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Highlights Microneedles (MNs) are used extensively for treating skin diseases due to their capability to provide less-invasive targeted drug delivery. Intelligent MNs can be fabricated from biocompatible materials with specialized properties, thereby providing improved treatment efficacy. Currently, there are limitations in the clinical application of MNs, highlighting the significance of further investigation to facilitate the translation of this innovative technology into patient treatment contexts.

Abstract Although promising, dendritic cell (DC) vaccines may not suffice to fully inhibit tumor progression alone, mainly due to the short expression time of the antigen in DC vaccines, immunosuppressive tumor microenvironment, and tumor antigenic modulation. Overcoming the limitations of DC vaccines is expected to further enhance their anti-tumor effects. In this study, we constructed a circRNA-loaded DC vaccine utilizing the inherent stability of circular RNA to enhance the expression level and duration of the antigen within the DC vaccine. Meanwhile we combined it with gemcitabine and validated their therapeutic efficacy in the Panc02 tumor model. We found that the use of DC vaccine alone can reach a tumor inhibition rate of 69%, and the effect was further enhanced when combined with gemcitabine, reaching a tumor inhibition rate of 89%. The combined treatment achieved a synergistic effect, which not only reduced immunosuppressive Tregs but also induced immunogenic cell death, leading to antigen spreading and reducing immune evasion caused by tumor antigenic modulation. As a result, the survival of the mice was significantly prolonged. Our research provides a promising approach for the clinical treatment of pancreatic cancer.

Cymodocea rotundata Asch. & Schweinf. 1870 (Cymodoceaceae) is a seagrass found in the tropical and temperate Indo-Pacific coastal waters. Seagrass beds composed of C. rotundata and other seagrasses form ecologically valuable ecosystems. In this study, the complete chloroplast genome of C. rotundata was sequenced and characterized for the first time. It is a circular genome of 158,311 bp in length, consisting of a large single-copy region (88,451 bp), a small single-copy region (18,836 bp), and a pair of inverted repeats (25,512 bp). A total of 130 genes were annotated, including 86 protein-coding genes (PCGs), 36 transfer RNA (tRNA) genes, and 8 ribosomal RNA (rRNA) genes. Seven PCGs and 6 tRNA genes contain 1 intron, and 3 PCGs contain 2 introns. In addition, 7 PCGs, 7 tRNA genes, and all the rRNA genes are multi-copy genes with 2 copies. Phylogenetic analysis shows that C. rotundata clusters with Syringodium isoetifolium in one clade, both belonging to the family Cymodoceaceae. This study provides new information to support further research on the phylogeny of Cymodoceaceae.

Halodule uninervis (Forssk.) Boiss. 1882 is a seagrass species. The complete chloroplast genome is 164,005 bp in length, with a GC content of 36.3%. This genome consists of a large single-copy region of 87,522 bp, a small single-copy region of 11,481 bp and a pair of inverse repeat regions of 32,501 bp each. A total of 131 genes were annotated in the genome, including 87 protein-coding genes, 36 tRNA genes, and 8 rRNA genes. Phylogenetic analysis revealed that H. uninervis shares the closest taxonomic relationship with Cymodocea rotundata and Syringodium isoetifolium, and all three species belong to the family Cymodoceaceae.

Abstract Background Our previous study has demonstrated a decreased colonic CD8+CD39+ T cells, enrichment of granzyme A (GZMA), was found in pediatric-onset colitis and inflammatory bowel disease (IBD) characterized by impaired intestinal barrier function. However, the influence of GZMA on intestinal barrier function remains unknown. Methods Western blotting(WB), real-time PCR (qPCR), immunofluorescence (IF) and in vitro permeability assay combined with intestinal organoid culture were used to detect the effect of GZMA on intestinal epithelial barrier function in vivo and in vitro. Luciferase, immunoprecipitation (IP) and subcellular fractionation isolation were performed to identify the mechanism through which GZMA modulated intestinal epithelial barrier function. Results Herein, we, for the first time, demonstrated that CD8+CD39+ T cells promoted intestinal epithelial barrier function through GZMA, leading to induce Occludin(OCLN) and Zonula Occludens-1(ZO-1) expression, which was attributed to enhanced CDX2-mediated cell differentiation caused by increased glutathione peroxidase 4(GPX4)-induced ferroptosis inhibition in vivo and in vitro. Mechanically, GZMA inhibited intestinal epithelial cellular PDE4B activation to trigger cAMP/PKA/CREB cascade signaling to increase CREB nuclear translocation, initiating GPX4 transactivity. In addition, endogenous PKA interacted with CREB, and this interaction was enhanced in response to GZMA. Most importantly, administration of GZMA could alleviate DSS-induced colitis in vivo. Conclusion These findings extended the novel insight of GZMA contributed to intestinal epithelial cell differentiation to improve barrier function, and enhacement of GZMA could be a promising strategy to patients with IBD.

