The complex tissue‐specific physiology that is orchestrated from the nano‐ to the macroscale, in conjugation with the dynamic biophysical/biochemical stimuli underlying biological processes, has ...inspired the design of sophisticated hydrogels and nanoparticle systems exhibiting stimuli‐responsive features. Recently, hydrogels and nanoparticles have been combined in advanced nanocomposite hybrid platforms expanding their range of biomedical applications. The ease and flexibility of attaining modular nanocomposite hydrogel constructs by selecting different classes of nanomaterials/hydrogels, or tuning nanoparticle‐hydrogel physicochemical interactions widely expands the range of attainable properties to levels beyond those of traditional platforms. This review showcases the intrinsic ability of hybrid constructs to react to external or internal/physiological stimuli in the scope of developing sophisticated and intelligent systems with application‐oriented features. Moreover, nanoparticle‐hydrogel platforms are overviewed in the context of encoding stimuli‐responsive cascades that recapitulate signaling interplays present in native biosystems. Collectively, recent breakthroughs in the design of stimuli‐responsive nanocomposite hydrogels improve their potential for operating as advanced systems in different biomedical applications that benefit from tailored single or multi‐responsiveness.
Stimuli‐responsive nanocomposite hydrogels represent leading biofunctional platforms due to their design flexibility and ability to operate as intelligent devices that intrinsically recognize and react to physiological or external stimuli inputs. This review delineates recent trends in their design and assembly and critically overviews flagship hybrids on their path to attain sophisticated self‐regulating activities or serving as remote‐controlled long‐term therapeutic modalities.
Gastric adenocarcinoma carries a poor prognosis, in part due to the late stage of diagnosis. Risk factors include
infection, family history of gastric cancer-in particular, hereditary diffuse gastric ...cancer and pernicious anaemia. The stages in the progression to cancer include chronic gastritis, gastric atrophy (GA), gastric intestinal metaplasia (GIM) and dysplasia. The key to early detection of cancer and improved survival is to non-invasively identify those at risk before endoscopy. However, although biomarkers may help in the detection of patients with chronic atrophic gastritis, there is insufficient evidence to support their use for population screening. High-quality endoscopy with full mucosal visualisation is an important part of improving early detection. Image-enhanced endoscopy combined with biopsy sampling for histopathology is the best approach to detect and accurately risk-stratify GA and GIM. Biopsies following the Sydney protocol from the antrum, incisura, lesser and greater curvature allow both diagnostic confirmation and risk stratification for progression to cancer. Ideally biopsies should be directed to areas of GA or GIM visualised by high-quality endoscopy. There is insufficient evidence to support screening in a low-risk population (undergoing routine diagnostic oesophagogastroduodenoscopy) such as the UK, but endoscopic surveillance every 3 years should be offered to patients with extensive GA or GIM. Endoscopic mucosal resection or endoscopic submucosal dissection of visible gastric dysplasia and early cancer has been shown to be efficacious with a high success rate and low rate of recurrence, providing that specific quality criteria are met.
Innate immune response against Brucella abortus involves activation of Toll-like receptors (TLRs) and NOD-like receptors (NLRs). Among the NLRs involved in the recognition of B. abortus are NLRP3 and ...AIM2. Here, we demonstrate that B. abortus triggers non-canonical inflammasome activation dependent on caspase-11 and gasdermin-D (GSDMD). Additionally, we identify that Brucella-LPS is the ligand for caspase-11 activation. Interestingly, we determine that B. abortus is able to trigger pyroptosis leading to pore formation and cell death, and this process is dependent on caspase-11 and GSDMD but independently of caspase-1 protease activity and NLRP3. Mice lacking either caspase-11 or GSDMD were significantly more susceptible to infection with B. abortus than caspase-1 knockout or wild-type animals. Additionally, guanylate-binding proteins (GBPs) present in mouse chromosome 3 participate in the recognition of LPS by caspase-11 contributing to non-canonical inflammasome activation as observed by the response of Gbpchr3-/- BMDMs to bacterial stimulation. We further determined by siRNA knockdown that among the GBPs contained in mouse chromosome 3, GBP5 is the most important for Brucella LPS to be recognized by caspase-11 triggering IL-1β secretion and LDH release. Additionally, we observed a reduction in neutrophil, dendritic cell and macrophage influx in spleens of Casp11-/- and Gsdmd-/- compared to wild-type mice, indicating that caspase-11 and GSDMD are implicated in the recruitment and activation of immune cells during Brucella infection. Finally, depletion of neutrophils renders wild-type mice more susceptible to Brucella infection. Taken together, these data suggest that caspase-11/GSDMD-dependent pyroptosis triggered by B. abortus is important to infection restriction in vivo and contributes to immune cell recruitment and activation.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson’s disease, but the precise physiological function of the protein remains ill-defined. Recently, our group proposed a ...model in which LRRK2 kinase activity is part of an EndoA phosphorylation cycle that facilitates efficient vesicle formation at synapses in the Drosophila melanogaster neuromuscular junctions.Flies harbor only one Lrrk gene, which might encompass the functions of both mammalian LRRK1 and LRRK2. We therefore studied the role of LRRK2 in mammalian synaptic function and provide evidence that knockout or pharmacological inhibition of LRRK2 results in defects in synaptic vesicle endocytosis, altered synaptic morphology and impairments in neurotransmission. In addition, our data indicate that mammalian endophilin A1 (EndoA1,also known as SH3GL2) is phosphorylated by LRRK2 in vitro at T73 and S75, two residues in the BAR domain. Hence, our results indicate that LRRK2 kinase activity has an important role in the regulation of clathrin-mediated endocytosis of synaptic vesicles and subsequent neurotransmission at the synapse.
