The Antimicrobial Effectiveness and Cytotoxicity of the Antibiotic-Loaded Chitosan: ECM Scaffolds

Background: The development of multifunctional wound dressings with the ability to control hemostasis, limit infection and promote rapid wound healing and constructive tissue remodeling has been a challenge for many years. In view of these challenges, a hybrid scaffold platform was developed that combined two different extracellular matrices (ECM): ECM from decellularized mammalian tissue and ECM (chitosan) from crustaceans. Both types of ECM have well established clinical benefits that support and promote wound healing and control hemostasis. This scaffold platform could also be augmented with antibiotics to provide bactericidal activity directly to the wound site. Methods: Four different scaffold formulations were developed containing chitosan supplemented with either 20% or 50% urinary bladder matrix (UBM) hydrogel or 1% (w/v) or 10% (w/v) UBM–ECM particulates. 100% chitosan scaffolds were used as controls. The scaffolds were augmented with either minocycline or rifampicin. Escherichia Coli and Staphylococcus Aureus were used to assesses antimicrobial efficacy and duration of activity, while neutral red uptake assays were performed to establish direct and indirect cytotoxicity. Results: Results showed that scaffold handling properties, scaffold integrity over time and the efficacy and release rate of loaded antibiotics could be modified by altering scaffold composition. Moreover, antibiotics were easily released from the scaffold and could remain effective for up to 24 h by modifying the scaffold composition. Variable results with cytotoxicity testing show that further work is required to optimize the scaffold formulations but these proof of principle experiments suggest that these scaffolds have potential as bioactive wound dressings

Searching for Earth analogues around the nearest stars: the disk age-metallicity relation and the age distribution in the Solar Neighbourhood

The chemical composition of Earth's atmosphere has undergone substantial evolution over the course of its history. It is possible, even likely, that terrestrial planets in other planetary systems have undergone similar changes; consequently, the age distribution of nearby stars is an important consideration in designing surveys for Earth-analogues. Valenti & Fischer (2005) provide age and metallicity estimates for 1039 FGK dwarfs in the Solar Neighbourhood. Using the Hipparcos catalogue as a reference to calibrate potential biases, we have extracted volume-limited samples of nearby stars from the Valenti-Fischer dataset. Unlike other recent investigations, our analysis shows clear evidence for an age-metallicity relation in the local disk, albeit with substantial dispersion at any epoch. The mean metallicity increases from -0.3 dex at a lookback time of ~10 Gyrs to +0.15 dex at the present day. Supplementing the Valenti-Fischer measurements with literature data to give a complete volume-limited sample, the age distribution of nearby FGK dwarfs is broadly consistent with a uniform star-formation rate over the history of the Galactic disk. In striking contrast, most stars known to have planetary companions are younger than 5 Gyrs; however, stars with planetary companions within 0.4 AU have a significantly flatter age distribution, indicating that those systems are stable on timescales of many Gyrs. Several of the older, lower metallicity host stars have enhanced [alpha/Fe] ratios, implying membership of the thick disk. If the frequency of terrestrial planets is also correlated with stellar metallicity, then the median age of such planetary system is likely to be ~3 Gyrs. We discuss the implications of this hypothesis in designing searches for Earth analogues among the nearby stars.Comment: Accepted for publication in Ap

Restoring mucosal barrier function and modifying macrophage phenotype with an extracellular matrix hydrogel: potential therapy for ulcerative colitis

