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The Yangtze River is the mother river of China. To promote the aquatic ecosystem protection of the great river, the Project of Yangtze Fisheries Resources and Environment Investigation (2017–2021) supported by the Ministry of Agriculture and Rural Affairs, P. R. China carried out by 24 institutes and universities that located in the Yangtze River basin surveys the status of (1) fish species composition and spatial distribution, (2) current fish abundance, (3) endangered fishes, (4) Yangtze finless porpoise, (5) aquatic eco-environments, (6) water-level fluctuation areas, (7) capture fisheries and recreational fisheries of the Yangtze River mainstream and 10 of its main tributaries, including Yalong River, Heng River, Min River (including Dadu River), Chishui River, Tuo River, Jialing River, Wu River, Han River, Dongting Lake and Poyang Lake. The results showed that there were 443 fish species (belonging to 163 genus, 37 families, and 18 orders) before 2017, but only 323 fish species (including 15 new recorded exotic species) were recorded in the project of 2017–2021. Among them, Cyprinus carpio, Carassius auratus, Hypophthalmichthys molitrix, Pelteobagrus fulvidraco, Coilia brachygnathus, Silurus asotus, Saurogobio dabryi, Ctenopharyngodon idellus, Pelteobagrus nitidus, Hemiculter leucisculus, Siniperca chuatsi, Coreius heterodon, Culter alburnus, Parabramis pekinensis, and Aristichthys nobilis were the dominant species across the whole Yangtze River system. It is estimated that there were 886 million individuals weighing 124.8 million kg, merely equivalent to 27.3% of the resources in 1950s, 30.9% of the resources in 1960s, or 58.7% of the resources in 1980s. In the new list of protected fishes that recorded in the Yangtze River system, only 15 of 29 were collected in this project of 2017–2021. Psephurus gladius has been affirmed to be Extinct by International Union for Conservation of Nature (IUCN). The wild individuals of Tenualosa reevesii and Luciobrama macrocephalus have disappeared for many years and maybe have been extinct already. Acipenser dabryanus has been affirmed to be Extinct in the Wild by IUCN. The natural propagations of A. sinensis, Myxocyprinus asiaticus and Trachidermus fasciatus have been interrupted for many years. The populations of Yangtze finless porpoise in the Yangtze River mainstream, Dongting Lake and Poyang Lake have steadily rising sizes and expanding distributions in 2017–2021. Parts of them migrate from one region to another with the seasons, which would result in the fluctuation of Yangtze finless porpoise population within some regions. The conventional indicators of water quality in the Yangtze River system were good and conformed to the water quality criteria of fishery in 2017–2021. In the last 40 years, the maximum surface water area in the Yangtze River basin extended to approximately 63,360 km2, the minimum surface water area covered approximately 26,396 km2, and the seasonal water-level fluctuation areas occupied approximately 36,964 km2. Compared with 1984–2000 period, the 2001–2020 period witnessed an overall decreasing trend in the frequency of surface water occurrence within about 25,869 km2 of aquatic areas. From 1984 to 2000 period to 2001–2020 period, permanent surface water has decreased by nearly 8,750 km2. In 2017, the fishermen were mainly 40–60 years old and their educational levels were mainly lower than junior high school. In 2017, most anglers were older than 40 and used hand rod and/or sea rod. Their average catch of each time was mainly less than 1 kg. Results suggested that the fishing ban in key waters of the Yangtze River basin is not only an ecological project of aquatic ecosystem conservation, but also a livelihood project for the fisherman to embrace industrial transformation and improve their living conditions. After the implementation of the fishing ban, the fisheries resources would gradually recover, and the Yangtze finless porpoise population size would also see a steady increase. However, the endangered species would remain threatened for a long time. The degraded waterbodies and water-level fluctuation areas would be the key restrictive factors for future aquatic ecosystem recovery in the Yangtze River basin. Since this survey was carried out before the fishing ban, the current results could provide a baseline for future evaluation of the effect of the Yangtze River fishing ban.

Traditional treatments against advanced non-small cell lung cancer (NSCLC) with high morbidity and mortality continue to be dissatisfactory. Given this situation, there is an urgent requirement for alternative modalities that provide lower invasiveness, superior clinical effectiveness, and minimal adverse effects. The combination of photodynamic therapy (PDT) and immunotherapy gradually become a promising approach for high-grade malignant NSCLC. Nevertheless, owing to the absence of precise drug delivery techniques as well as the hypoxic and immunosuppressive characteristics of the tumor microenvironment (TME), the efficacy of this combination therapy approach is less than ideal. In this study, we construct a novel nanoplatform that indocyanine green (ICG), a photosensitizer, loads into hollow manganese dioxide (MnO2) nanospheres (NPs) (ICG@MnO2), and then encapsulated in PD-L1 monoclonal antibodies (anti-PD-L1) reprogrammed exosomes (named ICG@MnO2@Exo-anti-PD-L1), to effectively modulate the TME to oppose NSCLC by the synergy of PDT and immunotherapy modalities. The ICG@MnO2@Exo-anti-PD-L1 NPs are precisely delivered to the tumor sites by targeting specially PD-L1 highly expressed cancer cells to controllably release anti-PD-L1 in the acidic TME, thereby activating T cell response. Subsequently, upon endocytic uptake by cancer cells, MnO2 catalyzes the conversion of H2O2 to O2, thereby alleviating tumor hypoxia. Meanwhile, ICG further utilizes O2 to produce singlet oxygen (1O2) to kill tumor cells under 808 nm near-infrared (NIR) irradiation. Furthermore, a high level of intratumoral H2O2 reduces MnO2 to Mn2+, which remodels the immune microenvironment by polarizing macrophages from M2 to M1, further driving T cells. Taken together, the current study suggests that the ICG@MnO2@Exo-anti-PD-L1 NPs could act as a novel drug delivery platform for achieving multimodal therapy in treating NSCLC.

Abstract Neutrophil infiltration plays a key role in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). However, pertinent mechanisms remain poorly elucidated. Here, we obtained the data from gene expression omnibus (GEO) and gene set enrichment analysis (GSEA) to identify and validate neutrophil-associated hub genes in CRSwNP. We found that four neutrophil-associated hub genes, namely ICAM1, IL-1β, TYROBP, and BCL2A1, were markedly upregulated and positively correlated with neutrophil infiltration levels in patients with CRSwNP. Subsequently, this was confirmed by real-time quantitative PCR. In conclusion, we identified the role of neutrophil infiltration in the pathophysiology of CRSwNP, which may be the potential targets for the diagnosis and treatment of CRSwNP.

Abstract Oil reservoirs, being one of the significant subsurface repositories of energy and carbon, host diverse microbial communities affecting energy production and carbon emissions. Viruses play crucial roles in the ecology of microbiomes, however, their distribution and ecological significance in oil reservoirs remain undetermined. Here, we assemble a catalogue encompassing viral and prokaryotic genomes sourced from oil reservoirs. The catalogue comprises 7229 prokaryotic genomes and 3,886 viral Operational Taxonomic Units (vOTUs) from 182 oil reservoir metagenomes. The results show that viruses are widely distributed in oil reservoirs, and 85% vOTUs in oil reservoir are detected in less than 10% of the samples, highlighting the heterogeneous nature of viral communities within oil reservoirs. Through combined microcosm enrichment experiments and bioinformatics analysis, we validate the ecological roles of viruses in regulating the community structure of sulfate reducing microorganisms, primarily through a virulent lifestyle. Taken together, this study uncovers a rich diversity of viruses and their ecological functions within oil reservoirs, offering a comprehensive understanding of the role of viral communities in the biogeochemical cycles of the deep biosphere.

Abstract Background Osteosarcoma (OS) is one of the most common primary malignant tumors of bone in children, which develops from osteoblasts and typically occurs during the rapid growth phase of the bone. Recently, Super-Enhancers(SEs)have been reported to play a crucial role in osteosarcoma growth and metastasis. Therefore, there is an urgent need to identify specific targeted inhibitors of SEs to assist clinical therapy. This study aimed to elucidate the role of BRD4 inhibitor GNE-987 targeting SEs in OS and preliminarily explore its mechanism. Methods We evaluated changes in osteosarcoma cells following treatment with a BRD4 inhibitor GNE-987. We assessed the anti-tumor effect of GNE-987 in vitro and in vivo by Western blot, CCK8, flow cytometry detection, clone formation, xenograft tumor size measurements, and Ki67 immunohistochemical staining, and combined ChIP-seq with RNA-seq techniques to find its anti-tumor mechanism. Results In this study, we found that extremely low concentrations of GNE-987(2–10 nM) significantly reduced the proliferation and survival of OS cells by degrading BRD4. In addition, we found that GNE-987 markedly induced cell cycle arrest and apoptosis in OS cells. Further study indicated that VHL was critical for GNE-987 to exert its antitumor effect in OS cells. Consistent with in vitro results, GNE-987 administration significantly reduced tumor size in xenograft models with minimal toxicity, and partially degraded the BRD4 protein. KRT80 was identified through analysis of the RNA-seq and ChIP-seq data. U2OS HiC analysis suggested a higher frequency of chromatin interactions near the KRT80 binding site. The enrichment of H3K27ac modification at KRT80 was significantly reduced after GNE-987 treatment. KRT80 was identified as playing an important role in OS occurrence and development. Conclusions This research revealed that GNE-987 selectively degraded BRD4 and disrupted the transcriptional regulation of oncogenes in OS. GNE-987 has the potential to affect KRT80 against OS.

