Life & Health Sciences

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Sterile Lung Inflammation Induced by Silica Exacerbates Mycobacterium tuberculosis Infection via STING-Dependent Type 2 Immunity


ABSTRACT

Lung inflammation induced by silica impairs host control of tuberculosis, yet the underlying mechanism remains unclear. Here, we show that silica-driven exacerbation of M. tuberculosis infection associates with raised type 2 immunity. Silica increases pulmonary Th2 cell and M2 macrophage responses, while reducing type 1 immunity after M. tuberculosis infection. Silica induces lung damage that prompts extracellular self-DNA release and activates STING. This STING priming potentiates M. tuberculosis DNA sensing by and activation of cGAS/STING, which triggers enhanced type I interferon (IFNI) response and type 2 immunity. cGAS-, STING-, and IFNAR-deficient mice are resistant to silica-induced exacerbation of M. tuberculosis infection. Thus, silica-induced self-DNA primes the host response to M. tuberculosis-derived nucleic acids, which increases type 2 immunity while reducing type 1 immunity, crucial for controlling M. tuberculosis infection. These data show how cGAS/STING pathway activation, at the crossroads of sterile inflammation and infection, may affect the host response to pathogens such as M. tuberculosis.


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The impact of IFNγ signaling in the pulmonary damage during Plasmodium berghei ANKA infection


ABSTRACT

Malaria is one of the most important parasitic infection in the world. Cerebral and pulmonary complications may occur after infection and are often lethal. Immune response plays an important role in controlling malaria infection; however, excessive inflammatory response can lead to severe disease. The present work aims to decipher the cellular and molecular events associated with brain and pulmonary pathology in response to blood stage Plasmodium berghei ANKA (PbA) infection. PbA infection in C57BL/6 wild-type (WT) mice induces experimental cerebral malaria (ECM), associated with strong pro-inflammatory response, brain damage, as well as paralysis, coma early death (around day 7 p.i.). Interestingly, IFNγ receptor deficient mice (IFNγR1-/-, C57BL/6 background) are resistant to ECM and died at a later time-point, due to the hyperparasitaemia and severe anemia. Here, we addressed the impact of IFNγR1 deficiency in the development of pulmonary damage during PbA infection. At day 7 post-infection, the broncho-alveolar lavage (BAL) allowed the quantitative analysis of total cells and proteins in the broncho-alveolar space of the animals. In addition, histological analysis and Western blot were performed to compare the cerebral and pulmonary compartments. As compared to PbA-infected WT mice, the histological sections confirmed a less intense accumulation of leukocytes as well as an absence of hemorrhages in the brains of IFNγR1-/- mice. In addition, the quantification of pro-apoptotic proteins (Granzyme B and cleaved caspase-3) in olfactory bulbs showed lower levels in IFNγR1-/- mice. While IFNγR1 deficient mice were fully resistant to brain pathology, those mice were partially protected for pulmonary damage, as observed by the levels of Granzyme B and cleaved caspase-3 in the lung parenchyma, leukocyte number in the broncho-alveolar space and pulmonary edema.


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Exploring the effects of trifluoromethyl group in the design of organocatalysts, enzyme inhibitors and in the conformational control of saturated nitrogen-containing heterocycles


ABSTRACT

The fluoroalkyl group plays an important role in the design of novel pharmacologically active agents since its introduction into organic compounds often leads to improved potency, stability and activity. Herein we wish to report an application of fluoroalkyl ketimines in decarboxylative Mannich reaction with a focus on the chemistry of unprotected NH-ketimines and heterocyclic ketimines. This study addresses the influence of the N-unprotected form of the ketimine function on the efficiency and selectivity of decarboxylative addition of malonic acid and its derivatives. The methods developed provide straightforward access to a range of valuable fluoroalkyl -amino acids and their derivatives promising as novel organofluorine building blocks.


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Effects of electro-conductive, biomaterial-based tissue scaffolds on stem cells and transdifferentiation-derived somatic cells


