Search

Abstract A quantity of recoverable barite exists in high-density waste drilling fluid. Based on the inefficiencies and complexities of existing recycling methods, a novel pre-treatment approach which includes clean-breaking, high-speed washing, ultrasonic dispersion, and microwave heating and a new depressant (Gellan Gum) was proposed. The floatability, separation efficiency and mechanism were discussed by SEM, adsorption capacity, zeta potential measurements and contact angle tests. The results of reverse flotation experiments results indicated that secondary water washing proves highly effective in enriching a significant quantity of barite solid phase. Subsequent microwave-ultrasonic and flotation can obtain barite of high quality with recovery and density reaching 81.5% and 4.238 g/cm3, respectively. It can be utilized directly in the preparation of drilling fluid. Mechanism studies shown that the per-treatments substantially enhances the barite grade while effectively eliminating low-density solid phases adhering to the barite surface, thus exposing additional contact points between the constituents so as to improve flotation separation. This new recovery scheme has environmental advantages and great reference value for the separation of barite within high-density waste drilling fluids.

Abstract Background This meta-analysis aimed to assess the safety and efficacy of robotic-assisted natural orifice specimen extraction surgery (NOSE) compared to traditional robotic transabdominal wall specimen retrieval surgery (TWSR) for colorectal cancer. Methods A systematic search was conducted in three electronic databases (PubMed, Web of Science and Embase) from inception to August 2023. Primary outcomes included postoperative complications, the number of lymph nodes harvested, overall survival and disease-free survival. Secondary outcomes included the postoperative visual analog scale (VAS) score, the additional use of analgesics, the restoration of gastrointestinal function, blood loss, the mean operation time, and length of postoperative hospital stay. Results In this meta-analysis, a total of 717 patients from 6 observational studies met the inclusion criteria. Compared with the TWSR group, the NOSE group had greater benefits in terms of overall postoperative complications [odds ratios (OR) 0.55; 95% confidence intervals (CI) = 0.34 to 0.89; P = 0.01, I 2 = 0%)], the number of lymph nodes harvested [weighted mean differences (WMD) = 1.18; 95% CI = 0.15 to 2.21; P = 0.02, I 2 = 0%)], the rate of wound infection (OR 0.17; 95% CI = 0.04 to 0.80; P = 0.02, I 2 = 0%), the passed flatus time (WMD = − 0.35 days; 95% CI = − 0.60 to − 0.10; P = 0.007, I 2 = 73%), the additional use of analgesics (OR 0.25; 95% CI = 0.15 to 0.40; P

Abstract Electrochemical reactions via carbocation intermediates remain fundamental transformations that build up molecular functionality and complexity in a sustainable manner. Enantioselective control of such processes is a great challenge in a highly ionic electrolyte solution. Here, we report an anodic generation of chiral α-imino carbocation intermediates by enamine catalysis. The chiral carbocation intermediates can be intercepted by a variety of nucleophiles such as alcohols, water and thiols with high stereoselectivity. The key SN1 step proceeds via a tertiary amine-mediated proton shuttle that facilitates facial selection in reacting with carbocation.

Abstract Hydrothermal carbonization (HTC) stands out as an eco-friendly, cost-effective method for generating renewable carbon-based materials from biomass. The HTC process yields products such as hydrochars and carbon dots (CDs), possessed of notable photocatalytic capabilities due to their unique physicochemical features. Additionally, pairing traditional photocatalysts with hydrochar derivatives elevates their performance, rendering them more effective. Recent times have witnessed a surge in interest in these hydrochar based photocatalysts (HC-photocatalysts). Their appeal stems from multiple attributes: impeccable performance, adaptability to visible light, and adjustable physicochemical properties. This review delves deep into the evolving landscape of these HC-photocatalysts, segmenting them into three distinct categories: hydrochars, hydrochar-based CDs (HC-CDs), and hydrochar-based composites (HC-composites). For each category, we dissect their synthesis routes, unravel the photocatalytic mechanisms, and explore various enhancement strategies. We further traverse their versatile applications, spanning environmental treatment, disinfection, energy conversion, and organic synthesis. In the end, we spotlight the prevailing challenges and uncharted territories in the domain of HC-photocatalysts. In essence, this review serves as a guide, furnishing a theoretical foundation and steering directions for future explorations and tangible implementations of HC-photocatalysts. Graphical Abstract

Abstract Nanosizing confers unique functions in materials such as graphene and quantum dots. Here, we present two nanoscale-covalent organic frameworks (nano-COFs) that exhibit exceptionally high activity for photocatalytic hydrogen production that results from their size and morphology. Compared to bulk analogues, the downsizing of COFs crystals using surfactants provides greatly improved water dispersibility and light-harvesting properties. One of these nano-COFs shows a hydrogen evolution rate of 392.0 mmol g−1 h−1 (33.3 μmol h−1), which is one of the highest mass-normalized rates reported for a COF or any other organic photocatalysts. A reverse concentration-dependent photocatalytic phenomenon is observed, whereby a higher photocatalytic activity is found at a lower catalyst concentration. These materials also show a molecule-like excitonic nature, as studied by photoluminescence and transient absorption spectroscopy, which is again a function of their nanoscale dimensions. This charts a new path to highly efficient organic photocatalysts for solar fuel production.

Customer numbers and comments have been extensively studied to increase hotel arrivals and loyalty, whereas the specific distribution and sentiment variations have received less attention. This study constructed a data set of hotel customers and the deep learning model was applied to quantify unstructured text, which can mine the distribution and sentiment variation patterns of different star hotel customers. The findings show that customers of different star-rated hotels have different variation patterns of sentiment and distribution. There is a negative correlation between the visit heat and sentiment of some high-star hotels in various administrative regions: regions with lower visit heat have higher sentiment scores. In addition, season and location are important factors that affect customers’ sentiments. This study is the first to use a quantitative approach to examine the distribution and sentiment variation patterns of hotel customers. It provides insights into appropriate marketing strategies for the hotel industry and offers practical suggestions to hotel customers.

Abstract Introduction Walking stands as the most prevalent physical activity in the daily lives of individuals and is closely associated with physical functioning and the aging process. Nonetheless, the precise cause-and-effect connection between walking and aging remains unexplored. The epigenetic clock emerges as the most promising biological indicator of aging, capable of mirroring the biological age of the human body and facilitating an investigation into the association between walking and aging. Our primary objective is to investigate the causal impact of walking with epigenetic age acceleration (EAA). Methods We conducted a two-sample two-way Mendelian randomization (MR) study to investigate the causal relationship between walking and EAA. Walking and Leisure sedentary behavior data were sourced from UK Biobank, while EAA data were gathered from a total of 28 cohorts. The MR analysis was carried out using several methods, including the inverse variance weighted (IVW), weighted median, MR-Egger, and robust adjusted profile score (RAPS). To ensure the robustness of our findings, we conducted sensitivity analyses, which involved the MR-Egger intercept test, Cochran’s Q test, and MR-PRESSO, to account for and mitigate potential pleiotropy. Results The IVW MR results indicate a significant impact of usual walking pace on GrimAge (BETA = − 1.84, 95% CI (− 2.94, − 0.75)), PhenoAge (BETA = − 1.57, 95% CI (− 3.05, − 0.08)), Horvath (BETA = − 1.09 (− 2.14, − 0.04)), and Hannum (BETA = − 1.63, 95% CI (− 2.70, − 0.56)). Usual walking pace is significantly associated with a delay in epigenetic aging acceleration (EAA) (P 0.05). Conclusion Our evidence demonstrates that a higher usual walking pace is associated with a deceleration of the acceleration of all four classical epigenetic clocks acceleration.

