Functional and gene network analyses of transcriptional signatures characterizing pre-weaned bovine mammary parenchyma or fat pad uncovered novel inter-tissue signaling networks during development

<p>Abstract</p> <p>Background</p> <p>The neonatal bovine mammary fat pad (<b>MFP</b>) surrounding the mammary parenchyma (<b>PAR</b>) is thought to exert proliferative effects on the PAR through secretion of local modulators of growth induced by systemic hormones. We used bioinformatics to characterize transcriptomics differences between PAR and MFP from ~65 d old Holstein heifers. Data were mined to uncover potential crosstalk through the analyses of signaling molecules preferentially expressed in one tissue relative to the other.</p> <p>Results</p> <p>Over 9,000 differentially expressed genes (<b>DEG</b>; False discovery rate ≤ 0.05) were found of which 1,478 had a ≥1.5-fold difference between PAR and MFP. Within the DEG highly-expressed in PAR vs. MFP (n = 736) we noted significant enrichment of functions related to cell cycle, structural organization, signaling, and DNA/RNA metabolism. Only actin cytoskeletal signaling was significant among canonical pathways. DEG more highly-expressed in MFP vs. PAR (n = 742) belong to lipid metabolism, signaling, cell movement, and immune-related functions. Canonical pathways associated with metabolism and signaling, particularly immune- and metabolism-related were significantly-enriched. Network analysis uncovered a central role of <it>MYC</it>, <it>TP53</it>, and <it>CTNNB1 </it>in controlling expression of DEG highly-expressed in PAR vs. MFP. Similar analysis suggested a central role for <it>PPARG</it>, <it>KLF2</it>, <it>EGR2</it>, and <it>EPAS1 </it>in regulating expression of more highly-expressed DEG in MFP vs. PAR. Gene network analyses revealed putative inter-tissue crosstalk between cytokines and growth factors preferentially expressed in one tissue (e.g., <it>ANGPTL1</it>, <it>SPP1</it>, <it>IL1B </it>in PAR vs. MFP; <it>ADIPOQ</it>, <it>IL13</it>, <it>FGF2</it>, <it>LEP </it>in MFP vs. PAR) with DEG preferentially expressed in the other tissue, particularly transcription factors or pathways (e.g., <it>MYC</it>, <it>TP53</it>, and actin cytoskeletal signaling in PAR vs. MFP; <it>PPARG </it>and LXR/RXR Signaling in MFP vs. PAR).</p> <p>Conclusions</p> <p>Functional analyses underscored a reciprocal influence in determining the biological features of MFP and PAR during neonatal development. This was exemplified by the potential effect that the signaling molecules (cytokines, growth factors) released preferentially (i.e., more highly-expressed) by PAR or MFP could have on molecular functions or signaling pathways enriched in the MFP or PAR. These bidirectional interactions might be required to coordinate mammary tissue development under normal circumstances or in response to nutrition.</p

Age-Related Changes in Cardiac Autonomic Modulation and Heart Rate Variability in Mice

Objective: The aim of this study was to assess age-related changes in cardiac autonomic modulation and heart rate variability (HRV) and their association with spontaneous and pharmacologically induced vulnerability to cardiac arrhythmias, to verify the translational relevance of mouse models for further in-depth evaluation of the link between autonomic changes and increased arrhythmic risk with advancing age. Methods: Heart rate (HR) and time- and frequency-domain indexes of HRV were calculated from Electrocardiogram (ECG) recordings in two groups of conscious mice of different ages (4 and 19 months old) (i) during daily undisturbed conditions, (ii) following peripheral β-adrenergic (atenolol), muscarinic (methylscopolamine), and β-adrenergic + muscarinic blockades, and (iii) following β-adrenergic (isoprenaline) stimulation. Vulnerability to arrhythmias was evaluated during daily undisturbed conditions and following β-adrenergic stimulation. Results: HRV analysis and HR responses to autonomic blockades revealed that 19-month-old mice had a lower vagal modulation of cardiac function compared with 4-month-old mice. This age-related autonomic effect was not reflected in changes in HR, since intrinsic HR was lower in 19-month-old compared with 4-month-old mice. Both time- and frequency-domain HRV indexes were reduced following muscarinic, but not β-adrenergic blockade in younger mice, and to a lesser extent in older mice, suggesting that HRV is largely modulated by vagal tone in mice. Finally, 19-month-old mice showed a larger vulnerability to both spontaneous and isoprenaline-induced arrhythmias. Conclusion: The present study combines HRV analysis and selective pharmacological autonomic blockades to document an age-related impairment in cardiac vagal modulation in mice which is consistent with the human condition. Given their short life span, mice could be further exploited as an aged model for studying the trajectory of vagal decline with advancing age using HRV measures, and the mechanisms underlying its association with proarrhythmic remodeling of the senescent heart

