Aggresome formation promotes ASK1/JNK signaling activation and stemness maintenance in ovarian cancer.

Aggresomes are the product of misfolded protein aggregation, and the presence of aggresomes has been correlated with poor prognosis in cancer patients. However, the exact role of aggresomes in tumorigenesis and cancer progression remains largely unknown. Herein, the multiomics screening reveal that OTUD1 protein plays an important role in retaining ovarian cancer stem cell (OCSC) properties. Mechanistically, the elevated OTUD1 protein levels lead to the formation of OTUD1-based cytoplasmic aggresomes, which is mediated by a short peptide located in the intrinsically disordered OTUD1 N-terminal region. Furthermore, OTUD1-based aggresomes recruit ASK1 via protein-protein interactions, which in turn stabilize ASK1 in a deubiquitinase-independent manner and activate the downstream JNK signaling pathway for OCSC maintenance. Notably, the disruption of OTUD1-based aggresomes or treatment with ASK1/JNK inhibitors, including ibrutinib, an FDA-approved drug that was recently identified as an MKK7 inhibitor, effectively reduced OCSC stemness (OSCS) of OTUD1high ovarian cancer cells. In summary, our work suggests that aggresome formation in tumor cells could function as a signaling hub and that aggresome-based therapy has translational potential for patients with OTUD1high ovarian cancer.

KDM5C-Mediated Recruitment of BRD4 to Chromatin Regulates Enhancer Activation and BET Inhibitor Sensitivity.

The BET family member BRD4 is a bromodomain-containing protein that plays a vital role in driving oncogene expression. Given their pivotal role in regulating oncogenic networks in various cancer types, BET inhibitors (BETi) have been developed, but the clinical application has been impeded by dose-limiting toxicity and resistance. Understanding the mechanisms of BRD4 activity and identifying predictive biomarkers could facilitate the successful clinical use of BETis. Herein, we show that KDM5C and BRD4 cooperate to sustain tumor cell growth. Mechanistically, KDM5C interacted with BRD4 and stimulated BRD4 enhancer recruitment. Moreover, binding of the BRD4 C-terminus to KDM5C stimulated the H3K4 demethylase activity of KDM5C. The abundance of both KDM5C-associated BRD4 and H3K4me1/3 determined the transcriptional activation of many oncogenes. Notably, depletion or pharmacologic degradation of KDM5C dramatically reduced BRD4 chromatin enrichment and significantly increased BETi efficacy across multiple cancer types in both tumor cell lines and patient-derived organoid models. Furthermore, targeting KDM5C in combination with BETi suppressed tumor growth in vivo in a xenograft mouse model. Collectively, this work reveals a KDM5C-mediated mechanism by which BRD4 regulates transcription, providing a rationale for incorporating BETi into combination therapies with KDM5C inhibitors to enhance treatment efficacy. SIGNIFICANCE: BRD4 is recruited to enhancers in a bromodomain-independent manner by binding KDM5C and stimulates KDM5C H3K4 demethylase activity, leading to synergistic effects of BET and KDM5C inhibitor combinations in cancer.

Viral vector-mediated transgene delivery with novel recombinase systems for targeting neuronal populations defined by multiple features.

A comprehensive understanding of neuronal diversity and connectivity is essential for understanding the anatomical and cellular mechanisms that underlie functional contributions. With the advent of single-cell analysis, growing information regarding molecular profiles leads to the identification of more heterogeneous cell types. Therefore, the need for additional orthogonal recombinase systems is increasingly apparent, as heterogeneous tissues can be further partitioned into increasing numbers of specific cell types defined by multiple features. Critically, new recombinase systems should work together with pre-existing systems without cross-reactivity in vivo. Here, we introduce novel site-specific recombinase systems based on ΦC31 bacteriophage recombinase for labeling multiple cell types simultaneously and a novel viral strategy for versatile and robust intersectional expression of any transgene. Together, our system will help researchers specifically target different cell types with multiple features in the same animal.

Momentum and thickness dependent excitonic and plasmonic properties of 2D h-BN and MoS2 restored from supercell calculations.

