DNA Demethylation Dynamics Bhutani, Nidhi; Burns, David M.; Blau, Helen M.
Cell,
09/2011, Letnik:
146, Številka:
6
Journal Article
Recenzirano
Odprti dostop
The discovery of cytosine hydroxymethylation (5hmC) suggested a simple means of demethylating DNA and activating genes. Further experiments, however, unearthed an unexpectedly complex process, ...entailing both passive and active mechanisms of DNA demethylation by the ten-eleven translocation (TET) and AID/APOBEC families of enzymes. The consensus emerging from these studies is that removal of cytosine methylation in mammalian cells can occur by DNA repair. These reports highlight that in certain contexts, DNA methylation is not fixed but dynamic, requiring continuous regulation.
Abstract
Metal-organic frameworks (MOFs) are a class of porous materials with unprecedented chemical and structural tunability. Their synthetic versatility, long-range order, and rich host–guest ...chemistry make MOFs ideal platforms for identifying design features for advanced functional materials. This review addresses synthetic approaches to control MOF attributes for realizing material properties such as charge conductivity, stability, surface area, and flexibility. Along with an updated account on MOFs employed in batteries and supercapacitors, new directions are outlined for advancing MOF research in emergent technologies such as solid-state electrolytes and battery operation in extreme environments.
Many major corporations and countries have made commitments to purchase or produce only “sustainable” palm oil, a commodity responsible for substantial tropical forest loss. Sustainability ...certification is the tool most used to fulfill these procurement policies, and around 20% of global palm oil production was certified by the Roundtable on Sustainable Palm Oil (RSPO) in 2017. However, the effect of certification on deforestation in oil palm plantations remains unclear. Here, we use a comprehensive dataset of RSPO-certified and noncertified oil palm plantations (∼188,000 km²) in Indonesia, the leading producer of palm oil, as well as annual remotely sensed metrics of tree cover loss and fire occurrence, to evaluate the impact of certification on deforestation and fire from 2001 to 2015. While forest loss and fire continued after RSPO certification, certified palm oil was associated with reduced deforestation. Certification lowered deforestation by 33% from a counterfactual of 9.8 to 6.6% y−1. Nevertheless, most plantations contained little residual forest when they received certification. As a result, by 2015, certified areas held less than 1% of forests remaining within Indonesian oil palm plantations. Moreover, certification had no causal impact on forest loss in peatlands or active fire detection rates. Broader adoption of certification in forested regions, strict requirements to avoid all peat, and routine monitoring of clearly defined forest cover loss in certified and RSPO member-held plantations appear necessary if the RSPO is to yield conservation and climate benefits from reductions in tropical deforestation.
1,3‐Enynes containing allylic hydrogens cis to the alkyne are shown to act as one‐carbon partners, rather than two‐carbon partners, in various rhodium‐catalyzed oxidative annulations. The mechanism ...of these unexpected transformations is proposed to occur through double CH activation, involving a hitherto rare example of the 1,4‐migration of a RhIII species. This phenomenon is general across a variety of substrates, and provides a diverse range of heterocyclic products.
When two become one: 1,3‐Enynes containing allylic hydrogen atoms cis to the alkyne are shown to act as one‐carbon partners, rather than two‐carbon partners, in various rhodium‐catalyzed oxidative annulations. The mechanism of these unexpected transformations is proposed to occur through double CH activation, involving a hitherto rare example of the 1,4‐migration of a RhIII species.
Cytoplasmic polyadenylation-induced translation controls germ cell development, neuronal synaptic plasticity and cellular senescence, a tumour-suppressor mechanism that limits the replicative ...lifespan of cells. The cytoplasmic polyadenylation element binding protein (CPEB) promotes polyadenylation by nucleating a group of factors including defective in germline development 2 (Gld2), a non-canonical poly(A) polymerase, on specific messenger RNA (mRNA) 3' untranslated regions (UTRs). Because CPEB regulation of p53 mRNA polyadenylation/translation is necessary for cellular senescence in primary human diploid fibroblasts, we surmised that Gld2 would be the enzyme responsible for poly(A) addition. Here we show that depletion of Gld2 surprisingly promotes rather than inhibits p53 mRNA polyadenylation/translation, induces premature senescence and enhances the stability of CPEB mRNA. The CPEB 3' UTR contains two miR-122 binding sites, which when deleted, elevate mRNA translation, as does an antagomir of miR-122. Although miR-122 is thought to be liver specific, it is present in primary fibroblasts and destabilized by Gld2 depletion. Gld4, a second non-canonical poly(A) polymerase, was found to regulate p53 mRNA polyadenylation/translation in a CPEB-dependent manner. Thus, translational regulation of p53 mRNA and cellular senescence is coordinated by Gld2/miR-122/CPEB/Gld4.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Methods for positionally selective remote C−H functionalizations are in high demand. Herein, we disclose the first heterogeneous ruthenium catalyst for meta‐selective C−H functionalizations, which ...enabled remote halogenations with excellent site selectivity and ample scope. The versatile heterogeneous Ru@SiO2 catalyst was broadly applicable and could be easily recovered and reused, which set the stage for the direct fluorescent labeling of purines. In contrast to palladium, rhodium, iridium, or cobalt complexes, solely the ruthenium catalysis manifold provided access to meta‐halogenated purine derivatives, illustrating the unique power of ruthenium C−H activation catalysis.