Background & Aims: Despite advances in therapeutic options, more than half of all patients with ulcerative colitis (UC) do not achieve long-term remission, many require colectomy, and the disease still has a marked negative impact on quality of life. Extracellular matrix (ECM) bioscaffolds facilitate the functional repair of many soft tissues by mechanisms that include mitigation of pro-inflammatory macrophage phenotype and mobilization of endogenous stem/progenitor cells. The aim of the present study was to determine if an ECM hydrogel therapy could influence outcomes in an inducible rodent model of UC. Methods: The dextran sodium sulfate (DSS)-colitis model was used in male Sprague Dawley rats. Animals were treated via enema with an ECM hydrogel and the severity of colitis was determined by clinical and histologic criteria. Lamina propria cells were isolated and the production of inflammatory mediators was quantified. Mucosal permeability was assessed in-vivo by administering TRITC-dextran and in-vitro using transepithelial electrical resistance (TEER). Results: ECM hydrogel therapy accelerated healing and improved outcome. The hydrogel was adhesive to colonic tissue, which allowed for targeted delivery of the therapy, and resulted in a reduction in clinical and histologic signs of disease. ECM hydrogel facilitated functional improvement of colonic epithelial barrier function and the resolution of the pro-inflammatory state of tissue macrophages. Conclusions: The present study shows that a nonsurgical and nonpharmacologic ECM-based therapy can abate DSS-colitis not by immunosuppression but by promoting phenotypic change in local macrophage phenotype and rapid replacement of the colonic mucosal barrie

Laboratory and tentative interstellar detection of trans-methyl formate using the publicly available Green Bank Telescope PRIMOS survey

The rotational spectrum of the higher-energy trans conformational isomer of methyl formate has been assigned for the first time using several pulsed-jet Fourier transform microwave spectrometers in the 6-60 GHz frequency range. This species has also been sought toward the Sagittarius B2(N) molecular cloud using the publicly available PRIMOS survey from the Green Bank Telescope. We detect seven absorption features in the survey that coincide with laboratory transitions of trans-methyl formate, from which we derive a column density of 3.1 (+2.6, -1.2) \times 10^13 cm-2 and a rotational temperature of 7.6 \pm 1.5 K. This excitation temperature is significantly lower than that of the more stable cis conformer in the same source but is consistent with that of other complex molecular species recently detected in Sgr B2(N). The difference in the rotational temperatures of the two conformers suggests that they have different spatial distributions in this source. As the abundance of trans-methyl formate is far higher than would be expected if the cis and trans conformers are in thermodynamic equilibrium, processes that could preferentially form trans-methyl formate in this region are discussed. We also discuss measurements that could be performed to make this detection more certain. This manuscript demonstrates how publicly available broadband radio astronomical surveys of chemically rich molecular clouds can be used in conjunction with laboratory rotational spectroscopy to search for new molecules in the interstellar medium.Comment: 40 pages, 7 figures, 4 tables; accepted for publication in Ap

Caring for a sick or injured child during the COVID‐19 pandemic lockdown in 2020 in the UK: An online survey of parents' experiences

Abstract Background During the COVID‐19 pandemic, the first UK lockdown (March to May 2020) witnessed a dramatic reduction in children presenting to primary/emergency care, creating concern that fear of the virus was resulting in children presenting late. Methods An online survey was co‐developed with UK parents to understand the impact of the lockdown on parents' help‐seeking for, and care of, their sick/injured child(ren). The survey was advertised through social media and snowballing to parents whose children had been ill/injured during the lockdown. Analysis used descriptive statistics, SPSSv25 and thematic analysis. Results The survey was fully completed by 198 UK parents. The majority asked for help (144/198): from their family doctor (78), national helplines (48) or an Emergency Department (23). Most reported that their decision‐making had not changed, although how they sought help had changed. A few parents reported that the severity and duration of illness had increased because of uncertainty about and/or difficulty accessing services. Parents did not always report seeking help for symptoms rated red or amber by the Royal College of Paediatrics and Child Health. Parents reported accessing information through the internet or using information that they already had. Parent Contribution This was a collaboration with parents from survey development to dissemination, with two parents being integral members of our research team. Conclusions Our questionnaire was completed by parents who were not deterred from seeking help for their sick or injured children. Even for these parents, the lockdown changes to services created uncertainty about, and barriers to, accessing medical help for their children

MHCII-mediated dialog between group 2 innate lymphoid cells and CD4+ T cells potentiates type 2 immunity and promotes parasitic helminth expulsion

