Synthetic/ECM-inspired hybrid platform for hollow microcarriers with ROS-triggered nanoporation hallmarks

Reactive oxygen species (ROS) are key pathological signals expressed in inflammatory diseases such as cancer, ischemic conditions and atherosclerosis. An ideal drug delivery system should not only be responsive to these signals but also should not elicit an unfavourable host response. This study presents an innovative platform for drug delivery where a natural/synthetic composite system composed of collagen type I and a synthesized polythioether, ensures a dual stimuli-responsive behaviour. Collagen type I is an extracellular matrix constituent protein, responsive to matrix metalloproteinases (MMP) cleavage per se. Polythioethers are stable synthetic polymers characterized by the presence of sulphur, which undergoes a ROS-responsive swelling switch. A polythioether was synthesised, functionalized and tested for cytotoxicity. Optimal conditions to fabricate a composite natural/synthetic hollow sphere construct were optimised by a template-based method. Collagen-polythioether hollow spheres were fabricated, revealing uniform size and ROS-triggered nanoporation features. Cellular metabolic activity of H9C2 cardiomyoblasts remained unaffected upon exposure to the spheres. Our natural/synthetic hollow microspheres exhibit the potential for use as a pathological stimuli-responsive reservoir system for applications in inflammatory diseases

the influence of pregnancy and the beginning of lactation on pelage traits in cashmere goats

The aim of this study was to investigate the effect of pregnancy followed by the beginning of lactation on fibre traits incashmere goats. Two groups of cashmere-bearing goats aged between 2-3 years were used. The control group (A) included12 non-lactating, non-pregnant subjects. The experimental group (B) included 12 goats mated during the first weekof June, in order to have pregnancy and the beginning of lactation coincide with the period when cashmere normallygrows. As expected, Liveweight significantly varied in Group B during the last two months of pregnancy, when foetalgrowth reaches its maximum, and following delivery. Hair patch weight, because of the continuous growth of primary andsecondary fibres, increased significantly during the trial (P<0.001). The physiological status considered negatively affected(P<0.05) the total mean growth rate of cashmere fibres and, as a result, their length. Cashmere daily growth ratevalues varied significantly (P<0.05) throughout the experiment, while the effect of the physiological status was notedonly in November – December. Furthermore, this parameter also seems to be influenced by climatic factors and, in particular,environmental temperature, as shown by the negative correlation (r = - 0.28; P<0.05) between cashmere dailygrowth rate and environmental temperature. Guard hair length and growth rate did not differ between the two groups,however, they were influenced by time. Cashmere yield and cashmere production were lower in group B (P<0.05). Nodifferences between groups were observed for cashmere diameter. Overall, pregnancy and the consequent period of lactationnegatively influenced cashmere rather than guard hair fibres. These negative effects were noted in quantitativeterms as yield and production dropped by 37% and 43%, respectively. We hypothesise that the complete overlap of pregnancyand lactation with the period of cashmere growth reduced the number of secondary active follicles and their degreeof activity and caused an increase in competition for the partitioning of nutrients between hair follicles and the graviduterus, first, and then the mammary gland, later

Inflated 3D ConvNet context analysis for violence detection

According to the Wall Street Journal, one billion surveillance cameras will be deployed around the world by 2021. This amount of information can be hardly managed by humans. Using a Inflated 3D ConvNet as backbone, this paper introduces a novel automatic violence detection approach that outperforms state-of-the-art existing proposals. Most of those proposals consider a pre-processing step to only focus on some regions of interest in the scene, i.e., those actually containing a human subject. In this regard, this paper also reports the results of an extensive analysis on whether and how the context can affect or not the adopted classifier performance. The experiments show that context-free footage yields substantial deterioration of the classifier performance (2% to 5%) on publicly available datasets. However, they also demonstrate that performance stabilizes in context-free settings, no matter the level of context restriction applied. Finally, a cross-dataset experiment investigates the generalizability of results obtained in a single-collection experiment (same dataset used for training and testing) to cross-collection settings (different datasets used for training and testing)

A worm gel-based 3D model to elucidate the paracrine interaction between multiple myeloma and mesenchymal stem cells

