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Abstract Background Eosinophilic asthma is a common subtype of severe asthma with high morbidity and mortality. The cytokine IL-5 has been shown to be a key driver of the development and progression of disease. Although approved monoclonal antibodies (mAbs) targeting IL-5/IL-5R have shown good safety and efficacy, some patients have inadequate responses and frequent dosing results in medication nonadherence. Results We constructed a novel trivalent bispecific nanobody (Nb) consisting of 3 VHHs that bind to 2 different epitopes of IL-5 and 1 epitope of albumin derived from immunized phage display libraries. This trivalent IL-5-HSA Nb exhibited similar IL-5/IL-5R blocking activities to mepolizumab (Nucala), an approved targeting IL-5 mAb. Surprisingly, this trivalent Nb was 58 times more active than mepolizumab in inhibiting TF-1-cell proliferation. In primate studies, the trivalent IL-5-HSA Nb showed excellent pharmacokinetic properties, and peripheral blood eosinophil levels remained significantly suppressed for two months after a single dose. In addition, the trivalent IL-5-HSA Nb could be produced on a large scale in a P. pastoris X-33 yeast system with high purity and good thermal stability. Conclusions These findings suggest that the trivalent bispecific IL-5-HSA Nb has the potential to be a next-generation therapeutic agent targeting IL-5 for the treatment of severe eosinophilic asthma. Graphical Abstract

Abstract Porcine deltacoronavirus (PDCoV) can experimentally infect a variety of animals. Human infection by PDCoV has also been reported. Consistently, PDCoV can use aminopeptidase N (APN) from different host species as receptors to enter cells. To understand this broad receptor usage and interspecies transmission of PDCoV, we determined the crystal structures of the receptor binding domain (RBD) of PDCoV spike protein bound to human APN (hAPN) and porcine APN (pAPN), respectively. The structures of the two complexes exhibit high similarity. PDCoV RBD binds to common regions on hAPN and pAPN, which are different from the sites engaged by two alphacoronaviruses: HCoV-229E and porcine respiratory coronavirus (PRCoV). Based on structure guided mutagenesis, we identified conserved residues on hAPN and pAPN that are essential for PDCoV binding and infection. We report the detailed mechanism for how a deltacoronavirus recognizes homologous receptors and provide insights into the cross-species transmission of PDCoV.

The establishment of a pre-metastatic niche is a key step preceding metastasis formation. Here the authors show that tumor-intrinsic Lin28B, a RNA-binding protein, has an essential role in the formation of an immune-suppressive pre-metastatic niche, promoting lung metastasis of breast cancer.

Methane (CH4) microseepage from petroleum basins is a significant contributor to the atmospheric CH4 budget. However, research about CH4 migration and release mechanism is still very limited. This work seeks to theorize and verify the migration and release mechanism of CH4 microseepage via field measurement and physical simulation, which, to the best of our knowledge, has not been reported in literature. Fluxes of CH4 microseepage from Dawanqi oilfield were measured, and three manifestations of release were observed, namely, continuous, flat, and episodic. Based on field observations, bench-scale physical simulation of CH4 migration through geological features of the oilfield was further conducted for 290 days. The results show that CH4 migration is mainly driven by buoyancy and diffusion. In continuous release, CH4 migration is mainly driven by buoyancy. In flat release, CH4 migration is dominated by diffusion. At low pressure, CH4 migrates upward slowly. As buoyancy increases, CH4 eventually break through the capillary pressure of the pore throat, causing spikes in CH4 concentrations in the layers above and reproducing episodic release observed during field measurement. Via field observation and verification by physical simulation, this work theorizes the migration mechanism of CH4 microseepage and its correlation with release types observed and confirms that counterbalance of buoyancy force and capillary pressure plays a critical role in episodic release of CH4 from oilfield. The findings of this study shed light on the migration mechanism and release manifestations of CH4 microseepage under different geological conditions and improve accuracy of estimating the flux of CH4 microseepage into atmosphere.

A biomacromolecule, named as β-galactoglucofurannan (SVPS2), was isolated from the cultivated parts of Sanghuangporus vaninii under the forest. Its primary and advanced structure was analyzed by a series of techniques including GC-MS, methylation, NMR, MALS as well as AFM. The results indicated that SVPS2 was a kind of 1, 5-linked β-Glucofurannan consisting of β-glucose, β-galactose and α-fucose with 23.4 KDa. It exhibited a single-stranded chain with an average height of 0.72 nm in saline solution. The immunostimulation test indicated SVPS2 could facilitate the initiation of the immune reaction and promote the secretion of cytokines in vitro. Moreover, SVPS2 could mediate the apoptosis of HT-29 cells by blocking them in S phase. Western blot assay revealed an upregulation of Bax, Cytochrome c and cleaved caspase-3 by SVPS2, accompanied by a downregulation of Bcl-2. These results collectively demonstrate that antitumor mechanism of SVPS2 may be associated with enhancing immune response and inducing apoptosis of tumor cells in vitro. Therefore, SVPS2 might be utilized as a promising therapeutic agent against colon cancer and functional food with immunomodulatory activity.

