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Abstract Crystalline-silicon heterojunction back contact solar cells represent the forefront of photovoltaic technology, but encounter significant challenges in managing charge carrier recombination and transport to achieve high efficiency. In this study, we produced highly efficient heterojunction back contact solar cells with a certified efficiency of 27.09% using a laser patterning technique. Our findings indicate that recombination losses primarily arise from the hole-selective contact region and polarity boundaries. We propose solutions to these issues and establish a clear relationship between contact resistivity, series resistance, and the design of the rear-side pattern. Furthermore, we demonstrate that the wafer edge becomes the main channel for current density loss caused by carrier recombination once electrical shading around the electron-selective contact region is mitigated. With the advanced nanocrystalline passivating contact, wafer edge passivation technologies and meticulous optimization of front anti-reflection coating and rear reflector, achieving efficiencies as high as 27.7% is feasible.

Abstract Background This study aimed to explore the clinical value of 3D video-assisted thoracoscopic surgery in dissecting recurrent laryngeal nerve lymph nodes in patients undergoing minimally invasive esophagectomy. Methods A retrospective cohort study was conducted on 205 patients, including 120 males, who underwent esophagectomy from May 2018 to May 2020 in the Department of Thoracic Surgery at the Affiliated Huai’an No.1 People’s Hospital of Nanjing Medical University. Perioperative parameters, including intraoperative blood loss, operation time, the number of dissected recurrent laryngeal nerve lymph nodes, the incidence and degree of postoperative recurrent laryngeal nerve injury, the volume of postoperative thoracic drainage, and postoperative complications, were compared between the 3D and 2D groups. Results There were no significant differences in the preoperative baseline data between these two groups (P > 0.05). The number of dissected recurrent laryngeal nerve lymph nodes in the 3D group was significantly higher than in the 2D group (P

Abstract Background Bacteriophage has been renewed attention as a new antibacterial agent due to the limitations of antibiotic treatment. Bacteriophages are generally thought to be highly host specific and even strain specific, but a small number of polyvalent bacteriophages have been found to infect bacteria of different genera. Results In this study, a virulent lytic bacteriophage (named Salmonella phage PSH-1) of Salmonella Enteritidis was isolated from the sewage samples of a large-scale pig farm, PSH-1 demonstrated lytic activity against four multidrug-resistant Salmonella Enteritidis isolates and Escherichia coli, and then its biological characteristics, genome and bacteriostatic ability were investigated. The results showed that the initial titer of PSH-1 was 1.15 × 1010 PFU/mL and the optimal multiplicity of infection (MOI) was 0.01, PSH-1 has stable activity in the range of pH 3.0–11.0. One-step growth curve showed that its latent period was 20 min, burst time was 80 min, and the burst was 495 particles. The whole-genome sequencing results revealed phage PSH-1 had a linear dsDNA with 48,466 bp length. The G/C content was 45.33%. Non-coding RNA genes and virulence factors were not found. Eighty- five open reading frames (ORFs) were identified after online annotation. By tests, the use of phage could succeed in controlling the artificial Salmonella contamination in milk at a range of temperatures. Conclusions This study reports a novel Salmonella Enteritidis phage PSH-1, which has a robust lytic ability, no virulence factors, and good stability. The characterization and genomic analysis of PSH-1 will develop our understanding of phage biology and diversity and provide a potential arsenal for controlling of salmonellosis.

Abstract Electromagnetic fields (EMFs) have emerged as an effective treatment for osteoporosis. However, the specific mechanism underlying their therapeutic efficacy remains controversial. Herein, we confirm the pro-osteogenic effects of 15 Hz and 0.4-1 mT low-frequency sinusoidal EMFs (SEMFs) on rat bone marrow mesenchymal stem cells (BMSCs). Subsequent miRNA sequencing reveal that miR-34b-5p is downregulated in both the 0.4 mT and 1 mT SEMFs-stimulated groups. To clarify the role of miR-34b-5p in osteogenesis, BMSCs are transfected separately with miR-34b-5p mimic and inhibitor. The results indicate that miR-34b-5p mimic transfection suppress osteogenic differentiation, whereas inhibition of miR-34b-5p promote osteogenic differentiation of BMSCs. In vivo assessments using microcomputed tomography, H&E staining, and Masson staining show that miR-34b-5p inhibitor injections alleviate bone mass loss and trabecular microstructure deterioration in ovariectomy (OVX) rats. Further validation demonstrates that miR-34b-5p exerts its effects by regulating STAC2 expression. Modulating the miR-34b-5p/STAC2 axis attenuate the pro-osteogenic effects of low-frequency SEMFs on BMSCs. These studies indicate that the pro-osteogenic effect of SEMFs is partly due to the regulation of the miR-34b-5p/STAC2 pathway, which provides a potential therapeutic candidate for osteoporosis.

Abstract Background The global prevalence of overweight and obesity in children under the age of five has emerged as a significant issue in recent years. Physical activity and fitness among children and adolescents have declined globally in the past few decades. Studies have indicated a link between levels of physical activity and cognitive performance in preschool children. Methods This quasi-experimental study investigated the effects of three different types of physical education programmes on the physical fitness and emotional competence of 239 preschoolers(mean age = 5.49 ± 0.60 years, 54.4% boys)in Haikou, China. The preschoolers were grouped based on which programme they were assigned to: the “Hello Sunshine” ball skills programme (HS group), ordinary physical education (OPE group), and free play (FP group). The “Hello Sunshine” ball skills programme used both a structured curriculum design and autonomous activity selection during outdoor time., which were conducive to children’s physical fitness.The National Physical Fitness Measurement Standards Manual and the shortened version of the Social Competence and Behavior Evaluation Scale (SCBE-30) were used to assess physical fitness and emotional competence, respectively. These assessments were conducted both before and after the ten-week intervention period. The analysis utilised a mixed-effects model for physical fitness and a mixed-model ANOVA for the SCBE data. Results The HS group and OPE group demonstrated significantly improvement in the standing long jump, 10-m shuttle run and balance beam walking than the FP group; meanwhile, only anxious-withdrawal levels showed a significant grouping effect and group-by-time interaction effect. After the intervention, both the HS group and the FP group showed significantly lower scores for anxiety compared to the OPE group, with no significant difference observed between the HS and FP groups. Conclusions The results suggested that structured ball skills programmes may promote physical fitness and reduce anxiety. The integration of effective physical exercise programmes into preschool curricula holds the potential for promoting holistic development.

Abstract Background Intervertebral disc degeneration (IVDD) is a common spine disease with inflammation as its main pathogenesis. Mulberroside A (MA), isolated from herbal medicine, possesses anti-inflammatory characteristics in many diseases. Whereas, there is little exploration of the therapeutic potential of MA on IVDD. This study aimed at the therapeutic potential of MA on IVDD in vivo and in vitro and the mechanism involved. Methods In vitro, western blotting, RT-qPCR, and immunofluorescence analysis were implemented to explore the bioactivity of MA on interleukin-1 beta (IL-1β)-induced inflammation nucleus pulposus cells (NPCs) isolated from Sprague-Dawley male rats. In vivo, X-ray and MRI were applied to measure the morphological changes, and histological staining and immunohistochemistry were employed to investigate the histological changes of intervertebral disc sections on puncture-induced IVDD rat models. Results In vitro, MA up-regulated the expression level of anabolic-related proteins (Aggrecan and Collagen II) and decreased catabolic-related proteins (Mmp2, Mmp3, Mmp9, and Mmp13) in IL-1β-induced NPCs. Furthermore, MA inhibits the production of pro-inflammatory factors (Inos, Cox-2, and Il-6) stimulated by IL-1β. Mechanistically, MA inhibited the signal transduction of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) pathways in IL-1β-induced NPCs. Moreover, MA might bind to Ppar-γ and then suppress the NF-kB pathway. In vivo experiment illustrated that MA mitigates the IVDD progression in puncture-induced IVDD model. X-ray and MRI images showed MA restore the disc height and T2-weighted signal intensity after puncturing. H&E and Safranin O/Fast Green also showed MA also alleviated morphological changes caused by acupuncture. In addition, MA reversed the expression level of Mmp13, Aggrecan, Collagen II, and Ppar-γ induced in IVDD models. Conclusions MA inhibited degenerative phenotypes in NPCs and alleviated IVDD progression via inhibiting the MAPK and NF-κB pathways; besides, MA suppressed the NF-κB pathway was attributed to activating Ppar-γ, those supported that MA or Ppar-γ might be a potential drug or target for IVDD.