Abstract Glycosphingolipids (GSLs) are essential components of cell membranes, particularly enriched in the nervous system. Altered molecular distributions of GSLs are increasingly associated with human diseases, emphasizing the significance of lipidomic profiling. Traditional GSL analysis methods are hampered by matrix effect from phospholipids and the difficulty in distinguishing structural isomers. Herein, we introduce a highly sensitive workflow that harnesses magnetic TiO2 nanoparticle-based selective enrichment, charge-tagging Paternò–Büchi reaction, and liquid chromatography-tandem mass spectrometry. This approach enables mapping over 300 distinct GSLs in brain tissues by defining sugar types, long chain bases, N-acyl chains, and the locations of desaturation and hydroxylation. Relative quantitation of GSLs across multiple structural levels provides evidence of dysregulated gene and protein expressions of FA2H and CerS2 in human glioma tissue. Based on the structural features of GSLs, our method accurately differentiates human glioma with/without isocitrate dehydrogenase genetic mutation, and normal brain tissue.

As a unique environmental regulation in China, the official accountability audit was piloted in 2014. With a focus on prioritizing the ecological environment, officials in pilot districts have implemented economic construction, adjusted industrial structures, and promoted coordinated development between the economy and environment. The effects of implementation have garnered widespread attention from society. However, there is limited research on the impact of an accountability audit on industrial structure adjustments. Using the “Accountability Audit of Officials for Natural Resource Assets (Trial)” released in 2015 as a quasi-natural experiment, this study collected panel data from 279 cities between 2013 and 2017. It then empirically analyzed the impact mechanism and effects of the accountability audit on industrial structure adjustment using the Propensity Score Matching and Difference-in-Differences model. The research findings indicate that the accountability audit directly impacted industrial structure adjustment, promoting the upgrading of the primary industry to the secondary industry and restricting the development of the tertiary industry. In addition, the audit is beneficial for enterprise entry, but not conducive to technological innovation, and has no significant impact on foreign direct investment. This conclusion fills a gap in the existing research and provides valuable insights for policymakers.

Abstract Penpulimab is an anti-programmed cell death-1 (PD-1) IgG1 antibody with no Fc gamma receptor (FcγR) binding activity, and thus theoretically reduced immune-related adverse events (irAEs) while maintaining efficacy. This single-arm, phase II trial conducted across 20 tertiary care centers in China enrolled adult patients with metastatic nasopharyngeal carcinoma (NPC) who had failed two or more lines of previous systemic chemotherapy. Patients received 200-mg penpulimab intravenously every 2 weeks (4 weeks per cycle) until disease progression or intolerable toxicities. The primary endpoint was objective response rate (ORR) per RECIST (version 1.1), as assessed by an independent radiological review committee. The secondary endpoints included progression-free survival (PFS) and overall survival (OS). One hundred thirty patients were enrolled and 125 were efficacy evaluable. At the data cutoff date (September 28, 2022), 1 patient achieved complete response and 34 patients attained partial response. The ORR was 28.0% (95% CI 20.3–36.7%). The response was durable, with 66.8% still in response at 9 months. Thirty-three patients (26.4%) were still on treatment. The median PFS and OS were 3.6 months (95% CI = 1.9–7.3 months) and 22.8 months (95% CI = 17.1 months to not reached), respectively. Ten (7.6%) patients experienced grade 3 or higher irAEs. Penpulimab has promising anti-tumor activities and acceptable toxicities in heavily pretreated metastatic NPC patients, supporting further clinical development as third-line treatment of metastatic NPC.

Abstract Background Intratumoral hemorrhage, though less common, could be the first clinical manifestation of glioma and is detectable via MRI; however, its exact impacts on patient outcomes remain unclear and controversial. The 2021 WHO CNS 5 classification emphasised genetic and molecular features, initiating the necessity to establish the correlation between hemorrhage and molecular alterations. This study aims to determine the prevalence of intratumoral hemorrhage in glioma subtypes and identify associated molecular and clinical characteristics to improve patient management. Methods Integrated clinical data and imaging studies of patients who underwent surgery at the Department of Neurosurgery at Peking Union Medical College Hospital from January 2011 to January 2022 with pathological confirmation of glioma were retrospectively reviewed. Patients were divided into hemorrhage and non-hemorrhage groups based on preoperative magnetic resonance imaging. A comparison and survival analysis were conducted with the two groups. In terms of subgroup analysis, we classified patients into astrocytoma, IDH-mutant; oligodendroglioma, IDH-mutant, 1p/19q-codeleted; glioblastoma, IDH-wildtype; pediatric-type gliomas; or circumscribed glioma using integrated histological and molecular characteristics, according to WHO CNS 5 classifications. Results 457 patients were enrolled in the analysis, including 67 (14.7%) patients with intratumoral hemorrhage. The hemorrhage group was significantly older and had worse preoperative Karnofsky performance scores. The hemorrhage group had a higher occurrence of neurological impairment and a higher Ki-67 index. Molecular analysis indicated that CDKN2B, KMT5B, and PIK3CA alteration occurred more in the hemorrhage group (CDKN2B, 84.4% vs. 62.2%, p = 0.029; KMT5B, 25.0% vs. 8.9%, p = 0.029; and PIK3CA, 81.3% vs. 58.5%, p = 0.029). Survival analysis showed significantly worse prognoses for the hemorrhage group (hemorrhage 18.4 months vs. non-hemorrhage 39.1 months, p = 0.01). In subgroup analysis, the multivariate analysis showed that intra-tumoral hemorrhage is an independent risk factor only in glioblastoma, IDH-wildtype (162 cases of 457 overall, HR = 1.72, p = 0.026), but not in other types of gliomas. The molecular alteration of CDK6 (hemorrhage group p = 0.004, non-hemorrhage group p

Abstract Background Intestinal metaplasia (IM) is classified into complete intestinal metaplasia (CIM) and incomplete intestinal metaplasia (IIM). Patients diagnosed with IIM face an elevated susceptibility to the development of gastric cancer, underscoring the critical need for early screening measures. In addition to the complexities associated with diagnosis, the exact mechanisms driving the progression of gastric cancer in IIM patients remain poorly understood. OLFM4 is overexpressed in several types of tumors, including colorectal, gastric, pancreatic, and ovarian cancers, and its expression has been associated with tumor progression. Methods In this study, we used pathological sections from two clinical centers, biopsies of IM tissues, precancerous lesions of gastric cancer (PLGC) cell models, animal models, and organoids to explore the role of OLFM4 in IIM. Results Our results show that OLFM4 expression is highly increased in IIM, with superior diagnostic accuracy of IIM when compared to CDX2 and MUC2. OLFM4, along with MYH9, was overexpressed in IM organoids and PLGC animal models. Furthermore, OLFM4, in combination with Myosin heavy chain 9 (MYH9), accelerated the ubiquitination of GSK3β and resulted in increased β-catenin levels through the Wnt signaling pathway, promoting the proliferation and invasion abilities of PLGC cells. Conclusions OLFM4 represents a novel biomarker for IIM and could be utilized as an important auxiliary means to delimit the key population for early gastric cancer screening. Finally, our study identifies cell signaling pathways involved in the progression of IM.

An unprecedented electrochemical oxidative trifunctionalization of olefins with diaryl disulfides/aryl thiols and N-chlorosuccinimide in an aqueous system is developed. Two C–Cl bonds, one C–S bond, and one SO bond are produced simultaneously in one step from simple and commercially available starting materials with clean energy. This tandem methodology features as mild reaction conditions, transition metal and additional oxidant free, broad substrate scope, good functional group compatibility, and gram scale preparation.

