Autoimmunity is thought to reflect an imbalance between regulatory T helper lymphocytes (Treg) and pathogenic, IL-17-secreting T helper (Th17) cells. Induction of both adaptive Treg and Th17 cells ...requires signalling from TGF-β. We now show that, in the context of TGF-β signalling, all-trans retinoic acid (ATRA) leads to increased induction of CD4⁺ T cells expressing the Treg specification factor forkhead box protein P3 (FoxP3) and decreased frequency of cells expressing IL-17, even in the presence of IL-6. Using a specific agonist and antagonist, as well as retroviral over-expression, we also provide evidence that the effects of ATRA are likely to be at least partially mediated by the nuclear retinoic acid receptor-α (RARα). These findings indicate that signalling through a specific nuclear retinoic acid receptor can favour the decision to adopt the Treg fate at the expense of Th17 fate. Specific agonists of RARα could, therefore, be considered candidates for the treatment of autoimmunity.
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•Designing genetically encoded fluorescence-based analyte biosensors is not trivial.•Many current design efforts take a nature-inspired, modular approach.•Individual sensor components ...can be engineered separately for desired properties.•Screening of large variant libraries is often required to optimize biosensors.
Biosensors that selectively report on the presence of specific small molecule analytes have applications in many fields of research, medicine and biotechnology. Here, we review recent advances and emerging approaches in the design and optimisation of genetically encoded fluorescence-based small molecule biosensors. We discuss how natural sensory proteins can be exploited to produce novel biosensors and the strategies for optimizing ligand specificity and fluorescence readout. Finally, we provide insight into high-throughput sensor optimisation and discuss the challenges that are faced when designing novel biosensors.
Emerging randomized controlled trials (RCTs) investigating the effect of green tea or green tea extract (GTE) supplementation on blood pressure (BP) among overweight and obese adults reported ...inconsistent findings.
To conduct a systematic review and meta-analysis to clarify the efficacy of green tea or GTE on BP among overweight and obese adults.
Electronic databases, conference proceedings and gray literature were searched systematically to include parallel and cross-over RCTs examining the efficacy of green tea or GTE on BP compared with placebo. Data were meta-analyzed using a random-effects model, to compare the mean difference of the change in BP from baseline in the intervention and the placebo groups.
Fourteen RCTs with 971 participants (47% women) were pooled for analysis. Green tea or GTE produced a significant effect on both SBP (mean difference -1.42 mmHg, 95% confidence interval -2.47 to -0.36, P = 0.008; I = 52%, P = 0.01 for heterogeneity) and DBP (mean difference -1.25 mmHg, 95% confidence interval -2.32 to -0.19, P = 0.02; I = 74%, P < 0.001 for heterogeneity), compared with placebo. The quality of evidence across studies was low. Similar results were found in subgroup and sensitivity analyses.
Among overweight and obese adults, green tea or GTE supplementation is found to cause a small but significant reduction in BP. More high-quality RCTs with large sample sizes are needed to further confirm the efficacy on BP and make strong recommendations for green tea or GTE supplementation among the overweight and obese adults.
Interferon (IFN) is widely recognised to be an integral part of the innate immune response to viral infection. Since its initial discovery in 1957 by Isaacs and Lindenmann, various IFN sub-types have ...been identified and there are now three distinct classes recognised-Type I (IFN-α and IFN-β), Type II (IFN-γ) and Type III (IFN-λ), distinguished by their differing receptors. As well as displaying profound antiviral activity in vivo, IFN has anti-proliferative, cytotoxic and anti-tumoural roles. In an attempt to harness their immunomodulatory potential, investigators and clinicians have investigated the use of IFNs for the treatment of human diseases with considerable success. For example, IFN-α preparations are now a critical component in the treatment of chronic Hepatitis C infection and IFN-β therapy is now the first line treatment for relapsing remitting multiple sclerosis. However, IFN therapy is also associated with significant morbidity and in some patients is poorly tolerated. In this review, we explore the scientific basis for IFN therapy and outline its therapeutic scope. We describe the commonly encountered side effects and attempt to explain the less well recognised pulmonary complications including emerging evidence of life threatening and irreversible pulmonary vascular pathology. Finally, we look to the future of interferon drug treatment, examining the potential for emerging therapies.
