The heparan sulfate proteoglycan syndecan-1 is proteolytically shed from the surface of multiple myeloma cells and is abundant in the bone marrow microenvironment where it promotes tumor growth, ...angiogenesis, and metastasis. In this study, we demonstrate for the first time that shed syndecan-1 present in the medium conditioned by tumor cells is taken up by bone marrow-derived stromal cells and transported to the nucleus. Translocation of shed syndecan-1 (sSDC1) to the nucleus was blocked by addition of exogenous heparin or heparan sulfate, pretreatment of conditioned medium with heparinase III, or growth of cells in sodium chlorate, indicating that sulfated heparan sulfate chains are required for nuclear translocation. Interestingly, cargo bound to sSDC1 heparan sulfate chains (i.e. hepatocyte growth factor) was transported to the nucleus along with sSDC1, and removal of heparan sulfate-bound cargo from sSDC1 abolished its translocation to the nucleus. Once in the nucleus, sSDC1 binds to the histone acetyltransferase enzyme p300, and histone acetyltransferase activity and histone acetylation are diminished. These findings reveal a novel function for shed syndecan-1 in mediating tumor-host cross-talk by shuttling growth factors to the nucleus and by altering histone acetylation in host cells. In addition, this work has broad implications beyond myeloma because shed syndecan-1 is present in high levels in many tumor types as well as in other disease states.
Power-to-liquids are a class of liquid drop-in fuels produced from electricity and carbon dioxide as the primary process inputs, which have the potential to reduce transportation’s climate impacts. ...We quantify the economic and life cycle environmental characteristics of four electrofuel technology pathways that rely on the Fischer–Tropsch synthesis but produce synthesis gas via different schemes: power-to-liquid (PtL) via electrolysis and a reverse water gas shift (RWGS) reaction; PtL via co-electrolysis; gasification of biomass-to-liquid (BtL); and a hybrid power- and biomass-to-liquid (PBtL) pathway. The results indicate that the hybrid PBtL pathway is the most environmentally and economically promising option for electrofuel production, with results highly dependent on input electricity source characteristics such as cost and emissions. The carbon intensities of electricity generation that must not be exceeded for electrofuels to have lower life cycle emissions than conventional diesel are 222, 116, and 143 gCO2e/kWh for PBtL, PtL electrolysis + RWGS, and PtL co-electrolysis, respectively. We characterize the PBtL pathway in more detail by combining spatially resolved data on biomass cultivation, electricity generation, and cost-optimized hydrogen production from renewable electricity in the United States (US). We find that the private emissions abatement cost for PBtL fuels varies between 740 and 2000 $/tCO2e, depending primarily on the location of fuel production.
Xerogels and porous materials for specific applications such as catalyst supports, CO2 capture, pollutant adsorption, and selective membrane design require fine control of pore structure, which in ...turn requires improved understanding of the chemistry and physics of growth, aggregation, and gelation processes governing nanostructure formation in these materials. We used time-resolved dynamic light scattering to study the formation of resorcinol-formaldehyde gels through a sol–gel process in the presence of Group I metal carbonates. We showed that an underlying nanoscale phase transition (independent of carbonate concentration or metal type) controls the size of primary clusters during the preaggregation phase; while the amount of carbonate determines the number concentration of clusters and, hence, the size to which clusters grow before filling space to form the gel. This novel physical insight, based on a close relationship between cluster size at the onset of gelation and average pore size in the final xerogel results in a well-defined master curve, directly linking final gel properties to process conditions, facilitating the rational design of porous gels with properties specifically tuned for particular applications. Interestingly, although results for lithium, sodium, and potassium carbonate fall on the same master curve, cesium carbonate gels have significantly larger average pore size and cluster size at gelation, providing an extended range of tunable pore size for further adsorption applications.
In animals, each sequence-specific transcription factor typically binds to thousands of genomic regions in vivo. Our previous studies of 20 transcription factors show that most genomic regions bound ...at high levels in Drosophila blastoderm embryos are known or probable functional targets, but genomic regions occupied only at low levels have characteristics suggesting that most are not involved in the cis -regulation of transcription. Here we use transgenic reporter gene assays to directly test the transcriptional activity of 104 genomic regions bound at different levels by the 20 transcription factors. Fifteen genomic regions were selected based solely on the DNA occupancy level of the transcription factor Kruppel. Five of the six most highly bound regions drive blastoderm patterns of reporter transcription. In contrast, only one of the nine lowly bound regions drives transcription at this stage and four of them are not detectably active at any stage of embryogenesis. A larger set of 89 genomic regions chosen using criteria designed to identify functional cis -regulatory regions supports the same trend: genomic regions occupied at high levels by transcription factors in vivo drive patterned gene expression, whereas those occupied only at lower levels mostly do not. These results support studies that indicate that the high cellular concentrations of sequence-specific transcription factors drive extensive, low-occupancy, nonfunctional interactions within the accessible portions of the genome.
