Fault reactivation and strain partitioning across the brittle-ductile transition

The so-called “brittle-ductile transition” is thought to be the strongest part of the lithosphere, and defines the lower limit of the seismogenic zone. It is characterized not only by a transition from localized to distributed (ductile) deformation, but also by a gradual change in microscale deformation mechanism, from microcracking to crystal plasticity. These two transitions can occur separately under different conditions. The threshold conditions bounding the transitions are expected to control how deformation is partitioned between localized fault slip and bulk ductile deformation. Here, we report results from triaxial deformation experiments on pre-faulted cores of Carrara marble over a range of confining pressures, and determine the relative partitioning of the total deformation between bulk strain and on-fault slip. We find that the transition initiates when fault strength (σ_{f}) exceeds the yield stress (σ_{y}) of the bulk rock, and terminates when it exceeds its ductile flow stress (σflow). In this domain, yield in the bulk rock occurs first, and fault slip is reactivated as a result of bulk strain hardening. The contribution of fault slip to the total deformation is proportional to the ratio (σ_{f} − σ_{y})/(σ_{flow} − σ_{y}). We propose an updated crustal strength profile extending the localized-ductile transition toward shallower regions where the strength of the crust would be limited by fault friction, but significant proportions of tectonic deformation could be accommodated simultaneously by distributed ductile flow

Time Dependent Mechanical Crack Closure as a Potential Rapid Source of Post-Seismic Wave Speed Recovery: Insights From Experiments in Carrara Marble

Seismological observations indicate strong variations in wave velocities around faults both co-seismically during earthquakes, and post-seismically. Recovery is commonly associated with a reduction in crack damage. Here, we explore the recovery associated with time-dependent mechanical closure of cracks. We report results from laboratory experiments conducted on dry cores of Carrara marble at room temperature. We deformed cylindrical samples in the semi-brittle regime to induce crack damage before subjecting them to hydrostatic and triaxial stress conditions for extended periods of time while recording dilatancy and wave speeds repeatedly. We report wave speed increases of up to 40% of the damage-induced wave speed drop in samples subject to hydrostatic loading. Moreover, we report the occurrence of significant wave speed increases contemporaneously with time-dependent creep in triaxially loaded samples. Wave speed recovery during creep is only observed below a threshold creep strain rate, a result we interpret as a transition from brittle to plastic creep with decreasing strain rate. We interpret the wave speed increase in terms of reduced crack density and increased contact area within the crack array, and show that around 40% of the total crack surface has to be closed to justify the observed wave speed recoveries. We propose that mechanical crack closure is driven by the viscous relaxation of the bulk rock under the influence of locked-in stresses at low confining pressure, and of the external stresses at higher confining pressure. Our study shows that mechanical crack closure is a significant source of time-dependent wave speed recovery

Identification of Post-Transcriptional Modulators of Breast Cancer Transcription Factor Activity Using MINDy

We have recently identified transcription factors (TFs) that are key drivers of breast cancer risk. To better understand the pathways or sub-networks in which these TFs mediate their function we sought to identify upstream modulators of their activity. We applied the MINDy (Modulator Inference by Network Dynamics) algorithm to four TFs (ESR1, FOXA1, GATA3 and SPDEF) that are key drivers of estrogen receptor-positive (ER+) breast cancer risk, as well as cancer progression. Our computational analysis identified over 500 potential modulators. We assayed 189 of these and identified 55 genes with functional characteristics that were consistent with a role as TF modulators. In the future, the identified modulators may be tested as potential therapeutic targets, able to alter the activity of TFs that are critical in the development of breast cancer

Designing Engaging Learning Experiences in Programming

In this paper we describe work to investigate the creation of engaging programming learning experiences. Background research informed the design of four fieldwork studies to explore how programming tasks could be framed to motivate learners. Our empirical findings from these four field studies are summarized here, with a particular focus upon one – Whack a Mole – which compared the use of a physical interface with the use of a screen-based equivalent interface to obtain insights into what made for an engaging learning experience. Emotions reported by two sets of participant undergraduate students were analyzed, identifying the links between the emotions experienced during programming and their origin. Evidence was collected of the very positive emotions experienced by learners programming with a physical interface (Arduino) in comparison with a similar program developed using a screen-based equivalent interface. A follow-up study provided further evidence of the motivation of personalized design of programming tangible physical artefacts. Collating all the evidence led to the design of a set of ‘Learning Dimensions’ which may provide educators with insights to support key design decisions for the creation of engaging programming learning experiences

