Deregulated calcium signaling in blood cancer: Underlying mechanisms and therapeutic potential

Intracellular calcium signaling regulates diverse physiological and pathological processes. In solid tumors, changes to calcium channels and effectors via mutations or changes in expression affect all cancer hallmarks. Such changes often disrupt transport of calcium ions (Ca$^{2+}$) in the endoplasmic reticulum (ER) or mitochondria, impacting apoptosis. Evidence rapidly accumulates that this is similar in blood cancer. Principles of intracellular Ca$^{2+}$ signaling are outlined in the introduction. We describe different Ca$^{2+}$-toolkit components and summarize the unique relationship between extracellular Ca$^{2+}$ in the endosteal niche and hematopoietic stem cells. The foundational data on Ca$^{2+}$ homeostasis in red blood cells is discussed, with the demonstration of changes in red blood cell disorders. This leads to the role of Ca$^{2+}$ in neoplastic erythropoiesis. Then we expand onto the neoplastic impact of deregulated plasma membrane Ca$^{2+}$ channels, ER Ca$^{2+}$ channels, Ca$^{2+}$ pumps and exchangers, as well as Ca$^{2+}$ sensor and effector proteins across all types of hematologic neoplasms. This includes an overview of genetic variants in the Ca$^{2+}$-toolkit encoding genes in lymphoid and myeloid cancers as recorded in publically available cancer databases. The data we compiled demonstrate that multiple Ca$^{2+}$ homeostatic mechanisms and Ca$^{2+}$ responsive pathways are altered in hematologic cancers. Some of these alterations may have genetic basis but this requires further investigation. Most changes in the Ca$^{2+}$-toolkit do not appear to define/associate with specific disease entities but may influence disease grade, prognosis, treatment response, and certain complications. Further elucidation of the underlying mechanisms may lead to novel treatments, with the aim to tailor drugs to different patterns of deregulation. To our knowledge this is the first review of its type in the published literature. We hope that the evidence we compiled increases awareness of the calcium signaling deregulation in hematologic neoplasms and triggers more clinical studies to help advance this field

Preparation of highly and generally enriched mammalian tissues for solid state NMR.

An appreciable level of isotope labelling is essential for future NMR structure elucidation of mammalian biomaterials, which are either poorly expressed, or unexpressable, using micro-organisms. We present a detailed protocol for high level (13)C enrichment even in slow turnover murine biomaterials (fur keratin), using a customized diet supplemented with commercial labelled algal hydrolysate and formulated as a gel to minimize wastage, which female mice consumed during pregnancy and lactation. This procedure produced approximately eightfold higher fur keratin labelling in pups, exposed in utero and throughout life to label, than in adults exposed for the same period, showing both the effectiveness, and necessity, of this approach.The authors would like to acknowledge funding from the Biotechnology and Biological Sciences Research Council for DGR and RR; Engineering and Physical Sciences Research Council for WYC and VWCW; National Institute of Health Research for RAB.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s10858-015-9977-

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Measuring psychological health in the perinatal period: workshop consensus statement, 19 March 2013

This consensus statement is the result of an invited workshop funded by the society for Reproductive and Infant Psychology on Measuring Psychological Health in the Perinatal Period which was held in Oxford on the 19th March 2013. The details of those who participated in the workshop can be found at the end of the consensus statement. The workshop evolved out of recognition that a major limitation to research and practice in the perinatal period is identifying valid, reliable and clinically relevant measures of psychological health

A fast extraction-free isothermal LAMP assay for detection of SARS-CoV-2 with potential use in resource-limited settings

BACKGROUND: To retain the spread of SARS-CoV-2, fast, sensitive and cost-effective testing is essential, particularly in resource limited settings (RLS). Current standard nucleic acid-based RT-PCR assays, although highly sensitive and specific, require transportation of samples to specialised laboratories, trained staff and expensive reagents. The latter are often not readily available in low- and middle-income countries and this may significantly impact on the successful disease management in these settings. Various studies have suggested a SARS-CoV-2 loop mediated isothermal amplification (LAMP) assay as an alternative method to RT-PCR. METHODS: Four previously published primer pairs were used for detection of SARS-CoV-2 in the LAMP assay. To determine optimal conditions, different temperatures, sample input and incubation times were tested. Ninety-three extracted RNA samples from St. George's Hospital, London, 10 non-extracted nasopharyngeal swab samples from Great Ormond Street Hospital for Children, London, and 92 non-extracted samples from Queen Elisabeth Central Hospital (QECH), Malawi, which have previously been tested for SARS-Cov-2 by quantitative reverse-transcription RealTime PCR (qRT-PCR), were analysed in the LAMP assay. RESULTS: In this study we report the optimisation of an extraction-free colourimetric SARS-CoV-2 LAMP assay and demonstrated that a lower limit of detection (LOD) between 10 and 100 copies/µL of SARS-CoV-2 could be readily detected by a colour change of the reaction within as little as 30 min. We further show that this assay could be quickly established in Malawi, as no expensive equipment is necessary. We tested 92 clinical samples from QECH and showed the sensitivity and specificity of the assay to be 86.7% and 98.4%, respectively. Some viral transport media, used routinely to stabilise RNA in clinical samples during transportation, caused a non-specific colour-change in the LAMP reaction and therefore we suggest collecting samples in phosphate buffered saline (which did not affect the colour) as the assay allows immediate sample analysis on-site. CONCLUSION: SARS-CoV-2 LAMP is a cheap and reliable assay that can be readily employed in RLS to improve disease monitoring and management

NMR spectroscopy of native and in vitro tissues implicates polyADP ribose in biomineralization.

Nuclear magnetic resonance (NMR) spectroscopy is useful to determine molecular structure in tissues grown in vitro only if their fidelity, relative to native tissue, can be established. Here, we use multidimensional NMR spectra of animal and in vitro model tissues as fingerprints of their respective molecular structures, allowing us to compare the intact tissues at atomic length scales. To obtain spectra from animal tissues, we developed a heavy mouse enriched by about 20% in the NMR-active isotopes carbon-13 and nitrogen-15. The resulting spectra allowed us to refine an in vitro model of developing bone and to probe its detailed structure. The identification of an unexpected molecule, poly(adenosine diphosphate ribose), that may be implicated in calcification of the bone matrix, illustrates the analytical power of this approach

The impact of curriculum hierarchies on the development of professional self in teaching: student-teachers of drama negotiating issues of subject status at the interface between drama and English

At the level of policy the relative ‘value’ of subjects is determined by their official curriculum designation, creating a hierarchy of learning within which particular subjects are categorised as optional to the educational experience of young people. This situation is well-illustrated by the marginalised position of drama in the National Curriculum for England and Wales in which drama appears as an adjunct to the ‘core’ subject English. Yet at school level drama has survived as a discrete and reasonably embedded subject. Drawing on questionnaire and interview data, I investigate the effects of this mismatch on the emergence of pedagogical content knowledge, linked to notions of professional self, in drama student-teachers at one university in the UK. Findings indicate that the student-teachers, whilst not entirely eschewing a less-regulated relationship between the two subjects, view the curriculum for English and its accompanying assessment regime as an inadequate host for drama. In addition, they regard teacher autonomy over curriculum content and pedagogy as indicative of a high degree of professional expertise. This suggests that a case can be made for re-evaluating the nature of the relationship between drama and English and its representation in policy-constructed curricula