Differential Mechanical Response of Mesenchymal Stem Cells and Fibroblasts to Tumor-Secreted Soluble Factors

The progression of neoplastic malignancies is a complex process resulting not only from the accumulation of mutations within tumor cells, but also modulation of the tumor microenvironment. Recent advances have shown that the recruitment and subsequent heterotypic interactions of stromal cells—including fibroblasts and bone marrow-derived mesenchymal stem cells (MSCs)—are crucial for carcinogenesis. Though extensive work has been done analyzing the signals that recruit these cells, the governing mechanical properties have not been fully investigated. Here, we report that despite their initial similarities, MSCs respond not only faster but also more dramatically to pro-migratory tumor-secreted soluble factors. Utilizing multiple particle tracking microrheology to probe the cytoskeletal mechanical properties, we show that MSCs stiffen completely within one hour, three times faster than fibroblasts. In addition, unlike fibroblasts, MSCs exposed to tumor-secreted soluble factors display a functionally different phenotype characterized by morphological elongation, decreased actin stress fiber density, and decreased adhesion. Quantitative real-time PCR indicates these phenomena occur based on differential expression of small GTPases RhoA and Cdc42, but not Rac1. These findings demonstrate a fundamental difference in the recruitment of fibroblasts and MSCs

Rapid transport of muco-inert nanoparticles in cystic fibrosis sputum treated with N -acetyl cysteine

Sputum poses a critical diffusional barrier that strongly limits the efficacy of drug and gene carriers in the airways of individuals with cystic fibrosis (CF). Previous attempts to enhance particle penetration of CF sputum have focused on either reducing its barrier properties via mucolytics, or decreasing particle adhesion to sputum constituents by coating the particle surface with non-mucoadhesive polymers, including polyethylene glycol (PEG). Neither approach has enabled particles to penetrate expectorated sputum at rates previously observed for non-mucoadhesive nanoparticles in human cervicovaginal mucus. Here, we sought to investigate whether a common mucolytic, N-acetyl cysteine (NAC), in combination with dense PEG coatings on particles, can synergistically enhance particle penetration across fresh undiluted CF sputum

Effectiveness of a symptom-clinic intervention delivered by general practitioners with an extended role for people with multiple and persistent physical symptoms in England:the Multiple Symptoms Study 3 pragmatic, multicentre, parallel-group, individually randomised controlled trial

BACKGROUND: People with multiple and persistent physical symptoms have impaired quality of life and poor experiences of health care. We aimed to evaluate the effectiveness of a community-based symptom-clinic intervention in people with multiple and persistent physical symptoms, hypothesising that this symptoms clinic plus usual care would be superior to usual care only.METHODS: The Multiple Symptoms Study 3 was a pragmatic, multicentre, parallel-group, individually randomised controlled trial conducted in 108 general practices in the UK National Health Service in four regions of England between Dec 6, 2018, and June 30, 2023. Participants were individually randomised (1:1) to the symptom-clinic intervention plus usual care or to usual care only via a computer-generated, pseudo-random list stratified by trial centre. Allocation was done by the trial statistician and concealed with a centralised, web-based randomisation system; masking participants was not possible due to the nature of the intervention. The symptom-clinic intervention was a sequence of up to four medical consultations that aimed to elicit a detailed clinical history, fully hear and validate the participant, offer rational explanations for symptoms, and assist the participant to develop ways of managing their symptoms; it was delivered by general practitioners with an extended role. The primary outcome was Patient Health Questionnaire-15 (PHQ-15) score 52 weeks after randomisation, analysed by intention to treat. The trial is registered on the ISRCTN registry (ISRCTN57050216).FINDINGS: 354 participants were randomly assigned; 178 (50%) were assigned to receive the community-based symptoms clinic plus usual care and 176 (50%) were assigned to receive usual care only. At the primary-outcome point of 52 weeks, PHQ-15 scores were 14·1 (SD 3·7) in the group receiving usual care and 12·2 (4·5) in the group receiving the intervention. The adjusted between-group difference of -1·82 (95% CI -2·67 to -0·97) was statistically significantly in favour of the intervention group (p&lt;0·0001). There were 39 adverse events in the group receiving usual care and 36 adverse events in the group receiving the intervention. There were no statistically significant between-group differences in the proportion of participants who had non-serious adverse events (-0·03, 95% CI -0·11 to 0·05) or serious adverse events (0·02, -0·02 to 0·07). No serious adverse event was deemed to be related to the trial intervention.INTERPRETATION: Our symptom-clinic intervention, which focused on explaining persistent symptoms to participants in order to support self-management, led to sustained improvement in multiple and persistent physical symptoms.FUNDING: UK National Institute for Health and Care Research.</p