Restrictive clinical trial eligibility criteria (EC) limit the number of patients who can enroll and potentially benefit from protocol-driven, investigational treatment plans and reduce the ...generalizability of trial results to the broader population. Following publication of expert stakeholder recommendations for broadening EC in 2017, the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (
) convened working groups to produce additional recommendations and analyze the potential impact on clinical trials using real-world data.
Multistakeholder working groups were appointed by an ASCO-
leadership group to propose recommendations for more inclusive EC related to: washout periods, concomitant medications, prior therapies, laboratory reference ranges and test intervals, and performance status.
The four working groups, ASCO Board of Directors, and
leadership support the recommendations included in this statement to modernize EC related to washout periods, concomitant medications, prior therapies, laboratory references ranges and test intervals, and performance status to make trial populations more inclusive and representative of cancer patient populations.
Implementation of the recommendations is intended to result in greater ease of determining patient eligibility. Increased opportunities for patient participation in research will help address longstanding underrepresentation of certain groups in clinical trials and produce evidence that is more informative for a broader patient population. More patients eligible will also likely speed clinical trial accrual.
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Malaria is a major public health problem that is actively being addressed in a global eradication campaign. Increased population mobility through international air travel has elevated the risk of ...re-introducing parasites to elimination areas and dispersing drug-resistant parasites to new regions. A simple genetic marker that quickly and accurately identifies the geographic origin of infections would be a valuable public health tool for locating the source of imported outbreaks. Here we analyse the mitochondrion and apicoplast genomes of 711 Plasmodium falciparum isolates from 14 countries, and find evidence that they are non-recombining and co-inherited. The high degree of linkage produces a panel of relatively few single-nucleotide polymorphisms (SNPs) that is geographically informative. We design a 23-SNP barcode that is highly predictive (~92%) and easily adapted to aid case management in the field and survey parasite migration worldwide.
To examine differences in adipose tissue distribution, lumbar vertebral bone mineral density (BMD), and muscle attenuation in adults with and without cerebral palsy (CP), and to determine the ...associations between morphologic characteristics.
Cross-sectional, retrospective analyses of archived computed tomography scans.
Clinical treatment and rehabilitation center.
Adults (N=352) with CP (age, 38.8±14.4y; body mass, 61.3±17.1kg; Gross Motor Function Classification System levels, I-V) and a matched cohort of neurotypical adults. Of the 41 adults with CP included in the study, 10 were not matchable because of low body masses.
Not applicable.
Computed tomography scans were assessed for visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas, psoas major area and attenuation in Hounsfield units (Hu), and cortical and trabecular BMDs.
Adults with CP had lower cortical (β=-63.41 Hu, P<.001) and trabecular (β=-42.24 Hu, P<.001) BMDs and psoas major areas (β=-374.51mm(2), P<.001) and attenuation (β=-9.21 Hu, P<.001) after controlling for age, sex, and body mass. Adults with CP had greater VAT (β=3914.81mm(2), P<.001) and SAT (β=4615.68mm(2), P<.001). Muscle attenuation was significantly correlated with trabecular (r=.51, P=.002) and cortical (r=.46, P<.01) BMD, whereas VAT was negatively associated with cortical BMD (β=-.037 Hu/cm(2), r(2)=.13, P=.03).
Adults with CP had lower BMDs, smaller psoas major area, greater intermuscular adipose tissue, and greater trunk adiposity than neurotypical adults. VAT and cortical BMD were inversely associated.
We previously established that six sequence-specific transcription factors that initiate anterior/posterior patterning in Drosophila bind to overlapping sets of thousands of genomic regions in ...blastoderm embryos. While regions bound at high levels include known and probable functional targets, more poorly bound regions are preferentially associated with housekeeping genes and/or genes not transcribed in the blastoderm, and are frequently found in protein coding sequences or in less conserved non-coding DNA, suggesting that many are likely non-functional.