Abstract This research delves into the dynamic behavior of acoustic levitation of the particle chain in a nonlinear standing wave field. Experimental acoustic levitation control tests reveal bifurcation and jump phenomena during dynamic adjustments to resonant cavity height. Employing the 10-particle chain experiments and the COMSOL simulation models, the Sine-Gordon 2D vibration model is established to study the dynamic deformation process of the particle chain. The study uncovers the nonlinear interaction of particle lateral vibrations, horizontal acoustic radiation force, and conical wave fields that generate the jumping standing wave field. Notably, the fourth particle acts as a prominent jumping critical point in the secondary standing wave field, facilitating the derivation of the particle chain’s nonlinear levitation dynamics. This discovery provides us with a new method to regulate the particle chain system.

Intracerebral hemorrhage (ICH) represents the most severe subtype of stroke, and the lack of effective clinical pharmacotherapies poses a substantial threat to human health. Hematoma plays a crucial role in determining the prognosis of ICH patients by causing primary mechanical extrusion, followed by secondary brain injuries, such as cerebral edema, iron-mediated oxidative stress, and inflammation resulting from its degradation products. 5α-androst-3β,5α,6β-triol (TRIOL) is a neuroprotective steroid currently undergoing phase II clinical trial for acute ischemic stroke with anti-oxidative and anti-inflammatory properties. However, whether TRIOL can protect brain against ICH injury remains unclear. In this study, we found that TRIOL significantly improved neurological function while reducing hematoma volume, cerebral edema, and tissue damage after ICH. Moreover, TRIOL enhanced microglial hematoma clearance through promoting CD36-mediated erythrophagocytosis and CD163-associated hemoglobin scavenging, while simultaneously reducing the release of microglial inflammatory factors and activating the antioxidative transcription factor Nrf2. Additionally, TRIOL inhibited neuron mediated hematoma absorption by suppressing heme oxygenase 2 (HO-2) and protected neurons against ICH-induced damage in vitro and in vivo. TRIOL also mitigated neuronal iron-dependent oxidative damage by increasing ferritin levels but decreasing divalent metal transporter 1 (DMT1) expression. Overall, these findings highlight the promising potential of TRIOL as a drug candidate for treating ICH.

As the share of the digital economy’s output continues to rise each year, the emergence of new industries such as e-commerce, mobile payments, and cloud computing has opened new avenues for carbon emission reduction (CER). Based on panel data from 30 provinces in China, this article systematically analyzes the CER pathways of China’s digital economy (DE) from the perspectives of direct effects, indirect effects, threshold effects, and heterogeneity analysis. The main conclusions are as follows: (1) China’s DE has a significant CER effect. (2) The DE can indirectly reduce regional carbon emissions (CE) by industrial structures and technological innovation, with the mediating effect of technological innovation being more significant than that of industrial structure. (3) Urbanization has threshold effects on the CER effect of China’s DE. Under the influence of urbanization, there is an inverted U-shaped relationship between DE and CE. (4) Heterogeneity analysis finds that, compared to other types of provinces, the CER effect of DE is stronger in non-resource-based and economically developed provinces. (5) We propose five tailored recommendations for CER: fostering the synergistic development of the DE and industrial structure, strengthening the role of technological innovation, advancing urbanization and carbon reduction in a differentiated manner, formulating distinct policies for resource-based and non-resource-based provinces, and enhancing the construction of digital infrastructure in less-developed regions. This article not only establishes a more comprehensive connection between the DE and CER, but also reveals the differences in the role of technological innovation, industrial structure optimization, urbanization and other factors in the carbon reduction effect of the DE through the comparison of different paths and mechanisms.

Abstract This study aims at the controllability of acoustically manipulated non-contact aggregation of bi-particle. Based on the acoustic wave radiation model of the transducer and the acoustic wave interference theory, the mathematical model between the spatial levitation point and the phase of the phased array ultrasonic array unit is established. A double-sided phased array test system was developed and the phase calculation algorithm for independently manipulating bi-particle was optimized. The algorithm is capable of independently distributing the energy applied to each levitation point. Through simulation and experiment, the horizontally aggregation characteristics of two levitated particles are investigated, and a interesting relationship between particles aggregation and standing wave phase difference is revealed, which follows the law of “attraction in the same phase but repulsion in the opposite phase”. By adjusting the tilt angle of the standing wave acoustic trap, the critical distance when particles to accelerate and collision is sharply reduced from 1.5λ to 0.5λ, which provides a new perspective and potential application path for acoustic manipulation technology.

