Electrical detection of magnetic skyrmions by non-collinear magnetoresistance

Magnetic skyrmions are localised non-collinear spin textures with high potential for future spintronic applications. Skyrmion phases have been discovered in a number of materials and a focus of current research is the preparation, detection, and manipulation of individual skyrmions for an implementation in devices. Local experimental characterization of skyrmions has been performed by, e.g., Lorentz microscopy or atomic-scale tunnel magnetoresistance measurements using spin-polarised scanning tunneling microscopy. Here, we report on a drastic change of the differential tunnel conductance for magnetic skyrmions arising from their non-collinearity: mixing between the spin channels locally alters the electronic structure, making a skyrmion electronically distinct from its ferromagnetic environment. We propose this non-collinear magnetoresistance (NCMR) as a reliable all-electrical detection scheme for skyrmions with an easy implementation into device architectures

The changing landscape of genetic testing and its impact on clinical and laboratory services and research in Europe

The arrival of new genetic technologies that allow efficient examination of the whole human genome (microarray, next-generation sequencing) will impact upon both laboratories (cytogenetic and molecular genetics in the first instance) and clinical/medical genetic services. The interpretation of analytical results in terms of their clinical relevance and the predicted health status poses a challenge to both laboratory and clinical geneticists, due to the wealth and complexity of the information obtained. There is a need to discuss how to best restructure the genetic services logistically and to determine the clinical utility of genetic testing so that patients can receive appropriate advice and genetic testing. To weigh up the questions and challenges of the new genetic technologies, the European Society of Human Genetics (ESHG) held a series of workshops on 10 June 2010 in Gothenburg. This was part of an ESHG satellite symposium on the 'Changing landscape of genetic testing', co-organized by the ESHG Genetic Services Quality and Public and Professional Policy Committees. The audience consisted of a mix of geneticists, ethicists, social scientists and lawyers. In this paper, we summarize the discussions during the workshops and present some of the identified ways forward to improve and adapt the genetic services so that patients receive accurate and relevant information. This paper covers ethics, clinical utility, primary care, genetic services and the blurring boundaries between healthcare and research

Optoacoustic detection of early therapy-induced tumor cell death using a targeted imaging agent

Purpose: The development of new treatments and their deployment in the clinic may be assisted by imaging methods that allow an early assessment of treatment response in individual patients. The C2A domain of Synaptotagmin-I (C2Am), which binds to the phosphatidylserine (PS) exposed by apoptotic and necrotic cells, has been developed as an imaging probe for detecting cell death. Multispectral optoacoustic tomography (MSOT) is a real-time and clinically applicable imaging modality that was used here with a near infrared (NIR) fluorophore-labeled C2Am to image tumor cell death in mice treated with a TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) agonist and with 5-fluorouracil (5-FU).Experimental Design: C2Am was labeled with a near infrared (NIR) fluorophore and injected intravenously into mice bearing human colorectal TRAIL-sensitive Colo205 and TRAIL-resistant HT-29 xenografts that had been treated with a potent agonist of TRAILR2 and in Colo205 tumors treated with 5-FU.Results: Three dimensional MSOT images of probe distribution showed development of tumor contrast within 3 h of probe administration and a signal-to-background ratio in regions containing dead cells of >10 after 24 h. A site-directed mutant of C2Am that is inactive in PS binding showed negligible binding. Tumor retention of the active probe was strongly correlated (R2=0.97, P valueConclusions: The rapid development of relatively high levels of contrast suggests that NIR fluorophore-labeled C2Am could be a useful optoacoustic imaging probe for detecting early therapy-induced tumor cell death in the clinic.The work was supported by a Cancer Research UK Programme grant (17242) and a Project grant from MedImmune to KMB and by the CRUK-EPSRC Imaging Centre in Cambridge and Manchester (16465)

Large introns in relation to alternative splicing and gene evolution: a case study of Drosophila bruno-3

Background: Alternative splicing (AS) of maturing mRNA can generate structurally and functionally distinct transcripts from the same gene. Recent bioinformatic analyses of available genome databases inferred a positive correlation between intron length and AS. To study the interplay between intron length and AS empirically and in more detail, we analyzed the diversity of alternatively spliced transcripts (ASTs) in the Drosophila RNA-binding Bruno-3 (Bru-3) gene. This gene was known to encode thirteen exons separated by introns of diverse sizes, ranging from 71 to 41,973 nucleotides in D. melanogaster. Although Bru-3's structure is expected to be conducive to AS, only two ASTs of this gene were previously described. Results: Cloning of RT-PCR products of the entire ORF from four species representing three diverged Drosophila lineages provided an evolutionary perspective, high sensitivity, and long-range contiguity of splice choices currently unattainable by high-throughput methods. Consequently, we identified three new exons, a new exon fragment and thirty-three previously unknown ASTs of Bru-3. All exon-skipping events in the gene were mapped to the exons surrounded by introns of at least 800 nucleotides, whereas exons split by introns of less than 250 nucleotides were always spliced contiguously in mRNA. Cases of exon loss and creation during Bru-3 evolution in Drosophila were also localized within large introns. Notably, we identified a true de novo exon gain: exon 8 was created along the lineage of the obscura group from intronic sequence between cryptic splice sites conserved among all Drosophila species surveyed. Exon 8 was included in mature mRNA by the species representing all the major branches of the obscura group. To our knowledge, the origin of exon 8 is the first documented case of exonization of intronic sequence outside vertebrates. Conclusion: We found that large introns can promote AS via exon-skipping and exon turnover during evolution likely due to frequent errors in their removal from maturing mRNA. Large introns could be a reservoir of genetic diversity, because they have a greater number of mutable sites than short introns. Taken together, gene structure can constrain and/or promote gene evolution

