Flow-distributed spikes for Schnakenberg kinetics

This is the post-print version of the final published paper. The final publication is available at link.springer.com by following the link below. Copyright @ 2011 Springer-Verlag.We study a system of reaction–diffusion–convection equations which combine a reaction–diffusion system with Schnakenberg kinetics and the convective flow equations. It serves as a simple model for flow-distributed pattern formation. We show how the choice of boundary conditions and the size of the flow influence the positions of the emerging spiky patterns and give conditions when they are shifted to the right or to the left. Further, we analyze the shape and prove the stability of the spikes. This paper is the first providing a rigorous analysis of spiky patterns for reaction-diffusion systems coupled with convective flow. The importance of these results for biological applications, in particular the formation of left–right asymmetry in the mouse, is indicated.RGC of Hong Kon

Risk of Cerebrovascular Events in 178 962 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The TYACSS (Teenage and Young Adult Cancer Survivor Study)

Background: Survivors of teenage and young adult (TYA) cancer are at risk of cerebrovascular events, but the magnitude of and extent to which this risk varies by cancer type, decade of diagnosis, age at diagnosis and attained age remains uncertain. This is the largest ever cohort study to evaluate the risks of hospitalisation for a cerebrovascular event among long-term survivors of TYA cancer. Methods:The population-based Teenage and Young Adult Cancer Survivor Study (N=178,962) was linked to Hospital Episode Statistics data for England to investigate the risks of hospitalisation for a cerebrovascular event among 5-year survivors of cancer diagnosed when aged 15-39 years. Observed numbers of first hospitalisations for cerebrovascular events were compared to that expected from the general population using standardised hospitalisation ratios (SHR) and absolute excess risks (AER) per 10,000 person-years. Cumulative incidence was calculated with death considered a competing risk. Results: Overall, 2,782 cancer survivors were hospitalised for a cerebrovascular event—40% higher than expected (SHR=1.4, 95% confidence interval [CI]=1.3-1.4). Survivors of central nervous system (CNS) tumours (SHR=4.6, CI=4.3-5.0), head & neck tumours (SHR=2.6, CI=2.2-3.1) and leukaemia (SHR=2.5, CI=1.9-3.1) were at greatest risk. Males had a significantly higher AER than females (AER=7 versus 3), especially among head & neck tumour survivors (AER=30 versus 11). By age 60, 9%, 6% and 5% of CNS tumour, head & neck tumour, and leukaemia survivors, respectively, had been hospitalised for a cerebrovascular event. Beyond age 60, every year 0.4% of CNS tumour survivors were hospitalised for a cerebral infarction (versus 0.1% expected. Whereas at any age, every year 0.2% of head & neck tumour survivors were hospitalised for a cerebral infarction 7 (versus 0.06% expected). Conclusions: Survivors of a CNS tumour, head & neck tumour, and leukaemia are particularly at risk of hospitalisation for a cerebrovascular event. The excess risk of cerebral infarction among CNS tumour survivors increases with attained age. For head & neck tumour survivors this excess risk remains high across all ages. These groups of survivors, and in particular males, should be considered for surveillance of cerebrovascular risk factors and potential pharmacological interventions for cerebral infarction prevention

4-dimensional functional profiling in the convulsant-treated larval zebrafish brain

This is the final version of the article. Available from Springer Nature via the DOI in this record.Functional neuroimaging, using genetically-encoded Ca(2+) sensors in larval zebrafish, offers a powerful combination of high spatiotemporal resolution and higher vertebrate relevance for quantitative neuropharmacological profiling. Here we use zebrafish larvae with pan-neuronal expression of GCaMP6s, combined with light sheet microscopy and a novel image processing pipeline, for the 4D profiling of chemoconvulsant action in multiple brain regions. In untreated larvae, regions associated with autonomic functionality, sensory processing and stress-responsiveness, consistently exhibited elevated spontaneous activity. The application of drugs targeting different convulsant mechanisms (4-Aminopyridine, Pentylenetetrazole, Pilocarpine and Strychnine) resulted in distinct spatiotemporal patterns of activity. These activity patterns showed some interesting parallels with what is known of the distribution of their respective molecular targets, but crucially also revealed system-wide neural circuit responses to stimulation or suppression. Drug concentration-response curves of neural activity were identified in a number of anatomically-defined zebrafish brain regions, and in vivo larval electrophysiology, also conducted in 4dpf larvae, provided additional measures of neural activity. Our quantification of network-wide chemoconvulsant drug activity in the whole zebrafish brain illustrates the power of this approach for neuropharmacological profiling in applications ranging from accelerating studies of drug safety and efficacy, to identifying pharmacologically-altered networks in zebrafish models of human neurological disorders.This work was funded by the Biological and Biotechnology Research Council (CASE studentship BB/L502510/1, with AstraZeneca Safety Health and Environment), and by the University of Exeter and AstraZeneca