Abstract The coronavirus disease 2019 (COVID‐19) pandemic has become a serious burden on global public health. Although therapeutic drugs against COVID‐19 have been used in many countries, their efficacy is still limited. We here reported nanobody (Nb) phage display libraries derived from four camels immunized with the SARS‐CoV‐2 spike receptor‐binding domain (RBD), from which 381 Nbs were identified to recognize SARS‐CoV‐2‐RBD. Furthermore, seven Nbs were shown to block interaction of human angiotensin‐converting enzyme 2 (ACE2) with SARS‐CoV‐2‐RBD variants and two Nbs blocked the interaction of human ACE2 with bat‐SL‐CoV‐WIV1‐RBD and SARS‐CoV‐1‐RBD. Among these candidates, Nb11‐59 exhibited the highest activity against authentic SARS‐CoV‐2 with 50% neutralizing dose (ND50) of 0.55 μg/ml. Nb11‐59 can be produced on large scale in Pichia pastoris, with 20 g/L titer and 99.36% purity. It also showed good stability profile, and nebulization did not impact its stability. Overall, Nb11‐59 might be a promising prophylactic and therapeutic molecule against COVID‐19, especially through inhalation delivery.

Background: Cisplatin resistance remains a major clinical obstacle to the successful treatment of non-small cell lung cancer (NSCLC). Scribble contributes to ROS-induced inflammation and cisplatin-elevated toxic reactive oxygen species (ROS) promotes cell death. However, it is unknown whether and how Scribble is involved in the cisplatin-related cell death and the underlying mechanism of Scribble in response to chemotherapies and in the process of oxidative stress in NSCLC. Methods: We used two independent cohorts of NSCLC samples derived from patients treated with platinum-containing chemotherapy and xenograft modeling in vivo. We analyzed the correlation between Scribble and Nox2 or Nrf2/PD-L1 both in vivo and in vitro, and explored the role of Scribble in cisplatin-induced ROS and apoptosis. Findings: Clinical analysis revealed that Scribble expression positively correlated with clinical outcomes and chemotherapeutic sensitivity in NSCLC patients. Scribble protected Nox2 protein from proteasomal degradation. Scribble knockdown induced cisplatin resistance by blocking Nox2/ROS and apoptosis in LRR domain-dependent manner. In addition, low levels of Scribble correlated with high levels of PD-L1 via activation of Nrf2 transcription in vivo and in vitro. Interpretations: Our study revealed that polarity protein Scribble increased cisplatin-induced ROS generation and is beneficial to chemotherapeutic outcomes in NSCLC. Although Scribble deficiency tends to lead to cisplatin resistance by Nox2/ROS and Nrf2/PD-L1, it is still possible that Scribble deficiency-induced PD-L1 may yield benefits in immunotherapy. Fund: National Key R&D Program of China, Strategic Priority Research Program of the Chinese Academy of Sciences, National Natural Science Foundation of China, China Postdoctoral Science Foundation. Keywords: NSCLC, Cisplatin sensitivity, Scribble, Nox2, ROS, PD-L1

Close-packed hexagonal array nanopores are widely used both in research and industry. A self-ordered nanoporous structure makes anodic aluminum oxide (AAO) one of the most popular nanomaterials. This paper describes the main formation mechanisms for AAO, the AAO fabrication process, and optical sensor applications. The paper is focused on four types of AAO-based optical biosensor technology: surface-Enhanced Raman Scattering (SERS), surface Plasmon Resonance (SPR), reflectometric Interference Spectroscopy (RIfS), and photoluminescence Spectroscopy (PL). AAO-based optical biosensors feature very good selectivity, specificity, and reusability.

Sansha Bay, facing the East China Sea, is characterised by high fish production (Pseudosciaena crocea, 91,000 t yr–1) and the polyculture of seaweeds (Saccharina japonica and Gracilaria lemaneiformis) and abalone (Haliotis discus hannai). To investigate the environmental effects of fish farming on sediments, surface (0–1 cm) sediments were collected from 41 stations grouped into four areas: fish, seaweed, and abalone farms and reference area. The physical and chemical parameters of these sediments were analysed. Nitrogen and phosphorus loadings from trash fish as feed were estimated to be 12,000 and 2,400 t yr–1, respectively, accounting for 90% and 86% of the total anthropogenic loading in Sansha Bay. However, no significant differences were observed in stable C and N isotope ratios, carbon-to-nitrogen ratio, total organic carbon, total nitrogen, total phosphorus, acid volatile sulfide, water content, and silt–clay fraction among the four areas (Kruskal–Wallis test, P > 0.05). Principal component and cluster analyses supported this conclusion, indicating that fish farming has no significant effect on the sediment. The amount of N removed by the cultured seaweed was estimated to be 288 t yr–1, accounting for only 2% of the N loaded from fish farming. The results suggested that the dispersion of fish farm-derived wastes were primarily facilitated by the topographic and hydrodynamic characteristics of Sansha Bay, such as its large depth (∼90 m), strong currents (1.4–1.9 m s–1), large tidal amplitude (5.4 m), and rapid exchange (

