A unified approach on Springer fibers in the hook, two-row and two-column cases

We consider the Springer fiber over a nilpotent endomorphism. Fix a Jordan basis and consider the standard torus relative to this. We deal with the problem to describe the flags fixed by the torus which belong to a given component of the Springer fiber. We solve the problem in the hook, two-row and two-column cases. We provide two main characterizations which are common to the three cases, and which involve dominance relations between Young diagrams and combinatorial algorithms. Then, for these three cases, we deduce topological properties of the components and their intersections.Comment: 42 page

Protease-activated receptor 4 variant p.Tyr157Cys reduces platelet functional responses and alters receptor trafficking

OBJECTIVE—: Protease-activated receptor 4 (PAR4) is a key regulator of platelet reactivity and is encoded by F2RL3, which has abundant rare missense variants. We aimed to provide proof of principle that rare F2LR3 variants potentially affect on platelet reactivity and responsiveness to PAR1 antagonist drugs and to explore underlying molecular mechanisms. APPROACH AND RESULTS—: We identified 6 rare F2RL3 missense variants in 236 cardiac patients, of which the variant causing a tyrosine 157 to cysteine substitution (Y157C) was predicted computationally to affect most on PAR4 structure. Y157C platelets from 3 cases showed reduced responses to PAR4-activating peptide and to α-thrombin compared with controls, but no reduction in responses to PAR1-activating peptide. Pretreatment with the PAR1 antagonist vorapaxar caused lower residual α-thrombin responses in Y157C platelets than in controls, indicating greater platelet inhibition. HEK293 cells transfected with a PAR4 Y157C expression construct had reduced PAR4 functional responses, unchanged total PAR4 expression but reduced surface expression. PAR4 Y157C was partially retained in the endoplasmic reticulum and displayed an expression pattern consistent with defective N-glycosylation. Mutagenesis of Y322, which is the putative hydrogen bond partner of Y157, also reduced PAR4 surface expression in HEK293 cells. CONCLUSIONS—: Reduced PAR4 responses associated with Y157C result from aberrant anterograde surface receptor trafficking, in part, because of disrupted intramolecular hydrogen bonding. Characterization of PAR4 Y157C establishes that rare F2RL3 variants have the potential to markedly alter platelet PAR4 reactivity particularly after exposure to therapeutic PAR1 antagonists

Tongue-surface movement patterns during speech and swallowing

The tongue has been frequently characterized as being composed of several functionally independent articulators. The question of functional regionality within the tongue was examined by quantifying the strength of coupling among four different tongue locations across a large number of consonantal contexts and participants. Tongue behavior during swallowing was also described. Vertical displacements of pellets affixed to the tongue were extracted from the x-ray microbeam database. Forty-six participants recited 20 vowel-consonant-vowel (VCV) combinations and swallowed 10 ccs of water. Tongue-surface movement patterns were quantitatively described by computing the covariance between the vertical time-histories of all possible pellet pairs. Phonemic differentiation in vertical tongue motions was observed as coupling varied predictably across pellet pairs with place of articulation. Moreover, tongue displacements for speech and swallowing clustered into distinct groups based on their coupling profiles. Functional independence of anterior tongue regions was evidenced by a wide range of movement coupling relations between anterior tongue pellets. The strengths and weaknesses of the covariance-based analysis for characterizing tongue movement are considered

Never Mind the Gap: Formative Assessment Confronted with Dewey’s and Gadamer’s Concept of Experience

The notion of “closing the learning gap” is widely used in the conceptualisation of formative assessment. It builds on an unarticulated assumption that students' learning can and should be controlled towards predefined outcomes. This article discusses this control assumption in the light of the concept of the American philosopher John Dewey and the German philosopher Hans‐Georg Gadamer. Their conceptualisation challenges the idea of learning as a linear and controllable process that results in stable and predictable outcomes. Using the concept of experience, we argue that learning follows a continuous circular movement where previous experiences condition future interpretations and that every experience changes the subject. This process of change is both unpredictable and diverse and requires that attention is paid to the uniqueness of each situation and to students as subjects. Following the discussion, we propose a model for considering the extensiveness and rigidity of formative assessment practices and that authors pay attention to whether they conceptualise formative assessment in a way that promotes student and teacher “gap closing” and control.publishedVersio

Functional filter for whole genome sequencing data identifies HHT and stress-associated non-coding SMAD4 polyadenylation site variants >5kb from coding DN

Acknowledgments: This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The work was cofounded by the National Institute for Health Research Imperial Biomedical Research Centre, the D’Almeida Charitable Trust, and Imperial College Healthcare NHS Trust. AA was supported by Prince Sultan Military Medical City, Saudi Arabia. MAA was supported by the National Institutes of Health (grant R35HL140019). The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. We thank the National Health Service staff of the UK Genomic Medicine Centres and the participants for their willing participation; the Genomics England Clinical Research Interface team, specifically Susan Walker, for separately reviewing bam file variant sequences; Charlotte Bevan, Michael Hubank and Santiago Vernia for helpful discussions and manuscript review; and our academic and public partners within the NIHR Imperial BRC’s Social Genetic and Environmental Determinants of Health (SGE) theme. We specifically thank the presented families for confirmation of their clinical phenotypes and consent to share in this manuscript. The views expressed are those of the authors and not necessarily those of funders, the NHS, the NIHR, or the Department of Health and Social Care.Peer reviewedPublisher PD

Intratumoral Hydrogen Peroxide With Radiation Therapy in Locally Advanced Breast Cancer: Results From a Phase 1 Clinical Trial.