Abstract Background Although papillary thyroid carcinoma (PTC) has a favorable prognosis, it could affect patient life quality and become a serious threat because of invasion and metastasis. Many investigations have suggested that circular RNAs (circRNAs) are involved in different cancer regulations. Nevertheless, circRNAs role in invasive PTC remains unclear. Methods In the present investigation, next-generation sequencing was applied to explore abnormal circRNA expression. The expression of circRNA phosphoglycerate dehydrogenase (circPHGDH) in PTC cell lines and tissues were examined. Then, we investigated regulatory mechanism and circPHGDH downstream targets using bioinformatics analysis and luciferase reporting analysis. Then transwell migration, Cell Counting Kit-8 (CCK8) and 5-ethynyl-2’-deoxyuridine (EdU) assays were used for cells migration and proliferation analysis. In vivo metastasis and tumorigenesis assays were also employed to evaluate the circPHGDH role in PTC. Results The data showcased that circPHGDH expression increased in both PTC cell lines and tissues, which suggested that circPHGDH functions in PTC progression. circPHGDH downregulation suppressed PTC invasion and proliferation in both in vivo and in vitro experiments. Bioinformatics and luciferase reporter results confirmed that both microRNA (miR)-122-5p and pyruvate kinase M2 subtype (PKM2) were downstream targets of circPHGDH. PKM2 overexpression or miR-122-5p suppression reversed PTC cell invasion and proliferation post silencing circPHGDH by restoring aerobic glycolysis. Conclusion Taken together, our research found that circPHGDH downregulation reduced PTC progression via miR-122-5p/PKM2 axis regulation mediated by aerobic glycolysis.

Abstract Rapeseed is a critical cash crop globally, and understanding its distribution can assist in refined agricultural management, ensuring a sustainable vegetable oil supply, and informing government decisions. China is the leading consumer and third-largest producer of rapeseed. However, there is a lack of widely available, long-term, and large-scale remotely sensed maps on rapeseed cultivation in China. Here this study utilizes multi-source data such as satellite images, GLDAS environmental variables, land cover maps, and terrain data to create the China annual rapeseed maps at 30 m spatial resolution from 2000 to 2022 (CARM30). Our product was validated using independent samples and showed average F1 scores of 0.869 and 0.971 for winter and spring rapeseed. The CARM30 has high spatial consistency with existing 10 m and 20 m rapeseed maps. Additionally, the CARM30-derived rapeseed planted area was significantly correlated with agricultural statistics (R2 = 0.65–0.86; p

Abstract In the human genome, heterozygous sites refer to genomic positions with a different allele or nucleotide variant on the maternal and paternal chromosomes. Resolving these allelic differences by chromosomal copy, also known as phasing, is achievable on a short-read sequencer when using a library preparation method that captures long-range genomic information. TELL-Seq is a library preparation that captures long-range genomic information with the aid of molecular identifiers (barcodes). The same barcode is used to tag the reads derived from the same long DNA fragment within a range of up to 200 kilobases (kb), generating linked-reads. This strategy can be used to phase an entire genome. Here, we introduce a TELL-Seq protocol developed for targeted applications, enabling the phasing of enriched loci of varying sizes, purity levels, and heterozygosity. To validate this protocol, we phased 2–200 kb loci enriched with different methods: CRISPR/Cas9-mediated excision coupled with pulse-field electrophoresis for the longest fragments, CRISPR/Cas9-mediated protection from exonuclease digestion for mid-size fragments, and long PCR for the shortest fragments. All selected loci have known clinical relevance: BRCA1, BRCA2, MLH1, MSH2, MSH6, APC, PMS2, SCN5A-SCN10A, and PKI3CA. Collectively, the analyses show that TELL-Seq can accurately phase 2–200 kb targets using a short-read sequencer.

Nano aluminum powder effectively enhances reactivity, thereby improving energy-containing materials' performance. To investigate micro-nano self-assembled aluminum powders' energy output and their application in composite explosives, we tested the heat of combustion and ignition characteristics (ignition delay, ignition energy, flame propagation speed) using oxygen bomb calorimetry and Hartmann tube. Results showed that the combustion heat decreased with increasing nano aluminum powder content. The addition of nano aluminum powders substantially decreased ignition delay and energy, enhancing the combustion rate and reactivity of aluminum powder dust. The ranking of reactivity among the five aluminum powders was as follows: μ@n-Al-10 % > μ@n-Al-5% > μ/n-Al-10 % > μ/n-Al-5% > μAl. Assessing explosives containing various aluminum powders showed that the self-assembled 5 % content sample had the highest heat of detonation at 8490 kJ/kg. Mechanical sensitivity increased with higher nano aluminum powder content, with explosives containing 5 % nano content exhibiting the highest safety performance.

Micro-expression is extensively studied due to their ability to fully reflect individuals' genuine emotions. However, accurate micro-expression recognition is a challenging task due to the subtle motion of facial muscle. Therefore, this paper introduces a Graph Attention Mechanism-based Motion Magnification Guided Micro-Expression Recognition Network (GAM-MM-MER) to amplify delicate muscle motions and focus on key facial landmarks. First, we propose a Swin Transformer-based network for micro-expression motion magnification (ST-MEMM) to enhance the subtle motions in micro-expression videos, thereby unveiling imperceptible facial muscle movements. Then, we propose a graph attention mechanism-based network for micro-expression recognition (GAM-MER), which optimizes facial key area maps and prioritizes adjacent nodes crucial for mitigating the influence of noisy neighbors, while attending to key feature information. Finally, experimental evaluations conducted on the CASME II and SAMM datasets demonstrate the high accuracy and effectiveness of the proposed network compared to state-of-the-art approaches. The results of our network exhibit significant superiority over existing methods. Furthermore, ablation studies provide compelling evidence of the robustness of our proposed network, substantiating its efficacy in micro-expression recognition.

Abstract As a highly dynamic tissue, bone is continuously rebuilt throughout life. Both bone formation by osteoblasts and bone resorption by osteoclasts constitute bone reconstruction homeostasis. The equilibrium of bone homeostasis is governed by many complicated signaling pathways that weave together to form an intricate network. These pathways coordinate the meticulous processes of bone formation and resorption, ensuring the structural integrity and dynamic vitality of the skeletal system. Dysregulation of the bone homeostatic regulatory signaling network contributes to the development and progression of many skeletal diseases. Significantly, imbalanced bone homeostasis further disrupts the signaling network and triggers a cascade reaction that exacerbates disease progression and engenders a deleterious cycle. Here, we summarize the influence of signaling pathways on bone homeostasis, elucidating the interplay and crosstalk among them. Additionally, we review the mechanisms underpinning bone homeostatic imbalances across diverse disease landscapes, highlighting current and prospective therapeutic targets and clinical drugs. We hope that this review will contribute to a holistic understanding of the signaling pathways and molecular mechanisms sustaining bone homeostasis, which are promising to contribute to further research on bone homeostasis and shed light on the development of targeted drugs.

Given the prevalence of Al/RDX energetic dust in industrial production, this study investigates their ignition safety and explosion hazards using Hartmann tubes and 20 L spherical explosion containers. The minimum ignition energy (MIE) increases from 20 mJ to 55 mJ as RDX content increases, indicating that adding RDX enlarges the effective particle size of the dust, thereby reducing its ignition sensitivity. A logistic regression model was used to develop a fitting equation for ignition probability, correlating dust concentration and ignition energy. The flame propagation velocity and explosion pressure of the energetic dust initially increase and then decrease with increasing RDX content. Optimal combustion characteristics were observed at 20 % RDX, with the maximum flame propagation velocity of 101 m s−1. However, the peak flame temperature decreases with increasing RDX content. The maximum explosion pressure and maximum explosion index at 1.77 MPa and 186.99 MPa m s−1 respectively, at 40 % RDX content. These findings highlight that 20 % RDX content yields the best combustion characteristics, while 40 % RDX content offers the maximum explosive potential, providing valuable insights for enhancing safety measures in industrial applications involving energetic dusts.

