An examination of the intersection of public discourses on sexualities with recent political, economic, and social shifts in the national context of Mexico and the Mexican diaspora in the United ...States.
Fluorescent photochromic molecules that exhibit distinct light‐triggered changes in their emission colors are highly desirable for the fabrication of smart soft materials and advanced photonic ...devices. α‐Cyanodiarylethenes, that is, α‐cyano‐functionalized diarylethenes, as alternative “non‐azo” Z/E photochromic molecular switches, are popular choices due to their unique characteristics such as their aggregation‐induced emission or aggregation‐induced‐enhanced emission behavior in their self‐assembled states, and visible changes in fluorescence colors during Z/E photoisomerization. In recent years, the development of fluorescent photochromic α‐cyanodiarylethene‐based compounds including α‐cyanostilbenes, dicyanodistyrylbenzenes, and diaryldicyanoethenes, has mainly focused on molecular design, photochemical and photophysical behavior in solution, and smart soft matter technologies. In this review, recent significant achievements in light‐responsive systems based on the Z/E photoisomerization of fluorescent photochromic α‐cyanodiarylethene switches that span the range from liquid crystals to gels and finally to self‐assembled nanostructures, are highlighted. The smart soft materials constructed from α‐cyanodiarylethene molecular switches find use in a plethora of areas, including display, sensing, encrypting, actuating, and biomedical imaging applications, among others. The review concludes with a brief perspective on some major challenges and opportunities for the future development of light‐responsive smart soft photonic materials.
α‐Cyanodiarylethenes, that is, α‐cyano‐functionalized diarylethenes, have attracted much attention as promising fluorescent photochromic molecular switches due to their unique luminescence properties and fascinating light‐responsive behavior. This review focuses on recent progress in the molecular designs of α‐cyanodiarylethenes, their photochemical and physical behavior, constructed photoswitchable soft materials as well as future advanced applications in a variety of fields.
T helper 17 (Th17) cells are pathogenic in many inflammatory diseases, but also support the integrity of the intestinal barrier in a non-inflammatory manner. It is unclear what distinguishes ...inflammatory Th17 cells elicited by pathogens and tissue-resident homeostatic Th17 cells elicited by commensals. Here, we compared the characteristics of Th17 cells differentiating in response to commensal bacteria (SFB) to those differentiating in response to a pathogen (Citrobacter rodentium). Homeostatic Th17 cells exhibited little plasticity towards expression of inflammatory cytokines, were characterized by a metabolism typical of quiescent or memory T cells, and did not participate in inflammatory processes. In contrast, infection-induced Th17 cells showed extensive plasticity towards pro-inflammatory cytokines, disseminated widely into the periphery, and engaged aerobic glycolysis in addition to oxidative phosphorylation typical for inflammatory effector cells. These findings will help ensure that future therapies directed against inflammatory Th17 cells do not inadvertently damage the resident gut population.
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•Tissue-resident, SFB-elicited Th17 cells are non-inflammatory•Citrobacter-elicited Th17 cells show high plasticity towards inflammatory cytokines•SFB Th17 cells are metabolically similar to resting memory cells•Citrobacter Th17 cells are highly glycolytic effector cells
The distinctions between inflammatory Th17 cells elicited by pathogens and tissue-resident homeostatic Th17 cells elicited by commensals are unclear. Omenetti et al. show that tissue-resident Th17 cells, in contrast to pathogen-elicited Th17 cells, exhibit little plasticity towards inflammatory cytokines, show muted metabolism, and do not participate in inflammatory reactions. These findings highlight the link between metabolic fitness and functional state.
