1,495 research outputs found
The enzymes LSD1 and Set1A cooperate with the viral protein HBx to establish an active hepatitis B viral chromatin state
Indexación: Web of ScienceWith about 350 million people chronically infected around the world hepatitis B is a major health problem. Template for progeny HBV synthesis is the viral genome, organized as a minichromosome (cccDNA) inside the hepatocyte nucleus. How viral cccDNA gene expression is regulated by its chromatin structure; more importantly, how the modulation of this structure impacts on viral gene expression remains elusive. Here, we found that the enzyme SetDB1 contributes to setting up a repressed cccDNA chromatin state. This repressive state is activated by the histone lysine demethylase-1 (LSD1). Consistently, inhibiting or reducing LSD1 levels led to repression of viral gene expression. This correlates with the transcriptionally repressive mark H3K9 methylation and reduction on the activating marks H3 acetylation and H3K4 methylation on viral promoters. Investigating the importance of viral proteins we found that LSD1 recruitment to viral promoters was dependent on the viral transactivator protein HBx. Moreover, the histone methyltransferase Set1A and HBx are simultaneously bound to the core promoter, and Set1A expression correlates with cccDNA H3K4 methylation. Our results shed light on the mechanisms of HBV regulation mediated by the cccDNA chromatin structure, offering new therapeutic targets to develop drugs for the treatment of chronically infected HBV patients.http://www.nature.com/articles/srep2590
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Reduced free asparagine in wheat grain resulting from a natural deletion of TaASNB2: investigating and exploiting diversity in the asparagine synthetase gene family to improve wheat quality
Background: Understanding the determinants of free asparagine concentration in wheat grain is necessary to reduce levels of the processing contaminant acrylamide in baked and toasted wheat products. Although crop management strategies can help reduce asparagine levels, breeders have limited options to select for genetic variation underlying this trait. Asparagine synthetase enzymes catalyse a critical step in asparagine biosynthesis in plants and, in wheat, are encoded by five homeologous gene triads that exhibit distinct expression profiles. Within this family, TaASN2 genes are highly expressed during grain development but TaASN-B2 is absent in some varieties.
Results:
Natural genetic diversity in the asparagine synthetase gene family was assessed in different wheat varieties revealing instances of presence/absence variation and other polymorphisms, including some predicted to affect the function of the encoded protein. The presence and absence of TaASN-B2 was determined across a range of UK and global common wheat varieties and related species, showing that the deletion encompassing this gene was already present in some wild emmer wheat genotypes. Expression profiling confirmed that TaASN2 transcripts were only detectable in the grain, while TaASN3.1 genes were highly expressed during the early stages of grain development. TaASN-A2 was the most highly expressed TaASN2 homeologue in most assayed wheat varieties. TaASN-B2 and TaASN-D2 were expressed at similar, lower levels in varieties possessing TaASN-B2. Expression of TaASN-A2 and TaASN-D2 did not increase to compensate for the absence of TaASN-B2, so total TaASN2 expression was lower in varieties lacking TaASN-B2. Consequently, free asparagine levels in field-produced grain were, on average, lower in varieties lacking TaASN-B2, although the effect was lost when free asparagine accumulated to very high levels as a result of sulphur deficiency.
Conclusions: Selecting wheat genotypes lacking the TaASN-B2 gene may be a simple and rapid way for breeders to reduce free asparagine levels in commercial wheat grain
Real-life management of patients with breakthrough cancer pain caused by bone metastases in Spain
Purpose: We aimed to explore the characteristics, and real-life therapeutic management of patients with breakthrough cancer pain (BTcP) caused by bone metastases in Spain, and to evaluate physicians' opinion of and satisfaction with prescribed BTcP therapy. Participants and methods: For the purposes of this study, an ad-hoc questionnaire was developed consisting of two domains: a) organizational aspects and care standards; b) clinical and treatment variables of bone metastatic BTcP patients. In addition, physicians' satisfaction with their prescribed BTcP therapy was assessed. Specialists collected data from up to five patients receiving treatment for BTcP caused by bone metastasis, all patients gave their consent to participate prior to inclusion. Results: A total of 103 cancer pain specialists (radiation oncologists [38.8%], pain specialists [33.0%], and palliative care (PC) specialists [21.4%]) were polled, and data on 386 BTcP patients with bone metastatic disease were collected. Only 33% of the specialists had implemented specific protocols for BTcP management, and 19.4% had established referral protocols for this group of patients. Half of all participants (50.5%) address quality of life and quality of care in their patients; however, only 27.0% did so from the patient's perspective, as they should do. Most patients had multiple metastases and were prescribed rapid-onset fentanyl preparations (71.2%), followed by immediate-release morphine (9.3%) for the treatment of BTcP. Rapid-onset fentanyl was prescribed more often in PC units (79.0%) than in pain units (75.9%) and radiation oncology units (61.1%) (p<0.01). Furthermore, most physicians (71.8%) were satisfied with the BTcP therapy prescribed. Conclusions: Our results demonstrate the need for routine assessment of quality of life in patients with bone BTcP. These findings also underscore the necessity for a multidisciplinary therapeutic strategy for breakthrough pain in clinical practice in Spain
rpoB Gene mutations in rifampin-resistant Mycobacterium tuberculosis identified by polymerase chain reaction single-stranded conformational polymorphism.