Exsolved nanoparticle catalysts have recently attracted broad research interest as they simultaneously combine the features of catalytic activity and chemical stability in various applications of energy conversion and storage. As the internal mechanism of in-situ exsolution is of prime significance for the optimization of its strategy, comprehensive research focused on the behaviors of in-situ segregation for metal (Mn, Fe, Co, Ni, Cu, Ag, Pt and Au)-substituted CeO2 is reported using first-principles calculations. An interesting link between the behaviors of metal growth from the ceria host and their microelectronic reconfigurations was established to understand the inherent attribute of metal self-regeneration, where a stair-stepping charge difference served as the inner driving force existing along the exsolving pathway, and the weak metal-coordinate associations synergistically facilitate the ceria’s in-situ growth. We hope that these new insights provide a microscopic insight into the physics of in-situ exsolution to gain a guideline for the design of nanoparticle socketed catalysts from bottom to top.

Meta-analysis is a statistical technique used to process an overall summary estimation, and the technique of meta-analysis is mostly used in medicine, social science, and psychology. In this manuscript, we aimed to combine the techniques of the Bonferroni mean (BM) operator based on circular Pythagorean fuzzy (CPF) sets, called the CPF Bonferroni mean (CPFBM) operator, and CPF weighted Bonferroni mean (CPFWBM) operator and described their special cases with the help of two parameters, "s" and "t", and some describable properties of them are also proposed. Further, we present the evaluation technique based on distance from average solution (EDAS) technique and the proposed operators. Moreover, we use some examples to show the flexibility and dominance of the proposed operators by comparing the proposed methods with some existing techniques.

Abstract Background Morphine is widely used to treat moderate-to-severe cancer pain. However, it causes various adverse effects, with morphine-induced fever being an extremely rare and poorly understood symptom. Case presentation We report the case of a 58-year-old Chinese woman with advanced lung cancer. Due to the ineffectiveness of tramadol for pain relief, her treatment regimen was switched to morphine. Following the change, she developed nausea, vomiting, dizziness, and elevated body temperature. A similar episode occurred subsequently. After a drug review, the pharmacist speculated that morphine was the most likely causative agent. Upon discontinuation of morphine, her body temperature returned to baseline levels. Conclusions This case highlights the need for healthcare providers to consider morphine as a potential cause of unexplained fever in patients. The fever may be caused by a hypersensitive response, as there was a significant increase in eosinophils during the fever episodes.

Abstract Background This study aimed to develop a comprehensive model based on five GLIM variables to predict the individual survival and provide more appropriate patient counseling. Methods This retrospective cohort study included 301 gastric cancer (GC) patients undergoing radical resection. C-reactive protein (CRP) as an inflammatory marker was included in GLIM criteria and a nomogram for predicting 5-year overall survival (OS) in GC patients was established. The Bootstrap repeated sampling for 1000 times was used for internal validation. Results Of the total 301 patients, 20 (6.64%) died within 5 years. CRP improved the sensitivity and accuracy of the survival prediction model (AUC = 0.782, 0.694 to 0.869 for the model without CRP; AUC = 0.880, 0.809 to 0.950 for the model adding CRP). Besides, a GLIM-based nomogram was established with an AUC of 0.889. The C-index for predicting OS was 0.878 (95% CI: 0.823 to 0.934), and the calibration curve fitted well. Decision curve analysis (DCA) showed the clinical utility of the nomogram based on GLIM. Conclusion The addition of CRP improved the sensitivity and accuracy of the survival prediction model. The 5-year survival probability of GC patients undergoing radical resection can be reliably predicted by the nomogram presented in this study.

