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Abstract Objectives This study aimed to compare the temperature rise, time consuming and cut quality of apicectomy using three different methods. Materials and methods Twenty-four single-rooted teeth were collected and divided into four groups operating apicectomy with a NINJA tip of a piezoelectric device (G1), a diamond bur with 300,000 rpm (G2), and Er: YAG laser at 200 mJ/ 30 Hz (G3) as well as 250 mJ/ 30 Hz (G4). The temperature elevation and time were recorded and the cut quality was evaluated via stereomicroscope and scanning electronic microscopy (SEM). Results The temperature increases for G1 was significantly higher than for G2. However, there was no significant difference between G1 and G2 with laser groups respectively. The median time for apicectomy was: 100.14s for G1, 22.65s for G2, 33.58s for G3, and 21.80s for G4. G1 is the most time-consuming group and there was no statistically significance in the comparisons with G2, G3 and G4. Cut quality was assessed by crack occurrence, smear layer formation and dentinal tubules exposed. The percentage of cracked teeth in G1 and G2 was 33.33% and for laser groups the percentage was 16.67% each. SEM showed that no smear layer formed and almost all dentinal tubules were exposed on resected surfaces for G3&G4, surfaces from G2 were partly covered by smear layer, and surfaces from G1 were fully covered by smear layer and with no dentinal tubules exposed. Conclusions Er: YAG laser and conventional rotary instruments were safe and efficient for apicectomy and with a better cut quality when compared with piezoelectric equipment. Er: YAG laser could be a promising technique for apicectomy and further studies are necessary, especially larger sample in vivo investigations, to verify the feasibility of Er: YAG laser in endodontic surgery.

Rhabdophis chiwen is currently found so far in Sichuan Province, China, where it predominantly feeds on earthworms and firefly larvae. In this study, we sequenced and analyzed the mitochondrial genome of R. chiwen, which measured 17,646 bp in length and encompassed 37 genes along with two control regions. The base composition revealed percentages of 33.20% A, 25.94% T, 13.27% G, and 27.59% C. Phylogenetic analyses indicate that R. chiwen belongs to the family Colubridae and forms a sister branch with R. tigrinus. This study successfully obtained the first complete mitochondrial genome of R. chiwen, offering crucial genetic data for its evolutionary history and conservation.

Abstract Background S100β is a biomarker of astroglial damage, the level of which is significantly increased following brain injury. However, the characteristics of S100β and its association with prognosis in patients with acute ischemic stroke following intravenous thrombolysis (IVT) remain unclear. Methods Patients in this multicenter prospective cohort study were prospectively and consecutively recruited from 16 centers. Serum S100β levels were measured 24 h after IVT. National Institutes of Health Stroke Scale (NIHSS) and hemorrhagic transformation (HT) were measured simultaneously. NIHSS at 7 days after stroke, final infarct volume, and modified Rankin Scale (mRS) scores at 90 days were also collected. An mRS score ≥ 2 at 90 days was defined as an unfavorable outcome. Results A total of 1072 patients were included in the analysis. The highest S100β levels (> 0.20 ng/mL) correlated independently with HT and higher NIHSS at 24 h, higher NIHSS at 7 days, larger final infarct volume, and unfavorable outcome at 3 months. The patients were divided into two groups based on dominant and non-dominant stroke hemispheres. The highest S100β level was similarly associated with the infarct volume in patients with stroke in either hemisphere (dominant: β 36.853, 95% confidence interval (CI) 22.659–51.048, P

Objective(s): Our previous study has showed that human amniotic mesenchymal stem cells (hAMSCs) transplantation improves neurological recovery after traumatic spinal cord injury (TSCI) in rats. However, less is known about the effects of exosomes derived from hAMSCs for TSCI. Here, we investigated whether hAMSCs-derived exosomes improve neurological recovery in TSCI rats and the underlying mechanisms. Materials and Methods: A rat traumatic spinal cord injury (TSCI) mode was established using a weight drop device. At 2 hr after TSCI, rats were administered either hAMSCs-derived exosomes or phosphate buffered saline via the tail vein. Locomotor recovery was evaluated by an open-field locomotor rating scale and gridwalk task. Spinal cord water content, hematoxylin and eosin (H&E) staining, Evans blue (EB) dye extravasation, immunofluorescence staining, and enzyme-linked immunosorbent were performed to elucidate the underlying mechanism.Results: hAMSCs-derived exosomes significantly reduced the numbers of ED1+ macrophages/microglia and caspase-3+cells and decreased the levels of reactive oxygen species, myeloperoxidase activity and inflammatory cytokines, such as tumor necrosis factor alpha, interleukin-6 and interleukin-1β. In addition, hAMSCs-derived exosomes significantly attenuated spinal cord water content and Evans blue extravasation, and enhanced angiogenesis and axonal regeneration. Finally, hAMSCs-derived exosomes also significantly reduced the lesion volume, inhibited astrogliosis, and improved functional recovery. Conclusion: Taken together, these findings demonstrate that hAMSCs-derived exosomes have favourable effects on rats after acute TSCI, and that they may serve as an alternative cell-free therapeutic approach for treating acute TSCI.

