PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation

PBRM1, a component of the chromatin remodeller SWI/SNF, is often deleted or mutated in human cancers, most prominently in renal cancers. Core components of the SWI/SNF complex have been shown to be important for the cellular response to hypoxia. Here we investigated how PBRM1 controls HIF-1alpha activity. We find that PBRM1 is required for HIF-1alpha transcriptional activity and protein levels. Mechanistically, PBRM1 is important for HIF-1alpha mRNA translation, as absence of PBRM1 results in reduced activly transalting HIF-1alpha mRNA. Interestingly, we find that PBRM1, but not BRG1, interacts with the m6A reader protein YTHDF2. HIF-1alpha mRNA is m6A modified, bound by PBRM1 and YTHDF2. PBRM1 is necessary for YTHDF2 binding to HIF-1alpha mRNA and reduction of YTHDF2 results in reduced HIF-1alpha protein expression in cells. Our results identify a SWI/SNF independent function for PBRM1, interacting with HIF-1alpha mRNA and the epitranscriptome machinery. Furthermore, our results suggests that the epitranscriptome associated proteins play a role in the control of hypoxia signalling pathway

Drug-coated balloons to improve femoropopliteal artery patency: rationale and design of the LEVANT 2 trial

Background Atherosclerotic peripheral artery disease (PAD) is common and results in limitations in quality of life and potential progression to limb loss. Options for therapy include medical therapy, supervised exercise, surgical revascularization, and, more recently, endovascular therapies to restore arterial perfusion to the limb. Endovascular revascularization has evolved over the past 2 decades, from percutaneous transluminal angioplasty (PTA) to self-expanding stents, atherectomy, laser angioplasty, and drug-eluting stents. Despite impressive technologic advances, PTA remains the standard of care at many institutions and is the recommended primary treatment modality for femoral-popliteal PAD according to current American College of Cardiology Foundation/American Heart Association guidelines. However, restenosis after PTA is common. Therefore, a significant clinical need remains for a device that is able to achieve more durable patency than PTA but does not require a permanent implant. Drug-coated balloons (DCBs) have the potential to address this need. Several randomized controlled clinical trials of PTA balloons coated with different formulations of paclitaxel have been conducted in Europe (N Engl J Med 2008;358:689-699) (Circulation 2008;118:1358-1365) (Circ Cardiovasc Interv 2012;5:831-840) (JACC Cardiovas Interv 2014;7:10-19) and demonstrated more durable efficacy than PTA with comparable safety. These studies were limited by small sample sizes and powered solely for an angiographic primary end point. The pivotal LEVANT 2 trial was designed in collaboration with the US Food and Drug Administration to demonstrate safety and efficacy in a large population and to obtain US Food and Drug Administration approval. Methods A prospective, multicenter, single-blind trial comparing the Lutonix DCB (Bard Lutonix; New Hope, MN) versus PTA for treatment of femoropopliteal PAD (LEVANT 2) is the first US-based 2:1 randomized controlled trial of 476 patients with femoral-popliteal PAD designed to demonstrate superior efficacy and noninferior safety of a novel paclitaxel DCB compared with PTA. The primary efficacy end point is primary patency at 12 months. The primary safety end point is composite freedom at 12 months from perioperative death, index limb amputation, reintervention, and limb-related mortality. A series of important secondary end points include physical functioning, quality of life, revascularizations, and alternative measures of patency. To minimize bias potential for confounding variables, LEVANT 2 (1) excluded patients stented after predilation before randomization, (2) incorporated very stringent criteria for bailout stenting, (3) did not count bailout stenting as a target lesion revascularization or failure of any end point, (4) required a blinded clinician to perform clinical evaluations at follow-up, and (5) required clinical assessment before review of duplex ultrasound results. Conclusions LEVANT 2 represents the first US-inclusive multicenter, randomized controlled trial to assess the safety and efficacy of a novel DCB compared with PTA as primary therapy for symptomatic PAD on the background of standard medical therapy

Hypoxia activates IKK-NF-κB and the immune response in <em>Drosophila melanogaster</em>

Hypoxia, or low oxygen availability, is an important physiological and pathological stimulus for multicellular organisms. Molecularly, hypoxia activates a transcriptional programme directed at restoration of oxygen homoeostasis and cellular survival. In mammalian cells, hypoxia not only activates the HIF (hypoxia-inducible factor) family, but also additional transcription factors such as NF-κB (nuclear factor κB). Here we show that hypoxia activates the IKK–NF-κB [IκB (inhibitor of nuclear factor κB)–NF-κB] pathway and the immune response in Drosophila melanogaster. We show that NF-κB activation is required for organism survival in hypoxia. Finally, we identify a role for the tumour suppressor Cyld, as a negative regulator of NF-κB in response to hypoxia in Drosophila. The results indicate that hypoxia activation of the IKK–NF-κB pathway and the immune response is an important and evolutionary conserved response

Resiliência: Estudo comparativo entre países (Portugal e Brasil) e géneros

info:eu-repo/semantics/publishedVersio

Small and mighty: adaptation of superphylum Patescibacteria to groundwater environment drives their genome simplicity.