In vitro metabolic fate of the synthetic cannabinoid receptor agonists QMPSB and QMPCB (SGT-11) including isozyme mapping and esterase activity

Quinolin-8-yl 4-methyl-3-(piperidine-1-sulfonyl)benzoate (QMPSB) and quinolin-8-yl 4-methyl-3-(piperidine-1-carbonyl)benzoate (QMPCB, SGT-11) are synthetic cannabinoid receptor agonists (SCRAs). Knowing their metabolic fate is crucial for the identification of toxicological screening targets and to predict possible drug interactions. The presented study aimed to identify the in vitro phase I/II metabolites of QMPSB and QMPCB and to study the contribution of different monooxygenases and human carboxylesterases by using pooled human liver S9 fraction (pHLS9), recombinant human monooxygenases, three recombinant human carboxylesterases, and pooled human liver microsomes. Analyses were carried out by liquid chromatography high-resolution tandem mass spectrometry. QMPSB and QMPCB showed ester hydrolysis, and hydroxy and carboxylic acid products were detected in both cases. Mono/dihydroxy metabolites were formed, as were corresponding glucuronides and sulfates. Most of the metabolites could be detected in positive ionization mode with the exception of some QMPSB metabolites, which could only be found in negative mode. Monooxygenase activity screening revealed that CYP2B6/CYP2C8/CYP2C9/CYP2C19/CYP3A4/CYP3A5 were involved in hydroxylations. Esterase screening showed the involvement of all investigated isoforms. Additionally, extensive non-enzymatic ester hydrolysis was observed. Considering the results of the in vitro experiments, inclusion of the ester hydrolysis products and their glucuronides and monohydroxy metabolites into toxicological screening procedures is recommended

Comparison of Two Porcine-Derived Materials for Repairing Abdominal Wall Defects in Rats

OBJECTIVE: The purpose of this study was to compare the mechanical properties, host responses and incorporation of porcine small intestine submucosa (PSIS) and porcine acellular dermal matrix (PADM) in a rat model of abdominal wall defect repair. MATERIALS AND METHODS: Prior to implantation, PSIS and PADM were prepared and evaluated in terms of structure and mechanical properties. Full-thickness abdominal wall defects were created in 50 Sprague-Dawley rats, and were repaired using either PSIS or PADM. Rats were sacrificed 1, 2, 4, 8 and 12 weeks post-repair and examined for herniation, infection, adhesions, contraction, and changes in the thickness and strength of the tissues incorporated at the defect sites. Histopathology and immunohistochemistry were performed to analyze inflammatory responses, collagen deposition and vascularization. RESULTS: PADM showed more dense collagen deposition and stronger mechanical properties than PSIS prior to implantation (P<0.01). However, the mechanical properties observed after integration with the surrounding native tissues was similar for PADM and PSIS. Both PADM and PSIS showed significant contraction by week 12. However, PADM tissue induced less adhesion and increased in thickness more slowly, and showed less infiltration by foreign giant cells, polymorphonuclear cells, and mononuclear cells. Improved remodeling of host tissue was observed after PSIS implantation, which was apparent from the orientation of bands of fibrous connective tissue, intermixed with newly formed blood vessels by Week 12. CONCLUSION: PSIS showed weaker mechanical properties prior to implantation. However, after implantation PSIS induced more pronounced host responses and showed better incorporation into host tissues than PADM

Quinpramine Ameliorates Rat Experimental Autoimmune Neuritis and Redistributes MHC Class II Molecules

Activation of inflammatory cells is central to the pathogenesis of autoimmune demyelinating diseases of the peripheral nervous system. The novel chimeric compound quinpramine—generated from imipramine and quinacrine—redistributes cholesterol rich membrane domains to intracellular compartments. We studied the immunological and clinical effects of quinpramine in myelin homogenate induced Lewis rat experimental autoimmune neuritis (EAN), a model system for acute human inflammatory neuropathies, such as the Guillain-Barré syndrome. EAN animals develop paresis of all limbs due to autoimmune inflammation of peripheral nerves. Quinpramine treatment ameliorated clinical disease severity of EAN and infiltration of macrophages into peripheral nerves. It reduced expression of MHC class II molecules on antigen presenting cells and antigen specific T cell proliferation both in vitro and in vivo. Quinpramine exerted its anti-proliferatory effect on antigen presenting cells, but not on responder T cells. Our data suggest that quinpramine represents a candidate pharmaceutical for inflammatory neuropathies

