Elemental geochemical evidence for the river-derived sources of trace metals in surface sediments from Hangzhou Bay, East China Sea.

Coastal estuaries are often heavily subject to riverine influences by the inputs of sediment from terrestrial sources. Hangzhou Bay (HZB) is threatened by the riverine derived trace metals from two large rivers of Qiantang River (QTR) and Yangtze River (YZR). However, previous studies mainly focused on the incidental transport from the largest river in China (YZR) and failed to simultaneously evaluate the contributions of these two rivers, especially the directly flowing river of QTR, by their trace elemental geochemical composition and distribution. Herein, a comprehensive study identified the river-derived sources of multiple trace metals in surface sediments which transported from both of the rivers. The sampling stations were separated into three regions of YZR, HZB, and QTR based on their spatial distributions of sediment grain size and components. The significant variations for most of the trace metals concentrations, except for Cd, Th, and U, were found among three regions (χ2 ≥ 8.22, p ≤ 0.016). The highest concentrations in HZB were mainly resulted from the grain size effect (68.82% of the total variance), while the highest concentrations of Sr, Cd, and Ba in YZR and Zr and Hf in QTR were attributed to the anthropogenic source (11.90%) and mineral composition (6.21%) of river basins. After normalized the diversity of multiple trace metals concentrations and the influence of grain size by ratios of Igeo and EFLi, three regions were effectively distinguished. It was indicated that As, Cd, and Sb were enriched in the sediments of rivers by anthropogenic source (EFLi > 1.5 and/or Igeo > 1). The results evidenced that, after removing the influence of grain size, elemental geochemical composition of the surface sediments confidently identified the river-derived anthropogenic sources of the enriched trace metals from two major rivers, and largely from YZR.

Exploring biased activation characteristics by molecular dynamics simulation and machine learning for the µ-opioid receptor.

Biased ligands selectively activating specific downstream signaling pathways (termed as biased activation) exhibit significant therapeutic potential. However, the conformational characteristics revealed are very limited for the biased activation, which is not conducive to biased drug development. Motivated by the issue, we combine extensive accelerated molecular dynamics simulations and an interpretable deep learning model to probe the biased activation features for two complex systems constructed by the inactive µOR and two different biased agonists (G-protein-biased agonist TRV130 and ß-arrestin-biased agonist endomorphin2). The results indicate that TRV130 binds deeper into the receptor core compared to endomorphin2, located between W2936.48 and D1142.50, and forms hydrogen bonding with D1142.50, while endomorphin2 binds above W2936.48. The G protein-biased agonist induces greater outward movements of the TM6 intracellular end, forming a typical active conformation, while the ß-arrestin-biased agonist leads to a smaller extent of outward movements of TM6. Compared with TRV130, endomorphin2 causes more pronounced inward movements of the TM7 intracellular end and more complex conformational changes of H8 and ICL1. In addition, important residues determining the two different biased activation states were further identified by using an interpretable deep learning classification model, including some common biased activation residues across Class A GPCRs like some key residues on the TM2 extracellular end, ECL2, TM5 intracellular end, TM6 intracellular end, and TM7 intracellular end, and some specific important residues of ICL3 for µOR. The observations will provide valuable information for understanding the biased activation mechanism for GPCRs.

Computational insights into diverse binding modes of the allosteric modulator and their regulation on dopamine D1 receptor.

