ABSTRACT
Feedback driven by jets from active galactic nuclei is believed to be responsible for reducing cooling flows in cool-core galaxy clusters. We use simulations to model feedback from ...hydrodynamic jets in isolated haloes. While the jet propagation converges only after the diameter of the jet is well resolved, reliable predictions about the effects these jets have on the cooling time distribution function only require resolutions sufficient to keep the jet-inflated cavities stable. Comparing different model variations, as well as an independent jet model using a different hydrodynamics code, we show that the dominant uncertainties are the choices of jet properties within a given model. Independent of implementation, we find that light, thermal jets with low momentum flux tend to delay the onset of a cooling flow more efficiently on a 50 Myr time-scale than heavy, kinetic jets. The delay of the cooling flow originates from a displacement and boost in entropy of the central gas. If the jet kinetic luminosity depends on accretion rate, collimated, light, hydrodynamic jets are able to reduce cooling flows in haloes, without a need for jet precession or wide opening angles. Comparing the jet feedback with a ‘kinetic wind’ implementation shows that equal amounts of star formation rate reduction can be achieved by different interactions with the halo gas: the jet has a larger effect on the hot halo gas while leaving the denser, star-forming phase in place, while the wind acts more locally on the star-forming phase, which manifests itself in different time-variability properties.
Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, ...consisting of AR
luminal tumor cells and AR
neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR
luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.
Manganese (Mn) is an essential element for humans, but exposure to high levels has been associated with adverse developmental outcomes. Early epidemiological studies evaluating the effect of Mn on ...fetal growth are inconsistent.
We investigated the association between maternal urinary Mn during pregnancy and the risk of low birth weight (LBW). Mn concentrations in maternal urine samples collected before delivery were measured in 816 subjects (204 LBW cases and 612 matched controls) recruited between 2012 and 2014 in Hubei Province, China.
The median Mn concentration in maternal urine was 0.69 μg/g creatinine. Compared to the medium tertile of Mn levels, an increased risk of LBW was observed for the lowest tertile (≤0.30 μg/g creatinine) adjusted odds ratio (OR) = 1.28; 95 % confidence interval (CI) = 0.67, 2.45, and a significantly increased risk of LBW was observed for the highest tertile (≥1.16 μg/g creatinine) adjusted OR = 2.04; 95 % CI = 1.12, 3.72. A curvilinear relationship between maternal urinary Mn and risk of LBW was observed, showing that the concentration at 0.43 μg/g creatinine was the point of inflection. Similar associations were observed among the mothers with female infants and among the younger mothers < 28 years old. However, among the mothers with male infants or the older mothers ≥ 28 years old, only higher levels of Mn were positively associated with LBW.
Lower or higher levels of maternal urinary Mn are associated with LBW, though only the association of LBW risk and higher levels of Mn was statistically significant. The findings also show that the associations may vary by maternal age and infant sex, but require confirmation in other populations.
Proximity labeling (PL) via biotinylation coupled with mass spectrometry (MS) captures spatial proteomes in cells. Large-scale processing requires a workflow minimizing hands-on time and enhancing ...quantitative reproducibility. We introduced a scalable PL pipeline integrating automated enrichment of biotinylated proteins in a 96-well plate format. Combining this with optimized quantitative MS based on data-independent acquisition (DIA), we increased sample throughput and improved protein identification and quantification reproducibility. We applied this pipeline to delineate subcellular proteomes across various compartments. Using the 5HT
2A
serotonin receptor as a model, we studied temporal changes of proximal interaction networks induced by receptor activation. In addition, we modified the pipeline for reduced sample input to accommodate CRISPR-based gene knockout, assessing dynamics of the 5HT
2A
network in response to perturbation of selected interactors. This PL approach is universally applicable to PL proteomics using biotinylation-based PL enzymes, enhancing throughput and reproducibility of standard protocols.
Synopsis
A proximity proteomics pipeline is developed for mapping subcellular proteomes and characterizing spatiotemporally resolved proximal interaction networks, ensuring high throughput and reproducible quantification.
This scalable proximity labeling pipeline integrates automated enrichment of biotinylated proteins with DIA-MS, enhancing the feasibility of large-scale proximity proteomic studies with improved sample throughput and reproducibility.
It effectively identifies location-specific proteins in various cellular compartments, highlighting its versatility in spatial proteomics applications.
It enables the delineation of activity-dependent proximal interaction networks associated with the 5HT
2A
receptor, capturing both transient and sustained interactions.
A modified pipeline for reduced sample input is applied to the analysis of the 5HT
2A
network dynamics in response to perturbation of selected interactors.
A proximity proteomics pipeline is developed for mapping subcellular proteomes and characterizing spatiotemporally resolved proximal interaction networks, ensuring improved throughput and reproducible quantification.