Neutrophils are critical for antifungal defense, but the mechanisms that clear hyphae and other pathogens that are too large to be phagocytosed remain unknown. We found that neutrophils sensed ...microbe size and selectively released neutrophil extracellular traps (NETs) in response to large pathogens, such as Candida albicans hyphae and extracellular aggregates of Mycobacterium bovis, but not in response to small yeast or single bacteria. NETs were fundamental in countering large pathogens in vivo. Phagocytosis via dectin-1 acted as a sensor of microbe size and prevented NET release by downregulating the translocation of neutrophil elastase (NE) to the nucleus. Dectin-1 deficiency led to aberrant NET release and NET-mediated tissue damage during infection. Size-tailored neutrophil responses cleared large microbes and minimized pathology when microbes were small enough to be phagocytosed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
To be effective, chemotherapy against tuberculosis (TB) must kill the intracellular population of the pathogen,
Mycobacterium tuberculosis
. However, how host cell microenvironments affect ...antibiotic accumulation and efficacy remains unclear. Here, we use correlative light, electron, and ion microscopy to investigate how various microenvironments within human macrophages affect the activity of pyrazinamide (PZA), a key antibiotic against TB. We show that PZA accumulates heterogeneously among individual bacteria in multiple host cell environments. Crucially, PZA accumulation and efficacy is maximal within acidified phagosomes. Bedaquiline, another antibiotic commonly used in combined TB therapy, enhances PZA accumulation via a host cell-mediated mechanism. Thus, intracellular localisation and specific microenvironments affect PZA accumulation and efficacy. Our results may explain the potent in vivo efficacy of PZA, compared to its modest in vitro activity, and its critical contribution to TB combination chemotherapy.
Cells respond to endolysosome damage by either repairing the damage or targeting damaged endolysosomes for degradation via lysophagy. However, the signals regulating the decision for repair or ...lysophagy are poorly characterised. Here, we show that the Parkinson's disease (PD)‐related kinase LRRK2 is activated in macrophages by pathogen‐ or sterile‐induced endomembrane damage. LRRK2 recruits the Rab GTPase Rab8A to damaged endolysosomes as well as the ESCRT‐III component CHMP4B, thereby favouring ESCRT‐mediated repair. Conversely, in the absence of LRRK2 and Rab8A, damaged endolysosomes are targeted to lysophagy. These observations are recapitulated in macrophages from PD patients where pathogenic LRRK2 gain‐of‐function mutations result in the accumulation of endolysosomes which are positive for the membrane damage marker Galectin‐3. Altogether, this work indicates that LRRK2 regulates endolysosomal homeostasis by controlling the balance between membrane repair and organelle replacement, uncovering an unexpected function for LRRK2, and providing a new link between membrane damage and PD.
Synopsis
Leucine‐rich repeat kinase 2 (LRRK2) has been linked to neurodegenerative and inflammatory diseases but it is unknown how LRKK2 activation occurs in these pathological conditions. Here, pathogen‐ or drug‐induced endomembrane damage is found to activate LRRK2 in macrophages, which in turn controls recruitment of membrane repair factors.
LRRK2 is activated upon endomembrane damage.
Endomembrane damage triggers LRRK2‐mediated phosphorylation of Rab8A.
Rab8A and ESCRT component CHMP4B are recruited to damaged endolysosomes in a LRRK2‐dependent manner.
In the absence of LRRK2 and Rab8A, damaged endolysosomes are disposed through lysophagy.
Macrophages from patients harbouring LRRK2 G2019S or R1441C mutation show accumulation of damaged endolysosomes.
LRRK2 phosphorylation of Rab8A GTPase promotes its co‐translocation with ESCRT component CHMP4B to damaged endolysosomes for their repair.
Resveratrol is a natural phenol with many positive effects for human health. However it is a photosensitive molecule with geometric isomerism, easily oxidised with short biological half-life and ...rapid metabolism and elimination. Thus, encapsulation of resveratrol is necessary. It has low solubility in water and in most of common oils. The goal of this work was to prepare oil-in-water emulsion stabilized by quinoa starch particles containing resveratrol. Quinoa starch particles were modified with Octenyl Succinic Anhydride (OSA) (degree of substitution 1.8%) to make them less hydrophilic. In order to compare starch effectivity as stabilizer, a common non-ionic surfactant Tween 20 was used to formulate surfactant stabilized emulsions. As dispersed phase a mixture of miglyol and orange oil in a volume ratio 1:9 was used in order to increase resveratrol solubility in the oily phase. Both types of emulsions were formulated in full coverage conditions with similar mean droplet size. Thus, differences in the emulsions properties observed only depend on the type of emulsifier.
Pickering emulsions stabilized by OSA-modified quinoa starch granules resulted more stable against creaming phenomena. The rheological behaviour was influenced by the type and the amount of dispersed phase used. Resveratrol encapsulation results revealed that formulations based on starch Pickering emulsions are an appropriate resveratrol carrier system for further use in functional food formulations, better than surfactant stabilized emulsions, leading to encapsulation efficiency (EE) values up to 98%, being more than twice that of the surfactant stabilized systems.
