Onset of Localization in Heterogeneous Interfacial Failure

We study numerically the failure of an interface joining two elastic materials under load using a fiber bundle model connected to an elastic half space. We find that the breakdown process follows the equal load sharing fiber bundle model without any detectable spatial correlations between the positions of the failing fibers until localization sets in. The onset of localization is an instability, not a phase transition. Depending on the elastic constant describing the elastic half space, localization sets in before or after the critical load causing the interface to fail completely, is reached. There is a crossover between failure due to localization or failure without spatial correlations when tuning the elastic constant, not a phase transition. Contrary to earlier claims based on models different from ours, we find that a finite fraction of fibers must fail before the critical load is attained, even in the extreme localization regime, i.e.\ for very small elastic constant. We furthermore find that the critical load remains finite for all values of the elastic constant in the limit of an infinitely large system.Comment: 4 pages, 5 figure

Screening for C3 Deficiency in Newborns Using Microarrays

BACKGROUND: Dried blood spot samples (DBSS) from newborns are widely used in neonatal screening for selected metabolic diseases and diagnostic possibilities for additional disorders are continuously being evaluated. Primary immunodeficiency disorders comprise a group of more than one hundred diseases, several of which are fatal early in life. Yet, a majority of the patients are not diagnosed due to lack of high-throughput screening methods. METHODOLOGY/PRINCIPAL FINDINGS: We have previously developed a system using reverse phase protein microarrays for analysis of IgA levels in serum samples. In this study, we extended the applicability of the method to include determination of complement component C3 levels in eluates from DBSS collected at birth. Normal levels of C3 were readily detected in 269 DBSS from healthy newborns, while no C3 was detected in sera and DBSS from C3 deficient patients. CONCLUSIONS/SIGNIFICANCE: The findings suggest that patients with deficiencies of specific serum proteins can be identified by analysis of DBSS using reverse phase protein microarrays.QC 20120213</p

VEGF-B hypertrophy predisposes to transition from diastolic to systolic heart failure in hypertensive rats

AIMS: Cardiac energy metabolism is centrally involved in heart failure (HF), although the direction of the metabolic alterations is complex and likely dependent on the particular stage of HF progression. Vascular endothelial growth factor B (VEGF-B) has been shown to modulate metabolic processes and to induce physiological cardiac hypertrophy; thus, it could be cardioprotective in the failing myocardium. This study investigates the role of VEGF-B in cardiac proteomic and metabolic adaptation in HF during aldosterone and high-salt hypertensive challenges. METHODS AND RESULTS: Male rats overexpressing the cardiac-specific VEGF-B transgene (VEGF-B TG) were treated for 3 or 6 weeks with deoxycorticosterone-acetate combined with a high-salt (HS) diet (DOCA + HS) to induce hypertension and cardiac damage. Extensive longitudinal echocardiographic studies of HF progression were conducted, starting at baseline. Sham-treated rats served as controls. To evaluate the metabolic alterations associated with HF, cardiac proteomics by mass spectrometry was performed. Hypertrophic non-treated VEGF-B TG hearts demonstrated high oxygen and adenosine triphosphate (ATP) demand with early onset of diastolic dysfunction. Administration of DOCA + HS to VEGF-B TG rats for 6 weeks amplified the progression from cardiac hypertrophy to HF, with a drastic drop in heart ATP concentration. Dobutamine stress echocardiographic analyses uncovered a significantly impaired systolic reserve. Mechanistically, the hallmark of the failing TG heart was an abnormal energy metabolism with decreased mitochondrial ATP, preceding the attenuated cardiac performance and leading to systolic HF. CONCLUSIONS: This study shows that the VEGF-B TG accelerates metabolic maladaptation which precedes structural cardiomyopathy in experimental hypertension and ultimately leads to systolic HF

Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P= 3.96 x 10(-14)). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.Peer reviewe

Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P= 3.96 x 10(-14)). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality

Cerebrospinal fluid pro-inflammatory cytokines differentiate parkinsonian syndromes

Abstract Introduction Neuroinflammation has been established to be part of the neuropathological changes in Parkinson’s disease (PD) and atypical parkinsonism (APD). Activated microglia play a key role in neuroinflammation by release of cytokines. Evidence of the disparity, if any, in the neuroinflammatory response between PD and APD is sparse. In this study, we investigated CSF cytokine profiles in patients with PD, multiple system atrophy (MSA), or progressive supranuclear palsy (PSP). Methods On a sensitive electrochemiluminescence-based platform (Quickplex, Meso Scale Discovery®), we examined a panel of C-reactive protein (CRP) and eight selected cytokines, IFN-γ, IL-10, IL-18, IL-1β, IL-4, IL-6, TGF-β1, and TNF-α, among patients with PD (n = 46), MSA (n = 35), and PSP (n = 39) or controls (n = 31). Additionally, CSF total tau protein levels were measured as a marker of nonspecific neurodegeneration for correlation estimates. Results CRP and the pro-inflammatory cytokines TNF-α, IL-1β, and Il-6 were statistically significantly elevated in MSA and PSP patients compared to PD patients but not compared to control patients. No analytes differed statistically significantly between MSA and PSP patients. The best diagnostic discrimination, evaluated by ROC curve (AUC 0.77, p = 007, 95% CI 0.660–0.867), between PD and MSA patients was seen for a subset of analytes: CRP, TNF-α, IL-1β, and IFN-γ. Conclusion Among the investigated cytokines and CRP, we found a statistically significant increase of microglia-derived cytokines in MSA and PSP patients compared to PD patients

Proteomic analysis of formalin-fixed paraffin-embedded glomeruli suggests depletion of glomerular filtration barrier proteins in two-kidney one-clip hypertensive rats

Background It is well known that hypertension may cause glomerular damage, but the molecular mechanisms involved are still incompletely understood. Methods In the present study, we used formalin-fixed paraffin-embedded (FFPE) tissue to investigate changes in the glomerular proteome in the non-clipped kidney of two-kidney one-clip (2K1C) hypertensive rats, with special emphasis on the glomerular filtration barrier. 2K1C hypertension was induced in 6-week-old Wistar Hannover rats (n = 6) that were sacrificed 23 weeks later and compared with age-matched sham-operated controls (n = 6). Tissue was stored in FFPE tissue blocks and later prepared on tissue slides for laser microdissection. Glomeruli without severe morphological damage were isolated, and the proteomes were analysed using liquid chromatography–tandem mass spectrometry. Results 2K1C glomeruli showed reduced abundance of proteins important for slit diaphragm complex, such as nephrin, podocin and neph1. The podocyte foot process had a pattern of reduced abundance of transmembrane proteins but unchanged abundances of the podocyte cytoskeletal proteins synaptopodin and α-actinin-4. Lower abundance of important glomerular basement membrane proteins was seen. Possible glomerular markers of damage with increased abundance in 2K1C were transgelin, desmin and acyl-coenzyme A thioesterase 1. Conclusions Microdissection and tandem mass spectrometry could be used to investigate the proteome of isolated glomeruli from FFPE tissue. Glomerular filtration barrier proteins had reduced abundance in the non-clipped kidney of 2K1C hypertensive rats