Digital Resources for Targeted Mathematics Support

SPIRIT Maths (Students’ Perceptions Informing and Redefining Innovative Teaching of Mathematics in Higher Education) is a project that was established in Munster Technological University (MTU) to investigate students’ attitudes towards mathematics and to explore a more student-centred development of mathematics resources. One of the aims of the project was to create a collection of student-preferred digital materials with a view to improving student engagement, building students’ confidence in mathematics and helping students to succeed in their mathematics modules.The findings of a survey disseminated to first year students in MTU indicated that students would be most likely to use the resources if they were geared towards their specific module; to maximise impact, resources were developed for two modules, one in Engineering and one in Business, that are each taken by large numbers of students. The resources were integrated on the learning management system and are available to all MTU students taking a mathematics module. Three interlinked digital resources were developed: (1) a series of interactive self-assessment questions, (2) corresponding videos showing worked solutions and (3) an associated bank of practice questions developed using a digital tutor to provide instant feedback. It is hoped that the complementary resources will facilitate student learning through a combination of active learning, explicit instruction and the ready availability of the resources.This article describes these resources and how they were developed, and outlines how these are being promoted to students. We also report on the feedback received from a small number of students who tested the resources and discuss how to measure student engagement with the resources

Soluble adenylyl cyclase links Ca2+ entry to Ca2+/cAMP-response element binding protein (CREB) activation in vascular smooth muscle

Ca2+-transcription coupling controls gene expression patterns that define vascular smooth muscle cell (VSMC) phenotype. Although not well understood this allows normally contractile VSMCs to become proliferative following vessel injury, a process essential for repair but which also contributes to vascular remodelling, atherogenesis and restenosis. Here we show that the Ca2+/HCO3−-sensitive enzyme, soluble adenylyl cyclase (sAC), links Ca2+ influx in human coronary artery smooth muscle cells (hCASMCs) to 3′,5′-cyclic adenosine monophosphate (cAMP) generation and phosphorylation of the transcription factor Ca2+/cAMP response element binding protein (CREB). Store-operated Ca2+ entry (SOCE) into hCASMCs expressing the FRET-based cAMP biosensor H187 induced a rise in cAMP that mirrored cytosolic [Ca2+]. SOCE also activated the cAMP effector, protein kinase A (PKA), as determined by the PKA reporter, AKAR4-NES, and induced phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and CREB. Transmembrane adenylyl cyclase inhibition had no effect on the SOCE-induced rise in cAMP, while sAC inhibition abolished SOCE-generated cAMP and significantly reduced SOCE-induced VASP and CREB phosphorylation. This suggests that SOCE in hCASMCs activates sAC which in turn activates the cAMP/PKA/CREB axis. sAC, which is insensitive to G-protein modulation but responsive to Ca2+, pH and ATP, may therefore act as an overlooked regulatory node in vascular Ca2+-transcription coupling

IL-17 Production from T Helper 17, Mucosal-Associated Invariant T, and γδ Cells in Tuberculosis Infection and Disease.

IL-17-producing cells have been shown to be important in the early stages of Mycobacterium tuberculosis (Mtb) infection in animal models. However, there are very little data on the role of IL-17 in human studies of tuberculosis (TB). We recruited TB patients and their highly exposed contacts who were further categorized based on results from an IFN-γ-release assay (IGRA): (1) IGRA positive (IGRA+) at recruitment (latently TB infected), (2) IGRA negative (IGRA-) at recruitment and 6 months [non-converters (NC)], and (3) IGRA- at recruitment and IGRA+ at 6 months (converters). Whole blood was stimulated with mycobacterial antigens and analyzed using T helper (Th) 17 multiplex cytokine assays. Th17, Vγ9Vδ2+, and CD161++Vα7.2+ mucosal-associated invariant T (MAIT) cells were analyzed by flow cytometry. The majority of IL-17 was produced by CD26+CD4+ Th17 cells (median 71%) followed by γδ T cells (6.4%) and MAIT cells (5.8%). TB patients had a significantly lower proportion of Th17 cells and CD4+CD161+Vα7.2+ cells producing both IL-17 and IFN-γ compared to LTBI subjects. IGRA NC had significantly lower levels of CD26-CD4+ and CD8+ MAIT cells producing IL-17 compared to IGRA C but had significantly higher levels of IL-17A, IL-17F, IL-21, and IL-23 in ESAT-6/CFP-10-stimulated supernatants compared to IGRA C. These data provide new insights into the role of IL-17 and IL-17-producing cells at three key stages of the Mtb infection spectrum