Abstract The aim of this study was to develop a machine learning-assisted rapid determination methodology for traditional Chinese Medicine Constitution. Based on the Constitution in Chinese Medicine Questionnaire (CCMQ), the most applied diagnostic instrument for assessing individuals’ constitutions, we employed automated supervised machine learning algorithms (i.e., Tree-based Pipeline Optimization Tool; TPOT) on all the possible item combinations for each subscale and an unsupervised machine learning algorithm (i.e., variable clustering; varclus) on the whole scale to select items that can best predict body constitution (BC) classifications or BC scores. By utilizing subsets of items selected based on TPOT and corresponding machine learning algorithms, the accuracies of BC classifications prediction ranged from 0.819 to 0.936, with the root mean square errors of BC scores prediction stabilizing between 6.241 and 9.877. Overall, the results suggested that the automated machine learning algorithms performed better than the varclus algorithm for item selection. Additionally, based on an automated machine learning item selection procedure, we provided the top three ranked item combinations with each possible subscale length, along with their corresponding algorithms for predicting BC classification and severity. This approach could accommodate the needs of different practitioners in traditional Chinese medicine for rapid constitution determination.

Editorial As early as about 2400 years ago, Mozi (original name Mo Di, Latinized as Micius), an ancient Chinese scientist, proposed the theory of pinhole imaging that demonstrates the fundamental principle of light behavior. About 700 years ago, Marco Polo, an Italian explorer, traveled to China along the Silk Road, marveled at the economic prosperity and the advanced technology of Hangzhou City in China, and described Hangzhou as “the most beautiful and splendid city in the world”. About 5 years ago, with the support of the China-proposed Belt-and-Road Initiative, it was in Hangzhou City that Professor Pavlos Savvidis, an Armenian-born Greek physicist, chose to work with more of his Chinese counterparts and took on the challenge of building a new research laboratory on quantum optoelectronics. He used to study and work in the UK, the USA, and Greece, but now in New China’s first new type of research university supported by the society—Westlake University. Traveling from West to East, traversing from one civilization to another, Professor Pavlos Savvidis delves into his unwavering quest for light in this issue of “Light People”, and discusses his tireless pursuit of excellence in the field of optoelectronics, which has garnered him widespread citation, recognition, and contribution to the global scientific community.

This study was conducted in Hezhang County, Bijie City, Guizhou Province. The soil in the zinc smelting area has been contaminated with cadmium, lead, and zinc. Therefore, these elements are the focus of this research. Rice husk biochar was used as the passivation material. The Fourier infrared spectrum was utilized to study the biochar’s morphology, element content, mineral composition, structure, and surface functional groups. Moreover, the physical and chemical properties of the biochar were analyzed to explore its passivation effect. Biochar is beneficial in the cleaning of cadmium, lead, and zinc minerals and can be used for the passivation of heavy metals in contaminated soil. This study aims to understand the detailed mechanism behind this process and provide experimental data and ideas for pollution control. The results indicate that the biochar contains many functional groups, including -OH, C-H, C-O, C=O, C=C, and C-O-C. It also consists of a significant quantity of potassium salt, calcite, and quartz. Biochar has a noticeable pore structure, and as the pyrolysis temperature increases, the pore structure becomes more developed and thinner, with a smooth surface. The main minerals in the soil are quartz, mica, zeolite, illite, and chlorite. The aromatic degree of biochar increased with pyrolysis temperature. In contrast, the aromatic degree and polarity first increased and then decreased. The 0.2-0.45 mm biochar exhibited the best passivation effect on cadmium, lead, and zinc.

Abstract In the study of obesity and diabetes, mice are widely used for experimental research, and fasting is a common procedure used to reset metabolism in mouse models. The fasting duration for experimental mice varies greatly in nutritional and metabolic studies, ranging from 2 to 48 h. This study aims to assess the optimal fasting duration for mice fed low- and high-fat diets over a short period of time. C57BL/6J mice were fed a low-fat diet (LFD) or high-fat diet (HFD) and fasted for 4, 6, 8, 10, 12, or 24 h. The effects of different conditions after fasting on the metabolic level of mice were explored, and the data were collected for analysis. Our data indicate that fasting has inconsistent effects on mice fed a low-fat or high-fat diet. To compare the metabolic differences between mice in different dietary levels and thereby secure better scientific data, mice should fast for 6 h in animal experiments. Fasting for 6 h is also recommended when comparing glucose tolerance with insulin tolerance.

Neuroinflammation is considered the principal pathogenic mechanism underlying neurodegenerative diseases, and the incidence of brain disorders is closely linked to dietary fat consumption and intestinal health. To investigate this relationship, 60 8-week-old C57BL/6J mice were subjected to a 20-week dietary intervention, wherein they were fed lard and soybean oil, each at 15% and 35% fat energy. At a dietary fat energy level of 35%, inflammation was observed in both the soybean oil and lard groups. Nevertheless, inflammation was more pronounced in the mice that were administered soybean oil. The process by which nerve cell structure is compromised, inflammatory factors are upregulated, brain antioxidant capacity is diminished, and the TLR4/MyD88/NF-κB p65 inflammatory pathway is activated resulting in damage to the brain-gut barrier. This, in turn, leads to a reduction in the abundance of Akkermansia and unclassified_f_Lachnospiraceae, as well as an increase in Dubosiella abundance, ultimately resulting in brain inflammation and damage. These results suggested that soybean oil induces more severe neuroinflammation compared to lard. Our study demonstrated that, at a dietary fat energy level of 35%, compared to soybean oil, lard could be the healthier option, the outcomes would help provide a reference basis for the selection of residents’ daily dietary oil.