Abstract
Elucidating how individual mutations affect the protein energy landscape is crucial for understanding how proteins evolve. However, predicting mutational effects remains challenging because ...of epistasis—the nonadditive interactions between mutations. Here, we investigate the biophysical mechanism of strain-specific epistasis in the nonstructural protein 1 (NS1) of influenza A viruses (IAVs). We integrate structural, kinetic, thermodynamic, and conformational dynamics analyses of four NS1s of influenza strains that emerged between 1918 and 2004. Although functionally near-neutral, strain-specific NS1 mutations exhibit long-range epistatic interactions with residues at the p85β-binding interface. We reveal that strain-specific mutations reshaped the NS1 energy landscape during evolution. Using NMR spin dynamics, we find that the strain-specific mutations altered the conformational dynamics of the hidden network of tightly packed residues, underlying the evolution of long-range epistasis. This work shows how near-neutral mutations silently alter the biophysical energy landscapes, resulting in diverse background effects during molecular evolution.
Objectives. Diabetic wound inflammation deficiencies lead to ulcer development and eventual amputation and disability. Our previous research demonstrates that myeloid-derived suppressor cells (MDSCs) ...accumulate during inflammation and promote chronic wound healing via the regulation of Kruppel-like factor 4 (KLF4). In this study, we aimed to investigate the potential roles of MDSCs and KLF4 in diabetic wound healing. Methods. An ob/ob mouse pressure ulcer (PU) model was used to evaluate the process of wound healing. The expression levels of KLF4 and IL-17A were measured by real-time PCR, and the population of MDSCs and Th17 cells was measured by flow cytometry. The levels of cytokines were determined by an immunosuppression assay. Results. KLF4 deficiency in the diabetic PU model resulted in decreased accumulation of MDSCs, increased expansion of Th17 cells, and significantly delayed wound healing. Conversely, KLF4 activation by APTO-253 accelerated wound healing accompanied by increased MDSC populations and decreased numbers of Th17 cells. MDSCs have been proven to mediate Th17 differentiation via cytokines, and our in vitro data showed that elevated KLF4 expression in MDSCs resulted in reduced Th17 cell numbers and, thus, decreased levels of cytokines indispensable for Th17 differentiation. Conclusions. Our study revealed a previously unreported function of KLF4-regulated MDSCs in diabetic wound healing and identified APTO-253 as a potential agent to improve the healing of pressure ulcers.
Microring modulators (MRMs) with CMOS electronics enable compact low power transmitter solutions for 400G Ethernet and co-packaged optical transceivers. In this article, we present a 3-D-integrated ...112-Gb/s pulse amplitude modulation (PAM)-4 optical transmitter (OTX) using silicon photonic MRM, on-chip laser, and co-packaged 28-nm CMOS driver. The 3-<inline-formula> <tex-math notation="LaTeX">V_{\mathrm {pp}} </tex-math></inline-formula> driver includes a lookup table (LUT)-based PAM-4 nonlinear equalizer to address static and dynamic MRM nonlinearities. An integrated thermal control method that is insensitive to input power fluctuations is proposed to compensate for the temperature sensitivity of MRMs. PAM-4 measurement results of our OTX at 112 Gb/s show that transmitter dispersion eye closure quaternary (TDECQ) < 1.5 dB is achieved from 28 °C to 55 °C with 7.4-pJ/bit energy efficiency including on-chip laser.
Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for ...serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. However, growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highly conserved ATP-binding subunits of DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD), we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models.
Background
Hepatocellular carcinoma (HCC) is one of the deadliest malignancies worldwide due to the lack of effective treatments. Chemoprevention in high-risk patients is a promising, alternative ...strategy. In this study, pioglitazone was investigated for its ability to prevent hepatocarcinogenesis in two rodent models of cirrhosis.
Methods
In the first model, male Wistar rats were given repeated, low-dose injections of diethylnitrosamine (DEN) to accurately recapitulate the progression of fibrosis to cirrhosis and HCC. In the second model, a single dose of DEN was administered to male C57Bl/6 pups at day fifteen followed by administration of a choline-deficient, L-amino acid defined, high-fat diet (CDAHFD) at week six for 24 weeks. Pioglitazone treatment started at the first signs of fibrosis in both models.
Results
Pioglitazone effectively reduced fibrosis progression and HCC development in both models. Gross tumor nodules were significantly reduced after pioglitazone treatment (7.4 ± 1.6 vs. 16.6 ± 2.6 in the rat DEN model and 5.86 ± 1.82 vs. 13.2 ± 1.25 in the mouse DEN+CDAHFD model). In both models, pioglitazone reduced the activation of mitogen-activated protein kinase (MAPK) and upregulated the hepato-protective AMP-activated protein kinase (AMPK) pathway via increasing circulating adiponectin production.
Conclusion
Pioglitazone is an effective agent for chemoprevention in rodents and could be repurposed as a multi-targeted drug for delaying liver fibrosis and hepatocarcinogenesis.
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