Abstract To study the degradation of lncRNAs in EPMI in rat brain tissue, this study provides a new direction for the estimation of EPMI. LncRNA high-throughput sequencing was performed on the brain tissues of hemorrhagic shock model rats at 0 h and 24 h, and the target lncRNAs were screened. Samples at 0, 1, 3, 6, 12, 18 and 24 h after death were collected, and miRNA-9 and miRNA-125b were used as reference genes. The relative expression levels of lncRNAs at each PMI were detected by RT–qPCR, and a functional model involving lncRNAs and EPMI was established. Samples were collected at 6, 9, 15, and 21 h after death for functional model verification. The expression of several lncRNAs decreased with the prolongation of EPMI, and the mathematical model established by several lncRNA indices exhibited good fit. The verification results of the multi-index joint function model are significantly better than those of the single-index function model, and the established model is more practical. There is a linear relationship between lncRNAs and EPMI, and the multi-index function model is significantly better than the single-index function model, which is important for EPMI inference in forensic pathology practice.

This is an article in the field of mineral processing engineering. The opper polymetallic ore in a high-altitude mining area in Xizang has a high oxidation rate and complex ore properties. In order to make full, efficient and comprehensive use of mineral resources, this article analyzes and studies the mineral properties and characteristics of the raw ore based on theory and practical experience. Finally, the flotation process with JM-1 sulfide agent, ZJ-1 collector, copper, lead and zinc mixed flotation of "sulfur before oxygen" as the key technology is determined. At the condition that the copper oxidation rate of the raw ore is 38.58%, the mixed concentrate grade sum of lead and zinc is 41.17%, and the recovery of copper, lead and zinc is 58.74%, 80.71% and 70.82%, respectively, after two roughing, three cleaning and two scavenging processes, which greatly improves the utilization effect and technical level of dressing. It also provides technical support and favorable basis for the improvement and innovation of mineral processing technology in the later stage.

Abstract Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy. Targeted radionuclide therapy delivers radiation directly to tumor sites. LNC1004 is a fibroblast activation protein (FAP)-targeting radiopharmaceutical, conjugated with the albumin binder Evans Blue, which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies. Herein, we demonstrate that 68Ga/177Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts. Radionuclide therapy with 177Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells. The combination of 177Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice, with mice showing 100% tumor rejection upon rechallenge. Immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication, CD8+ T-cell activation and expansion, M1 macrophage counts, antitumor activity of neutrophils, and T-cell receptor diversity. A preliminary clinical study demonstrated that 177Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers. Further, scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment. This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation. In conclusion, our data supported the efficacy of immunotherapy combined with 177Lu-LNC1004 for cancer patients with FAP-positive tumors.

Objective: To explore the effect of fucoidan on esophageal cancer and analyze its mechanism. Methods: MTT assay was used to analyze the inhibition rate of cell proliferation, Hoechst33258 staining and flow cytometry were used to detect cell apoptosis, and DCFH-DA probe was used to detect ROS level, and Western blot was used to analyze levels of Nrf2, HO-1, NQO-1, Bcl-2, Bax and caspase-3, which were used to observe its effects on fucoidan-regulated cell proliferation and Nrf2/ROS signaling pathway. The tumor formation experiment in nude mice verified the effects of fucoidan on tumor weight, tumor volume and levels of Nrf2, HO-1 and NQO-1 in nude mice. Results: The proliferation of ECA109 cells was significantly inhibited by fucoidan from 1 to 16 µg/mL, and the IC50 was 3.26 µg/mL at 48 h. Compared with the control group (0.1%DMSO), ECA109 cells treated with 1, 2, and 4 µg/mL fucoidan showed obvious apoptotic characteristics, such as nuclear condensation, irregular chromatin contraction and apoptotic bodies, which (extremely) significantly promoted the apoptosis of ECA109 cells and significantly down-regulated the expression level of Bcl-2.The expression levels of Bax and Cleaved-caspase-3 were significantly increased, ROS levels were significantly increased, and Nrf2, HO-1, and NQO-1 protein levels were significantly decreased (P

ABSTRACT Hantaviruses are rodent-borne viruses that cause severe disease in infected humans. In the New World, major hantaviruses include Andes virus (ANDV) and Sin Nombre virus (SNV) causing hantavirus pulmonary syndrome. In the Old World, major hantaviruses include Hantaan virus (HTNV) and Puumala virus (PUUV) causing hemorrhagic fever with renal syndrome. Here, we produced a pan-hantavirus therapeutic (SAB-163) comprised of fully human immunoglobulin purified from the plasma of transchromosomic bovines (TcB) vaccinated with hantavirus DNA plasmids coding for the major glycoproteins of ANDV, SNV, HTNV, and PUUV. SAB-163 has potent neutralizing antibodies (PRNT50 > 200,000) against the four targeted hantavirus and cross-neutralization against several other heterotypic hantaviruses. At a dosage of 10 mg/kg, SAB-163 is bioavailable in Syrian hamsters out to 70 days post-treatment with a half-life of 10–15 days. At this same dosage, SAB-163 administered 1 day before, or 5 days after exposure, protected all hamsters from lethal disease caused by ANDV. At a higher dose, partial but significant protection was achieved as late as day 6. SAB-163 also protected hamsters in the HTNV, PUUV, and SNV infection models when administered 1 day before or up to 3 days after challenge. This pan-hantavirus therapeutic is attractive because it is fully human, multi-targeted, safe, stable at 4°C, and effective in animal models. SAB-163 was evaluated for safety in GLP human tissue binding studies and a GLP rabbit toxicity study at 365 and 730 mg/kg and is investigational new drug enabled for phase 1 clinical trial(s).IMPORTANCEThis candidate polyclonal human IgG product was produced using synthetic gene-based vaccines and transgenic cows. Having now gone through cGMP production, GLP safety testing, and efficacy testing in animals, SAB-163 is the world’s most advanced anti-hantavirus antibody-based medical countermeasure, aside from convalescent human plasma. Importantly, SAB-163 targets the most prevalent hantaviruses on four continents.

The emergence of multidrug-resistant Pseudomonas aeruginosa isolates is a growing concern for public health, necessitating new therapeutic strategies. Gallium nitrate [Ga(NO3)3], a medication for cancer-related hypercalcemia, has attracted great attention due to its ability to inhibit P. aeruginosa growth and biofilm formation by disrupting iron metabolism. However, the antibacterial efficacy of Ga(NO3)3 is not always satisfactory. It is imperative to investigate the factors that affect the bactericidal effects of Ga(NO3)3 and to identify new ways to enhance its efficacy. This study focused on the impact of pH on P. aeruginosa resistance to Ga(NO3)3, along with the underlying mechanism. The results indicate that acidic conditions could increase the effectiveness of Ga(NO3)3 against P. aeruginosa by promoting the production of pyochelin and gallium uptake. Subsequently, using glutamic acid, a clinically compatible acidic amino acid, the pH was significantly lowered and enhanced the bactericidal and inhibitory efficacy of Ga(NO3)3 against biofilm formation by P. aeruginosa, including a reference strain PA14 and several multidrug-resistant clinical isolates. Furthermore, we used an abscess mouse model to evaluate this combination in vivo; the results show that the combination of glutamic acid and Ga(NO3)3 significantly improved P. aeruginosa clearance. Overall, the present study demonstrates that acidic conditions can increase the sensitivity of P. aeruginosa to Ga(NO3)3. Combining glutamic acid and Ga(NO3)3 is a potential strategy for the treatment of P. aeruginosa infections.

