Intrinsic Regulation of Brain Inflammatory Responses

It is now well accepted that inflammatory responses in brain contribute to the genesis and evolution of damage in neurological diseases, trauma, and infection. Inflammatory mediators including cytokines, cell adhesion molecules, and reactive oxygen species including NO are detected in human brain and its animal models, and interventions that reduce levels or expression of these agents provide therapeutic benefit in many cases. Although in some cases, the causes of central inflammatory responses are clear—for example those due to viral infection in AIDS dementia, or those due to the secretion of proinflammatory substances by activated lymphocytes in multiple sclerosis—in other conditions the factors that allow the initiation of brain inflammation are not well understood; nor is it well known why brain inflammatory activation is not as well restricted as it is in the periphery. The concept is emerging that perturbation of endogenous regulatory mechanisms could be an important factor for initiation, maintenance, and lack of resolution of brain inflammation. Conversely, activation of intrinsic regulatory neuronal pathways could provide protection in neuroinflammatory conditions. This concept is the extension of the principle of central neurogenic neuroprotection formulated by Donald Reis and colleagues, which contends the existence of neuronal circuits that protect the brain against the damage initiated by excitotoxic injury. In this paper we will review work initiated in the Reis laboratory establishing that activation of endogenous neural circuits can exert anti-inflammatory actions in brain, present data suggesting that these effects could be mediated by noradrenaline, and summarize recent studies suggesting that loss of noradrenergic locus ceruleus neurons contributes to inflammatory activation in Alzheimer's disease.     

Double muscling in Marchigiana beef breed is caused by a stop codon in the third exon of myostatin gene

Double muscling is a partially recessive trait present in some beef breeds. It shows a high frequency in some breeds, while in others the frequency is low, and double-muscled individuals are rare. The double muscling is caused by an allelic series of mutations that cause a loss of function of the myostatin gene ( GDF8). We describe here a new mutation in the myostatin gene in Marchigiana breed, a typical beef breed of Central Italy, in which rare double-muscling individuals have been described. A PCR product of the third exon was sequenced in subjects phenotypically showing double muscling, and a G > T transversion was discovered that introduces a premature stop codon. The variant found adds to the large series of mutations present in cattle, and particularly to the only two causative of double muscling in the third exon. A PCR-RFLP test is described for the rapid and effective identification of both heterozygous and homozygous subjects. It was applied to a larger survey carried on the same and also in two other beef breeds, Chianina and Romagnola. Further individuals carrying the new variant were found in Marchigiana, but none in the other breeds. The results may be important for a better comprehension of the role of myostatin in muscular development, for commercial use and for the inference of phylogeny of this gene.     

Genetic analysis of candidate genes modifying the age-at-onset in Huntington’s disease

The expansion of a polymorphic CAG repeat in the HD gene encoding huntingtin has been identified as the major cause of Huntington’s disease (HD) and determines 42–73% of the variance in the age-at-onset of the disease. Polymorphisms in huntingtin interacting or associated genes are thought to modify the course of the disease. To identify genetic modifiers influencing the age at disease onset, we searched for polymorphic markers in the GRIK2, TBP, BDNF, HIP1 and ZDHHC17 genes and analysed seven of them by association studies in 980 independent European HD patients. Screening for unknown sequence variations we found besides several silent variations three polymorphisms in the ZDHHC17 gene. These and polymorphisms in the GRIK2, TBP and BDNF genes were analysed with respect to their association with the HD age-at-onset. Although some of the factors have been defined as genetic modifier factors in previous studies, none of the genes encoding GRIK2, TBP, BDNF and ZDHHC17 could be identified as a genetic modifier for HD.Electronic Supplementary Material Supplementary material is available to authorised users in the online version of this article at .     

Polyunsaturated fatty acid pattern in liver and erythrocyte phospholipids from obese patients

Objective: Our aim was to study the fatty acid (FA) composition of liver phospholipids and its relation to that in erythrocyte membranes from patients with obese nonalcoholic fatty liver disease (NAFLD), as an indication of lipid metabolism alterations leading to steatosis. Research Methods and Procedures: Eight control subjects who underwent antireflux surgery and 12 obese patients with NAFLD who underwent subtotal gastrectomy with a gastro‐jejunal anastomosis in Roux‐en‐Y were studied. The oxidative stress status of patients was assessed by serum F₂‐isoprostanes levels (gas chromatography/negative ion chemical ionization tandem mass spectrometry). Analysis of FA composition of liver and erythrocyte phospholipids was carried out by gas‐liquid chromatography. Results: Patients with NAFLD showed serum F₂‐isoprostanes levels 84% higher than controls. Compared with controls, liver phospholipids from obese patients exhibited significantly 1) lower levels of 20:4n‐6, 22:5n‐3, 22:6n‐3 [docosahexaenoic acid (DHA)], total long‐chain polyunsaturated FA (LCPUFA), and total n‐3 LCPUFA, 2) higher 22:5n‐6 [docosapentaenoic acid (DPAn‐6)] levels and n‐6/n‐3 LCPUFA ratios, and 3) comparable levels of n‐6 LCPUFA. Levels of DHA and DPAn‐6 in liver were positively correlated with those in erythrocytes (r = 0.77 and r = 0.90, respectively; p < 0.0001), whereas DHA and DPAn‐6 showed a negative association in both tissues (r = ?0.79, p < 0.0001 and r = ?0.58, p < 0.01, respectively), associated with lower DHA/DPAn‐6 ratios. Discussion: Obese patients with NAFLD showed marked alterations in the polyunsaturated fatty acid pattern of the liver. These changes are significantly correlated with those found in erythrocytes, thus suggesting that erythrocyte FA composition could be a reliable indicator of derangements in liver lipid metabolism in obese patients.     

