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Abstract The retina, an anatomical extension of the brain, forms physiological connections with the visual cortex of the brain. Although retinal structures offer a unique opportunity to assess brain disorders, their relationship to brain structure and function is not well understood. In this study, we conducted a systematic cross-organ genetic architecture analysis of eye-brain connections using retinal and brain imaging endophenotypes. We identified novel phenotypic and genetic links between retinal imaging biomarkers and brain structure and function measures from multimodal magnetic resonance imaging (MRI), with many associations involving the primary visual cortex and visual pathways. Retinal imaging biomarkers shared genetic influences with brain diseases and complex traits in 65 genomic regions, with 18 showing genetic overlap with brain MRI traits. Mendelian randomization suggests bidirectional genetic causal links between retinal structures and neurological and neuropsychiatric disorders, such as Alzheimer’s disease. Overall, our findings reveal the genetic basis for eye-brain connections, suggesting that retinal images can help uncover genetic risk factors for brain disorders and disease-related changes in intracranial structure and function.

Abstract CD8+ T-cell exhaustion is a promising prognostic indicator of sepsis-induced acute respiratory distress syndrome (ARDS). Patients with sepsis-related ARDS had reduced levels of HSP90AA1. However, whether the changes in CD8+ T cells were related to HSP90α, encoded by the HSP90AA1 gene, was unclear. This study aimed to examine the regulatory mechanism of HSP90α and its impact on CD8+ T-cell exhaustion in lipopolysaccharide (LPS)-induced acute lung injury (ALI). In this study, by conducting a mouse model of ALI, we found that one week after LPS-induced ALI, CD8+ T cells showed exhaustion characteristics. At this time, proliferation and cytokine release in CD8+ T cells were reduced. The inhibitory costimulatory factors PD-1 and Tim-3, on the other hand, were enhanced. Meanwhile, the expression of HSP90α and STAT1 decreased significantly. The in vitro studies showed that HSP90α stimulation or inhibition affected the CD8+ T-cell exhaustion phenotype. Interference with STAT1 reduced the expression of HSP90α and impaired its regulation of CD8+ T cells. The Co-Immunoprecipitation results indicated that HSP90α can directly or indirectly bind to TOX to regulate TOX expression and downstream signal transduction. In summary, by inhibiting TOX-mediated exhaustion signaling pathways, HSP90α inhibited CD8+ T-cell exhaustion in ALI. The participation of STAT1 in the regulation of HSP90α was required.

Abstract Background Exploration of adaptive evolutionary changes at the genetic level in vaginal microbial communities during different stages of cervical cancer remains limited. This study aimed to elucidate the mutational profile of the vaginal microbiota throughout the progression of cervical disease and subsequently establish diagnostic models. Methods This study utilized a metagenomic dataset consisting of 151 subjects classified into four categories: invasive cervical cancer (CC) (n = 42), cervical intraepithelial neoplasia (CIN) (n = 43), HPV-infected (HPVi) patients without cervical lesions (n = 34), and healthy controls (n = 32). The analysis focused on changes in microbiome abundance and extracted information on genetic variation. Consequently, comprehensive multimodal microbial signatures associated with CC, encompassing taxonomic alterations, mutation signatures, and enriched metabolic functional pathways, were identified. Diagnostic models for predicting CC were established considering gene characteristics based on single nucleotide variants (SNVs). Results In this study, we screened and analyzed the abundances of 18 key microbial strains during CC progression. Additionally, 71,6358 non-redundant mutations were identified, predominantly consisting of SNVs that were further annotated into 25,773 genes. Altered abundances of SNVs and mutation types were observed across the four groups. Specifically, there were 9847 SNVs in the HPV-infected group and 14,892 in the CC group. Furthermore, two distinct mutation signatures corresponding to the benign and malignant groups were identified. The enriched metabolic pathways showed limited similarity with only two overlapping pathways among the four groups. HPVi patients exhibited active nucleotide biosynthesis, whereas patients with CC demonstrated a significantly higher abundance of signaling and cellular-associated protein families. In contrast, healthy controls showed a distinct enrichment in sugar metabolism. Moreover, biomarkers based on microbial SNV abundance displayed stronger diagnostic capability (cc.AUC = 0.87) than the species-level biomarkers (cc.AUC = 0.78). Ultimately, the integration of multimodal biomarkers demonstrated optimal performance for accurately identifying different cervical statuses (cc.AUC = 0.86), with an acceptable performance (AUC = 0.79) in the external testing set. Conclusions The vaginal microbiome exhibits specific SNV evolution in conjunction with the progression of CC, and serves as a specific biomarker for distinguishing between different statuses of cervical disease.

Background & Aims: The lymphatic system plays crucial roles in maintaining fluid balance and immune regulation. Studying the liver lymphatics has been considered challenging, as common lymphatic endothelial cell (LyEC) markers are expressed by other liver cells. Additionally, isolation of sufficient numbers of LyECs has been challenging because of their extremely low abundance (

Abstract Background Acute type A aortic dissection (AAAD) is a devastating disease. Human aortic smooth muscle cells (HASMCs) exhibit decreased proliferation and increased apoptosis, and integrin α5β1 and FAK are important proangiogenic factors involved in regulating angiogenesis. The aim of this study was to investigate the role of integrin α5β1 and FAK in patients with AAAD and the potential underlying mechanisms. Methods Aortic tissue samples were obtained from 8 patients with AAAD and 4 organ donors at Zhongshan Hospital of Fudan University. The level of apoptosis in the aortic tissues was assessed by immunohistochemical (IHC) staining and terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assays. The expression of integrin α5β1 and FAK was determined. Integrin α5β1 was found to be significantly expressed in HASMCs, and its interaction with FAK was assessed via coimmunoprecipitation (Co-IP) analysis. Proliferation and apoptosis were assessed by Cell Counting Kit-8 (CCK-8) assays and flow cytometry after integrin α5β1 deficiency. Results The levels of integrin α5β1 and FAK were both significantly decreased in patients with AAAD. Downregulating the expression of integrin α5β1-FAK strongly increased apoptosis and decreased proliferation in HASMCs, indicating that integrin α5β1-FAK might play an important role in the development of AAAD. Conclusions Downregulation of integrin α5β1-FAK is associated with increased apoptosis and decreased proliferation in aortic smooth muscle cells and may be a potential therapeutic strategy for AAAD.

Abstract Objective Our current study aimed to assess the relationship between TNF-related apoptosis-inducing ligand (TRAIL) and ferroptosis in non-small cell lung cancer (NSCLC) development. Methods The expression of TRAIL was detected by western blot, RT-qRCR and immunohistochemistry. The viability of NSCLC cells was analyzed by CCK-8 kit. The migration and invasion of NSCLC cells were detected by wound healing assay and transwell assay, respectively. Labile iron pool (LIP) was detected based on the calcein-acetoxymethyl ester method. Ferrous iron (Fe2+) and iron levels were assessed by detection kits. The levels of superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) were measured using corresponding detection kits. Mice tumor xenograft models were used for the in vivo research. Results The expression of TRAIL was reduced in H1299, NCL-H1395, and A549 cells compared with BEAS-2B cells. The up-regulation of TRAIL expression significantly reduced cell viability, invasion, and migration of H1299 and A549 cells. TRAIL reduced the expression of ferroptosis-related genes (FTH1, GPX4, and SLC7A11), increased the levels of LIP, iron, and Fe2+, and promoted lipid peroxidation, thereby predisposing NSCLC cells to ferroptosis. TRAIL up-regulated the expression of phosphate modification of ASK-1 and JNK. ASKI-1 inhibitor GS-4977 attenuated the effects of TRAIL on the viability, migration, invasion, and ferroptosis of H1299 cells. Furthermore, TRAIL further suppressed tumor growth and ferroptosis in mice tumor xenograft models. Conclusion We indicated that overexpression of TRAIL induced ferroptosis in NSCLC cells and exerted anti-tumor effects. Mechanistically, TRAIL promoted ferroptosis by the activation of the ASK-1/JNK1 pathway. Our results may provide new therapeutic strategies for NSCLC.