Multiple myeloma (MM) is a malignancy of terminally-differentiated plasma cells that develops mainly inside the bone marrow (BM) microenvironment. It is well known that autocrine and paracrine signals are responsible for the progression of this disease but the precise mechanism and contributions from single cell remain largely unknown. Mesenchymal stem cells (MSC) are an important cellular component of the BM: they support MM growth by increasing its survival and chemo-resistance, but little is known about the paracrine signaling pathways. Three-dimensional (3D) models of MM-MSC paracrine interactions are much more biologically-relevant than simple 2D models and are considered essential for detailed studies of MM pathogenesis. Herein we present a novel 3D co-culture model designed to mimic the paracrine interaction between MSC and MM cells. MSC were embedded within a previously characterized thermoresponsive block copolymer worm gel that can induce stasis in human pluripotent stem cells (hPSC) and then co-cultured with MM cells. Transcriptional phenotyping of co-cultured cells indicated the dysregulation of genes that code for known disease-relevant factors, and also revealed IL-6 and IL-10 as upstream regulators. Importantly, we have identified a synergistic paracrine signaling pathway between IL-6 and IL-10 that plays a critical role in sustaining MM cell proliferation. Our findings indicate that this 3D co-culture system is a useful model to investigate the paracrine interaction between MM cells and the BM microenvironment in vitro. This approach has revealed a new mechanism that promotes the proliferation of MM cells and suggested a new therapeutic target

High-resolution sequencing of DNA G-quadruplex secondary structures in the human genome

This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/nbt.3295During active transcription and replication chromatin architecture is altered, allowing formation of DNA secondary structures. G-quadruplexes (G4s) have emerged as important regulatory DNA structures and have been associated with genomic instability, genetic diseases and cancer progression. Experimental evidence for G4 prevalence in the entire human genome is still lacking. We present a high-resolution sequencing-based method that detected 716,310 distinct G4s in the human genome, more than predicted by computational methods, including structural variants previously uncharacterised in a genomic context. We observed high G4-density in functional regions, such as 5’ UTRs and splicing sites, and in genes not predicted to have such structures (BRCA1 and BRCA2). We found a significant association of G4 formation with oncogenes and tumor suppressors, and with Somatic Copy-Number Alterations (SCNAs) that act as cancer drivers. Our results support that G4s are promising targets for cancer intervention and suggest novel candidates for further biological and mechanistic studies.We are grateful to the Biotechnology and Biological Sciences Research Council (BBSRC) and Illumina® for the studentship supporting V.C (BB/I015477/1). The S.B. research group is supported by programme funding from Cancer Research UK and from the European Research Council and project funding from BBSRC

Ocular Itch Relief with Alcaftadine 0.25% Versus Olopatadine 0.2% in Allergic Conjunctivitis: Pooled Analysis of Two Multicenter Randomized Clinical Trials

Introduction: The efficacy and safety of the once-daily topical ophthalmic solutions, alcaftadine 0.25% and olopatadine 0.2%, in preventing ocular itching associated with allergic conjunctivitis were evaluated. Methods: Pooled analysis was conducted of two double-masked, multicenter, active- and placebo-controlled studies using the conjunctival allergen challenge (CAC) model of allergic conjunctivitis. Subjects were randomized 1:1:1 to receive alcaftadine 0.25%, olopatadine 0.2%, or placebo. The primary efficacy measure was subject-evaluated mean ocular itching at 3 min post-CAC and 16 h after treatment instillation. Secondary measures included ocular itching at 5 and 7 min post-CAC. Ocular itch was determined over all time points measured (3, 5, and 7 min) post-CAC and the proportion of subjects with minimal itch (itch score <1) and zero itch (itch score = 0) was also assessed. Results: A total of 284 subjects were enrolled in the two studies. At 3 min post-CAC and 16 h after treatment instillation, alcaftadine 0.25% achieved a significantly lower mean itch score compared with olopatadine 0.2% (0.50 vs. 0.87, respectively; P = 0.0006). Alcaftadine demonstrated a significantly lower mean itch score over all time points compared with olopatadine (0.68 vs. 0.92, respectively; P = 0.0390); both alcaftadine- and olopatadine-treated subjects achieved significantly lower overall mean ocular itching scores compared with placebo (2.10; P < 0.0001 for both actives). Minimal itch over all time points was reported by 76.1% of alcaftadine-treated subjects compared with 58.1% of olopatadine-treated subjects (P = 0.0121). Treatment with alcaftadine 0.25% and olopatadine 0.2% was safe and well tolerated; no serious adverse events were reported. Conclusion: Once-daily alcaftadine 0.25% ophthalmic solution demonstrated greater efficacy in prevention of ocular itching compared with olopatadine 0.2% at 3 min post-CAC (primary endpoint), and over all time points, 16 h post-treatment instillation. Alcaftadine and olopatadine both provided effective relief compared with placebo and were generally well tolerated. Electronic supplementary material The online version of this article (doi:10.1007/s12325-014-0155-3) contains supplementary material, which is available to authorized users

COVID19 outbreak in Lombardy, Italy: An analysis on the short-term relationship between air pollution, climatic factors and the susceptibility to SARS-CoV-2 infection