•Formulation of OSA-modified starch Pickering emulsions containing Resveratrol.•Comparison of emulsions stabilized with surfactant and particles.•Rheological properties of emulsion stabilized by solid particles.•Stability study combining Miglyol 812 and Orange oil as dispersed phase.•Pickering emulsions led to Resveratrol EE values in the range 89.9–98.3%.
The application of nanoparticles for drug or gene delivery promises benefits in the form of single‐cell‐specific therapeutic and diagnostic capabilities. Many methods of cell transfection rely on ...unspecific means to increase the transport of genetic material into cells. Targeted transport is in principle possible with magnetically propelled micromotors, which allow responsive nanoscale actuation and delivery. However, many commonly used magnetic materials (e.g., Ni and Co) are not biocompatible, possess weak magnetic remanence (Fe3O4), or cannot be implemented in nanofabrication schemes (NdFeB). Here, it is demonstrated that co‐depositing iron (Fe) and platinum (Pt) followed by one single annealing step, without the need for solution processing, yields ferromagnetic FePt nanomotors that are noncytotoxic, biocompatible, and possess a remanence and magnetization that rival those of permanent NdFeB micromagnets. Active cell targeting and magnetic transfection of lung carcinoma cells are demonstrated using gradient‐free rotating millitesla fields to drive the FePt nanopropellers. The carcinoma cells express enhanced green fluorescent protein after internalization and cell viability is unaffected by the presence of the FePt nanopropellers. The results establish FePt, prepared in the L10 phase, as a promising magnetic material for biomedical applications with superior magnetic performance, especially for micro‐ and nanodevices.
Biocompatible hard nanomagnets that can easily be fabricated are shown to enable active gene delivery. Co‐depositing iron (Fe) and platinum (Pt) followed by an annealing step yields noncytotoxic ferromagnetic FePt nanopropellers that possess a remanence and magnetization that rival those of NdFeB micromagnets. This study describes the fabrication and material characterization, and shows that FePt is promising for microrobotics and biomedical applications.
Aims/hypothesis
The Di@bet.es Study is the first national study in Spain to examine the prevalence of diabetes and impaired glucose regulation.
Methods
A population-based, cross-sectional, cluster ...sampling study was carried out, with target population being the entire Spanish population. Five thousand and seventy-two participants in 100 clusters (health centres or the equivalent in each region) were randomly selected with a probability proportional to population size. Participation rate was 55.8%. Study variables were a clinical and demographic structured survey, lifestyle survey, physical examination (weight, height, BMI, waist and hip circumference, blood pressure) and OGTT (75 g).
Results
Almost 30% of the study population had some carbohydrate disturbance. The overall prevalence of diabetes mellitus adjusted for age and sex was 13.8% (95% CI 12.8, 14.7%), of which about half had unknown diabetes: 6.0% (95% CI 5.4, 6.7%). The age- and sex-adjusted prevalence rates of isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT) and combined IFG–IGT were 3.4% (95% CI 2.9, 4.0%), 9.2% (95% CI 8.2, 10.2%) and 2.2% (95% CI 1.7, 2.7%), respectively. The prevalence of diabetes and impaired glucose regulation increased significantly with age (
p
< 0.0001), and was higher in men than in women (
p
< 0.001).
Conclusions/interpretation
The Di@bet.es Study shows, for the first time, the prevalence rates of diabetes and impaired glucose regulation in a representative sample of the Spanish population.
Mycobacterium tuberculosis is an intracellular pathogen persisting within phagosomes through interference with phagolysosome biogenesis. Here we show that stimulation of autophagic pathways in ...macrophages causes mycobacterial phagosomes to mature into phagolysosomes. Physiological induction of autophagy or its pharmacological stimulation by rapamycin resulted in mycobacterial phagosome colocalization with the autophagy effector LC3, an elongation factor in autophagosome formation. Autophagy stimulation increased phagosomal colocalization with Beclin-1, a subunit of the phosphatidylinositol 3-kinase hVPS34, necessary for autophagy and a target for mycobacterial phagosome maturation arrest. Induction of autophagy suppressed intracellular survival of mycobacteria. IFN-γ induced autophagy in macrophages, and so did transfection with LRG-47, an effector of IFN-γ required for antimycobacterial action. These findings demonstrate that autophagic pathways can overcome the trafficking block imposed by
M. tuberculosis. Autophagy, which is a hormonally, developmentally, and, as shown here, immunologically regulated process, represents an underappreciated innate defense mechanism for control of intracellular pathogens.
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