The excessive application and loss of pesticides poses a great risk to the ecosystem, and the environmental safety assessment of pesticides is time-consuming and expensive using traditional animal toxicity tests. In this work, a pesticide acute toxicity dataset was created for silkworm integrating extensive experiments and various common pesticide formulations considering the sensitivity of silkworm to adverse environment, its economic value in China, and a gap in machine learning (ML) research on the toxicity prediction of this species, which addressed the previous limitation of only being able to predict toxicity classification without specific toxicity values. A new comprehensive voting model (CVR) was developed based on ML, combined with three regression algorithms, namely, Bayesian Ridge (BR), K Neighbors Regressor (KNN), Random Forest Regressor (RF) to accurately calculate lethal concentration 50 % (LC50). Three conformal models were successfully constructed, marking the first combination of conformal models with confidence intervals to predict silkworm toxicity. Further, the mechanism by analyzing structural alerts was summarized, and identified 25 warning structures, 24 positive compounds and 14 negative compounds. Importantly, a novel comprehensive prediction system was constructed that can provide LC50 and confidence intervals, structural alerts analysis, lipid-water partition coefficient (LogP) and similarity analysis, which can comprehensively evaluate the ecological toxicity risk of substances to make up for the incomplete toxicity data of new pesticides. The validity and generalization of the CVR model were verified by an external validation set. In addition, five new, low-toxic and green pesticide alternatives were designed through 50,000 cycles. Moreover, our software and ST Profiler can provide low-cost information access to accelerate environmental risk assessment, which can predict not only a single chemical, but also batches of chemicals, simply by inputting the SMILES / CAS / (Chinese / English) name of chemicals.

Abstract Excitonic systems, facilitated by optical pumping, electrostatic gating or magnetic field, sustain composite particles with fascinating physics. Although various intriguing excitonic phases have been revealed via global measurements, the atomic-scale accessibility towards excitons has yet to be established. Here, we realize the ground-state interlayer exciton complexes through the intrinsic charge transfer in monolayer YbCl3/graphite heterostructure. Combining scanning tunneling microscope and theoretical calculations, the excitonic in-gap states are directly profiled. The out-of-plane excitonic charge clouds exhibit oscillating Rydberg nodal structure, while their in-plane arrangements are determined by moiré periodicity. Exploiting the tunneling probe to reflect the shape of charge clouds, we reveal the principal quantum number hierarchy of Rydberg series, which points to an excitonic energy-level configuration with unusually large binding energy. Our results demonstrate the feasibility of mapping out the charge clouds of excitons microscopically and pave a brand-new way to directly investigate the nanoscale order of exotic correlated phases.

Abstract Background The repair of peripheral nerve injury poses a clinical challenge, necessitating further investigation into novel therapeutic approaches. In recent years, bone marrow mesenchymal stromal cell (MSC)-derived mitochondrial transfer has emerged as a promising therapy for cellular injury, with reported applications in central nerve injury. However, its potential therapeutic effect on peripheral nerve injury remains unclear. Methods We established a mouse sciatic nerve crush injury model. Mitochondria extracted from MSCs were intraneurally injected into the injured sciatic nerves. Axonal regeneration was observed through whole-mount nerve imaging. The dorsal root ganglions (DRGs) corresponding to the injured nerve were harvested to test the gene expression, reactive oxygen species (ROS) levels, as well as the degree and location of DNA double strand breaks (DSBs). Results The in vivo experiments showed that the mitochondrial injection therapy effectively promoted axon regeneration in injured sciatic nerves. Four days after injection of fluorescently labeled mitochondria into the injured nerves, fluorescently labeled mitochondria were detected in the corresponding DRGs. RNA-seq and qPCR results showed that the mitochondrial injection therapy enhanced the expression of Atf3 and other regeneration-associated genes in DRG neurons. Knocking down of Atf3 in DRGs by siRNA could diminish the therapeutic effect of mitochondrial injection. Subsequent experiments showed that mitochondrial injection therapy could increase the levels of ROS and DSBs in injury-associated DRG neurons, with this increase being correlated with Atf3 expression. ChIP and Co-IP experiments revealed an elevation of DSB levels within the transcription initiation region of the Atf3 gene following mitochondrial injection therapy, while also demonstrating a spatial proximity between mitochondria-induced DSBs and CTCF binding sites. Conclusion These findings suggest that MSC-derived mitochondria injected into the injured nerves can be retrogradely transferred to DRG neuron somas via axoplasmic transport, and increase the DSBs at the transcription initiation regions of the Atf3 gene through ROS accumulation, which rapidly release the CTCF-mediated topological constraints on chromatin interactions. This process may enhance spatial interactions between the Atf3 promoter and enhancer, ultimately promoting Atf3 expression. The up-regulation of Atf3 induced by mitochondria further promotes the expression of downstream regeneration-associated genes and facilitates axon regeneration.

IntroductionRecent studies have emphasized the intricate connection between exercise and cognition, focusing on specific cognitive processes and their correlations with specific motor skills. However, research on the impact of the qualitative aspects of movement on both short- and long-term cognitive performance is limited. In this quasi-experimental study, we investigate the impact of a 10-week fancy rope-skipping intervention on motor coordination and selective attention of 7–9-year-old children.MethodsA total of 60 primary school students from Changbin School in Haikou participated and completed the study from October to December 2022. The 60 participants were divided into a fancy rope-skipping group and a control group. Children's motor coordination was assessed using the Körperkoordinations Test für Kinder (KTK), while selective attention was evaluated using the d2 Test of Attention. Children were assessed at baseline and after the 10-week intervention.ResultsCompared with the control group, the scores for the total KTK and for the hopping for height, jumping sideways, and moving sideways sub-items were significantly higher in the rope-skipping group after the intervention, with a significant interaction effect between time and intervention. Attention concentration improved in the rope-skipping group and had a significant interaction effect between time and intervention compared with the control group; the effects of the intervention on other aspects of selective attention were unclear.ConclusionsOur study suggests that a 10-week fancy rope-skipping intervention may potentially enhance motor coordination and selective attention accuracy in children aged 7–9 years.

IntroductionPseudomonas aeruginosa is a ubiquitous pathogen that causes various infectious diseases through the regulation of quorum sensing (QS). The strategy of interfering with the QS systems of P. aeruginosa, coupled with a reduction in the dosage of conventional antibiotics, presents a potential solution to treating infection and mitigating antibiotic resistance. In this study, seven cinnamoyl hydroxamates were synthesized to evaluate their inhibitory effects on QS of P. aeruginosa. Among these cinnamic acid derivatives, we found cinnamoyl hydroxamic acid (CHA) and 3-methoxy-cinnamoyl hydroxamic acid (MCHA) were the two most effective candidates. Furtherly, the effect of CHA and MCHA on the production of virulence factors and biofilm of P. aeruginosa were evaluated. Ultimately, our study may offer promising potential for treating P. aeruginosa infections and reducing its virulence.MethodsThe disc diffusion test were conducted to evaluate inhibitory effects on QS of seven cinnamoyl hydroxamates. The influence of CHA and MCHA on the production of virulence and flagellar motility of P. aeruginosa was furtherly explored. Scanning electron microscopy (SEM) experiment were conducted to evaluate the suppression of CHA and MCHA on the formed biofilm of P. aeruginosa. RT-qPCR was used to detect rhlI, lasA, lasB, rhlA, rhlB, and oprL genes in P. aeruginosa. In silico docking study was performed to explore the molecular mechanism of CHA and MCHA. The synergistic effects of CHA with gentamicin were detected on biofilm cell dispersal.ResultAfter treatment of CHA or MCHA, the production of multiple virulence factors, including pyocyanin, proteases, rhamnolipid, and siderophore, and swimming and swarming motilities in P. aeruginosa were inhibited significantly. And our results showed CHA and MCHA could eliminate the formed biofilm of P. aeruginosa. RT-qPCR revealed that CHA and MCHA inhibited the expression of QS related genes in P. aeruginosa. Molecular docking indicated that CHA and MCHA primarily inhibited the RhlI/R system in P. aeruginosa by competing with the cognate signaling molecule C4-HSL.Additionally, CHA exhibited potent synergistic effects with gentamicin on biofilm cell dispersal.DiscussionP. aeruginosa is one of the most clinically and epidemiologically important bacteria and a primary cause of catheter-related urinary tract infections and ventilator-associated pneumonia. This study aims to explore whether cinnamoyl hydroxamates have inhibitory effects on QS. And our results indicate that CHA and MCHA, as two novel QSIs, offer promising potential for treating P. aeruginosa infections and reducing its virulence.