Remote control: A reusable heterogeneous ruthenium complex was developed for meta‐C−H functionalization reactions on purine derivatives. Chemo‐ and positionally selective C−H halogenation reactions and diversification with a fluorescent label were thus accomplished.
The full control of positional selectivity is of prime importance in C-H activation technology. Chelation assistance served as the stimulus for the development of a plethora of ortho-selective arene ...functionalizations. In sharp contrast, meta-selective C-H functionalizations continue to be scarce, with all ruthenium-catalysed transformations currently requiring difficult to remove or modify nitrogen-containing heterocycles. Herein, we describe a unifying concept to access a wealth of meta-decorated arenes by a unique arene ligand effect in proximity-induced ruthenium(II) C-H activation catalysis. The transformative nature of our strategy is mirrored by providing a step-economical entry to a range of meta-substituted arenes, including ketones, acids, amines and phenols-key structural motifs in crop protection, material sciences, medicinal chemistry and pharmaceutical industries.
Summary Background The effect of HIV pre-exposure prophylaxis (PrEP) depends on uptake, adherence, and sexual practices. We aimed to assess these factors in a cohort of HIV-negative people at risk of ...infection. Methods In our cohort study, men and transgender women who have sex with men previously enrolled in PrEP trials (ATN 082, iPrEx, and US Safety Study) were enrolled in a 72 week open-label extension. We measured drug concentrations in plasma and dried blood spots in seroconverters and a random sample of seronegative participants. We assessed PrEP uptake, adherence, sexual practices, and HIV incidence. Statistical methods included Poisson models, comparison of proportions, and generalised estimating equations. Findings We enrolled 1603 HIV-negative people, of whom 1225 (76%) received PrEP. Uptake was higher among those reporting condomless receptive anal intercourse (416/519 81% vs 809/1084 75%, p=0·003) and having serological evidence of herpes (612/791 77% vs 613/812 75% p=0·03). Of those receiving PrEP, HIV incidence was 1·8 infections per 100 person-years, compared with 2·6 infections per 100 person-years in those who concurrently did not choose PrEP (HR 0·51, 95% CI 0·26–1·01, adjusted for sexual behaviours), and 3·9 infections per 100 person-years in the placebo group of the previous randomised phase (HR 0·49, 95% CI 0·31–0·77). Among those receiving PrEP, HIV incidence was 4·7 infections per 100 person-years if drug was not detected in dried blood spots, 2·3 infections per 100 person-years if drug concentrations suggested use of fewer than two tablets per week, 0·6 per 100 person-years for use of two to three tablets per week, and 0·0 per 100 person-years for use of four or more tablets per week (p<0·0001). PrEP drug concentrations were higher among people of older age, with more schooling, who reported non-condom receptive anal intercourse, who had more sexual partners, and who had a history of syphilis or herpes. Interpretation PrEP uptake was high when made available free of charge by experienced providers. The effect of PrEP is increased by greater uptake and adherence during periods of higher risk. Drug concentrations in dried blood spots are strongly correlated with protective benefit. Funding US National Institutes of Health.
Artificial intelligence isn't Burns, David M
CMAJ. Canadian Medical Association journal,
2020-Mar-16, 2020-03-16, 20200316, Letnik:
192, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Seeking to compare the reasoning of human and artificial intelligence (AI) in the context of medical diagnosis is an overly optimistic anthropomorphism. The term AI, as used to describe machine ...learning algorithms employed in this domain, is itself a misnomer. This is apparent when comparing modern machine learning algorithms based on artificial neural networks to nonneural algorithms. Logistic regression, established in the 1800s, is the machine learning algorithm most commonly applied to structured medical data for diagnostic and prognostic purposes. The same nomenclature of learning or trainingis equally well applied to this algorithm that has been used for centuries. Simply put, machine learning algorithms are mathematical formulae with free parameters derived retrospectively from clinical data. These formulae are not intelligent according to even the most generous of definitions, and they have no capacity for reasoning. It is notable that nonneural machine learning algorithms are still the most accurate for structured clinical data and continue to dominate the field. Neural network algorithms do not provide intelligence, but they do provide the capacity to model more complex unstructured data and incorporate this information into predictive tools.
Chiral cyclopentadienyl rhodium complexes promote highly enantioselective enol‐directed C(sp2)‐H functionalization and oxidative annulation with alkynes to give spiroindenes containing all‐carbon ...quaternary stereocenters. High selectivity between two possible directing groups, as well as control of the direction of rotation in the isomerization of an O‐bound rhodium enolate into the C‐bound isomer, appear to be critical for high enantiomeric excesses.
Take the high rhod: Chiral cyclopentadienyl rhodium complexes promote enantioselective enol‐directed C(sp2)–H functionalization and oxidative annulation with alkynes to give spiroindenes containing all‐carbon quaternary stereocenters. High selectivity between two directing groups, as well as control of the direction of rotation in the isomerization of a rhodium enolate intermediate, appear to be critical for high enantiomeric excesses.
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