The safety implications of aluminum powder and petroleum ether have garnered significant attention as two typical materials in the production process of energetic materials. To investigate the effect of the common solvent petroleum ether on the ignition and explosion characteristics of aluminum powder, ignition energy, flame propagation characteristics, and explosion pressure of three aluminum powder sizes and their mixtures with petroleum ether through a Hartmann tube test device and a 20 L spherical explosion vessel test system. Findings show that the ignition energy of aluminum powder initially decreases and then increases with the increase of petroleum ether content. At the petroleum ether concentration of 5.5 % and 11 %, the minimum ignition energies of the mixed systems of Al-Flake, Al-T4, and Al-T2 are 1–20 mJ, 5–30 mJ, 450–485 mJ, and 1–20 mJ, 5–25 mJ, 440–480 mJ, respectively. Lower than the minimum ignition energy of the original sample (1–30 mJ, 10–40 mJ, 470–510 mJ), indicating that the aluminum powder dust containing low concentration solvent (5.5%, 11 %) is more sensitive to an electric spark. The ignition energy of the mixed system is rather increased when the content of petroleum ether is further increased to 16.5 %. On the contrary, the probability of ignition and the electric spark sensitivity are decreased. With the addition of petroleum ether to Al-Flake and Al-T4, the flame propagation speed slightly decreases and the phase duration lengthens. The flame propagation characteristics and combustion state of Al-T2 with large particles remained largely unchanged after the addition of petroleum ether. During the 20 L spherical explosion vessel test, the maximum explosion pressure and explosion index of the mixed samples initially increase and then decrease with the increase in petroleum ether concentration. A small quantity of petroleum ether intensifies the reaction intensity of aluminum dust. At an aluminum powder dust concentration of 250 g m-3, the explosion pressure and explosion index of Al-Flake and Al-T4 peak at a petroleum ether content of 5.5 %, while Al-T2 reaches its peak at 11 %.

Abstract Background The diagnosis of glioma has advanced since the release of the WHO 2021 classification with more molecular alterations involved in the integrated diagnostic pathways. Our study aimed to present our experience with the clinical features and management of astrocytoma, IDH mutant based on the latest WHO classification. Methods Patients diagnosed with astrocytoma, IDH‐mutant based on the WHO 5th edition classification of CNS tumors at our center from January 2009 to January 2022 were included. Patients were divided into WHO 2–3 grade group and WHO 4 grade group. Integrate diagnoses were retrospectively confirmed according to WHO 2016 and 2021 classification. Clinical and MRI characteristics were reviewed, and survival analysis was performed. Results A total of 60 patients were enrolled. 21.67% (13/60) of all patients changed tumor grade from WHO 4th edition classification to WHO 5th edition. Of these, 21.43% (6/28) of grade II astrocytoma and 58.33% (7/12) of grade III astrocytoma according to WHO 4th edition classification changed to grade 4 according to WHO 5th edition classification. Sex (p = 0.042), recurrent glioma (p = 0.006), and Ki‐67 index (p

Reinforced concrete (RC) bent structures are widely used in single-story industrial buildings, with a considerable portion of them located in high-intensity seismic areas. Therefore, it is significant to study the seismic performance of the RC bent column while keeping construction costs in mind. To evaluate the seismic performance of the RC bent column from an economic perspective, pseudo-static tests combined with construction cost analysis were first carried out on three RC bent columns designed according to different versions of Chinese codes. A numerical simulation method based on the extended finite element method (XFEM) for the RC bent column was then established and verified. Subsequently, the relationship between the local damage index related to the apparent damage characteristics and the overall damage index was established by conducting numerical analysis on RC bent columns with different design parameters. Based on the established relationship between the local and overall damage indexes, a calculation method for the residual bearing capacity based on apparent damage was developed. The results show that, when compared to the constructional requirements in the Chinese code for seismic design of industrial and civil buildings published in 1978 (TJ11–78), the constructional requirements in the Chinese code for seismic design of buildings published in 1989 (GBJ11–89) can effectively reduce the stress concentration at the column bottom and delay the formation of the plastic hinge with minimal cost increase, while the constructional requirements in the Chinese code for seismic design of buildings published in 2016 (GB50011–2010) can further effectively reduce the damage to the upper column. Besides, the constructional requirements in GBJ11–89 and GB50011–2010 can improve the energy dissipation and maximum bearing capacity of the RC bent column while decrease the cost/ductility coefficient by more than 5.0 %. The proposed calculation method can effectively predict the residual bearing capacity of earthquake-damaged RC bent columns by comparing the calculation results to the test results.

Triple negative breast cancer (TNBC) has a high recurrence rate, metastasis rate and mortality rate. The aim of this study is to identify new targets for the treatment of TNBC. Clinical samples are used for screening deubiquitinating enzymes (DUBs). MDA-MB-231 cells and a TNBC mouse model are used for in vitro and in vivo experiments, respectively. Western blot analysis is used to detect the protein expressions of DUBs, zinc finger E-box binding homeobox 1 (ZEB1), and epithelial-mesenchymal transition (EMT)-related markers. Colony formation and transwell assays are used to detect the proliferation, migration and invasion of TNBC cells. Wound healing assay is used to detect the mobility of TNBC cells. Immunoprecipitation assay is used to detect the interaction between breast cancer susceptibility gene 1/2-containing complex subunit 3 (BRCC3) and ZEB1. ZEB1 ubiquitination levels, protein stability, and protein degradation are also examined. Pathological changes in the lung tissues are detected via HE staining. Our results show a significant positive correlation between the expressions of BRCC3 and ZEB1 in clinical TNBC tissues. Interference with BRCC3 inhibits TNBC cell proliferation, migration, invasion and EMT. BRCC3 interacts with ZEB1 and interferes with BRCC3 to inhibit ZEB1 expression by increasing ZEB1 ubiquitination. Interference with BRCC3 inhibits TNBC cell tumorigenesis and lung metastasis in vivo. In all, this study demonstrates that BRCC3 can increase the stability of ZEB1, upregulate ZEB1 expression, and promote the proliferation, migration, invasion, EMT, and metastasis of TNBC cells, providing a new direction for cancer therapy.

Abstract Objective To evaluate the early and mid-term outcomes of open repair in patients with thoracoabdominal aortic aneurysm (TAAA) after thoracic endovascular aortic repair (TEVAR). Methods This was a retrospective single center study. Data were retrospectively collected and analyzed for consecutive patients undergoing open TAAA repair (TAAAR) after TEVAR from November 2016 to June 2021. Indications for TAAAR included aneurysm progression due to endoleak, persisted false lumen perfusion, proximal/distal disease progression, and aorta rupture. The risk factor of operative mortality was analyzed by multivariable logistic regression model and the survival was evaluated by Kaplan–Meier. Results Sixty-three patients who met the inclusion criteria for the study were identified. The mean age at TAAAR was 41 ± 12 years and 43 (68.3%) were male. Marfan syndrome (MFS) was presented in 39 patients (61.9%). 60 (95.2%) patients presented with post-dissection aneurysm and 3 (4.8%) patients with degenerative aneurysm. The extent of TAAA was Crawford I in 9 (14.3%), II in 22 (34.9%), III in 23 (36.5%), and IV in 9 (14.3%). Emergent TAAAR was done in 10 (15.9%) patients, and deep hypothermic circulatory arrest was used in 22 (34.6%). Endograft was explanted in 31 (49.2%). Operative mortality was 11 (17.5%). Stroke, paraplegia, and acute kidney failure occurred in 5 (7.9%), 7 (11.1%), and 6 (9.5%) patients, respectively. Pulmonary complications occurred in 19 (30.2%) patients. The estimated survival was 74.8 ± 4.9% at 5 years. Late reoperations were performed in 2 patients at 2.5 years and 1.3 years, respectively. Conclusions In this series of TAAA after TEVAR, TAAAR was related with a high risk of operative mortality and morbidity and the midterm outcomes represented a durable treatment and were respectable.