Abstract Acute appendicitis is one of the common acute abdominal diseases in pediatrics. However, the implementation of radiological examination guided endoscopic retrograde appendicitis therapy (ERAT) in adults is limited in children. Our previous research explored the non-invasive guidance of high-frequency ultrasound (HFUS) for ERAT and achieved good therapeutic effects. This study mainly focuses on exploring the application value of HFUS in the feasibility assessment of ERAT in children with appendicitis. 163 children with appendicitis received ERAT guided by HFUS were analyzed retrospectively. According to the parameters evaluated by HFUS before and during ERAT, the results indicated that the distance between the appendix orifice and the ileocecal valve significantly affected the time required for the guidewire to enter the appendix cavity (P

In detecting hypersonic vehicles, the radar echo signal is coupled with an intra-pulse Doppler frequency (I-D frequency) component caused by relative motion of a plasma sheath (PSh) and the vehicle, which can induce the phenomenon of a ghost target in a one-dimensional range profile. In order to investigate the I-D frequency generated by the relative motion of a PSh, this study transforms a linear frequency modulated (LFM) signal into a single carrier frequency signal based on echo signal equivalent time delay-dechirp processing and realizes high resolution and fast extraction of the I-D frequency coupled with the frequency-domain echo signal. Furthermore, by relying on the computation of the surface flow field of the RAMC-II Blunt Cone Reentry Vehicle, the coupled I-D frequency in the radar echo signal of a PSh-enveloped target under circumstances of typical altitudes and carrier frequencies is extracted and further investigated, revealing the variation law of I-D frequency. The key findings of this study provide a novel approach for suppressing anomalies in radar detection of PSh-enveloped targets as well as effective detecting and as robust target tracking.

Abstract Unrest began in July 2021 at Askja volcano in the Northern Volcanic Zone (NVZ) of Iceland. Its most recent eruption, in 1961, was predominantly effusive and produced ∼0.1 km3 lava field. The last plinian eruption at Askja occurred in 1875. Geodetic measurements between 1983 and 2021 detail subsidence of Askja, decaying in an exponential manner. At the end of July 2021, inflation was detected at Askja volcano, from GNSS observations and Sentinel‐1 interferograms. The inflationary episode can be divided into two periods from the onset of inflation until September 2023. An initial period until 20 September 2021 when geodetic models suggest transfer of magma (or magmatic fluids) from within the shallowest part of the magmatic system (comprising an inflating and deflating source), potentially involving silicic magma. A following period when one source of pressure increase at shallow depth can explain the observations.

BackgroundPolymyxin B (PMB) and polymyxin E (colistin, CST) are polymyxin antibiotics, which are considered last-line therapeutic options against multidrug-resistant Gram-negative bacteria in serious infections. However, there is increasing risk of resistance to antimicrobial drugs. Effective efflux pump inhibitors (EPIs) should be developed to help combat efflux pump-mediated antibiotic resistance.MethodsChryseobacterium sp. PL22-22A was isolated from aquaculture sewage under selection with 8 mg/L PMB, and then its genome was sequenced using Oxford Nanopore and BGISEQ-500 platforms. Cpr (Chryseobacterium Polymyxins Resistance) genes encoding a major facilitator superfamily-type tripartite efflux system, were found in the genome. These genes, and the gene encoding a truncation mutant of CprB from which sequence called CprBc was deleted, were amplified and expressed/co-expressed in Escherichia coli DH5α. Minimum inhibitory concentrations (MICs) of polymyxins toward the various E. coli heterologous expression strains were tested in the presence of 2–128 mg/L PMB or CST. The pumping activity of CprABC was assessed via structural modeling using Discovery Studio 2.0 software. Moreover, the influence on MICs of baicalin, a novel MFS EPI, was determined, and the effect was analyzed based on homology modeling.ResultsMultidrug-resistant bacterial strain Chryseobacterium sp. PL22-22A was isolated in this work; it has notable resistance to polymyxin, with MICs for PMB and CST of 96 and 128 mg/L, respectively. A novel MFS-type tripartite efflux system, named CprABC, was identified in the genome of Chryseobacterium sp. PL22-22A. Heterologous expression and EPI assays indicated that the CprABC system is responsible for the polymyxin resistance of Chryseobacterium sp. PL22-22A. Structural modeling suggested that this efflux system provides a continuous conduit that runs from the CprB funnel through the CprC porin domain to pump polymyxins out of the cell. A specific C-terminal α-helix, CprBc, has an activation function on polymyxin excretion by CprB. The flavonoid compound baicalin was found to affect the allostery of CprB and/or obstruct the substrate conduit, and thus to inhibit extracellular polymyxin transport by CprABC.ConclusionNovel MFS-type tripartite efflux system CprABC in Chryseobacterium sp. PL22-22A mediates resistance to polymyxins, and baicalin is a promising EPI.

PurposeTo explore the clinical value of contrast-enhanced ultrasound (CEUS) quantitative analysis in the evaluation and prognosis of neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC).MethodsEighty-three consecutive patients undergoing neoadjuvant chemoradiotherapy and total mesorectal excision for LARC were retrospectively included. According to pathological results, patients were categorized into complete or incomplete response groups. Differences in ultrasonic parameters, pathological results, and clinical data between groups were evaluated. The cutoff point for a complete response as determined by quantitative analysis of CEUS was assessed using a receiver operating characteristic curve; additionally, overall survival (OS) and progression-free survival (PFS) were analyzed.ResultsOf the 83 patients, 12 (14.5%) achieved a complete response and 71 (85.5%) did not. There were significant between-group differences in carcinoembryonic antigen (CEA) levels, differentiation degree, proportion of tumor occupying the lumen, anterior-posterior and superior-inferior diameters of the lesion, and intensity of enhancement (P

Abstract The PI3K/AKT pathway plays an essential role in tumour development. NOD-like receptors (NLRs) regulate innate immunity and are implicated in cancer, but whether they are involved in PI3K/AKT pathway regulation is poorly understood. Here, we report that NLRP6 potentiates the PI3K/AKT pathway by binding and destabilizing p85α, the regulatory subunit of PI3K. Mechanistically, NLRP6 recruits the E3 ligase RBX1 to p85α and ubiquitinates lysine 256 on p85α, which is recognized by the autophagy cargo receptor OPTN, causing selective autophagic degradation of p85α and subsequent activation of the PI3K/AKT pathway by reducing PTEN stability. We further show that loss of NLRP6 suppresses cell proliferation, colony formation, cell migration, and tumour growth in glioblastoma cells in vitro and in vivo. Disruption of the NLRP6/p85α interaction using the Pep9 peptide inhibits the PI3K/AKT pathway and generates potent antitumour effects. Collectively, our results suggest that NLRP6 promotes p85α degradation via selective autophagy to drive tumorigenesis, and the interaction between NLRP6 and p85α can be a promising therapeutic target for tumour treatment.

Abstract Exploiting the fundamental features of quantum mechanics, an entanglement-based quantum network offers a promising platform for many dramatic applications such as multi-user cryptography. Nevertheless, the implementation of a large-scale quantum network in real-world scenarios remains challenging owing to the multiple scattering events in complex environment, particularly those frequency-sensitive scatterings that disturb quantum correlation both spatially and temporally. Here, we demonstrate the frequency-insensitive spatiotemporal control of entangled photons in a fully connected network by leveraging a Fourier-transform setup and the genetic algorithm. Such an approach can effectively improve the entanglement distribution process through a multimode fiber while the quantum characteristic of the network can be maintained well after the spatiotemporal shaping. Our scheme can serve as a bridging technology to establish entanglement between remote nodes of spectrally interconnected quantum systems and has great potential applications in future real-world quantum networks.

Abstract Background The treatment of extensive stage small‐cell lung cancer (ES‐SCLC) has only made modest progress in the past decade, with two immune checkpoint inhibitors (ICIs), atezolizumab and durvalumab, approved for the treatment of SCLC by January 2022. However, currently, there is limited real‐world data on ES‐SCLC patients received immunotherapy. Methods We retrospectively collected and analyzed the demographic and treatment data of ES‐SCLC patients at the First Affiliated Hospital of Guangzhou Medical University from January 2017 to January 2022. Survival and prognosis information was obtained through follow‐up. Results A total of 353 ES‐SCLC patients were included, of which 165 received immunotherapy combined with chemotherapy as the first‐line (FL) treatment (chemo‐immune group), and 188 received chemotherapy (chemotherapy group). The objective response rate (ORR) and disease control rate (DCR) of patients receiving immunotherapy as the FL treatment were better than the chemotherapy group (76.97% vs. 48.40%, p

Abstract Exploiting the fantastic features of quantum mechanics, a hyperentangled quantum network encoded in multiple degree of freedoms (DOF), e.g., polarization and orbital angular momentum DOFs, can encode more qubits per transmitted photon and offers a promising platform for many dramatic applications. Here, we demonstrate such a hyperentangled multiuser network with a fully connected network architecture by using dense wavelength division multiplexing and entanglement transfer technique. Three hyperentangled states in polarization and time-energy DOFs are multiplexed to three single mode fibers to form the fully connected network architecture. Then, three interferometric quantum gates are utilized for transferring quantum entanglement from time-energy to orbital angular momentum DOF. The experimental results reveal a high quality of the hyperentanglement of the constructed network with the entangled state fidelity of higher than 96%. Our approach can provide a novel way to construct a large-scale hyperentangled network that can support various kinds of quantum tasks like superdense coding and teleportation.