Abstract Background Suaeda australis is one of typical halophyte owing to high levels of salt tolerance. In addition, the bZIP gene family assumes pivotal functions in response to salt stress. However, there are little reports available regarding the bZIP gene family in S. australis. Results In this study, we successfully screened 44 bZIP genes within S. australis genome. Subsequently, we conducted an extensive analysis, encompassing investigations into chromosome location, gene structure, phylogenetic relationship, promoter region, conserved motif, and gene expression profile. The 44 bZIP genes were categorized into 12 distinct groups, exhibiting an uneven distribution among the 9 chromosomes of S. australis chromosomes, but one member (Sau23745) was mapped on unanchored scaffolds. Examination of cis-regulatory elements revealed that bZIP promoters were closely related to anaerobic induction, transcription start, and light responsiveness. Comparative transcriptome analysis between ST1 and ST2 samples identified 2,434 DEGs, which were significantly enriched in some primary biological pathways related to salt response-regulating signaling based on GO and KEGG enrichment analysis. Expression patterns analyses clearly discovered the role of several differently expressed SabZIPs, including Sau08107, Sau08911, Sau11415, Sau16575, and Sau19276, which showed higher expression levels in higher salt concentration than low concentration and a response to salt stress. These expression patterns were corroborated through RT-qPCR analysis. The six differentially expressed SabZIP genes, all localized in the nucleus, exhibited positive regulation involved in the salt stress response. SabZIP14, SabZIP26, and SabZIP36 proteins could bind to the promoter region of downstream salt stress-related genes and activate their expressions. Conclusions Our findings offer valuable insights into the evolutionary trajectory of the bZIP gene family in S. australis and shed light on their roles in responding to salt stress. In addition to fundamental genomic information, these results would serve as a foundational framework for future investigations into the regulation of salt stress responses in S. australis.

Abstract Background The aim of this study was to describe our preliminary experience in the procedure of laparoscopic radical resection of hilar cholangiocarcinoma and to evaluate its feasibility, safety, and clinical efficacy. Methods A retrospective analysis was conducted on 44 patients with hilar cholangiocarcinoma who underwent laparoscopic surgery at our hospital from August 2019 to September 2023. Clinical data were collected from these patients, including 13 cases of Bismuth type I, 17 cases of Bismuth type II, 5 cases of Bismuth type IIIa, and 9 cases of Bismuth type IIIb. Results Laparoscopic radical resection of hilar cholangiocarcinoma was successfully performed in 38 patients (86.3%). Among the remaining patients, 3 required vascular reconstruction to complete radical surgery and were converted to laparotomies, while 3 others underwent T-tube drainage only due to unresectable metastases. The median operation time was 285 min (range, 190–450), and the median estimated blood loss was 360 mL (range, 260–1200). The postoperative hospital stay duration was 14.3 ± 3.6 days. No perioperative mortality was observed. Postoperative pathological examination revealed negative microscopic margins (R0) in 39 cases and positive microscopic margins (R1) in 2 cases. Postoperative complications occurred in 8 patients (18.1%), with 4 cases (9.0%) of Grade I, 3 cases (6.8%) of Grade II, 1 case (2.2%) of Grade IIIa, and no Grade IIIb or IV complications. The median overall survival for patients who underwent radical R0 resection was 30.4 months (range, 5.3–43.6). The Disease-free survival rates were 73.6% at 1 year, 61.2% at 2 years, and 40.1% at 3 years. Conclusion Total laparoscopic radical resection of hilar cholangiocarcinoma can be performed safely, feasibly, and effectively by experienced surgeons after an accurate preoperative evaluation.

Abstract Objective The purpose of this study was to investigate the long-term consequences on the cervical spine after Anterior transcorporeal percutaneous endoscopy cervical discectomy (ATc-PECD) from the biomechanical standpoint. Methods A three-dimensional model of the normal cervical spine C2-T1 was established using finite element method. Subsequently, a disc degeneration model and degeneration with surgery model were constructed on the basis of the normal model. The same loading conditions were applied to simulate flexion, extension, lateral bending and axial rotation of the cervical spine. We calculated the cervical range of motion (ROM), intradiscal pressure, and intravertebral body pressure under different motions for observing changes in cervical spine biomechanics after surgery. At the same time, we combined the results of a long-term follow-up of the ATc-PECD, and used imaging methods to measure vertebral and disc height and cervical mobility, the Japanese Orthopaedic Association (JOA) score and visual analog scale (VAS) score were used to assess pain relief and neurological functional recovery. Results The long-term follow-up results revealed that preoperative JOA score, neck VAS score, hand VAS score, IDH, VBH, and ROM for patients were 9.49 ± 2.16, 6.34 ± 1.68, 5.14 ± 1.48, 5.95 ± 0.22 mm, 15.41 ± 1.68 mm, and 52.46 ± 9.36° respectively. It changed to 15.71 ± 1.13 (P