Abstract Predictive markers and prognostic models are useful for the individualization of cancer treatment. In this study, we sought to identify clinical and molecular factors to predict overall survival in recurrent glioma patients receiving bevacizumab-containing regimens. A cohort of 102 patients was retrospectively collected from June 2011 to January 2022 at our institution. A nomogram was generated by Cox regression and feature selection algorithms based on 19 clinicopathological and 60 molecular variables. The model's performance was internally evaluated by bootstrapping in terms of discrimination and calibration. The median overall survival from the initiation of bevacizumab administration to death or last follow-up was 11.6 months (95% CI: 9.2–13.8 months) for all 102 patients, 10.2 months (95% CI: 6.4–13.3 months) for 66 patients with grade 4 tumors, and 13.8 months (lower limit of 95% CI: 11.5 months) for 36 patients with tumors of grade lower or not available. In the final model, a lower WHO 2021 grade (Grade lower or not available vs. Grade 4, HR: 0.398, 95% CI: 0.223–0.708, p = 0.00172), having received adjuvant radiochemotherapy (Yes vs. No, HR: 0.488, 95% CI: 0.268–0.888, p = 0.0189), and wildtype EGFR (Wildtype vs. Altered, HR: 0.193, 95% CI: 0.0506–0.733, p = 0.0157; Not available vs. Altered, HR: 0.386, 95% CI: 0.184–0.810, p = 0.0118) were significantly associated with longer overall survival in multivariate Cox regression. The overall concordance index was 0.652 (95% CI: 0.566–0.714), and the areas under the time-dependent curves for 6-, 12-, and 18-month overall survival were 0.677 (95% CI: 0.516–0.816), 0.654 (95% CI: 0.470–0.823), and 0.675 (95% CI: 0.491–0.860), respectively. A prognostic model for overall survival in recurrent glioma patients treated with bevacizumab-based therapy was established and internally validated. It could serve as a reference tool for clinicians to assess the extent the patients may benefit from bevacizumab and stratify their treatment response.

Abstract Background Primary thyroid lymphoma (PTL) is a rare malignant disorder, and ultrasound plays an important role in PTL diagnosis and follow-up surveillance. Prediction of refractory/relapse events in PTL patients is an essential issue, yet no ultrasonic PTL features have been discovered to be related to refractory/local relapse events. Methods From January 2008 to September 2022, newly diagnosed PTL patients in our center who underwent standard first-line treatment and received an ultrasound examination before treatment were enrolled. Data regarding patients’ clinical and sonographic features, as well as their therapeutic responses were collected. Subjects with an ideal prognosis were compared to those with refractory/relapse events. Results In total, 37 PTL patients were analyzed, including 26 with diffuse large B-cell lymphoma, 2 with follicular lymphoma and 9 with mucosa-associated lymphoid tissue lymphoma. During the median follow-up of 25 months, 30 patients obtained a complete response, 4 were refractory patients, and 3 experienced local relapse. No significant difference was detected in the baseline clinical characteristics between patients with an ideal prognosis and those with refractory/local relapse events. In terms of sonographic features, however, an event-free survival (EFS) curve comparison revealed that patients with bilobar enlargement (defined as an anterior-posterior diameter > 2.5 cm on both sides of thyroid lobes) had a poorer EFS than those without (P 2.5 cm for both thyroid lobes or PTL patients of the diffuse ultrasound type could be prone to refractory/local relapse events.

The drilling of printed circuit board (PCB) using micro-drills is an important processing method in modern industry. A protective film with good lubricating and anti-wear properties is generally applied to improve the processing problems of micro-drills during operation. In this study, the effects of C2H2 flow rate on the microstructure, mechanical, and tribological properties of a-C:H films deposited by plasma enhanced chemical vapor deposition (PECVD) technique were investigated. The results showed that when the C2H2 flow rate was low, varying the flow rate had little effect on the microstructure of the prepared a-C:H films. However, when the C2H2 flow rate was greater than 210 sccm, the increase in flow rate caused large particles of carbon clusters to aggregate on the surface of a-C:H films, which resulting in an increase Ra value. Not only did it reduce the adhesion between the film and the substrate, but it also deteriorated the mechanical and tribological properties of the a-C:H film produced. In addition, a-C:H films were also deposited on the micro-drill, and were used for drilling tests on the PCBs to evaluate its servce capability. The optimal parameters of a-C:H film deposited on the micro-drill surface were obtained by observing the morphology of the micro-drill surface after drilling and the hole accuracy statistics. The results showed that a-C:H film deposited on the surface of the micro-drill showed the best machining performance when the C2H2 flow rate was 180 sccm. The surface wear of micro-drill was minimal, the entanglement of tangled chips was minimal. The value of the process capability index (CPK) after 500, 1000, and 2000 drilling of PCB boards was 5.95, 4.33, and 3.15 respectively, which showed the highest drilling accuracy. This is mainly attributed to the better overall properties of the a-C:H films prepared at C2H2 flow rate of 180 sccm, such as lower surface roughness, lowest residual stress, higher hardness, better adhesion, and lower friction coefficient.

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 Introduction The main generator of delayed onset muscle soreness (DOMS) is still unknown. This study aimed to clarify the main generator of DOMS. Methods Twelve participants performed eccentric exercise (EE) on lower legs. MRI and ultrasound were used to assess changes of calf muscle and deep fascia before and after EE. These results were then compared to the muscle pain level. Results Compared to baseline, muscle pain peaked at 24–48 h after EE (downstairs 22.25 ± 6.196, 57.917 ± 9.298, F = 291.168, p

Abstract Hydroxyl radicals (OH) determine the tropospheric self-cleansing capacity, thus regulating air quality and climate. However, the state-of-the-art mechanisms still underestimate OH at low nitrogen oxide and high volatile organic compound regimes even considering the latest isoprene chemistry. Here we propose that the reactive aldehyde chemistry, especially the autoxidation of carbonyl organic peroxy radicals (R(CO)O2) derived from higher aldehydes, is a noteworthy OH regeneration mechanism that overwhelms the contribution of the isoprene autoxidation, the latter has been proved to largely contribute to the missing OH source under high isoprene condition. As diagnosed by the quantum chemical calculations, the R(CO)O2 radicals undergo fast H-migration to produce unsaturated hydroperoxyl-carbonyls that generate OH through rapid photolysis. This chemistry could explain almost all unknown OH sources in areas rich in both natural and anthropogenic emissions in the warm seasons, and may increasingly impact the global self-cleansing capacity in a future low nitrogen oxide society under carbon neutrality scenarios.

Abstract Accurate identification and localization of multiple abnormalities are crucial steps in the interpretation of chest X-rays (CXRs); however, the lack of a large CXR dataset with bounding boxes severely constrains accurate localization research based on deep learning. We created a large CXR dataset named CXR-AL14, containing 165,988 CXRs and 253,844 bounding boxes. On the basis of this dataset, a deep-learning-based framework was developed to identify and localize 14 common abnormalities and calculate the cardiothoracic ratio (CTR) simultaneously. The mean average precision values obtained by the model for 14 abnormalities reached 0.572-0.631 with an intersection-over-union threshold of 0.5, and the intraclass correlation coefficient of the CTR algorithm exceeded 0.95 on the held-out, multicentre and prospective test datasets. This framework shows an excellent performance, good generalization ability and strong clinical applicability, which is superior to senior radiologists and suitable for routine clinical settings.

Abstract Immune checkpoint blockades have been prized in circumventing and ablating the impediments posed by immunosuppressive receptors, reaching an exciting juncture to be an innovator in anticancer therapy beyond traditional therapeutics. Thus far, approved immune checkpoint blockades have principally targeted PD-1/PD-L1 and CTLA-4 with exciting success in a plethora of tumors and yet are still trapped in dilemmas of limited response rates and adverse effects. Hence, unveiling new immunotherapeutic targets has aroused immense scientific interest in the hope of expanding the clinical application of immune checkpoint blockades to scale new heights. Human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, is enriched on various malignant cells and is involved in the hindrance of immune effector cells and the facilitation of immunosuppressive cells. HLA-G stands out as a crucial next-generation immune checkpoint showing great promise for the benefit of cancer patients. Here, we provide an overview of the current understanding of the expression pattern and immunological functions of HLA-G, as well as its interaction with well-characterized immune checkpoints. Since HLA-G can be shed from the cell surface or released by various cells as free soluble HLA-G (sHLA-G) or as part of extracellular vesicles (EVs), namely HLA-G-bearing EVs (HLA-GEV), we discuss the potential of sHLA-G and HLA-GEV as predictive biomarkers. This review also addresses the advancement of HLA-G-based therapies in preclinical and clinical settings, with a focus on their clinical application in cancer.