The comprehension and manipulation of the propagation characteristics of elementary excitations, such as excitons and plasmons, play a crucial role in tailoring the optical properties of low-dimensional materials. To this end, investigations into the momentum (q) dispersions of excitons and plasmons in confined geometry are required fundamentally. Due to advancements in momentum-resolved spectroscopy techniques, research on the q-dependent excitons or plasmons in low-dimensional materials is beginning to emerge. However, previous simulations of low-dimensional systems are adversely affected by the artificial vacuum spacing employed in the supercell approximation. Furthermore, the significance of layer thickness in determining the excitonic and plasmonic characteristics of two-dimensional (2D) materials remains largely unexplored in the context of finite q. Therefore, an extensive investigation into the momentum and thickness dependent behaviours of both excitons and plasmons in 2D materials, which are free of the influence of vacuum spacing, is lacking at present. In this article, we develop a restoration procedure to eliminate the influence of vacuum spacing, and obtain a comprehensive picture of momentum and layer thickness dependent excitonic and plasmonic properties of 2D hexagonal boron nitride (h-BN) and molybdenum disulphide (MoS2). Our restored simulations are not only found to be in excellent agreement with available experiments, but also elucidate the roles of momentum and layer thickness in the excitonic and plasmonic properties of 2D h-BN and MoS2. We further unveil the dimensionality effect on the dispersion characteristics of excitons and plasmons in h-BN and MoS2. Our contribution will hopefully promote the understanding of the elementary excitations propagating in low-dimensional materials and pave the way for next-generation nanophotonic and optoelectronic devices.

A bacteria-derived tetramerized protein ameliorates nonalcoholic steatohepatitis in mice via binding and relocating acetyl-coA carboxylase.

Increased de novo lipogenesis (DNL) is a major feature of nonalcoholic steatohepatitis (NASH). None of the drugs targeting the catalytic activity of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in the DNL process, have been approved by the FDA. Whether cytosolic ACC1 can be regulated spatially remains to be explored. Herein, we find that streptavidin (SA), which is a bacterium-derived tetrameric protein, forms cytosolic condensates and efficiently induces a spatial re-localization of ACC1 in liver cells, concomitant with inhibited lipid accumulation. Both SA tetrameric structure and multivalent protein interaction are required for condensate formation. Interestingly, the condensates are further characterized as gel-like membraneless organelle (SAGMO) and significantly restrict the cytosolic dispersion of ACC1 and fatty acid synthase. Notably, AAV-mediated delivery of SA partially blocks mouse liver DNL and ameliorates NASH without eliciting hypertriglyceridemia. In summary, our study shows that insulating lipogenesis-related proteins by SAGMO might be effective for NASH treatment.

Assessment of HCHO in Beijing during 2009 to 2020 using satellite observation and numerical model: Spatial characteristic and impact factor.

Formaldehyde (HCHO) is an air pollutant that has a detrimental effect on human health and atmospheric environment. Until now, satellite observation has been increasingly a valuable source for monitoring the unconventional atmospheric pollutants due to the limited availability of ground-based HCHO data. Here, we used Ozone Monitoring Instrument (OMI) and the weather research and forecasting with chemistry (WRF-Chem) model to synergistically analyze the spatiotemporal variations of tropospheric HCHO in Beijing during 2009-2020, and the response of O3 to HCHO and NO2 in hotspots. We also discuss the multiple factors influencing the variation of HCHO and identify potential source area. The results indicated that HCHO column concentration is higher in eastern Beijing, and peaking in 2018 (16.68 × 1015 mol/cm2). O3 shows a good response to HCHO, with higher HCHO and NO2 photolysis leading to O3 increase in summer. In winter, decreasing HCHO and increasing NO2 inhibits the formation of O3. Transportation emissions contributed the most to HCHO, followed by the industrial sector, while residential sources have long-term effects. Isoprene produced by plants is one of the main sources of HCHO, whereas meteorological conditions can affect production efficiency. Biomass burning contributes less. Moreover, HCHO in Beijing is affected by the combined effects of local emission and external transport, and Hebei is the potential source area. This study reveals HCHO has a great accumulation potential in cities and highlights the dominant role of anthropogenic emissions, but also need to consider the influence of natural factors and regional transport.

Analysis of atmospheric SO2 in Sichuan-Chongqing region based on OMI data.

The Sichuan-Chongqing region is the leader and growth pole of economic development in western China. With the rapid development of economy and unique geographical environment, high concentration of sulfur dioxide air pollution has existed for a long time in Sichuan-Chongqing area. Based on 10 years of remote sensing data, this paper studies the temporal and spatial distribution characteristics, stability, and influencing factors of sulfur dioxide in this area. Based on potential sources, the impact of surrounding areas on sulfur dioxide in Sichuan and Chongqing is analyzed. The results shows that the spatial distribution of sulfur dioxide in the Sichuan-Chongqing region is higher in the southeast and lower in the west. The Midwest region has low fluctuation and good stability. The time distribution shows obvious seasonal regularity. The concentration of sulfur dioxide is affected by socio-economic factors and natural factors. In this study, it is found that the distribution of sulfur dioxide is closely related to PM2.5, which provides an important reference for the comprehensive management of air pollution. The OMI data effectively reflects the distribution and change of atmospheric sulfur dioxide in the Sichuan-Chongqing region, and provides certain ideas for air pollution control in the Sichuan-Chongqing region and other regions in China.