Abstract Fatigue failure is invariably the most crucial failure mode for metallic structural components. Most microstructural strategies for enhancing fatigue resistance are effective in suppressing either crack initiation or propagation, but often do not work for both synergistically. Here, we demonstrate that this challenge can be overcome by architecting a gradient structure featuring a surface layer of nacre-like nanolaminates followed by multi-variant twinned structure in pure titanium. The polarized accommodation of highly regulated grain boundaries in the nanolaminated layer to cyclic loading enhances the structural stability against lamellar thickening and microstructure softening, thereby delaying surface roughening and thus crack nucleation. The decohesion of the nanolaminated grains along horizonal high-angle grain boundaries gives rise to an extraordinarily high frequency (≈1.7 × 103 times per mm) of fatigue crack deflection, effectively reducing fatigue crack propagation rate (by 2 orders of magnitude lower than the homogeneous coarse-grained counterpart). These intriguing features of the surface nanolaminates, along with the various toughening mechanisms activated in the subsurface twinned structure, result in a fatigue resistance that significantly exceeds those of the homogeneous and gradient structures with equiaxed grains. Our work on architecting the surface nanolaminates in gradient structure provides a scalable and sustainable strategy for designing more fatigue-resistant alloys.

Abstract Rhabdophis nuchalis, a snake widely distributed in China, possesses a unique trait: glands beneath the skin on its neck and back, known as nucho-dorsal glands. These features make it a valuable subject for studying genetic diversity and the evolution of complex traits. In this study, we obtained a high-quality chromosome-level reference genome of R. nuchalis using MGI short-read sequencing, PacBio Revio long-read sequencing, and Hi-C sequencing techniques. The final assembly comprised 1.92 Gb of the R. nuchalis genome, anchored to 20 chromosomes (including 9 macrochromosomes and 11 microchromosomes), with a contig N50 of 104.79 Mb, a scaffold N50 of 204.96 Mb, and a BUSCO completeness of 97.50%. Additionally, we annotated a total of 1.09 Gb of repetitive sequences (which constitute 56.51% of the entire genome) and identified 22,057 protein-coding genes. This high-quality reference genome of R. nuchalis furnishes essential genomic data for comprehending the genetic diversity and evolutionary history of the species, as well as for facilitating species conservation efforts and comparative genomics studies.

Abstract Pressure ulcers (PU) are caused by persistent long-term pressure, which compromises the integrity of the epidermis, dermis, and subcutaneous adipose tissue layer by layer, making it difficult to heal. Platelet products such as platelet lysate (PL) can promote tissue regeneration by secreting numerous growth factors based on clinical studies on skin wound healing. However, the components of PL are difficult to retain in wounds. Gelatin methacrylate (GelMA) is a photopolymerizable hydrogel that has lately emerged as a promising material for tissue engineering and regenerative medicine. The PL liquid was extracted, flow cytometrically detected for CD41a markers, and evenly dispersed in the GelMA hydrogel to produce a surplus growth factor hydrogel system (PL@GM). The microstructure of the hydrogel system was observed under a scanning electron microscope, and its sustained release efficiency and biological safety were tested in vitro. Cell viability and migration of human dermal fibroblasts, and tube formation assays of human umbilical vein endothelial cells were applied to evaluate the ability of PL to promote wound healing and regeneration in vitro. Real-time polymerase chain reaction (PCR) and western blot analyses were performed to elucidate the skin regeneration mechanism of PL. We verified PL’s therapeutic effectiveness and histological analysis on the PU model. PL promoted cell viability, migration, wound healing and angiogenesis in vitro. Real-time PCR and western blot indicated PL suppressed inflammation and promoted collagen I synthesis by activating STAT3. PL@GM hydrogel system demonstrated optimal biocompatibility and favorable effects on essential cells for wound healing. PL@GM also significantly stimulated PU healing, skin regeneration, and the formation of subcutaneous collagen and blood vessels. PL@GM could accelerate PU healing by promoting fibroblasts to migrate and secrete collagen and endothelial cells to vascularize. PL@GM promises to be an effective and convenient treatment modality for PU, like chronic wound treatment.

Abstract Breast reconstruction is essential for improving the appearance of patients after cancer surgery. Traditional breast prostheses are not appropriate for those undergoing partial resections and cannot detect and treat locoregional recurrence. Personalized shape prostheses that can smartly sense tumor relapse and deliver therapeutics are needed. A 3D‐printed prosthesis that contains a therapeutic hydrogel is developed. The hydrogel, which is fabricated by crosslinking the polyvinyl alcohol with N1‐(4‐boronobenzyl)‐N3‐(4‐boronophenyl)‐N1, N1, N3, N3‐tetramethylpropane‐1,3‐diaminium, is responsive to reactive oxygen species (ROS) in the tumor microenvironment. Specifically, RSL3, a ferroptosis inducer that is loaded in hydrogels, can trigger tumor ferroptosis. Intriguingly, RSL3 encapsulated in the ROS‐responsive hydrogel exerts antitumor effects by increasing the numbers of tumor‐infiltrated CD4+ T cells, CD8+ T cells, and M1 macrophages while reducing the number of M2 macrophages. Therefore, this new prosthesis not only allows personalized shape reconstruction, but also detects and inhibits tumor recurrence. This combination of aesthetic appearance and therapeutic function can be very beneficial for breast cancer patients undergoing surgery.

