Evidence for sex difference in the CSF/plasma albumin ratio in ~20 000 patients and 335 healthy volunteers

Given sex‐related differences in brain disorders, it is of interest to study if there is a sex difference in the permeability of the blood‐cerebrospinal fluid barrier (BCSFB) and the blood‐brain barrier (BBB). The CSF/serum albumin ratio (Q_Alb) is a standardized biomarker that evaluates the function of these barriers. In previous studies, contradictory results have been reported with respect to sex difference using this quotient, possibly because of small population sizes and heterogeneity with respect to ages. Q_Alb measurements in more than 20 000 patients between 1 and 90 years visiting our hospitals revealed a significant sex difference in all age groups also when excluding patients with pathologically high CSF albumin > 400 mg/L. Similar pattern was found in 335 healthy volunteers in similar age intervals. Although also other factors are likely important, our observation is consistent with lower integrity of the brain barriers in males. If the difference in Q_Alb is caused mainly by a difference in barrier function, this may require different drug doses and strategies for efficient central nervous system (CNS) delivery in males and females, as well as it may indicate differences in brain metabolism. Moreover, our study emphasizes that different reference values should be used both for different ages and sexes.     

Tissue-enhanced plasma proteomic analysis for disease stratification in amyotrophic lateral sclerosis

Background

It is unclear to what extent pre-clinical studies in genetically homogeneous animal models of amyotrophic lateral sclerosis (ALS), an invariably fatal neurodegenerative disorder, can be informative of human pathology. The disease modifying effects in animal models of most therapeutic compounds have not been reproduced in patients. To advance therapeutics in ALS, we need easily accessible disease biomarkers which can discriminate across the phenotypic variants observed in ALS patients and can bridge animal and human pathology. Peripheral blood mononuclear cells alterations reflect the rate of progression of the disease representing an ideal biological substrate for biomarkers discovery.

Methods

We have applied TMTcalibrator?, a novel tissue-enhanced bio fluid mass spectrometry technique, to study the plasma proteome in ALS, using peripheral blood mononuclear cells as tissue calibrator. We have tested slow and fast progressing SOD1G93A mouse models of ALS at a pre-symptomatic and symptomatic stage in parallel with fast and slow progressing ALS patients at an early and late stage of the disease. Immunoassays were used to retest the expression of relevant protein candidates.

Results

The biological features differentiating fast from slow progressing mouse model plasma proteomes were different from those identified in human pathology, with only processes encompassing membrane trafficking with translocation of GLUT4, innate immunity, acute phase response and cytoskeleton organization showing enrichment in both species. Biological processes associated with senescence, RNA processing, cell stress and metabolism, major histocompatibility complex-II linked immune-reactivity and apoptosis (early stage) were enriched specifically in fast progressing ALS patients. Immunodetection confirmed regulation of the immunosenescence markers Galectin-3, Integrin beta 3 and Transforming growth factor beta-1 in plasma from pre-symptomatic and symptomatic transgenic animals while Apolipoprotein E differential plasma expression provided a good separation between fast and slow progressing ALS patients.

Conclusions

These findings implicate immunosenescence and metabolism as novel targets for biomarkers and therapeutic discovery and suggest immunomodulation as an early intervention. The variance observed in the plasma proteomes may depend on different biological patterns of disease progression in human and animal model.

     

Reproductive biology of Aechmea bracteata (Sw.) Griseb. (Bromelioideae: Bromeliaceae)

• Individuals of Aechmea bracteata show inflorescences with red scape bracts and odourless, yellow, tubular diurnal flowers, with closely arranged sexual organs, producing a large amount of fruits.
• In order to investigate the reproductive system of this species, a suite of characters was assessed: phenology, floral morphology and biology, nectar production dynamics, and fruit and seed production and germination, as a result of controlled pollination crosses. The study was conducted during two flowering seasons in wild populations in Yucatán, Mexico.
• Results suggest an annual flowering pattern with one flowering peak; flowers were diurnal, showing partial dichogamy (protandry)‐herkogamy, anthers and stigma become mature before floral aperture, which could lead to self‐pollination, nectar is produced during anthesis, varying in volume and total sugar concentration during the day; fruits and seeds were produced in all experimental crosses (cross‐pollination, obligated cross‐pollination, assisted and unassisted selfing, geitonogamy and apomixis), as well as high percentage seed germination.
• Several species of Aechmea are reportedly self‐compatible and autogamous, as suggested by results of selfing and non‐assisted selfing crosses, but these results are negated by the presence of apomixis, indicating that the species is apomictic. This is the first report of this breeding system for subgenus Aechmea and the sixth for Bromeliaceae. Polyembryony is here suggested for the first time in this genus and family based on the fact that more seeds were recorded that expected based on ovule numbers. Finally, when performing experimental crosses, estimating reproductive success based on number of seeds is a better approach than number of fruits, due to the effect of pseudogamy.

     

Functional CD169 on Macrophages Mediates Interaction with Dendritic Cells for CD8+ T Cell Cross-Priming

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Oxysterols and neurodegenerative diseases

In contrast to their parent molecule cholesterol, two of its side-chain oxidized metabolites are able to cross the blood–brain barrier. There is a concentration-driven flux of 24S-hydroxycholesterol (24S-OHC) from the brain into the circulation, which is of major importance for elimination of excess cholesterol from the brain. The opposite flux of 27-hydroxycholesterol (27-OHC) from the circulation into the brain may regulate a number of key enzymes within the brain. In vitro experiments suggest that the balance between the levels of these two molecules may be of importance for the generation of β-amyloid peptides. In primary cultures of rat hippocampal cells 27-OHC is able to suppress expression of the activity regulated cytoskeleton-associated protein (Arc), a protein important in memory consolidation which is reduced in patients with Alzheimer’s disease (AD). In the present work we explore the possibility that the flux of 27-OHC from the circulation into the brain represents the missing link between AD and hypercholesterolemia, and discuss the possibility that modification of this flux may be a therapeutic strategy. Lastly, we discuss the use of oxysterols as diagnostic markers in neurodegenerative disease.     

Differential responses of three grasses to defoliation,water and light availability

Grazing not only modifies the structure and functioning of grasslands, it also changes micro-environmental conditions that alter the availability of resources. The aim of this study was to analyze the response of grasses with different photosynthetic pathways (C₃/C₄), growth forms (prostrate/erect), and grazing responses (increaser/decreaser) to defoliation and resource availability. In a greenhouse, we performed a factorial experiment with three factors: defoliation, light, and water and three species: Axonopus affinis (C₄ prostrate, increaser), Coelorachis selloana (C₄ erect, decreaser), and Bromus auleticus (C₃ erect, decreaser). We measured the relative growth rate (RGR), biomass assignment, and specific leaf area. The RGR of both C₄ species was affected by light availability, while the decreaser C₃ did not respond to any factor. Biomass allocation to leaves and stolons changed with the interaction between light and water in the C₄ prostrate species (increaser). In the C₄ erect grass (decreaser), biomass allocation was more affected by defoliation under low levels of light and water. Low light availability and defoliation reduced the assignment to leaves, while the allocation to rhizomes increased. Species-specific responses to resources availability that are modified by grazing were related to photosynthetic pathway, growth form, and grazing responses. Biomass allocation was related to strategies to avoid and/or tolerate grazing. The investment to leaves was limited by light and water availability in prostrate species, while in erect grasses it was controlled by defoliation and water availability. Our results highlight the importance of species responses to changes in resource availability associated to grazing regimes.