Prostate Cancer Risk Is not Altered by TP53AIP1 Germline Mutations in a German Case-Control Series

Prostate cancer susceptibility has previously been associated with truncating germline variants in the gene TP53AIP1 (tumor protein p53 regulated apoptosis inducing protein 1). For two apparently recurrent mutations (p.Q22fs and p.S32X) a remarkable OR of 5.1 was reported for prostate cancer risk. Since these findings have not been validated so far, we genotyped p.Q22fs and p.S32X in two German series with a total of 1,207 prostate cancer cases and 1,495 controls. The truncating variants were not significantly associated with prostate cancer in none of the two cohorts, nor in the combined analysis [odds ratio (OR) = 1.16; 95% confidence interval (CI 95%) = 0.62–2.15; p = 0.66]. Carriers showed no significant differences in family history of prostate cancer, age at diagnosis, Gleason score or PSA at diagnosis when compared to non-carrier prostate cancer cases. The large sample size of the combined cohort rejects a high-risk effect greater than 2.2 and indicates a limited role of TP53AIP1 in prostate cancer predisposition

The potential of Virtual Reality as anxiety management tool: a randomized controlled study in a sample of patients affected by Generalized Anxiety Disorder

Background: Generalized anxiety disorder (GAD) is a psychiatric disorder characterized by a constant and unspecific anxiety that interferes with daily-life activities. Its high prevalence in general population and the severe limitations it causes, point out the necessity to find new efficient strategies to treat it. Together with the cognitive-behavioural treatments, relaxation represents a useful approach for the treatment of GAD, but it has the limitation that it is hard to be learned. To overcome this limitation we propose the use of virtual reality (VR) to facilitate the relaxation process by visually presenting key relaxing images to the subjects. The visual presentation of a virtual calm scenario can facilitate patients' practice and mastery of relaxation, making the experience more vivid and real than the one that most subjects can create using their own imagination and memory, and triggering a broad empowerment process within the experience induced by a high sense of presence. According to these premises, the aim of the present study is to investigate the advantages of using a VR-based relaxation protocol in reducing anxiety in patients affected by GAD. Methods/Design: The trialis based on a randomized controlled study, including three groups of 25 patients each (for a total of 75 patients): (1) the VR group, (2) the non-VR group and (3) the waiting list (WL) group. Patients in the VR group will be taught to relax using a VR relaxing environment and audio-visual mobile narratives; patients in the non-VR group will be taught to relax using the same relaxing narratives proposed to the VR group, but without the VR support, and patients in the WL group will not receive any kind of relaxation training. Psychometric and psychophysiological outcomes will serve as quantitative dependent variables, while subjective reports of participants will be used as qualitative dependent variables. Conclusion: We argue that the use of VR for relaxation represents a promising approach in the treatment of GAD since it enhances the quality of the relaxing experience through the elicitation of the sense of presence. This controlled trial will be able to evaluate the effects of the use of VR in relaxation while preserving the benefits of randomization to reduce bias

Ipl1/aurora kinase suppresses S-CDK-driven spindle formation during prophase I to ensure chromosome integrity during meiosis

Cells coordinate spindle formation with DNA repair and morphological modifications to chromosomes prior to their segregation to prevent cell division with damaged chromosomes. Here we uncover a novel and unexpected role for Aurora kinase in preventing the formation of spindles by Clb5-CDK (S-CDK) during meiotic prophase I and when the DDR is active in budding yeast. This is critical since S-CDK is essential for replication during premeiotic S-phase as well as double-strand break induction that facilitates meiotic recombination and, ultimately, chromosome segregation. Furthermore, we find that depletion of Cdc5 polo kinase activity delays spindle formation in DDR-arrested cells and that ectopic expression of Cdc5 in prophase I enhances spindle formation, when Ipl1 is depleted. Our findings establish a new paradigm for Aurora kinase function in both negative and positive regulation of spindle dynamics