Abstract The development of coalbed methane (CBM) in China is susceptible to the influence of microstructure. Therefore, it is crucial to understand the extension laws of hydraulic fractures and engineering responses in coal reservoirs affected by microstructure development. Utilizing the Dahebian block in western Guizhou as the study area, this investigation examines the coal reservoir characteristics, fracturing, and drainage engineering analysis of the well DC1 group in the region. The aim is to discuss the spatial distribution characteristics of hydraulic fractures, geological controlling factors influenced by microstructure, and their corresponding engineering responses. The results indicate that, for coal reservoirs unaffected by microstructure, the extension laws of the fracture network in both longitudinal and planar directions are influenced by burial depth and the regional stress field. In the microstructural belt, tectonic stress dominates, causing changes in the ground stress field. Consequently, the hydraulic fracture network deviates from the direction of the maximum principal stress during the extension process. When a secondary fracture is nearby, the hydraulic fracture network extends towards the shortest path radial secondary fracture direction, leading to a rapid increase in fracture width per unit length until it intersects with the secondary fracture. Additionally, the presence of secondary joints near the microfault structure decreases fracturing pressure and results in a dense distribution of the fracture network. This promotes the formation of a complex fracture network, favorable for fracturing. The extension of the fracture network in complex structural development areas is influenced by the microfault structure between wells, which is reflected in the fracturing construction pressure and fluid output. This accounts for the significant variations in the early drainage performance of CBM wells.

To assess the clinical applicability of a semi-quantitative luciferase immunosorbent assay (LISA) for detecting antibodies against Treponema pallidum antigens TP0171 (TP15), TP0435 (TP17), and TP0574 (TP47) in diagnosing and monitoring syphilis. LISA for detection of anti-TP15, TP17, and TP47 antibodies were developed and evaluated for syphilis diagnosis using 261 serum samples (161 syphilis, 100 non-syphilis). Ninety serial serum samples from 6 syphilis rabbit models (3 treated, 3 untreated) and 110 paired serum samples from 55 syphilis patients were used to assess treatment effects by utilizing TRUST as a reference. Compared to TPPA, LISA-TP15, LISA-TP17, and LISA-TP47 showed a sensitivity of 91.9%, 96.9%, and 98.8%, specificity of 99%, 99%, and 98%, and AUC of 0.971, 0.992, and 0.995, respectively, in diagnosing syphilis. Strong correlations (rs = 0.89–0.93) with TPPA were observed. In serial serum samples from rabbit models, significant differences in the relative light unit (RLU) were observed between the treatment and control group for LISA-TP17 (days 31–51) and LISA-TP47 (day 41). In paired serum samples from syphilis patients, TRUST titres and the RLU of LISA-TP15, LISA-TP17, and LISA-TP47 decreased post-treatment (P

Abstract The COVID-19 disease is an ongoing global health concern. Although vaccination provides some protection, people are still susceptible to re-infection. Ostensibly, certain populations or clinical groups may be more vulnerable. Factors causing these differences are unclear and whilst socioeconomic and cultural differences are likely to be important, human genetic factors could influence susceptibility. Experimental studies indicate SARS-CoV-2 uses innate immune suppression as a strategy to speed-up entry and replication into the host cell. Therefore, it is necessary to understand the impact of variants in immunity-associated human proteins on susceptibility to COVID-19. In this work, we analysed missense coding variants in several SARS-CoV-2 proteins and their human protein interactors that could enhance binding affinity to SARS-CoV-2. We curated a dataset of 19 SARS-CoV-2: human protein 3D-complexes, from the experimentally determined structures in the Protein Data Bank and models built using AlphaFold2-multimer, and analysed the impact of missense variants occurring in the protein–protein interface region. We analysed 468 missense variants from human proteins and 212 variants from SARS-CoV-2 proteins and computationally predicted their impacts on binding affinities for the human viral protein complexes. We predicted a total of 26 affinity-enhancing variants from 13 human proteins implicated in increased binding affinity to SARS-CoV-2. These include key-immunity associated genes (TOMM70, ISG15, IFIH1, IFIT2, RPS3, PALS1, NUP98, AXL, ARF6, TRIMM, TRIM25) as well as important spike receptors (KREMEN1, AXL and ACE2). We report both common (e.g., Y13N in IFIH1) and rare variants in these proteins and discuss their likely structural and functional impact, using information on known and predicted functional sites. Potential mechanisms associated with immune suppression implicated by these variants are discussed. Occurrence of certain predicted affinity-enhancing variants should be monitored as they could lead to increased susceptibility and reduced immune response to SARS-CoV-2 infection in individuals/populations carrying them. Our analyses aid in understanding the potential impact of genetic variation in immunity-associated proteins on COVID-19 susceptibility and help guide drug-repurposing strategies.

