374 research outputs found
Antibacterial Activity of Small Molecules Which Eradicate Methicillin-Resistant Staphylococcus aureus Persisters
The serious challenge posed by multidrug-resistant bacterial infections with concomitant treatment failure and high mortality rates presents an urgent threat to the global health. We herein report the discovery of a new class of potent antimicrobial compounds that are highly effective against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The compounds were efficiently synthesized in one-pot employing a cascade of Groebke-Blackburn-Bienayme and aza-Michael addition reactions. Phenotypic screening of the pilot library against various bacterial species including methicillin-sensitive and MRSA strains, has identified potent chemotypes with minimal inhibitory concentrations (MIC) of 3.125-6.25 mu g/ml. The most potent compounds were fast-acting at eradicating exponentially growing MRSA, with killing achieved after 30 min of exposure to the compounds. They were also able to kill MRSA persister cells which are tolerant to most available medications. Microscopic analysis using fluorescence microscope and atomic force microscope indicate that these compounds lead to disruption of bacterial cell envelopes. Most notably, bacterial resistance toward these compounds was not observed after 20 serial passages in stark contrast to the significant resistance developed rapidly upon exposure to a clinically relevant antibiotic. Furthermore, the compounds did not induce significant hemolysis to human red blood cells. In vivo safety studies revealed a high safety profile of these motifs. These small molecules hold a promise for further studies and development as new antibacterial agents against MRSA infections.This work was supported by the generous grants from the
IsDB-Transformers Fund and the Research Funding Department,
University of Sharjah, UAE (CoV19-0306)
Universal representation by Boltzmann machines with Regularised Axons
It is widely known that Boltzmann machines are capable of representing
arbitrary probability distributions over the values of their visible neurons,
given enough hidden ones. However, sampling -- and thus training -- these
models can be numerically hard. Recently we proposed a regularisation of the
connections of Boltzmann machines, in order to control the energy landscape of
the model, paving a way for efficient sampling and training. Here we formally
prove that such regularised Boltzmann machines preserve the ability to
represent arbitrary distributions. This is in conjunction with controlling the
number of energy local minima, thus enabling easy \emph{guided} sampling and
training. Furthermore, we explicitly show that regularised Boltzmann machines
can store exponentially many arbitrarily correlated visible patterns with
perfect retrieval, and we connect them to the Dense Associative Memory
networks.Comment: 12 pages. Updated reference
A NOVEL INDEX OF ABUNDANCE OF JUVENILE YELLOWFIN TUNA IN THE ATLANTIC OCEAN DERIVED FROM ECHOSOUNDER BUOYS
The collaboration with the Spanish vessel-owners associations and the buoy-providers
companies, has made it possible the recovery of the information recorded by the satellite linked
GPS tracking echosounder buoys used by the Spanish tropical tuna purse seiners and associated
fleet in the Atlantic since 2010. These instrumental buoys inform fishers remotely in real-time
about the accurate geolocation of the FAD and the presence and abundance of fish aggregations
underneath them. Apart from its unquestionable impact in the conception of a reliable CPUE
index from the tropical purse seine tuna fisheries fishing on FADs, echosounder buoys have also
the potential of being a privileged observation platform to evaluate abundances of tunas and
accompanying species using catch-independent data. Current echosounder buoys provide a
single acoustic value without discriminating species or size composition of the fish underneath
the FAD. Therefore, it has been necessary to combine the echosounder buoys data with fishery
data, species composition and average size, to obtain a specific indicator. This paper presents a
novel index of abundance of juvenile yellowfin tuna in the Atlantic Ocean derived from
echosounder buoys for the period 2010-2018
Reprogramming human T cell function and specificity with non-viral genome targeting.
Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells
The 3D Bioprinted Scaffolds for Wound Healing
Skin tissue engineering and regeneration aim at repairing defective skin injuries and progress in wound healing. Until now, even though several developments are made in this field, it is still challenging to face the complexity of the tissue with current methods of fabrication. In this review, short, state-of-the-art on developments made in skin tissue engineering using 3D bioprinting as a new tool are described. The current bioprinting methods and a summary of bioink formulations, parameters, and properties are discussed. Finally, a representative number of examples and advances made in the field together with limitations and future needs are provided
Identification of miRNAs and Their Target Genes Associated with Sunitinib Resistance in Clear Cell Renal Cell Carcinoma Patients
Sunitinib has greatly improved the survival of clear cell renal cell carcinoma (ccRCC) patients in recent years. However, 20–30% of treated patients do not respond. To identify miRNAs and genes associated with a response, comparisons were made between biopsies from responder and non-responder ccRCC patients. Using integrated transcriptomic analyses, we identified 37 miRNAs and 60 respective target genes, which were significantly associated with the NF-kappa B, PI3K-Akt and MAPK pathways. We validated expression of the miRNAs (miR-223, miR-155, miR-200b, miR-130b) and target genes (FLT1, PRDM1 and SAV1) in 35 ccRCC patients. High levels of miR-223 and low levels of FLT1, SAV1 and PRDM1 were associated with worse overall survival (OS), and combined miR-223 + SAV1 levels distinguished responders from non-responders (AUC = 0.92). Using immunohistochemical staining of 170 ccRCC patients, VEGFR1 (FLT1) expression was associated with treatment response, histological grade and RECIST (Response Evaluation Criteria in Solid Tumors) score, whereas SAV1 and BLIMP1 (PRDM1) were associated with metachronous metastatic disease. Using in situ hybridisation (ISH) to detect miR-155 we observed higher tumoural cell expression in non-responders, and non-tumoural cell expression with increased histological grade. In summary, our preliminary analysis using integrated miRNA-target gene analyses identified several novel biomarkers in ccRCC patients that surely warrant further investigation
Scientific Advice on the estimation of surplus for Sustainable Fisheries Partnership Agreements.
Scientific advice on the concept of surplus, as defined by the UNCLOS, was provided for three types of Sustainable Fisheries Partnership Agreements (SFPAs): i) Mixed SFPAs in West Africa, ii) Tuna SFPAs and iii) SFPA with Greenland. For Mixed SFPAs in West Africa, methods for surplus computation were defined, including alternatives for cases of data limited stocks. These methods may use as input five parameters that could be obtained from those recent stocks assessments that are representative of the current stock status. Surplus estimates would need to be regularly updated (ideally, yearly), according to every new stock assessments and following the enforcement of a management plan (or, by default, according to a transition scheme towards reaching Fmsy in 2020). In the case of West African transboundary stocks, a theoretical share of the surplus could be calculated using a standard rule based on historical catches within EEZs. The Surplus concept is not applicable for Tuna SFPAs, due to the high migratory character of tuna or tuna-like species, the fact that these stocks are mostly found in areas beyond national jurisdictions, the lack of direct estimates of local abundance and impossibility to calculate the capacity of the coastal States. For the SFPA with Greenland, Surplus is considered as any TAC allocated to Greenland and not utilised by this coastal State
Evaluation of miCRovascular rarefaction in vascUlar Cognitive Impairment and heArt faiLure (CRUCIAL): Study protocol for an observational study
INTRODUCTION: Microvascular rarefaction, the functional reduction in perfused microvessels and structural reduction of microvascular density, seems to be an important mechanism in the pathophysiology of small blood vessel related disorders including vascular cognitive impairment (VCI) due to cerebral small vessel disease and heart failure with preserved ejection fraction (HFpEF). Both diseases share common risk factors including hypertension, diabetes mellitus, obesity, and ageing; in turn, these co-morbidities are associated with microvascular rarefaction. Our consortium aims to investigate novel non-invasive tools to quantify microvascular health and rarefaction in both organs, as well as surrogate biomarkers for cerebral and/or cardiac rarefaction (via sublingual capillary health, vascular density of the retina, and RNA content of circulating extracellular vesicles), and to determine whether microvascular density relates to disease severity. METHODS/DESIGN: The clinical research program of CRUCIAL consists of four observational cohort studies. We aim to recruit 75 VCI patients, 60 HFpEF patients, 60 patients with severe aortic stenosis (AS) undergoing surgical aortic valve replacement as a pressure overload HFpEF model, and 200 elderly participants with mixed comorbidities to serve as controls. Data collected will include medical history, physical examination, cognitive testing, advanced brain and cardiac MRI, ECG, echocardiography, sublingual capillary health, optical coherence tomography angiography (OCTa), extracellular vesicles RNA analysis and myocardial remodelling-related serum biomarkers. The AS cohort undergoing surgery will also have myocardial biopsy for histological microvascular assessment. DISCUSSION: CRUCIAL will examine the pathophysiological role of microvascular rarefaction in VCI and HFpEF using advanced brain and cardiac MRI techniques. Furthermore, we will investigate surrogate biomarkers for non-invasive, faster, easier, and cheaper assessment of microvascular density since these are more likely to be disseminated into widespread clinical practice. If microvascular rarefaction is an early marker of developing small vessel diseases, then measuring rarefaction may allow pre-clinical diagnosis, with implications for screening, risk stratification, and prevention. Further knowledge of the relevance of microvascular rarefaction and its underlying mechanisms may provide new avenues for research and therapeutic targets
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