Crack growth behavior of SBR, NR and BR rubber compounds: comparison of Pure-Shear versus Strip Tensile test

Fatigue crack growth experiments on different carbon black–filled rubber compounds have been carried out to evaluate the influence of pure-shear and strip tensile testing mode by using sine and pulse as waveforms. In a previous set of experimental investigations regarding the influence of both waveform and tested material, it was found that the mode I of crack opening sometimes propagates too quickly to be properly monitored in tests involving strip-tensile specimens. An alternative test methodology based on pure-shear test mode has been investigated, optimizing both the shape of the specimen and the test equipment. Data obtained from the different compound formulations were consistent with the theoretical background and resulted in similar ranking of compound crack growth resistance for the two testing modes; in addition, pure-shear mode showed a higher sensitivity to formula variations

Genetic variants in the NOTCH4 gene influence the clinical features of migraine

BACKGROUND: Recent studies suggested an important role for vascular factors in migraine etiopathogenesis. Notch4 belongs to a family of transmembrane receptors that play an important role in vascular development and maintenance. The aim of this study was to test the hypothesis that polymorphisms of the NOTCH4 gene would modify the occurrence and the clinical features of migraine. FINDINGS: Using a case–control strategy, we genotyped 239 migraine patients and 264 controls for three different non-synonymous polymorphisms (T320A, G835V, R1346P) of the NOTCH4 gene and for the (CTG) n-encoding polyleucine polymorphism in exon 1. Although the analyzed polymorphisms resulted not associated with migraine, the clinical characteristics of our patients were significantly influenced by the different NOTCH4 genotypes. Longer duration of disease and severity of neurovegetative symptoms during headache attacks were associated with the R1346P and G835V polymorphisms, respectively. In female patients, worsening of migraine symptoms at menarche was significantly correlated with T320A polymorphism. CONCLUSIONS: Our study shows that genetic variations within the NOTCH4 gene significantly modify the clinical characteristics of migraine and may have a role in disease pathogenesis

Most brain disease-associated and eQTL haplotypes are not located within transcription factor DNase-seq footprints in brain

Dense genotyping approaches have revealed much about the genetic architecture both of gene expression and disease susceptibility. However, assigning causality to genetic variants associated with a transcriptomic or phenotypic trait presents a far greater challenge. The development of epigenomic resources by ENCODE, the Epigenomic Roadmap and others has led to strategies that seek to infer the likely functional variants underlying these genome-wide association signals. It is known, for example, that such variants tend to be located within areas of open chromatin, as detected by techniques such as DNase-seq and FAIRE-seq. We aimed to assess what proportion of variants associated with phenotypic or transcriptomic traits in human brain are located within transcription factor binding sites. The bioinformatic tools, Wellington and HINT, were used to infer transcription factor footprints from existing DNase-seq data derived from central nervous system tissues with high spatial resolution. This dataset was then employed to assess the likely contribution of altered transcription factor binding to both expression quantitative trait loci (eQTL) and genome-wide association study (GWAS) signals. Surprisingly, we show that most haplotypes associated with GWAS or eQTL phenotypes are located outside of DNase-seq footprints. This could imply that DNase-seq footprinting is too insensitive an approach to identify a large proportion of true transcription factor binding sites. Importantly, this suggests that prioritising variants for genome engineering studies to establish causality will continue to be frustrated by an inability of footprinting to identify the causative variant within a haplotype

Association between migraine and HLA–DRB1 gene polymorphisms

We examined the distribution of HLA–DRB1 alleles in a cohort of 255 Italian migraine patients and in a control group of 325 healthy subjects. The frequency of DRB1*12 allele was found to be significantly reduced (p=0.02) in patients with migraine while the DRB1*16 allele was significantly increased (p=0.04) in comparison with controls. When the patients were divided into disease subgroups (migraine with and without aura), HLA–DRB1**16 allele was significantly increased (p<0.05) only in migraine without aura patients. We conclude that, in Italian patients, migraine is associated with different alleles of the HLA–DRB1 locus. Our data suggest the presence of a genetic susceptibility factor for migraine within the HLA region

Severe acute respiratory syndrome coronavirus 2 may exploit human transcription factors involved in retinoic acid and interferon-mediated response: a hypothesis supported by an in silico analysis

The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19), resulting in acute respiratory disease, is a worldwide emergency. Because recently it has been found that SARS-CoV is dependent on host transcription factors (TF) to express the viral genes, efforts are required to understand the molecular interplay between virus and host response. By bioinformatic analysis, we investigated human TF that can bind the SARS-CoV-2 sequence and can be involved in viral transcription. In particular, we analysed the key role of TF involved in interferon (IFN) response. We found that several TF could be induced by the IFN antiviral response, specifically some induced by IFN-stimulated gene factor 3 (ISGF3) and by unphosphorylated ISGF3, which were found to promote the transcription of several viral open reading frame. Moreover, we found 22 TF binding sites present only in the sequence of virus infecting humans but not bat coronavirus RaTG13. The 22 TF are involved in IFN, retinoic acid signalling and regulation of transcription by RNA polymerase II, thus facilitating its own replication cycle. This mechanism, by competition, may steal the human TF involved in these processes, explaining SARS-CoV-2's disruption of IFN-I signalling in host cells and the mechanism of the SARS retinoic acid depletion syndrome leading to the cytokine storm. We identified three TF binding sites present exclusively in the Brazilian SARS-CoV-2 P.1 variant that may explain the higher severity of the respiratory syndrome. These data shed light on SARS-CoV-2 dependence from the host transcription machinery associated with IFN response and strengthen our knowledge of the virus's transcription and replicative activity, thus paving the way for new targets for drug design and therapeutic approaches