The Multifunctional Host Defense Peptide SPLUNC1 Is Critical for Homeostasis of the Mammalian Upper Airway

Otitis media (OM) is a highly prevalent pediatric disease caused by normal flora of the nasopharynx that ascend the Eustachian tube and enter the middle ear. As OM is a disease of opportunity, it is critical to gain an increased understanding of immune system components that are operational in the upper airway and aid in prevention of this disease. SPLUNC1 is an antimicrobial host defense peptide that is hypothesized to contribute to the health of the airway both through bactericidal and non-bactericidal mechanisms. We used small interfering RNA (siRNA) technology to knock down expression of the chinchilla ortholog of human SPLUNC1 (cSPLUNC1) to begin to determine the role that this protein played in prevention of OM. We showed that knock down of cSPLUNC1 expression did not impact survival of nontypeable Haemophilus influenzae, a predominant causative agent of OM, in the chinchilla middle ear under the conditions tested. In contrast, expression of cSPLUNC1 was essential for maintenance of middle ear pressure and efficient mucociliary clearance, key defense mechanisms of the tubotympanum. Collectively, our data have provided the first in vivo evidence that cSPLUNC1 functions to maintain homeostasis of the upper airway and, thereby, is critical for protection of the middle ear

Nocturnal plant respiration is under strong non-temperature control

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability: The leaf respiration data measured as part of this study and collected from the literature together with annual gridded JULES output generated in simulations of this study are available at https://doi.org/10.5281/zenodo.7037530. WFDEI meteorological forcing data is available at the DATAGURU website for climate-related data at Lund University (https://DATAGURU.lu.se, then go to “Explore available datasets”). This allows extraction of data from the global domain, a user-defined grid box or region for a specified time interval. Ftp downloads are possible via the unix/linux command line, site = ftp.iiasa.ac.at, username = rfdata and password = forceDATA, this takes the user to the WATCH Forcing DATA files, then switch to the WFDEI directory using: ‘cd WFDEI’. The /WFDEI directory includes files listing grid box elevations and locations Annual CO2 concentrations are available at https://gml.noaa.gov/ccgg/trends/gl_data.html Source data are provided with this paper.Code availability: Python code for data analysis is available under https://doi.org/10.5281/zenodo.7037530. This study uses JULES, two branches of JULES-vn5.2. https://code.metoffice.gov.uk/trac/jules/browser/main/branches/dev/linamercado/r14338_circadian at revision 22682 for TDQ10 simulations and https://code.metoffice.gov.uk/trac/jules/browser/main/branches/dev/douglasclark/vn5.2_diurnal_resp at revision 22681 for simulations with constant Q10 which are available on the Met Office Science Repository System (MOSRS; https://code.metoffice.gov.uk/trac/jules; registration required https://jules.jchmr.org/content/getting-started). Simulations were performed using Rose suites u-ce999 (new formulation) and u-ce859 for simulations with constant Q10, and u-bs101 (with new formulation) and u-ce767 for simulations with TDQ10 also available through MOSRS.Most biological rates depend on the rate of respiration. Temperature variation is typically considered the main driver of daily plant respiration rates, assuming a constant daily respiration rate at a set temperature. Here, we show empirical data from 31 species from temperate and tropical biomes to demonstrate that the rate of plant respiration at a constant temperature decreases monotonically with time through the night, on average by 25% after 8 h of darkness. Temperature controls less than half of the total nocturnal variation in respiration. A new universal formulation is developed to model and understand nocturnal plant respiration, combining the nocturnal decrease in the rate of plant respiration at constant temperature with the decrease in plant respiration according to the temperature sensitivity. Application of the new formulation shows a global reduction of 4.5 -6 % in plant respiration and an increase of 7-10% in net primary production for the present-day.Natural Environment Research Council (NERC)University of ExeterMet Office Hadley Centre Climate Programm

IGFBP3 mRNA expression in benign and malignant breast tumors

INTRODUCTION: Most previous studies have focused on evaluating the association between circulating insulin-like growth factor binding protein 3 (IGFBP-3) levels and breast cancer risk. Emerging evidence over the past few years suggests that IGFBP-3 may act directly on mammary epithelial cells. METHODS: To understand the role of IGFBP-3 in breast tumorigenesis, we investigated IGFBP3 mRNA expression levels in benign and malignant breast tumors and their adjacent normal tissues using real-time quantitative PCR. RESULTS: Cancer tissues had significantly lower IGFBP3 expression than benign tumor tissues (p < 0.001). IGFBP3 expressions in both tumor and adjacent tissues were higher in patients who had proliferative benign tumors than in those who had non-proliferative benign tumors. Among patients with benign breast disease, IGFBP3 expression in the tumor was significantly higher than that in their adjacent normal tissue. There were no apparent associations of IGFBP3 expression in cancer tissues with either overall survival or disease-free survival in a cohort of 521 patients with breast cancer. CONCLUSION: Our findings suggest that the expression level of IGFBP3 in breast tissues may be involved in breast tumorigenesis