Gout is a disease characterized by the deposition of monosodium urate (MSU) crystals in the joints. Continuous gout episodes may lead to unresolved inflammatory responses and tissue damage. We ...investigated the effects of a high‐fiber diet and acetate, a short‐chain fatty acid (SCFA) resulting from the metabolism of fiber by gut microbiota, on the inflammatory response in an experimental model of gout in mice. Injection of MSU crystals into the knee joint of mice induced neutrophil influx and inflammatory hypernociception. The onset of inflammatory response induced by MSU crystals was not altered in animals given a high‐fiber diet, but the high‐fiber diet induced faster resolution of the inflammatory response. Similar results were obtained in animals given the SCFA acetate. Acetate was effective, even when given after injection of MSU crystals at the peak of the inflammatory response and induced caspase‐dependent apoptosis of neutrophils that accounted for the resolution of inflammation. Resolution of neutrophilic inflammation was associated with decreased NF‐κB activity and enhanced production of anti‐inflammatory mediators, including IL‐10, TGF‐β, and annexin A1. Acetate treatment or intake of a high‐fiber diet enhanced efferocytosis, an effect also observed in vitro with neutrophils treated with acetate. In conclusion, a high‐fiber diet or one of its metabolic products, acetate, controls the inflammatory response to MSU crystals by favoring the resolution of the inflammatory response. Our studies suggest that what we eat plays a determinant role in our capacity to fine tune the inflammatory response. Introduction
Beneficial effects of HF and acetate production in a model of gout, by inducing pro‐resolutive mediators and neutrophil apoptosis in the joint.
•The pandemic urges us to advancing a new and different framing on industrial policy.•Industrial policy plays a key role to tackle dramatic societal challenges.•We have reached a turning point on ...industrial policy, sustainability and development.•We need a new analytical framework on industrial policy governance and implementation.•Industrial policy in a post-Covid19 era should foster sustainable human development.
National and local societies all around the world are fighting the most dramatic global public health emergency of our time, which has soon become an economic, social and human crisis touching all key dimensions of our lives.
Within an inevitable revamping attention on the need for government intervention to face the challenges raised by the Covid19 pandemic, industrial policy is appearing as a central piece of the puzzle. As production dynamics in every country is highly affected by the crisis, industrial policy is considered part of the response to solve dramatic economic and social problems deriving by extraordinary levels of unemployment, deprivation and poverty.
In this paper, we argue that a turning point on the connection between industrial policy, sustainability and development has been reached, highlighting the need to rethink its theoretical foundations as well as its governance and implementation processes for a new role in our post-Covid 19 societies.
Therefore, the research question underlying this paper deals primarily with the nexus between the debate on industrial policy and its effects in terms of human development, social cohesion and sustainability. For this reason, we attempt at closing the gap between different strands of literature, whose integrated connection leads to a new analytical framework with real-world implications on the role of industrial policy, not only as tool for productive dynamics, but also as a leverage for sustainable human development.
All in all, we aim at contributing to the debate on our post-Covid19 economies and societies in two ways: firstly, by providing a new integrated analytical framework on industrial policy to steer a sustainable structural change of our economies and societies towards sustainable human development; secondly, by identifying preliminary implications on industrial policy governance and implementation, investing in the accurate and transparent design of industrial policy in the post-Covid19 era.
We demonstrate the feasibility of fabricating cost-effective and robust laser-induced graphene (LIG) flexible heaters with an innovative technique based on the photothermal production of graphene ...with a foam-like morphology. The produced devices are precisely defined on a bare polyimide substrate without the need of photomasks by employing a computer numerical control (CNC) driven laser diode. The electrical properties of the LIG-based heaters can be tailored by adjusting the laser power. The resulting conductive material exhibits electrical and chemical properties which are similar to the ones for graphene such as a negative temperature coefficient of −0.46 m°C−1 and a maximum operating temperature of around 400 °C. The developed heaters can outperform the existing emerging technologies showing a very rapid and stable response up to 225 °C with the extra features of flexibility, biocompatibility, and environmental friendliness.