China is the largest aquaculture country in the world, with mariculture production accounting for more than 50% of the total production in the world. In 2021, the production of shellfish in China increased to 1.546 × 107 tons, accounting for approximately 70% of the mariculture production. Filter-feeding bivalves such as oysters and clams are the main species of mariculture in China. In addition to the important economic values, filter-feeding bivalves influence ecosystem nutrient cycling through feeding, metabolism, and biodeposition and play roles in increasing the water transparency, preventing harmful algal blooms, controlling eutrophication, and promoting carbon storage. The physiological activities of filter-feeding bivalves, especially ingestion and metabolism, form the link between planktonic and benthic ecosystems, and their physiological indicators are the basic parameters for evaluating the energy budget and carrying capacity. However, although researchers have conducted a series of studies on the physiological activities of filter-feeding bivalves, some limitations in monitoring and the subsequent data processing remain. Therefore, it is urgent to improve the measurement of the physiological activities of filter-feeding bivalves, including the accuracy of data collection and the rigorousness of data processing, to ensure the accuracy of the experimental results.Mudflats are located in the interaction zone between the land and sea and are important areas for the habitat, growth, and reproduction of several macrobenthic organisms. As the dominant species of macrobenthic communities, mudflat-buried shellfish play a crucial role in the material and energy flows of a mudflat ecosystem. However, recently, with the expansion of shellfish aquaculture, the mudflat environment has been deteriorating accompanied by a series of ecological problems, such as high mortality and slow growth rates and alteration in the structure of phytoplankton community, which has led to significant losses to the shellfish aquaculture industry. Therefore, the ability of the ecosystem to support shellfish production must be evaluated, and its carrying capacity must be estimated. Generally, numerical methods for estimating the carrying capacity of shellfish based on food limiting indicators include physical-biological ecosystem modelling, trophodynamic modeling, and energy balance modeling. Current methodologies for estimating shellfish carrying capacity are divided into two main categories: dynamic and static modellings. Compared with the dynamic estimation model, static estimation methods are based on the environment of the target area and the key physiological parameters of shellfish and have been widely applied in some aquaculture areas such as Sanggou Bay, Jiaozhou Bay, and Zhangzidao in China.Here, to explore the energy budget and carrying capacity of the surf clam, Mactra veneriformis, and the estuarine clam, Potamocorbula laevis, in Geligang, Liaodong Bay, a portable particle counter and a continuous oxygen monitoring system were used in combination with flow-through chambers to detect the feeding and metabolic parameters of M. veneriformis and P. laevis. Furthermore, the carrying capacity of two mudflat-buried bivalves in Liaodong Bay was estimated based on the organic carbon supply-demand balance model. The results indicated that 1) the clearance rates of M. veneriformis and P. laevis were (4.87±0.85) L/(h·g) and (6.46±2.25) L/(h·g), respectively, and the oxygen consumption rates were (0.94±0.45) mg/(h·g) and (0.22±0.14) mg/(h·g), respectively. The energy absorption of M. veneriformis and P. laevis ranged from 748.97 to 1 333.52 J/(h·g), and 931.55 to 1 647.08 J/(h·g), respectively. 2) Using organic carbon supply-demand balance model combined with the primary productivity and shellfish clearance rate, we found that the carrying capacity of M. veneriformis in Geligang, Liaodong Bay, was 57, 47, and 34 ind./m2 for age-1 (total wet weight 6.7 g), age-2 (total wet weight 9.3 g) and age-3 (total wet weight 14.6 g), respectively; and the carrying capacity of P. laevis was 346, 143, and 99 ind./m2 for age-1 (total wet weight 0.14 g), age-2 (total wet weight 0.69 g), and age-3 (total wet weight 1.25 g), respectively. These results provide basic data for the rational exploitation and utilization of shellfish resources and the conservation of biodiversity in a mudflat ecosystem.

An innovative approach was pursued for sustainable packaging design using Cycle Generative Adversarial Networks (CycleGANs), tailored for wood packaging engraving. The methodology includes four phases: user participatory design, assembly scheme design, detailed Finite Element Analysis (FEA) optimization, and computer numerical control (CNC) engraving production. Each phase targets sustainability from design to final product, minimizing environmental impact and economic costs. Emphasizing early user participation helps adapt designs to user needs and environmental standards. Innovations such as real-time updates of packaging patterns via cloud-based iterations and an FEA optimization system enhance durability and aesthetics. This approach improves the environmental footprint and recyclability of conventional wood packaging. The research aims to shift perceptions in the packaging industry towards more sustainable practices, showcasing the practical applications of advanced digital tools in traditional manufacturing. It offers a scalable model for integrating sustainability into packaging design, providing valuable insights and inspiring future innovations in environmentally friendly practices across the industry.