Adipogenic and energy metabolism gene networks in longissimus lumborum during rapid post-weaning growth in Angus and Angus × Simmental cattle fed high-starch or low-starch diets

<p>Abstract</p> <p>Background</p> <p>Transcriptional networks coordinate adipocyte differentiation and energy metabolism in rodents. The level of fiber and starch in diets with adequate energy content fed to young cattle has the potential to alter intramuscular adipose tissue development in skeletal muscle. Post-weaning alterations in gene expression networks driving adipogenesis, lipid filling, and intracellular energy metabolism provide a means to evaluate long-term effects of nutrition on longissimus muscle development across cattle types.</p> <p>Results</p> <p><it>Longissimus lumborum </it>(LL) from Angus (n = 6) and Angus × Simmental (A × S; n = 6) steer calves (155 ± 10 days age) fed isonitrogenous high-starch (HiS; 1.43 Mcal/kg diet dry matter; n = 6) or low-starch (LoS; 1.19 Mcal/kg diet dry matter; n = 6) diets was biopsied at 0, 56, and 112 days of feeding for transcript profiling of 31 genes associated with aspects of adipogenesis and energy metabolism. Intake of dietary energy (9.44 ± 0.57 Mcal/d) across groups during the study did not differ but feed efficiency (weight gain/feed intake) during the first 56 days was greater for steers fed HiS. Expression of <it>PPARG </it>increased ca. 2-fold by day 56 primarily due to HiS in A × S steers. Several potential <it>PPARG</it>-target genes (e.g., <it>ACACA</it>, <it>FASN</it>, <it>FABP4</it>, <it>SCD</it>) increased 2.5-to-25-fold by day 56 across all groups, with responses (e.g., <it>FASN</it>, <it>FABP4</it>) being less pronounced in A × S steers fed LoS. This latter group of steers had markedly greater blood plasma glucose (0.99 vs. 0.79 g/L) and insulin (2.95 vs. 1.17 μg/L) by day 112, all of which were suggestive of insulin resistance. Interactions were observed for <it>FABP4</it>, <it>FASN</it>, <it>GPAM</it>, <it>SCD</it>, and <it>DGAT2</it>, such that feeding A × S steers high-starch and Angus steers low-starch resulted in greater fold-changes by day 56 or 112 (<it>GPAM</it>). Marked up-regulation of <it>INSIG1 </it>(4-to-8-fold) occurred throughout the study across all groups. <it>SREBF1 </it>expression, however, was only greater on day 112 namely due to LoS in A × S steers. The lipogenic transcription factor <it>THRSP </it>was 6-to-60-fold greater by day 56 primarily due to HiS in A × S steers, constituting the greatest response among all genes.</p> <p>Conclusion</p> <p>Results involving gene markers of mature adipocytes (e.g., <it>PPARG</it>, <it>THRSP</it>, <it>SCD</it>) provided evidence of intramuscular adipose tissue differentiation during the early portion of the growing phase. The resulting gene networks underscored a central role for <it>PPARG </it>in controlling transcription of genes which are known to co-ordinately regulate adipocyte differentiation and lipid filling in non-ruminants. Unlike rodents, <it>INSIG1 </it>appears to play an important role in cattle muscle adipogenesis. We propose that a network of transcription regulators and nuclear receptors including <it>PPARG</it>-target genes,<it> INSIG1</it>, and <it>THRSP</it>, coordinate activation of adipocyte differentiation and lipid filling at an early age.</p

Low levels of vitamin D are common in primary antiphospholipid syndrome with thrombotic disease.