In this study, we present a novel CNC-based technique for fabricating laser induced graphene films on bare polyimide substrate. The conductive films are used for flexible thin-film heaters that show a high mechanical and thermal robustness. Display omitted
Cleavage activation of the hemagglutinin (HA) protein by host proteases is a crucial step in the infection process of influenza A viruses (IAV). However, IAV exists in eighteen different HA subtypes ...in nature and their cleavage sites vary considerably. There is uncertainty regarding which specific proteases activate a given HA in the human respiratory tract. Understanding the relationship between different HA subtypes and human-specific proteases will be valuable in assessing the pandemic potential of circulating viruses. Here we utilized fluorogenic peptides mimicking the HA cleavage motif of representative IAV strains causing disease in humans or of zoonotic/pandemic potential and tested them with a range of proteases known to be present in the human respiratory tract. Our results show that peptides from the H1, H2 and H3 subtypes are cleaved efficiently by a wide range of proteases including trypsin, matriptase, human airway tryptase (HAT), kallikrein-related peptidases 5 (KLK5) and 12 (KLK12) and plasmin. Regarding IAVs currently of concern for human adaptation, cleavage site peptides from H10 viruses showed very limited cleavage by respiratory tract proteases. Peptide mimics from H6 viruses showed broader cleavage by respiratory tract proteases, while H5, H7 and H9 subtypes showed variable cleavage; particularly matriptase appeared to be a key protease capable of activating IAVs. We also tested HA substrate specificity of Factor Xa, a protease required for HA cleavage in chicken embryos and relevant for influenza virus production in eggs. Overall our data provide novel tool allowing the assessment of human adaptation of IAV HA subtypes.
Respiratory syncytial virus (RSV) is a major cause of diseases of the respiratory tract in young children and babies, being mainly associated with bronchiolitis. RSV infection occurs primarily in ...pulmonary epithelial cells and, once infection is established, an immune response is triggered and neutrophils are recruited. In this study, we investigated the mechanisms underlying NET production induced by RSV. We show that RSV induced the classical ROS-dependent NETosis in human neutrophils and that RSV was trapped in DNA lattices coated with NE and MPO. NETosis induction by RSV was dependent on signaling by PI3K/AKT, ERK and p38 MAPK and required histone citrullination by PAD-4. In addition, RIPK1, RIPK3 and MLKL were essential to RSV-induced NETosis. MLKL was also necessary to neutrophil necrosis triggered by the virus, likely promoting membrane-disrupting pores, leading to neutrophil lysis and NET extrusion. Finally, we found that RSV infection of alveolar epithelial cells or lung fibroblasts triggers NET-DNA release by neutrophils, indicating that neutrophils can identify RSV-infected cells and respond to them by releasing NETs. The identification of the mechanisms responsible to mediate RSV-induced NETosis may prove valuable to the design of new therapeutic approaches to treat the inflammatory consequences of RSV bronchiolitis in young children.
Molybdenum disulfide (MoS2) and related transition metal chalcogenides can replace expensive precious metal catalysts such as Pt for the hydrogen evolution reaction (HER). The relations between the ...nanoscale properties and HER activity of well‐controlled 2H and Li‐promoted 1T phases of MoS2, as well as an amorphous MoS2 phase, have been investigated and a detailed comparison is made on Mo−S and Mo−Mo bond analysis under operando HER conditions, which reveals a similar bond structure in 1T and amorphous MoS2 phases as a key feature in explaining their increased HER activity. Whereas the distinct bond structure in 1T phase MoS2 is caused by Li+ intercalation and disappears under harsh HER conditions, amorphous MoS2 maintains its intrinsic short Mo−Mo bond feature and, with that, its high HER activity. Quantum‐chemical calculations indicate similar electronic structures of small MoS2 clusters serving as models for amorphous MoS2 and the 1T phase MoS2, showing similar Gibbs free energies for hydrogen adsorption (ΔGH*) and metallic character.
The big short: The presence of shorter Mo−Mo bonds in MoS2 is reported to enhance the electrocatalytic hydrogen evolution activity. Similar electronic and catalytic properties of 1T and amorphous MoS2, in contrast to 2H MoS2, are caused by shorter Mo−Mo and Mo−S bonds. This short Mo−Mo bond feature in 1T MoS2 is caused by Li intercalation and unstable under HER conditions, whereas it is intrinsic and stable for amorphous MoS2.
PDF