Abstract Background Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by impaired glucose and galactose utilization as well as proximal renal tubular dysfunction. Methods Clinical, biochemical, genetic, treatment, and follow-up data for 11 pediatric patients with FBS were retrospectively analysed. Results Hepatomegaly (10/11), short stature (10/11) and hypophosphataemic rickets (7/11) were the most common initial symptoms. At diagnosis, all patients had decreased fasting blood glucose (FBG), plasma bicarbonate (HCO3 −) and serum phosphorus, as well as elevated liver transaminases, alkaline phosphatase (AKP) and proximal renal tubular dysfunction. Two infant patients were misdiagnosed with transient neonatal diabetes mellitus. After therapy with uncooked cornstarch and conventional rickets treatment, remission of hepatomegaly was observed in all patients, with significant improvements in pre-prandial blood glucose, liver transaminases, triglyceride, plasma HCO3 − and AKP (p G (p.L406R) (allele frequency: 4/22, 18%). Patients with biallelic missense variants showed milder metabolic acidosis than those with null variants. Two of five patients from nonconsanguineous families with rare homozygous variations showed 5.3 Mb and 36.6 Mb of homozygosity surrounding the variants, respectively; a region of homozygosity (ROH) involving the entire chromosome 3 covering the SLC2A2 gene, suggesting uniparental disomy 3, was detected in one patient. Conclusions Early diagnosis of FBS is difficult due to the heterogeneity of initial symptoms. Although short stature is a major issue of treatment for FBS, rhGH is not recommended in FBS patients who have normal GH stimulation tests. Patients with biallelic null variants may require alkali supplementation since urine bicarbonate loss is genetically related. ROH is a mechanism for rare homozygous variants of FBS in nonconsanguineous families.

To study the applicability of the Integrated Multi-satellitE Retrievals for GPM (IMERG) precipitation products to typhoon precipitation, taking Typhoon In-Fa in 2021 as an example, this paper evaluates the IMERG precipitation estimation capabilities and the cause of errors using hourly precipitation data from 563 national meteorological stations in the eastern region of China, FY-4A AGRI infrared brightness temperature data, and Global Precipitation Measurement Dual-Frequency Precipitation Radar (GPM DPR) data. The results indicate that IMERG precipitation estimation shows good spatial consistency compared to observations, with a correlation coefficient of 0.75. IMERG precipitation products exhibit an overall consistent underestimation, the performance varies with different precipitation intensities, As precipitation intensity increases, the degree of underestimation also grows. IMERG products slightly overestimate weak precipitation. For precipitation below 10 mm·h-1, IMERG estimations are slightly larger than the observations, but for precipitation above 40 mm·h-1, IMERG estimations are significantly smaller than the observations. However, an overall underestimation of the IMERG products can be indicated that the line was below the diagonal, which calculated by the least square method between the IMERG estimations and observations. The error of infrared-derived precipitation within IMERG is larger than that from microwave retrieval, with a root mean square error of7.8 mm for hourly precipitation, and it overlooks warm cloud precipitation in Typhoon In-Fa. The accuracy of microwave retrieval for different types of precipitation also varies, which shows better performance in stratiform precipitation with concentrated particle number concentration (dBNw) and particle effective radius (D0) compared to convective precipitation with dispersed dBNw and D0. The high-intensity precipitation estimates retrieved from both infrared and microwave are weaker than those of observations, resulting in underestimated precipitation by IMERG precipitation estimations.

Abstract Background Health Technology Assessment (HTA) in China has recently expanded from purely academic research to include policy or decision-oriented practice, especially after HTA evidence was used to update the National Reimbursement Drug List for the first time in 2017. This study aims to identify the progress and challenges of HTA development from 2016 to 2021 and inform policies and decisions to promote further HTA development in China. Methods We conducted a cross-sectional web-based survey with policy makers, researchers and industry-providers in China in 2016 and 2021 respectively. The ‘Mapping of HTA Instrument’, was utilized to assess the HTA development across eight domains: Institutionalization, Identification, Priority setting, Assessment, Appraisal, Reporting, Dissemination of findings and conclusions, and Implementation in policy and practice. To reduce the influence of confounders and compare the mapping outcomes between the 2016 and 2021 groups, we conducted 1:1 Propensity Score Matching (PSM). Univariate analysis was conducted to compare the differences between the two groups. The overall results were further compared with those of a mapping study that included ten countries. Results In total, 212 and 255 respondents completed the survey in 2016 and 2021, respectively. The total score of the HTA development level in China in 2021 was higher than that in 2016 before PSM (89.38 versus 83.96). Following PSM, 183 respondents from the 2016 and 2021 groups were matched. Overall, the mean scores for most indicators in the Institutionalization domain and Dissemination domain in 2021 were higher than those in 2016 (P

Polymethoxyflavones (PMFs) are a type of uncommon dietary flavonoids, characterized by more than one methoxy group, which exist in limited plant species, like Citrus species and Kaempferia parviflora. In addition, different PMFs, such as nobiletin, sinensetin, tangeretin, and casticin, have been isolated from these natural sources. PMFs have received increasing attention due to their multiple bioactivities, such as antioxidant, anti-inflammatory, anti-cancer, metabolic regulatory, immunoregulatory, neuroprotective, and skin protective effects. These bioactivities of PMFs should be associated with the regulation of critical molecular targets and the interaction with gut microbiota. In order to provide a comprehensive and updated review of PMFs, their natural sources, refined extraction, biosynthesis, metabolism, and bioactivities are summarised and discussed, with the emphasis on the molecular mechanisms of PMFs on regulating different chronic diseases. Overall, PMFs may be promising flavonoids to the forefront of nutraceuticals for the prevention and/or treatment of certain human chronic diseases.

Thinned unripe kiwifruits (TUK) are considered the major agro by-products in kiwifruit production. To promote their potential applications, polyphenols and biological effects of unripe fruits from nine commercial kiwifruit cultivars were compared. Our findings showed that TUK were rich in bioactive polyphenols, which varied greatly by different cultivars. Indeed, catechin, epicatechin, procyanidin PB1, procyanidin B2, protocatechuic acid, neochlorogenic acid, and gallic acid were measured as the major phenolic components in most TUK, with the highest levels observed in ‘Hongao’ and ‘Cuiyu’ cultivars. Furthermore, TUK exerted strong in vitro antioxidant capacities, inhibitory effects on digestive enzymes, and anti-inflammatory activities. Particularly, their stronger antioxidant effects and inhibitory effects on digestive enzymes were probably attributed to their higher contents of phenolic compounds, especially procyanidin B2. Collectively, our findings reveal that TUK are potential resources of valuable polyphenols, which can be exploited as natural antioxidants and natural inhibitors of α-glucosidase and α-amylase.

Purpose: To report the observation that the efficacy of topical glaucoma treatment improved after surgical correction of ectropion in a 71-year-old male with a known history of glaucoma. Observations: The patient initially presented for tearing and lid malposition and was found to have bilateral elevated intraocular pressures (IOP) in addition to bilateral lower eyelid ectropion. IOP control was initially prioritized over ectropion repair, with IOP remaining elevated despite topical glaucoma treatment and selective laser trabeculoplasty. Sequential unilateral ectropion repair was then carried out, with topical glaucoma treatment resumed after the first repair. It was observed that the IOP improved with topical glaucoma treatment on each side after ectropion repair, despite no changes to medications nor dosing. Conclusions and importance: The efficacy of topical glaucoma treatment is dependent on drop availability and absorption. While recent efforts to increase drop efficacy have been focused on engineering formulations that increase retention or corneal penetration, our case highlights that in selected glaucoma patients, correction of lid malposition may serve as an effective way to improve drop efficacy.