Allosteric drugs hold the promise of addressing many challenges in the current drug development of GPCRs. However, the molecular mechanism underlying their allosteric modulations remain largely elusive. The dopamine D1 receptor (DRD1), a member of Class A GPCRs, is critical for treating psychiatric disorders, and LY3154207 serves as its promising positive allosteric modulator (PAM). In the work, we utilized extensive Gaussian-accelerated molecular dynamics simulations (a total of 41µs) for the first time probe the diverse binding modes of the allosteric modulator and their regulation effects, based on the DRD1 and LY3154207 as representative. Our simulations identify four binding modes of LY3154207 (one boat mode, two metastable vertical modes and a novel cleft-anchored mode), in which the boat mode is the most stable while there three modes are similar in the stability. However, it is interesting to observed that the most stable boat mode inversely exhibits the weakest positive allosteric effect on influencing the orthosteric ligand binding and maintaining the activity of the transducer binding site. It should result from its induced weaker correlation between the allosteric site and the orthosteric site, and between the orthosteric site and the transducer binding site than the other three binding modes, as well as its weakened interaction between a crucial activation-related residue (S2025.46) and the orthosteric ligand (dopamine). Overall, the work offers atomic-level information to advance our understanding of the complex allosteric regulation on GPCRs, which is beneficial to the allosteric modulator design and development.

Ecosystem dynamics and hypoxia control in the East China Sea: A bottom-up and top-down perspective.

Decades of overfishing have greatly altered the community structure in the East China Sea (ECS). The decrease of top predators in the food web has weakened the control exerted from higher trophic levels. As a result, the biomass of benthic crustaceans, representing the third trophic level, has increased. This has probably led to a restriction of the second trophic level, diminishing its ability to control primary producer biomass. Consequently, the ecological pyramid of trophic levels in the ECS has been altered, reducing the top-down control on the first trophic level. This has made algal blooms more susceptible to occur under nutrient loads, temperate temperatures, and light availability. The reduced abundance of the fourth trophic levels has caused a larger portion of primary productivity to sink directly to the benthic community, bypassing the food web. This influx of sinking organic matter has resulted in organic enrichment in the bottom waters, impacting the biomass and diversity of benthic organisms. Furthermore, it has intensified anthropogenic carbon storage in the sediment. Subsequently, intense decomposition processes occur, leading to the development of anoxia and even hypoxia. The seasonal hypoxia off the Changjiang Estuary can be attributed to the combined influence of top-down control and bottom-up control related to nutrient loading, and terrestrial inputs. In order to mitigate extreme hypoxia events, it is necessary to implement comprehensive fisheries policies that prioritize the maintenance of a healthy and functional ecosystem. This approach should go beyond relying solely on watershed management strategies to regulate riverine inputs. PLAIN LANGUAGE SUMMARY: Decades of overfishing changed the food web in the East China Sea and weaken the resistance of ecosystem to hypoxia. Commercial fishing on top predators decreases the fourth trophic level while relatively increases the third trophic represented by crab and shrimp, which enhances grazing on the zooplankton. The decrease of the second trophic level fails to control the biomass of phytoplankton, thus more primary productivities directly sink to the benthic community and cause organic enrichment. The elevated flux of organic matters to the bottom waters causes the thrive of the carbs and shrimps, as well as more remineralization processes and eventually low oxygen level. Unlike the bottom-up perspective of hypoxia mechanism off the Changjiang Estuary, which is from the nutrient load, phytoplankton bloom, quick sink, effective decomposition and eventually hypoxia, the top-down control focuses on the changes of ecosystem structure and thus derived hindered energy transfer, changed community structure, enhanced carbon sink, elevated remineralization and ultimately hypoxia. These two mechanisms combine with each other and control the seasonal hypoxia off the Changjiang Estuary and even other coastal regions around the world.

Gene inversion led to the emergence of brackish archaeal heterotrophs in the aftermath of the Cryogenian Snowball Earth.

Land-ocean interactions greatly impact the evolution of coastal life on earth. However, the ancient geological forces and genetic mechanisms that shaped evolutionary adaptations and allowed microorganisms to inhabit coastal brackish waters remain largely unexplored. In this study, we infer the evolutionary trajectory of the ubiquitous heterotrophic archaea Poseidoniales (Marine Group II archaea) presently occurring across global aquatic habitats. Our results show that their brackish subgroups had a single origination, dated to over 600 million years ago, through the inversion of the magnesium transport gene corA that conferred osmotic-stress tolerance. The subsequent loss and gain of corA were followed by genome-wide adjustment, characterized by a general two-step mode of selection in microbial speciation. The coastal family of Poseidoniales showed a rapid increase in the evolutionary rate during and in the aftermath of the Cryogenian Snowball Earth (∼700 million years ago), possibly in response to the enhanced phosphorus supply and the rise of algae. Our study highlights the close interplay between genetic changes and ecosystem evolution that boosted microbial diversification in the Neoproterozoic continental margins, where the Cambrian explosion of animals soon followed.

