Abstract
The observed massive end of the galaxy stellar mass function is steeper than its predicted dark matter halo counterpart in the standard Λ cold dark matter paradigm. In this paper, we ...investigate the impact of active galactic nuclei (AGN) feedback on star formation in massive galaxies. We isolate the impact of AGN by comparing two simulations from the HORIZON suite, which are identical except that one also includes supermassive black holes (SMBHs) and related feedback models. This allows us to cross-identify individual galaxies between simulations and quantify the effect of AGN feedback on their properties, including stellar mass and gas outflows. We find that massive galaxies (M
* ≥ 1011 M⊙) are quenched by AGN feedback to the extent that their stellar masses decrease by up to 80 per cent at z = 0. SMBHs affect their host halo through a combination of outflows that reduce their baryonic mass, particularly for galaxies in the mass range 109 M⊙ ≤ M
* ≤ 1011 M⊙, and a disruption of central gas inflows, which limits in situ star formation. As a result, net gas inflows on to massive galaxies, M
* ≥ 1011 M⊙, drop by up to 70 per cent. We measure a redshift evolution in the stellar mass ratio of twin galaxies with and without AGN feedback, with galaxies of a given stellar mass showing stronger signs of quenching earlier on. This evolution is driven by a progressive flattening of the M
SMBH–M
* relation with redshift, particularly for galaxies with M
* ≤ 1010 M⊙. M
SMBH/M
* ratios decrease over time, as falling average gas densities in galaxies curb SMBH growth.
Accurate cosmology from upcoming weak lensing surveys relies on knowledge of the total matter power spectrum at per cent level at scales k < 10 h Mpc^−1, for which modelling the impact of baryonic ...physics is crucial. We compare measurements of the total matter power spectrum from the Horizon cosmological hydrodynamical simulations: a dark-matter-only run, one with full baryonic physics, and another lacking active galactic nucleus (AGN) feedback. Baryons cause a suppression of power at k ≃ 10 h Mpc^−1 of |${\lt}15{{\ \rm per\ cent}}$| at |$z$| = 0, and an enhancement of a factor of a few at smaller scales due to the more efficient cooling and star formation. The results are sensitive to the presence of the highest mass haloes in the simulation and the distribution of dark matter is also impacted up to a few per cent. The redshift evolution of the effect is non-monotonic throughout |$z$| = 0−5 due to an interplay between AGN feedback and gas pressure, and the growth of structure. We investigate the effectiveness of an analytic ‘baryonic correction model’ in describing our results. We require a different redshift evolution and propose an alternative fitting function with four free parameters that reproduces our results within |$5{{\ \rm per\ cent}}$|. Compared to other simulations, we find the impact of baryonic processes on the total matter power spectrum to be smaller at |$z$| = 0. Correspondingly, our results suggest that AGN feedback is not strong enough in the simulation. Total matter power spectra from the Horizon simulations are made publicly available at https://www.horizon-simulation.org/catalogues.html.
The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A ...secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC tumors, as has been reported for other tumor types. We used five PDAC tumorgraft models that retain specific characteristics of tumors of origin to evaluate the antitumor efficacy of JQ1. Tumor-bearing mice were treated with JQ1 (50 mg/kg daily for 21 or 28 days). Expression analyses were performed with tumors harvested from host mice after treatment with JQ1 or vehicle control. An nCounter PanCancer Pathways Panel (NanoString Technologies) of 230 cancer-related genes was used to identify gene products affected by JQ1. Quantitative RT-PCR, immunohistochemistry and immunoblots were carried out to confirm that changes in RNA expression reflected changes in protein expression. JQ1 inhibited the growth of all five tumorgraft models (P<0.05), each of which harbors a KRAS mutation; but induced no consistent change in expression of c-Myc protein. Expression profiling identified CDC25B, a regulator of cell cycle progression, as one of the three RNA species (TIMP3, LMO2 and CDC25B) downregulated by JQ1 (P<0.05). Inhibition of tumor progression was more closely related to decreased expression of nuclear CDC25B than to changes in c-Myc expression. JQ1 and other agents that inhibit the function of proteins with bromodomains merit further investigation for treating PDAC tumors. Work is ongoing in our laboratory to identify effective drug combinations that include JQ1.
The ability to control nanostructure shape and dimensions presents opportunities to design materials in which their macroscopic properties are dependent upon the nature of the nanoparticle. Although ...particle morphology has been recognized as a crucial parameter, the exploitation of the potential shape-dependent properties has, to date, been limited. Herein, we demonstrate that nanoparticle shape is a critical consideration in the determination of nanocomposite hydrogel properties. Using translationally relevant calcium-alginate hydrogels, we show that the use of poly(L-lactide)-based nanoparticles with platelet morphology as an adhesive results in a significant enhancement of adhesion over nanoparticle glues comprised of spherical or cylindrical micelles. Furthermore, gel nanocomposites containing platelets showed an enhanced resistance to breaking under strain compared to their spherical and cylindrical counterparts. This study opens the doors to a change in direction in the field of gel nanocomposites, where nanoparticle shape plays an important role in tuning mechanical properties.
The association of obesity susceptibility variants with change in body mass index (BMI) across the life course is not well understood.