Abstract In this case report, we describe two unusual presentations of varicella-zoster virus (VZV) reactivation without rash, a condition known as Zoster Sine Herpete (ZSH). In Case 1, a 58-year-old woman presented with severe right-sided chest pain under her breast that radiated to the ipsilateral back. After the initial workup ruled out cardiac and musculoskeletal etiologies, the characteristic dermatomal distribution of pain made us suspect VZV reactivation. A diagnosis of ZSH was made with positive VZV IgG and IgM serologies and symptomatic relief after famciclovir treatment. In Case 2, a 43-year-old woman presented with a severe headache and resolved sharp right flank pain. She was diagnosed with varicella meningitis after cerebrospinal fluid showed positive VZV DNA. Intravenous acyclovir treatment resulted in symptom resolution. The most common presentation of VZV reactivation is Herpes Zoster, or shingles, making ZSH a frequently missed diagnosis. High clinical suspicion is warranted to prevent life-threatening complications of ZSH.

IntroductionThe practice of participatory art has been found to support the promotion, prevention, and management of health across the lifespan. However, clinical trials investigating the benefits of creative activities curated with and conducted in museums among older adults in East Asia remains limited.MethodsThe current research utilized a single-site, open-label randomized control trial (RCT) to evaluate a standardized Participatory ‘A’rt-Based Activity On ‘Health’ of Older Community-Dwellers – the Singapore A-Health Intervention. Outcome measures include frailty as assessed by the Centre of Excellence on Longevity Self-administered Questionnaire, wellbeing as assessed by the Warwick-Edinburgh Mental Wellbeing Scales, and quality of life as assessed by the EuroQol-5D. 112 participants aged 60 and above were randomized into the intervention group (n = 56) or an inactive control group (n = 56). Participants completed four standardized online self-administered assessments at baseline, 5-week, 9-week and 12-week follow-up during the intervention period.ResultsLinear mixed model analyses revealed no statistically significant differences between the intervention group and control group for all outcome measures. However, within the intervention group, a consistent significant reduction in frailty was observed across time from baseline to 9 weeks (MD −0.44, 95% CI −0.85 to −0.039, p = 0.032), 5-weeks to 9-weeks (MD −0.64, 95% CI −1.03 to −0.24, p = 0.002), and 5-weeks to 12-weeks (MD −0.51, 95% CI −0.91 to −0.10, p = 0.014). Moreover, the post-test mean wellbeing score in the intervention group significantly improved over time at 9-weeks (MD 1.65, 95% CI 0.09 to 3.22, p = 0.039) and 12-week (MD 2.42, 95% CI 0.67 to 4.16, p = 0.006) as compared to baseline scores.DiscussionThe findings demonstrate the potential of a structured art and museum-based intervention as a resource for promoting health among aging populations. Such benefits transcend social, cultural, and societal contexts.Clinical trial registrationClinicalTrial.gov, NCT05945589.

IntroductionArt and museum-based interventions are gaining increasing recognition for their potential as low-risk activities for older adults, offering numerous physical, cognitive, and emotional benefits. However, there remains a dearth of knowledge regarding the science of implementation as well as the factors and processes that contribute to their effectiveness from the perspectives of intervention participants.MethodsThe current research draws on the qualitative evaluation data obtained from a larger mixed-method randomized control trial that evaluated a standardized Participatory “A”rt-Based Activity On “Health” of Older Community-Dwellers—the Singapore A-Health Intervention. Adopting a participatory action research approach, the primary objective is to critically examine the lived experiences and health impact of the Singapore A-Health Intervention with a secondary objective to uncover strategies for optimized implementation outcomes. All 56 participants who completed the intervention filled out a program evaluation survey and a nested sample of 30 participants completed a series of acceptability focus groups.ResultsDescriptive analyses of the program evaluation survey data revealed that 96.2% of participants were satisfied with the overall experience of the Singapore A-Health intervention (M = 9.00, SD = 1.76), reported that the intervention positively impacted their quality of life (M = 8.90, SD = 1.43), and social wellbeing (M = 8.92, SD = 1.43). Thematic analysis with a grounded theory approach on the qualitative focus group data revealed three interrelated themes detailing how the Singapore A-Health Intervention contributed to positive health and wellbeing outcomes (1. A-Health Experience, 2. Wellbeing Outcomes, 3. Enabling Factors) and nine subthemes (1a. Intellectual Stimulation, 1b. Positive Stress, 1c. Peer Interaction, 2a. Interpersonal Bonds, 2b. Personal Growth, 2c. Mindful Living, 3a. Integrated Support, 3b. Session Design, 3c. Mode of Engagement).DiscussionThis investigation provides important insights to the Singapore A-Health intervention’s effectiveness for enhancing wellbeing among older adults, as well as the factors that enable successful program implementation. These findings offer a culturally unique perspective on the benefits of art and museum interventions, while underscoring the imperative need for strong partnership and collaborations among community stakeholders in supporting the health and wellbeing of ageing populations.

Limited follow-up data is available on the recovery of Omicron COVID-19 patients after acute illness. It is also critical to understand persistence of neutralizing antibody (NAb) and of T-cell mediated immunity and the role of hybrid immunity in preventing SARS-CoV-2 reinfection. This prospective cohort study included Omicron COVID-19 individuals from April to June 2022 in Shanghai, China, during a large epidemic caused by the Omicron BA.2 variant. A total of 8945 patients from three medical centres were included in the follow up programme from November 2022 to February 2023. Of 6412 individuals enrolled for the long COVID analysis, 605 (9.4%) individuals experienced at least one sequelae, mainly had fatigue and mental symptoms specific to Omicron BA.2 infection compared with other common respiratory tract infections. During the second-visit, 548 (12.1%) cases of Omicron reinfection were identified. Hybrid immunity with full and booster vaccination had reduced risk of SARS-CoV-2 reinfection by 0.29-fold (95% CI: 0.63–0.81) and 0.23-fold (95% CI: 0.68–0.87), respectively. For 469 participants willing to the hospital during the first visit, those who received full (72 [IQR, 36–156]) or booster (64 [IQR, 28–132]) vaccination had significantly higher neutralizing antibody titers than those with incomplete vaccination (36 [IQR, 16–79]). Moreover, non-reinfection cases had higher neutralizing antibody titers (64 [IQR, 28–152]) compared to reinfection cases (32 [IQR, 20–69]).

ABSTRACT Coronaviruses (CoVs), which pose a serious threat to human and animal health worldwide, need to hijack host factors to complete their replicative cycles. However, the current study of host factors involved in CoV replication remains unknown. Here, we identified a novel host factor, mammalian lethal with sec-13 protein 8 (mLST8), which is a common subunit of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), and is critical for CoV replication. Inhibitor and knockout (KO) experiments revealed that mTORC1, but not mTORC2, is essential for transmissible gastroenteritis virus replication. Furthermore, mLST8 KO reduced the phosphorylation of unc-51-like kinase 1 (ULK1), a factor downstream of the mTORC1 signaling pathway, and mechanistic studies revealed that decreased phosphorylation of the mTORC1 downstream factor ULK1 promoted the activation of autophagy, which is responsible for antiviral replication in mLST8 KO cells. Then, transmission electron microscopy indicated that both mLST8 KO and autophagy activator inhibited the formation of double-membrane vesicles in early viral replication. Finally, mLST8 KO and autophagy activator treatment could also inhibit the replication of other CoVs, indicating a conserved relationship between autophagy activation and CoV replication. In summary, our work reveals that mLST8 is a novel host regulator of CoV replication, which provides new insights into the mechanism of CoV replication and can facilitate the development of broad-spectrum antiviral drugs. IMPORTANCE CoVs are highly variable, and existing CoV vaccines are still limited in their ability to address mutations in CoVs. Therefore, the need to improve our understanding of the interaction of CoVs with the host during viral replication and to find targets for drugs against CoVs is urgent. Here, we found that a novel host factor, mLST8, is critical for CoV infection. Further studies showed that mLST8 KO inhibited the mTORC1 signaling pathway, and we found that autophagy activation downstream of mTORC1 was the main cause of antiviral replication in mLST8 KO cells. Autophagy activation impaired the formation of DMVs and inhibited early viral replication. These findings deepen our understanding of the CoV replication process and provide insights into potential therapeutic applications.