The levels of flavor compounds and hazardous compounds are important indicators for evaluating high-temperature roasted food. In this paper, the effect of tea pre-marination on non-volatile compounds, volatile compounds, and hazardous compounds in roasted chicken. The results showed that the total content of key umami non-volatile compounds in roasted chicken marinated with green tea, white tea, and black tea increased by 17.43 % to 100.11 %. The content of alkenes, alcohols, aldehydes, and ketones in high-temperature roasted chicken marinated with oolong tea and yellow tea was increased. Different teas had varying inhibitory effects on hazardous compounds in high-temperature roasted chicken, while green tea exhibited the highest inhibition efficacy. The inhibition rates of green tea for ACY, 5-HMF, HCAs, and PAHs were 72.12 %, 69.87 %, 92.49 %, and 14.92 %, respectively. Flavonoids in tea may play an important role in the flavor enhancement and hazardous compounds inhibition of high-temperature roasted chicken.

Tomato yellow leaf curl China virus (TYLCCNV) viruliferous Mediterranean (MED) whitefly infestation in tobacco plants elevated hydrogen peroxide (H2O2) levels more than non-viruliferous ones. To unravel the underlying mechanisms behind the phenomenon, comparative analyses of plant transcriptome and enzyme activities of reactive oxygen species (ROS) scavengers were conducted in this study. Compared to the control, a total of 4032 and 6853 differentially expressed genes (DEGs) were identified in the plants following the infestations of non-viruliferous and TYLCCNV-viruliferous MED, respectively. Gene ontology analysis of DEGs suggested substantial transcriptional reprogramming of diverse cellular processes, particularly in the biotic stress response pathways of tobacco plants. Respiratory burst oxidase homologs related genes and important kinases putatively involved in plant defense were differentially modulated in tobacco plants in response to the non-viruliferous and TYLCCNV-viruliferous whitefly MED infestation. The analysis reported here lays out a strong foundation for future investigations into the mechanisms of ROS-associated plant defense mediating the interactions between B. tabaci and begomoviruses.

In vitro drug screening endeavors to replicate cellular states closely resembling those encountered in vivo, thereby maximizing the fidelity of drug effects and responses within the body. Decellularized extracellular matrix (dECM)-based materials offer a more authentic milieu for crafting disease models, faithfully emulating the extracellular components and structural complexities encountered by cells in vivo. This review discusses recent advancements in leveraging dECM-based materials as biomaterials for crafting cell models tailored for drug screening. Initially, we delineate the biological functionalities of diverse ECM components, shedding light on their potential influences on disease model construction. Further, we elucidate the decellularization techniques and methodologies for fabricating cell models utilizing dECM substrates. Then, the article delves into the research strides made in employing dECM-based models for drug screening across a spectrum of ailments, including tumors, as well as heart, liver, lung, and bone diseases. Finally, the review summarizes the bottlenecks, hurdles, and promising research trajectories associated with the dECM materials for drug screening, alongside their prospective applications in personalized medicine. Together, by encapsulating the contemporary research landscape surrounding dECM materials in cell model construction and drug screening, this review underscores the vast potential of dECM materials in drug assessment and personalized therapy.

Streptococcus pneumoniae is a common pathogen associated with community-acquired bacterial meningitis, characterized by high morbidity and mortality rates. While vaccination reduces the incidence of meningitis, many survivors experience severe brain damage and corresponding sequelae. The pathogenesis of pneumococcal meningitis has not been fully elucidated. Currently, meningitis requires bacterial disruption of the blood – brain barrier, a process that involves the interaction of bacterial surface components with host cells and various inflammatory responses. This review delineates the global prevalence, pathogenesis, and treatment strategies of pneumococcal meningitis. The objective is to enhance the thorough comprehension of the clinical manifestations and biological mechanisms of the disease, thereby enabling more efficient prevention, diagnosis, and therapeutic interventions.

AbstractA series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor, pracinostat. In enzymatic assays, compound 3b, containing a 2-acyliminobenzimidazole moiety and hydroxamic acid side chain, could inhibit both ALK and HDAC6 (IC50 = 16 nM and 1.03 µM, respectively). Compound 3b also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC50, 4.9 nM). Moreover, 3b inhibited the proliferation of several cancer cell lines, including ALK-addicted H2228 cells. To evaluate its potential for treating cancers in vivo, 3b was used in a human A549 xenograft model with BALB/c nude mice. At 20 mg/kg, 3b inhibited tumour growth by 85% yet had a negligible effect on mean body weight. These results suggest a attracting route for the further research and optimisation of dual ALK/HDAC inhibitors.