ABSTRACT

ABSTRACT The combination of stem cell therapy with a supportive scaffold is a promising approach to improving tissue engineering. We aim producing novel material composites that may serve as artificial Extracellular Matrix (ECM). The natural ECM is composed of an organic (protein, polysaccharide) and inorganic (i.e. hydroxy-apatite) components that when combined with the cells form a tissue. ECM is an integral part of every tissue that besides providing the environment for cells to grow, it also improves tissue’s mechanical properties. It provides elasticity, flexibility and durability for the tissue. Tissue engineering approaches utilize artificial materials (biomaterials) as a substitute of natural ECM. The process of producing tissue scaffolds obtained from biodegradable polymers has become a very intensively researched area for the past several years. Most of the current work focuses on the design and preparation of scaffolds with use of various production technologies and different natural materials like chitosan, collagen, elastin and different synthetic ones, like polymer polycaprolactone (PCL), poly(lactic acid) (PLA), poly(ethylene oxide) (PEO). The objective of this study was to check the impact of the biomaterials on various cell types, and compare their growth pattern. Biodegradable PCL, and five of its hybrids: PCL+SHAP (SHAP, synthetic hydroxyapatite), PCL+NHAP (NHAP, natural hydroxyapatite), PCL+PLGA (PLGA, poly(lactide-co-glycolide), PCL+CaCO3, PCL+SHAP+NHAP+CaCO3 as well as one non degradable biomaterial: polyacrylonitryl (PAN), were tested. For the experiments four different cell types were used: human dermal skin fibroblasts, B16F10 (mouse melanoma cells), HSkMEC (Human Skin Microvascular Endothelial Cells) and HEPC-CB1 (Human Endothelial Progenitor Cells –Cord Blood 1). Impacts of the biomaterials on cells were assessed: 1) by measuring cytotoxic effect of the biomaterials liquid extracts and 2) by direct contact test. The ability of cells to attach to the biomaterials was tested as well as cells’ potential to growth and proliferate on the surface of the biomaterials. None of the tested biomaterials was cytotoxic towards the tested cells, making them a potential valuable raw ingredient for 3D scaffold development that would find its applications in tissue engineering. The differences in efficiency of cells attachment and proliferation between tested biomaterials and cells lines were observed. In addition, a stimulating effect of the biomaterials on cells growth was also detected.


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Self-DNA release and STING-dependent sensing drives inflammation to cigarette smoke in mice


ABSTRACT

Cigarette smoke exposure is a leading cause of chronic obstructive pulmonary disease (COPD), a major health issue characterized by airway inflammation with fibrosis and emphysema. Here we demonstrate that acute exposure to cigarette smoke causes respiratory barrier damage with the release of self-dsDNA in mice. This triggers the DNA sensor cGAS (cyclic GMP-AMP synthase) and stimulator of interferon genes (STING), driving type I interferon (IFN I) dependent lung inflammation, which are attenuated in cGAS, STING or type I interferon receptor (IFNAR) deficient mice. Therefore, we demonstrate a critical role of self-dsDNA release and of the cGAS-STING-type I interferon pathway upon cigarette smoke-induced damage, which may lead to therapeutic targets in COPD.


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Ultrasound Image Improvement by Code Bit Elongation


ABSTRACT

This paper analyses the influence of the transducer bandwidth on the compression and the axial resolution of an ultrasound image. The distortion of an electrical signal visible in the final image is a major problem in ultrasonography. To solve this problem, the bit length in Golay-complementary sequences was elongated, narrowing the fractional bandwidth of the coded sequences. Therefore, more energy of the burst signal could be transferred through the ultrasound transducer. The experimental results obtained for transmission of the complementary Golay-coded sequences with two different bit lengths – one-cycle and two-cycles – have been compared, and the efficiency of the pulse compression and its influence on the axial resolution for two fractional bandwidths have been discussed. The results are presented for two transducers having a fractional bandwidth of 25% and 80% and operating at a 6-MHz frequency. The results obtained show that the elongation of the Golay single bit length (doubled in our case) compensate for the limited transducer bandwidth. 2D ultrasound images of a tissue-mimicking phantom are presented and demonstrate the benefits of the use of two-cycle bit length.


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Transcriptomics supports local sensory regulation in the antenna of the kissing bug


ABSTRACT

Rhodnius prolixus has become a model for revealing the molecular bases of insect sensory biology due to the publication of its genome, its well characterized behavioural repertoire and the advent of NGS technologies. Gene expression modulation underlies behaviour-triggering processes at peripheral and central levels. Still, the regulation of sensory-related gene transcription in sensory organs is poorlyunderstood. Here we study the genetic bases of plasticity in antennal sensory function, using R. prolixus as
an insect model. Antennal expression of neuromodulatory genes such as those coding for neuropeptides, neurohormones and their receptors was characterized by means of RNA-Seq. New nuclear receptor and takeout gene sequences were identified for this species, as well as those of enzymes involved in the biosynthesis and processing of neuropeptides and biogenic amines. We report a broad repertoire of neuromodulatory and endocrine genes expressed in antennae and suggest that they modulate sensory
neuron function locally. Diverse neuropeptide-coding genes showed consistent expression in the antennae of all stages studied. Future studies should characterize the contribution of these modulatory components acting over antennal sensory processes to assess the relative contribution of peripheral and central regulatory systems on the plastic expression of insect behaviour.


