The yeast histone deacetylase Rpd3 can be recruited to promoters to repress transcription initiation. Biochemical, genetic, and gene-expression analyses show that Rpd3 exists in two distinct ...complexes. The smaller complex, Rpd3C(S), shares Sin3 and Ume1 with Rpd3C(L) but contains the unique subunits Rco1 and Eaf3. Rpd3C(S) mutants exhibit phenotypes remarkably similar to those of Set2, a histone methyltransferase associated with elongating RNA polymerase II. Chromatin immunoprecipitation and biochemical experiments indicate that the chromodomain of Eaf3 recruits Rpd3C(S) to nucleosomes methylated by Set2 on histone H3 lysine 36, leading to deacetylation of transcribed regions. This pathway apparently acts to negatively regulate transcription because deleting the genes for Set2 or Rpd3C(S) bypasses the requirement for the positive elongation factor Bur1/Bur2.
Aerosol deposition from the 2010 eruption of the Icelandic volcano Eyjafjallajökull resulted in significant dissolved iron (DFe) inputs to the Iceland Basin of the North Atlantic. Unique ship‐board ...measurements indicated strongly enhanced DFe concentrations (up to 10 nM) immediately under the ash plume. Bioassay experiments performed with ash collected at sea under the plume also demonstrated the potential for associated Fe release to stimulate phytoplankton growth and nutrient drawdown. Combining Fe dissolution measurements with modeled ash deposition suggested that the eruption had the potential to increase DFe by >0.2 nM over an area of up to 570,000 km2. Although satellite ocean color data only indicated minor increases in phytoplankton abundance over a relatively constrained area, comparison of in situ nitrate concentrations with historical records suggested that ash deposition may have resulted in enhanced major nutrient drawdown. Our observations thus suggest that the 2010 Eyjafjallajökull eruption resulted in a significant perturbation to the biogeochemistry of the Iceland Basin.
Key Points
Volcanic ash deposition results in enhanced iron and aluminium in Iceland Basin
Ash derived iron supply causes nitrate drawdown in seasonal HNLC region
Ash stimulates phytoplankton growth in bioassay experiment
Nuclear receptor-binding SET domain-containing 2 (NSD2) is the primary enzyme responsible for the dimethylation of lysine 36 of histone 3 (H3K36), a mark associated with active gene transcription and ...intergenic DNA methylation. In addition to a methyltransferase domain, NSD2 harbors two proline-tryptophan-tryptophan-proline (PWWP) domains and five plant homeodomains (PHDs) believed to serve as chromatin reading modules. Here, we report a chemical probe targeting the N-terminal PWWP (PWWP1) domain of NSD2. UNC6934 occupies the canonical H3K36me2-binding pocket of PWWP1, antagonizes PWWP1 interaction with nucleosomal H3K36me2 and selectively engages endogenous NSD2 in cells. UNC6934 induces accumulation of endogenous NSD2 in the nucleolus, phenocopying the localization defects of NSD2 protein isoforms lacking PWWP1 that result from translocations prevalent in multiple myeloma (MM). Mutations of other NSD2 chromatin reader domains also increase NSD2 nucleolar localization and enhance the effect of UNC6934. This chemical probe and the accompanying negative control UNC7145 will be useful tools in defining NSD2 biology.
Rewiring of Genetic Networks in Response to DNA Damage Bandyopadhyay, Sourav; Mehta, Monika; Kuo, Dwight ...
Science (American Association for the Advancement of Science),
12/2010, Letnik:
330, Številka:
6009
Journal Article
Recenzirano
Odprti dostop
Although cellular behaviors are dynamic, the networks that govern these behaviors have been mapped primarily as static snapshots. Using an approach called differential epistasis mapping, we have ...discovered widespread changes in genetic interaction among yeast kinases, phosphatases, and transcription factors as the cell responds to DNA damage. Differential interactions uncover many gene functions that go undetected in static conditions. They are very effective at identifying DNA repair pathways, highlighting new damage-dependent roles for the Slt2 kinase, Pph3 phosphatase, and histone variant Htz1. The data also reveal that protein complexes are generally stable in response to perturbation, but the functional relations between these complexes are substantially reorganized. Differential networks chart a new type of genetic landscape that is invaluable for mapping cellular responses to stimuli.
Obesity is associated with increased blood pressure (BP), which in turn increases the risk of cardiovascular diseases. We found that the increase in leptin levels seen in diet-induced obesity (DIO) ...drives an increase in BP in rodents, an effect that was not seen in animals deficient in leptin or leptin receptors (LepR). Furthermore, humans with loss-of-function mutations in leptin and the LepR have low BP despite severe obesity. Leptin’s effects on BP are mediated by neuronal circuits in the dorsomedial hypothalamus (DMH), as blocking leptin with a specific antibody, antagonist, or inhibition of the activity of LepR-expressing neurons in the DMH caused a rapid reduction of BP in DIO mice, independent of changes in weight. Re-expression of LepRs in the DMH of DIO LepR-deficient mice caused an increase in BP. These studies demonstrate that leptin couples changes in weight to changes in BP in mammalian species.
Display omitted
•Leptin is the link between obesity and increased blood pressure•Leptin acts through the dorsomedial hypothalamus to increase blood pressure•Blockade of leptin signaling reduces blood pressure in obese mice•Humans with defects in leptin signaling are protected from obesity hypertension
Leptin is found to be the link between obesity and increased blood pressure. Blocking leptin action reduces blood pressure in obese mice with clinical studies in humans, suggesting that defects in leptin signaling may protect against hypertension associated with obesity.
Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy ...homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEK-ERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.