Abstract The recent experimental confirmation of perovskite monolayers has sparked ongoing efforts in their prediction and synthesis, showcasing their flexible tunable band gap and potential in advanced functional devices. Although large-scale computational designs have been successfully performed for inorganic perovskite monolayers, the complexity introduced by organic cations hinders the same approaches applied to the hybrid halide perovskite monolayers. To address this challenge, we have proposed a high-throughput first-principles computational workflow that automates the design of hybrid halide perovskite monolayers. We strategically reduce the complexity of the configurations by analyzing the orientation of cations and the structural symmetry. Over 400 hybrid halide perovskite monolayers have been designed, and their structures and fundamental properties are stored in the database. Correlation analyses show a strong correlation between band gaps and metal-halogen-metal bond angles or metal-halogen bond lengths, consistent with prior studies for bulk and layered perovskites. The underlying physics that the band gap is modulated by the antibonding in the metal-halogen bond makes band gap engineering of hybrid halide perovskite monolayers feasible. Accordingly, initial research on lateral heterojunctions and solar cells has been conducted to explore the potential practical applications of the designed hybrid halide perovskite monolayers. Our study lays the foundation for further exploration of hybrid halide perovskite monolayers and highlights promising opportunities for their potential applications in electronic and optical devices.

Abstract Background Evidence from observational studies indicates that lung cancer screening (LCS) guidelines with high rates of lung cancer (LC) underdiagnosis, and although current screening guidelines have been updated and eligibility criteria for screening have been expanded, there are no studies comparing the efficiency of LCS guidelines in Chinese population. Methods Between 2005 and 2022, 31,394 asymptomatic individuals were screened using low-dose computed tomography (LDCT) at our institution. Demographic data and relevant LC risk factors were collected. The efficiency of the LCS for each guideline criteria was expressed as the efficiency ratio (ER). The inclusion rates, eligibility rates, LC detection rates, and ER based on the different eligibility criteria of the four guidelines were comparatively analyzed. The four guidelines were as follows: China guideline for the screening and early detection of lung cancer (CGSL), the National Comprehensive Cancer Network (NCCN), the United States Preventive Services Task Force (USPSTF), and International Early Lung Cancer Action Program (I-ELCAP). Results Of 31,394 participants, 298 (155 women, 143 men) were diagnosed with LC. For CGSL, NCCN, USPSTF, and I-ELCAP guidelines, the eligibility rates for guidelines were 13.92%, 6.97%, 6.81%, and 53.46%; ERe for eligibility criteria were 1.46%, 1.64%, 1.51%, and 1.13%, respectively; and for the inclusion rates, they were 19.0%, 9.5%, 9.3%, and 73.0%, respectively. LCs which met the screening criteria of CGSL, NCCN, USPSTF, and I-ELCAP guidelines were 29.2%, 16.4%, 14.8%, and 86.6%, respectively. The age and smoking criteria for CGSL were stricter, hence resulting in lower rates of LC meeting the screening criteria. The CGSL, NCCN, and USPSTF guidelines showed the highest underdiagnosis in the 45–49 age group (17.4%), while the I-ELCAP guideline displayed the highest missed diagnosis rate (3.0%) in the 35–39 age group. Males and females significantly differed in eligibility based on the criteria of the four guidelines (P

Abstract Low damping characteristics have always been a key sticking points in the development of gas bearings. The application of squeeze film dampers can significantly improve the damping performance of gas lubricated bearings. This paper proposed a novel hermetic diaphragm squeeze film damper (HDSFD) for oil-free turbomachinery supported by gas lubricated bearings. Several types of HDSFDs with symmetrical structure were proposed for good damping performance. By considering the compressibility of the damper fluid, based on hydraulic fluid mechanics theory, a dynamic model of HDSFDs under medium is proposed, which successfully reflects the frequency dependence of force coefficients. Based on the dynamic model, the effects of damper fluid viscosity, bulk modulus of damper fluid, thickness of damper fluid film and plunger thickness on the dynamic stiffness and damping of HDSFDs were analyzed. An experimental test rig was assembled and series of experimental studies on HDSFDs were conducted. The damper fluid transverse flow is added to the existing HDSFD concept, which aims to make the dynamic force coefficients independent of frequency. Although the force coefficient is still frequency dependent, the damping coefficient at high frequency excitation with damper fluid supply twice as that without damper fluid supply. The results serve as a benchmark for the calibration of analytical tools under development.

Abstract Background Gastric cancer is one of the most common tumors worldwide, and most patients are deprived of treatment options when diagnosed at advanced stages. PRDM14 has carcinogenic potential in breast and non-small cell lung cancer. however, its role in gastric cancer has not been elucidated. Methods We aimed to elucidate the expression of PRDM14 using pan-cancer analysis. We monitored the expression of PRDM14 in cells and patients using quantitative polymerase chain reaction, western blotting, and immunohistochemistry. We observed that cell phenotypes and regulatory genes were influenced by PRDM14 by silencing PRDM14. We evaluated and validated the value of the PRDM14-derived prognostic model. Finally, we predicted the relationship between PRDM14 and small-molecule drug responses using the Connectivity Map and The Genomics of Drug Sensitivity in Cancer databases. Results PRDM14 was significantly overexpressed in gastric cancer, which identified in cell lines and patients’ tissues. Silencing the expression of PRDM14 resulted in apoptosis promotion, cell cycle arrest, and inhibition of the growth and migration of GC cells. Functional analysis revealed that PRDM14 acts in epigenetic regulation and modulates multiple DNA methyltransferases or transcription factors. The PRDM14-derived differentially expressed gene prognostic model was validated to reliably predict the patient prognosis. Nomograms (age, sex, and PRDM14-risk score) were used to quantify the probability of survival. PRDM14 was positively correlated with sensitivity to small-molecule drugs such as TPCA-1, PF-56,227, mirin, and linsitinib. Conclusions Collectively, our findings suggest that PRDM14 is a positive regulator of gastric cancer progression. Therefore, it may be a potential therapeutic target for gastric cancer.

In the process of constructional backfilling coal mining (CBCM), the demand for the strength of cemented gangue backfill (CGB) samples varies with different backfill rates. It is planned to adjust the strength of CGB samples by changing the proportion of fly ash in the dosage of cement-fly ash binary cementitious material (hereinafter referred to as the proportion of fly ash), and conduct uniaxial compression tests on CGB samples with different proportions of fly ash (0−90%) to explore the range of strength control of CGB samples, and analyze the failure morphology of the samples using digital image correlation technology, and analyze the brittle ductile failure mode of the samples using AE events. The strength of coal gangue and the strength of cement-fly ash binary cementitious material with different fly ash proportions are measured using the pressure cylinder method and uniaxial compression test, respectively, and the mechanism of strength formation of CGB samples is revealed based on the relationship between the strength of coal gangue and the strength of cement-fly ash binary cementitious material. The research results indicate that the strength of CGB decreases with the increase of proportion of fly ash, achieving a larger range of strength control for CGB: 1.77−30.04 MPa. The failure morphology and the brittle ductile failure mode of samples with different replacement rates of CGB samples are different, and the corresponding strength range of the samples is also different, Material properties have undergone fundamental changes. As the proportion of fly ash increases, in terms of the failure morphology, CGB samples transition from shear failure (0−50% proportion of fly ash) to tensile shear composite failure (60%−80% proportion of fly ash) and then to tensile failure (90% proportion of fly ash), corresponding to the strength ranges are 20.8−30.04 MPa, 5.63−12.35 MPa, and 1.77 MPa; In terms of the brittle ductile failure mode, the samples transition from brittle-ductile failure (0−40% proportion of fly ash) to ductile failure (50%−90% proportion of fly ash), corresponding to the strength ranges are 24.64−30.04 MPa and 1.77−20.8 MPa. The strength of CGB is determined by the strength of the cement-fly ash binary cementitious material (1.43−55.5 MPa) and the strength of coal gangue (with an average strength of 4.43 MPa). Cement-fly ash binary cementitious material contributes significantly to the strength of CGB, while coal gangue limits the strength of CGB. The obtained experimental results provide a certain reference for the strength selection of filling materials in CBCM.

Abstract To analyze the clinical characteristics and to improve clinicians’ understanding of multiple pulmonary sclerosing pneumocytoma (PSP) patients. A total of 36 PSP patients with multiple tumor characteristics were identified from the literature search. They were compared with 43 solitary PSP patients diagnosed and treated in our hospital in the past 5 years. Thus, the pathogenesis, clinical symptoms, diagnosis methods, treatment strategies, and prognosis of pulmonary sclerosing pneumocytoma (PSP) patients with multiple tumors were explored. Patients with multiple PSP are mostly distributed in Asia (88.89%) and are females (83.33%). PSP can be located in any one lobe (19.44%), or grow across ipsilateral lobes (44.44%), or even, bilateral lobes (36.11%). It can be accompanied by metastasis (9.09%) and is prone to misdiagnosis (27.78%). Compared with solitary PSP, the occurrence age of multiple PSP was younger (mean ± standard deviation [SD]: 40.36 ± 18.12: 51.28 ± 12.74 years), but there was no significant difference in sex, tumor size (mean ± SD: 43.54 ± 46.18: 30.56 ± 17.62 mm), or symptoms. Individualized surgical resection is required for treatment, including pneumonectomy (17.65%), lobectomy (23.53%), subpulmonary lobectomy (38.24%), or combined lobectomy (5.88%). Multiple PSP is relatively rare. Surgical resection within a limited time should be the main treatment for such patients. The prognosis of patients with multiple PSP is generally good, but inappropriate diagnosis and treatment plans may lead to poor prognosis.

Abstract Background Community-acquired pneumonia (CAP) is a common and serious condition that can be caused by a variety of pathogens. However, much remains unknown about how these pathogens interact with the lower respiratory commensals, and whether any correlation exists between the dysbiosis of the lower respiratory microbiota and disease severity and prognosis. Methods We conducted a retrospective cohort study to investigate the composition and dynamics of sputum microbiota in patients diagnosed with CAP. In total, 917 sputum specimens were collected consecutively from 350 CAP inpatients enrolled in six hospitals following admission. The V3-V4 region of the 16 S rRNA gene was then sequenced. Results The sputum microbiota in 71% of the samples were predominately composed of respiratory commensals. Conversely, 15% of the samples demonstrated dominance by five opportunistic pathogens. Additionally, 5% of the samples exhibited sterility, resembling the composition of negative controls. Compared to non-severe CAP patients, severe cases exhibited a more disrupted sputum microbiota, characterized by the highly dominant presence of potential pathogens, greater deviation from a healthy state, more significant alterations during hospitalization, and sparser bacterial interactions. The sputum microbiota on admission demonstrated a moderate prediction of disease severity (AUC = 0.74). Furthermore, different pathogenic infections were associated with specific microbiota alterations. Acinetobacter and Pseudomonas were more abundant in influenza A infections, with Acinetobacter was also enriched in Klebsiella pneumoniae infections. Conclusion Collectively, our study demonstrated that pneumonia may not consistently correlate with severe dysbiosis of the respiratory microbiota. Instead, the degree of microbiota dysbiosis was correlated with disease severity in CAP patients.

Abstract SETD3 is an essential host factor for the replication of a variety of enteroviruses that specifically interacts with viral protease 2A. However, the interaction between SETD3 and the 2A protease has not been fully characterized. Here, we use X-ray crystallography and cryo-electron microscopy to determine the structures of SETD3 complexed with the 2A protease of EV71 to 3.5 Å and 3.1 Å resolution, respectively. We find that the 2A protease occupies the V-shaped central cleft of SETD3 through two discrete sites. The relative positions of the two proteins vary in the crystal and cryo-EM structures, showing dynamic binding. A biolayer interferometry assay shows that the EV71 2A protease outcompetes actin for SETD3 binding. We identify key 2A residues involved in SETD3 binding and demonstrate that 2A’s ability to bind SETD3 correlates with EV71 production in cells. Coimmunoprecipitation experiments in EV71 infected and 2A expressing cells indicate that 2A interferes with the SETD3-actin complex, and the disruption of this complex reduces enterovirus replication. Together, these results reveal the molecular mechanism underlying the interplay between SETD3, actin, and viral 2A during virus replication.

Abstract Objective To determine whether quantitative parameters of detector-derived dual-layer spectral computed tomography (DLCT) can reliably identify epidermal growth factor receptor (EGFR) mutation status in patients with non-small cell lung cancer (NSCLC). Methods Patients with NSCLC who underwent arterial phase (AP) and venous phase (VP) DLCT between December 2021 and November 2022 were subdivided into the mutated and wild-type EGFR groups following EGFR mutation testing. Their baseline clinical data, conventional CT images, and spectral images were obtained. Iodine concentration (IC), iodine no water (INW), effective atomic number (Zeff), virtual monoenergetic images, the slope of the spectral attenuation curve (λHU), enhancement degree (ED), arterial enhancement fraction (AEF), and normalized AEF (NAEF) were measured for each lesion. Results Ninety-two patients (median age, 61 years, interquartile range [51, 67]; 33 men) were evaluated. The univariate analysis indicated that IC, normalized IC (NIC), INW and ED for the AP and VP, as well as Zeff and λHU for the VP were significantly associated with EGFR mutation status (all p

Abstract Neuroblastoma (NB) is a common childhood tumor with a high incidence worldwide. The regulatory role of RNA N6-methyladenosine (m6A) in gene expression has attracted significant attention, and the impact of methyltransferase-like 14 (METTL14) on tumor progression has been extensively studied in various types of cancer. However, the specific influence of METTL14 on NB remains unexplored. Using data from the Target database, our study revealed significant upregulation of METTL14 expression in high-risk NB patients, with strong correlation with poor prognosis. Furthermore, we identified ETS1 and YY1 as upstream regulators that control the expression of METTL14. In vitro experiments involving the knockdown of METTL14 in NB cells demonstrated significant inhibition of cell proliferation, migration, and invasion. In addition, suppressing METTL14 inhibited NB tumorigenesis in nude mouse models. Through MeRIP-seq and RNA-seq analyses, we further discovered that YWHAH is a downstream target gene of METTL14. Mechanistically, we observed that methylated YWHAH transcripts, particularly those in the 5′ UTR, were specifically recognized by the m6A “reader” protein YTHDF1, leading to the degradation of YWHAH mRNA. Moreover, the downregulation of YWHAH expression activated the PI3K/AKT signaling pathway, promoting NB cell activity. Overall, our study provides valuable insights into the oncogenic effects of METTL14 in NB cells, highlighting its role in inhibiting YWHAH expression through an m6A-YTHDF1-dependent mechanism. These findings also suggest the potential utility of a biomarker panel for prognostic prediction in NB patients.

ObjectiveWe conducted this meta-analysis to comprehensively explore the prognostic value of the preoperative plasma fibrinogen in Asian patients diagnosed with urothelial cancer (UC).MethodsAfter a systematic search of Web of Science, PubMed, and Embase before May 2024, we included 10 studies in our meta-analysis. The hazard ratios (HRs) with 95% confidence interval (CI) for overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), and progression free survival (PFS) were estimated using fixed effect model.ResultsThis meta-analysis included a total of 2875 patients. UC patients with an elevated preoperative plasma fibrinogen had worse OS (pooled HR: 2.13, 95% CI: 1.81-2.51; P

ABSTRACT Background The aim of this study is to investigate the radiological features of primary pulmonary invasive mucinous adenocarcinoma (IMA) in a relatively large population to help improve its further understanding and its accuracy of initial diagnosis. Methods This retrospective study included consecutive patients with pathologically confirmed primary pulmonary IMA from January 2019 to December 2021. According to tumor morphology, IMAs were divided into regular nodule/mass, irregular, and large consolidative types. According to tumor density, IMAs were divided into solid, halo, part‐solid, pure ground‐glass, and cystic types. ANOVA, chi‐square, or Fisher exact tests were used to analyze the differences in radiological and clinicopathological characteristics of IMA according to morphological and density subtypes. Results We analyzed 312 patients. Pulmonary IMA tended to occur in the elderly, with a slightly higher number of women than men. IMA showed a predominance in the lower lobe and adjacent to pleura. IMA of regular nodule/mass, irregular, and large consolidative types accounted for 80.8% (252/312), 13.8% (43/312), and 5.4% (17/312), respectively. Solid, halo, part‐solid, pure ground‐glass, and cystic IMAs accounted for 55.8% (174/312), 28.2% (88/312), 11.2% (35/312), 1.3% (4/312), and 3.5% (11/312), respectively. The lobulated (76.9%), spiculated (63.5%), and air bronchogram (56.7%) signs were common in IMA. Dead branch sign (88.2%), angiogram sign (88.2%), and satellite nodules/skipping lesions (47.1%) were common in large‐consolidative‐type IMA. Kirsten rat sarcoma viral oncogene mutations were common (56.1%), whereas epidermal growth factor receptor mutations were relatively rare (2.3%). Conclusions Pulmonary IMA of regular nodule/mass type and solid type were the most common at the initial diagnosis. Detailed radiological features can aid in the differential diagnosis of IMA.

Background Oxylipin metabolism plays an essential role in glioma progression and immune modulation in the tumor microenvironment. Lipid metabolic reprogramming has been linked to macrophage remodeling, while the understanding of oxylipins and their catalyzed enzymes lipoxygenases in the regulation of glioma-associated microglia/macrophages (GAMs) remains largely unexplored.Methods To explore the pathophysiological relevance of oxylipin in human glioma, we performed Ultra-high performance liquid chromatography-MS/MS (UHPLC-MS/MS) analysis in human glioma and non-tumor brain tissues. To comprehensively investigate the role of arachidonate lipoxygenase 5 (ALOX5) in glioma, we performed in vivo bioluminescent imaging, immunofluorescence staining and flow cytometry analysis on tumors from orthotopic glioma-bearing mice. We developed an ALOX5-targeted nanobody, and tested its anti-glioma efficacy of combination therapy with α-programmed cell death protein-1 (PD-1).Results In this study, we found that ALOX5 and its oxylipin 5-hydroxyeicosatetraenoic acid (5-HETE) are upregulated in glioma, accumulating programmed death-ligand 1 (PD-L1)+ M2-GAMs and orchestrating an immunosuppressive tumor microenvironment. Mechanistically, 5-HETE derived from ALOX5-overexpressing glioma cells, promotes GAMs migration, PD-L1 expression, and M2 polarization by facilitating nuclear translocation of nuclear factor erythroid 2-related factor 2. Additionally, a nanobody targeting ALOX5 is developed that markedly suppresses 5-HETE efflux from glioma cells, attenuates M2 polarization of GAMs, and consequently ameliorates glioma progression. Furthermore, the combination therapy of the ALOX5-targeted nanobody plus α-PD-1 exhibits superior anti-glioma efficacy.Conclusions Our findings reveal a pivotal role of the ALOX5/5-HETE axis in regulating GAMs and highlight the ALOX5-targeted nanobody as a potential therapeutic agent, which could potentiate immune checkpoint therapy for glioma.

Abstract Complex entangled states are the key resources for measurement-based quantum computations, which is realised by performing a sequence of measurements on initially entangled qubits. Executable quantum algorithms in the graph-state quantum computing model are determined by the entanglement structure and the connectivity of entangled qubits. By generalisation from graph-type entanglement in which only the nearest qubits interact to a new type of hypergraph entanglement in which any subset of qubits can be arbitrarily entangled via hyperedges, hypergraph states represent more general resource states that allow arbitrary quantum computation with Pauli universality. Here we report experimental preparation, certification and processing of complete categories of four-qubit hypergraph states under the principle of local unitary equivalence, on a fully reprogrammable silicon-photonic quantum chip. Genuine multipartite entanglement for hypergraph states is certificated by the characterisation of entanglement witness, and the observation of violations of Mermin inequalities without any closure of distance or detection loopholes. A basic measurement-based protocol and an efficient resource state verification by color-encoding stabilizers are implemented with local Pauli measurement to benchmark the building blocks for hypergraph-state quantum computation. Our work prototypes hypergraph entanglement as a general resource for quantum information processing.

Abstract Background Lamiophlomis rotata (Benth.) Kudo (L. rotata), the oral Traditional Tibetan herbal medicine, is adopted for treating knife and gun wounds for a long time. As previously demonstrated, total iridoid glycoside extract of L. rotata (IGLR) induced polarization of M2 macrophage to speed up wound healing. In diabetic wounds, high levels inflammatory and chemotactic factors are usually related to high reactive oxygen species (ROS) levels. As a ROS target gene, nuclear factor erythroid 2-related factor 2 (NRF2), influences the differentiation of monocytes to M1/M2 macrophages. Fortunately, iridoid glycosides are naturally occurring active compounds that can be used as the oxygen radical scavenger. Nevertheless, the influence of IGLR in diabetic wound healing and its associated mechanism is largely unclear. Materials and methods With macrophages and dermal fibroblasts in vitro, as well as a thickness excision model of db/db mouse in vivo, the role of IGLR in diabetic wound healing and the probable mechanism of the action were investigated. Results Our results showed that IGLR suppressed oxidative distress and inflammation partly through the NRF2/cyclooxygenase2 (COX2) signaling pathway in vitro. The intercellular communication between macrophages and dermal fibroblasts was investigated by the conditioned medium (CM) of IGLR treatment cells. The CM increased the transcription and translation of collagen I (COL1A1) and alpha smooth muscle actin (α-SMA) within fibroblasts. With diabetic wound mice, the data demonstrated IGLR activated the NRF2/KEAP1 signaling and the downstream targets of the pathway, inhibited COX2/PEG2 signaling and decreased the interaction inflammatory targets of the axis, like interleukin-1beta (IL-1β), interleukin 6 (IL-6), apoptosis-associated speck-like protein (ASC), cysteinyl aspartate specific proteinase1 (caspase1) and NOD-like receptor-containing protein 3 (NLRP3).In addition, the deposition of COL1A1, and the level of α-SMA, and Transforming growth factor-β1 (TGF-β1) obviously elevated, whereas that of pro-inflammatory factors reduced in the diabetic wound tissue with IGLR treatment. Conclusion IGLR suppressed oxidative distress and inflammation mainly through NRF2/COX2 axis, thus promoting paracrine and accelerating wound healing in diabetes mice. Graphical Abstract

Abstract Cysteine protease inhibitor 1 (CST1) is a cystatin superfamily protein that inhibits cysteine protease activity and is reported to be involved in the development of many malignancies. Mitochondrial oxidative phosphorylation (OXPHOS) also plays an important role in cancer cell growth regulation. However, the relationship and roles of CST1 and OXPHOS in esophageal squamous cell carcinoma (ESCC) remains unclear. In our pilot study, CST1 was shown the potential of promoting ESCC migration and invasion by the activation of MEK/ERK pathway. Transcriptome sequencing analysis revealed that CST1 is closely associated with OXPHOS. Based on a real-time ATP rate assay, mitochondrial complex I enzyme activity assay, immunofluorescence, co-immunoprecipitation, and addition of the OXPHOS inhibitor Rotenone and MEK/ERK inhibitor PD98059, we determined that CST1 affects mitochondrial complex I enzyme activity by interacting with the GRIM19 protein to elevate OXPHOS levels, and a reciprocal regulatory relationship exists between OXPHOS and the MEK/ERK pathway in ESCC cells. Finally, an in vivo study demonstrated the potential of CST1 in ESCC metastasis through regulation of the OXPHOS and MEK/ERK pathways. This study is the first to reveal the oncogenic role of CST1 in ESCC development by enhancing mitochondrial respiratory chain complex I activity to activate the OXPHOS/MEK/ERK axis, and then promote ESCC metastasis, suggesting that CST1/OXPHOS is a promising target for ESCC treatment.

Abstract Background Glioblastoma (GBM) is a relatively prevalent primary tumor of the central nervous system in children, characterized by its high malignancy and mortality rates, along with the intricate challenges of achieving complete surgical resection. Recently, an increasing number of studies have focused on the crucial role of super-enhancers (SEs) in the occurrence and development of GBM. This study embarks on the task of evaluating the effectiveness of MZ1, an inhibitor of BRD4 meticulously designed to specifically target SEs, within the intricate framework of GBM. Methods The clinical data of GBM patients was sourced from the Chinese Glioma Genome Atlas (CGGA) and the Gene Expression Profiling Interactive Analysis 2 (GEPIA2), and the gene expression data of tumor cell lines was derived from the Cancer Cell Line Encyclopedia (CCLE). The impact of MZ1 on GBM was assessed through CCK-8, colony formation assays, EdU incorporation analysis, flow cytometry, and xenograft mouse models. The underlying mechanism was investigated through RNA-seq and ChIP-seq analyses. Results In this investigation, we made a noteworthy observation that MZ1 exhibited a substantial reduction in the proliferation of GBM cells by effectively degrading BRD4. Additionally, MZ1 displayed a notable capability in inducing significant cell cycle arrest and apoptosis in GBM cells. These findings were in line with our in vitro outcomes. Notably, MZ1 administration resulted in a remarkable decrease in tumor size within the xenograft model with diminished toxicity. Furthermore, on a mechanistic level, the administration of MZ1 resulted in a significant suppression of pivotal genes closely associated with cell cycle regulation and epithelial-mesenchymal transition (EMT). Interestingly, our analysis of RNA-seq and ChIP-seq data unveiled the discovery of a novel prospective oncogene, SDC1, which assumed a pivotal role in the tumorigenesis and progression of GBM. Conclusion In summary, our findings revealed that MZ1 effectively disrupted the aberrant transcriptional regulation of oncogenes in GBM by degradation of BRD4. This positions MZ1 as a promising candidate in the realm of therapeutic options for GBM treatment.

Abstract Background Type 2 diabetes mellitus (T2DM) is closely linked to metabolic syndrome, characterised by insulin resistance, hyperglycaemia, abnormal lipid metabolism, and chronic inflammation. Diabetic ulcers (DUs) comprise consequential complications that arise as a result of T2DM. To investigate, db/db mice were used for the disease model. The findings demonstrated that a scaffold made from a combination of rhubarb charcoal-crosslinked chitosan and silk fibroin, designated as RCS/SF, was able to improve the healing process of diabetic wounds in db/db mice. However, previous studies have primarily concentrated on investigating the impacts of the RSC/SF scaffold on wound healing only, while its influence on the entire body has not been fully elucidated. Material and methods The silk fibroin/chitosan sponge scaffold containing rhubarb charcoal was fabricated in the present study using a freeze-drying approach. Subsequently, an incision with a diameter of 8 mm was made on the dorsal skin of the mice, and the RCS/SF scaffold was applied directly to the wound for 14 days. Subsequently, the impact of RCS/SF scaffold therapy on hepatic lipid metabolism was assessed through analysis of serum and liver biochemistry, histopathology, quantitative real-time PCR (qRT-PCR), immunohistochemistry, and Western blotting. Results The use of the RCS/SF scaffold led to an enhancement in the conditions associated with serum glucolipid metabolism in db/db mice. An assessment of hepatic histopathology further confirmed this enhancement. Additionally, the qRT-PCR analysis revealed that treatment with RCS/SF scaffold resulted in the downregulation of genes associated with fatty acid synthesis, fatty acid uptake, triglyceride (TG) synthesis, gluconeogenesis, and inflammatory factors. Moreover, the beneficial effect of the RCS/SF scaffold on oxidative stress was shown by assessing antioxidant enzymes and lipid peroxidation. Additionally, the network pharmacology analysis verified that the adenosine monophosphate-activated protein kinase (AMPK) signalling pathway had a vital function in mitigating non-alcoholic fatty liver disease (NAFLD) by utilizing R. officinale. The measurement of AMPK, sterol regulatory element binding protein 1 (SREBP1), fatty acid synthase (FASN), and acetyl CoA carboxylase (ACC) gene and protein expression provided support for this discovery. Furthermore, the molecular docking investigations revealed a robust affinity between the active components of rhubarb and the downstream targets of AMPK (SREBP1 and FASN). Conclusion By regulating the AMPK signalling pathway, the RCS/SF scaffold applied topically effectively mitigated hepatic lipid accumulation, decreased inflammation, and attenuated oxidative stress. The present study, therefore, emphasises the crucial role of the topical RCS/SF scaffold in regulating hepatic lipid metabolism, thereby confirming the concept of "external and internal reshaping".

Abstract Background Acute myeloid leukemia (AML) is a malignancy of the hematopoietic system, and childhood AML accounts for about 20% of pediatric leukemia. ANP32B, an important nuclear protein associated with proliferation, has been found to regulate hematopoiesis and CML leukemogenesis by inhibiting p53 activity. However, recent study suggests that ANP32B exerts a suppressive effect on B-cell acute lymphoblastic leukemia (ALL) in mice by activating PU.1. Nevertheless, the precise underlying mechanism of ANP32B in AML remains elusive. Results Super enhancer related gene ANP32B was significantly upregulated in AML patients. The expression of ANP32B exhibited a negative correlation with overall survival. Knocking down ANP32B suppressed the proliferation of AML cell lines MV4-11 and Kasumi-1, along with downregulation of C-MYC expression. Additionally, it led to a significant decrease in H3K27ac levels in AML cell lines. In vivo experiments further demonstrated that ANP32B knockdown effectively inhibited tumor growth. Conclusions ANP32B plays a significant role in promoting tumor proliferation in AML. The downregulation of ANP32B induces cell cycle arrest and promotes apoptosis in AML cell lines. Mechanistic analysis suggests that ANP32B may epigenetically regulate the expression of MYC through histone H3K27 acetylation. ANP32B could serve as a prognostic biomarker and potential therapeutic target for AML patients.

Among persons born in China before 1980 and tested for vaccinia virus Tiantan strain (VVT), 28.7% (137/478) had neutralizing antibodies, 71.4% (25/35) had memory B-cell responses, and 65.7% (23/35) had memory T-cell responses to VVT. Because of cross-immunity between the viruses, these findings can help guide mpox vaccination strategies in China.

Metamaterials have experienced rapid development in recent years. Absorbers made of metamaterials play a crucial role in electromagnetic applications and other fields. The design of metamaterials is usually simulated using simulation software and optimized by traditional algorithms, which is time-consuming and difficult to optimize; deep learning, an emerging method, is gradually being used for both forward and inverse design of metamaterials, but few methods can simultaneously generate the geometric structure of metamaterials and meet the requirements of multiple physical spectra. This paper proposes an improved conditional variational autoencoder (conditional VAE), that is composed by an encoder and a decoder. The encoder generates a Gaussian distribution while acting as an inverse generated network to predict the corresponding geometric parameters. The decoder can generate absorption spectra that satisfy the requirements according to the conditions. By adding batch normalization and spectral normalization in network training, the convergence of the neural network is accelerated, and the stability of the network is increased. The results show that the encoder and decoder can accurately predict the geometric parameters and the absorption spectrum according to the conditions, proving the feasibility of the method. A structural sample of an absorber was processed and tested for verification. The method provides an effective way for the target design of absorbers and a new approach for the design of other electromagnetic metamaterials.

Abstract Background We aimed to develop a combined model based on radiomics and computed tomography (CT) imaging features for use in differential diagnosis of benign and malignant subcentimeter (≤ 10 mm) solid pulmonary nodules (SSPNs). Methods A total of 324 patients with SSPNs were analyzed retrospectively between May 2016 and June 2022. Malignant nodules (n = 158) were confirmed by pathology, and benign nodules (n = 166) were confirmed by follow-up or pathology. SSPNs were divided into training (n = 226) and testing (n = 98) cohorts. A total of 2107 radiomics features were extracted from contrast-enhanced CT. The clinical and CT characteristics retained after univariate and multivariable logistic regression analyses were used to develop the clinical model. The combined model was established by associating radiomics features with CT imaging features using logistic regression. The performance of each model was evaluated using the area under the receiver-operating characteristic curve (AUC). Results Six CT imaging features were independent predictors of SSPNs, and four radiomics features were selected after a dimensionality reduction. The combined model constructed by the logistic regression method had the best performance in differentiating malignant from benign SSPNs, with an AUC of 0.942 (95% confidence interval 0.918–0.966) in the training group and an AUC of 0.930 (0.902–0.957) in the testing group. The decision curve analysis showed that the combined model had clinical application value. Conclusions The combined model incorporating radiomics and CT imaging features had excellent discriminative ability and can potentially aid radiologists in diagnosing malignant from benign SSPNs. Relevance statement The model combined radiomics features and clinical features achieved good efficiency in predicting malignant from benign SSPNs, having the potential to assist in early diagnosis of lung cancer and improving follow-up strategies in clinical work. Key points • We developed a pulmonary nodule diagnostic model including radiomics and CT features. • The model yielded the best performance in differentiating malignant from benign nodules. • The combined model had clinical application value and excellent discriminative ability. • The model can assist radiologists in diagnosing malignant from benign pulmonary nodules. Graphical Abstract

[This corrects the article DOI: 10.1371/journal.ppat.1003231.].

The recent remarkable success of mesoporous silica nanoparticle (MSN) technology has stimulated intensive efforts to expand nanoparticle strategies to treat various diseases. However, as an anti-tumor drug delivery system, traditional MSN is prone to clearance by the host immune system, resulting in suboptimal pharmacokinetics and inadequate drug concentrations in tumors. The emergence of biomimetic drug delivery systems has effectively addressed these challenges. In this study, we aimed to develop a biomimetic drug delivery system based on MSN to achieve both immune evasion and tumor targeting. To this end, we coated folic acid-modified mesoporous silica (FMSN) cores with lipid-hybridized macrophage membranes (HEs) through co-extrusion, yielding FMSN@HEs. Initially, we demonstrated effective retention of key proteins Integrin α4 and Integrin β1 in the HEs, leading to significantly reduced clearance of FMSN@HEs by phagocytes in vitro. CCK-8 experiments validated the ability of CUR-FMSN@HEs to effectively inhibit the proliferation of tumor cells. In tumor-bearing mice, FMSN@HEs exhibited stronger tumor targeting and penetration abilities compared to MSN without HEs. The immune escape and tumor-targeting properties of the FMSN@HEs suggest that they could be used as novel bionic drug carriers, potentially providing more options for antitumor therapy.

Abstract Deciphering cellular interactions is essential to both understand the mechanisms underlying a broad range of human diseases, but also to manipulate therapies targeting these diseases. Here, the formation of cell doublets resulting from specific membrane ligand‐receptor interactions is discovered. Based on this phenomenon, the study developed DoubletSeeker, a novel high‐throughput method for the reliable identification of ligand‐receptor interactions. The study shows that DoubletSeeker can accurately identify T cell receptor (TCR)‐antigen interactions with high sensitivity and specificity. Notably, DoubletSeeker effectively captured paired TCR‐peptide major histocompatibility complex (pMHC) information during a highly complex library‐on‐library screening and successfully identified three mutant TCRs that specifically recognize the MART‐1 epitope. In turn, DoubletSeeker can act as an antigen discovery platform that allows for the development of novel immunotherapy targets, making it valuable for investigating fundamental tumor immunology.

Abstract Background To rehabilitate the depleted fish resources of the Yangtze River Basin, China, a 10-year fishing ban has been implemented. This national initiative has attracted worldwide attention. The present study aimed to explore the ecological process and recovery effectiveness of this complete fishing ban in the Chishui River, the first river where the fishing ban was enacted in the Yangtze River Basin. Changes in fish resources were analyzed based on investigations conducted 5 years before (2012–2016) and 5 years after (2017–2021) the implementation of the fishing ban in four reaches along the longitudinal gradient. Results A total of 140 fish species, including 127 native and 13 exotic species, were collected during the study period. The number of fish species as well as the diversity indices showed no significant temporal changes. However, 11 native species that had disappeared for many years appeared again after the fishing ban. The occurrence rates of some key protected species, Procypris rabaudi, Acipenser dabryanus, Euchiloglanis davidi and Myxocyprinus asiaticus, increased after the fishing ban, while Coreius guichenoti, Percocypris pingi, Onychostoma angustistomata and Leptobotia rubrilabris showed no obvious recovery. The fish assemblage structure in nearly all reaches (except the headwater) showed significant temporal changes with an increase in the relative abundance of larger body-sized species. The population structure of most dominant species improved greatly with the mean standard length and the mean body weight as well as the proportion of larger-sized individuals clearly increasing. In addition, the density of fishes changed dramatically with the catch per unit effort (CPUE) increasing by 140–210% for different study reaches. Conclusions The present study confirmed that the complete fishing closure is an effective measure to facilitate fish resources recovery. These results provide valuable references for evaluating the effectiveness of the 10-year fishing ban policy in the entire Yangtze River.

Metformin is the initial medication recommended for the treatment of type 2 diabetes mellitus (T2DM). In addition to diabetes treatment, the function of metformin also can be anti-aging, antiviral, and anti-inflammatory. Nevertheless, further exploration is required to fully understand its mode of operation. Historically, the liver has been acknowledged as the main location where metformin reduces glucose levels, however, there is increasing evidence suggesting that the gastrointestinal tract also plays a significant role in its action. In the gastrointestinal tract, metformin effects glucose uptake and absorption, increases glucagon-like peptide-1 (GLP-1) secretion, alters the composition and structure of the gut microbiota, and modulates the immune response. However, the side effects of it cannot be ignored such as gastrointestinal distress in patients. This review outlines the impact of metformin on the digestive system and explores potential explanations for variations in metformin effectiveness and adverse effects like gastrointestinal discomfort.

Abstract Background This study aimed to investigate the radiological, pathological, and prognostic characteristics of large consolidative‐type pulmonary invasive mucinous adenocarcinomas (IMA). Methods We retrospectively reviewed 738 patients who confirmed IMA between January 2010 and August 2022, and two radiologists reviewed imaging data to determine subtypes. We included 41 patients with pathologically large consolidative‐type IMA. We analyzed their radiological, pathological, and prognostic characteristics. The recurrence‐free survival (RFS) and overall survival (OS) were determined using the Kaplan–Meier method. Results Most lesions were located in the lower lobe, with 46.3% patients showing multiple lesions. Halo, angiogram, vacuole, air bronchogram, and dead branch sign were observed in 97.6%, 73.2%, 63.4%, 61.0%, and 61.0% of the cases, respectively. Unevenly low enhancement was observed in 88.89% of patients. T3 and T4 pathological stages were observed in 50.0% and 30.6% of patients, respectively. Lymph node metastasis was observed in 16.7% patients, with no distant metastasis. Spread‐through air spaces and intrapulmonary dissemination were observed in 27.8% and 19.4% patients, respectively. Moreover, Kirsten rat sarcoma viral oncogene mutations were found in 68.6% of cases, and no epidermal growth factor receptor mutations were seen. Among all mutation sites, G12V mutation is the most common, accounting for 40%. The average RFS and OS were 19.4 and 66.4 months, respectively, with 3‐year RFS and OS rates of 30.0% and 75.0%, respectively. Pleural invasion and lymph node metastasis were independent risk factors for diagnosis. Conclusion Halo, vacuole, angiogram, and dead branch signs were frequently observed in consolidative‐type IMA. Kirsten rat sarcoma viral oncogene mutations are common in consolidative‐type IMA, especially site G12V, whereas epidermal growth factor receptor mutations were rare; therefore, gene immunotherapy was more difficult. Most patients were in stage T3–T4; however, lymph node metastasis was rare.

Summary: Influenza A virus (IAV) represents a constant public health threat. The single-stranded, segmented RNA genome of IAV is replicated in host cell nuclei as a series of 8 ribonucleoprotein complexes (vRNPs) with RNA structures known to exert essential function to support viral replication. Here, we investigate RNA secondary structures and RNA interactions networks of the IAV genome and construct an in vivo structure model for each of the 8 IAV genome segments. Our analyses reveal an overall in vivo and in virio resemblance of the IAV genome conformation but also wide disparities among long-range and intersegment interactions. Moreover, we identify a long-range RNA interaction that exerts an essential role in genome packaging. Disrupting this structure displays reduced infectivity, attenuating virus pathogenicity in mice. Our findings characterize the in vivo RNA structural landscape of the IAV genome and reveal viral RNA structures that can be targeted to develop antiviral interventions.

Background: Apathy is a common neuropsychiatric manifestations in Parkinson’s disease (PD), but neural network mechanisms still remain elusive. We aim to investigate the topological alteration of the brain structural network in PD with apathy. Method: In the present study, a total of 47 apathetic PD (aPD) patients, 37 non-apathetic PD (naPD) patients, and 40 healthy controls (HCs) were enrolled. Diffusion tensor imaging (DTI) in conjunction with graph-theoretic approaches were used to explore the alterations of topological properties of the WM structural network arising from apathy in PD. One-way analysis of covariance and post hoc analyses were performed to explore differences among the three groups. Correlations were ascertained to examine relationships between the Starkstein Apathy Scale (AS) scores and significantly different network metrics among the three groups. Results: Both aPD and naPD patients remained small-world topology. However, compared with the naPD patients, aPD patients showed increased clustering coefficient (Cp) at the global level. At the regional level, aPD exhibited decreased nodal properties, mainly in the right dorsolateral prefrontal cortex (DLPFC), the right caudate nucleus (CAU), the right hippocampus, and the right superior parietal gyrus. Further, AS scores were negatively correlated with degree centrality of the right DLPFC (r = −0.254, p = 0.020) and the right CAU ( r = −0.357, p = 0.001) in the pooled patients with PD. Conclusions: The findings suggested that apathy in PD presented relatively optimized global topological properties of the brain structural network and disrupted topological organization of the regional network, particularly involving the fronto-striatal-limbic circuits. The altered topological properties of abnormal brain regions might be used to understand the physiopathologic mechanism of the neural network in aPD patients.

Abstract Background In China, over 50% of lung cancer cases occur in nonsmokers. Thus, identifying high‐risk individuals for targeted lung cancer screening is crucial. Beyond age and smoking, determining other risk factors for lung cancer in the Asian population has become a focal point of research. Using 30,000 participants in the prospectively enrolled cohort at China's National Cancer Center (NCC) over the past 14 years, we categorized participants by risk, with an emphasis on nonsmoking females. Materials and Methods Between November 2005 and December 2019, 31,431 individuals voluntarily underwent low‐dose computed tomography (LDCT) scans for lung cancer screening at the NCC. We recorded details like smoking history, exposure to hazards, and family history of malignant tumors. Using the 2019 NCCN criteria, participants were categorized into high‐, moderate‐, and low‐risk groups. Additionally, we separated non‐high‐risk groups into female never smokers (aged over 40) exposed to second‐hand smoke (SHS) and others. Any positive results from initial scans were monitored per the I‐ELCAP protocol (2006), and suspected malignancies were addressed through collaborative decisions between patients and physicians. We analyzed and compared the detection rates of positive results, confirmed lung cancers, and cancer stages across risk, age, and gender groups. Results Out of 31,431 participants (55.9% male, 44.1% female), 3695 (11.8%) showed positive baseline LDCT scans with 197 (0.6%; 106 females, 91 males) confirmed as lung cancer cases pathologically. Malignancy rate by age was 0.1% among those aged under 40 years, 0.4% among those aged 40–49 years, 0.8% among those aged 50–59 years, and 1.2% among those aged 60 years and older. From the 25,763 participants (56.9% male, 43.1% female) who completed questionnaires, 1877 (7.3%) were categorized as high risk, 6500 (25.2%) as moderate risk, and 17,386 (67.5%) as low risk. Of the 23,886 in the non‐high‐risk category, 8041 (33.7%) were females over 40 years old exposed to SHS. The high‐risk group showed the highest lung cancer detection rate at 1.4%. However, females exposed to SHS had a notably higher detection rate than the rest of the non‐high‐risk group (1.1% vs. 0.5%; p