Here we show that an additional 15 transcription factors that regulate other aspects of embryo patterning show a similar quantitative continuum of function and binding to thousands of genomic regions in vivo. Collectively, the 21 regulators show a surprisingly high overlap in the regions they bind given that they belong to 11 DNA binding domain families, specify distinct developmental fates, and can act via different cis-regulatory modules. We demonstrate, however, that quantitative differences in relative levels of binding to shared targets correlate with the known biological and transcriptional regulatory specificities of these factors.
It is likely that the overlap in binding of biochemically and functionally unrelated transcription factors arises from the high concentrations of these proteins in nuclei, which, coupled with their broad DNA binding specificities, directs them to regions of open chromatin. We suggest that most animal transcription factors will be found to show a similar broad overlapping pattern of binding in vivo, with specificity achieved by modulating the amount, rather than the identity, of bound factor.
The endothelium plays a central role in the maintenance of vascular homeostasis. One of the main effectors of endothelial dysfunction is ANG II, and pharmacological approaches to limit ANG II ...bioactivity remain the cornerstone of cardiovascular therapeutics. Angiotensin converting enzyme-2 (ACE2) has been identified as a critical negative modulator of ANG II bioactivity, counterbalancing the effects of ACE in determining net tissue ANG II levels; however, the role of ACE2 in the vasculature remains unknown. In the present study, we hypothesized that ACE2 is a novel target to limit endothelial dysfunction and atherosclerosis. To this aim, we performed in vitro gain and loss of function experiments in endothelial cells and evaluated in vivo angiogenesis and atherosclerosis in apolipoprotein E-knockout mice treated with AdACE2. ACE2-deficient mice exhibited impaired endothelium-dependent relaxation. Overexpression of ACE2 in human endothelial cells stimulated endothelial cell migration and tube formation, and limited monocyte and cellular adhesion molecule expression; effects that were reversed in ACE2 gene silenced and endothelial cells isolated from ACE2-deficient animals. ACE2 attenuated ANG II-induced reactive oxygen species production in part through decreasing the expression of p22phox. The effects of ACE2 on endothelial activation were attenuated by pharmacological blockade of ANG-(1-7) with A779. ACE2 promoted capillary formation and neovessel maturation in vivo and reduced atherosclerosis in apolipoprotein E-knockout mice These data indicate that ACE2, in an ANG-(1-7)-dependent fashion, functions to improve endothelial homeostasis via a mechanism that may involve attenuation of NADPHox-induced reactive oxygen species production. ACE2-based treatment approaches may be a novel approach to limit aberrant vascular responses and atherothrombosis.
Identifying the genomic regions bound by sequence-specific regulatory factors is central both to deciphering the complex DNA cis-regulatory code that controls transcription in metazoans and to ...determining the range of genes that shape animal morphogenesis. We used whole-genome tiling arrays to map sequences bound in Drosophila melanogaster embryos by the six maternal and gap transcription factors that initiate anterior-posterior patterning. We find that these sequence-specific DNA binding proteins bind with quantitatively different specificities to highly overlapping sets of several thousand genomic regions in blastoderm embryos. Specific high- and moderate-affinity in vitro recognition sequences for each factor are enriched in bound regions. This enrichment, however, is not sufficient to explain the pattern of binding in vivo and varies in a context-dependent manner, demonstrating that higher-order rules must govern targeting of transcription factors. The more highly bound regions include all of the over 40 well-characterized enhancers known to respond to these factors as well as several hundred putative new cis-regulatory modules clustered near developmental regulators and other genes with patterned expression at this stage of embryogenesis. The new targets include most of the microRNAs (miRNAs) transcribed in the blastoderm, as well as all major zygotically transcribed dorsal-ventral patterning genes, whose expression we show to be quantitatively modulated by anterior-posterior factors. In addition to these highly bound regions, there are several thousand regions that are reproducibly bound at lower levels. However, these poorly bound regions are, collectively, far more distant from genes transcribed in the blastoderm than highly bound regions; are preferentially found in protein-coding sequences; and are less conserved than highly bound regions. Together these observations suggest that many of these poorly bound regions are not involved in early-embryonic transcriptional regulation, and a significant proportion may be nonfunctional. Surprisingly, for five of the six factors, their recognition sites are not unambiguously more constrained evolutionarily than the immediate flanking DNA, even in more highly bound and presumably functional regions, indicating that comparative DNA sequence analysis is limited in its ability to identify functional transcription factor targets.
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