Abstract
Neuroinflammation in the brain contributes to the pathogenesis of Parkinson’s disease (PD), but the potential dysregulation of peripheral immunity has not been systematically investigated ...for idiopathic PD (iPD). Here we showed an elevated peripheral cytotoxic immune milieu, with more terminally-differentiated effector memory (TEMRA) CD8 T, CD8
+
NKT cells and circulating cytotoxic molecules in fresh blood of patients with early-to-mid iPD, especially females, after analyzing > 700 innate and adaptive immune features. This profile, also reflected by fewer CD8
+
FOXP3
+
T cells, was confirmed in another subcohort. Co-expression between cytotoxic molecules was selectively enhanced in CD8 TEMRA and effector memory (TEM) cells. Single-cell RNA-sequencing analysis demonstrated the accelerated differentiation within CD8 compartments, enhanced cytotoxic pathways in CD8 TEMRA and TEM cells, while CD8 central memory (TCM) and naïve cells were already more-active and transcriptionally-reprogrammed. Our work provides a comprehensive map of dysregulated peripheral immunity in iPD, proposing candidates for early diagnosis and treatments.
Highlights ► Four seasonal influenza vaccines were characterized before and after stresses. ► The vaccines were stressed by temperature and freeze-thawing. ► Fluorescence, light scatter and ...microscopy methods were used. ► Structural changes and aggregation were investigated without sample dilution. ► The four seasonal influenza vaccines had different properties.
Aquaculture practices continuously seek to improve efficiency to produce larger fish at lower cost. Selective breeding within brood stocks can result in undesirable effects, promoting hatcheries to ...use outbreeding to increase or maintain genetic diversity. This practice however, could result in the introduction of wild behavioural phenotypes unable to adapt to captive-living conditions. Using four hatchery first-generation hybrid crosses and two fully domesticated stocks of Chinook salmon (Oncorhynchus tshawytscha) in British Columbia, we examined behavioural responses to common aquaculture practices such as abrupt environmental change and novel feed types in juvenile fish. Controlling for mass, we found crosses varied in their behaviours to a novel setting and preferences for natural versus commercial diets. These differences were furthermore associated with rearing environment and stock-level growth rate and body size. Our results suggest selecting for phenotypes that behaviourally exhibit better coping mechanisms and greater flexibility in response to change is possible, and when in combination with growth metrics, should be an integral part of producing the desired farmed fish. Behaviours that allow commercial anadromous fish to easily transition to captive environmental conditions can benefit production and also animal welfare.
Many players regulating the CD4+ T cell-mediated inflammatory response have already been identified. However, the critical nodes that constitute the regulatory and signaling networks underlying CD4 ...T cell responses are still missing. Using a correlation-network-guided approach, here we identified VIMP (VCP-interacting membrane protein), one of the 25 genes encoding selenoproteins in humans, as a gene regulating the effector functions of human CD4 T cells, especially production of several cytokines including IL2 and CSF2. We identified VIMP as an endogenous inhibitor of cytokine production in CD4 effector T cells via both the E2F5 transcription regulatory pathway and the Ca2+/NFATC2 signaling pathway. Our work not only indicates that VIMP might be a promising therapeutic target for various inflammation-associated diseases but also shows that our network-guided approach can significantly aid in predicting new functions of the genes of interest.
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•VIMP is temporally upregulated after TCR stimulation in human CD4 effector T cells•VIMP inhibits cytokine expression in human CD4 effector T cells•VIMP inhibits cytokine expression via the NFATC2/Ca2+ signaling pathway•VIMP inhibits cytokine expression by controlling E2F5 expression
Immunology; Cell Biology; Systems Biology
The discovery of upstream regulatory genes of a gene of interest still remains challenging. Here we applied a scalable computational method to unbiasedly predict candidate regulatory genes of ...critical transcription factors by searching the whole genome. We illustrated our approach with a case study on the master regulator FOXP3 of human primary regulatory T cells (Tregs). While target genes of FOXP3 have been identified, its upstream regulatory machinery still remains elusive. Our methodology selected five top-ranked candidates that were tested via proof-of-concept experiments. Following knockdown, three out of five candidates showed significant effects on the mRNA expression of FOXP3 across multiple donors. This provides insights into the regulatory mechanisms modulating FOXP3 transcriptional expression in Tregs. Overall, at the genome level this represents a high level of accuracy in predicting upstream regulatory genes of key genes of interest.