Spherulite‐Like Micelles Song, Shaofei; Zhou, Hang; Ye, Shuyang ...
Angewandte Chemie (International ed.),
May 3, 2021, Letnik:
60, Številka:
19
Journal Article
Recenzirano
One‐dimensional (1D) and 2D structures by crystallization‐driven self‐assembly of block copolymers (BCPs) can form fascinating hierarchical structures through secondary self‐assembly. But examples of ...3D structures formed via hierarchical self‐assembly are rare. Here we report seeded growth experiments in decane of a poly(ferrocenyldimethylsilane) BCP with an amphiphilic corona forming block in which lenticular platelets grow into classic spherulite‐like uniform colloidally stable structures. These 3D objects are spherically symmetric on the exterior, but asymmetric near the core, where there is a more open structure consisting of sheaf‐like leaves. The most remarkable aspect of these experiments is that growth stops at different stages of growth process, depending upon how much unimer is added in the seeded growth step. The system provides a model for studying spherulitic growth where real‐time observations on their growth at different stages remains challenging.
A crystalline‐coil block copolymer with an amphiphilic corona‐forming block leads to formation of 3D spherulite‐like micelles by crystallization‐driven self‐assembly and seeded growth in dilute solution. Micelle growth can be stopped at any stage depending on the unimer feed ratio and provides a powerful model for studying the spherulite growth process.
Cancer vaccines may be harnessed to incite immunity against poorly immunogenic tumors, however they have failed in therapeutic settings. Poor antigenicity coupled with systemic and intratumoral ...immune suppression have been significant drawbacks. RNA encoding for tumor associated or specific epitopes can serve as a more immunogenic and expeditious trigger of anti-tumor immunity. RNA stimulates innate immunity through toll like receptor stimulation producing type I interferon, and it mediates potent adaptive responses. Since RNA is inherently unstable, delivery systems have been developed to protect and deliver it to intended targets in vivo. In this review, we discuss liposomes as RNA delivery vehicles and their role as cancer vaccines.
Increasing evidence indicates that gut microbiota may influence colorectal cancer risk. Diet, particularly fibre intake, may modify gut microbiota composition, which may affect cancer risk. We ...investigated the relationship between dietary fibre intake and gut microbiota in adults. Using 16S rRNA gene sequencing, we assessed gut microbiota in faecal samples from 151 adults in two independent study populations: National Cancer Institute (NCI), n 75, and New York University (NYU), n 76. We calculated energy-adjusted fibre intake based on FFQ. For each study population with adjustment for age, sex, race, BMI and smoking, we evaluated the relationship between fibre intake and gut microbiota community composition and taxon abundance. Total fibre intake was significantly associated with overall microbial community composition in NYU (P=0·008) but not in NCI (P=0·81). In a meta-analysis of both study populations, higher fibre intake tended to be associated with genera of class Clostridia, including higher abundance of SMB53 (fold change (FC)=1·04, P=0·04), Lachnospira (FC=1·03, P=0·05) and Faecalibacterium (FC=1·03, P=0·06), and lower abundance of Actinomyces (FC=0·95, P=0·002), Odoribacter (FC=0·95, P=0·03) and Oscillospira (FC=0·96, P=0·06). A species-level meta-analysis showed that higher fibre intake was marginally associated with greater abundance of Faecalibacterium prausnitzii (FC=1·03, P=0·07) and lower abundance of Eubacterium dolichum (FC=0·96, P=0·04) and Bacteroides uniformis (FC=0·97, P=0·05). Thus, dietary fibre intake may impact gut microbiota composition, particularly class Clostridia, and may favour putatively beneficial bacteria such as F. prausnitzii. These findings warrant further understanding of diet-microbiota relationships for future development of colorectal cancer prevention strategies.