Coastal eutrophication driven by long-distance transport of large river nutrient loads, the case of Xiangshan Bay, China.

With accelerating anthropogenic activities, the overloading of land-derived nutrients and the resultant eutrophication are threatening coastal aquatic habitats worldwide. In semi-enclosed coastal bays, eutrophication is always considered a local problem that can be mitigated by nutrient reduction at a regional scale. However, as the main nutrient drains major global river discharges can have far-reaching effects over hundreds of kilometers alongshore, which are usually not precisely recognized in local coastal zone management. Here, we first quantified the contributions from both local and remote nutrient sources in Xiangshan Bay (XSB), a eutrophic semi-enclosed bay in China 200 km south of the mouth of the Changjiang River (CJR, the world's third largest river), employing a salinity-based conservative mixing model. We found that the nutrients in Xiangshan Bay were mainly supplied by intruded coastal water fed by CJR discharge, contributing 63 % of dissolved inorganic nitrogen (DIN), 65 % of dissolved silicon (DSi), and 49 % of dissolved inorganic phosphorus (DIP) during the summer of 2017, and 75 % of DIN, 75 % of DSi and 60 % of DIP during the winter of 2019. Additionally, long-term interannual trends in the nutrient concentrations of XSB were generally synchronous with those of the downstream portion of the CJR, indicating that CJR discharge seems to be a strong driver of the eutrophication observed in XSB. In contrast, the impact of local nutrient inputs, such as riverine sewage drainage, aquaculture, biogenic activities, and elemental recycling, was much lower and was regionally limited to the inner bay. Interestingly, the DIP contributions of the local and remote sources were similar, indicating the greater relevance of the internal process. Overall, to mitigate eutrophication in large river-adjacent coastal bays, the inter-regional united practices for nutrient source regulation and ecosystem restoration should be permanently applied along the entire river basin-estuary-coastal continuum.

Vertical variation of bacterial production and potential role in oxygen loss in the southern Bay of Bengal.

Marine environments wherein long-term microbial oxygen consumption exceeds oxygen replenishment can be associated with oxygen minimum zones (OMZ). The Bay of Bengal OMZ (BOB-OMZ) is one of the most intense OMZs globally. To assess the contribution of bacterial oxygen consumption to oxygen loss in BOB-OMZ, we measured bacterial production (BP), temperature, salinity, and dissolved oxygen (DO) in the whole water column. We then compared the estimated bacterial oxygen demand (BOD) with diapycnal oxygen supply (DOS) at depths of 50-200 m in the southern BOB in January 2020. The average BP was 3.53 ± 3.15 µmol C m-3 h-1 in the upper 200 m of four stations, which was lower than those reported in other tropical waters. The vertical distribution of BP differed between the open ocean and nearshore areas. In the open ocean, temperature and DO were the most important predictors for BP in the whole water column. In the nearshore areas, when DO increased sharply from the suboxic state, extremely high BP occurred at 200 m. The average estimated BOD/DOS could reach up to 153% at depths of 50-200 m, indicating advection and anticyclonic eddies probably are important DO replenishment pathways in the BOB.

Diversity and salinity adaptations of ammonia oxidizing archaea in three estuaries of China.

