Enzymes catalysing the methylation of the 5-position of cytosine (mC) have essential roles in regulating gene expression and maintaining cellular identity. Recently, TET1 was found to hydroxylate the ...methyl group of mC, converting it to 5-hydroxymethyl cytosine (hmC). Here we show that TET1 binds throughout the genome of embryonic stem cells, with the majority of binding sites located at transcription start sites (TSSs) of CpG-rich promoters and within genes. The hmC modification is found in gene bodies and in contrast to mC is also enriched at CpG-rich TSSs. We provide evidence further that TET1 has a role in transcriptional repression. TET1 binds a significant proportion of Polycomb group target genes. Furthermore, TET1 associates and colocalizes with the SIN3A co-repressor complex. We propose that TET1 fine-tunes transcription, opposes aberrant DNA methylation at CpG-rich sequences and thereby contributes to the regulation of DNA methylation fidelity.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar ...macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution. During the fibrotic phase, monocyte-derived alveolar macrophages differ significantly from tissue-resident alveolar macrophages in their expression of profibrotic genes. A population of monocyte-derived alveolar macrophages persisted in the lung for one year after the resolution of fibrosis, where they became increasingly similar to tissue-resident alveolar macrophages. Human homologues of profibrotic genes expressed by mouse monocyte-derived alveolar macrophages during fibrosis were up-regulated in human alveolar macrophages from fibrotic compared with normal lungs. Our findings suggest that selectively targeting alveolar macrophage differentiation within the lung may ameliorate fibrosis without the adverse consequences associated with global monocyte or tissue-resident alveolar macrophage depletion.
Mechanical property anisotropy is one of the issues that are limiting the industrial adoption of additive manufacturing (AM) Ti-6Al-4V components. To improve the deposits’ microstructure, the effect ...of high-pressure interpass rolling was evaluated, and a flat and a profiled roller were compared. The microstructure was changed from large columnar prior
β
grains that traversed the component to equiaxed grains that were between 56 and 139
μ
m in size. The repetitive variation in Widmanstätten
α
lamellae size was retained; however, with rolling, the overall size was reduced. A “fundamental study” was used to gain insight into the microstructural changes that occurred due to the combination of deformation and deposition. High-pressure interpass rolling can overcome many of the shortcomings of AM, potentially aiding industrial implementation of the process.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Borrowing Hydrogen in the Activation of Alcohols Hamid, Malai Haniti S. A.; Slatford, Paul A.; Williams, Jonathan M. J.
Advanced synthesis & catalysis,
July 2, 2007, Volume:
349, Issue:
10
Journal Article
Peer reviewed
Alcohols can be temporarily converted into carbonyl compounds by the metal‐catalysed removal of hydrogen. The carbonyl compounds are reactive in a wider range of transformations than the precursor ...alcohols and can react in situ to give imines, alkenes, and α‐functionalised carbonyl compounds. The metal catalyst, which had borrowed the hydrogen, then returns it to the transformed carbonyl compound, leading to an overall process in which alcohols can be converted into amines, compounds containing CC bonds and β‐functionalised alcohols.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
AIM: The Red Sea is characterised by a unique fauna and historical periods of desiccation, hypersalinity and intermittent isolation. The origin and contemporary composition of reef‐associated taxa in ...this region can illuminate biogeographical principles about vicariance and the establishment (or local extirpation) of existing species. Here we aim to: (1) outline the distribution of shallow water fauna between the Red Sea and adjacent regions, (2) explore mechanisms for maintaining these distributions and (3) propose hypotheses to test these mechanisms. LOCATION: Red Sea, Gulf of Aden, Arabian Sea, Arabian Gulf and Indian Ocean. METHODS: Updated checklists for scleractinian corals, fishes