In the context of global climate change, one central interest is an improved understanding of the global carbon cycle. A large number of studies have investigated carbon cycling and associated elements, mainly nitrogen and phosphorus. However, as an essential element for diatom growth, Si has been largely ignored. Si is the second most abundant element and is widely distributed on Earth. The chemical weathering of silicates on land and photosynthesis of diatoms in the ocean play an important role in atmospheric CO2 levels at various timescales. Diatoms are the primary producers in the ocean and account for as much as 40% of the annual ocean carbon fixation, which have an absolute requirement for Si to form siliceous cells. The main mechanism underlying ocean carbon sinks is a "biological pump." The biological pump is driven by the biological Si pump to a large extent. Therefore, the biogeochemical process of Si has become one of the key research issues for global environmental change.Based on previous studies, the regulation and influence of the Si biogeochemical cycle on the carbon cycle are discussed in this review. The coupling effect and mechanism of the Si and carbon cycles in shellfish culture ecosystems were analyzed and the key research questions were explored. Chemical weathering of silicates and the cycling of their products form the basis of Si biogeochemistry. CO2 is consumed during weathering reactions. Therefore, silicate weathering on land represents an important sink for atmospheric CO2. Furthermore, at the geological timescale, primary silicate mineral weathering is the source of secondary silicate. Terrestrial plants absorb soluble silica through their root system during growth. Amorphous silica deposited in plant tissue after maturity is called phytolith. Phytoliths have excellent geochemical stability and occlude a certain amount of organic carbon during the formation process. The organic carbon occluded within phytolith is called phytolith-occluded carbon (PhytOC) and is buried in the soil. PhytOC is released into the soil with phytolith and may be preserved in soils for several thousands of years. As a consequence, PhytOC in terrestrial ecosystems could be significant potential carbon sinks globally due to the refractory phytolith. Primarily through river input, the dissolved silicate (DSi) is transported into the coastal ocean (approximately 84% of DSi input to the oceans). As the major primary producer, diatoms absorb DSi during growth and account for a large fraction of the total carbon fixation in the modern oceans. DSi is converted into biogenic silica via biological processes, is transported to the deep ocean, and is finally buried into sediments with organic carbon in the marine ecosystem. Thus, by controlling the contribution of diatoms to the total primary production, DSi can affect the carbon cycle in oceans. The carbon pump is driven by the Si pump.Mariculture has developed quickly in recent decades. Shellfish, which are dominated by filter-feeding species, are the main mariculture species. The filter-feeding shellfish consume particulate organic carbon as phytoplankton and use dissolved inorganic carbon to build their shell during growth. Filter-feeding shellfish are an import fishery carbon sink. As one of the important feed sources of filter-feeding shellfish, diatoms form fishery carbon sinks in coastal shellfish culture areas. Silicate is an essential salt for diatom growth. Consequently, the carbon sink of filter-feeding shellfish culture is connected with DSi through diatoms. Si could play an important role in driving the formation of carbon sinks in filter-feeding shellfish culture. Hence, it is necessary to consider all processes and coupling effects in the study of the Si biogeochemical cycle. It is important to understand its role in the carbon sinks of shellfish culture.Nowadays, in many systems, human perturbation has resulted in a decline in the ratio of Si: N to 1:1 or less, with severe impacts on the quality and structure of aquatic ecosystems. DSi limitation has been reported in many studies, in both coastal and marine waters. DSi limitation causes shifts from diatoms to non-siliceous algae and is supposedly related to the decreasing export of carbon. A shift from diatoms to other species would enhance the recycling of organic matter in the upper water column because diatoms are very effective in carbon sequestration. DSi limitation has also appeared in some aquaculture bays in China, such as Jiaozhou Bay and Laizhou Bay, in spring. Regarding future directions, it is suggested that more research be conducted on Si biogeochemistry in shellfish culture systems and coupling with the carbon cycle. The subsequent results could evaluate the role of Si in the carbon sink of filter-feeding shellfish culture. Future studies are expected to provide ideas for alleviating Si deficiency in the aquaculture bay and exploring the expansion path in shellfish farming.

Crassostrea gigas, also known as Pacific oysters, are economic shellfish with the widest range of cultivation, the highest yield in the world, and the most important type of mariculture shellfish in China. However, many C. gigas have died during summer in coastal areas worldwide in recent decades. In 2008, the mortality rate of C. gigas cultured in France reached 40%–100%. In 2009, the mortality rate of C. gigas in some area of Sanggou Bay reached 51%. In 2019, the mortality rate of the Rushan area reached 50%–90%, with the death peak occurring in middle and late August. There were many reasons for the large-scale death of C. gigas, such as temperature, dissolved oxygen, salinity, disease, food availability, and reproduction levels, among which high temperature was the most important abiotic stress factor. The high temperature in summer disturbed the enzyme metabolism of C. gigas, resulting in slow or impeded growth. Furthermore, the reproduction and spawning of C. gigas caused a large amount of protein consumption, and physical weakness combined with high-temperature stress induced many deaths. Therefore, considering the problems faced by C. gigas culture during high summer temperatures, the introduction of new varieties will increase the economic benefits to the industry.Due to its high sterility, triploid C. gigas has attributes such as a fast growth rate, resilience excellent economic characteristics, and high energy conversion efficiency. In recent years, a certain farmed scale has formed in China, especially in northern coastal areas. There have been many studies on the biological and physiological differences between triploid and diploid C. gigas worldwide, mainly focusing on the differences in growth characteristics, soft tissue components, gonadal development, disease resistance, and gill structure. However, comparisons between triploid and diploid C. gigas feeding, metabolic physiology, energy budget, and carbon budget have not been reported. Focusing on the specific period of high temperatures in summer, this study investigated the feeding and metabolic physiological characteristics of triploid and diploid C. gigas using the field flow method, and compared and analyzed their energy allocation strategies in response to a high-temperature environment. The study provide data support for revealing the physiological differences caused by the ploidy effect of C. gigas in order to assist with evaluating the culture capacity.Triploid and diploid C. gigas were selected as research objects in August 2022 to analyze the differences in feeding and metabolic physiology and energy/carbon allocation strategies during high temperatures in summer. Physiological parameters related to intake and metabolism, such as water filtration rate, absorption efficiency, oxygen consumption rate, and ammonia discharge rate, were determined based on the field flow method in Sanggou Bay, Rongcheng, Shandong Province, and energy allocation and carbon allocation were estimated based on the principle of the energy budget. The results revealed that the water filtration rate and assimilation efficiency of triploid C. gigas were higher than those of diploid C. gigas, but there were no significant differences (P > 0.05). There were significant differences in the oxygen consumption rate and ammonia discharge rate between triploid and diploid C. gigas (P < 0.05). The oxygen consumption rate of triploid C. gigas was significantly lower than that of diploid C. gigas (P < 0.05), but ammonia discharge rate was significantly higher than that of diploid C. gigas (P < 0.01). The results of the energy and carbon budget analyses showed that the feeding energy/carbon and assimilation energy/carbon values of triploid C. gigas were higher than those of diploid C. gigas, but there was no significant difference (P > 0.05). There were significant differences in respiratory energy/carbon, excretion energy/carbon, and growth power between triploid and diploid C. gigas (P < 0.05). Respiratory energy/carbon values of triploid C. gigas were significantly lower than those of diploid C. gigas (P < 0.05), but excretion energy/carbon and growth power values were significantly higher than those of diploid C. gigas (P < 0.05). The oxygen/nitrogen ratio of triploid and diploid C. gigas fluctuated in the range of 7.91–14.11 and 59.81–94.19, respectively. Moreover, the main energy supply substances of triploid C. gigas were proteins, while the main energy supply substances of diploid C. gigas were carbohydrates and fats. These results revealed the differences in energy allocation patterns associated with the ploidy effect of C. gigas during high temperatures in summer.From the perspective of individual physiology and ecology, this study found that, compared with diploid C. gigas, triploid C. gigas showed certain advantages in energy allocation strategies by adjusting feeding and metabolic physiological behaviors during the high-temperature summer. However, the internal molecular mechanism of response strategies adopted by triploid C. gigas to cope with an adverse environment is still unclear. Further interpretation at the molecular level needs to be combined with omics and other systems biology techniques.