Control of interjoint coordination during the swing phase of normal gait at different speeds

BACKGROUND: It has been suggested that the control of unconstrained movements is simplified via the imposition of a kinetic constraint that produces dynamic torques at each moving joint such that they are a linear function of a single motor command. The linear relationship between dynamic torques at each joint has been demonstrated for multijoint upper limb movements. The purpose of the current study was to test the applicability of such a control scheme to the unconstrained portion of the gait cycle – the swing phase. METHODS: Twenty-eight neurologically normal individuals walked along a track at three different speeds. Angular displacements and dynamic torques produced at each of the three lower limb joints (hip, knee and ankle) were calculated from segmental position data recorded during each trial. We employed principal component (PC) analysis to determine (1) the similarity of kinematic and kinetic time series at the ankle, knee and hip during the swing phase of gait, and (2) the effect of walking speed on the range of joint displacement and torque. RESULTS: The angular displacements of the three joints were accounted for by two PCs during the swing phase (Variance accounted for – PC1: 75.1 ± 1.4%, PC2: 23.2 ± 1.3%), whereas the dynamic joint torques were described by a single PC (Variance accounted for – PC1: 93.8 ± 0.9%). Increases in walking speed were associated with increases in the range of motion and magnitude of torque at each joint although the ratio describing the relative magnitude of torque at each joint remained constant. CONCLUSION: Our results support the idea that the control of leg swing during gait is simplified in two ways: (1) the pattern of dynamic torque at each lower limb joint is produced by appropriately scaling a single motor command and (2) the magnitude of dynamic torque at all three joints can be specified with knowledge of the magnitude of torque at a single joint. Walking speed could therefore be altered by modifying a single value related to the magnitude of torque at one joint

The design of a learning environment based on the theory of multiple intelligence and the study its effectiveness on the achievements, attitudes and retention of students

AbstractMultiple intelligences theory (MIT) which takes into account students’ individual differences has an important role in the teaching and learning process. In this study a novel learning environment based on MIT which takes students’ interests and needs into an account has been developed. Many activities were carried out depending on students’ intelligence types. The effects of different activities on students’ achievements, attitudes toward chemistry and retention of knowledge in periodical features’ variety at the 10th class were measured and compared. The comparison between experimental group, which was instructed through MIT learning strategies and materials, and control group thought by traditional methods was observed. The research was applied in the first semester of 2009-2010 education years. The study carried out on 75 high school students in Izmir. The application of the study was lasted for 8 weeks containing methods and tests’ practices. Following MIT assessment survey, achievement test and attitude scales were used to analyze its effectiveness. Based on the theories and literature data, an instructional material included concept maps, puzzles, stories, classical music in background, group games, and photos about periodic features’ variety as an alternative to traditional written material. As a result of statistical analysis there were significant differences between achievement post-test and attitudes post-test towards chemistry course of control and experimental groups. Consequently, instructional methods needed to be varied so students could use their intellectual strengths to better understand topics, increase their intrinsic motivation, intervention and encourage active student engagement to improve learning at middle school level

Prototype effect and the persuasiveness of generalizations

An argument that makes use of a generalization activates the prototype for the category used in the generalization. We conducted two experiments that investigated how the activation of the prototype affects the persuasiveness of the argument. The results of the experiments suggest that the features of the prototype overshadow and partly overwrite the actual facts of the case. The case is, to some extent, judged as if it had the features of the prototype instead of the features it actually has. This prototype effect increases the persuasiveness of the argument in situations where the audience finds the judgment more warranted for the prototype than for the actual case (positive prototype effect), but decreases persuasiveness in situations where the audience finds the judgment less warranted for the prototype than for the actual case (negative prototype effect)

Co3O4 Nanocrystals on Graphene as a Synergistic Catalyst for Oxygen Reduction Reaction