and non‐coral invertebrates were used to determine species richness in the Red Sea and the rest of the Arabian Peninsula and assess levels of endemism. Fine‐scale diversity and abundance of reef fishes within the Red Sea were explored using ecological survey data. RESULTS: Within the Red Sea, we recorded 346 zooxanthellate and azooxanthellate scleractinian coral species of which 19 are endemic (5.5%). Currently 635 species of polychaetes, 211 echinoderms and 79 ascidians have been documented, with endemism rates of 12.6%, 8.1% and 16.5% respectively. A preliminary compilation of 231 species of crustaceans and 137 species of molluscs include 10.0% and 6.6% endemism respectively. We documented 1071 shallow fish species, with 12.9% endemic in the entire Red Sea and 14.1% endemic in the Red Sea and Gulf of Aden. Based on ecological survey data of endemic fishes, there were no major changes in species richness or abundance across 1100 km of Saudi Arabian coastline. MAIN CONCLUSIONS: The Red Sea biota appears resilient to major environmental fluctuations and is characterized by high rates of endemism with variable degrees of incursion into the Gulf of Aden. The nearby Omani and Arabian Gulfs also have variable environments and high levels of endemism, but these are not consistently distinct across taxa. The presence of physical barriers does not appear to explain species distributions, which are more likely determined by ecological plasticity and genetic diversity.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Disruption of the blood–brain barrier (BBB) and cerebral edema are the major pathogenic mechanisms leading to neurological dysfunction and death after ischemic stroke. The brain protects itself ...against infarction via activation of endogenous antioxidant defense mechanisms, and we here report the first evidence that sulforaphane-mediated preactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target heme oxygenase-1 (HO-1) in the cerebral vasculature protects the brain against stroke. To induce ischemic stroke, Sprague-Dawley rats were subjected to 70min middle cerebral artery occlusion (MCAo) followed by 4, 24, or 72h reperfusion. Nrf2 and HO-1 protein expression was upregulated in cerebral microvessels of peri-infarct regions after 4–72h, with HO-1 preferentially associated with perivascular astrocytes rather than the cerebrovascular endothelium. In naïve rats, treatment with sulforaphane increased Nrf2 expression in cerebral microvessels after 24h. Upregulation of Nrf2 by sulforaphane treatment prior to transient MCAo (1h) was associated with increased HO-1 expression in perivascular astrocytes in peri-infarct regions and cerebral endothelium in the infarct core. BBB disruption, lesion progression, as analyzed by MRI, and neurological deficits were reduced by sulforaphane pretreatment. As sulforaphane pretreatment led to a moderate increase in peroxynitrite generation, we suggest that hormetic preconditioning underlies sulforaphane-mediated protection against stroke. In conclusion, we propose that pharmacological or dietary interventions aimed to precondition the brain via activation of the Nrf2 defense pathway in the cerebral microvasculature provide a novel therapeutic approach for preventing BBB breakdown and neurological dysfunction in stroke.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A catalytic redox-neutral method for the synthesis of spirolactams proceeding through the dearomative spirocyclization of N-aryl alkynamides is reported. In contrast to stoichiometric activating ...agents employed for related transformations, we show that the use of 5 mol % of Au(PPh3)Cl and AgOTf in dichloroethane at 50–80 °C leads to selective spirocyclization, furnishing the products in yields of 35–87%. The substrate scope of the reaction is good, with both electron-donating and electron-withdrawing groups being tolerated around the arene ring, as well as substitution at the amide nitrogen. The identity of the para-alkoxy group on the arene ring is key to achieving selectivity for spirocyclization over alternative mechanistic pathways. While the presence of a para-methoxy group leads to trace amounts of the desired spirolactams, the para-tert-butoxy or para-hydroxy substrate analogues furnish the spirolactams in good yield with high selectivity.