Abstract Background Pancreatic cancer (PC) is one of the most malignant cancers with highly aggressiveness and poor prognosis. N6-methyladenosine (m6A) have been indicated to be involved in PC development. Glucan Branching Enzyme 1 (GBE1) is mainly involved in cell glycogen metabolism. However, the function of GBE1 and Whether GBE1 occurs m6A modification in PC progression remains to be illustrated. Methods The clinical prognosis of GBE1 was analyzed through online platform. The expression of GBE1 was obtained from online platform and then verified in normal and PC cell lines. Lentivirus was used to generated GBE1 stable-overexpression or knockdown PC cells. Cell Counting Kit (CCK-8), colony formation assay, sphere formation assay and flow cytometry assay were conducted to analyze cell proliferation and stemness ability in vitro. Subcutaneous and orthotopic mouse models were used to verify the function of GBE1 in vivo. RNA immunoprecipitation (RIP) assay, RNA stability experiment and western blots were conducted to explore the molecular regulation of GBE1 in PC. Results GBE1 was significantly upregulated in PC and associated with poor prognosis of PC patients. Functionally, GBE1 overexpression facilitated PC cell proliferation and stemness-like properties, while knockdown of GBE1 attenuated the malignancy of PC cells. Importantly, we found the m6A modification of GBE1 RNA, and WTAP and IGF2BP3 was revealed as the m6A regulators to increase GBE1 mRNA stability and expression. Furthermore, c-Myc was discovered as a downstream gene of GBE1 and functional rescue experiments showed that overexpression of c-Myc could rescue GBE1 knockdown-induced PC cell growth inhibition. Conclusions Our study uncovered the oncogenic role of GBE1/c-Myc axis in PC progression and revealed WTAP/IGF2BP3-mediated m6A modification of GBE1, which highlight the potential application of GBE1 in the targeted therapy of PC.

Abstract Objectives Patients with traumatic brain injury (TBI) often suffer memory and cognitive impairments, and oxiracetam‐like drugs are considered to have a positive impact on these symptoms potentially. However, the efficacy and safety of L‐oxiracetam and oxiracetam in TBI patients have not been sufficiently investigated. Methods The study adopts a multicenter, randomized, double‐blind, parallel‐group, phase 3 clinical trial design in 74 centers across 51 hospitals in China. A total of 590 TBI patients meeting criteria will be randomly allocated into three groups in a 2:2:1 ratio: L‐oxiracetam group, oxiracetam group, and placebo group. The treatment period is 14 days, with a follow‐up period of 90 days. The primary outcome measure is the change in the Loewenstein Occupational Therapy Cognitive Assessment score at 90 days after treatment. Secondary outcomes include changes in other cognitive assessments, neurological function, activities of daily living, and safety assessments. Discussion There is no robust evidence to suggest that L‐oxiracetam and oxiracetam can enhance memory and cognitive function in patients with mild to moderate TBI. This study has the potential to answer this crucial clinical question. Trial registration chinadrugtrials.org.cn, identifier CTR20192539; ClinicalTrials.gov, identifier NCT04205565.

Abstract Background A standard surgical procedure for patients with small early-stage lung adenocarcinomas remains unknown. Hence, we aim in this study to assess the clinical utility of the consolidation-to-tumor ratio (CTR) when treating patients with small (2 cm) early stage lung cancers. Methods A retrospective cohort of 298 sublobar resection and 266 lobar resection recipients for early stage lung adenocarcinoma ≤ 2 cm was assembled from the First Affiliated Hospital of Chongqing Medical University between 2016 and 2019. To compare survival rates among the different groups, Kaplan-Meier curves were calculated, and the log-rank test was used. A multivariate Cox proportional hazard model was constructed utilizing variables that were significant in univariate analysis of survival. Results In the study, 564 patients were included, with 298 patients (52.8%) undergoing sublobar resection and 266 patients (47.2%) undergoing lobar resection. Regarding survival results, there was no significant difference in the 5-year overall survival (OS, P = 0.674) and 5-year recurrence-free survival (RFS, P = 0.253) between the two groups. Cox regression analyses showed that CTR ≥ 0.75(P 56 years (P = 0.007), and sublobar resection(P = 0.001) could predict worse survival. After examining survival results based on CTR categorization, we segmented the individuals into three categories: CTR

Traditional Chinese Medicine (TCM) formulations serve as a multi-component pharmacological combination therapy with various potential targets and have collected extensive knowledge regarding the in vivo efficacy of treating cardiovascular disorders in clinical practice for thousands of years. However, the obscurity of the chemicals and the molecular mechanisms are impediments to their continued growth and globalization. Therefore, new modern medications based on the combination of beneficial TCM components with precise clinical efficacy are required. The goal of this study was to find the best combination of Achyranthes bidentata Blume (AB) and Paeonia lactiflora Pall. (PL) for hypertension with liver yang hyperactivity (HLYH). The integrated research consisting of principal component analysis (PCA), metabolomics, microbiology, and weighted correlation network analysis (WGCNA) were used to find the optimal combination of AB-PL combinations and reveal the mechanism of action. The result showed AB-PL (2:3) had a substantial protective impact on HLYH, as shown by lower blood pressure, improved liver yang hyperactivity, reduced cardiac remodeling and malondialdehyde (MDA), and increased NO content. Furthermore, the essential elements for AB-PL reducing hypertension may be related to 135 metabolites and 23 microorganisms. In conclusion, our findings support the efficacy of herbal remedies in the treatment of hypertension and provide some pharmacological evidence for the ongoing development of novel modern Chinese drugs for cardiovascular disorders.

Hepatocellular carcinoma (HCC) is a primary liver cancer with high pathogenicity and extremely poor prognosis. The role of circular RNAs (circRNAs) in HCC carcinogenesis and progression remains to be determined. Based on the analysis of HCC-related databases, as well as the expression analysis and identification of 25 HCC patient tissues and HCC cell lines, we found that the hsa_circ_0031431 (circCOCH) is significantly highly expressed in HCC tissues and cell lines. High circCOCH expression is associated with enhanced tumor proliferation and metastasis, and knocking down circCOCH can inhibit the growth of HCC in vivo and in vitro. Mechanistic studies show that circCOCH upregulates the expression of epidermal growth factor receptor (EGFR) through sponge miR-450a, thereby activating the Phosphoinositide 3-kinases (PI3Ks) cell pathway to promote HCC proliferation and metastasis. Futhermore, we found that IGF2BP3 mediates the biogenesis of circCOCH. The present study provides innovative insights into the role of circRNAs in the etiology of HCC carcinogenesis and might serve as a new promising therapeutic target for HCC.

Abstract Background The immunoglobulin superfamily protein Trem2 (triggering receptor expressed on myeloid cells 2) is primarily expressed on myeloid cells where it functions to regulate macrophage‐related immune response induction. While macrophages are essential mediators of diabetic wound healing, the specific regulatory role that Trem2 plays in this setting remains to be established. Objective This study was developed to explore the potential importance of Trem2 signalling in diabetic wound healing and to clarify the underlying mechanisms through which it functions. Methods and results Following wound induction, diabetic model mice exhibited pronounced upregulation of Trem2 expression, which was primarily evident in macrophages. No cutaneous defects were evident in mice bearing a macrophage‐specific knockout of Trem2 (T2‐cKO), but they induced more pronounced inflammatory responses and failed to effectively repair cutaneous wounds, with lower levels of neovascularization, slower rates of wound closure, decreased collagen deposition following wounding. Mechanistically, we showed that interleukin (IL)‐4 binds directly to Trem2, inactivating MAPK/AP‐1 signalling to suppress the expression of inflammatory and chemoattractant factors. Co‐culture of fibroblasts and macrophages showed that macrophages from T2‐cKO mice suppressed the in vitro activation and proliferation of dermal fibroblasts through upregulation of leukaemia inhibitory factor (Lif). Injecting soluble Trem2 in vivo was also sufficient to significantly curtail inflammatory responses and to promote diabetic wound healing. Conclusions These analyses offer novel insight into the role of IL‐4/Trem2 signalling as a mediator of myeloid cell‐fibroblast crosstalk that may represent a viable therapeutic target for efforts to enhance diabetic wound healing.

Abstract RNA splicing is a dynamic molecular process in response to environmental stimuli and is strictly regulated by the spliceosome. Sm proteins, constituents of the spliceosome, are key components that mediate splicing reactions; however, their potential role in hepatocellular carcinoma (HCC) is poorly understood. In the study, SNRPD2 (PD2) is found to be the most highly upregulated Sm protein in HCC and to act as an oncogene. PD2 modulates DDX39A intron retention together with HNRNPL to sustain the DDX39A short variant (39A_S) expression. Mechanistically, 39A_S can mediate MYC mRNA nuclear export to maintain high MYC protein expression, while MYC in turn potentiates PD2 transcription. Importantly, digitoxin can directly interact with PD2 and has a notable cancer‐suppressive effect on HCC. The study reveals a novel mechanism by which DDX39A senses oncogenic MYC signaling and undergoes splicing via PD2 to form a positive feedback loop in HCC, which can be targeted by digitoxin.

Background: Retroperitoneal liposarcoma (RLPS) typically shows limited response to standard chemotherapy, presenting a challenge in treating advanced or metastatic RLPS. Objective: This study aimed to evaluate the potential advantages of a combined therapeutic strategy utilizing eribulin, anlotinib, and camrelizumab. Design: Between December 2020 and March 2023, this retrospective study enrolled patients with advanced or metastatic RLPS who received treatment at Peking University Cancer Hospital Sarcoma Center. The treatment regimen involved eribulin plus anlotinib and camrelizumab administered every 3 weeks (Q3W). Methods: Efficacy was assessed following the Response Evaluation Criteria in Solid Tumors version 1.1, while safety was evaluated using the Common Terminology Criteria for Adverse Events version 5.0. Results: The study included 47 patients with RLPS with a median age of 55.5 years. Patients received a median of 4.5 (range, 2–21) cycles of treatment. Notably, partial response was observed in 8 patients (18.2%), while 25 (56.8%) exhibited stable disease. The objective response rate (ORR) and disease control rate were 18.2% and 75%, respectively. Significant differences in ORR were observed among histological subtypes (well-differentiated vs de-differentiated vs myxoid: 0 vs 17.9% vs 50%; p = 0.039). Six patients underwent surgery before disease progression, and one patient with myxoid liposarcoma (MLPS) had a pathological complete response. With a median follow-up of 21.8 (range, 2.7–30.7) months, the median progression-free survival (mPFS) was 6.9 (95% confidence interval (CI), 4.7–9.1) months, and the 6-month PFS rate was 60.5%. Based on various histological subtypes, the mPFS was 8.4 (95% CI, 4.1–12.7) months with well-differentiated liposarcoma, 5.8 (95% CI, 3.3–8.3) months with de-differentiated liposarcoma and not reached with MLPS, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 36 (76.6%) patients, with grade 3 or higher TRAEs in 21 (44.7%) patients. The most common TRAEs were neutropenia (53.2%), proteinuria (21.3%), and anorexia (21.3%). Conclusion: The combined treatment strategy involving eribulin, anlotinib, and camrelizumab showed promising efficacy and manageable safety in patients with advanced or metastatic RLPS, particularly in those with MLPS.

Background: Traumatic brain injury (TBI) is a common neurosurgical disease in emergency rooms with poor prognosis, imposing severe burdens on patients and their families. Evidence indicates that piracetam and compound porcine cerebroside and ganglioside injection (CPCGI) can improve cognitive levels in TBI patients to enhance functional prognosis, but there is still a research gap regarding the efficacy of CPCGI. This study aims to determine the effectiveness and safety of CPCGI in improving cognitive and functional outcomes in TBI patients. Methods: This study is a multicenter, randomized, parallel-group, double-blind trial aiming to recruit 900 adult patients with mild to moderate TBI. After providing informed consent, 600 patients will be randomly assigned to the CPCGI group (20 ml/d, for 14 days), and 300 patients will be randomized to the piracetam group as a control (20 ml/d, for 14 days), followed up for 3 months after treatment. The primary outcome is the change in the Montreal Cognitive Assessment (MoCA) score from baseline after 3 months. The main secondary outcome measures include Mini-Mental State Examination (MMSE) scores, Glasgow Outcome Scale-Extended (GOS-E), and the Barthel Index at 1 and 3 months. Discussion: This multi-center clinical trial aims to provide high-quality evidence on the efficacy and safety of CPCGI in improving cognitive and functional outcomes in mild to moderate TBI patients. Trial registration: ChiCTR2000040466, date of registration: November 28, 2020.

Ecosystem degradation and decline are central issues that urgently require resolution within global environmental protection efforts. Accordingly, accurately analyzing the spatiotemporal evolution of regional ecological environmental quality and exploring its natural and anthropogenic driving factors of ecological environmental quality are crucial for protecting regional ecological environments and advancing sustainable development strategies. Therefore, this study created a new remote sensing ecological index to investigate the patterns of ecological quality change in vegetation-covered areas over a long time series and identified the intensity and local response relationships of various driving factors, including climate, topography, soil, and urbanization. The results revealed an upward trend in the ecological quality of the Heilongjiang region, with a high degree of spatial autocorrelation in ecological quality. The ecological grades in forest-covered areas significantly surpassed those in other vegetated, urban, and desert regions. Through a collaborative analysis of various geographical statistical methods, the intensities of the driving factors and their local response relationships were determined. This study provides a method for accurately and rapidly assessing regional ecological environmental quality and exploring the complex interactions of driving factors, thus offering a theoretical basis for monitoring regional-scale ecological conditions, balancing ecological and economic development, and informing environmental protection policies.

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.