Catalysts for oxygen reduction and evolution reactions are at the heart of key renewable energy technologies including fuel cells and water splitting. Despite tremendous efforts, developing oxygen electrode catalysts with high activity at low costs remains a grand challenge. Here, we report a hybrid material of Co3O4 nanocrystals grown on reduced graphene oxide (GO) as a high-performance bi-functional catalyst for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). While Co3O4 or graphene oxide alone has little catalytic activity, their hybrid exhibits an unexpected, surprisingly high ORR activity that is further enhanced by nitrogen-doping of graphene. The Co3O4/N-doped graphene hybrid exhibits similar catalytic activity but superior stability to Pt in alkaline solutions. The same hybrid is also highly active for OER, making it a high performance non-precious metal based bi-catalyst for both ORR and OER. The unusual catalytic activity arises from synergetic chemical coupling effects between Co3O4 and graphene.Comment: published in Nature Material

The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer

Background: Pre-clinical studies have demonstrated synergistic anti-tumour effects of chemotherapy (CT) and zoledronic acid (ZOL). Within the AZURE trial, designed to determine whether the addition of ZOL to neoadjuvant therapy improves disease outcomes, a subgroup received neoadjuvant CT. We report a retrospective evaluation comparing pathological response in the primary tumour between treatment groups. Methods: In total, 205 patients received neoadjuvant CT±ZOL (CT+ZOL, n=102; CT, n=103). The primary end point was pathologically assessed residual invasive tumour size (RITS) at surgery. Secondary end points were pathological complete response (pCR) rate and axillary nodal involvement. Following review of surgical pathology reports (n=195), outcome differences between groups were assessed adjusting for potential response modifiers. Results: Baseline characteristics and CT treatments were similar. In multivariate analysis, allowing for biological and clinical factors known to influence tumour response, the adjusted mean RITS in CT and CT+ZOL groups were 27.4 and 15.5 mm, respectively, giving a difference in means of 12 mm (95% confidence interval: 3.5–20.4 mm; P=0.006). The pCR rate was 6.9% in the CT group and 11.7% in the CT+ZOL group (P=0.146). There was no difference in axillary nodal involvement (P=0.6315). Conclusion: These data suggest a possible direct anti-tumour effect of ZOL in combination with CT, warranting formal evaluation in prospective studies

Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia.

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease

MIR376A is a regulator of starvation-induced autophagy

Background: Autophagy is a vesicular trafficking process responsible for the degradation of long-lived, misfolded or abnormal proteins, as well as damaged or surplus organelles. Abnormalities of the autophagic activity may result in the accumulation of protein aggregates, organelle dysfunction, and autophagy disorders were associated with various diseases. Hence, mechanisms of autophagy regulation are under exploration. Methods: Over-expression of hsa-miR-376a1 (shortly MIR376A) was performed to evaluate its effects on autophagy. Autophagy-related targets of the miRNA were predicted using Microcosm Targets and MIRanda bioinformatics tools and experimentally validated. Endogenous miRNA was blocked using antagomirs and the effects on target expression and autophagy were analyzed. Luciferase tests were performed to confirm that 3’ UTR sequences in target genes were functional. Differential expression of MIR376A and the related MIR376B was compared using TaqMan quantitative PCR. Results: Here, we demonstrated that, a microRNA (miRNA) from the DlkI/Gtl2 gene cluster, MIR376A, played an important role in autophagy regulation. We showed that, amino acid and serum starvation-induced autophagy was blocked by MIR376A overexpression in MCF-7 and Huh-7 cells. MIR376A shared the same seed sequence and had overlapping targets with MIR376B, and similarly blocked the expression of key autophagy proteins ATG4C and BECN1 (Beclin 1). Indeed, 3’ UTR sequences in the mRNA of these autophagy proteins were responsive to MIR376A in luciferase assays. Antagomir tests showed that, endogenous MIR376A was participating to the control of ATG4C and BECN1 transcript and protein levels. Moreover, blockage of endogenous MIR376A accelerated starvation-induced autophagic activity. Interestingly, MIR376A and MIR376B levels were increased with different kinetics in response to starvation stress and tissue-specific level differences were also observed, pointing out to an overlapping but miRNA-specific biological role. Conclusions: Our findings underline the importance of miRNAs encoded by the DlkI/Gtl2 gene cluster in stress-response control mechanisms, and introduce MIR376A as a new regulator of autophagy