Short-term exposure to air pollution, as well as to climate variables have been linked to a higher incidence of respiratory viral diseases. The study aims to assess the short-term influence of air pollution and climate on COVID19 incidence in Lombardy (Italy), during the early stage of the outbreak, before the implementation of the lockdown measures. The daily number of COVID19 cases in Lombardy from February 25th to March 10th, 2020, and the daily average concentrations up to 15 days before the study period of particulate matter (PM10, PM2.5), O3, SO2, and NO2 together with climate variables (temperature, relative humidity – RH%, wind speed, precipitation), were analyzed. A univariable mixed model with a logarithm transformation as link function was applied for each day, from 15 days (lag15) to one day (lag1) before the day of detected cases, to evaluate the effect of each variable. Additionally, change points (Break Points-BP) in the relationship between incident cases and air pollution or climatic factors were estimated. The results did not show a univocal relationship between air quality or climate factors and COVID19 incidence. PM10, PM2.5 and O3 concentrations in the last lags seem to be related to an increased COVID19 incidence, probably due to an increased susceptibility of the host. In addition, low temperature and low wind speed in some lags resulted associated with increased daily COVID19 incidence. The findings observed suggest that these factors, in particular conditions and lags, may increase individual susceptibility to the development of viral infections such as SARS-CoV-2

Omalizumab decreases exacerbation frequency, oral intake of corticosteroids and peripheral blood eosinophils in atopic patients with uncontrolled asthma.

Omalizumab is a humanized monoclonal anti-IgE antibody approved in 2005 by the European Medicine Agency (EMA) for the treatment of severe persistent allergic asthma, which remains inadequately controlled despite optimal therapy with high doses of inhaled corticosteroids and long-acting β2-adrenergic agonists. Within this context, the present observational study refers to 16 patients currently treated with omalizumab at the Respiratory Unit of "Magna Græcia" University Hospital located in Catanzaro, Italy, whose anti- IgE therapy was started in the period included between March 2007 and February 2010, thus lasting at least 10 months. After 40 weeks of add-on treatment with omalizumab, very relevant decreases were detected, in comparison with pre-treatment mean (± standard deviation) values, in monthly exacerbation numbers (from 1.1 ± 0.6 to 0.2 ± 0.4; p < 0.01) and oral corticosteroid consumption (from 22.6 ± 5.0 to 1.2 ± 2.9 mg/day of prednisone; p < 0.01). These changes were associated with stable improvements in lung function, expressed as increases of both FEV1 (from 53.6 ± 14.6% to 77.0 ± 14.9% of predicted values; p < 0.01) and FEV1/FVC ratio (from 56.3 ± 9.5% to 65.8 ± 9.2%; p < 0.01). Moreover, in 5 patients who persistently had increased numbers of eosinophils (mean ± SD: 15.9 ± 8.0% of total WBC count; absolute number: 1,588.0 ± 956.9/μl) despite a long-lasting therapy with inhaled and systemic corticosteroids, the peripheral counts of these cells decreased down to near normal levels (mean ± SD: 6.3 ± 2.3% of total WBC count; absolute number: 462.0 ± 262.3/μl) after 16 weeks of treatment with omalizumab. Therefore, this descriptive evaluation confirms the efficacy of add-on omalizumab therapy in selected patients with exacerbation-prone, chronic allergic uncontrolled asthma, requiring a continuous intake of oral corticosteroids

Color stabilization of apulian red wines through the sequential inoculation of starmerella bacillaris and saccharomyces cerevisiae

Mixed fermentation using Starmerella bacillaris and Saccharomyces cerevisiae has gained attention in recent years due to their ability to modulate the qualitative parameters of enological interest, such as the color intensity and stability of wine. In this study, three of the most important red Apulian varieties were fermented through two pure inoculations of Saccharomyces cerevisiae strains or the sequential inoculation of Saccharomyces cerevisiae after 48 h from Starmerella bacillaris. The evolution of anthocyanin profiles and chromatic characteristics were determined in the produced wines at draining off and after 18 months of bottle aging in order to assess the impact of the different fermentation protocols on the potential color stabilization and shelf-life. The chemical composition analysis showed titratable acidity and ethanol content exhibiting marked differences among wines after fermentation and aging. The 48 h inoculation delay produced wines with higher values of color intensity and color stability. This was ascribed to the increased presence of compounds, such as stable A-type vitisins and reddish/violet ethylidene-bridge flavonol-anthocyanin adducts, in the mixed fermentation. Our results proved that the sequential fermentation of Starmerella bacillaris and Saccharomyces cerevisiae could enhance the chromatic profile as well as the stability of the red wines, thus improving their organoleptic quality