In ancestry-stratified models of 5962 European American (EA), ...2080 African American (AA) and 1582 Hispanic American (HA) individuals from the National Longitudinal Study of Adolescent to Adult Health (Add Health), we examined associations between 34 obesity single-nucleotide polymorphisms (SNPs) with per year change in BMI, measured by the slope from a growth-curve analysis of two or more BMI measurements between adolescence and young adulthood. For SNPs nominally associated with BMI change (P<0.05), we interrogated age differences within data collection Wave and time differences between age categories that overlapped between Waves.
We found SNPs in/near FTO, MC4R, MTCH2, TFAP2B, SEC16B and TMEM18 were significantly associated (P<0.0015≈0.05/34) with BMI change in EA and the ancestry-combined meta-analysis. rs9939609 in FTO met genome-wide significance at P<5e-08 in the EA and ancestry-combined analysis, respectively Beta(se)=0.025(0.004);Beta(se)=0.021(0.003). No SNPs were significant after Bonferroni correction in AA or HA, although five SNPs in AA and four SNPs in HA were nominally significant (P<0.05). In EA and the ancestry-combined meta-analysis, rs3817334 near MTCH2 showed larger effects in younger respondents, whereas rs987237 near TFAP2B, showed larger effects in older respondents across all Waves. Differences in effect estimates across time for MTCH2 and TFAP2B are suggestive of either era or cohort effects.
The observed association between variants in/near FTO, MC4R, MTCH2, TFAP2B, SEC16B and TMEM18 with change in BMI from adolescence to young adulthood suggest that the genetic effect of BMI loci varies over time in a complex manner, highlighting the importance of investigating loci influencing obesity risk across the life course.
We present our parameterizations of the log(NeIIIlambda3869/OIIlambda3727) (Ne3O2) and log(OIIIlambda5007/OIIlambda3727) (O3O2) ratios as diagnostics of ionization parameter in star-forming galaxies. ...Our calibrations are based on the Starburst99/Mappings III photoionization models, which extend up to the extremely high values of ionization parameter found in high-redshift galaxies. While similar calibrations have been presented previously for O3O2, this is the first such calibration of Ne3O2. We illustrate the tight correlation between these two ratios for star-forming galaxies and discuss the underlying physics that dictates their very similar evolution. Based on this work, we propose the Ne3O2 ratio as a new and useful diagnostic of ionization parameter for star-forming galaxies. Given the Ne3O2 ratio's relative insensitivity to reddening, this ratio is particularly valuable for use with galaxies that have uncertain amounts of extinction. The short wavelengths of the Ne3O2 ratio can also be applied out to very high redshifts, extending studies of galaxies' ionization parameters out to z ~ 1.6 with optical spectroscopy and z ~ 5.2 with ground-based near-infrared spectra.
Background Despite South Africa’s substantial reduction in vertical HIV transmission (VHT), national paediatric HIV elimination is not yet attained. National and Western Cape Province (WC) HIV ...guidelines recommend enhanced postnatal prophylaxis for infants at high risk for VHT, identified in the WC 2015/2016 guidelines by any single high-risk criterion (maternal antiretroviral therapy (ART)
Cisplatin and paclitaxel are active in triple-negative breast cancer (TNBC). Despite different mechanisms of action, effective predictive biomarkers to preferentially inform drug selection have not ...been identified. The homologous recombination deficiency (HRD) assay (Myriad Genetics, Inc.) detects impaired double-strand DNA break repair and may identify patients with BRCA1/2-proficient tumors that are sensitive to DNA-targeting therapy. The primary objective of TBCRC 030 was to detect an association of HRD with pathologic response residual cancer burden (RCB)-0/1 to single-agent cisplatin or paclitaxel.
This prospective phase II study enrolled patients with germline BRCA1/2 wild-type/unknown stage I–III TNBC in a 12-week randomized study of preoperative cisplatin or paclitaxel. The HRD assay was carried out on baseline tissue; positive HRD was defined as a score ≥33. Crossover to an alternative chemotherapy was offered if there was inadequate response.
One hundred and thirty-nine patients were evaluable for response, including 88 (63.3%) who had surgery at 12 weeks and 51 (36.7%) who crossed over to an alternative provider-selected preoperative chemotherapy regimen due to inadequate clinical response. HRD results were available for 104 tumors (74.8%) and 74 (71.1%) were HRD positive. The RCB-0/1 rate was 26.4% with cisplatin and 22.3% with paclitaxel. No significant association was observed between HRD score and RCB response to either cisplatin odds ratio (OR) for RCB-0/1 if HRD positive 2.22 (95% CI: 0.39–23.68) or paclitaxel OR for RCB-0/1 if HRD positive 0.90 (95% CI: 0.19–4.95). There was no evidence of an interaction between HRD and pathologic response to chemotherapy.
In this prospective preoperative trial in TNBC, HRD was not predictive of pathologic response. Tumors were similarly responsive to preoperative paclitaxel or cisplatin chemotherapy.
•This trial prospectively evaluated the predictive capacity of the HRD biomarker for pathologic response in early TNBC.•Pathologic responses to preoperative cisplatin or taxane monotherapy in germline BRCA1/2 wild-type TNBC were similar.•HRD score was not predictive of pathologic response to either cisplatin or paclitaxel chemotherapy.•HRD testing cannot be recommended as a tool to select chemotherapy agents in the management of early-stage TNBC.
The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly ...expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED50<200 nM), alone and cocultured with bone marrow stromal cells (BMSCs) or osteoclasts (OC). SINEs trigger nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins followed by growth arrest and apoptosis in MM cells. They further block c-myc, Mcl-1, and nuclear factor κB (NF-κB) activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NF-κB and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM.
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