Group 2 innate lymphoid cells (ILC2s) release interleukin-13 (IL-13) during protective immunity to helminth infection and detrimentally during allergy and asthma. Using two mouse models to deplete ILC2s in vivo, we demonstrate that T helper 2 (Th2) cell responses are impaired in the absence of ILC2s. We show that MHCII-expressing ILC2s interact with antigen-specific T cells to instigate a dialog in which IL-2 production from T cells promotes ILC2 proliferation and IL-13 production. Deletion of MHCII renders IL-13-expressing ILC2s incapable of efficiently inducing Nippostrongylus brasiliensis expulsion. Thus, during transition to adaptive T cell-mediated immunity, the ILC2 and T cell crosstalk contributes to their mutual maintenance, expansion and cytokine production. This interaction appears to augment dendritic-cell-induced T cell activation and identifies a previously unappreciated pathway in the regulation of type-2 immunity

Gravitationally lensed quasars and supernovae in future wide-field optical imaging surveys

Cadenced optical imaging surveys in the next decade will be capable of detecting time-varying galaxy-scale strong gravitational lenses in large numbers, increasing the size of the statistically well-defined samples of multiply-imaged quasars by two orders of magnitude, and discovering the first strongly-lensed supernovae. We carry out a detailed calculation of the likely yields of several planned surveys, using realistic distributions for the lens and source properties and taking magnification bias and image configuration detectability into account. We find that upcoming wide-field synoptic surveys should detect several thousand lensed quasars. In particular, the LSST should find 8000 lensed quasars, 3000 of which will have well-measured time delays, and also ~130 lensed supernovae, which is compared with ~15 lensed supernovae predicted to be found by the JDEM. We predict the quad fraction to be ~15% for the lensed quasars and ~30% for the lensed supernovae. Generating a mock catalogue of around 1500 well-observed double-image lenses, we compute the available precision on the Hubble constant and the dark energy equation parameters for the time delay distance experiment (assuming priors from Planck): the predicted marginalised 68% confidence intervals are \sigma(w_0)=0.15, \sigma(w_a)=0.41, and \sigma(h)=0.017. While this is encouraging in the sense that these uncertainties are only 50% larger than those predicted for a space-based type-Ia supernova sample, we show how the dark energy figure of merit degrades with decreasing knowledge of the the lens mass distribution. (Abridged)Comment: 17 pages, 10 figures, 3 tables, accepted for publication in MNRAS; mock LSST lens catalogue may be available at http://kipac-prod.stanford.edu/collab/research/lensing/mocklen

Matrix-Bound Nanovesicles: The Effects of Isolation Method upon Yield, Purity, and Function

Identification of matrix-bound nanovesicles (MBV) as ubiquitous components of the extracellular matrix (ECM) raises questions regarding their biologic functions and their potential theranostic application. Unlike liquid-phase extracellular vesicles (e.g., exosomes), MBV are tightly bound to the ECM, which makes their isolation and harvesting more challenging. The indiscriminate use of different methods to harvest MBV can alter or disrupt their structural and/or functional integrity. The objective of the present study was to compare the effect of various MBV harvesting methods upon yield, purity, and biologic activity. Combinations of four methods to solubilize the ECM (collagenase [COL], liberase [LIB], or proteinase K [PK] and nonenzymatic elution with potassium chloride) and four isolation methods (ultracentrifugation, ultrafiltration [UF], density barrier, and size exclusion chromatography [SEC]) were used to isolate MBV from urinary bladder-derived ECM. All combinations of solubilization and isolation methods allowed for the harvesting of MBV, however, distinct differences were noted. The highest yield, purity, cellular uptake, and biologic activity were seen with MBV isolated by a combination of liberase or collagenase followed by SEC. The combination of proteinase K and UF was shown to have detrimental effects on bioactivity. The results show the importance of selecting appropriate MBV harvesting methods for the characterization and evaluation of MBV and for analysis of their potential theranostic application

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors