SF3B1 facilitates HIF1-signaling and promotes malignancy in pancreatic cancer

Mutations in the splicing factor SF3B1 are frequently occurring in various cancers and drive tumor progression through the activation of cryptic splice sites in multiple genes. Recent studies also demonstrate a positive correlation between the expression levels of wild-type SF3B1 and tumor malignancy. Here, we demonstrate that SF3B1 is a hypoxia-inducible factor (HIF)-1 target gene that positively regulates HIF1 pathway activity. By physically interacting with HIF1α, SF3B1 facilitates binding of the HIF1 complex to hypoxia response elements (HREs) to activate target gene expression. To further validate the relevance of this mechanism for tumor progression, we show that a reduction in SF3B1 levels via monoallelic deletion of Sf3b1 impedes tumor formation and progression via impaired HIF signaling in a mouse model for pancreatic cancer. Our work uncovers an essential role of SF3B1 in HIF1 signaling, thereby providing a potential explanation for the link between high SF3B1 expression and aggressiveness of solid tumors

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Fluid-mode flutter in plane transonic flows

We investigate the flutter behavior of 1) a typical-section OAT15A airfoil with a heave and a pitch degree of freedom and 2) a generic symmetric airfoil of variable thickness equipped with a flexible trailing-edge plate by means of RANS simulations. The linearized flutter stability problem in the pre-buffet region is approached with three different techniques: A Newton-based root search involving the p-k approximation (NPK), a rational function approximation (RFA) of the fluid-structure coupled frequency response and a time-domain eigenvalue identification on the coupled impulse response obtained via succesive convolution (SCM). We emphasize on flutter instabilities resulting from the coupling of a structural mode and a fluid mode in separated flow. We conclude that the buffet onset should be regarded as the flutter boundary in the limiting case of zero density and buffeting is essentially flutter

Comparison of Hydraulic and Tracer Tomography for Discrete Fracture Network Inversion

Fractures serve as highly conductive preferential flow paths for fluids in rocks, which are difficult to exactly reconstruct in numerical models. Especially, in low-conductive rocks, fractures are often the only pathways for advection of solutes and heat. The presented study compares the results from hydraulic and tracer tomography applied to invert a theoretical discrete fracture network (DFN) that is based on data from synthetic cross-well testing. For hydraulic tomography, pressure pulses in various injection intervals are induced and the pressure responses in the monitoring intervals of a nearby observation well are recorded. For tracer tomography, a conservative tracer is injected in different well levels and the depth-dependent breakthrough of the tracer is monitored. A recently introduced transdimensional Bayesian inversion procedure is applied for both tomographical methods, which adjusts the fracture positions, orientations, and numbers based on given geometrical fracture statistics. The used Metropolis-Hastings-Green algorithm is refined by the simultaneous estimation of the measurement error&rsquo;s variance, that is, the measurement noise. Based on the presented application to invert the two-dimensional cross-section between source and the receiver well, the hydraulic tomography reveals itself to be more suitable for reconstructing the original DFN. This is based on a probabilistic representation of the inverted results by means of fracture probabilities

SF3B1 facilitates HIF1-signaling and promotes malignancy in pancreatic cancer

Mutations in the splicing factor SF3B1 are frequently occurring in various cancers and drive tumor progression through the activation of cryptic splice sites in multiple genes. Recent studies also demonstrate a positive correlation between the expression levels of wild-type SF3B1 and tumor malignancy. Here, we demonstrate that SF3B1 is a hypoxia-inducible factor (HIF)-1 target gene that positively regulates HIF1 pathway activity. By physically interacting with HIF1α, SF3B1 facilitates binding of the HIF1 complex to hypoxia response elements (HREs) to activate target gene expression. To further validate the relevance of this mechanism for tumor progression, we show that a reduction in SF3B1 levels via monoallelic deletion of Sf3b1 impedes tumor formation and progression via impaired HIF signaling in a mouse model for pancreatic cancer. Our work uncovers an essential role of SF3B1 in HIF1 signaling, thereby providing a potential explanation for the link between high SF3B1 expression and aggressiveness of solid tumors.ISSN:2666-3864ISSN:2211-124

Lewy body dementia: Overcoming barriers and identifying solutions.

Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public-health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public-domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating therapeutic development and improving patient care. This white paper outlines the opportunities for bridging the major LBD gaps and creates the framework for collaboration in that endeavor. HIGHLIGHTS: A group representing academia, government, industry, and consulting expertise was convened to discuss current progress in Dementia with Lewy Body care and research. Consideration of expert opinion,natural language processing of the literature as well as publicly available data bases, and Delphi inspired discussion led to a proposed consensus document of priorities for the field

Lewy body dementia: Overcoming barriers and identifying solutions.

Publication status: PublishedFunder: Lewy Body Dementia Association; doi: http://dx.doi.org/10.13039/100017312Funder: National Institute for Health Research for the Newcastle (NIHR) Biomedical Research CentreFunder: Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia ProgramFunder: Little Family Foundation; doi: http://dx.doi.org/10.13039/100010277Funder: Ted Turner and Family LBD Functional Genomics ConProgramFunder: American Brain Foundation; doi: http://dx.doi.org/10.13039/100005331Funder: Douglas Herthel DVM Memorial FundFunder: GE Healthcare; doi: http://dx.doi.org/10.13039/100006775Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public-health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public-domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating therapeutic development and improving patient care. This white paper outlines the opportunities for bridging the major LBD gaps and creates the framework for collaboration in that endeavor. HIGHLIGHTS: A group representing academia, government, industry, and consulting expertise was convened to discuss current progress in Dementia with Lewy Body care and research. Consideration of expert opinion,natural language processing of the literature as well as publicly available data bases, and Delphi inspired discussion led to a proposed consensus document of priorities for the field