The gut microbiota undergoes substantial changes in COVID-19 patients; yet, the utility of these alterations as prognostic biomarkers at the time of hospital admission, and its correlation with immunological and hematological parameters, remains unclear. The objective of this study is to investigate the gut microbiota's dynamic change in critically ill patients with COVID-19 and evaluate its predictive capability for clinical outcomes alongside immunological and hematological parameters. In this study, anal swabs were consecutively collected from 192 COVID-19 patients (583 samples) upon hospital admission for metagenome sequencing. Simultaneously, blood samples were obtained to measure the concentrations of 27 cytokines and chemokines, along with hematological and biochemical indicators. Our findings indicate a significant correlation between the composition and dynamics of gut microbiota with disease severity and mortality in COVID-19 patients. Recovered patients exhibited a higher abundance of Veillonella and denser interactions among gut commensal bacteria compared to deceased patients. Furthermore, the abundance of gut commensal bacteria exhibited a negative correlation with the concentration of proinflammatory cytokines and organ damage markers. The gut microbiota upon admission showed moderate prognostic prediction ability with an AUC of 0.78, which was less effective compared to predictions based on immunological and hematological parameters (AUC 0.80 and 0.88, respectively). Noteworthy, the integration of these three datasets yielded a higher predictive accuracy (AUC 0.93). Our findings suggest the gut microbiota as an informative biomarker for COVID-19 prognosis, augmenting existing immune and hematological indicators.

In this study, the FTIR spectrometer-based rotating double-sided reflective mirror (RDRM) is presented. By introducing the RDRM and corner reflector, an optical path difference (Opd) is generated between the two separated light beams. The instrument is highly stable. Spectral restoration is achieved by the scale, which is precalculated using a laser interferogram. This method suppresses the influence of non-linearity and inherent errors on the restored spectrum. We elaborate on this principle through a theoretical analysis and simulation. Based on a set of design parameters, we successfully restored the spectrum with spectral resolution of 0.25 cm−1 through scale in the case of error (average is –13.88 μm and the mean square deviation is 5.7 μm). The relative spectral mean square error (SMSE) is 0.0013 and the spectral correlation coefficient (SCC) is 0.9997.

Abstract Colorectal cancer (CRC) has become a global health problem which has almost highest morbidity and mortality in all types of cancers. This study aimed to uncover the biological functions and underlying mechanism of MCM8 in the development and progression of CRC. The expression level of MCM8 was found to be upregulated in CRC tissues and significantly associated with tumor grade and patients’ survival. Knocking down MCM8 expression in CRC cells could restrain cell growth and cell motility while promoting cell apoptosis in vitro, as well as inhibit tumor growth in xenograft mice model. Based on the RNA screening performing on CRC cells with or without MCM8 knockdown and the following IPA analysis, CHSY1 was identified as a potential target of MCM8 in CRC, whose expression was also found to be higher in tumor tissues than in normal tissues. Moreover, it was demonstrated that MCM8 may regulate the expression of CHSY1 through affecting its NEDD4-mediated ubiquitination, both of which synergistically execute tumor promotion effects on CRC. In conclusion, the outcomes of our study showed the first evidence that MCM8 act as a tumor promotor in CRC, and may be a promising therapeutic target of CRC treatment.

Abstract Bats, recognized as considerable reservoirs for coronaviruses (CoVs), serve as natural hosts for several highly pathogenic CoVs, including SARS-CoV and SARS-CoV-2. Investigating the bat CoV community provides insights into the origin for highly pathogenic CoVs and highlights bat CoVs with potential spillover risks. This study probes the evolution, recombination, host range, geographical distribution, and cross-species transmission characteristics of bat CoVs across China and its associated CoVs in other regions. Through detailed research on 13,064 bat samples from 14 provinces of China, 1141 CoV strains are found across 10 subgenera and one unclassified Alpha-CoV, generating 399 complete genome sequences. Within bat CoVs, 11 new CoV species are identified and 425 recombination events are detected. Bats in southern China, particularly in Yunnan province, exhibit a pronounced diversity of CoVs. Limited sampling and low detection rates exist for CoVs in Myotacovirus, Nyctacovirus, Hibecovirus, Nobecovirus in China. The genus Myotis is highlighted as a potential ancestral host for Alpha-CoV, with the genus Hipposideros suggested as a likely progenitor host for bat-associated Beta-CoV, indicating the complexity of cross-species transmission dynamics. Through the comprehensive analysis, this study enriches the understanding of bat CoVs and offers a valuable resource for future research.

Abstract One of the characteristics of leukemia is that it contains multiple rearrangements of signal transduction genes and overexpression of non-mutant genes, such as transcription factors. As an important regulator of hematopoietic stem cell development and erythropoiesis, LMO2 is considered an effective carcinogenic driver in T cell lines and a marker of poor prognosis in patients with AML with normal karyotype. LDB1 is a key factor in the transformation of thymocytes into T-ALL induced by LMO2, and enhances the stability of carcinogenic related proteins in leukemia. However, the function and mechanism of LMO2 and LDB1 in AML remains unclear. Herein, the LMO2 gene was knocked down to observe its effects on proliferation, survival, and colony formation of NB4, Kasumi-1 and K562 cell lines. Using mass spectrometry and IP experiments, our results showed the presence of LMO2/LDB1 protein complex in AML cell lines, which is consistent with previous studies. Furthermore, in vitro and in vivo experiments revealed that LDB1 is essential for the proliferation and survival of AML cell lines. Analysis of RNA-seq and ChIP-Seq results showed that LDB1 could regulate apoptosis-related genes, including LMO2. In LDB1-deficient AML cell lines, the overexpression of LMO2 partially compensates for the proliferation inhibition. In summary, our findings revealed that LDB1 played an important role in AML as an oncogene, and emphasize the potential importance of the LMO2/LDB1 complex in clinical treatment of patients with AML.

Abstract A pediatric patient suffered from renal and hepatic abscesses (through hepatorenal space) and recovered by antibiotics and other therapies. By clinical analysis, the multi-organ abscesses might be caused by bloodstream-disseminated infection. In order to identify the pathogen, we collected kidney biopsy tissue, swabs, and plasma samples, and used metagenomics next-generation sequencing (mNGS) and some traditional methods. The results revealed that polymicrobial especially anaerobic bacteremia (Bacteroides fragilis, et al.) contributed to the abscess formation. What is more, systematic human adenovirus C (HAdV-C) infection was shown, and the virus was isolated. The titer of HAdV-2 neutralizing antibodies was 1/4 in the plasma after symptoms onset. Although the exact mechanism of HAdV-2 infection in multiple abscess formation has not been clarified, the case of multi-organ abscesses in the context of polymicrobial especially anaerobic bacteremia and HAdV infection in healthy children is infrequent.

Abstract The bat coronaviruses (CoV) BANAL-20-52 and BANAL-20-236 are two newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) closely related coronaviruses (SC2r-CoV) and the genome of BANAL-20-52 shares the highest homology with SARS-CoV-2. However, the risk of their potential zoonotic transmission has not been fully evaluated. Here, we determined their potential host susceptibility among 13 different bat species and 26 different animal species, and found that both might have extensive host ranges, indicating high zoonotic transmission potential. We also determined the cryo-EM structures of BANAL-20-52 and BANAL-20-236 S proteins at pH 5.5 and the complex of BANAL-20-236 S1 and Rhinolophus affinis ACE2, and found that both trimeric S proteins adopt all three receptor binding domains (RBDs) in “closed” conformation and are more compact than SARS-CoV-2. Strikingly, the unique sugar moiety at N370 of bat SC2r-CoVs acts like a “bolt” and crosses over two neighboring subunits, facilitating the S proteins in the locked conformation and underpinning the architecture stability. Removal of the glycosylation at N370 by a T372A substitution substantially enhances virus infectivity but becomes highly sensitive to trypsin digestion at pH 5.5, a condition roughly mimicking the insectivorous bat’s stomach digestion. In contrast, WT S proteins of SC2r-CoVs showed considerable resistance to trypsin digestion at pH 5.5, indicating that the highly conserved T372 in bat CoVs might result from the selective advantages in stability during the fecal-oral transmission over A372. Moreover, the results of cross-immunogenicity among S proteins of SARS-CoV-2, BANAL-20-52, and BANAL-20-236 showed that A372 pseudoviruses are more sensitive to anti-S sera than T372, indicating that immune evasion might also play a role in the natural selection of T372 over A372 during evolution. Finally, residues 493 and 498 of the S protein affect host susceptibility, and residue 498 also influences the immunogenicity of the S protein. Together, our findings aid a better understanding of the molecular basis of CoV entry, selective evolution, and immunogenicity and highlight the importance of surveillance of susceptible hosts of these viruses to prevent potential outbreaks.