Background Adverse left ventricular remodeling after myocardial infarction (MI) compromises cardiac function and increases heart failure risk. Until now, comprehension of the role transcription factor EB (TFEB) plays after MI is limited. Objectives The purpose of this study was to describe the effects of TFEB on fibroblasts differentiation and extracellular matrix expression after MI. Methods AAV9 (adeno-associated virus) mediated up- and down-regulated TFEB expressions were generated in C57BL/6 mice two weeks before the MI modeling. Echocardiography, Masson, Sirius red staining immunofluorescence, and wheat germ agglutinin staining were performed at 3 days, and 1, 2, and 4 weeks after MI modeling. Fibroblasts collected from SD neonatal rats were transfected by adenovirus and siRNA, and cell counting kit-8 (CCK8), immunofluorescence, wound healing and Transwell assay were conducted. Myocardial fibrosis-related proteins were identified by Western blot. PNU-74654 (100 ng/mL) was used for 12 hours to inhibit β-catenin-TCF/LEF1 complex. Results The up-regulation of TFEB resulted in reduced fibroblasts proliferation and its differentiation into myofibroblasts in vitro studies. A significant up-regulation of EF and down-regulation of myocyte area was shown in the AAV9-TFEB group. Meanwhile, decreased protein level of α-SMA and collagen I were observed in vitro study. TFEB didn’t affect the concentration of β-catenin. Inhibition of TFEB, which promoted cell migration, proliferation and collagen I expression, was counteracted by PNU-74654. Conclusions TFEB demonstrated potential in restraining fibrosis after MI by inhibiting the Wnt/β-catenin signaling pathway.

Abstract Estimating the timing of velocity changes (break points) in Global Navigation Satellite System (GNSS) coordinate time series is required for understanding various Earth processes and how they may couple with each other. We jointly estimate break points, noise parameters and their uncertainties in GNSS time series using Bayesian interference. Synthetic data experiments demonstrate that time‐correlated noise can cause spurious estimates of break points for small velocity change and suggest the lower limits of velocity change for reliable estimates. A case study at the Krafla volcanic system shows increased rift‐perpendicular movementof 7.6–9.8 mm/yr, preceding by 23–77 days the 2014 Bárðarbunga rifting episode that occurred ∼120 km to the south (maximum likelihood estimates). These far‐field velocity anomalies occur in the same period as enhanced near‐field seismicity and deformation before the dike intrusion at Bárðarbunga, possibly indicating the coupling between the two volcanic systems through a deep partial melt zone.

Summary: Droplet-based single-cell RNA-seq (scRNA-seq) data are plagued by ambient contaminations caused by nucleic acid material released by dead and dying cells. This material is mixed into the buffer and is co-encapsulated with cells, leading to a lower signal-to-noise ratio. Although there exist computational methods to remove ambient contaminations post-hoc, the reliability of algorithms in generating high-quality data from low-quality sources remains uncertain. Here, we assess data quality before data filtering by a set of quantitative, contamination-based metrics that assess data quality more effectively than standard metrics. Through a series of controlled experiments, we report improvements that can minimize ambient contamination outside of tissue dissociation, via cell fixation, improved cell loading, microfluidic dilution, and nuclei versus cell preparation; many of these parameters are inaccessible on commercial platforms. We provide end-users with insights on factors that can guide their decision-making regarding optimizations that minimize ambient contamination, and metrics to assess data quality.

ObjectivesAiming at the replacement of propellers behind surface ships with pumpjet propulsion systems, this paper introduces a novel method for predicting full-scale power performance based on statistical learning. MethodsPump performance maps originating from the neural network learning of existing pumpjet thrust coefficient maps and matched to a ship's drag line from model tests are used to determine the pumpjet's full-scale power performance behind a large surface ship. To validate its precision and availability, traditional complete model tests including the ship model drag test, pump model open water test and ship-pumpjet self-propulsion test are completed to determine the full-scale benchmark power performance under different ship speeds.ResultsThe prediction errors of the pumpjet's rotation speed, thrust and power under different self-propulsion ship speeds from 18 knots to the design point of 30 knots are smaller than 5.4%, with no more than 2% from the design condition. As for the ship-propulsor interaction amplitude, the surface ship-pumpjet subsystem lies between ship-propeller interaction and ship-waterjet pump interaction with a thrust deduction coefficient approaching zero. From this point of view, the pumpjet propulsion system behind a surface ship can be recognized as a transitional stage from the propeller-shaft configuration to the waterjet propulsion system.ConclusionsThe method proposed herein can predict the full-scale power performance of a pumpjet propulsion system behind a ship while advancing pumpjet propulsion system design and applications for new large-scale surface warships.

Abstract Background Sputum biopsies offer unique advantages such as non-invasiveness and convenient collection. The one investigation so far on sputum for genome profiling in advanced non-small cell lung cancer (aNSCLC) suggested promising performance. However, it remains undefined whether clinicohistologic characteristics were associated with performance and how this knowledge could help guide choice of liquid biopsy. Methods Targeted sequencing with a 520-gene panel was performed on prospectively collected matched tumor tissue (TIS), plasma (PLA), and sputum supernatant (SPU) from 71 aNSCLC patients (NCT05034445). Genomic alteration detection was characterized in a series of aspects and interrogated for association with 14 clinicohistologic features. Nomograms were constructed with logistic regression for predicting the liquid biopsy type with greater sensitivity. Results Compared with PLA, SPU showed comparable quality control metrics, mutation detection rate (SPU: 67.6%, PLA: 70.4%), concordance with tumor tissue (67.6% vs. 73.2%), and correlation with tissue-based tumor mutation burden levels (r = 0.92 vs. 0.94). For driver alterations, detection was less sensitive with SPU (50.0%) than PLA (63.5%) in the entire cohort but similarly or more sensitive in patients with centrally located lung tumors or smoking history or for altered ALK or KRAS. Two nomograms were constructed and enabled predicting the probability of superior sensitivity with SPU with moderate to borderline high accuracy. Conclusion In addition to demonstrating comparable performance in multiple aspects, this study is the first to propose nomograms for choosing liquid biopsy based on clinicohistologic characteristics. Future research is warranted to delineate the clinical utility of sputum for genome profiling.

To quantitatively investigate the relationship between earthquakes and ionospheric anomalies, this paper presents a statistical study of pre-earthquake vertical total electron content (VTEC) variations. A total of 1522 shallow (≤60 km) strong (Mw≥6.0) earthquakes in the global area during 2000-2020 are selected, and classified according to different magnitudes, latitudes and focal depths. A quartile-based process with different lengths of sliding windows, equaling 10 days, 15 days and 27 days, respectively, has been utilized to detect VTEC anomalies. The abnormal level is first defined, and then VTEC anomalies occurrence probabilities (Po) and occurrence rates (PE) within 1-10 days before 1522 earthquakes have been calculated. Besides, VTEC anomalies occurrence rates of the background days (PN) are also calculated. The results show that the significant correlation between Po and epicentral latitudinal locations could be observed within 1-10 days before earthquakes. The values of Po increase with larger magnitudes in the equatorial and low-latitude regions, but decrease with greater magnitudes in the mid- and high-latitude regions to some degree. Within 1-5 days before earthquakes, the overall trend of PE shows an increase with larger magnitudes, but the correlation between the values of PE and magnitudes is relatively weak in the southern mid- and high-latitude regions. There is no evident causality between PN and the magnitude, and most of the values of PE/PN are larger than 1, indicating that VTEC anomalies within a few days before earthquakes are probably related with the forthcoming earthquakes. Moreover, when the abnormal level exceeds 60%, different sliding window lengths have a significant impact on the values of Po and PE in the mid- and high-latitude regions. In particular, there are obvious systematic deviations between the values of Po obtained from different sliding windows in the southern mid- and high-latitude regions. However, the selection of the optimal sliding window needs to be further studied.