Regulating voltage-gated ion channels with nanobodies

In this work, Morgenstern and colleagues describe an approach involving functionalized nanobodies which decrease the activity of voltage-gated Ca2+ channels associated with β1 subunits and promote their removal from the surface membrane of neurons and muscle

Store-operated calcium channels in skin.

The skin is a complex organ that acts as a protective layer against the external environment. It protects the internal tissues from harmful agents, dehydration, ultraviolet radiation and physical injury as well as conferring thermoregulatory control, sensation, immunological surveillance and various biochemical functions. The diverse cell types that make up the skin include 1) keratinocytes, which form the bulk of the protective outer layer; 2) melanocytes, which protect the body from ultraviolet radiation by secreting the pigment melanin; and 3) cells that form the secretory appendages: eccrine and apocrine sweat glands, and the sebaceous gland. Emerging evidence suggests that store-operated Ca2+ entry (SOCE), whereby depletion of intracellular Ca2+ stores triggers Ca2+ influx across the plasma membrane, is central to the normal physiology of these cells and thus skin function. Numerous skin pathologies including dermatitis, anhidrotic ectodermal dysplasia, hyperhidrosis, hair loss and cancer are now linked to dysfunction in SOCE proteins. Principal amongst these are the stromal interaction molecules (STIMs) that sense Ca2+ depletion and Orai channels that mediate Ca2+ influx. In this review, the roles of STIM, Orai and other store-operated channels are discussed in the context of keratinocyte differentiation, melanogenesis, and eccrine sweat secretion. We explore not only STIM1-Orai1 as drivers of SOCE, but also independent actions of STIM, and emerging signal cascades stemming from their activities. Roles are discussed for the elusive transient receptor potential canonical channel (TRPC) complex in keratinocytes, Orai channels in Ca2+-cyclic AMP signal crosstalk in melanocytes, and Orai isoforms in eccrine sweat gland secretion

TRPC1 channel clustering during store-operated Ca²⁺ entry in keratinocytes.

Skin is the largest organ in the human body with ∼95% of its surface made up of keratinocytes. These cells maintain a healthy skin barrier through regulated differentiation driven by Ca2+-transcriptional coupling. Many important skin conditions arise from disruption of this process although not all stages are fully understood. We know that elevated extracellular Ca2+ at the skin surface is detected by keratinocyte Gαq-coupled receptors that signal to empty endoplasmic reticulum Ca2+ stores. Orai channel store-operated Ca2+ entry (SOCE) and Ca2+ influx via "canonical" transient receptor potential (TRPC)-composed channels then activates transcription factors that drive differentiation. While STIM-mediated activation of Orai channels following store depletion is well defined, how TRPC channels are activated is less clear. Multiple modes of TRPC channel activation have been proposed, including 1) independent TRPC activation by STIM, 2) formation of Orai-TRPC-STIM complexes, and 3) the insertion of constitutively-active TRPC channels into the membrane during SOCE. To help distinguish between these models, we used high-resolution microscopy of intact keratinocyte (HaCaT) cells and immunogold transmission electron microscopy (TEM) of HaCaT plasma membrane sheets. Our data shows no evidence of significant insertion of Orai1 or TRPC subunits into the membrane during SOCE. Analysis of transmission electron microscopy data shows that during store-depletion and SOCE, Orai1 and TRPC subunits form separate membrane-localized clusters that migrate towards each other. This clustering of TRPC channel subunits in keratinocytes may support the formation of TRPC-STIM interactions at ER-plasma membrane junctions that are distinct from Orai-STIM junctions