Ammonia-oxidizing archaea (AOA) are ubiquitously found in diverse habitats and play pivotal roles in the nitrogen and carbon cycle, especially in estuarine and coastal environments. Despite the fact that the diversity and distribution of AOA are thought to be tightly linked to habitats, little is known about the relationship that underpins their genomic traits, adaptive potentials, and ecological niches. Here, we have characterized and compared the AOA community in three estuaries of China using metagenomics. AOA were the dominant ammonia oxidizers in the three estuaries. Through phylogenetic analyses, five major AOA groups were identified, including the Nitrosomarinus-like, Nitrosopumilus-like, Aestuariumsis-like, Nitrosarchaeum-like, and Nitrosopelagicus-like groups. Statistical analyses showed that the aquatic and sedimentary AOA communities were mainly influenced by spatial factors (latitude and water depth) and environmental factors (salinity, pH, and dissolved oxygen) in estuaries, respectively. Compared to AOA dwelling in terrestrial and marine habitats, estuarine AOA encoded more genes involved in glucose and amino acid metabolism, transport systems, osmotic control, and cell motility. The low proteome isoelectric points (pI), high content of acidic amino acids, and the presence of potassium ion and mechanosensitive channels suggest a "salt-in" strategy for estuarine AOA to counteract high osmolarity in their surroundings. Our findings have indicated potential adaptation strategies and highlighted their importance in the estuarine nitrogen and carbon cycles. KEY POINTS: • Spatial and environmental factors influence water and sediment AOA respectively. • Estuarine AOA share low proteome isoelectric value and high acid amino acids content. • AOA adaptation to estuaries is likely resulted from their unique genomic features.

Impacts of Atlantic water intrusion on interannual variability of the phytoplankton community structure in the summer season of Kongsfjorden, Svalbard under rapid Arctic change.

Atlantification, known as impacts of high-latitude Atlantic water inflows on the Arctic Ocean has strengthened owing to climate change, corresponding to the rapid ice retreat in the Arctic. The relationship between phytoplankton and environmental changes in the Arctic on the interannual scale is unclear because of the lack of long-time series data. In this study, we discuss the ecological response to Atlantic water intrusion in the Kongsfjorden,Svalbard. We measured chlorophyll a and photosynthesis pigments for the water column samples from a fixed section along the Kongsfjorden to study the response of phytoplankton biomass and communities to Atlantic water intrusion in the summer season from 2007 to 2018. The results showed that dinoflagellates, prasinophytes, cryptophytes, and chlorophytes consistently accounted for over 50% of the total biomass, with the distinct annual variation of chlorophyll a. Bioavailable nitrogen was the main limiting factor on phytoplankton growth in the study area, as inferred by its concentration and nutrients ratios. The relationship between phytoplankton and water mass analysis suggested that the intrusion of Atlantic water in Kongsfjorden may cause interannual variability of the phytoplankton biomass and community structure by influencing the nutrient supply and water stratification in the fjord region. Our study provides insights into the ongoing impact of Atlantification on the phytoplankton community in the Arctic fjord.

Suppressing gas swelling in self-assembled Li4Ti5O12 (400) for high-performance rechargeable batteries.

Lithium titanate is a promising anode material for lithium-ion batteries due to its high-rate capability and long-cycle duration. However, gas swelling during electrochemical reactions has hindered its industrial application. Here, we synthesize self-assembled (400)-orientation lithium titanate (SA-LTONF) with ultrafine nanoparticles using a feasible thermal method. The SA-LTONF with an organic carbon coating exhibited superior electrochemical performance. To understand such high-rate capability, we perform density functional theory (DFT) calculations which elucidate the orientation-dependent electrochemical mechanism of hydrogen evolution and the atomically dynamic mechanism of lithium-ion migration in Li4Ti5O12 and Li7Ti5O12. Our findings provide a unique insight into the gas generation and ultrafast lithium-ion transportation in lithium titanate and offer guidance for nanoarchitecture construction and materials design of lithium titanate for commercial applications.

Biogeochemical and physical controls on ammonium accumulation on the Chukchi shelf, western Arctic Ocean.