In the context of global climate change and the water-carbon peak target, improving water security in arid regions is a persistent challenge in global water resources management. Water diversion projects can serve as an important measure to effectively alleviate the uneven distribution of water resources, achieve rational allocation and efficient utilization of water resources. However, how to achieve the maximization of comprehensive benefits during the process of water allocation is also an urgent problem that needs to be solved. This study focuses on the Middle Route Project of the South to North Water Diversion Project in China, selecting four important municipalities and provinces during 2015 to 2021, namely Beijing, Tianjin, Hebei Province, and Henan Province, based on the actual benefits of the water receiving areas of the middle line project. Nine representative indicators related to social, economic, and ecological benefits were selected to evaluate the optimal combination of water resource allocation in the water receiving areas along the central line, in order to achieve the maximum comprehensive benefits and solve the problems of high water safety guarantee requirements and difficult balanced water distribution in urban agglomerations in the water receiving areas. Through the calculation of the Markovsky theoretical model, the results show that when 79.9% of the water conveyance is used to generate social benefits, 15.8% of the water conveyance is used to generate ecological benefits, and 4.5% of the water conveyance is used to generate economic benefits, the project achieves the maximum comprehensive benefits. This computational model method can be used to provide technical support and scientific reference for the optimal allocation of water resources in cross regional water transfer projects.

A sea-crossing bridge is typically constructed in a marine environment with complex piers, and is susceptible to severe scour at the foundation. This study presents a numerical investigation on flow and scour around a complex pier, specifically focusing on a real-world sea-crossing bridge in China. A comprehensive CFD model incorporating hydrodynamic, free surface, sediment transport, and morphological models is employed for numerical modeling. Additionally, a wind shear stress model is considered to accurately simulate wind generation. The validation of the CFD model is achieved through comparison with experimental data of scour around a cylinder, demonstrating its capability to accurately replicate scour morphology and the temporal evolution of scour depth. Subsequently, the validated model is utilized for full-scale simulation of scour around the complex bridge pier under different wind, wave, and current conditions. The results indicate that compared to single piers with uniform cross-sectional shapes, flow patterns around complex piers are much more complicated. Scour predominantly occurs around the first row of group piles, while downstream piles experience less scour due to the sheltering effect from upstream piles. Furthermore, it becomes evident that the current exerts greater influence on pier scour than waves and wind, while the latter two factors primarily influence the superstructure of the bridge.

Abstract The increased transmissibility of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Delta and Omicron variants due to their complex mutations has been confirmed by many studies, but the disease severity caused by these two variants and vaccine efficacy have not been clearly concluded. This meta‐analysis evaluated and compared disease severity and vaccine efficacy for infection with these two variants. Databases were searched on July 29, 2022, for original studies. Data extracted included participants, hospitalization rate, intensive care unit (ICU) admission rate, mortality rate, and vaccination status. Total 15 studies (570,713 subjects) were included. The risk of hospitalization, ICU admission and death in patients with Delta were increased compared with patients with Omicron, especially hospitalization (Log risk ratio [RR]: 1.09, 95% confidence interval [CI]: 0.65–1.53). The Delta was associated with a higher risk of death in the unvaccinated population (Log RR: 0.48, 95% CI: 0.04–0.93). No significant differences in the risk of severe illness between BA.1 and BA.2 were observed. All three risks were reduced in fully vaccinated populations infected with Delta and Omicron. The existing evidence shows that the inherent virulence and disease severity of Omicron are reduced compared with Delta, and fully vaccination is effective in preventing severe infection of both variants.

ABSTRACT This study investigated oxidative damage and exocrine dysfunction of fetal pancreas caused by maternal nutritional restriction. Eighteen ewes carrying singleton fetus were randomly divided into control group (CG, ad libitum, 0.67 MJ ME/BW0.75/d, n = 6), restricted group 1 (RG1, 0.33 MJ ME/BW0.75/d, n = 6), and restricted group 2 (RG2, 0.18 MJ ME/BW0.75/d, n = 6) at d 90 of pregnancy. Maternal undernutrition was imposed from d 90 to 140 of pregnancy. At 140 d of gestation, fetal blood and pancreas tissue were collected to determine fetal pancreatic extracellular matrix, antioxidant capacity, and indicators of exocrine dysfunction. With the decrease of maternal nutrition, the fetal body weight, pancreatic weight, and DNA content were reduced in RG2 compared with CG, and increased and thickened collagen fibers were observed in RG2. Fetuses in RG2 exhibited increased collagen 3 (COL3) and fibronectin (FN) levels relative to CG, and the COL1:COL3 ratio was lower than that of the CG. For RG1, we found increased COL3 compared with CG. Malondialdehyde, serum amylase, and serum lipase in fetal pancreas in RG2 increased, but the total antioxidant capacity (T-AOC) decreased compared with the CG. The impaired ovine fetal pancreas growth, antioxidant imbalance, and pancreatic exocrine dysfunction are induced by maternal undernutrition during late pregnancy.

Regular use of Thai kratom has been linked to reduced blood triglyceride levels and body mass index (BMI) in healthy individuals. We analyzed Green Thai Kratom (GTK) and Red Thai Kratom (RTK) to investigate their effects on pancreatic digestive enzymes. The ethanol extracts of GTK and RTK inhibited lipase activity more strongly than alpha-glucosidase activity, suggesting the presence of lipase inhibitors. Mitragynine, the major compound in GTK, showed potent lipase inhibition and moderate alpha-glucosidase inhibition. Quercetin, found in both extracts, strongly inhibited alpha-glucosidase but had limited effects on lipase. These findings suggest that mitragynine and quercetin may hinder triglyceride and starch digestion. Combination inhibition studies revealed synergistic effects between mitragynine and quercetin on alpha-glucosidase activity. Additionally, both GTK and RTK extracts reduced fat accumulation in 3T3-L1 adipocyte cells, with quercetin specifically inhibiting Acetyl-CoA carboxylase 1 (ACC1), a key enzyme in fatty acid biosynthesis. Thus, GTK and RTK extracts, particularly mitragynine and quercetin, exhibit potential anti-obesity effects. We report the novel finding that Thai kratom inhibits de novo fatty acid synthesis by targeting ACC1, resulting in decreased fat accumulation in adipocytes. Regular use of Thai kratom in specific populations may improve blood triglyceride levels and reduce BMI by inhibiting lipase, alpha-glucosidase, and ACC1 activity. Further clinical trials are needed to determine optimal dosage, duration, toxicity levels, and potential side effects of Kratom use.

The aim of this study was to explore whether a robot-assisted (RA) technique has advantages over the conventional fluoroscopy-assisted (FA) technique in clinical and radiological outcomes and whether it could decrease the incidence of mis-implantations of pedicle screws in adolescent idiopathic scoliosis (AIS) correction surgery. A total of 101 patients with AIS were recruited (RA group: 45 patients underwent RA screw insertion; FA group: 56 patients underwent FA screw insertion). When comparing the radiological data between the two groups, the major and secondary curves were both corrected proficiently with no difference in Cobb angle comparison at the last follow-up, suggesting that both the RA technique and the FA technique could lead to efficient radiographic correction and similar clinical outcomes (all, p > 0.05). In the RA group, operation time, blood loss, and transfusion volume were significantly greater than those in the FA group, while the accuracy of screw implantations in patients with AIS with a thoracic scoliotic curve in the RA group was higher than that in the FA group. In conclusion, both the RA and FA techniques could approach proficient radiographic correction and similar clinical outcomes in AIS surgery. Compared with the conventional fluoroscopy technique, the RA technique might improve the accuracy of screw implantations in patients with AIS with a thoracic scoliotic curve, while the increased operation time, blood loss, and transfusion volume might be the disadvantages due to the preliminary stage of the learning curve.

Abstract Background Secondary nosocomial infections, which are commonly caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) and vancomycin-resistant Enterococcus faecium (VRE), often develop in septic patients. This study aimed to identify the origin of secondary systemic pathogens and reveal the underlying mechanism of infection. Methods In this prospective, observational case–control study, a total of 34 septic patients, 33 non-septic intensive care unit (ICU) patients and 10 healthy individuals serving as controls were enrolled. Three hundred and twelve fecal samples were collected and subjected to 16S rRNA gene amplicon sequencing. Metagenome sequencing was performed to identify the homology between dominant CRKP or VRE in the intestine and pathogens isolated from secondary infectious sites. C57/BL mice were established as pseudo germ-free animal model by pretreatment with broad-spectrum antibiotics for two weeks. Results The abundance and diversity of the gut microbiota in septic patients was drastically decreased one week after ICU admission, potentially leading to the enrichment of antibiotic-resistant bacteria, such as CRKP. Furthermore, secondary bloodstream and abdominal infections caused by CRKP or VRE in septic patients occurred after intestinal colonization with the predominant bacterial species. Genomic analysis showed that bacteria isolated from secondary infection had high homology with the corresponding predominant intestinal opportunistic pathogens. In addition, animal model experiments validated the hypothesis that the administration of antibiotics caused the enrichment of CRKP and VRE among the intestinal microbiota, increasing the likelihood of permeation of other tissues and potentially causing subsequent systemic infection in pseudo germ-free mice. Conclusion Our study indicated that the pathogens causing secondary infection in septic patients might originate from the intestinal colonization of pathogens following broad-spectrum antibiotic treatment.

Programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors and PD-1 inhibitors plus chemotherapy combination regimens have been widely used in the first-line treatment of advanced non-small cell lung cancer(NSCLC), but patients with low PD-L1 expression have limited objective response and survival benefits. Existing treatment regimens are still difficult to fully meet the clinical needs of patients in the real world. Therefore, researchers are still exploring novel superactive treatment options to further improve the efficacy and survival prognosis of different sub-groups in NSCLC. Dual immunotherapy [such as the combination of PD-1 and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) inhibitors] has shown considerable long-term survival benefits in a variety of tumors and has also shown broad clinical prospects in NSCLC. In addition to exploring different emerging combination options, how to accurately identify the optimal-benefit groups through predictive biomarkers and how to effectively manage the safety of combination immunotherapy through multidisciplinary collaboration are also the focus of dual immunotherapy. This article reviews the mechanism of action, research progress, predictive biomarkers and future exploration directions of dual immunotherapy.

Brain tumors have been proved challenging to treat. Here we established a Multi-Target Neural Differentiation (MTND) therapeutic cocktail to achieve effective and safe treatment of brain malignancies by targeting the important hallmarks in brain cancers: poor cell differentiation and compromised cell cycle. In-vitro and in-vivo experiments confirmed the significant therapeutic effect of our MTND therapy. Significantly improved therapeutic effects over current first-line chemo-drugs have been identified in clinical cells, with great inhibition of the growth and migration of tumor cells. Further in-vivo experiments confirmed that sustained MTND treatment showed a 73% reduction of the tumor area. MTND also induced strong expression of phenotypes associated with cell cycle exit/arrest and rapid neural reprograming from clinical glioma cells to glutamatergic and GABAergic expressing cells, which are two key neuronal types involved in many human brain functions, including learning and memory. Collectively, MTND induced multi-targeted genotypic expression changes to achieve direct neural conversion of glioma cells and controlled the cell cycle/tumorigenesis development, helping control tumor cells’ malignant proliferation and making it possible to treat brain malignant tumors effectively and safely. These encouraging results open avenues to developing new therapies for brain malignancies beyond cytotoxic agents, providing more effective medication recommendations with reduced toxicity.

Abstract Introduction Given that many pregnant women have chronic hepatitis B virus (HBV) infection and that gestational diabetes mellitus (GDM) is linked to poor maternal and neonatal outcomes, we looked into the relationship between the hepatitis B surface antigen (HBsAg) and GDM to see if a high HBV DNA load is linked to a higher risk of GDM in chronic maternal HBsAg carriers. Materials and methods Our study included 39,539 pregnant women who gave birth at the Third Affiliated Hospital of Guangzhou Medical University in Guangzhou, China, between January 1, 2009, and December 31, 2019. The patients were divided into two groups: HBsAg negative (36,500) and positive (3039). The viral load levels of 1250 HBsAg-positive women who had tested their HBV DNA load during pregnancy were separated into three groups. We utilized univariate and multivariable logistical regression analysis to determine the relationship between maternal chronic HBsAg carrier and GDM. Results Being HBsAg positive was discovered to be an independent risk factor for GDM.Pre-pregnancy Obesity and advanced age were linked to an increased incidence of GDM. Those with a high HBV DNA load (> 106 IU/mL) had a higher risk of GDM than HBsAg-positive women with a low viral load (

BackgroundRheumatoid arthritis (RA) is an autoimmune disease characterized by erosive arthritis, and current treatments for RA fall short of the outcomes expected by clinicians and patients.ObjectivesThis study aimed to identify novel therapeutic and prognostic targets in RA at the genomic level and to screen desirable compounds with potential inhibitory effects on GZMB.MethodsWe performed differential gene analysis on GSE55235 and GSE55457 from Gene Expression Omnibus (GEO) and then obtained the intersection of the two differentially expressed genes (DEGs) lists by drawing Venn diagrams. Then we performed protein-protein interaction (PPI) network analysis, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis on the DEGs of the intersection. Next, we downloaded the crystal structure of Granzyme B (GZMB). Molecular docking technology was used to screen potential inhibitors of GZMB in subsequent experiments, and we then analyzed the toxicity and water solubility of these potential inhibitors for future drug experiments. Finally, whether the docking of these small molecules with GZMB is stable is tested by molecular dynamics.ResultsA total of 352 mutual DEGs were identified. Twenty hub genes were obtained according to PPI network analysis, among which the GZMB gene attracted the attention of our research. Three potent natural compounds, ZINC000004557101, ZINC000012495776, and ZINC000038143593, bound to GZMB, show better binding affinity. Furthermore, they are predicted to own low Ames mutagenicity, developmental toxicity potential, rodent carcinogenicity, and high tolerance to cytochrome P4502D6. Molecular dynamics simulations show that ZINC000004557101 and GZMB have more advantageous potential energy and can exist stably in a natural environment. Moreover, we finally verified the inhibitory effect of ZINC000004557101 on granzyme B by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Western blotting experiment.ConclusionRA patients showed increased GZMB expression. ZINC000004557101 is a potential drug targeting GZMB for treating RA.

The flowers of tea plants (Camellia sinensis), as well as tea leaves, contain abundant secondary metabolites and are big potential resources for the extraction of bioactive compounds or preparation of functional foods. However, little is known about the biosynthesis and transcriptional regulation mechanisms of those metabolites in tea flowers, such as terpenoid, flavonol, catechins, caffeine, and theanine. This study finely integrated target and nontarget metabolism analyses to explore the metabolic feature of developing tea flowers. Tea flowers accumulated more abundant terpenoid compounds than young leaves. The transcriptome data of developing flowers and leaves showed that a higher expression level of later genes of terpenoid biosynthesis pathway, such as Terpene synthases gene family, in tea flowers was the candidate reason of the more abundant terpenoid compounds than in tea leaves. Differently, even though flavonol and catechin profiling between tea flowers and leaves was similar, the gene family members of flavonoid biosynthesis were selectively expressed by tea flowers and tea leaves. Transcriptome and phylogenetic analyses indicated that the regulatory mechanism of flavonol biosynthesis was perhaps different between tea flowers and leaves. However, the regulatory mechanism of catechin biosynthesis was perhaps similar between tea flowers and leaves. This study not only provides a global vision of metabolism and transcriptome in tea flowers but also uncovered the different mechanisms of biosynthesis and transcriptional regulation of those important compounds.

BackgroundCheckpoint inhibitor–related pneumonitis (CIP) is a lethal immune-related adverse event. However, the development process of CIP, which may provide insight into more effective management, has not been extensively examined.MethodsWe conducted a multicenter retrospective analysis of 56 patients who developed CIP. Clinical characteristics, radiological features, histologic features, and laboratory tests were analyzed. After a comprehensive analysis, we proposed acute, subacute, and chronic phases of CIP and summarized each phase’s characteristics.ResultsThere were 51 patients in the acute phase, 22 in the subacute phase, and 11 in the chronic phase. The median interval time from the beginning of CIP to the different phases was calculated (acute phase: ≤4.9 weeks; subacute phase: 4.9~13.1 weeks; and chronic phase: ≥13.1 weeks). The symptoms relieved from the acute phase to the chronic phase, and the CIP grade and Performance Status score decreased (P

Under the influence of global warming, the problem of sea-level rise is becoming increasingly prominent. The northern part of the South China Sea (SCS) is low lying, with intense economic development, and densely populated. These characteristics make the region extremely sensitive to the consequences of rising sea levels. This study aims to reveal the trends of sea-level changes in the northern SCS and provide scientific insights into the potential flooding risks in low-lying areas. To achieve this, the Ensemble Empirical Mode Decomposition (EEMD) method is used to analyze the water level time series data from three tide gauges along the coast of Hong Kong. This analysis reveals the multidimensional change characteristics and response mechanisms of the sea level in the SCS. The findings reveal distinct seasonal, interannual, decadal, and interdecadal variations in sea-level changes. Furthermore, we explore the impact of the El Niño-Southern Oscillation (ENSO) on sea-level changes in the study area, finding a 6-month lagged correlation between the sea level and ENSO. Spatially, the rate of sea-level change is faster in nearshore areas than in the open ocean and higher in the northern regions than in the southern regions. The Multifractal Detrended Fluctuation Analysis (MF-DFA) method is employed to analyze the sea-level change time series, revealing long-range correlations and multifractal characteristics. In addition, we propose a sea-level prediction method that combines EEMD with Long Short-Term Memory (LSTM) neural networks and conducts empirical research on sea-level changes in the northern South China Sea. The results indicate that the EEMD-LSTM model outperforms the standalone LSTM model in terms of predictive accuracy, effectively eliminating noise from signals and providing a valuable reference. In summary, this research delves into the multiscale characteristics and influencing factors of sea-level changes in the northern SCS, proposing an improved sea-level prediction method that integrates EEMD and LSTM. The findings lay the groundwork for evaluating the risks of sea-level rise in low-lying regions of the northern SCS and inform future response strategies.