ABSTRACT Background and Aims Early stage administration of Paxlovid has been shown to improve the prognosis of mild to moderate COVID‐19 patients with high risk. However, few evidence was validated in severe COVID‐19 patients with hypoxemia. It is also unclear whether delayed usage of Paxlovid affected prognosis in COVID‐19 patients or not. Methods In this multiple‐centers prospective study, we collected the clinical data in hospitalized severe adult Omicron infection patients with hypoxemia. All patients were divided into two groups according to the time of Paxlovid usage after the symptom onset: early group (Paxlovid administration in 5 days after symptom onset) and delayed group (Paxlovid administration beyond 5 days after symptom onset). The 28‐day composite outcomes were evaluated. Results Totally 198 hospitalized severe omicron‐infected subjects with hypoxemia were enrolled. There was no difference between the two groups about the baseline characteristics and laboratory parameters, except for leukocytes (5.29 × 109 vs. 7.90 × 109/L, p = 0.01) and albumin levels (35 vs. 31 g/L, p = 0.04). The 28‐day composite outcomes in early group were slightly lower than that in delayed group but with no difference (12.8% vs. 16.67%, p = 0.602). The viral clearance ratio at Day 7 after Paxlovid treatment in early group was higher than that in delayed group (79.48% vs. 58.33%, p = 0.029). The medium hospitalized duration in early group was shorter than that in delayed group (11.31 vs. 15.32 days, p = 0.005). Logistic analysis showed the independent risk factors of prognosis including underlying diseases ≥ 3 kinds (ORR = 1.72), d‐dimer ≥ 2.0 μg/mL (ORR = 1.35), and MODS (ORR = 14.01). Conclusions In Omicron‐infected subjects with hypoxemia, early usage of Paxlovid received benefits in hospitalized time and viral clearance, but delayed usage did not result in a worse composite prognosis. This result might provide direct evidence of antiviral strategy in severe Omicron infection subjects with hypoxemia.

Abstract Engineered liver lobule is highly practical in hepatic disease treatment, while constructing a 3D biomimetic lobule with a heterogeneous architecture on a large scale is challenging. Here, inspired by the natural architectural construction of hepatic lobules, biomimetic hepatic lobules are proposed with coaxially through‐pores for nutrient exchange via microfluidic technology. This multi‐channel microfluidic chip is made by parallelly installing capillaries. Sodium alginate (Alg) is pumped through its central channel, while Ca2+‐loaded gelatin methacrylate (GelMA) solutions encapsulating hepatocytes, mesenchymal stem cells, and endothelia cells are pumped through surrounding channels, respectively. The rapid gelation of Alg and Ca2+ brings about an in situ formation of Alg fiber, with heterogeneous multi‐cell‐laden GelMA microcarriers forming around it. The peeled‐off microcarriers each featured with a coaxially through pore, simulating the cord‐like structure of hepatic lobule and facilitating nutrients exchange. Meanwhile, the spatially anisotropic arrangement of cells highly simulates the hepatic architecture. It is demonstrated that by transplanting these biomimetic microparticles into liver in situ, the failed liver in rat shows increased regeneration and decreased necrosis. These results indicated that the microfluidic multi‐compartmental microcarriers provide a new strategy to engineer 3D artificial livers for clinical translation.

Abstract Invasion and migration are the key hallmarks of cancer, and aggressive growth is a major factor contributing to treatment failure and poor prognosis in glioblastoma. Protein arginine methyltransferase 6 (PRMT6), as an epigenetic regulator, has been confirmed to promote the malignant proliferation of glioblastoma cells in previous studies. However, the effects of PRMT6 on glioblastoma cell invasion and migration and its underlying mechanisms remain elusive. Here, we report that PRMT6 functions as a driver element for tumor cell invasion and migration in glioblastoma. Bioinformatics analysis and glioma sample detection results demonstrated that PRMT6 is highly expressed in mesenchymal subtype or invasive gliomas, and is significantly negatively correlated with their prognosis. Inhibition of PRMT6 (using PRMT6 shRNA or inhibitor EPZ020411) reduces glioblastoma cell invasion and migration in vitro, whereas overexpression of PRMT6 produces opposite effects. Then, we identified that PRMT6 maintains the protein stability of EZH2 by inhibiting the degradation of EZH2 protein, thereby mediating the invasion and migration of glioblastoma cells. Further mechanistic investigations found that PRMT6 inhibits the transcription of TRAF6 by activating the histone methylation mark (H3R2me2a), and reducing the interaction between TRAF6 and EZH2 to enhance the protein stability of EZH2 in glioblastoma cells. Xenograft tumor assay and HE staining results showed that the expression of PRMT6 could promote the invasion of glioblastoma cells in vivo, the immunohistochemical staining results of mouse brain tissue tumor sections also confirmed the regulatory relationship between PRMT6, TRAF6, and EZH2. Our findings illustrate that PRMT6 suppresses TRAF6 transcription via H3R2me2a to enhance the protein stability of EZH2 to facilitate glioblastoma cell invasion and migration. Blocking the PRMT6-TRAF6-EZH2 axis is a promising strategy for inhibiting glioblastoma cell invasion and migration.

Abstract Neurotransmitters are key modulators in neuro-immune circuits and have been linked to tumor progression. Medullary thyroid cancer (MTC), an aggressive neuroendocrine tumor, expresses neurotransmitter calcitonin gene-related peptide (CGRP), is insensitive to chemo- and radiotherapies, and the effectiveness of immunotherapies remains unknown. Thus, a comprehensive analysis of the tumor microenvironment would facilitate effective therapies and provide evidence on CGRP’s function outside the nervous system. Here, we compare the single-cell landscape of MTC and papillary thyroid cancer (PTC) and find that expression of CGRP in MTC is associated with dendritic cell (DC) abnormal development characterized by activation of cAMP related pathways and high levels of Kruppel Like Factor 2 (KLF2), correlated with an impaired activity of tumor infiltrating T cells. A CGRP receptor antagonist could offset CGRP detrimental impact on DC development in vitro. Our study provides insights of the MTC immunosuppressive microenvironment, and proposes CGRP receptor as a potential therapeutic target.