The use of polymerase chain reaction-single-stranded conformational polymorphism (PCR-SSCP) to study rpoB gene mutations in rifampin-resistant (RIFr) Mycobacterium tuberculosis has yielded contradictory results. To determine the sensitivity of this method, we analyzed 35 RIFr strains and 11 rifampin-susceptible (RIFs) strains, using the DNA sequencing of the core region of rpoB for comparison. Of the RIFr, 24 had a PCR-SSCP pattern identical to that of H37Rv; the other 11 had four different patterns. The 11 RIFs had PCR-SSCP patterns identical to that of H37Rv. The sensitivity of the assay was 31.4%; its specificity was 100%. We observed a strong correlation between the degree of resistance and the type of mutation
Primary Angioplasty in a Catastrophic Presentation: Acute Left Main Coronary Total Occlusion—The ATOLMA Registry
Objectives. To determine the outcome predictors of in-hospital mortality in acute total occlusion of the left main coronary artery (ATOLMA) patients referred to emergent angioplasty and to describe the clinical presentation and the long-term outcome of these patients.Background. ATOLMA is an uncommon angiographic finding that usually leads to a catastrophic presentation. Limited and inconsistent data have been previously reported regarding true ATOLMA, yet comprehensive knowledge remains scarce.Methods. This is a multicenter retrospective cohort that includes patients presenting with myocardial infarction due to a confirmed ATOLMA who underwent emergency percutaneous coronary intervention (PCI).Results. In the period of the study, 7930 emergent PCI were performed in the five participating centers, and 46 of them had a true ATOLMA (0.58%). At admission, cardiogenic shock was present in 89% of patients, and cardiopulmonary resuscitation was required in 67.4%. All the patients had right dominance. Angiographic success was achieved in 80.4% of the procedures, 13 patients (28.2%) died during the catheterization, and the in-hospital mortality rate was 58.6% (27/46). At one-year and at the final follow-up, 18 patients (39%) were alive, including four cases successfully transplanted. Multivariate analysis showed that postprocedural TIMI flow was the only independent predictor of in-hospital mortality (OR 0.23, (95% CI 0.1-0.36),p<0.001).Conclusions. Our study confirms that the clinical presentation of ATOLMA is catastrophic, presenting a high in-hospital mortality rate; nevertheless, primary angioplasty in this setting is feasible. Postprocedural TIMI flow resulted as the only independent predictor of in-hospital mortality. In-hospital survivors presented an encouraging outcome. ATOLMA and left dominance could be incompatible with life
Discovery and physical characterization as the first response to a potential asteroid collision: The case of 2023 DZ2
Near-Earth asteroids (NEAs) that may evolve into impactors deserve detailed
threat assessment studies. Early physical characterization of a would-be
impactor may help in optimizing impact mitigation plans. We first detected NEA
2023~DZ on 27--February--2023. After that, it was found to have a Minimum
Orbit Intersection Distance (MOID) with Earth of 0.00005~au as well as an
unusually high initial probability of becoming a near-term (in 2026) impactor.
We aim to perform a rapid but consistent dynamical and physical
characterization of 2023~DZ as an example of a key response to mitigate
the consequences of a potential impact. We use a multi-pronged approach,
drawing from various methods (observational/computational) and techniques
(spectroscopy/photometry from multiple instruments), and bringing the data
together to perform a rapid and robust threat assessment.} The visible
reflectance spectrum of 2023~DZ is consistent with that of an X-type
asteroid. Light curves of this object obtained on two different nights give a
rotation period =6.27430.0005 min with an amplitude
=0.570.14~mag. We confirm that although its MOID is among the smallest
known, 2023~DZ will not impact Earth in the foreseeable future as a
result of secular near-resonant behaviour. Our investigation shows that
coordinated observation and interpretation of disparate data provides a robust
approach from discovery to threat assessment when a virtual impactor is
identified. We prove that critical information can be obtained within a few
days after the announcement of the potential impactor.Comment: Accepted for publication in Astronomy and Astrophysics, 15 page
Tensor Analyzing Powers for Quasi-Elastic Electron Scattering from Deuterium
We report on a first measurement of tensor analyzing powers in quasi-elastic
electron-deuteron scattering at an average three-momentum transfer of 1.7
fm. Data sensitive to the spin-dependent nucleon density in the deuteron
were obtained for missing momenta up to 150 MeV/ with a tensor polarized
H target internal to an electron storage ring. The data are well described
by a calculation that includes the effects of final-state interaction,
meson-exchange and isobar currents, and leading-order relativistic
contributions.Comment: 4 pages, 3 figure
An ancestry informative marker set for determining continental origin: validation and extension using human genome diversity panels
<p>Abstract</p> <p>Background</p> <p>Case-control genetic studies of complex human diseases can be confounded by population stratification. This issue can be addressed using panels of ancestry informative markers (AIMs) that can provide substantial population substructure information. Previously, we described a panel of 128 SNP AIMs that were designed as a tool for ascertaining the origins of subjects from Europe, Sub-Saharan Africa, Americas, and East Asia.</p> <p>Results</p> <p>In this study, genotypes from Human Genome Diversity Panel populations were used to further evaluate a 93 SNP AIM panel, a subset of the 128 AIMS set, for distinguishing continental origins. Using both model-based and relatively model-independent methods, we here confirm the ability of this AIM set to distinguish diverse population groups that were not previously evaluated. This study included multiple population groups from Oceana, South Asia, East Asia, Sub-Saharan Africa, North and South America, and Europe. In addition, the 93 AIM set provides population substructure information that can, for example, distinguish Arab and Ashkenazi from Northern European population groups and Pygmy from other Sub-Saharan African population groups.</p> <p>Conclusion</p> <p>These data provide additional support for using the 93 AIM set to efficiently identify continental subject groups for genetic studies, to identify study population outliers, and to control for admixture in association studies.</p
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