencies approaching 20%, suggesting how macrophages sustain HIV‐1 replication in vivo. Finally, we reveal a SAMHD1‐dependent antiretroviral activity of histone deacetylase inhibitors acting via p53 activation. These data provide a basis for host‐directed therapeutic approaches aimed at limiting HIV‐1 burden in macrophages that may contribute to curative interventions.     

Confirmation of quantitative trait loci affecting fatness in chickens

In this report we describe the analysis of an advanced intercross line (AIL) to confirm the quantitative trait locus (QTL) regions found for fatness traits in a previous study. QTL analysis was performed on chromosomes 1, 3, 4, 15, 18, and 27. The AIL was created by random intercrossing in each generation from generation 2 (G₂) onwards until generation 9 (G₉) was reached. QTL for abdominal fat weight (AFW) and/or percentage abdominal fat (AF%) on chromosomes 1, 3 and 27 were confirmed in the G₉ population. In addition, evidence for QTL for body weight at the age of 5 (BW5) and 7 (BW7) weeks and for the percentage of intramuscular fat (IF%) were found on chromosomes 1, 3, 15, and 27. Significant evidence for QTL was detected on chromosome 1 for BW5 and BW7. Suggestive evidence was found on chromosome 1 for AFW, AF% and IF%, on chromosome 15 for BW5, and on chromosome 27 for AF% and IF%. Furthermore, evidence on the chromosome-wise level was found on chromosome 3 for AFW, AF%, and BW7 and on chromosome 27 for BW5. For chromosomes 4 and 18, test statistics did not exceed the significance threshold.     

Long-term response to genomic selection: effects of estimation method and reference population structure for different genetic architectures

Background

Genomic selection has become an important tool in the genetic improvement of animals and plants. The objective of this study was to investigate the impacts of breeding value estimation method, reference population structure, and trait genetic architecture, on long-term response to genomic selection without updating marker effects.

Methods

Three methods were used to estimate genomic breeding values: a BLUP method with relationships estimated from genome-wide markers (GBLUP), a Bayesian method, and a partial least squares regression method (PLSR). A shallow (individuals from one generation) or deep reference population (individuals from five generations) was used with each method. The effects of the different selection approaches were compared under four different genetic architectures for the trait under selection. Selection was based on one of the three genomic breeding values, on pedigree BLUP breeding values, or performed at random. Selection continued for ten generations.

Results

Differences in long-term selection response were small. For a genetic architecture with a very small number of three to four quantitative trait loci (QTL), the Bayesian method achieved a response that was 0.05 to 0.1 genetic standard deviation higher than other methods in generation 10. For genetic architectures with approximately 30 to 300 QTL, PLSR (shallow reference) or GBLUP (deep reference) had an average advantage of 0.2 genetic standard deviation over the Bayesian method in generation 10. GBLUP resulted in 0.6% and 0.9% less inbreeding than PLSR and BM and on average a one third smaller reduction of genetic variance. Responses in early generations were greater with the shallow reference population while long-term response was not affected by reference population structure.

Conclusions

The ranking of estimation methods was different with than without selection. Under selection, applying GBLUP led to lower inbreeding and a smaller reduction of genetic variance while a similar response to selection was achieved. The reference population structure had a limited effect on long-term accuracy and response. Use of a shallow reference population, most closely related to the selection candidates, gave early benefits while in later generations, when marker effects were not updated, the estimation of marker effects based on a deeper reference population did not pay off.     

Glucocorticoid receptor gene polymorphisms and disease activity during pregnancy and the postpartum period in rheumatoid arthritis

Introduction

The mechanism underlying the spontaneous improvement of rheumatoid arthritis (RA) during pregnancy and the subsequent postpartum flare is incompletely understood, and the disease course varies widely between pregnant RA patients. In pregnancy, total and free levels of cortisol increase gradually, followed by a postpartum decrease to prepregnancy values. The glucocorticoid receptor (GR) polymorphisms BclI and N363S are associated with relatively increased glucocorticoid (GC) sensitivity, whereas the 9β and ER22/23EK polymorphisms of the GR gene are associated with a relatively decreased GC sensitivity. We examined the relation between the presence of these GR polymorphisms and level of disease activity and disease course of RA during pregnancy and postpartum.

Methods

We studied 147 participants of the PARA study (Pregnancy-Induced Amelioration of Rheumatoid Arthritis study), a prospective study investigating the natural improvement during pregnancy and the postpartum flare in women with RA. Patients were visited, preferably before pregnancy, at each trimester and at three postpartum time points. On all occasions, disease activity was scored by using DAS28. All patients were genotyped for the GR polymorphisms BclI, N363S, 9β, and ER22/23EK and divided in groups harboring either polymorphisms conferring increased GC sensitivity (BclI and N363S; GC-S patients) or polymorphisms conferring decreased GC sensitivity (9β or 9β + ER22/23EK; GC-I patients). Data were analyzed by using a mixed linear model, comparing GC-S patients with GC-I patients with respect to improvement during pregnancy and the postpartum flare. The cumulative disease activity was calculated by using time-integrated values (area under the curve, AUC) of DAS28 in GC-I patients versus GC-S patients. Separate analyses were performed according to the state of GC use.

Results

GC-S patients treated with GC had a significantly lower AUC of DAS28 in the postpartum period than did GC-I patients. This difference was not observed in patients who were not treated with GCs. During pregnancy, GC-S and GC-I patients had comparable levels of disease activity and course of disease.

Conclusions

Differences in relative GC sensitivity, as determined by GR polymorphisms, are associated with the level of disease activity in the postpartum period in GC-treated patients, but they do not seem to influence the course of the disease per se.     

Stability and enzyme separation: Integral representation of the solutions

Two enzymes, cross-coupled through their respective products, are membrane-bound and thereby separated from each other. The cross-coupling is of opposite character and diffusion limited, i.e. an activation-inhibition couple with a diffusion-induced time-lag. In this paper an integral representation for the solutions of the dynamic equations is developed using the Green's function technique, and an application to morphological changes in the mitochrondrion is discussed.     

Cooperativity in F-actin filaments on binding of myosin subfragments, demonstrated by fluorescence of 1, N6- ethenoadenosine diphosphate.

The fluorescence lifetime of 1,N⁶-ethenoadenosine diphosphate (?-ADP) is 33 ns when bound to F-actin at 4 °C. When heavy meromyosin or myosin subfragment-1 binds to the F-actin filament, the lifetime of ?-ADP drops, reaching 29 ns when every actin monomer is bound to a myosin head. The change in lifetime is a consequence of cooperative conformational changes among the actin monomers. The results of these experiments support the contention that there are differences in the ways in which the two heads of the myosin molecule interact with the actin filament.