Purpose Hydrogen peroxide (H2O2) plays a vital role in normal cellular processes but at supraphysiological concentrations causes oxidative stress and cytotoxicity, a property that is potentially exploitable for the treatment of cancer in combination with radiation therapy (RT). We report the first phase 1 trial testing the safety and tolerability of intratumoral H2O2 + external beam RT as a novel combination in patients with breast cancer and exploratory plasma marker analyses investigating possible mechanisms of action.Methods and materials Twelve patients with breast tumors ≥3 cm (surgically or medically inoperable) received intratumoral H2O2 with either 36 Gy in 6 twice-weekly fractions (n = 6) or 49.5 Gy in 18 daily fractions (n = 6) to the whole breast ± locoregional lymph nodes in a single-center, nonrandomized study. H2O2 was mixed in 1% sodium hyaluronate gel (final H2O2 concentration 0.5%) before administration to slow drug release and minimize local discomfort. The mixture was injected intratumorally under ultrasound guidance twice weekly 1 hour before RT. The primary endpoint was patient-reported maximum intratumoral pain intensity before and 24 hours postinjection. Secondary endpoints included grade ≥3 skin toxicity and tumor response by ultrasound. Blood samples were collected before, during, and at the end of treatment for cell-death and immune marker analysis.Results Compliance with H2O2 and RT was 100%. Five of 12 patients reported moderate pain after injection (grade 2 Common Terminology Criteria for Adverse Events v4.02) with median duration 60 minutes (interquartile range, 20-120 minutes). Skin toxicity was comparable to RT alone, with maintained partial/complete tumor response relative to baseline in 11 of 12 patients at last follow-up (median 12 months). Blood marker analysis highlighted significant associations of TRAIL, IL-1β, IL-4, and MIP-1α with tumor response.Conclusions Intratumoral H2O2 with RT is well tolerated with no additional toxicity compared with RT alone. If efficacy is confirmed in a randomized phase 2 trial, the approach has potential as a cost-effective radiation response enhancer in multiple cancer types in which locoregional control after RT alone remains poor

Ancient DNA from giant panda (Ailuropoda melanoleuca) of south-western China reveals genetic diversity loss during the holocene

The giant panda was widely distributed in China and south-eastern Asia during the middle to late Pleistocene, prior to its habitat becoming rapidly reduced in the Holocene. While conservation reserves have been established and population numbers of the giant panda have recently increased, the interpretation of its genetic diversity remains controversial. Previous analyses, surprisingly, have indicated relatively high levels of genetic diversity raising issues concerning the efficiency and usefulness of reintroducing individuals from captive populations. However, due to a lack of DNA data from fossil specimens, it is unknown whether genetic diversity was even higher prior to the most recent population decline. We amplified complete cytb and 12s rRNA, partial 16s rRNA and ND1, and control region sequences from the mitochondrial genomes of two Holocene panda specimens. We estimated genetic diversity and population demography by analyzing the ancient mitochondrial DNA sequences alongside those from modern giant pandas, as well as from other members of the bear family (Ursidae). Phylogenetic analyses show that one of the ancient haplotypes is sister to all sampled modern pandas and the second ancient individual is nested among the modern haplotypes, suggesting that genetic diversity may indeed have been higher earlier during the Holocene. Bayesian skyline plot analysis supports this view and indicates a slight decline in female effective population size starting around 6000 years B.P., followed by a recovery around 2000 years ago. Therefore, while the genetic diversity of the giant panda has been affected by recent habitat contraction, it still harbors substantial genetic diversity. Moreover, while its still low population numbers require continued conservation efforts, there seem to be no immediate threats from the perspective of genetic evolutionary potential

When assessment defines the content—understanding goals in between teachers and policy

© 2020 The Authors. The Curriculum Journal published by John Wiley & Sons Ltd on behalf of British Educational Research Association.Education policy development internationally reflect a widespread expansion of learning outcome orientation in policy, curricula and assessment. In this paper, teachers’ perceptions about their work are explored, as goals and assessment play a more prominent role driven by the introduction of a learning outcomes‐oriented system. This is investigated through interviews of Norwegian teachers and extensive policy analysis of Norwegian policy documents. The findings indicate that the teachers are finding ways to negotiate and adjust to the language in the policies investigated in this study. Furthermore, the findings show that the teachers have developed their professional language according to the policies. The teachers referred to their self‐made criteria and goal sheets as central tools in explicating what is to be learned. In many ways, the tools for assessment, thus determine the content of education as well as what is valued in the educational system.publishedVersio