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Surgical Anatomy of the insula


ABSTRACT

The insula was for a long time considered as one of the most challenging areas of the brain. This is mainly related to its location, deep and medial to the frontoparietal, temporal, and fronto-orbital opercula. Another difficulty is the content of the lateral fossa, located between the insula and the opercula, which contains the trunks, stem, arteries, and cortical branches of the insular (M2) and opercular (M3) segments of the middle cerebral artery (MCA). Finally, the insula is surrounded by several white matter tracts and cortical structures having important functional roles, especially for language in the dominant hemisphere; the insula is indeed located between a dorsal phonological stream, centered by the arcuate fasciculus and lateral to the posterior insula, and a ventral semantic system, medial to the ventral aspect of the insula and centered by the inferior fronto-occipital fasciculus (IFOF). This chapter reviews some of these surgically relevant anatomical relationships.


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The Debated Toxic Role of Aggregated TDP-43 in Amyotrophic Lateral Sclerosis: A Resolution in Sight?


ABSTRACT

Transactive Response DNA-Binding Protein-43 (TDP-43) is an RNA/DNA binding protein that forms phosphorylated and ubiquitinated aggregates in the cytoplasm of motor neurons in Amyotrophic Lateral Sclerosis (ALS), which is a hallmark of this disease. ALS is a neurodegenerative condition affecting the upper and lower motor neurons. Even though the aggregative property of TDP-43 is considered a cornerstone of ALS, there has been major controversy regarding the functional link between TDP-43 aggregates and cell death. In this review, we attempt to reconcile the current literature surrounding this debate by discussing the results and limitations of the published data relating TDP-43 aggregates to cytotoxicity, as well as therapeutic perspectives of TDP-43 aggregate clearance. We point out key data suggesting that the formation of TDP-43 aggregates and the capacity to self-template and propagate among cells as a “prion-like” protein, another pathological property of TDP-43 aggregates, are a significant cause of motor neuronal death. We discuss the disparities among the various studies, particularly with respect to the type of models and the different forms of TDP-43 utilized to evaluate cellular toxicity. We also examine how these disparities can interfere with the interpretation of the results pertaining to a direct toxic effect of TDP-43 aggregates. Furthermore, we present perspectives for improving models in order to better uncover the toxic role of aggregated TDP-43. Finally, we review the recent studies on the enhancement of the cellular clearance mechanisms of autophagy, the ubiquitin proteasome system, and endocytosis in an attempt to counteract TDP-43 aggregation-induced toxicity. Altogether, the data available so far encourage us to suggest that the cytoplasmic aggregation of TDP-43 is key for the neurodegeneration observed in motor neurons in ALS patients. The corresponding findings provide novel avenues toward early therapeutic interventions and clinical outcomes for ALS management.


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Green Bio-Assisted Synthesis, Characterization and Biological Evaluation of Biocompatible ZnO NPs Synthesized from Different Tissues of Milk Thistle (Silybum marianum)


ABSTRACT

The purpose of the current study was green synthesis of ZnO-nanoparticles (NPs) from different tissues of Silybum marianum (L.) Gaernt. (i.e., seeds, wild plant, in vitro derived plantlets and callus cultures) followed by extensive characterization and evaluation of their biological potency. ZnO-NPs thus synthesized were subjected to characterization using standard techniques
such as XRD, FTIR and SEM. Thermal stability of synthesized NPs was also evaluated using thermo-gravimetric analysis. Highly stable crystalline NPs with size ranging between 30.8 and 46.0 nm were obtained from different tissues of S. marianum. These NPs have revealed a wide range of biological applications showing antioxidant, moderate α-amylase inhibitor, antibacterial and cytotoxicpotencies. The highest antibacterial activity (20 0.98 mm) was shown by seed extract-mediated ZnO NPs against Staphylococcus aureus (ATCC-6538). Seed extract-mediated ZnO NPs also showed the most potent antioxidant activity (27.7 .9 gAAE/mg, 23.8 0.7 gAAE/mg and 12.7 1.9% total antioxidant capacity (TAC), total reducing power (TRP) and DPPH-free radical scavenging assay (FRSA), respectively). All of the synthesized ZnO NPs also showed cytotoxic activity against
the hepato-cellular carcinoma (HepG2) human cells. Interestingly, these ZnO NPs were also highly biocompatible, as evidenced by the brine shrimp lethality and human red blood cells hemolytic assays. Among all of the NPs synthesized and used, the effect of seed extract-mediated NPs was found to be most promising for future applications.