It is of great significance to find a scientific way to assess the water quality of the Middle Route of the South-North Water Diversion Project. In this paper, the spatio-temporal changes of the 26 water quality indicators in eight key monitoring stations along the Middle Route since the project was put into use were analyzed, and the modified Nemerow index method was employed to assess the water quality of the route in its early stage of operation. The results show that the water quality remained good in the period of study. Important water quality indicators were identified, including temperature, permanganate index, dissolved oxygen, total phosphorus, total nitrogen, mercury content, and density of planktonic algae. It is advised that potential ecological risks related to algae and shellfish reproduction in the open canal deserve special attention. HIGHLIGHTS The water quality of the MR-SNWTP since the operation was analyzed.; The modified Nemerow index method was applied to the South-North Water Diversion Project.; The performance of the single factor method and the modified Nemerow index method was compared.; The water quality indicators that deserve special attention were pointed out.; The suggestion of strengthening monitoring of potential risks posed by algae was put forward.;

Microglia are involved in the regulation of cerebral homeostasis and pathogen confrontation. There is, however, evidence showing that excessive microglia activation is implicated in various age-related cerebral diseases. On the other hand, microglia may experience complex changes of polarization in pathological insults, i.e., from a proinflammatory M1 to an anti-inflammatory M2 phenotype, which differentially contribute to the exacerbation or alleviation of cellular injury. Remolding the phenotype of microglia or inhibiting the excessive activation of microglia seems to be a promising approach against neurodegenerative pathologies. Since δ-opioid receptor (DOR) activation exhibits a strong protective capacity against various neuronal injuries, especially the hypoxic/ischemic injury, we asked if the DOR-induced neuroprotection is associated with its effect on microglia. We explored this fundamental issue by using pharmacological and genetic approaches in the BV2 cell line, a general type of microglial cells. The results showed that DOR expression significantly increased in the activated microglial M2 phenotype, but slightly decreased in the microglial M1 phenotype. Hypoxia induced dual polarizations of BV2 cells with an increase in DOR expression. Administration of a specific DOR agonist, UFP-512, largely inhibited lipopolysaccharide (LPS) or hypoxia-induced microglial M1 activation and inflammatory activity with high concentrations of UFP-512 being effective to reverse the interleukin-4 (IL4)-induced microglial activation. Consistent with these observations, inhibiting DOR or knocking-down DOR promoted the excessive activation of BV2 cells in both M1 and M2 directions, while DOR overexpression did the opposite. Furthermore, the PC12 cells exposed to the conditioned medium of BV2 cells treated by UFP-512 grew better than those treated directly with UFP-512 under LPS or hypoxic insults. DOR inhibitor naltrindole could block all the effects of DOR activation. The medium from the BV2 cells with DOR knock-down decreased the viability of PC12 cell, while the medium from the BV2 cells with DOR overexpression largely attenuated LPS or hypoxic injury in the PC12 cells. These first data suggest a close linkage between DOR expression/function and microglial polarization and a critical role of DOR in negative controlling microglial activation. Our work provides a novel clue for new protective strategies against neurodegenerative pathophysiology through DOR-mediated regulation of microglia.

BackgroundRearranged during transfection (RET) fusion is a kind of uncommon mutation (about 1%) in non-small cell lung cancer (NSCLC). Although selective tyrosine kinase inhibitors (TKI) (selpercatinib and pralsetinib) have been available, there are no real-world data about the difference in the efficacy between RET-TKI and other regimens in China.MethodsWe conducted a multicenter retrospective analysis of 49 patients with RET-fusion-positive NSCLC. The characteristics and the clinical outcomes with RET-TKI, multi-kinase inhibitor (MKI), systematic chemotherapy, and immune-checkpoint inhibitor (ICI)-based regimens were evaluated.ResultsOf the 92 treatments in patients included, RET-TKI was administered 24 times (26.1%), systematic chemotherapy was 35 times (38.0%), ICI-based regimens was 26 times (28.3%), and MKI was 7 times (7.6%). RET-TKI had a higher objective response rate than the chemotherapy and ICI-based regimens (63.6% vs. 14.3% vs. 21.0%, p < 0.001). The median progress-free survival (mPFS) of RET-TKI, chemotherapy, immunotherapy, and MKI was 16.9 (95% CI: 1.8–32.0) months, 11.9 (95% CI: 7.7–16.1) months, 6.7 (95% CI: 2.9–10.5) months, and 2.8 (95% CI: 1.1–4.4) months, respectively. The mPFS of RET-TKI was longer than MKI and immunotherapy (p < 0.001), while without difference with chemotherapy (p = 0.096). Moreover, chemotherapy had longer mPFS than MKI (p < 0.001). In subgroup analysis, patients with brain metastases in RET-TKI treatment had worse mPFS than the one of patients without brain metastases (6.1 (95% CI: 0.0–13.9) months and 8.5 (95% CI: 6.3–10.6) months, p = 0.012). For patients having chemotherapy with or without angiogenesis inhibitors, the mPFS was 12.0 (95% CI: 11.05–13.02) months and 9.1 (95% CI: 8.31–9.89) months (p = 0.468). In the group of ICI-based regimens, the expression level of PD-L1 did not affect the mPFS of ICI [PD-L1 (+) vs. PD-L1 (–): 4.7 (95% CI: 1.8–9.0) months vs. 7.6 (95% CI: 1.1–14.0) months, p = 0.910]. For overall patients, ECOG PS score, therapy lines, and therapeutic regimens were the independent factors affecting the prognosis.ConclusionsIn RET-fusion-positive NSCLC, RET-TKI is the best choice for a better response rate and PFS. In addition, chemotherapy which may bring a good PFS, is still a good choice for this group of patients.

BackgroundDysfunction of the immune system would disturb the intestinal homeostasis and lead to inflammatory bowel disease (IBD). Dendritic cells (DCs) help maintain intestinal homeostasis and immediately respond to pathogens or injuries once the mucosa barriers are destroyed during IBD. G protein-coupled receptors(GPR)174 is an essential regulator of immunity that is widely expressed in most immune cells, including DCs. However, the role of GPR174 in regulating the immune function of DC in colitis has not been investigated.MethodsDextran sodium sulfate (DSS) was administered to establish the mice colitis model. Data of weight, length of colon, disease activity index (DAI), and macroscopic scores were collected. The flow cytometry was used to detect the infiltrations of T cells and DCs, the mean fluorescence intensity (MFI) of CD80, CD86, CD40, and major histocompatibility complex-II (MHC-II). And T cells proliferataion was measured by carboxyfluorescein diacetate succinimidyl ester (CFSE). The expression of cytokines (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), interferon-γ (IFN-γ), interleukin -4 (IL-4)) and GPR174 mRNA were measured by Elisa, quantitative polymerase chain reaction (qPCR), and immunofluorescence. RNA of bone-marrow-derived dendritic cells (BMDCs) was extracted for sequencing. Adoptive transfer of BMDCs was administrated intravenously.ResultsGpr174-/- mice exposed to 3% DSS showed significant alleviation characterized by reduced loss of weight, more minor colon damage, and better DAI and macroscopic scores. The expression of pro-inflammatory cytokines (TNF-α, IL-6) decreased, while anti-inflammatory cytokine (IL-10) increased compared with WT mice. In vitro, Gpr174-/- BMDCs showed less maturity, with a declined expression of MHC-II, CD80, CD86 and reduced TNF-α, higher IL-10 after LPS stimulation. Gpr174-/- BMDCs were less capable of activating OT-II naïve CD4+ T cells than WT BMDCs and induced more Th0 cells to differentiate into Treg while less into Th1. Furthermore, the transcriptome sequencing analysis exhibited that Gpr174 participated in TNF-α (NF-κB) signaling, leukocyte transendothelial migration, and Th1/Th2 cell differentiation pathways. Adoptive transfer of Gpr174-/- BMDCs to WT mice ameliorated DSS-induced colitis.ConclusionOur study indicated that GPR174 was involved in the pathogenesis of IBD by regulating the maturation of the dendritic cells to maintain immune homeostasis. TNF-α (NF-κB) signaling pathway, leukocyte transendothelial migration, and Th1/Th2 cell differentiation pathways may be the target pathway.

