Background and Purpose
Cannabidiol has been reported to act as an antagonist at cannabinoid CB1 receptors. We hypothesized that cannabidiol would inhibit cannabinoid agonist activity through negative ...allosteric modulation of CB1 receptors.
Experimental Approach
Internalization of CB1 receptors, arrestin2 recruitment, and PLCβ3 and ERK1/2 phosphorylation, were quantified in HEK 293A cells heterologously expressing CB1 receptors and in the STHdhQ7/Q7 cell model of striatal neurons endogenously expressing CB1 receptors. Cells were treated with 2‐arachidonylglycerol or Δ9‐tetrahydrocannabinol alone and in combination with different concentrations of cannabidiol.
Key Results
Cannabidiol reduced the efficacy and potency of 2‐arachidonylglycerol and Δ9‐tetrahydrocannabinol on PLCβ3‐ and ERK1/2‐dependent signalling in cells heterologously (HEK 293A) or endogenously (STHdhQ7/Q7) expressing CB1 receptors. By reducing arrestin2 recruitment to CB1 receptors, cannabidiol treatment prevented internalization of these receptors. The allosteric activity of cannabidiol depended upon polar residues being present at positions 98 and 107 in the extracellular amino terminus of the CB1 receptor.
Conclusions and Implications
Cannabidiol behaved as a non‐competitive negative allosteric modulator of CB1 receptors. Allosteric modulation, in conjunction with effects not mediated by CB1 receptors, may explain the in vivo effects of cannabidiol. Allosteric modulators of CB1 receptors have the potential to treat CNS and peripheral disorders while avoiding the adverse effects associated with orthosteric agonism or antagonism of these receptors.
A cosmology calculator that computes times and distances as a function of redshift for user‐defined cosmological parameters has been made available online. This paper gives the formulae used by the ...cosmology calculator and discusses some of its implementation. A version of the calculator that allows one to specify the equation‐of‐state parameterwand
\documentclass{aastex} \usepackage{amsbsy} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{bm} \usepackage{mathrsfs} \usepackage{pifont} \usepackage{stmaryrd} \usepackage{textcomp} \usepackage{portland,xspace} \usepackage{amsmath,amsxtra} \usepackageOT2,OT1{fontenc} \newcommand\cyr{ \renewcommand\rmdefault{wncyr} \renewcommand\sfdefault{wncyss} \renewcommand\encodingdefault{OT2} \normalfont \selectfont} \DeclareTextFontCommand{\textcyr}{\cyr} \pagestyle{empty} \DeclareMathSizes{10}{9}{7}{6} \begin{document} \landscape $w^{\prime }$ \end{document}
, and one for converting the light‐travel times usually given in the popular press into redshifts, is also located at the same site.
The transcriptional coactivators CREB-binding protein (CBP) and p300 undergo a particularly rich set of interactions with disordered and partly ordered partners, as a part of their ubiquitous role in ...facilitating transcription of genes. CBP and p300 contain a number of small structured domains that provide scaffolds for the interaction of disordered transactivation domains from a wide variety of partners, including p53, hypoxia-inducible factor 1α (HIF-1α), NF-κB, and STAT proteins, and are the targets for the interactions of disordered viral proteins that compete with cellular factors to disrupt signaling and subvert the cell cycle. The functional diversity of the CBP/p300 interactome provides an excellent example of the power of intrinsic disorder to facilitate the complexity of living systems.
Los Estados soberanos más pequeños del mundo, que de hecho comprenden la mayoría de los Estados soberanos en todo el mundo, tienen mucho que enseñarnos sobre las diferentes interpretaciones del ...poder. La gran parte de los estudios de relaciones internacionales (ir) se han centrado tradicionalmente en el poder como control o coerción; sin embargo, el poder también puede significar capacidad, que se logra a través de lo que este artículo identifica como agencia creativa. Aquí, la agencia creativa se define como la capacidad de acuerdo con la forma en que uno interpreta el poder y los beneficios asociados con ese poder. Por lo tanto, ciertos componentes del poder, como la hegemonía regional o global, pueden no ser relevantes para la agencia creativa; por el contrario, una identidad cultural fuerte o una economía de nicho puede ser esencial. Este artículo divide los Estados pequeños en tres categorías: (1) 2 microestados, definidos aquí como Estados con poblaciones de menos de medio millón y/o un área no marítima de menos de 1,000 kilómetros cuadrados; (2) Estados con poblaciones de entre medio millón y un millón; y (3) Estados considerados pequeños principalmente en relación con sus vecinos más grandes. Utiliza ejemplos de todas estas categorías para ilustrar el fenómeno de la agencia creativa con respecto a la formación del Estado y el tipo de gobierno y gobernanza. Debido a que el enfoque del artículo es la pedagogía, el texto incluye referencias a temas clave que los instructores pueden presentar con Estados pequeños, así como a trabajos representativos sobre Estados pequeños de ciencias políticas, derecho, historia y antropología
Biomaterials for Skin Substitutes Sheikholeslam, Mohammadali; Wright, Meghan E E; Jeschke, Marc G ...