Accurate precipitation prediction is very important for meteorological disaster prevention, water resources management, and agricultural decision making. To improve the accuracy of precipitation prediction, a hybrid model based on variational mode decomposition (VMD), crested porcupine optimization algorithm (CPO), and long short-term memory model (LSTM) is proposed in this paper. The model first uses VMD to decompose the precipitation time series into intrinsic mode functions of different frequencies to capture the multi-scale characteristics of precipitation data. Then, the CPO algorithm is used to optimize LSTM adaptive parameters to improve the global search ability and robustness of the model. Finally, the decomposed precipitation component is input into the LSTM network to learn the spatiotemporal dependence relationship and improve the ability of long-term prediction. The experimental results show that compared with the traditional LSTM model, CPO-LSTM model, and VMD-LSTM model, the hybrid model achieves better performance in many evaluation indices and effectively improves the accuracy of precipitation prediction. The application of the model can provide an effective tool for the fields of meteorology and water resources management, as well as provide new ideas for related research.

Background The majority of anti-programmed cell-death 1 (PD-1) monoclonal antibodies (mAbs) use S228P mutation IgG4 as the structural basis to avoid the activation of immune cells or complement. However, little attention has been paid to the Fc–Fc interactions between IgG4 and other IgG Fc fragments that could result in adverse effects. Fc-null IgG1 framework is a potential safer alternative to avoid the undesirable Fc–Fc interactions and Fc receptor binding derived effects observed with IgG4. This study provides a comprehensive evaluation of anti-PD-1 mAbs of these two frameworks.Methods Trastuzumab and rituximab (both IgG1), wildtype IgG1 and IgG4 were immobilized on nitrocellulose membranes, coated to microplates and biosensor chips, and bound to tumor cells as targets for Fc–Fc interactions. Wildtype IgG1 and IgG4, anti-PD-1 mAb nivolumab (IgG4 S228P), penpulimab (Fc-null IgG1), and tislelizumab (Fc-null IgG4 S228P-R409K) were assessed for their binding reactions to the immobilized IgG proteins and quantitative kinetic data were obtained. To evaluate the effects of the two anti-PD-1 mAbs on immune responses mediated by trastuzumab and rituximab in the context of combination therapy, we employed classic immune models for antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement dependent cytotoxicity. Tumor-bearing mouse models, both wildtype and humanized, were used for in vivo investigation. Furthermore, we also examined the effects of IgG1 and IgG4 on diverse immune cell populationsResults Experiments demonstrated that wildtype IgG4 and nivolumab bound to immobilized IgG through Fc–Fc interactions, diminishing antibody-dependent cell-mediated cytotoxicity and phagocytosis reactions. Quantitative analysis of kinetic parameters suggests that nivolumab and wildtype IgG4 exhibit comparable binding affinities to immobilized IgG1 in both non-denatured and denatured states. IgG4 exerted inhibitory effects on various immune cell types. Wildtype IgG4 and nivolumab both promoted tumor growth in wildtype mouse models. Conversely, wildtype IgG1, penpulimab, and tislelizumab did not show similar adverse effects.Conclusions Fc-null IgG1 represents a safer choice for anti-PD-1 immunotherapies by avoiding both the adverse Fc–Fc interactions and Fc-related immune inhibitory effects of IgG4. Fc-null IgG4 S228P-R409K and Fc-null IgG1 displayed similar structural properties and benefits. This study contributes to the understanding of immunotherapy resistance and the advancement of safer immune therapies for cancer.

Multiple isozymes are encoded in the Caenorhabditis elegans genome for the various sphingolipid biosynthesis reactions, but the contributions of individual isozymes are characterized only in part. We developed a simple but effective reversed-phase liquid chromatography-tandem mass spectrometry (RPLC-MS/MS) method that enables simultaneous identification and quantification of ceramides (Cer), glucosylceramides (GlcCer), and sphingomyelins (SM) from the same MS run. Validating this sphingolipid profiling method, we show that nearly all 47 quantifiable sphingolipid species found in young adult worms were reduced upon RNA interference (RNAi) of sptl-1 or elo-5, which are both required for synthesis of the id17:1 sphingoid base. We also confirm that HYL-1 and HYL-2, but not LAGR-1, constitute the major ceramide synthase activity with different preference for fatty acid substrates, and that CGT-3, but not CGT-1 and CGT-2, plays a major role in producing GlcCers. Deletion of sms-5 hardly affected SM levels. RNAi of sms-1, sms-2, and sms-3 all lowered the abundance of certain SMs with an odd-numbered N-acyl chains (mostly C21 and C23, with or without hydroxylation). Unexpectedly, sms-2 RNAi and sms-3 RNAi elevated a subset of SM species containing even-numbered N-acyls. This suggests that sphingolipids containing even-numbered N-acyls could be regulated separately, sometimes in opposite directions, from those containing odd-numbered N-acyls, which are presumably monomethyl branched chain fatty acyls. We also find that ceramide levels are kept in balance with those of GlcCers and SMs. These findings underscore the effectiveness of this RPLC-MS/MS method in studies of C. elegans sphingolipid biology.

Study area: China Study focus: Drought is an extremely serious disaster, typically characterized by slow onset, long duration, and cumulative impacts on multifaceted aspects. Developing a combined index that integrates its various characteristics can help deepen our understanding of drought evolution and provide accurate references for farmers to take drought mitigation measures. In this study, we proposed a Modified version of the Type Response-Aided Drought Index (MTRADI), simultaneously considering the various responses of different vegetation and the slow-varying properties of drought development. New hydrological insights for the regions: The suitability of MTRADI was evaluated through correlation analysis with Palmer Drought Severity Index (PDSI) and qualitative comparison with Meteorological Drought Composite Index (MCI) maps. The MTRADI achieved significantly higher correlation coefficients with the PDSI, outperforming other combined drought indices. Based on the run theory, Mann-Kendall (MK) test, and Sen’s slope, drought characteristics and trends in mainland China during 2001–2020 were analyzed and the results show that drought frequency and severity are relatively higher in eastern Inner Mongolia, North China Plain, and Northeast of China. Furthermore, areas with significant wetting trends are observed to be mainly distributed near the Hu line, indicating that the water conditions in China are gradually improving at the transition zone of arid and humid climate regions.

Vegetation Condition Index (VCI), as a widely used drought index for monitoring vegetation drought stress and estimating drought trends, is constructed by normalizing the long-term satellite-based Normalized Difference Vegetation Index (NDVI) data. However, under global greening, vegetation across different regions has shown an increasing trend in greenness, which may cause VCI to inherit the greening trend in NDVI and further hamper its ability in drought trend analysis. Therefore, this study quantitatively explored the underlying relationship among VCI, global greening, and drought from 2001 to 2021 to examine the utility of VCI in a changing environment. Multi-source indicators were employed as surrogates for vegetation greenness and drought, respectively. Particularly, the Leaf Area Index (LAI) and Net Primary Production (NPP) were used as proxies for vegetation greenness while the Root-Zone Soil Moisture (RZSM), Palmer Drought Severity Index (PDSI), and Standardized Precipitation-Evapotranspiration Index (SPEI) were used for drought indices. Based on Sen’s slope estimator, Mann-Kendall (MK) test, and partial correlation analysis, our results show that the proportion of pixels with an increasing trend in VCI is approximately 38.5%, which is similar to the greenness-related indices (i.e., NPP [26.47%] and LAI [59.14%]), and is significantly higher than the other drought indices (i.e., RZSM [19.83%], PDSI [10.38%], and SPEI [9.32%]). Furthermore, our results demonstrate that the VCI, as a drought index, exhibits a closer correlation with greenness-related indicators (LAI and NPP) than other drought indices (RZSM, PDSI, and SPEI). These results reveal the potential limitations in the practical applications of VCI and could enhance our understanding of vegetation dynamics and drought trends, especially in the current greening globe. Additionally, this study serves as a cautionary note for the scientific community involved in drought monitoring, emphasizing that the VCI may not be a suitable tool for evaluating long-term trends in drought impacts on vegetation.