The selection for a single organismal trait like growth in breeding programs of farmed aquaculture species can counterintuitively lead to lowered harvestable biomass. We outbred a domesticated ...aquaculture stock of Chinook salmon (Oncorhynchus tshawytscha (Walbaum in Artedi, 1792)) with seven wild stocks from British Columbia, Canada. We then examined how functionally related traits underlying energy management – diel variation in cortisol and foraging, social, and movement behaviours — predicted stock-level variation in growth during the freshwater life history stage, which is a performance metric under aquaculture selection. Outbreeding generated significant variation in diel cortisol secretion and behaviours across stocks, and these traits co-varied, suggesting tight integration despite hybridization. The coupling of nighttime cortisol exposure with the daytime behavioural phenotype was the strongest predictor of stock-level variation in body mass. Our results suggest that selection for an integrated phenotype rather than on a single mechanistic trait alone can generate the greatest effect on aquaculture fish growth under outbreeding practices. Furthermore, selecting for these traits at the stock level may increase efficiency of farming methods designed to consistently maximize fish performance on a large scale.
A differential profilometry technique is adapted to the problem of measuring the roughness of hollow glass fibres by use of immersion objectives and index-matching liquid. The technique can achieve ...picometer level sensitivity. Cross validation with AFM measurements is obtained through use of vitreous silica step calibration samples. Measurements on the inner surfaces of fibre-sized glass capillaries drawn from high purity suprasil F300 tubes show a sub-nanometer roughness, and the roughness power spectrum measured in the range 5 · 10(-3) m(-1) 10(-1) m(-1) is consistent with the description of the glass surface as a superposition of frozen capillary waves. The surface roughness spectrum of two capillary tubes of differing compositions can be quantitatively distinguished.
Mesoporous silicon can be used as isolating substrate for the integration of radiofrequency (RF) passive devices. The higher is the porous silicon (PS) thickness, the better are the RF performances. ...However, an increase of PS thickness induces a raise of strain in the substrate.
In this work, the strain of 6 inches PS substrates which has been generated during electrochemical etching and post anodization annealing steps are studied. It is shown that, if the anodization process is not well-controlled, the consequences can be cracks of the PS layer or a high wafer curvature which prevents device from integration with a standard process. It is also demonstrated that different kinds of defects due to PS stress can be also observed on full wafer PS layers and localized PS substrates as well.
•Electrochemical anodization of large area Si wafers is studied.•Process steps involved in stress generation into wafers are identified.•Complex RF devices were integrated on localized porous silicon regions.
Stress hormones are believed to skew the CD4 T‐cell differentiation towards a Th2 response via a T‐cell‐extrinsic mechanism. Using isolated primary human naïve and memory CD4 T cells, here we show ...that both adrenergic‐ and glucocorticoid‐mediated stress signalling pathways play a CD4 naïve T‐cell‐intrinsic role in regulating the Th1/Th2 differentiation balance. Both stress hormones reduced the Th1 programme and cytokine production by inhibiting mTORC1 signalling via two parallel mechanisms. Stress hormone signalling inhibited mTORC1 in naïve CD4 T cells (1) by affecting the PI3K/AKT pathway and (2) by regulating the expression of the circadian rhythm gene, period circadian regulator 1 (PER1). Both stress hormones induced the expression of PER1, which inhibited mTORC1 signalling, thus reducing Th1 differentiation. This previously unrecognized cell‐autonomous mechanism connects stress hormone signalling with CD4 T‐cell differentiation via mTORC1 and a specific circadian clock gene, namely PER1.
Using primary human naïve and memory CD4 T cells, here we show that both adrenergic‐ and glucocorticoid‐mediated stress signalling pathways play a CD4 naïve T‐cell‐intrinsic role in regulating the Th1/Th2 differentiation balance. Both stress hormones induced the expression of period circadian regulator 1 (PER1), which inhibited mTORC1 signalling, thus reducing Th1 differentiation.
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