Introduction: In the continuous advancement of urbanization, abandoned buildings are a huge challenge in achieving sustainable development goals. If these legacy buildings are not properly handled, they will cause a huge burden on society, economy, and the environment. Based on the material flow analysis method, an evaluation index system was constructed for legacy building resources, and a systematic study was conducted on the reuse pathways of their waste.Methods: This study focuses on the material flow, reuse pathways, and resource utilization strategies of legacy construction waste, aiming to improve the reuse efficiency of waste building materials and promote the achievement of sustainable development goals. In the study, indicator design was used to quantify the obstacles to the reuse of legacy construction waste, and social and economic costs were analyzed to ensure the comprehensiveness and scientificity of the research.Results: The experimental results show that the waste recycling rate under the implementation of this strategy reached 82.7%, and the resource utilization rate increased by 50.1%. For the obstacles to the reuse of construction waste, the network density reaches 0.052, and the overall network structure shows a lack of concentration, indicating that the current management methods for construction waste reuse have further optimization space.Discussion: The study effectively promotes the sustainable utilization of legacy buildings in cities, which is of great significance for improving the quality of urban space and promoting sustainable social development.

Abstract The efficient synthesis of chiral 2,2‐disubstituted indolin‐3‐ones is of great importance due to its significant synthetic and biological applications. However, catalytic enantioselective methods for de novo synthesis of such heterocycles remain scarce. Herein, a novel cyclizative rearrangement of readily available anilines and vicinal diketones for the one‐step construction of enantioenriched 2,2‐disubstituted indolin‐3‐ones is presented. The reaction proceeds through a self‐sorted [3+2] heteroannulation/regioselective dehydration/1,2‐ester shift process. Only chiral phosphoric acid is employed to promote the entire sequence and simplify the manipulation of this protocol. Various common aniline derivatives are successfully applied to asymmetric synthesis as 1,3‐binuclephiles for the first time. Remarkably, the observed stereoselectivity is proposed to originate from an amine‐directed regio‐ and enantioselective ortho‐Csp2‐H addition of the anilines to the ketones. A range of synthetic transformations of the resulting products are demonstrated as well.

Pregnant women are a special group that is sensitive to adverse external stimuli, causing metabolic abnormalities and adverse pregnancy outcomes. Microplastics (MPs), an environmental pollutant widely used in various fields, can induce a variety of toxic responses in mammals. Recent studies verified an association between MPs and metabolic disorders. Our research built a gestational mouse model in which polystyrene microplastics (PS-MPs) of 1 μm size were consumed at concentrations of 0.1, 1, and 10 mg/L during pregnancy. Results indicated that PS-MPs induced placental malfunction and fetal growth retardation. Significant glucose disorders, decreased liver function, hepatic inflammation, and oxidative stress were also observed after PS-MPs exposure. The hepatic SIRT1/IRS1/PI3K pathway was inhibited in the 10 mg/L PS-MPs exposure group. Our study found that PS-MPs activated inflammatory response and oxidative stress by increasing hepatic lipopolysaccharide (LPS) that inhibited the hepatic SIRT1/IRS1/PI3K pathway, ultimately leading to insulin resistance, glucose metabolism disorders, and adverse pregnancy outcomes. This study provides a basis for preventing environment-related gestational diabetes and concomitant adverse pregnancy outcomes.

Objective To investigate the effects of 12-week weight-bearing dance aerobics (WBDA) on muscle morphology, strength and functional fitness in older women. Methods This controlled study recruited 37 female participants (66.31y ± 3.83) and divided them into intervention and control groups according to willingness. The intervention group received 90-min WBDA thrice a week for 12 weeks, while the control group maintained normal activities. The groups were then compared by measuring muscle thickness, fiber length and pennation angle by ultrasound, muscle strength using an isokinetic multi-joint module and functional fitness, such as 2-min step test, 30-s chair stand, chair sit-and-reach, TUG and single-legged closed-eyed standing test. The morphology, strength, and functional fitness were compared using ANCOVA or Mann-Whitney U test to study the effects of 12 weeks WBDA. Results Among all recruited participants, 33 completed all tests. After 12 weeks, the thickness of the vastus intermedius (F = 17.85, P < 0.01) and quadriceps (F = 15.62, P < 0.01) was significantly increased in the intervention group compared to the control group, along with a significant increase in the torque/weight of the knee flexor muscles (F = 4.47, P = 0.04). Similarly, the intervention group revealed a significant improvement in the single-legged closed-eyed standing test (z = −2.16, P = 0.03) compared to the control group. Conclusion The study concluded that compared to the non-exercising control group, 12-week WBDA was shown to thicken vastus intermedius, increase muscle strength, and improve physical function in older women. In addition, this study provides a reference exercise program for older women.

Abstract Background Intervertebral disk degeneration (IVDD) is a common spine disease, and inflammation is considered to be one of its main pathogenesis. Apigetrin (API) is a natural bioactive flavonoid isolated from various herbal medicines and shows attractive anti‐inflammatory and antioxidative properties; whereas, there is no exploration of the therapeutic potential of API on IVDD. Here, we aim to explore the potential role of API on IVDD in vivo and in vitro. Methods In vitro, western blotting, real‐time quantitative polymerase chain reaction, and immunofluorescence analysis were implemented to explore the bioactivity of API on interleukin‐1 beta (IL‐1β)‐induced inflammatory changes in nucleus pulposus cells (NPCs). In vivo, histological staining and immunohistochemistry were employed to investigate the histological changes of intervertebral disk sections on puncture‐induced IVDD rat models. Results In vitro, API played a crucial role in anti‐inflammation and autophagy enhancement in IL‐1β‐induced NPCs. API improved inflammation by inhibiting the nuclear factor‐kappaB and mitogen‐activated protein kinas pathways, whereas it promoted autophagy via the phosphatidylinositol 3‐kinase/AKT/mammalian target of the rapamycin pathway. Furthermore, in vivo experiment illustrated that API mitigates the IVDD progression in puncture‐induced IVDD model. Conclusions API inhibited degenerative phenotypes and promoted autophagy in vivo and in vitro IVDD models. Those suggested that API might be a potential drug or target for IVDD.

Advanced stages of breast cancer are frequently complicated by bone metastases, which cause significant cancer-related bone destruction and mortality. However, the early precise theranostics of bone metastasis remains a formidable challenge in clinical practice. Herein,a novel all-in-one nanotheranostic system (ABI NYs) combining NIR-II FL/PA dual-modal imaging with photothermal-immunity therapeutic functionalities in one component was designed to precisely localize bone metastasis microscopic lesions and achieve complete tumor ablation at an early stage. The surface modification of the nanosystem with ibandronate (IBN) facilitates both passive and active targeting, significantly improving the detection rate of bone metastasis and suppressing the bone resorption. Superior photothermal performance produces sufficient heat to kill tumor cells while stimulating the upregulation of heat shock proteins 70 (HSP70), which triggers the immunogenic cell death (ICD) effect and the anti-tumor immune response. These all-in-one nanosystems precisely demonstrated early lesion localization in bone metastases and total tumor ablation with a single integration via “one-component, multi-functions” technique. To sum up, ABI NYs, as novel biomineralizing nanosystems integrated with anti-tumor and bone repair, present a synergistic therapy strategy, providing insight into the theranostics of bone metastases and clinical research.

Abstract Quinoline‐based fibroblast activation protein (FAP) inhibitor (FAPI)‐based positron emission tomography (PET) imaging and radioligand therapy (RLT) are being investigated for use in a wide variety of diseases, and recent results have been promising. This review summarizes the current status of FAPI radiopharmaceuticals in PET imaging of malignant tumors and benign conditions and compares their diagnostic efficacy with 18F‐fluorodeoxyglucose. In addition, we summarize the previously published FAP‐targeted RLT data and discuss its current clinical use and future potential. Our qualitative summary can inform future research directions, medical guidelines, and optimal clinical decision‐making.

Background/Objectives: Osteoarthritis (OA) is a prevalent degenerative disease globally, characterized by cartilage degradation and joint dysfunction. Current treatments are insufficient for halting OA progression. Irigenin (IRI), a flavonoid extracted from natural plants with anti-inflammatory and antioxidant properties, has demonstrated potential in mitigating inflammation and oxidative stress in various diseases; however, its effects on OA remain unexplored. This study aims to evaluate the therapeutic effects of IRI on OA through in vivo and in vitro experiments and to elucidate the underlying molecular mechanisms. Methods: In vitro, chondrocytes were exposed to hydrogen peroxide (H2O2) to induce an oxidative stress environment and were then treated with IRI. Western blotting, RT-qPCR, immunofluorescence staining assays, flow cytometry, and apoptosis assays were employed to assess the effects of IRI on chondrocyte matrix homeostasis, inflammatory response, and apoptosis. In vivo, an OA rat model was treated with regular IRI injections, and therapeutic effects were evaluated using micro-CT, histological staining, and immunohistochemistry assays. Results: IRI treatment restored matrix homeostasis in chondrocytes and effectively suppressed H2O2-induced inflammation and apoptosis. Subsequent studies further revealed that IRI exerts its therapeutic effects by activating the Nrf2/HO-1 pathway. Inhibition of Nrf2 expression in chondrocytes partially blocked the anti-inflammatory and antioxidant effects of IRI. In the OA rat model, regular IRI injections effectively ameliorated cartilage degeneration. Conclusions: This study identifies IRI as a promising strategy for OA treatment by modulating inflammation and apoptosis through the Nrf2/HO-1 pathway.