One HACCP, two approaches: experiences with and perceptions of the Hazard Analysis and Critical Control Points (HACCP) food safety management systems in the US and the EU

This paper explores the differences in the use of the Hazard Analysis Critical Control Point (HACCP) system to manage food safety risks in the food chain from farm to fork in the EU and the US. In particular, this paper investigates the current uses and potential expansion of HACCP as a mechanism for the delivery of safe agricultural products, particularly safe produce. It considers not only whether HACCP systems are the best mode of governance for delivering safe food, and describes why HACCP has achieved an important role in the regulatory framework that governs food safety, but asks why this role is different in the EU and US. Within the EU, HACCP is compulsory at all stages of the food chain other than primary production, whereas the mandatory use of HACCP in the US is less widespread. However, the empirical work found that HACCP is being used by businesses in both the EU and US as a basis for organizing their business, even when not required by regulation. Using data derived from semi-structured interviews with regulatory actors in the EU and US, this paper argues that the different approach to HACCP is a result of differing ideas about the role that it plays in the governance of food safety, and the different concepts of the role of regulation in securing safe food. Finally, the paper explores the difficulties of utilizing HACCP to manage produce safety risks, and raises further challenges that must be met in order to ensure that HACCP can successfully fulfill its potential as a governance mechanism

Coronary Atherosclerotic Plaque Activity and Future Coronary Events

This study was funded by a Wellcome Trust Senior Investigator Award (WT103782AIA). Image analysis was supported by National Institutes for Health (R34HL161195 and 1R01HL135557). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Wellcome Trust or the National Institutes of Health. The British Heart Foundation supports DEN (CH/09/002, RG/16/10/32375, RE/18/5/34216), MRD (FS/SCRF/21/32010), NLM (CH/F/21/90010, RG/20/10/34966, RE/18/5/34216) AJM (AA/18/3/34220) and MCW (FS/ICRF/20/26002) and DD (FS/RTF/20/30009, NH/19/1/34595, PG/18/35/33786, PG/15/88/31780, PG/17/64/33205). MRD is the recipient of the Sir Jules Thorn Award for Biomedical Research 2015 (15/JTA). PJS is supported by outstanding investigator award National Institutes for Health (R35HL161195). JK is supported by the National Science Centre 2021/41/B/NZ5/02630. EvB is supported by SINAPSE (www.sinapse.ac.uk). AB is supported by a Clinical Research Training Fellowships (MR/V007254/1). DD is supported by Chest Heart and Stroke Scotland (19/53), Tenovus Scotland (G.18.01), and Friends of Anchor and Grampian NHS-Endowments. The Edinburgh Clinical Research Facilities, Edinburgh Imaging facility and Edinburgh Clinical Trials Unit are supported by the National Health Service Research Scotland through National Health Service Lothian Health Board. The Leeds Clinical Research Facilities are supported by the UK National Institute for Health Research (NIHR) via its Clinical Research Facility programme. The work at Cedars-Sinai Medical Center (the Los Angeles site) was supported in part by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission. The Chief Investigator and Edinburgh Clinical Trials Unit had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Peer reviewedPostprin

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Increased Sensitivity to Mirror Symmetry in Autism