Lysosomes are the primary degradative compartment within cells and there have been significant advances over the past decade toward understanding how lysosome homeostasis is maintained. Lysosome ...repopulation ensures sustained autophagy function, a fundamental process that protects against disease. During macroautophagy/autophagy, cellular debris is sequestered into phagophores that mature into autophagosomes, which then fuse with lysosomes to generate autolysosomes in which contents are degraded. Autophagy cannot proceed without the sufficient generation of lysosomes, and this can be achieved via their de novo biogenesis. Alternatively, during autophagic lysosome reformation (ALR), lysosomes are generated via the recycling of autolysosome membranes. During this process, autolysosomes undergo significant membrane remodeling and scission to generate membrane fragments, that mature into functional lysosomes. By utilizing membranes already formed during autophagy, this facilitates an efficient pathway for re-deriving lysosomes, particularly under conditions of prolonged autophagic flux. ALR dysfunction is emerging as an important disease mechanism including for neurodegenerative disorders such as hereditary spastic paraplegia and Parkinson disease, neuropathies including Charcot-Marie-Tooth disease, lysosome storage disorders, muscular dystrophy, metabolic syndrome, and inflammatory and liver disorders. Here, we provide a comprehensive review of ALR, including an overview of its dynamic spatiotemporal regulation by MTOR and phosphoinositides, and the role ALR dysfunction plays in many diseases.
Micro-eukaryotic diversity is poorly documented at all taxonomic levels and the phylogenetic affiliation of many taxa - including many well-known and common organisms - remains unknown. Among these ...incertae sedis taxa are Archerella flavum (Loeblich and Tappan, 1961) and Amphitrema wrightianum (Archer, 1869) (Amphitremidae), two filose testate amoebae commonly found in Sphagnum peatlands. To clarify their phylogenetic position, we amplified and sequenced the SSU rRNA gene obtained from four independent DNA extractions of A. flavum and three independent DNA extractions of A. wrightianum. Our molecular data demonstrate that genera Archerella and Amphitrema form a fully supported deep-branching clade within the Labyrinthulomycetes (Stramenopiles), together with Diplophrys sp. (ATCC50360) and several environmental clones obtained from a wide range of environments. This newly described clade we named Amphitremida is diverse genetically, ecologically and physiologically. Our phylogenetic analysis suggests that osmotrophic species evolved most likely from phagotrophic ancestors and that the bothrosome, an organelle that produces cytoplasmic networks used for attachment to the substratum and to absorb nutrients from the environments, appeared lately in labyrithulomycete evolution.
Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) is an organophosphate flame retardant used around the world. Within zebrafish, we previously showed that initiation of TDCIPP exposure during cleavage ...(0.75 h post-fertilization, hpf) results in epiboly disruption at 6 hpf, leading to dorsalized embryos by 24 hpf, a phenotype that mimics the effects of dorsomorphin (DMP), a bone morphogenetic protein (BMP) antagonist that dorsalizes embryos in the absence of epiboly defects. The objective of this study was to (1) investigate the role of BMP signaling in TDCIPP-induced toxicity during early embryogenesis, (2) identify other pathways and processes targeted by TDCIPP, and (3) characterize the downstream impacts of early developmental defects. Using zebrafish as a model, we first identified a sensitive window for TDCIPP-induced effects following exposure initiation at 0.75 hpf. We then investigated the effects of TDCIPP on the transcriptome during the first 24 h of development using mRNA sequencing and amplicon sequencing. Finally, we relied on whole-mount immunohistochemistry, dye-based labeling, and morphological assessments to study abnormalities later in embryonic development. Overall, our data suggest that the initiation of TDCIPP exposure during early blastula alters the normal trajectory of early embryogenesis by inducing gastrulation defects and aberrant germ-layer formation, leading to abnormal tissue and organ development within the embryo.
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