Background This study aims to examine the relationship between functional movements and golf performance using the Golf Specific Functional Movement Screen (GSFMS). Methods This cross-sectional study included a total of 56 collegiate golfers (aged 20.89 ± 0.99 years, height of 174.55 ± 7.76 cm, and weight 68.48 ± 9.30 kg) who met the criteria, and were recruited from Hainan Normal University in June 2022. The participants’ golf motor skills (1-yard putt, 10-yard putt, 25-yard chip, 130/100-yard set shot, driver, and 9-hole stroke play) were tested and the GSFMS (e.g., pelvic tilt, pelvic rotation, and torso rotation) was used. Results There were significant weak or moderate correlations between the variables. Furthermore, a multiple linear regression analysis found that pelvic rotation and lower-body rotation abilities can significantly predict golf skill levels, which collectively explain 31.2% of the variance in golf skill levels among collegiate golfers (Adjusted R2 = 0.312, F = 2.663, p < 0.05). Standardised β values indicate that pelvic rotation (β = 0.398) has a more substantial impact on golf skill levels than lower-body rotation (β = 0.315). Conclusions This study found the weak to moderate correlations between the GSFMS and golf performance, and pelvic rotation and lower-body rotation abilities, thus predicting golf skills. Our findings provide novel insights into the relationship between functional abilities and comprehensive skill performance within the context of the Gray Cook’s Movement Pyramid model, and provide theoretical support and practical reference for collegiate golf motor-skill learning and sports injury prevention.

IntroductionConsiderable evidence has unveiled a potential correlation between gut microbiota and spinal degenerative diseases. However, only limited studies have reported the direct association between gut microbiota and spinal stenosis. Hence, in this study, we aimed to clarify this relationship using a two-sample mendelian randomization (MR) approach.Materials and MethodsData for two-sample MR studies was collected and summarized from genome-wide association studies (GWAS) of gut microbiota (MiBioGen, n = 13, 266) and spinal stenosis (FinnGen Biobank, 9, 169 cases and 164, 682 controls). The inverse variance-weighted meta-analysis (IVW), complemented with weighted median, MR-Egger, weighted mode, and simple mode, was used to elucidate the causality between gut microbiota and spinal stenosis. In addition, we employed mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and the MR-Egger intercept test to assess horizontal multiplicity. Cochran’s Q test to evaluate heterogeneity, and “leave-one-out” sensitivity analysis to determine the reliability of causality. Finally, an inverse MR analysis was performed to assess the reverse causality.ResultsThe IVW results indicated that two gut microbial taxa, the genus Eubacterium fissicatena group and the genus Oxalobacter, have a potential causal relationship with spinal stenosis. Moreover, eight potential associations between genetic liability of the gut microbiota and spinal stenosis were implied. No significant heterogeneity of instrumental variables or horizontal pleiotropy were detected. In addition, “leave-one-out” sensitivity analysis confirmed the reliability of causality. Finally, the reverse MR analysis revealed that no proof to substantiate the discernible causative relationship between spinal stenosis and gut microbiota.ConclusionThis analysis demonstrated a possible causal relationship between certain particular gut microbiota and the occurrence of spinal stenosis. Further studies focused on the mechanism of gut microbiota-mediated spinal stenosis can lay the groundwork for targeted prevention, monitoring, and treatment of spinal stenosis.

BackgroundAutosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized primarily by congenital microcephaly and intellectual disability but without extra-central nervous system malformations. This investigation aimed to elucidate the genetic underpinnings of microcephaly in a patient from a Chinese consanguineous family.MethodsA comprehensive clinical assessment, including brain magnetic resonance imaging (MRI), electroencephalogram (EEG), and genetic analyses, was conducted to evaluate the patient’s condition. Whole-exome sequencing (WES) was employed to identify the causative gene, followed by Sanger sequencing, to confirm the mutation and its segregation within the family. Reverse transcript polymerase chain reaction (RT-PCR) was utilized to detect changes in splicing. Western blot was employed to reveal the difference of protein expression level between the wild-type and mutant WDR62 in vitro.ResultsThe patient exhibited classic MCPH symptoms, including microcephaly, recurrent epilepsy, delayed psychomotor development, and intellectual disability. Additionally, asymmetrical limb length was noted as a prominent feature. MRI findings indicated reduced brain volume with cortical malformations, while EEG demonstrated heightened sharp wave activity. A molecular analysis uncovered a novel homozygous variant c.4154–6 C > G in the WDR62 intron, and a functional analysis confirmed the pathogenicity of this mutation, resulting in the formation of an abnormal transcript with premature termination codons.ConclusionThis study enhances our understanding of the genetic heterogeneity associated with MCPH and highlights the pivotal role of genetic testing in the diagnosing and managing of rare neurodevelopmental disorders. Furthermore, it highlights the potential of emerging genetic therapies in treating conditions such as MCPH2.

Abstract Esophageal cancer is a highly malignant disease with poor prognosis. Despite recent advances in the study of esophageal cancer, there has been only limited improvement in the treatment and prognosis. N6-methyladenosine (m6A), a type of RNA modification, has been extensively investigated and is involved in many biological behaviors, including tumorigenesis and progression. Thus, more research on m6A modification may increase our understanding of esophageal cancer pathogenesis and provide potential targets. In our study, we integrated the public data of esophageal cancer from The Cancer Genome Atlas (TCGA) and Gene-Expression Omnibus (GEO) databases. Unsupervised clustering analysis was used to classify patients into different groups. Gene set variation analysis (GSVA) was performed in a nonparametric and unsupervised mode. We evaluated immune cell infiltration by single sample gene set enrichment analysis (ssGSEA). Differentially expressed genes (DEGs) among m6A clusters were identified using Empirical Bayesian approach. Both multivariate and univariate Cox regression models were used for prognostic analysis. We provided an overview of gene variation and expression of 23 m6A regulators in esophageal cancer, as well as their effects on survival. Based on the overall expression level of m6A regulators, patients were classified into three m6A clusters (A-C) with different immune cell infiltration abundance, gene expression signatures and prognosis. Among m6A clusters, we identified 206 DEGs, according to which patients were classified into 4 gene clusters (A-D). Quantitative m6A score was calculated for each patient based on those DEGs with significant impact on survival. The infiltration of all types of immune cells except type 2 T helper (Th2) cells were negatively correlated with m6A score. M6Acluster C exhibited the lowest m6A score, the most abundant immune cell infiltration, and the worst prognosis, suggesting an immune excluded phenotype. Consistently, gene cluster D with the lowest m6A score showed the worst prognosis. In short, patients with esophageal cancer showed different m6A modification patterns. Quantitative scoring indicated that patients with the lowest m6A score exhibited the most abundant immune cell infiltration and the poorest prognosis. This m6A scoring system is promising to assess m6A modification pattern, characterize immune infiltration and guide personalized treatment and prognostic prediction.

Abstract Background Suspension culture is widely used in the establishment of efficient plant regeneration systems, as well as in the mass production of plant secondary metabolites. However, the establishment of a suspension culture system of Cunninghamia lanceolata is genotype-dependent given that proembryogenic masses (PEMs) are prone to browning during this process in recalcitrant genotypes. Previously, we reported that the plant peptide hormone phytosulfokine (PSK) can tremendously decrease the hydrogen peroxide (H2O2) level and help to initiate somatic embryogenesis (SE) in recalcitrant C. lanceolata genotypes. However, to date, no studies have revealed whether or how PSK may contribute to the establishment of a suspension culture system in these recalcitrant genotypes. Results Here, we demonstrated that exogenous application of PSK effectively inhibited PEM browning during suspension culture in a recalcitrant genotype of C. lanceolata. Comparative time-series transcriptome profiling showed that redox homeostasis underwent drastic fluctuations when PEMs were cultured in liquid medium, while additional PSK treatment helped to maintain a relatively stable redox homeostasis. Interestingly, PSK seemed to have a dual effect on peroxidases (PRXs), with PSK simultaneously transcriptionally repressing ROS-producing PRXs and activating ROS-scavenging PRXs. Furthermore, determination of H2O2 and MDA content, as well as cell viability, showed that exogenous PSK treatment inhibited PEM browning and safeguarded PEM suspension culture by decreasing the H2O2 level and increasing PEM activity. Conclusions Collectively, these findings provide a valuable tool for the future establishment of large-scale C. lanceolata PEM suspension culture without genotype limitations.