Editorial Qu Yuan, a renowned ancient Chinese poet, once pondered in his work Heavenly Inquiry: “If the sun’s light is absent, from where does the radiance of the Hero Flower emanate?” The ability to see clearly in the darkest of nights has long been a sought-after magical power by humans. It holds not only immense technological significance for computer vision and remote sensing but also profound implications for transcending the dichotomy between day and night in our daily lives. Professor Fanglin Bao from Westlake University has made significant breakthroughs in this field, bringing us closer to a world where we can transform night into day. His groundbreaking research on Heat-Assisted Detection and Ranging (HADAR) and night vision was featured as the cover story in Nature on July 26, 2023. For this issue of “Light People”, Professor Fanglin Bao will share his research journey and the captivating story behind HADAR.

Abstract Osteoarthritis (OA) is the most prevalent form of arthritis, characterized by a complex pathogenesis. One of the key factors contributing to its development is the apoptosis of chondrocytes triggered by oxidative stress. Involvement of peroxisome proliferator-activated receptor gamma (PPARγ) has been reported in the regulation of oxidative stress. However, there remains unclear mechanisms that through which PPARγ influences the pathogenesis of OA. The present study aims to delve into the role of PPARγ in chondrocytes apoptosis induced by oxidative stress in the context of OA. Primary human chondrocytes, both relatively normal and OA, were isolated and cultured for the following study. Various assessments were performed, including measurements of cell proliferation, viability and cytotoxicity. Additionally, we examined cell apoptosis, levels of reactive oxygen species (ROS), nitric oxide (NO), mitochondrial membrane potential (MMP) and cytochrome C release. We also evaluated the expression of related genes and proteins, such as collagen type II (Col2a1), aggrecan, inducible nitric oxide synthase (iNOS), caspase-9, caspase-3 and PPARγ. Compared with relatively normal cartilage, the expression of PPARγ in OA cartilage was down-regulated. The proliferation of OA chondrocytes decreased, accompanied by an increase in the apoptosis rate. Down-regulation of PPARγ expression in OA chondrocytes coincided with an up-regulation of iNOS expression, leading to increased secretion of NO, endogenous ROS production, and decrease of MMP levels. Furthermore, we observed the release of cytochrome C, elevated caspase-9 and caspase-3 activities, and reduction of the components of extracellular matrix (ECM) Col2a1 and aggrecan. Accordingly, utilization of GW1929 (PPARγ Agonists) or Z-DEVD-FMK (caspase-3 inhibitor) can protect chondrocytes from mitochondrial-related apoptosis and alleviate the progression of OA. During the progression of OA, excessive oxidative stress in chondrocytes leads to apoptosis and ECM degradation. Activation of PPARγ can postpone OA by down-regulating caspase-3-dependent mitochondrial apoptosis pathway.

Abstract Background Understanding the molecular mechanisms of Alzheimer’s disease (AD) has important clinical implications for guiding therapy. Impaired amyloid beta (Aβ) clearance is critical in the pathogenesis of sporadic AD, and blood monocytes play an important role in Aβ clearance in the periphery. However, the mechanism underlying the defective phagocytosis of Aβ by monocytes in AD remains unclear. Methods Initially, we collected whole blood samples from sporadic AD patients and isolated the monocytes for RNA sequencing analysis. By establishing APP/PS1 transgenic model mice with monocyte-specific cystatin F overexpression, we assessed the influence of monocyte-derived cystatin F on AD development. We further used a nondenaturing gel to identify the structure of the secreted cystatin F in plasma. Flow cytometry, enzyme-linked immunosorbent assays and laser scanning confocal microscopy were used to analyse the internalization of Aβ by monocytes. Pull down assays, bimolecular fluorescence complementation assays and total internal reflection fluorescence microscopy were used to determine the interactions and potential interactional amino acids between the cystatin F protein and Aβ. Finally, the cystatin F protein was purified and injected via the tail vein into 5XFAD mice to assess AD pathology. Results Our results demonstrated that the expression of the cystatin F protein was specifically increased in the monocytes of AD patients. Monocyte-derived cystatin F increased Aβ deposition and exacerbated cognitive deficits in APP/PS1 mice. Furthermore, secreted cystatin F in the plasma of AD patients has a dimeric structure that is closely related to clinical signs of AD. Moreover, we noted that the cystatin F dimer blocks the phagocytosis of Aβ by monocytes. Mechanistically, the cystatin F dimer physically interacts with Aβ to inhibit its recognition and internalization by monocytes through certain amino acid interactions between the cystatin F dimer and Aβ. We found that high levels of the cystatin F dimer protein in blood contributed to amyloid pathology and cognitive deficits as a risk factor in 5XFAD mice. Conclusions Our findings highlight that the cystatin F dimer plays a crucial role in regulating Aβ metabolism via its peripheral clearance pathway, providing us with a potential biomarker for diagnosis and potential target for therapeutic intervention.

