Excellence in Supervision: Training Site Supervisors/Mentors

This essay reports on a survey of AFTE supervisors and summarizes their wisdom, challenges and joys.

Targeted disruption of the heat shock protein 20–phosphodiesterase 4D (PDE4D) interaction protects against pathological cardiac remodelling in a mouse model of hypertrophy

Phosphorylated heat shock protein 20 (HSP20) is cardioprotective. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model of pressure overload mediated hypertrophy, we show that peptide disruption of the HSP20–phosphodiesterase 4D (PDE4D) complex results in attenuation of action potential prolongation and protection against adverse cardiac remodelling. The later was evidenced by improved contractility, decreased heart weight to body weight ratio, and reduced interstitial and perivascular fibrosis. This study demonstrates that disruption of the specific HSP20–PDE4D interaction leads to attenuation of pathological cardiac remodelling

Apospory appears to accelerate onset of meiosis and sexual embryo sac formation in sorghum ovules

<p>Abstract</p> <p>Background</p> <p>Genetically unreduced (2<it>n</it>) embryo sacs (ES) form in ovules of gametophytic apomicts, the 2<it>n </it>eggs of which develop into embryos parthenogenetically. In many apomicts, 2<it>n </it>ES form precociously during ovule development. Whether meiosis and sexual ES formation also occur precociously in facultative apomicts (capable of apomictic and sexual reproduction) has not been studied. We determined onset timing of meiosis and sexual ES formation for 569 <it>Sorghum bicolor </it>genotypes, many of which produced 2<it>n </it>ES facultatively.</p> <p>Results</p> <p>Genotype differences for onset timing of meiosis and sexual ES formation, relative to ovule development, were highly significant. A major source of variation in timing of sexual germline development was presence or absence of apomictic ES, which formed from nucellar cells (apospory) in some genotypes. Genotypes that produced these aposporous ES underwent meiosis and sexual ES formation precociously. Aposporous ES formation was most prevalent in subsp. <it>verticilliflorum </it>and in breeding lines of subsp. <it>bicolor</it>. It was uncommon in land races.</p> <p>Conclusions</p> <p>The present study adds meiosis and sexual ES formation to floral induction, apomictic ES formation, and parthenogenesis as processes observed to occur precociously in apomictic plants. The temporally diverse nature of these events suggests that an epigenetic memory of the plants' apomixis status exists throughout its life cycle, which triggers, during multiple life cycle phases, temporally distinct processes that accelerate reproduction.</p

Use of a cAMP BRET Sensor to Characterize a Novel Regulation of cAMP by the Sphingosine 1-Phosphate/G13 Pathway

Regulation of intracellular cyclic adenosine 3',5'-monophosphate (cAMP) is integral in mediating cell growth, cell differentiation, and immune responses in hematopoietic cells. To facilitate studies of cAMP regulation we developed a BRET (bioluminescence resonance energy transfer) sensor for cAMP, CAMYEL (cAMP sensor using YFP-Epac-RLuc), which can quantitatively and rapidly monitor intracellular concentrations of cAMP in vivo. This sensor was used to characterize three distinct pathways for modulation of cAMP synthesis stimulated by presumed Gs-dependent receptors for isoproterenol and prostaglandin E2. Whereas two ligands, uridine 5'-diphosphate and complement C5a, appear to use known mechanisms for augmentation of cAMP via Gq/calcium and Gi, the action of sphingosine 1-phosphate (S1P) is novel. In these cells, S1P, a biologically active lysophospholipid, greatly enhances increases in intracellular cAMP triggered by the ligands for Gs-coupled receptors while having only a minimal effect by itself. The enhancement of cAMP by S1P is resistant to pertussis toxin and independent of intracellular calcium. Studies with RNAi and chemical perturbations demonstrate that the effect of S1P is mediated by the S1P2 receptor and the heterotrimeric G13 protein. Thus in these macrophage cells, all four major classes of G proteins can regulate intracellular cAMP

Patient focused registries can improve health, care, and science.