Abstract Morpholines and morpholinones are important building blocks in organic synthesis and pharmacophores in medicinal chemistry, however, C3-disubstituted morpholines/morpholinones are extremely difficult to access. Here we show the ZnCl2-catalyzed cyclizative 1,2-rearrangement for the efficient synthesis of morpholinones bearing aza-quaternary stereocenters. A series of structurally diverse C3-disubstituted morpholin-2-ones which are difficultly accessible by existing methods were efficiently constructed from readily available two achiral linear compounds. Notably, mechanistic studies reveal that this reaction proceeds via an unusual sequence of direct formal [4 + 2] heteroannulation regioselectively delivering specific α-iminium/imine hemiacetals followed by a 1,2-esters or amides shift process, which is different from the reported mechanism of the aza-benzilic ester rearrangements.

In this paper, a quantitative ground risk assessment mechanism is proposed in which urban ground features are extracted based on high-resolution data in a satellite image when unmanned aerial vehicles (UAVs) operate in urban areas. Ground risk distributions are estimated and a risk map is constructed with a multi-layer method considering the comprehensive risk imposed by UAV operations. The urban ground feature extraction is first implemented by employing a K-Means clustering method to an actual satellite image. Five main categories of the ground features are classified, each of which is composed of several sub-categories. Three more layers are then obtained, which are a population density layer, a sheltering factor layer, and a ground obstacle layer. As a result, a three-dimensional (3D) risk map is formed with a high resolution of 1 m × 1 m × 5 m. For each unit in this risk map, three kinds of risk imposed by UAV operations are taken into account and calculated, which include the risk to pedestrians, risk to ground vehicles, and risk to ground properties. This paper also develops a method of the resolution conversion to accommodate different UAV operation requirements. Case study results indicate that the risk levels between the fifth and tenth layers of the generated 3D risk map are relatively low, making these altitudes quite suitable for UAV operations.

Abstract Ligamentum flavum hypertrophy (LFH) is the main physiological and pathological mechanism of lumbar spinal canal stenosis (LSCS). The specific mechanism for LFH has not been completely clarified. In this study, bioinformatic analysis, human ligamentum flavum (LF) tissues collection and analysis, and in vitro and in vivo experiments were conducted to explore the effect of decorin (DCN) on LFH pathogenesis. Here, we found that TGF-β1, collagen I, collagen III, α-SMA and fibronectin were significantly upregulated in hypertrophic LF samples. The DCN protein expression in hypertrophic LF samples was higher than that in non-LFH samples, but the difference was not significant. DCN inhibited the expression of TGF-β1-induced fibrosis-associated proteins in human LF cells, including collagen I, collagen III, α-SMA, and fibronectin. ELISAs showed that TGF-β1 can upregulate PINP and PIIINP in the cell supernatant, and this effect was inhibited after DCN administration. Mechanistic studies revealed that DCN suppressed TGF-β1-induced fibrosis by blocking the TGF-β1/SMAD3 signaling pathway. In addition, DCN ameliorated mechanical stress-induced LFH in vivo. In summary, our findings indicated that DCN ameliorated mechanical stress-induced LFH by antagonizing the TGF-β1/SMAD3 signaling pathway in vitro and in vivo. These findings imply that DCN is a potential therapeutic candidate for ligamentum flavum hypertrophy.

Rosa davurica Pall. var. davurica is a member of the plant family Rosaceae. Although R. davurica has high application value, its chloroplast genome sequence has not been reported. This study aims to reveal the genetic characteristics of the chloroplast genome of Rosa roxburghii. The length of its total chloroplast DNA is 156,971 bp, with 37.22% G/C content. Its chloroplast genome has two inverted repeat (IRa and IRb) regions totaling 26,051 bp which are separated by a large single copy (LSC) region of 86,032 bp and a small single copy (SSC) region of 18,837 bp. The genome contains 131 independent genes (86 protein-coding, 37 tRNA, and 8 rRNA), and there are 18 repeated genes within the IR region. Among these genes, 17 genes contained one or two introns. The phylogenetic analysis showed that R. davurica was relatively close to other Rosa species, such as the Rosa hybrid.

Pre-trained language models have achieved striking success in natural language processing (NLP), leading to a paradigm shift from supervised learning to pre-training followed by fine-tuning. The NLP community has witnessed a surge of research interest in improving pre-trained models. This article presents a comprehensive review of representative work and recent progress in the NLP field and introduces the taxonomy of pre-trained models. We first give a brief introduction of pre-trained models, followed by characteristic methods and frameworks. We then introduce and analyze the impact and challenges of pre-trained models and their downstream applications. Finally, we briefly conclude and address future research directions in this field.

Abstract Background Pipkin type III femoral head fractures are relatively rare injuries. Few studies have explored and described the treatment and outcomes of Pipkin type III femoral head fractures. The purpose of this study was to evaluate the efficacy of open reduction and internal fixation (ORIF) in treating Pipkin type III femoral head fractures. Methods We retrospectively reviewed 12 patients with Pipkin type III femoral head fractures who underwent ORIF from July 2010 and January 2018. The complications and reoperations were recorded. The visual analog scale (VAS) pain score, Harris hip score (HHS), Thompson–Epstein criteria, and SF-12 score [including the physical component summary (PCS) and the mental component summary (MCS)] were used for functional assessment. Results Among the 12 patients, ten were males and two were females, with a mean age of 34.2 ± 11.9 years. The median follow-up time was 6 years (range 4–8 years). Five patients (42%) developed osteonecrosis of the femoral head, and one patient (8%) developed nonunion. These six patients (50%) underwent total hip arthroplasty (THA). One patient (8%) developed heterotopic ossification and underwent ectopic bone excision; this patient also presented with post-traumatic arthritis. The mean final VAS pain score and HHS were 4.1 ± 3.1 points and 62.8 ± 24.4 points, respectively. According to the Thompson–Epstein criteria, there was one patient (8%) with excellent, four patients (33%) with good, one patient (8%) with fair, and six patients (50%) with poor outcomes. The PCS score and MCS score were 41.7 ± 34.7 points and 63.2 ± 14.5 points, respectively. Conclusion Limited by the high incidence of osteonecrosis of the femoral head, it is difficult to achieve satisfactory functional outcomes when treating Pipkin type III femoral head fractures using ORIF, and a primary THA may be considered. However, for younger patients, considering the survivorship of prosthesis, ORIF may be recommended with the proviso that the patient is fully informed of the high complication rate associated with this procedure. Level of evidence: IV.

Summary: Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARγ is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARγ interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor κB signaling. However, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing interleukin-6 (IL-6) levels in the TME and endowing macrophages with tumor-promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARγ to inhibit TRAF6-IL-6-STAT3 signaling. This study unravels lactate-driven macrophage function remodeling by inhibition of RARγ expression and highlights NDGA as a candidate compound for treating CRC.

Since SARS-CoV-2 emerged in late 2019, it spread from China to the rest of the world. An initial concern was the potential for vaccine- or antibody-dependent enhancement (ADE) of disease as had been reported with other coronaviruses. To evaluate this, we first developed a ferret model by exposing ferrets to SARS-CoV-2 by either mucosal inoculation (intranasal/oral/ocular) or inhalation using a small particle aerosol. Mucosal inoculation caused a mild fever and weight loss that resolved quickly; inoculation via either route resulted in virus shedding detected in the nares, throat, and rectum for 7-10 days post-infection. To evaluate the potential for ADE, we then inoculated groups of ferrets intravenously with 0.1, 0.5, or 1 mg/kg doses of a human polyclonal anti-SARS-CoV-2 IgG from hyper-immunized transchromosomic bovines (SAB-185). Twelve hours later, ferrets were challenged by mucosal inoculation with SARS-CoV-2. We found no significant differences in fever, weight loss, or viral shedding after infection between the three antibody groups or the controls. Signs of pathology in the lungs were noted in infected ferrets but no differences were found between control and antibody groups. The results of this study indicate that healthy, young adult ferrets of both sexes are a suitable model of mild COVID-19 and that low doses of specific IgG in SAB-185 are unlikely to enhance the disease caused by SARS-CoV-2.