Deficiency of the X-inactivation escaping gene KDM5C in clear cell renal cell carcinoma promotes tumorigenicity by reprogramming glycogen metabolism and inhibiting ferroptosis.

Background: Clear cell renal cell carcinoma (ccRCC) is characterized by glycogen-laden, unexplained male predominance, and frequent mutations in the Von Hippel-Lindau (VHL) gene and histone modifier genes. Besides, poor survival rates of ccRCC patients seem to be associated with up-regulation of the pentose phosphate pathway (PPP). However, the mechanism underlying these features remains unclear. Methods: Whole exome sequencing was used to identify the gene mutation that implicated in the rewired glucose metabolism. RNA-seq analyses were performed to evaluate the function of KDM5C in ccRCC. Furthermore, heavy isotope tracer analysis and metabolites quantification assays were used to study how KDM5C affects intracellular metabolic flux. To provide more in vivo evidence, we generated the Kdm5c-/- mice by CRISPR-Cas9 mediated gene knockout and performed the xenografts with KDM5C overexpressing or depleted cell lines. Results: A histone demethylase gene KDM5C, which can escape from X-inactivation and is predominantly mutated in male ccRCC patients, was identified to harbor the frameshift mutation in the ccRCC cell line with the highest glycogen level, while the restoration of KDM5C significantly reduced the glycogen level. Transcriptome and metabolomic analysis linked KDM5C to metabolism-related biological processes. KDM5C specifically regulated the expression of several hypoxia-inducible factor (HIF)-related genes and Glucose-6-phosphate dehydrogenase (G6PD) that were involved in glycogenesis/glycogenolysis and PPP, respectively, mainly through the histone demethylase activity of KDM5C. Depletion of KDM5C increased the production of glycogen, which was then directed to glycogenolysis to generate glucose-6-phosphate (G6P) and subsequently PPP to produce nicotinamide adenine dinucleotide phosphate hydride (NADPH) and glutathione (GSH), thus conferring cells resistance to reactive oxygen species (ROS) and ferroptosis. KDM5C re-expression suppressed the glucose flux through PPP and re-sensitized cancer cells to ferroptosis. Notably, Kdm5c-knockout mice kidney tissues exhibited elevated glycogen level, reduced lipid peroxidation and displayed a transformation of renal cysts into hyperplastic lesions, implying a cancer-protective benefit of ferroptosis. Furthermore, KDM5C deficiency predicted the poor prognosis, and clinically relevant KDM5C mutants failed to suppress glycogen accumulation and promoted ferroptosis as wild type. Conclusion: This work revealed that a histone modifier gene inactive mutation reprogramed glycogen metabolism and helped to explain the long-standing puzzle of male predominance in human cancer. In addition, our findings may suggest the therapeutic value of targeting glycogen metabolism in ccRCC.

Absorbable aerosols based on OMI data: a case study in three provinces of Northeast China.

In order to assess the status of aerosol pollution in three selected Northeast Provinces of China, Ozone Monitoring Instrument/Aura Near UV Aerosol Optical Depth and Single Scattering Albedo 1-orbit L2 Swath 13 × 24km V003 (OMAERUV) daily product data was used to evaluate (1) the ultraviolet aerosol index (UVAI) temporal and spatial distribution of the three Northeast Provinces from 2009 to 2018; (2) the potential pollution source areas of provincial capital cities; and (3) future trend changes. Furthermore, the influencing factors were also analyzed and are discussed herein. The results show that the UVAI in the Northeast Provinces exhibit an overall increasing trend, with an average annual increase rate of 2.99%. Seasonally, the UVAI increasing trend in winter is higher than in spring which in turn is higher than autumn. And summer has the least increasing trend. In addition, the external source of absorbent aerosol transmission is mainly in the southwest. Moreover, the overall UVAI remains relatively constant in the central part of the region, and increases slightly and significantly in the south and north directions. In general, spring, autumn, and winter all exhibit increasing trends in varying degrees. The difference between the forecasted and actual UVAI values in the Northeast Provinces does not exceed 10%; thus, the forecasting reliability is good. Also, UVAI has different degrees of correlation with natural factors, such as precipitation and temperature. With respect to social factors, UVAI and population density (a social factor) are positively correlated in 98.2% of the study area, demonstrating that there is a strong positive correlation between UVAI and smoke and dust emissions.