Eugene Nelson and colleagues call for registries of care data to be transformed into patient centred interactive learning systemsThis work is supported by funding from the Robert Wood Johnson Foundation (Grants: #71211 and 72313), the Cystic Fibrosis Foundation (Grant #OCONNO04Q10), and the Crohn’s and Colitis Foundation of America Quality of Care Initiative (Grant #3372). TSM was funded by the Multidisciplinary Clinical Research Center for Musculoskeletal Diseases at Dartmouth (P60 AR-062799, A. Tosteson, PI), sponsored by the National Institute for Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. EE was funded by The Swedish Research Council for Health, Work Life and Welfare (#2014-4238). MDW is supported by a Wellcome Trust Senior Investigator award (WT09789).This is the final version of the article. It first appeared from BMJ Group via https://doi.org/10.1136/bmj.i331

A professional development model to integrate computational thinking into middle school science through codesigned storylines

This article describes a professional development (PD) model, the CT-Integration Cycle, that supports teachers in learning to integrate computational thinking (CT) and computer science principles into their middle school science and STEM instruction. The PD model outlined here includes collaborative design (codesign; Voogt et al., 2015) of curricular units aligned with the Next Generation Science Standards (NGSS) that use programmable sensors. Specifically, teachers can develop or modify curricular materials to ensure a focus on coherent, student-driven instruction through the investigation of scientific phenomena that are relevant to students and integrate CT and sensor technology. Teachers can implement these storylines and collaboratively reflect on their instructional practices and student learning. Throughout this process, teachers may develop expertise in CT-integrated science instruction as they plan and use instructional practices aligned with the NGSS and foreground CT. This paper describes an examination of a group of five middle school teachers&rsquo; experiences during one iteration of the CT-Integration Cycle, including their learning, planning, implementation, and reflection on a unit they codesigned. Throughout their participation in the PD, the teachers expanded their capacity to engage deeply with CT practices and thoughtfully facilitated a CT-integrated unit with their students.</p

Characterization of rare spontaneous Human Immunodeficiency Virus viral controllers attending a national United Kingdom clinical service using a combination of serology and molecular diagnostic assays

Background We report outcomes and novel characterization of a unique cohort of 42 individuals with persistently indeterminate human immunodeficiency virus (HIV) status, the majority of whom are HIV viral controllers. Methods Eligible individuals had indeterminate or positive HIV serology, but persistently undetectable HIV ribonucleic acid (RNA) by commercial assays and were not taking antiretroviral therapy (ART). Routine investigations included HIV Western blot, HIV viral load, qualitative HIV-1 deoxyribonucleic acid (DNA), coinfection screen, and T-cell quantification. Research assays included T-cell activation, ART measurement, single-copy assays detecting HIV-1 RNA and DNA, and plasma cytokine quantification. Human immunodeficiency virus seropositivity was defined as ≥3 bands on Western blot; molecular positivity was defined as detection of HIV RNA or DNA. Results Human immunodeficiency virus infection was excluded in 10 of 42 referrals, remained unconfirmed in 2 of 42, and was confirmed in 30 of 42, who were identified as HIV elite controllers (ECs), normal CD4 T-cell counts (median 820/mL, range 805–1336), and normal CD4/CD8 ratio (median 1.8, range 1.2–1.9). Elite controllers had a median duration of elite control of 6 years (interquartile range = 4–14). Antiretroviral therapy was undetected in all 23 subjects tested. Two distinct categories of ECs were identified: molecular positive (n = 20) and molecular negative (n = 10). Conclusions Human immunodeficiency virus status was resolved for 95% of referrals with the majority diagnosed as EC. The clinical significance of the 2 molecular categories among ECs requires further investigation

Intracranial self-stimulation in FAST and SLOW mice: effects of alcohol and cocaine

Sensitivity to the stimulant and rewarding effects of alcohol may be genetically-correlated traits that predispose individuals to developing an alcohol use disorder