Display omitted
Display omitted
•Mutations in KSR2 are associated with obesity in humans•Mutations affect ERK signaling and impair the oxidation of glucose and fatty acids•Patients display hyperphagia, insulin resistance, and a reduced basal metabolic rate•KSR2 is an important regulator of energy intake and expenditure in humans
Mutations in KSR2, a scaffolding protein involved in multiple signaling pathways, lead to severe metabolic alterations that cause early onset obesity in humans.
Abstract only Background: The aim of DEFUSE 2 is to determine if predefined MRI profiles predict clinical and imaging outcomes following endovascular reperfusion therapy. Methods: This prospective, ...NIH funded, multi-center study enrolled consecutive acute stroke patients in whom an MRI scan could be obtained immediately prior to intra-arterial therapy. A follow-up MRI was performed within 12 hrs of completion of the procedure and again at 5 days. PWI and DWI lesion volumes were determined using a fully automated software program (RAPID). Lesion growth (infarct volume on 5 day FLAIR - baseline DWI volume) was compared for patients with and without the Target mismatch profile based on whether early reperfusion occurred. The Target mismatch profile was defined as PWI(Tmax>6s) / DWI >1.8, DWI <70 mL and PWI(Tmax>10s) <100 mL. Early reperfusion was defined as a >50% reduction in PWI volume following the procedure. The incidence and extent of DWI reversal was assessed and the fate of PWI lesions that were not reperfused was determined. Favorable clinical response was defined as an improvement in NIHSS ≥8 or 0-1 at 30 days. Results: This abstract represents a preliminary analysis of 71 of 101 patients who were treated with endovascular therapy (final results to be presented). Among the 54 patients with Target mismatch, early reperfusion was achieved in 70% and was associated with less infarct growth (relative median growth 210% vs. 450%, p=0.01) and a higher rate of favorable clinical response (OR=5.4; 95%CI 1.5-19.2). In patients without the Target mismatch profile (N= 13) early reperfusion was not associated with a reduction in infarct growth (relative median growth was 220% in both reperfusers and non-reperfusers; p=0.94) or an increased rate of favorable clinical response (OR=0.1; 95%CI 0.004-2.2). 96% of all voxels that were DWI positive at baseline were incorporated into the final infarct (assessed on the co-registered 5 day FLAIR); only 3 of 71 patients had FLAIR volumes that were smaller than the baseline DWI lesion (mean difference 3 mL). 80% of the voxels that had a PWI lesion (Tmax>6s) on the post-procedure scan were incorporated into the final infarct. The correlation between the union of the baseline DWI + early follow-up PWI lesion and the 5 day FLAIR volume was high (r=0.84; p< 0.0001). In 82% of the patients, the day 5 FLAIR volume was as at least as large as the union of the baseline DWI + early follow-up PWI lesion. Conclusion: Patients with the Target mismatch profile who achieve early reperfusion following intra-arterial therapy have less infarct growth and more favorable clinical outcomes. In contrast, no benefit of reperfusion was evident for non-Target mismatch patients. Baseline DWI lesions are virtually always fully incorporated into the final infarct volume, regardless of reperfusion. Tissue that remains hypoperfused (Tmax >6s) following endovascular therapy reliably progresses to infarction.
ABSTRACTPritchard, HJ, Barnes, MJ, Stewart, RJC, Keogh, JWL, and McGuigan, MR. Short-term training cessation as a method of tapering to improve maximal strength. J Strength Cond Res 32(2)458–465, ...2018—The aim of this study was to determine the effects of 2 different durations of training cessation on upper- and lower-body maximal strength performance and to investigate the mechanisms underlying performance changes following short-term training cessation. Eight resistance trained males (23.8 ± 5.4 years, 79.6 ± 10.2 kg, 1.80 ± 0.06 m, relative deadlift 1 repetition maximum of 1.90 ± 0.30 times bodyweight BW) each completed two 4-week strength training periods followed by either 3.5 days (3.68 ± 0.12 days) or 5.5 days (5.71 ± 0.13 days) of training cessation. Testing occurred pretraining (T1), on the final day of training (T2), and after each respective period of training cessation (T3). Participants were tested for salivary testosterone and cortisol, plasma creatine kinase, psychological profiles, and performance tests (countermovement jump CMJ, isometric midthigh pull, and isometric bench press IBP) on a force plate. Participantsʼ BW increased significantly over time (p = 0.022). The CMJ height and IBP peak force showed significant increases over time (p = 0.013, 0.048, and 0.004, respectively). Post hoc testing showed a significant increase between T1 and T3 for both CMJ height and IBP peak force (p = 0.022 and 0.008 with effect sizes of 0.30 and 0.21, respectively). No other significant differences were seen for any other measures. These results suggest that a short period of strength training cessation can have positive effects on maximal strength expression, perhaps because of decreases in neuromuscular fatigue.
The rise in lower extremity amputations due to nonhealing of foot ulcers in diabetic patients calls for rapid improvement in effective treatment regimens. Administration of growth factors (GFs) are ...thought to offer an off‐the‐shelf treatment; however, the dose‐ and time‐dependent efficacy of the GFs together with the hostile environment of diabetic wound beds impose a major hindrance in the selection of an ideal route for GF delivery. As an alternative, the delivery of therapeutic genes using viral and nonviral vectors, capable of transiently expressing the genes until the recovery of the wounded tissue offers promise. The development of implantable biomaterial dressings capable of modulating the release of either single or combinatorial GFs/genes may offer solutions to this overgrowing problem. This article reviews the state of the art on gene and protein delivery and the strategic optimization of clinically adopted delivery strategies for the healing of diabetic wounds.
PDF