Spatial variability of ammonium concentrations along repeat transects were examined on the Chukchi shelf during 2012-2018. Two distinct near-bottom high ammonium pools (>1 µmol/kg) near 67.5°N and 72.5°N of the transects were identified in all years. The accumulation of ammonium in the regions is driven primarily by a combination of biogeochemical processes (e.g., dynamic bacterial remineralization of organic matter) and physical controls (e.g., strong density-contrast barrier limits upward mixing of ammonium). The ammonium pool on the shelf may became larger in the expectation of the stronger bacterial remineralization following elevate primary production, and may have potential impact on the structure and productivity of ecosystem on the Chukchi shelf.

Constructing a cancer stem cell related prognostic model for predicting immune landscape and drug sensitivity in colorectal cancer.

Background: Colorectal cancer (CRC) ranks the second malignancy with high incidence and mortality worldwide. Cancer stem cells (CSCs) function critically in cancer progression and metastasis via the interplay with immune cells in tumor microenvironment. This study aimed to identify important CSC marker genes and parsed the role of these marker genes in CRC. Materials and methods: CRC samples' single-cell RNA sequencing data and bulk transcriptome data were utilized. Seurat R package annotated CSCs and identified CSC marker genes. Consensus clustering subtyped CRC samples based on CSC marker genes. Immune microenvironment, pathway and oxidative stress analysis was performed using ESTIMATE, MCP-counter analysis and ssGSEA analysis. A prognostic model was established by Lasso and stepAIC. Sensitivity to chemotherapeutic drugs was determined by the biochemical half maximal inhibitory concentration with pRRophetic R package. Results: We identified a total of 29 CSC marker genes related to disease-specific survival (DSS). Two clusters (CSC1 and CSC2) were determined, and CSC2 showed shorter DSS, a larger proportion of late-stage samples, and higher oxidative stress response. Two clusters exhibited differential activation of biological pathways associated with immune response and oncogenic signaling. Drug sensitivity analysis showed that 44 chemotherapy drugs were more sensitive to CSC2 that those in CSC1. We constructed a seven-gene prognostic model (DRD4, DPP7, UCN, INHBA, SFTA2, SYNPO2, and NXPH4) that was effectively to distinguish high-risk and low-risk patients. 14 chemotherapy drugs were more sensitive to high-risk group and 13 chemotherapy drugs were more sensitive to low-risk group. Combination of higher oxidative stress and risk score indicated dismal prognosis. Conclusion: The CSC marker genes we identified may help to further decipher the role of CSCs in CRC development and progression. The seven-gene prognostic model could serve as an indicator for predicting the response to immunotherapy and chemotherapy as well as prognosis of CRC patients.

The distribution and enrichment of trace elements in surface and core sediments from the Changjiang River Estuary, China: Evidence for anthropogenic inputs and enhanced availability of rare earth elements (REE).

Huge amount of trace metals emitted through manmade activities are carried by the Changjiang River into the East China Sea. Most of them deposit in the Changjiang River Estuary and threaten the regional aquatic environment. In this study, major and trace elements of 34 archive surface sediments and two cores are examined. Sequential extraction procedures were also performed on surface sediments from 12 sites. We found that Tl, Tm, Er show distinct accumulation in surface sediments in the order of Tm > Tl > Er. Particularly, abnormally elevated HREE are observed mainly in those sites near the mouth of the estuary. Most elements exhibit an obvious reduction in the upper 30 cm of core B8, reflecting a decrease of sediment discharge from Changjiang River runoff. The increase of some trace elements recorded in the upper 20 cm of core C3 demonstrates a distinct local anthropogenic input in recent years.

Nuclear export of BATF2 enhances colorectal cancer proliferation through binding to CRM1.