BackgroundAnxiety and depression are common in patients with chronic obstructive pulmonary disease (COPD), especially older adult patients. This can complicate the disease progression and lead to increased clinical and economic burden. We sought to investigate the clinical and economic burdens associated with the presence of anxious and/or depressive symptoms among older adult COPD patients.MethodsWe screened 579 patients aged over 60 years and diagnosed with COPD via a lung function test following the 2017 Global Initiative Chronic Obstructive Lung Disease (GOLD) guidelines. Anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS) through face-to-face interviews at admission. Follow-up was conducted by telephone calls at 6, 12, 18, 24, and 36 months after discharge to assess clinical and economic burden. COPD-anxiety and/or depression patients were matched to patients without anxiety and depression (COPD-only) using propensity scores. Multivariate regression models were used to compare clinical and economic burden between COPD-anxiety and/or depression and COPD-only groups.ResultsCompared with COPD-only patients, COPD patients complicated with anxiety and/or depression had increased clinical burden, including higher COPD-related outpatient visits, COPD-related hospitalizations, and length of COPD-related hospitalizations (p

Purpose: To establish a high-performance liquid chromatography (HPLC) method that simultaneously monitors the concentrations of sulfamethoxazole (SMZ) and trimethoprim (TMP) in the plasma of patients with melioidosis during the intensive or eradication phase. Method: The study established and verified the feasibility of HPLC method using aminopyrine as an internal standardand trichloroacetic acid as precipitant to dilute the supernatant after plasma sample treatment and chromatographic separation by Acutfex YS-C8 column (4.6 × 250 mm, 5 µm) gradient elution. The mobile phase A consisted of 1000 mL of ultrapure water plus 2 mL of triethylamine with the pH adjusted to 6.0 using glacial acetic acid, while the mobile phase B was acetonitrile. The system operated using gradient elution at a flow rate of 1.0 mL·min-1and a wavelength of 240 nm. The established method was then used to measure the plasma concentrations of SMZ and TMP in 11 melioidosis patients from the Hainan region in China. Results: SMZ and TMP showed good linearity between concentrations of 0.6–190 μg·mL−1 and 0.1–25 μg·mL−1, respectively (r values 0.9997 and 1, respectively), with a recovery rate of (102.33 ± 1.42)%-(107.12 ± 1.41)% for SMZ and (93.85 ± 3.61)%-(105.67 ± 0.42)% for TMP. Both SMZ and TMP exhibited precision and stability, with relative standard deviations below 15 %. The peak concentration range was 8.77–102.94 μg·mL−1 for SMZ and 1.89–11.27 μg·mL−1 for TMP. Conclusion: The analyses used in this study verified the HPLC method had good linearity, accuracy, and precision and can therefore be used to monitor the plasma concentrations of combined TMP/SMZ therapy in melioidosis patients.

Spontaneous spinal epidural hematoma (SSEH) is an uncommon condition that can lead to severe neurological injuries, often accompanied by back pain. Pregnancy is identified as a risk factor for SSEH. Early diagnosis of SSEH presents challenges due to its atypical manifestations and the use of intraspinal anesthesia and analgesic techniques. In this case, we present the instance of a 29-year-old woman who initially received epidural labor analgesia during the first stage of labor but subsequently required a cesarean section under epidural anesthesia according to amniotic fluid turbidity. Unfortunately, the anomalous recovery of neurological function in her left lower extremity was not given sufficient attention at an early stage, and paralysis in the non-puncture segment occurred 45.5 hours after the initial puncture. Interestingly, she did not experience any back pain during these procedures. MRI examination and consultation with neurosurgeons confirmed the diagnosis of SSEH, prompting the patient to undergo emergency decompression surgery. She made an incomplete recovery 17 months after the operation. This case emphasizes the importance of considering the possibility of SSEH in pregnant women undergoing epidural analgesia, highlighting the need for spinal imaging and early neurosurgical interventions to facilitate treatment.

Abstract Electromagnetic fields (EMF) are increasing in popularity as a safe and non-invasive therapy. On the one hand, it is widely acknowledged that EMF can regulate the proliferation and differentiation of stem cells, promoting the undifferentiated cells capable of osteogenesis, angiogenesis, and chondroblast differentiation to achieve bone repair purpose. On the other hand, EMF can inhibit tumor stem cells proliferation and promote apoptosis to suppress tumor growth. As an essential second messenger, intracellular calcium plays a role in regulating cell cycle, such as proliferation, differentiation and apoptosis. There is increasing evidence that the modulation of intracellular calcium ion by EMF leads to differential outcomes in different stem cells. This review summarizes the regulation of channels, transporters, and ion pumps by EMF-induced calcium oscillations. It furtherly discusses the role of molecules and pathways activated by EMF-dependent calcium oscillations in promoting bone and cartilage repair and inhibiting tumor stem cells growth.

Abstract Osteoarthritis (OA) is a common joint disease and is the main cause of physical disability in the elderly. Currently, there is no adequate therapeutic strategy to reverse the progression of OA. Many natural plant extracts have received attention in the treatment of OA due to their potential anti-inflammatory properties, and reduced incidence of adverse events. Dioscin (Dio), a natural steroid saponin, has been demonstrated to inhibit the release of inflammatory cytokines in mouse and rat models of various diseases, and has a protective effect in chronic inflammatory diseases. However, whether Dio alleviates OA progression remains to be explored. In this research, our purposes were to investigate the therapeutic potential of Dio in OA. The results demonstrated that Dio exerted anti-inflammatory effects by repressing NO, PGE2, iNOS and COX-2. Moreover, the application of Dio could repress IL-1β-induced overexpression of matrix metalloproteinases (MMPs, including MMP1, MMP3, and MMP13) and ADAMTS-5, and improve the synthesis of collagen II and aggrecan, which contribute to the maintenance of chondrocyte matrix homeostasis. The underlying mechanism involved the inhibition of the MAPK and NF-κB signaling pathways by Dio. Furthermore, the treatment of Dio significantly improved the pain behaviors of rat OA models. The in vivo study revealed that Dio could ameliorate cartilage erosion and degradation. These results collectively indicate that Dio can be used as a promising and effective agent for the therapy of OA.

Abstract Background Streptococcus mutans is a well-known oral pathogen that plays a critical role in the development of dental caries. Many studies have been directed to discover the chemical compounds present in natural products to inhibit the growth and biofilm formation activity of S. mutans. Thymus essential oils exhibit good inhibition on the growth and pathogenesis of S. mutans. However, details about the active compounds in Thymus essential oil and the inhibition mechanism still remain unclear. The aim of this study was to investigate the antimicrobial activity of 6 Thymus species (Three samples of Thymus vulgaris, two samples of Thymus zygis, and one sample of Thymus satureioides essential oils) on S. mutans, to identify the potential active components, and to reveal the underlying mechanism. Methods The composition of Thymus essential oils was analyzed by gas chromatography-mass spectrometry. And its antibacterial effect was evaluated based on the bacterial growth, acid production, biofilm formation and genetic expression of virulence factors by S. mutans. Potential active components of the Thymus essential oil were identified using molecular docking and correlation analysis. Results GC–MS analysis showed that the major components in the 6 Spain Thymus essential oils were linalool, α-terpineol, p-cymene, thymol and carvacrol. MIC and MBC analysis showed that 3 Thymus essential oils showed very sensitive antimicrobial activity, and were chosen for further analysis. The 3 Thymus essential oil exhibited a significant inhibitory effect on acid production, adherence and biofilm formation of S. mutans and the expression of virulence genes, such as brpA, gbpB, gtfB, gtfC, gtfD, vicR, spaP and relA. Correlation analysis showed that phenolic components, such as carvacrol and thymol, were positively related to DIZ value, which suggests that they are the potential antimicrobial components. Molecular docking between the Thymus essential oil components and virulence proteins also found that carvacrol and thymol exhibited strong binding affinity with functional domains of virulence genes. Conclusions Thymus essential oil showed significant inhibition against the growth and pathogenesis of S. mutans depending on their composition and concentration. And phenolic compounds, such as carvacrol and thymol, are the major active components. Thymus essential oil could be used in oral healthcare products as a potential anti-caries ingredient.