Can autistic people see the forest for the trees? Ongoing uncertainty about the integrity and role of global processing in autism gives special importance to the question of how autistic individuals group local stimulus attributes into meaningful spatial patterns. We investigated visual grouping in autism by measuring sensitivity to mirror symmetry, a highly-salient perceptual image attribute preceding object recognition. Autistic and non-autistic individuals were asked to detect mirror symmetry oriented along vertical, oblique, and horizontal axes. Both groups performed best when the axis was vertical, but across all randomly-presented axis orientations, autistics were significantly more sensitive to symmetry than non-autistics. We suggest that under some circumstances, autistic individuals can take advantage of parallel access to local and global information. In other words, autistics may sometimes see the forest and the trees, and may therefore extract from noisy environments genuine regularities which elude non-autistic observers

The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes

The genomic landscape of breast cancer is complex, and inter- and intra-tumour heterogeneity are important challenges in treating the disease. In this study, we sequence 173 genes in 2,433 primary breast tumours that have copy number aberration (CNA), gene expression and long-term clinical follow-up data. We identify 40 mutation-driver (Mut-driver) genes, and determine associations between mutations, driver CNA profiles, clinical-pathological parameters and survival. We assess the clonal states of Mut-driver mutations, and estimate levels of intra-tumour heterogeneity using mutant-allele fractions. Associations between PIK3CA mutations and reduced survival are identified in three subgroups of ER-positive cancer (defined by amplification of 17q23, 11q13-14 or 8q24). High levels of intra-tumour heterogeneity are in general associated with a worse outcome, but highly aggressive tumours with 11q13-14 amplification have low levels of intra-tumour heterogeneity. These results emphasize the importance of genome-based stratification of breast cancer, and have important implications for designing therapeutic strategies.The METABRIC project was funded by Cancer Research UK, the British Columbia Cancer Foundation and Canadian Breast Cancer Foundation BC/Yukon. This sequencing project was funded by CRUK grant C507/A16278 and Illumina UK performed all the sequencing. The authors also acknowledge the support of the University of Cambridge, Hutchinson Whampoa, the NIHR Cambridge Biomedical Research Centre, the Cambridge Experimental Cancer Medicine Centre, the Centre for Translational Genomics (CTAG) Vancouver and the BCCA Breast Cancer Outcomes Unit. We thank the Genomics, Histopathology, and Biorepository Core Facilities at the Cancer Research UK Cambridge Institute, and the Addenbrooke’s Human Research Tissue Bank (supported by the National Institute for Health Research Cambridge Biomedical Research Centre).This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms1147

WISE x SuperCOSMOS photometric redshift catalog: 20 million galaxies over 3pi steradians

We cross-match the two currently largest all-sky photometric catalogs, mid-infrared WISE and SuperCOSMOS scans of UKST/POSS-II photographic plates, to obtain a new galaxy sample that covers 3pi steradians. In order to characterize and purify the extragalactic dataset, we use external GAMA and SDSS spectroscopic information to define quasar and star loci in multicolor space, aiding the removal of contamination from our extended-source catalog. After appropriate data cleaning we obtain a deep wide-angle galaxy sample that is approximately 95% pure and 90% complete at high Galactic latitudes. The catalog contains close to 20 million galaxies over almost 70% of the sky, outside the Zone of Avoidance and other confused regions, with a mean surface density of over 650 sources per square degree. Using multiwavelength information from two optical and two mid-IR photometric bands, we derive photometric redshifts for all the galaxies in the catalog, using the ANNz framework trained on the final GAMA-II spectroscopic data. Our sample has a median redshift of z_{med} = 0.2 but with a broad dN/dz reaching up to z>0.4. The photometric redshifts have a mean bias of |delta_z|~10^{-3}, normalized scatter of sigma_z = 0.033 and less than 3% outliers beyond 3sigma_z. Comparison with external datasets shows no significant variation of photo-z quality with sky position. Together with the overall statistics, we also provide a more detailed analysis of photometric redshift accuracy as a function of magnitudes and colors. The final catalog is appropriate for `all-sky' 3D cosmology to unprecedented depths, in particular through cross-correlations with other large-area surveys. It should also be useful for source pre-selection and identification in forthcoming surveys such as TAIPAN or WALLABY