The aim of this study was to assess vitamin D (vit.D) levels in patients with primary antiphospholipid syndrome (PAPS), the association between hypovitaminosis D and clinical manifestations, and the effect of vit.D supplementation on serum levels. Vit.D serum levels of 115 PAPS patients, classified according to the 2006 revised criteria at the Rheumatology Department, Brescia, and of 128 voluntary healthy donors (NHD) were tested in collaboration with DiaSorin (Saluggia, Italy) using the LIAISON® chemiluminescent immunoassay. Clinical data were derived from clinical charts. Vit.D deficiency was more prevalent in PAPS than NHD (17% vs 5%). During the summer, vit.D levels were lower in PAPS than NHD (median 28 vs 40.1 ng/mL, P<0.01). PAPS were subdivided according to clinical characteristics (thrombotic vs obstetric). Both groups had lower vit.D levels compared to NHD. Thrombotic PAPS had significantly lower levels than obstetric PAPS (median 20.8 vs 33.3, P<0.01). Sixteen patients (14%) received oral 25-OH vit.D supplementation (average 400 UI/die), but 63% of them did not reach serum levels above 30 ng/mL. PAPS showed significantly lower levels of vit.D than NHD. Hypovitaminosis D was seen to cluster in patients with thrombosis which may suggest that the lack of vit.D could be one of the many factors involved in the thrombotic process. Low-dose supplementation did not seem to be effective in a small group of patients

A transient cortical state with sleep-like sensory responses precedes emergence from general anesthesia in humans

During awake consciousness, the brain intrinsically maintains a dynamical state in which it can coordinate complex responses to sensory input. How the brain reaches this state spontaneously is not known. General anesthesia provides a unique opportunity to examine how the human brain recovers its functional capabilities after profound unconsciousness. We used intracranial electrocorticography and scalp EEG in humans to track neural dynamics during emergence from propofol general anesthesia. We identify a distinct transient brain state that occurs immediately prior to recovery of behavioral responsiveness. This state is characterized by large, spatially distributed, slow sensory-evoked potentials that resemble the K-complexes that are hallmarks of stage two sleep. However, the ongoing spontaneous dynamics in this transitional state differ from sleep. These results identify an asymmetry in the neurophysiology of induction and emergence, as the emerging brain can enter a state with a sleep-like sensory blockade before regaining responsivity to arousing stimuli.National Institutes of Health (U.S.) (Grant K99-MH111748)National Institutes of Health (U.S.) (Grant R00-NS080911)National Institutes of Health (U.S.) (Grant DP2-OD006454)National Institutes of Health (U.S.) (Grant S10-RR023401)National Institutes of Health (U.S.) (Grant R01- NS062092)National Institutes of Health (U.S.) (Grant R01AG056015)National Institutes of Health (U.S.) (Grant P01GM118269)National Institutes of Health (U.S.) (Grant R01-EB009282

S7A:6 Baseline serum levels of baff or april are independent predictors of sledai response after 12 months of treatment with belimumab in patients with refractory systemic lupus erythematosus