BACKGROUND: During the tumourigenesis and development of colorectal cancer (CRC), the inactivation of tumour suppressor genes is closely involved, although detailed molecular mechanisms remain elusive. Accumulating studies, including ours, have demonstrated that basic leucine zipper transcription factor ATF (activating transcription factor)-like 2 (BATF2) is a capable tumour suppressor that localises in the nucleus. However, its different subcellular localisation, potential functions and underlying mechanisms are unclear. METHODS: The translocation of BATF2 and its clinical relevance were detected using CRC samples, cell lines and xenograft nude mice. Candidate BATF2-binding proteins were screened using co-immunoprecipitation, quantitative label-free liquid chromatography-tandem mass spectrometry proteomic analysis, Western blotting and immunofluorescence. Recombinant plasmids, point mutations and siRNAs were applied to clarify the binding sites between BATF2 and chromosome region maintenance 1 (CRM1). RESULTS: The present study found that BATF2 was mainly localised in the cytoplasm, rather than nucleus, of CRC cells in vitro and in vivo, while cytoplasmic BATF2 expression was inversely correlated with the prognosis of CRC patients. Furthermore, we identified the nuclear export and subsequent ubiquitin-mediated degradation of BATF2 in CRC cells. Mechanistically, a functional nuclear export sequence (any amino acid) was characterised in BATF2 protein, through which BATF2 bound to CRM1 and translocated out of nucleus, ultimately enhancing CRC growth via inducing activator protein 1 (AP-1)/cyclin D1/phosphorylated retinoblastoma protein (pRb) signalling pathway. Additionally, nuclear export of BATF2 can be retarded by the mutation of NES in BATF2 or the knockdown of CRM1, whereas CRM1 expression was negatively associated with nuclear BATF2 expression and the prognosis of CRC patients. CONCLUSION: These findings revealed the biological effects and underlying mechanisms of cytoplasmic localisation of BATF2. Furthermore, suppressing nuclear export of BATF2 via mutating its NES region or inhibiting CRM1 expression may serve as a promising therapeutic strategy against CRC.

The Changjiang River plume shifts from carbon source to sink when net community production exceeds a threshold in early autumn.

Estuaries are crucial components of the global ocean carbon cycle due to their high productivity. However, our understanding of the carbon source-sink dynamics at the air-sea interface of estuaries is incomplete, largely due to the rapidly changing environmental conditions. To address this, we conducted a study in early autumn 2016 using high-resolution biogeochemical data collected through buoy observations in the Changjiang River plume (CRP). Using a mass balance approach, we examined the factors driving changes in the sea surface partial pressure of carbon dioxide (pCO2) and quantified the net community production (NCP) in the mixed layer. We also explored the relationship between NCP and the carbon source-sink dynamics at the air-sea interface. Our results revealed that biological activities (64.0 %) and seawater mixing (19.7 %, including lateral transport and vertical mixing) were the dominant factors controlling changes in sea surface pCO2 during the study period. Moreover, NCP in the mixed layer was affected by factors such as light availability and the presence of respired organic carbon associated with vertical mixing of seawater. Notably, we observed a strong correlation between NCP and the difference in pCO2 between air and sea (δpCO2), with a threshold NCP value of 308.4 mmol m-2 d-1 identified as an indicator of the transition from a CO2 source to a sink in the CRP. Hence, we suggest that the NCP in a specific ocean box has a threshold, beyond which the air-sea interface in estuaries will change from a carbon source to a carbon sink, and vice versa.

Size-fractionated N2 fixation off the Changjiang Estuary during summer.