Abstract Background Rat sarcoma viral oncogene homolog (RAS) gene mutation is a common molecular event in colorectal cancer (CRC). The prognosis of mCRC (metastatic colorectal cancer) patients with RAS mutation is poor and capecitabine and oxaliplatin (CapeOx) plus bevacizumab has shown to be one of the standard therapeutic regimens as first line for these patients with objective response rate (ORR) of ~ 50% and median progression-free survival (mPFS) of 8–9 months. Immunotherapy, especially anti-programmed death 1 (PD-1) monoclonal antibody has demonstrated ground-breaking results in deficient mismatch repair (dMMR) / microsatellite instability-high (MSI-H) mCRC patients. However, the response rate of in microsatellite stable (MSS) patients is extremely low. In addition, preclinical studies have demonstrated that anti-Vascular endothelial growth factor (VEGF) agents, such as bevacizumab, can induce tumor vascular normalization and enhance antitumor immunity. Previous study indicated the combination of chemotherapy, anti-VEGF agents (bevacizumab) with immune checkpoint inhibitors may have promising clinical activity in RAS mutant, MSS refractory mCRC patients. Based on these evidences, we will explore the combination of CapeOx with bevacizumab and sintilimab (anti-PD-1 monoclonal antibody) in RAS mutant, MSS mCRC patients as first-line therapy. Methods This is a randomized, open-label, multicentric clinical trial. In the sintilimab arm, patients will receive sintilimab in combination with CapeOx and bevacizumab. In the control arm, patients will receive CapeOx and bevacizumab. This trial will recruit 494 patients from 20 centers and randomly (1:1) disseminated into two groups. The primary endpoint is the PFS. The secondary endpoints include overall survival, safety, ORR, and disease control rate. Discussion This study may provide new ideas for optimizing oncology treatment planning for RAS mutant, MSS mCRC patients in the first-line set. Trial registration This study is short for BBCAPX and has been registered at clinicaltrials.gov registry with identifier NCT05171660.

Abstract Background Immune inflammatory responses play an important role in spinal cord injury (SCI); however, the beneficial and detrimental effects remain controversial. Many studies have described the role of neutrophils, macrophages, and T lymphocytes in immune inflammatory responses after SCI, although little is known about the role of B lymphocytes, and immunosuppression can easily occur after SCI. Methods A mouse model of SCI was established, and HE staining and Nissl staining were performed to observe the pathological changes. The size and morphology of the spleen were examined, and the effects of SCI on spleen function and B cell levels were detected by flow cytometry and ELISA. To explore the specific mechanism of immunosuppression after SCI, B cells from the spleens of SCI model mice were isolated using magnetic beads and analyzed by 4D label-free quantitative proteomics. The level of inflammatory cytokines and iron ions were measured, and the expression of proteins related to the Tom20 pathway was quantified by western blotting. To clarify the relationship between iron ions and B cell pyroptosis after SCI, we used FeSO4 and CCCP, which induce oxidative stress to stimulate SCI, to interfere with B cell processes. siRNA transfection to knock down Tom20 (Tom20-KD) in B cells and human B lymphocytoma cell was used to verify the key role of Tom20. To further explore the effect of iron ions on SCI, we used deferoxamine (DFO) and iron dextran (ID) to interfere with SCI processes in mice. The level of iron ions in splenic B cells and the expression of proteins related to the Tom20–Bax–caspase–gasdermin E (GSDME) pathway were analyzed. Results SCI could damage spleen function and lead to a decrease in B cell levels; SCI upregulated the expression of Tom20 protein in the mitochondria of B cells; SCI could regulate the concentration of iron ions and activate the Tom20–Bax–caspase–GSDME pathway to induce B cell pyroptosis. Iron ions aggravated CCCP-induced B cell pyroptosis and human B lymphocytoma pyroptosis by activating the Tom20–Bax–caspase–GSDME pathway. DFO could reduce inflammation and promote repair after SCI by inhibiting Tom20–Bax–caspase–GSDME-induced B cell pyroptosis. Conclusions Iron overload activates the Tom20–Bax–caspase–GSDME pathway after SCI, induces B cell pyroptosis, promotes inflammation, and aggravates the changes caused by SCI. This may represent a novel mechanism through which the immune inflammatory response is induced after SCI and may provide a new key target for the treatment of SCI.

All cells release extracellular vesicles (EVs) as part of their normal physiology. As one of the subtypes, exosomes (EXOs) have an average size range of approximately 40 nm–160 nm in diameter. Benefiting from their inherent immunogenicity and biocompatibility, the utility of autologous EXOs has the potential for both disease diagnosis/treatment. EXOs are generally employed as “bioscaffolds” and the whole diagnostic and therapeutic effects are mainly ascribed to exogenous cargos on the EXOs, such as proteins, nucleic acids, and chemotherapeutic agents and fluorophores delivered into specific cells or tissues. Surface engineering of EXOs for cargo loadings is one of the prerequisites for EXO-mediated diagnosis/treatment. After revisiting EXO-mediated diagnosis/treatment, the most popular strategies to directly undertake loadings of exogenous cargos on EXOs include genetic and chemical engineering. Generally, genetically-engineered EXOs can be merely produced by living organisms and intrinsically face some drawbacks. However, chemical methodologies for engineered EXOs diversify cargos and extend the functions of EXOs in the diagnosis/treatment. In this review, we would like to elucidate different chemical advances on the molecular level of EXOs along with the critical design required for diagnosis/treatment. Besides, the prospects of chemical engineering on the EXOs were critically addressed. Nevertheless, the superiority of EXO-mediated diagnosis/treatment via chemical engineering remains a challenge in clinical translation and trials. Furthermore, more chemical crosslinking on the EXOs is expected to be explored. Despite substantial claims in the literature, there is currently no review to exclusively summarize the chemical engineering to EXOs for diagnosis/treatment. We envision chemical engineering of EXOs will encourage more scientists to explore more novel technologies for a wider range of biomedical applications and accelerate the successful translation of EXO-based drug “bioscaffolds” from bench to bedside.

Background: Breast cancer (BC) ranks as the most prevalent malignancy affecting women globally, with apoptosis playing a pivotal role in its pathological progression. Despite the crucial role of apoptosis in BC development, there is limited research exploring the relationship between BC prognosis and apoptosis-related genes (ARGs). Therefore, this study aimed to establish a BC-specific risk model centered on apoptosis-related factors, presenting a novel approach for predicting prognosis and immune responses in BC patients. Methods: Utilizing data from The Cancer Gene Atlas (TCGA), Cox regression analysis was employed to identify differentially prognostic ARGs and construct prognostic models. The accuracy and clinical relevance of the model, along with its efficacy in predicting immunotherapy outcomes, were evaluated using independent datasets, Receiver Operator Characteristic (ROC) curves, and nomogram. Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were used to predict potential mechanical pathways. The CellMiner database is used to assess drug sensitivity of model genes. Results: A survival risk model comprising eight prognostically relevant apoptotic genes (PMAIP1, TP53AIP1, TUBA3D, TUBA1C, BCL2A1, EMP1, GSN, F2) was established based on BC patient samples from TCGA. Calibration curves validated the ROC curve and nomogram, demonstrating excellent accuracy and clinical utility. In samples from the Gene Expression Omnibus (GEO) datasets and immunotherapy groups, the low-risk group (LRG) demonstrated enhanced immune cell infiltration and improved immunotherapy responses. Model genes also displayed positive associations with sensitivity to multiple drugs, including vemurafenib, dabrafenib, PD-98059, and palbociclib. Conclusions: This study successfully developed and validated a prognostic model based on ARGs, offering new insights into prognosis and immune response prediction in BC patients. These findings hold promise as valuable references for future research endeavors in this field.

The glucose-lowering drug metformin alters the composition of the gut microbiome in patients with type 2 diabetes mellitus (T2DM) and other diseases. Nevertheless, most studies on the effects of this drug have relied on fecal samples, which provide limited insights into its local effects on different regions of the gut. Using a high-fat diet (HFD)-induced mouse model of T2DM, we characterize the spatial variability of the gut microbiome and associated metabolome in response to metformin treatment. Four parts of the gut as well as the feces were analyzed using full-length sequencing of 16S rRNA genes and targeted metabolomic analyses, thus providing insights into the composition of the microbiome and associated metabolome. We found significant differences in the gut microbiome and metabolome in each gut region, with the most pronounced effects on the microbiomes of the cecum, colon, and feces, with a significant increase in a variety of species belonging to Akkermansiaceae, Lactobacillaceae, Tannerellaceae, and Erysipelotrichaceae. Metabolomics analysis showed that metformin had the most pronounced effect on microbiome-derived metabolites in the cecum and colon, with several metabolites, such as carbohydrates, fatty acids, and benzenoids, having elevated levels in the colon; however, most of the metabolites were reduced in the cecum. Thus, a wide range of beneficial metabolites derived from the microbiome after metformin treatment were produced mainly in the colon. Our study highlights the importance of considering gut regions when understanding the effects of metformin on the gut microbiome and metabolome.