Abstract Background Neoadjuvant therapy favors the prognosis of various cancers, including esophagogastric junction cancer (EGC). However, the impacts of neoadjuvant therapy on the number of dissected lymph nodes (LNs) have not yet been evaluated in EGC. Methods We selected EGC patients from the Surveillance, Epidemiology, and End Results (SEER) database (2006–2017). The optimal number of resected LNs was determined using X-tile software. Overall survival (OS) curves were plotted with the Kaplan–Meier method. Prognostic factors were evaluated using univariate and multivariate COX regression analyses. Results Neoadjuvant radiotherapy significantly decreased the mean number of LN examination compared to the mean number of patients without neoadjuvant therapy (12.2 vs. 17.5, P = 0.003). The mean LN number of patients with neoadjuvant chemoradiotherapy was 16.3, which was also statistically lower than 17.5 (P = 0.001). In contrast, neoadjuvant chemotherapy caused a significant increase in the number of dissected LNs (21.0, P 19 LNs had a better prognosis than those with 1–19 LNs (P 9 LNs had a better prognosis than those with 1–9 LNs (P

During hydraulic fracturing of waxy shale oil reservoirs, the presence of fracturing fluid can influence the phase behavior of the fluid within the reservoir, and heat exchange between the fluids causes wax precipitation that impacts reservoir development. To investigate multiscale fluid phase transition and microscale flow impacted by fracturing fluid injection, this study conducted no-water phase behavior experiments, water injection wax precipitation experiments, and water-condition phase behavior experiments using a nanofluidic chip model. The results show that in the no-water phase experiment, the gasification occurred first in the large cracks, while the matrix throat was the last, and the bubble point pressure difference between the two was 12.1 MPa. The wax precipitation phenomena during fracturing fluid injection can be divided into granular wax in cracks, flake wax in cracks, and wax precipitation in the matrix throat, and the wax mainly accumulated in the microcracks and remained in the form of particles. Compared with the no-water conditions, the large cracks and matrix throat bubble point in the water conditions decreased by 6.1 MPa and 3.5 MPa, respectively, and the presence of the water phase reduced the material occupancy ratio at each pore scale. For the smallest matrix throat, the final gas occupancy ratio under the water conditions decreased from 32% to 24% in the experiment without water. This study provides valuable insight into reservoir fracture modification and guidance for the efficient development of similar reservoirs.

ABSTRACT The emergence and rapid spread of multi-drug-resistant (MDR) bacteria pose a serious threat to global healthcare. Although the synergistic effect of rafoxanide and colistin was reported, little is known regarding the potential mechanism of this synergy, particularly against chromosomal-mediated colistin-resistant Klebsiella pneumoniae. In the present study, we elucidated the synergistic effect of rafoxanide and colistin against chromosomal-mediated colistin-resistant Klebsiella pneumoniae isolates from human (KP-9) and swine (KP-1) infections. Treatment with 1 mg/L rafoxanide overtly reversed the MIC max to 512-fold. Time-kill assays indicated that rafoxanide acted synergistically with colistin against the growth of KP-1 and KP-9. Mechanistically, we unexpectedly found that the combination destroys the inner-membrane integrity, and ATP synthesis was also quenched, albeit, not via F1F0-ATPase; thereby also inhibiting the activity of efflux pumps. Excessive production of reactive oxygen species (ROS) was also an underlying factor contributing to the bacterial-killing effect of the combination. Transcriptomic analysis unraveled overt heterogeneous expression as treated with both administrations compared with monotherapy. Functional analysis of these differentially expressed genes (DEGs) targeted to the plasma membrane and ATP-binding corroborated phenotypic screening results. These novel findings highlight the synergistic mechanism of rafoxanide in combination with colistin which effectively eradicates chromosomal-mediated colistin-resistant Klebsiella pneumoniae. IMPORTANCE The antimicrobial resistance of Klebsiella pneumoniae caused by the abuse of colistin has increased the difficulty of clinical treatment. A promising combination (i.e., rafoxanide+ colistin) has successfully rescued the antibacterial effect of colistin. However, we still failed to know the potential effect of this combination on chromosome-mediated Klebsiella pneumoniae. Through a series of in vitro experiments, as well as transcriptomic profiling, we confirmed that the MIC of colistin was reduced by rafoxanide by destroying the inner-membrane integrity, quenching ATP synthesis, inhibiting the activity of the efflux pump, and increasing the production of reactive oxygen species. In turn, the expression of relevant colistin resistance genes was down-regulated. Collectively, our study revealed rafoxanide as a promising colistin adjuvant against chromosome-mediated Klebsiella pneumoniae.

Chikungunya fever (CHIF), a vector-borne disease transmitted mainly by Aedes albopictus and Aedes aegypti, is caused by Chikungunya virus (CHIKV) infection. To date, it is estimated that 39% of the world’s population is at risk of infection for living in countries and regions where CHIKV is endemic. However, at present, the cellular receptors of CHIKV remains not clear, and there are no specific drugs and vaccines for CHIF. Here, the cytotoxicity of calpain-2 protein activity inhibitor III and specific siRNA was detected by MTT assays. The replication of CHIKV was detected by qPCR amplification and plaque assay. Western blot was used to determine the level of the calpain-2 protein and vimentin protein. Immunofluorescence was also operated for detecting the rearrangement of vimentin protein. Our results indicated that calpain-2 protein activity inhibitor III and specific siRNA might suppress CHIKV replication. Furthermore, CHIKV infection led to vimentin remodeling and formation of cage-like structures, which could be inhibited by the inhibitor III. In summary, we confirmed that calpain-2 protein influenced chikungunya virus replication and regulated vimentin rearrangement caused by chikungunya virus infection, which could be important for understanding the biological significance of CHIKV replication and the future development of antiviral strategies.

Aim: Evidence from overlapping systematic reviews (SRs) and meta-analyses (MAs) has yielded conflicting results on the treatment of irritable bowel syndrome (IBS) with fecal microbiota transplantation (FMT). To thoroughly gather, assess, and synthesize evidence on FMT for IBS, we carried out the present study.Methods: A comprehensive search was conducted in Cochrane Library, Web of Science, PubMed, and Embase from inception to May 2023. Tools for assessing the methodological quality, reporting quality, and confidence in outcomes, including A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR-2), Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), and the Grading of Recommendations Assessment, Development and Evaluation (GRADE).Results: Seven eligible SRs/MAs were finally included in this overview. By AMSTAR-2, the methodological quality of SRs/MAs included five that were very low quality, one that was low quality, and one that was high quality. According to PRISMA, limitations were associated with items 5 (Method: Protocol and Registration), 8 (Method: Search), and 27 (Funding). In GRADE, a total of 19 outcomes were included in the seven reviews, of which 12 outcomes were low quality and seven outcomes were moderate quality. Imprecision due to small sample size was the primary factor leading to evidence downgrading.Conclusion: We conclude that there is insufficient evidence to determine whether FMT has a more beneficial effect on patient with IBS than placebo treatment. Well-designed, larger trails are needed to provide evidence in this field. In addition, selection of donor, route of administration, dosage, and frequency still need to be determined.

Summary: Pandemic SARS-CoV-2 has undergone rapid evolution resulting in the emergence of many variants with mutations in the spike protein, some of which appear to evade antibody neutralization, transmit more efficiently, and/or exhibit altered virulence. This raises significant concerns regarding the efficacy of anti-S monoclonal antibody-based therapeutics which have failed against variant SARS-CoV-2 viruses. To address this concern, SAB-185, a human anti-SARS-CoV-2 polyclonal antibody was generated in the DiversitAb platform. SAB-185 exhibited equivalent, robust in vitro neutralization for Munich, Alpha, Beta, Gamma, and Δ144-146 variants and, although diminished, retained PRNT50 and PRNT80 neutralization endpoints for Delta and Omicron variants. Human ACE2 transgenic Syrian hamsters, which exhibit lethal SARS-CoV-2 disease, were protected from mortality after challenge with the Munich, Alpha, Beta, Delta, and Δ144-146 variants and clinical signs after non-lethal Omicron BA.1 infection. This suggests that SAB-185 may be an effective immunotherapy even in the presence of ongoing viral mutation.