Recent evidence has shown active N2 fixation in coastal eutrophic waters, yet the rate and controlling factors remain poorly understood, particularly in large estuaries. The Changjiang Estuary (CE) and adjacent shelf are characterized by fresh, nitrogen-replete Changjiang Diluted Water (CDW) and saline, nitrogen-depletion intruded Kuroshio water (Taiwan Warm Current and nearshore Kuroshio Branch Current), where N2 fixation may be contributed by different groups (i.e., Trichodesmium and heterotrophic diazotrophs). Here, for the first time, we provide direct measurement of size-fractionated N2 fixation rates (NFRs) off the CE during summer 2014 using the 15N2 bubble tracer method. The results demonstrated considerable spatial variations (southern > northern; offshore > inshore) in surface and depth-integrated NFRs, averaging 0.83 nmol N L-1 d-1 and 24.3 µmol N m-2 d-1, respectively. The highest bulk NFR (99.9 µmol N m-2 d-1; mostly contributed by >10 µm fraction) occurred in the southeastern East China Sea, where suffered from strong intrusion of the Kuroshio water characterized by low N/P ratio (<10) and abundant Trichodesmium (up to 10.23 × 106 trichomes m-2). However, low NFR (mostly contributed by <10 µm fraction) was detected in the CE controlled by the CDW, where NOx concentration (up to 80 µmol L-1) and N/P ratio (>100) were high and Trichodesmium abundance was low. The >10 µm fraction accounted for 60% of depth-integrated bulk NFR over the CE and adjacent shelf. We speculated that the present NFR of >10 µm fraction was mostly supported by Trichodesmium. Spearman rank correlation indicated that the NFR was significantly positively correlated with Trichodesmium abundance, salinity, temperature and Secchi depth, but was negatively with turbidity, N/P ratio, NOx, and chlorophyll a concentration. Our study suggests that distribution and size structure of N2 fixation off the CE are largely regulated by water mass (intruded Kuroshio water and CDW) movement and associated diazotrophs (particularly Trichodesmium) and nutrient conditions.

Multi-omics integration analysis of GPCRs in pan-cancer to uncover inter-omics relationships and potential driver genes.

G protein-coupled receptors (GPCRs) are the largest drug target family. Unfortunately, applications of GPCRs in cancer therapy are scarce due to very limited knowledge regarding their correlations with cancers. Multi-omics data enables systematic investigations of GPCRs, yet their effective integration remains a challenge due to the complexity of the data. Here, we adopt two types of integration strategies, multi-staged and meta-dimensional approaches, to fully characterize somatic mutations, somatic copy number alterations (SCNAs), DNA methylations, and mRNA expressions of GPCRs in 33 cancers. Results from the multi-staged integration reveal that GPCR mutations cannot well predict expression dysregulation. The correlations between expressions and SCNAs are primarily positive, while correlations of the methylations with expressions and SCNAs are bimodal with negative correlations predominating. Based on these correlations, 32 and 144 potential cancer-related GPCRs driven by aberrant SCNA and methylation are identified, respectively. In addition, the meta-dimensional integration analysis is carried out by using deep learning models, which predict more than one hundred GPCRs as potential oncogenes. When comparing results between the two integration strategies, 165 cancer-related GPCRs are common in both, suggesting that they should be prioritized in future studies. However, 172 GPCRs emerge in only one, indicating that the two integration strategies should be considered concurrently to complement the information missed by the other such that obtain a more comprehensive understanding. Finally, correlation analysis further reveals that GPCRs, in particular for the class A and adhesion receptors, are generally immune-related. In a whole, the work is for the first time to reveal the associations between different omics layers and highlight the necessity of combing the two strategies in identifying cancer-related GPCRs.

[Clinical Characteristics and Survival Analysis of Patients with Chronic Myelomonocytic Leukemia].