Corporate green innovation has undergone mountainous growth during the last decade, which has led to an essential accumulation of knowledge in the recent literature. This study conducts a systematic literature review of green innovation research in business economic discipline to understand corporate green innovation’s internal and external origin drivers. We explored the drivers, mediating and moderating effects, and consequences of individual conceptual frameworks following internal and external origins. Using a systematic literature review (SLR) and a content analysis approach, the PRISMA model included 91 published research articles for the review. The findings reveal the following critical conclusions: (a) both internal origin and external origin drivers stimulate the development of corporate green innovation; (b) the internal origin drivers are particularly more relevant in developing proactive and reactive green product and process innovation, whereas external origin drivers foster the development of reactive green innovations; however, (c) the role of corporate board is crucial in navigating and mitigating external origin uncertainties through building strategic goals and actively engaging with top management team based on firm-specific capabilities and resources for proactive green innovation development. This is the first systematic review to adapt a comprehensive content analysis approach to uncover internal and external origin drivers of green innovation under resource dependence theory and its complementary notions in comparison to notable business management theories. The findings of the review paper highlight various future research opportunities and practical implications for firms opting for green innovation development.

In marine ranching aquaculture, dissolved oxygen (DO) is a crucial parameter that directly impacts the survival, growth, and profitability of cultured organisms. To effectively guide the early warning and regulation of DO in aquaculture waters, this study proposes a hybrid model for spatiotemporal DO prediction named PCA-ISSA-DAM-Bi-GRU. Firstly, principal component analysis (PCA) is applied to reduce the dimensionality of the input data and eliminate data redundancy. Secondly, an improved sparrow search algorithm (ISSA) based on multi strategy fusion is proposed to enhance the optimization ability and convergence speed of the standard SSA by optimizing the population initialization method, improving the location update strategies for discoverers and followers, and introducing a Cauchy-Gaussian mutation strategy. Thirdly, a feature and temporal dual attention mechanism (DAM) is incorporated to the baseline temporal prediction model Bi-GRU to construct a feature extraction network DAM-Bi-GRU. Fourthly, the ISSA is utilized to optimize the hyperparameters of DAM-Bi-GRU. Finally, the proposed model is trained, validated, and tested using water quality and meteorological parameter data collected from a self-built LoRa+5G-based marine ranching aquaculture monitoring system. The results show that: (1) Compared with the baseline model Bi-GRU, the addition of PCA, ISSA and DAM module can effectively improve the prediction performance of the model, and their fusion is effective; (2) ISSA demonstrates superior capability in optimizing model hyperparameters and convergence speed compared to traditional methods such as standard SSA, genetic algorithm (GA), and particle swarm optimization (PSO); (3) The proposed hybrid model achieves a root mean square error (RMSE) of 0.2136, a mean absolute percentage error (MAPE) of 0.0232, and a Nash efficient (NSE) of 0.9427 for DO prediction, outperforming other similar data-driven models such as IBAS-LSTM and IDA-GRU. The prediction performance of the model meets the practical needs of precise DO prediction in aquaculture.

The operation effects of a source-side carbon capture power plant (CCPP) and power-to-gas (P2G) equipment do not match. The response range of the load-side traditional demand response strategy is small, and the adjustment period is limited, which leads to the problem that the complementary potential of low-carbon characteristics on both sides of the source and load is not fully utilized. This article proposes an electricity–heat coupling system scheduling strategy considering the complementary low-carbon characteristics of “source-load.” First, the low-carbon operation characteristics of CCPP and P2G with integrated, flexible operations are analyzed, and a source-side CCPP-P2G comprehensive flexible operation mode is proposed. Second, based on the characteristics of flexible adjustment and mutual substitution of electricity and heat load, a load-side comprehensive demand response method is proposed. Finally, the complementary mechanism of low-carbon characteristics on both sides of the source and load is analyzed, and a low-carbon economic dispatch model of the electricity–heat coupling system is constructed to realize the source–load collaborative low-carbon operations. The simulation analysis verifies that the proposed strategy can give full play to the energy time shift advantages of the source-side CCPP and P2G and improve the economic and environmental benefits of the system operations.

From the molecular to the cellular to the tissue level, vascular aging is regulated by a complex network involving numerous mechanisms and diseases, and our knowledge of any one level is incomplete and biased. To date, due to the diversity and complexity of the influencing factors, no international standard has been established. Therefore, in this study, we aimed to analyze the global research trends and potential hotspots related to vascular aging. We extracted the relevant publications between January 2003 and December 2023 from the Web of Science Core Collection. VOSviewer and CiteSpace software were used to quantitatively and qualitatively analyze the authors, countries, institutions, and journals in the field of vascular aging. The total number of publications on vascular aging between January 2003 and December 2023 was 1044, showing a steady increase. The United States and the University of Oklahoma published the highest number of research papers in the field. Ungvari Zoltan from the University of Oklahoma was the most productive author (47 papers) on vascular aging, specializing in endothelial cell failure, microcirculation, and aging. Burst detection of keywords revealed that endothelial dysfunction and vascular smooth muscle cells had the highest burst strength, suggesting that these are the current research hot spots in vascular aging research. In conclusion, senescence-associated secretory phenotype, reactive oxygen species, genetic instability, and an imbalance of protein homeostasis, trigger an inflammatory response that affects vascular endothelial and smooth muscle cell function, ultimately leading to vascular aging. This research provides insights into recent advances and preventive strategies in the field of vascular aging.