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IJS, KILJ, NUK, PNG, UL, UM
Obesity associated cardiovascular risks such as hypertension are serious medical conditions that increase mortality. The brain autonomic networks play an important role in the regulation of ...cardiovascular function and metabolism. Therefore, obesity may represent a cardiovascular‐metabolic coupling and possible crosstalk in the central autonomic networks. We and others have previously shown the existence of shared nuclei in the autonomic networks innervating cardiovascular organs such as the kidney and metabolic organs such as the liver and brown adipose tissue (BAT). However, whether there are shared neurons within these nuclei associated with these three organs is unknown. To address this, two groups of mice received injections of pseudorabies virus (PRV) expressing a green fluorescent protein (GFP) into both kidneys and PRV expressing a red fluorescent protein (RFP) in either the interscapular BAT (iBAT) or the left lobe of the liver. The animals were sacrificed 5‐7 days post‐injection and perfused. The brains were extracted, sectioned at 50 µm thickness, stained, and imaged with confocal microscopy. Sections were matched to the mouse atlas (Franklin & Paxinos) and neurons co‐expressing GFP and RFP throughout the brain were identified. We found several nuclei in which neurons were co‐labeled with GFP (kidney) and RFP (BAT or liver). Interestingly, co‐expression does not appear limited to nuclei of specific regions in the brain. Instead, co‐expression was observed in many nuclei from cortical and subcortical regions to hypothalamic areas, midbrain, and brainstem nuclei. Indeed, co‐expressing neurons were observed in areas such as the cortical regions (motor cortex and amygdala), hypothalamic nuclei (paraventricular nucleus (PVN), lateral hypothalamus (LH), and dorsomedial hypothalamus (DMH)), midbrain regions such as the periaqueductal gray, and brainstem nuclei such as the locus coeruleus (LC). In general, there appeared to be two scenarios for shared nuclei: 1) in regions such as LH, nucleus of the solitary tract, and dorsal motor nucleus of vagus there was very little co‐expression, and 2) in regions such as PVN, DMH, LC, and motor cortex there was moderate to high levels of co‐expression. This is the first study to provide anatomical evidence for crosstalk between the autonomic networks regulating cardiovascular and metabolic functions. Moreover, our data demonstrate that crosstalk between the autonomic networks controlling cardiovascular and metabolic functions is distributed throughout the central nervous system.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Climate models project a distinct seasonality to future changes in daily extreme precipitation. In particular, models project that over land in the extratropical Northern Hemisphere the summer ...response is substantially weaker than the winter response in percentage terms. Here we decompose the projected response into thermodynamic and dynamic contributions and show that the seasonal contrast arises due to a negative dynamic contribution in northern summer, and a positive dynamic contribution and an anomalously strong thermodynamic contribution in northern winter. The negative dynamic contribution in northern summer is due to weakened ascent and is strongly correlated with decreases in mean near‐surface relative humidity. Finally, we show that the summer‐winter contrast is also evident in observed trends of daily precipitation extremes in northern midlatitudes, which provides support for the contrast found in climate‐model simulations.
Plain Language Summary
Extreme rainfall is a highly impactful aspect of the water cycle, and it is now well‐established that global warming tends to increase the severity of extreme rainfall events. However, while this increase holds robustly on global scales, there is significant uncertainty associated with understanding the response of extreme rainfall to warming in different regions of the world and in different seasons. Here we focus on understanding changes in extreme rainfall in summer and winter over Northern Hemisphere extratropical land. We find that global warming has a contrasting impact on extreme rainfall over this region depending on the season considered. In winter, there are large increases in extreme rainfall with warming relative to the climatology, whereas in summer the changes are much weaker. We use a simple, physics‐based approach to decompose these changes into contributions from changes in temperature and changes in ascent. Our results show that the contrasting seasonal response over this region is mostly due to decreases in extreme ascent with warming in summer, and that the “summer‐winter” contrast is already present in observed changes of extreme rainfall since the mid‐20th century.
Key Points
Over Northern Hemisphere extratropical land, the projected fractional increase of precipitation extremes is weaker in summer than winter
The summer‐winter contrast is mostly driven by weakened extreme ascent in summer, correlated with decreased surface relative humidity
The summer‐winter contrast is also evident in observations of historical changes in daily precipitation extremes, consistent with CMIP5 models
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The master transcription factors play integral roles in the pluripotency transcription circuitry of embryonic stem cells (ESCs). How they selectively activate expression of the pluripotency network ...while simultaneously repressing genes involved in differentiation is not fully understood. Here, we define a requirement for the INO80 complex, a SWI/SNF family chromatin remodeler, in ESC self-renewal, somatic cell reprogramming, and blastocyst development. We show that Ino80, the chromatin remodeling ATPase, co-occupies pluripotency gene promoters with the master transcription factors, and its occupancy is dependent on OCT4 and WDR5. At the pluripotency genes, Ino80 maintains an open chromatin architecture and licenses recruitment of Mediator and RNA polymerase II for gene activation. Our data reveal an essential role for INO80 in the expression of the pluripotency network and illustrate the coordination among chromatin remodeler, transcription factor, and histone-modifying enzyme in the regulation of the pluripotent state.
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•INO80 is required for ESC self-renewal, reprogramming, and blastocyst development•INO80 occupies pluripotency gene promoter regions, which is dependent on Wdr5 and Oct4•INO80 maintains an open chromatin structure and recruits Mediator and Pol II•INO80 binding distinguishes active genes from those repressed by master TFs
INO80 is required for ESC self-renewal, reprogramming, and blastocyst development. It activates pluripotency genes by maintaining an open chromatin structure at promoters to recruit Mediator and Pol II.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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