Background Belimumab, a monoclonal antibody targeting BlyS (B lymphocyte stimulator), is used in refractory Systemic Lupus Erythematosus (SLE). Pivotal clinical trials showed that SLE patients with positive anti-dsDNA antibodies and reduced levels of C3 and/or C4 fractions were those more likely to be responders to treatment. Our study aims at exploring predictors of response to Belimumab in the post-marketing experience in consecutive SLE patients treated at a single centre. Methods Twenty-one patients received Belimumab intravenously at standard regimen (10 mg/kg at 0–15–30 days and then every 4 weeks). Anti-dsDNA were tested by Farr assay and C3/C4 levels by nephelometry. Biomarkers belonging to the TNF superfamily and related to B cell activity (BAFF, APRIL, sBCMA, sCD40L, sTACI, TWEAK) were tested by ELISA. All laboratory parameters were tested at baseline and every 6 months afterwards. SLE disease activity was assessed by SLEDAI-2K score. General linear modelling and correlation analysis were performed using SPSS. Results Enrolled patients were 2 males and 19 females with a median (25th-75th percentile) age of 38 (31–42) years. The disease duration at time of Belimumab start was 12 (8–19) years. The baseline SLEDAI score was 6 (4–9), the anti-dsDNA level was 26 (11–99) UI/ml, and their C3 and C4 level was 72 (56–86) and 9 (7–15) mg/dL, respectively. All the parameters of the TNF superfamily showed moderate/strong correlation (r values ranging from 0.543 and 0.989, p In contrast, C3, C4, anti-dsDNA, and SLEDAI were less likely to predict relative SLEDAI change at 12 month of Belimumab treatment (uncontrolled model: C3 p=0.410; C4 p=0.778; anti-dsDNA p=0.412) in this cohort of patients preselected for the treatment with Belimumab. Conclusions In this preselected 'real-life' cohort of refractory SLE patients fulfilling the requirements for Belimumab treatment baseline serum levels of BAFF or APRIL are independent predictors of response to treatment. Therefore, BAFF and APRIL could be useful for response estimation in patients qualifying for Belimumab treatment

Nap sleep spindle correlates of intelligence

Contains fulltext : 152518.pdf (publisher's version ) (Open Access)Sleep spindles are thalamocortical oscillations in non-rapid eye movement (NREM) sleep, that play an important role in sleep-related neuroplasticity and offline information processing. Several studies with full-night sleep recordings have reported a positive association between sleep spindles and fluid intelligence scores, however more recently it has been shown that only few sleep spindle measures correlate with intelligence in females, and none in males. Sleep spindle regulation underlies a circadian rhythm, however the association between spindles and intelligence has not been investigated in daytime nap sleep so far. In a sample of 86 healthy male human subjects, we investigated the correlation between fluid intelligence and sleep spindle parameters in an afternoon nap of 100 minutes. Mean sleep spindle length, amplitude and density were computed for each subject and for each derivation for both slow and fast spindles. A positive association was found between intelligence and slow spindle duration, but not any other sleep spindle parameter. As a positive correlation between intelligence and slow sleep spindle duration in full-night polysomnography has only been reported in females but not males, our results suggest that the association between intelligence and sleep spindles is more complex than previously assumed

Hemispheric reconfigurations in Northern Amazonia: The ‘Three Guianas’ amid regional change and Brazilian hegemony

© 2016 Southseries Inc., www.thirdworldquarterly.com. Regional and hemispheric reconfigurations in Latin America and the Caribbean are increasingly mediated by Brazilian power, and the engagement of Guyana, Suriname and French Guiana with this emerging context is intriguing. They are tentatively moving away from a Caribbean region with which they are culturally contiguous, towards a South American continent in which they are geographically located. This is partly a reflection of the gradual opening up of the Northern Amazonian space that they share collectively, and also with Venezuela and Brazil. These processes are occurring as cause and effect of Brazil’s emergence as a regional–and even regionally hegemonic–power. With reference to wider debates on regionalism and hegemony, we analyse the uncertain consequences of these shifts

CD28null CD4 T-cell expansions in autoimmune disease suggest a link with cytomegalovirus infection

Immunosenescence is thought to contribute to the increase of autoimmune diseases in older people. Immunosenescence is often associated with the presence of an expanded population of CD4 T cells lacking expression of CD28 (CD28null). These highly cytotoxic CD4 T cells were isolated from disease-affected tissues in patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, or other chronic inflammatory diseases and their numbers appeared to be linked to disease severity. However, we recently demonstrated that the common herpes virus, cytomegalovirus (CMV), not ageing, is the major driver of this subset of cytotoxic T cells. In this review, we discuss how CMV might potentiate and exacerbate autoimmune disease through the expansion of CD28null CD4 T cells