BackgroundThe newly defined superphylum Patescibacteria such as Parcubacteria (OD1) and Microgenomates (OP11) has been found to be prevalent in groundwater, sediment, lake, and other aquifer environments. Recently increasing attention has been paid to this diverse&nbsp;superphylum including &gt;&nbsp;20 candidate phyla&nbsp;(a large part of the candidate phylum radiation, CPR) because it refreshed our view of the tree of life. However, adaptive traits contributing to its prevalence are still not well known.ResultsHere, we investigated the genomic features and metabolic pathways of Patescibacteria in groundwater through genome-resolved metagenomics analysis of &gt; 600 Gbp sequence data. We observed that, while the members of Patescibacteria have reduced genomes (~ 1 Mbp) exclusively, functions essential to growth and reproduction such as genetic information processing were retained. Surprisingly, they have sharply reduced redundant and nonessential functions, including specific metabolic activities and stress response systems. The Patescibacteria have ultra-small cells and simplified membrane structures, including flagellar assembly, transporters, and two-component systems. Despite the lack of CRISPR viral defense, the bacteria may evade predation through deletion of common membrane phage receptors and other alternative strategies, which may explain the low representation of prophage proteins in their genomes and lack of CRISPR. By establishing the linkages between bacterial features and the groundwater environmental conditions, our results provide important insights into the functions and evolution of this CPR group.ConclusionsWe found that Patescibacteria has streamlined many functions while acquiring advantages such as avoiding phage invasion, to adapt to the groundwater environment. The unique features of small genome size, ultra-small cell size, and lacking CRISPR of this large lineage are bringing new understandings on life of Bacteria. Our results provide important insights into the mechanisms for adaptation of the superphylum in the groundwater environments, and demonstrate a case where less is more, and small is mighty

SINHCAF/FAM60A and SIN3A specifically repress HIF 2α expression

The SIN3A–HDAC (histone deacetylase) complex is a master transcriptional repressor, required for development but often deregulated in disease. Here, we report that the recently identified new component of this complex, SINHCAF (SIN3A and HDAC-associated factor)/FAM60A (family of homology 60A), links the SIN3A–HDAC co-repressor complex function to the hypoxia response. We show that SINHCAF specifically represses HIF-2α mRNA and protein expression, via its interaction with the transcription factor SP1 (specificity protein 1) and recruitment of HDAC1 to the HIF-2α promoter. SINHCAF control over HIF-2α results in functional cellular changes in in vitro angiogenesis and viability. Our analysis reveals an unexpected link between SINHCAF and the regulation of the hypoxia response

Structure of the mitochondrial control region and flanking tRNA genes of Mugil cephalus

We cloned and sequenced the mitochondrial (mt) control region (CR) and flanking transfer RNA genes (T, P, and F) of the striped mullet, Mugil cephalus and designed species-specific primers to amplify the entire CR in specimens from the Pacific (Hawaii), the Gulf of Mexico, and the Atlantic. We verified the absence of heteroplasmy and nuclear mtDNA duplications of this region in the organisms sampled, finding an extraordinary level of sequence divergence (mean 38-75% Tamura &amp; Nei distance- ) between fish from both Oceans, including Japan. The CR of the mullet was variable in length (845-930 bp) and contained structural elements in common with other CRs, including a central conserved segment flanked by hypervariable regions and smaller conserved sequence blocks. Termination associated sequences, however, were not found. The CR of the striped mullet was rich in AT (~67%) and poor in GC

Fashionably Late? Building up the Milky Way's Inner Halo

Using a sample of 248 metal-poor stars (RR Lyraes, red giants and RHB stars) which is remarkable for the accuracy of its 6-D kinematical data, we find a new component for the local halo which has an axial ratio c/a ~ 0.2, a similar flattening to the thick disk. It has a small prograde rotation but is supported by velocity anisotropy, and contains more intermediate-metallicity stars (with -1.5 < [Fe/H] < -1.0) than the rest of our sample. We suggest that this component was formed quite late, during or after the formation of the disk. It formed either from the gas that was accreted by the last major mergers experienced by the Galaxy, or by dynamical friction of massive infalling satellite(s) with the halo and possibly the stellar disk or thick disk. The remainder of the stars in our sample exhibit a clumpy distribution in energy and angular momentum, suggesting that the early, chaotic conditions under which the inner halo formed were not violent enough to erase the record of their origins. The clumpy structure suggests that a relatively small number of progenitors were responsible for building up the inner halo, in line with theoretical expectations. We find a difference in mean binding energy between the RR Lyrae variables and the red giants in our sample, suggesting that more of the RR Lyraes in the sample belong to the outer halo, and that the outer halo may be somewhat younger, as first suggested by Searle and Zinn (1978). We also find that the RR Lyrae mean rotation is more negative than the red giants, which is consistent with the recent result of Carollo et al.(2007) that the outer halo has a retrograde rotation and with the difference in kinematics seen between RR Lyraes and BHB stars by Kinman et al.(2007).Comment: 16 pages, 10 figures, this version accepted by Ap