Background: Dysfunction of liver sinusoidal endothelial cells (LSECs) is permissive for the progression of liver fibrosis and cirrhosis and responsible for its clinical complications. Here, we have mapped the spatial distribution of heterogeneous liver ECs in normal vs cirrhotic mouse livers and identified zone-specific transcriptomic changes of LSECs associated with liver cirrhosis using scRNA-seq technology. Approach & Results: Cirrhosis was generated in endothelial specific green fluorescent protein (GFP) reporter mice through carbon tetrachloride inhalation for 12 weeks. GFP-positive liver EC populations were isolated from control and cirrhotic mice by FACS. We identified 6 clusters of liver EC populations including 3 clusters of LSECs, 2 clusters of vascular ECs and 1 cluster of lymphatic ECs. Based on previously reported LSEC-landmarks, we mapped the 3 clusters of LSECs in zones 1, 2, and 3, and determined phenotypic changes in each zone between control and cirrhotic mice. We found genes representing capillarization of LSECs (eg, CD34) as well as extracellular matrix genes were most upregulated in LSECs of zone 3 in cirrhotic mice, which may contribute to the development of basement membranes. LSECs in cirrhotic mice also demonstrated decreased expression of endocytic receptors, most remarkably in zone 3. Transcription factors (Klf2 [Kruppel-like factor-2], Klf4 [Kruppel-like factor-4], and AP-1) that induce nitric oxide production in response to shear stress were downregulated in LSECs of all zones in cirrhotic mice, implying increased intrahepatic vascular resistance. Conclusion: This study deepens our knowledge of the pathogenesis of liver cirrhosis at a spatial, cell-specific level, which is indispensable for the development of novel therapeutic strategies to target the most dysfunctional liver ECs.

As a frontier issue of physics and material, the structures and related properties of borides have been extensively investigated in fundamental science. The search for pressure-induced stable compounds has become a feasible approach to acquire borides that are inaccessible at atmospheric pressure. Combined with state-of-the-art swarm intelligence structure prediction and first-principles calculations, we systematically explored the Rb-B system and uncovered a series of unprecedented RbB, Rb_{2}B_{3}, RbB_{3}, RbB_{6}, RbB_{8}, and RbB_{10} under high pressure. It is found that the catenation of boron evolves from linear chain to layered sheets, clusterlike units, and further to three-dimensional tunnel structures with increasing boron content. Among them, RbB_{6} and RbB_{8} are expected phonon-mediated superconductors with T_{c} of ∼12 K and superhard material with a hardness of ∼37 GPa at ambient pressure, respectively. Additionally, RbB_{8} is a suitable precursor for obtaining the superconducting o-B_{16} boron allotrope by removing Rb due to its better stability than isomorphic SrB_{8}. The current results provide insights into the design of unforeseen borides and illustrate intriguing B-B bonding features originating from Rb → B charge transfer under pressures.

Alteplase is the only FDA-approved drug for thrombolysis in acute ischemic stroke (AIS). Meanwhile, several thrombolytic drugs are deemed to be promising candidates to substitute alteplase. This paper evaluates the efficacy and safety of urokinase, ateplase, tenecteplase, and reteplase for intravenous AIS therapy by computational simulations of the pharmacokinetics and pharmacodynamics combined with a local fibrinolysis model. The performances of the drugs are evaluated by comparing clot lysis time, plasminogen activator inhibitor (PAI) inhibition resistance, intracranial hemorrhage (ICH) risk, and activation time from drug administration to clot lysis. Our results reveal that urokinase has the quickest lysis completion but the highest ICH risk due to excess fibrinogen depletion in systemic plasma. While tenecteplase and alteplase have very similar thrombolysis efficacy, tenecteplase has a lower risk of ICH and better resistance to PAI-1. Among the four simulated drugs, reteplase has the slowest fibrinolysis rate, but fibrinogen concentration in systemic plasma is unaffected during thrombolysis.

Introduction: The present study aimed to evaluate the influence of biological characteristics of hepatocellular carcinoma (HCC) on the Liver Imaging Reporting and Data System (LI-RADS) v2017 category of contrast-enhanced ultrasound (CEUS) in patients with high risk and compare the outcomes among different categories after radical resection. Methods: Between June 2017 and December 2020, standardized CEUS data of liver nodules were prospectively collected from multiple centers across China. We conducted a retrospective analysis of the prospectively collected data on HCCs measuring no more than 5 cm as diagnosed by pathology. LI-RADS categories were assigned after thorough evaluation of CEUS features. Then, CEUS LI-RADS categories and major features were compared in different differentiation, Ki-67 and microvascular invasion (MVI) statuses. Differences in recurrence-free survival (RFS) among different LI- RADS categories were further analyzed. Results: A total of 293 HCC nodules in 293 patients were included. This study revealed significant differences in the CEUS LI-RADS category of HCCs among differentiation (p 0.05). With a median follow-up of 23 months, HCCs assigned to different CEUS LI-RADS classes showed no significant differences in RFS after resection. Conclusions: Biological characteristics of HCC, including differentiation and level of Ki-67 expression could influence major features of CEUS and impact the CEUS LI-RADS category. HCCs in different CEUS LI-RADS categories showed no significant differences in RFS after resection.

Waves or tsunamis in the onshore area could induce severe scour at the structure foundations, threatening the stability of the structure. This paper presents a numerical study of the solitary wave-induced flow and scour around a square onshore structure. A CFD model coupled with hydrodynamic and sediment transport models is first validated through a large-scale laboratory experiment, which shows that the model can well reproduce the flow and scour characteristics. Subsequently, based on the reliable numerical results, the flow field and scour development during wave inundation of the structure are explored. It is found that the development of the simulated scour depth is faster at the early stage compared to that in the experimental result. The results also show that the scour starts at the front corner of the structure, which is also the position of the maximum scour depth. The scour develops rapidly at the early stage and is almost completed in the first half of the wave period. In addition, the results demonstrate that bed scouring increases the wave force on the structure due to the increase in the flow velocity near the bed, which needs to be considered, especially in the shallow-water scour scenario. Finally, a simplified prediction equation is proposed for the temporal development of the scour depth.

BackgroundWhile immune checkpoint inhibitors (ICIs) are a beacon of hope for non-small cell lung cancer (NSCLC) patients, they can also cause adverse events, including checkpoint inhibitor pneumonitis (CIP). Research shows that the inflammatory immune microenvironment plays a vital role in the development of CIP. However, the role of the immune microenvironment (IME) in CIP is still unclear.MethodsWe collected a cohort of NSCLC patients treated with ICIs that included eight individuals with CIP (CIP group) and 29 individuals without CIP (Control group). CIBERSORT and the xCell algorithm were used to evaluate the proportion of immune cells. Gene set enrichment analysis (GSEA) and single-sample GSEA (ssGSEA) were used to evaluate pathway activity. The ridge regression algorithm was used to analyze drug sensitivity.ResultsCIBERSORT showed significantly upregulated memory B cells, CD8+ T cells, and M1 Macrophages in the CIP group. The number of memory resting CD4+ T cells and resting NK cells in the CIP group was also significantly lower than in the Control group. The XCell analysis showed a higher proportion of Class-switched memory B-cells and M1 Macrophages in the CIP group. Pathway analysis showed that the CIP group had high activity in their immune and inflammatory response pathways and low activity in their immune exhaustion related pathway.ConclusionsIn this study, we researched CIP patients who after ICIs treatment developed an inflammatory IME, which is characterized by significantly increased activated immune cells and expression of inflammatory molecules, as well as downregulated immunosuppressive lymphocytes and signaling pathways. The goal was to develop theoretical guidance for clinical guidelines for the treatment of CIP in the future.