Abstract Background To explore the clinical application value of pre‐conception expanded carrier screening (PECS) in the Chinese Han ethnicity population of childbearing age. Methods The results of genetic testing of infertile parents who underwent PECS in the Reproductive Medicine Center of the Second Affiliated Hospital of Zhengzhou University, China, from September 2019 to December 2021, were retrospectively analyzed. The carrier rate of single gene disease, the detection rate of high‐risk parents, and the clinical outcome of high‐risk parents were statistically analyzed. Results A total of 1372 Chinese Han ethnicity patients underwent PECS, among which 458 patients underwent the extended 108‐gene test, their overall carrier rate was 31.7%, and the detection rate of high‐risk parents was 0.3%. The highest carrier rates were SLC22A (2.4%), ATP7B (2.4%), MMACHC (2.2%), PAH (1.8%), GALC (1.8%), MLC1 (1.3%), UNC13D (1.1%), CAPN3 (1.1%), and PKHD1 (1.1%). There were 488 women with fragile X syndrome—FMR1 gene detection, and 6 patients (1.2%) had FMR1 gene mutation. A total of 426 patients were screened for spinal muscular atrophy—SMN1, and the carrier rate was 3.5%, and the detection rate of parents' co‐carrier was 0.5%. Conclusion Monogenic recessive hereditary diseases had a high carrier rate in the population. Pre‐pregnancy screening could provide good prenatal and postnatal care guidance for patients and preimplantation genetic testing for monogenic/single gene disorders (PGT‐M) and prenatal diagnosis could provide more precise reproductive choices for high‐risk parents.

Colitis caused by infections, especially Salmonella, has long been a common disease, underscoring the urgency to understand its intricate pathogenicity in colonic tissues for the development of effective anti-bacterial approaches. Of note, colonic epithelial cells, which form the first line of defense against bacteria, have received less attention, and the cross-talk between epithelial cells and bacteria requires further exploration. In this study, we revealed that the critical anti-bacterial effector, TFEB, was primarily located in colonic epithelial cells rather than macrophages. Salmonella-derived LPS significantly promoted the expression and nuclear translocation of TFEB in colonic epithelial cells by inactivating the mTOR signaling pathway in vitro, and this enhanced nuclear translocation of TFEB was also confirmed in a Salmonella-infected mouse model. Further investigation uncovered that the infection-activated TFEB contributed to the augmentation of anti-bacterial peptide expression without affecting the intact structure of the colonic epithelium or inflammatory cytokine expression. Our findings identify the preferential distribution of TFEB in colonic epithelial cells, where TFEB can be activated by infection to enhance anti-bacterial peptide expression, holding promising implications for the advancement of anti-bacterial therapeutics.

BackgroundPediatric cerebral palsy (CP) is a non-progressive brain injury syndrome characterized by central motor dysfunction and insufficient brain coordination ability. The etiology of CP is complex and often accompanied by diverse complications such as intellectual disability and language disorders, making clinical treatment difficult. Despite the availability of pharmacological interventions, rehabilitation programs, and spasticity relief surgery as treatment options for CP, their effectiveness is still constrained. Electroacupuncture (EA) stimulation has demonstrated great improvements in motor function, but its comprehensive, objective therapeutic effects on pediatric CP remain to be clarified.MethodsWe present a case of a 5-year-old Chinese female child who was diagnosed with CP at the age of 4. The patient exhibited severe impairments in motor, language, social, and cognitive functions. We performed a 3-month period of EA rehabilitation, obtaining resting state functional magnetic resonance imaging (rs-fMRI) of the patient at 0 month, 3 months and 5 months since treatment started, then characterized brain functional connectivity patterns in each phase for comparison.ResultsAfter a 12-month follow-up, notable advancements were observed in the patient’s language and social symptoms. Changes of functional connectivity patterns confirmed this therapeutic effect and showed specific benefits for different recovery phase: starting from language functions then modulating social participation and other developmental behaviors.ConclusionThis is a pioneering report demonstrating the longitudinal effect of EA stimulation on functional brain connectivity in CP patients, suggesting EA an effective intervention for developmental disabilities (especially language and social dysfunctions) associated with pediatric CP.

Background Studies showed that vascular endothelial growth factor (VEGF) inhibitors could improve therapeutic efficacy of PD-1/PD-L1 antibodies by transforming the immunosuppressive tumor microenvironment (TME) into an immunoresponsive TME. Ivonescimab is a first-in-class, humanized tetravalent bispecific antibody targeting PD-1 and VEGF-A simultaneously. Here, we report the first-in-human, phase 1a study of ivonescimab in patients with advanced solid tumors.Methods Patients with advanced solid tumors were treated with ivonescimab 0.3, 1, 3, 10, 20 or 30 mg/kg intravenously every 2 weeks using a 3+3+3 dose escalation design. Dose expansion occurred at 10 and 20 mg/kg in selected tumor types. The primary objective was to assess the safety and tolerability, and to determine the maximum tolerated dose (MTD). The secondary objectives included pharmacokinetics, pharmacodynamics and preliminary antitumor activity based on Response Evaluation Criteria in Solid Tumors V.1.1.Results Between October 2, 2019 and January 14, 2021, a total of 51 patients were enrolled and received ivonescimab. Two dose-limiting toxicities were reported at 30 mg/kg. The MTD of ivonescimab was 20 mg/kg every 2 weeks. Grade≥3 treatment-related adverse events (TRAEs) occurred in 14 patients (27.5%). The most common TRAEs of any grade were rash (29.4%), arthralgia (19.6%), hypertension (19.6%), fatigue (17.6%), diarrhea (15.7%) and pruritus (11.8%). The most common grade≥3 TRAEs were hypertension (7/51, 13.7%), alanine aminotransferase increased (3/51, 5.2%), aspartate aminotransferase increased (2/51, 3.9%) and colitis (2/51, 3.9%). Of 47 patients who had at least one postbaseline assessment, the confirmed objective response rate was 25.5% (12/47) and disease control rate was 63.8% (30/47). Among 19 patients with platinum-resistant ovarian cancer, 5 patients (26.3%) achieved partial response (PR). Efficacy signals were also observed in patients with mismatch repair proficient (pMMR) colorectal cancer, non-small cell lung cancer, and both MMR deficient and pMMR endometrial cancer.Conclusions Ivonescimab demonstrated manageable safety profiles and promising efficacy signals in multiple solid tumors. Exploration of alternative dosing regimens of ivonescimab monotherapy and combination therapies is warranted.Trial registration number NCT04047290.

The Late Ordovician–Early Silurian period witnessed the Phanerozoic mass extinction, glacial events, and volcanic events. Paleoweathering indexes chemical index of alteration (CIA), chemical index of weathering (CIW), and plagioclase index of alteration (PIA) indicated that the source area weathering changed from weak to moderate to intense. CIA values in the upper Zhongbao formation ranged from 66.71% to 73.97%, indicating a drier and colder climate. Upward, the CIA values on the bottom of the Mayinggou formation returned to the high value quickly (from 73.86% to 81.31%), suggesting that the ice age ended, the climate became warmer and wetter, and the sea level rose. The Al2O3–(CaO*+Na2O)–K2O triangular plots, Hf-La/Th, and SiO2–Al2O3/TiO2 bivariate plots inferred that the source of the siltstones in the two formations is mostly from the felsic igneous rocks. The samples from the Zhongbao–Mayinggou formations have chondrite-normalized rare earth element (REE) patterns similar to that of the North Qilian volcanic arc rocks. Geochemical discrimination plots displayed that the sediments of the Zhongbao–Mayinggou formations came from the active continental margin setting.