[Analysis of Ultraviolet Aerosol Index in Guangdong-Hong Kong-Macao Greater Bay Area].

This study examines the current aerosol pollution scenario in the Guangdong-Hong Kong-Macao (GHM) Greater Bay Area, based on OMAERUV daily data products, to define the spatial and temporal distribution from 2008 to 2019 and predict variation trends of the ultraviolet aerosol index (UVAI). Changes and potential source areas were analyzed, and their influencing factors were identified. The annual time series of UVAI in the GHM Greater Bay Area showed a downward trend, with an average annual decrease of 2.3%; the monthly time series showed an inverted "V" shape beginning in spring, with the highest seasonal UVAI occurring in spring, followed by winter and autumn. Summer exhibited the lowest UVAI; spatially, the central region has consistently exhibited high values, with an average annual UVAI of 0.35 calculated over 12 years. The distribution of UVAI in the time series is mainly sustainable, and 82.69% of the area will show a downward trend in the future. The main potential sources from beyond the study area are carbon sources and marine biological sources produced by eastern industry; the main potential sources of UVAI are carbon and biomass sources in spring, biomass aerosol sources in summer, and carbon sources in autumn. It accounts for the largest proportion, and aerosol sources of sand and dust in winter have increased. Through correlation analysis, aerosols and PM2.5 were found to be interdependent. Industrial production activities are an important contributor of atmospheric aerosols, and precipitation can reduce the atmosphere. Due to the aerosol content produced by industrial production, secondary industrial activities will accelerate the formation of aerosols when the temperature rises.

Polypseudorotaxane functionalized magnetic nanoparticles as a dual responsive carrier for roxithromycin delivery.

A magnetic-pH dual responsive drug delivery system was prepared for antibacterial therapy to reduce the side effects on nonpathological cells or tissues. Iron oxide (Fe3O4) core was surface-functionalized with silane coupling agents to link ß­cyclodextrin (ß-CD) (CDMNP), and a polypseudorotaxanes shell where polyethyleneglycol chains threaded much CD molecules was further prepared on the magnetic Fe3O4 core (CDMNP-PEG-CD) to enhance loading capacity of roxithromycin (ROX). CDMNP-PEG-CD with a hydrodynamic diameter of ~168 nm was cytocompatible, superparamagnetic, magnetic-responsive and stable for 180 min of storage. No significant interaction with serum albumin was shown for the nanocomposites. The in vitro release from ROX-loaded CDMNP-PEG-CD nanocomposites was about 76% of total drug within 30 min at pH 1.0, 1.6-fold of that at pH 7.4 and 2-fold of that at pH 8.0, presenting pH-responsive drug release behaviors. The nanocomposites showed positive antibacterial activity against both E. coli and S. aureus based on an agar diffusion method. The antibacterial activity of the nanocomposites was more sensitive against E. coli than S. aureus, and the inhibition halo against E. coli was 85% more than that of Fe3O4. CDMNP-PEG-CD nanocomposites allowed for the localization and fast concentration of hydrophobic drugs, providing a broad potential range of therapeutic applications.

Cell-loaded carboxymethylcellulose microspheres sustain viability and proliferation of ATDC5 cells.

Cell-loaded carboxymethylcellulose (CMC) microspheres were generated via a flow focusing microfluidic device, with a final aim to obtain viable ATDC5 aggregates with sustained proliferation capacity. We synthesized various CMC with phenolic groups (CMC-Ph) and demonstrated that high CMC-Ph molecular weight, high CMC-Ph concentration (>0.8 g/ml) or long culturing period had obvious inhibition effect on ATDC5 proliferation, but low horseradish peroxidase concentration (HRP, <0.4 mg/ml) did not. CMC-Ph gels being obtained through HRP/H2O2 reaction showed an enhancing strength and decreasing break stain as the molecular weight of CMC-Ph increased, along with a decreasing gelation time. The microfluidics-based synthesis of cell-loaded microspheres with great design flexibilities was achieved using CMC-Ph with weight-average molecular weight of 1.0 × 105. ATDC5 cells were viable up to 41 days of culture and proliferated gradually with increasing culture time. High cell density in CMC-Ph solution and high fetal bovine serum concentration in culture medium were prone to forming cell aggregates. Isolated cells from the microspheres showed the typical spherical morphology of undifferentiated ATDC5. Therefore, CMC-Ph microspheres might be used as cell aggregates depots to study cell-cell or cell-biomaterials functions for tissue engineering applications.