Advanced healthcare materials,
03/2018, Letnik:
7, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Patients with extensive burns rely on the use of tissue engineered skin due to a lack of sufficient donor tissue, but it is a challenge to identify reliable and economical scaffold materials and ...donor cell sources for the generation of a functional skin substitute. The current review attempts to evaluate the performance of the wide range of biomaterials available for generating skin substitutes, including both natural biopolymers and synthetic polymers, in terms of tissue response and potential for use in the operating room. Natural biopolymers display an improved cell response, while synthetic polymers provide better control over chemical composition and mechanical properties. It is suggested that not one material meets all the requirements for a skin substitute. Rather, a composite scaffold fabricated from both natural and synthetic biomaterials may allow for the generation of skin substitutes that meet all clinical requirements including a tailored wound size and type, the degree of burn, the patient age, and the available preparation technique. This review aims to be a valuable directory for researchers in the field to find the optimal material or combination of materials based on their specific application.
How to make a sex chromosome Wright, Alison E; Dean, Rebecca; Zimmer, Fabian ...
Nature communications,
07/2016, Letnik:
7, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Sex chromosomes can evolve once recombination is halted between a homologous pair of chromosomes. Owing to detailed studies using key model systems, we have a nuanced understanding and a rich review ...literature of what happens to sex chromosomes once recombination is arrested. However, three broad questions remain unanswered. First, why do sex chromosomes stop recombining in the first place? Second, how is recombination halted? Finally, why does the spread of recombination suppression, and therefore the rate of sex chromosome divergence, vary so substantially across clades? In this review, we consider each of these three questions in turn to address fundamental questions in the field, summarize our current understanding, and highlight important areas for future work.
Sex chromosome evolution begins when recombination between a homologous pair of chromosomes is halted. Here, Wright
et al.
review our current understanding of the causes and mechanisms of recombination suppression between incipient sex chromosomes and suggest future directions for the field.
The partitioning of intracellular space beyond membrane-bound organelles can be achieved with collections of proteins that are multivalent or contain low-complexity, intrinsically disordered regions. ...These proteins can undergo a physical phase change to form functional granules or other entities within the cytoplasm or nucleoplasm that collectively we term "assemblage." Intrinsically disordered proteins (IDPs) play an important role in forming a subset of cellular assemblages by promoting phase separation. Recent work points to an involvement of assemblages in disease states, indicating that intrinsic disorder and phase transitions should be considered in the development of therapeutics.
Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. One of the hallmarks of ALT cancer is the excessively ...clustered telomeres in promyelocytic leukemia (PML) bodies, represented as large bright telomere foci. Here, we present a model system that generates telomere clustering in nuclear polySUMO (small ubiquitin-like modification)/polySIM (SUMO-interacting motif) condensates, analogous to PML bodies, and thus artificially engineered ALT-associated PML body (APB)-like condensates in vivo. We observed that the ALT-like phenotypes (i.e., a small fraction of heterogeneous telomere lengths and formation of C circles) are rapidly induced by introducing the APB-like condensates together with BLM through its helicase domain, accompanied by ssDNA generation and RPA accumulation at telomeres. Moreover, these events lead to mitotic DNA synthesis (MiDAS) at telomeres mediated by RAD52 through its highly conserved N-terminal domain. We propose that the clustering of large amounts of telomeres in human cancers promotes ALT that is mediated by MiDAS, analogous to
type II ALT survivors.
We report a trifluoromethylarene reductive coupling method that dramatically expands the scope of difluorobenzylic substructures accessible via C–F bond functionalization. Catalytic quantities of a ...Lewis base, combined with a disilane reagent in formamide solvent, promotes the replacement of a single trifluoromethyl fluorine atom with a silylated hemiaminal functional group. The reaction proceeds through a difluorobenzyl silane intermediate that can also be isolated. Together, these defluorinated products are shown to provide rapid access to over 20 unique difluoroalkylarene scaffolds.
Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. By analyzing telomerase-positive cells and their human TERC ...knockout-derived ALT human cell lines, we show that ALT cells harbor more fragile telomeres representing telomere replication problems. ALT-associated replication defects trigger mitotic DNA synthesis (MiDAS) at telomeres in a RAD52-dependent, but RAD51-independent, manner. Telomeric MiDAS is a conservative DNA synthesis process, potentially mediated by break-induced replication, similar to type II ALT survivors in
Saccharomyces cerevisiae
. Replication stresses induced by ectopic oncogenic expression of cyclin E, G-quadruplexes, or R-loop formation facilitate the ALT pathway and lead to telomere clustering, a hallmark of ALT cancers. The TIMELESS/TIPIN complex suppresses telomere clustering and telomeric MiDAS, whereas the SMC5/6 complex promotes them. In summary, ALT cells exhibit more telomere replication defects that result in persistent DNA damage responses at telomeres, leading to the engagement of telomeric MiDAS (spontaneous mitotic telomere synthesis) that is triggered by DNA replication stress, a potential driver of genomic duplications in cancer.
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