Estimated Glomerular Filtration Rate,All-Cause Mortality and Cardiovascular Diseases Incidence in a Low Risk Population: The MATISS Study

Background

Chronic kidney disease (CKD) independently increases the risk of death and cardiovascular disease (CVD) in the general population. However, the relationship between estimated glomerular filtration rate (eGFR) and CVD/death risk in a general population at low risk of CVD has not been explored so far.

Design

Baseline and longitudinal data of 1465 men and 1459 women aged 35-74 years participating to the MATISS study, an Italian general population cohort, were used to evaluate the role of eGFR in the prediction of all-cause mortality and incident CVD.

Methods

Bio-bank stored sera were used to evaluate eGFR at baseline. Serum creatinine was measured on thawed samples by means of an IDMS-calibrated enzymatic method. eGFR was calculated by the CKD-EPI formula.

Results

At baseline, less than 2% of enrolled persons had eGFR < 60 mL/min/1.73m² and more than 70% had a 10-year cardiovascular risk score < 10%. In people 60 or more years old, the first and the last eGFR quintiles (<90 and ≥109 mL/min/1.73m², respectively) were associated to an increased risk for both all-cause mortality (hazard ratio 1.6, 95% confidence interval 1.2-2.1 and 4.3, 1.6-11.7, respectively) and incident CVD (1.6, 1.0-2.4 and 7.0, 2.2-22.9, respectively), even if adjusted for classical risk factors.

Conclusions

These findings strongly suggest that in an elderly, general population at low risk of CVD and low prevalence of reduced renal filtration, even a modest eGFR reduction is related to all-cause mortality and CVD incidence, underlying the potential benefit to this population of considering eGFR for their risk prediction.     

Carbon pump dynamics and limited organic carbon burial during OAE1a

Oceanic Anoxic Events (OAEs) are conspicuous intervals in the geologic record that are associated with the deposition of organic carbon (OC)-rich marine sediment, linked to extreme biogeochemical perturbations, and characterized by widespread ocean deoxygenation. Mechanistic links between the marine biological carbon pump (BCP), redox conditions, and organic carbon burial during OAEs, however, remain poorly constrained. In this work we reconstructed the BCP in the western Tethys Ocean across OAE1a (~120 Mya) using sediment geochemistry and OC mass accumulation rates (OC_Acc). We find that OC_Acc were between 0.006 and 3.3 gC m⁻² yr⁻¹, with a mean value of 0.79 ± 0.78 SD gC m⁻² yr⁻¹—these rates are low and comparable to oligotrophic regions in the modern oceans. This challenges longstanding assumptions that oceanic anoxic events are intervals of strongly elevated organic carbon burial. Numerical modelling of the BCP, furthermore, reveals that such low OC fluxes are only possible with either or both low to moderate OC export fluxes from ocean surface waters, with rates similar to oligotrophic (nutrient-poor, <30 gC m⁻² yr⁻¹) and mesotrophic (moderate-nutrients, ~50–100 gC m⁻² yr⁻¹) regions in the modern ocean, and stronger than modern vertical OC attenuation. The low OC fluxes thus reflect a relatively weak BCP. Low to moderate productivity is further supported by palaeoecological and geochemical evidence and was likely maintained through nutrient limitation that developed in response to the burial and sequestration of phosphorus in association with iron minerals under ferruginous (anoxic iron-rich) ocean conditions. Without persistently high productivity, ocean deoxygenation during OAE1a was more likely driven by other physicochemical and biological factors including ocean warming, changes in marine primary producer community composition, and fundamental shifts in the efficiency of the BCP with associated effects and feedbacks.     

IFN-α Regulates Blimp-1 Expression via miR-23a and miR-125b in Both Monocytes-Derived DC and pDC

Type I interferon (IFN-I) have emerged as crucial mediators of cellular signals controlling DC differentiation and function. Human DC differentiated from monocytes in the presence of IFN-α (IFN-α DC) show a partially mature phenotype and a special capability of stimulating CD4+ T cell and cross-priming CD8+ T cells. Likewise, plasmacytoid DC (pDC) are blood DC highly specialized in the production of IFN-α in response to viruses and other danger signals, whose functional features may be shaped by IFN-I. Here, we investigated the molecular mechanisms stimulated by IFN-α in driving human monocyte-derived DC differentiation and performed parallel studies on peripheral unstimulated and IFN-α-treated pDC. A specific miRNA signature was induced in IFN-α DC and selected miRNAs, among which miR-23a and miR-125b, proved to be negatively associated with up-modulation of Blimp-1 occurring during IFN-α-driven DC differentiation. Of note, monocyte-derived IFN-α DC and in vitro IFN-α-treated pDC shared a restricted pattern of miRNAs regulating Blimp-1 expression as well as some similar phenotypic, molecular and functional hallmarks, supporting the existence of a potential relationship between these DC populations. On the whole, these data uncover a new role of Blimp-1 in human DC differentiation driven by IFN-α and identify Blimp-1 as an IFN-α-mediated key regulator potentially accounting for shared functional features between IFN-α DC and pDC.