OBJECTIVE: To investigate the clinical characteristics, prognostic factors and efficacy of hypomethylating agent (HMA) in patients with chronic myelomonocytic leukemia (CMML). METHODS: The clinical data of 37 newly diagnosed patients with CMML was analyzed retrospectively, and their clinical characteristics and the efficacy of HMA were summarized. Kaplan-Meier and Log-rank test were used for univariate survival analysis, and Cox proportional hazards regression model was used for multivariate analysis. RESULTS: The median age at diagnosis was 67 years old. Their common manifestations included fatigue, bleeding, abnormal blood routine and fever. Most patients had splenomegaly. According to FAB classification, there were 6 cases of myelodysplastic CMML and 31 cases of myeloproliferative CMML, while according to WHO classification, 8 patients belonged to CMML-0, 9 patients to CMML-1 and 20 patients to CMML-2. At the time of diagnosis, the median white blood cell count was 32.84×109/L, median hemoglobin (Hb) was 101 g/L, median platelet count was 65×109/L, median absolute monocyte count was 9.53×109//L, median absolute neutrophil count (ANC) was 11.29×109//L and median lactate dehydrogenase (LDH) was 374 U/L. Cytogenetic abnormalities were found in 4 cases among the 31 patients who underwent karyotype analysis or fluorescence in situ hybridization detection. There were 12 patients who had analyzable results and gene mutations were identified in 11 cases, including ASXL1, NRAS, TET2, SRSF2 and RUNX1. Among the 6 patients who were treated with HMA and could be evaluated for efficacy, 2 patients achieved complete remission, 1 patient achieved partial remission and 2 patients achieved clinical benefit. Compared with the non-HMA treatment group, overall survival (OS) time was not significantly prolonged in the HMA treatment group. Univariate analysis showed that Hb<100 g/L, ANC≥12×109/L, LDH≥250 U/L and peripheral blood (PB) blasts ≥5% were significantly associated with poor OS, while WHO classification CMML-2, Hb<100 g/L, ANC≥12×109/L, LDH≥250 U/L and PB blasts≥5% were significantly associated with poor leukemia-free survival (LFS) (P<0.05). Multivariate analysis showed that ANC≥12×109/L and PB blasts≥5% were significantly associated with poor OS and LFS (P<0.05). CONCLUSION: CMML has high heterogeneity in clinical characteristics, genetic changes, prognosis and treatment response. HMA can not significantly improve the survival of CMML patients. ANC≥12×109/L and PB blasts≥5% are independent prognostic factors of OS and LFS in patients with CMML.

Deubiquitinase OTUB2 promotes intrahepatic cholangiocarcinoma progression by stabilizing the CTNNB1-ZEB1 axis.

Aberrant regulation of ubiquitination is an essential fundamental process in tumors, especially intrahepatic cholangiocarcinoma (iCCA). We reported that OTUB2, an OTU deubiquitinase, is upregulated in iCCA and stabilizes the CTNNB1-ZEB1 axis, resulting in epithelial-mesenchymal transition (EMT) and iCCA metastasis. Mechanistically, OTUB2 promotes CTNNB1 expression by interacting with the E3 ligase TRAF6. OTUB2 inhibits the lysosomal degradation of CTNNB1 by interacting with TRAF6 and thus regulates the progression of iCCA through ZEB1. Clinically, high OTUB2 expression is related to increased ZEB1 expression and activity and reduced overall survival in iCCA patients. Therefore, advanced iCCA patients may benefit from drugs targeting OTUB2 and its pathway.

Echinococcus multilocularis Calreticulin Interferes with C1q-Mediated Complement Activation.

As a zoonotic disease caused by Echinococcus multilocularis larvae, alveolar echinococcosis (AE) is one of the most severe forms of parasitic infection. Over a long evolutional process E. multilocularis has developed complex strategies to escape host immune attack and survive within a host. However, the mechanisms underlying immune evasion remain unclear. Here we investigated the binding activity of E. multilocularis calreticulin (EmCRT), a highly conserved Ca2+-binding protein, to human complement C1q and its ability to inhibit classical complement activation. ELISA, Far Western blotting and immunoprecipitation results demonstrated that both recombinant and natural EmCRTs bound to human C1q, and the interaction of recombinant EmCRT (rEmCRT) inhibited C1q binding to IgM. Consequently, rEmCRT inhibited classical complement activation manifested as decreasing C4/C3 depositions and antibody-sensitized cell lysis. Moreover, rEmCRT binding to C1q suppressed C1q binding to human mast cell, HMC-1, resulting in reduced C1q-induced mast cell chemotaxis. According to these results, E. multilocularis expresses EmCRT to interfere with C1q-mediated complement activation and C1q-dependent non-complement activation of immune cells, possibly as an immune evasion strategy of the parasite in the host.