Abstract The flexibility and stability of transparent electrodes play a crucial role in the growing popularity of flexible devices, especially in potential wearable electronics. To date, various solution-coating techniques have been developed for fabricating silver nanowire (AgNW) flexible bioelectronics. However, achieving the orderly distributed patterns of AgNW without undesirable aggregations still poses a grand challenge. Here, an approach to realize regular patterned ultrathin AgNW networks on a freestanding electrospun PVDF-TrFE frame by evaporation-induced self-assembly is proposed. The patterning mechanism of evaporating AgNW colloidal suspension is investigated from experimental and theoretical analysis. The influence of evaporation-induced flow inside colloidal freestanding membranes on forming regular square hole-shaped arrays, selective deposition of AgNW, and aligning them along the artificial pinning array are addressed. Owing to the orderly arrangement of AgNW networks, the resultant flexible electrode achieves ultrathin thickness (about 5 μm), high optical transmittance (87.8%), and low sheet resistance (8.4 Ω·sq−1) with a relatively low dosage of AgNW (9 μg·cm−2). The electrode exhibits excellent durability during cyclic bending (50,000 times) and stretching (50% strain). The resistance remains virtually unchanged during 200 days in everyday environments. Furthermore, the excellent conformability and breathability of the flexible transparent electrode attached to the human skin demonstrates its potential application as an e-skin sensor. Our findings reliably urge a simple approach to underscore better outcomes with effective patterns by self-assembly of AgNW for highly conformal wearable electronics.

Gene duplication, as a prevalent phenomenon in the tree of life, provides a potential substrate for evolution. However, its role in the Aurantioideae remains unclear. In this study, we systematically identified, for the first time, a comprehensive landscape of five types of gene duplication in the genomes of 26 species within Aurantioideae, focusing on dissecting the duplication patterns, their potential evolutionary significance, and their impact on gene function and expression. Our results showed that the tandem duplication (TD) was a predominant duplication type and confirmed a shared ancient whole-genome duplication (γWGD) event within Aurantioideae. Ka/Ks indicated that all duplication types are under purifying selection pressure, with TD and proximal duplication (PD) undergoing rapid functional divergence. Gene Ontology (GO) enrichment analysis revealed functional specialization among different duplication types, collectively contributing to genome evolution. In addition, comparing the gene expression differentiation of the five gene duplication types between the outer and inner pericarps of Citrus maxima ‘Huazhouyou’, it was found that the proportion of gene expression differentiation in the exocarp was generally higher, suggesting tissue-specific functional roles for duplicated genes in the peel. Furthermore, gene conversion events revealed that Citrus sinensis and Citrus maxima ‘Huazhouyou’ experienced more gene conversion events, supporting that C. sinensis originated through hybridization with C. maxima as the maternal parent. Finally, the comparative analysis of gene families among 26 species in Aurantioideae revealed that small gene families (1–3 members) accounted for a substantial proportion in all species, indicating a lack of recent large-scale genome duplication events in this subfamily. These findings fill a gap in the understanding of gene duplication in Aurantioideae and provide a theoretical foundation for exploring the evolutionary mechanisms and breeding improvements within this group. Additionally, our study offers new insights into the contribution of gene duplication to functional diversification and ecological adaptation in other plants.

Abstract Solid‐state batteries represent the future of energy storage technology, offering improved safety and energy density. Garnet‐type Li7La3Zr2O12 (LLZO) solid‐state electrolytes‐based solid‐state lithium batteries (SSLBs) stand out for their appealing material properties and chemical stability. Yet, their successful deployment depends on conquering interfacial challenges. This review article primarily focuses on the advancement of interfacial engineering for LLZO‐based SSLBs. We commence with a concise introduction to solid‐state electrolytes and a discussion of the challenges tied to interfacial properties in LLZO‐based SSLBs. We deeply explore the correlations between structure and properties and the design principles vital for achieving an ideal electrode/electrolyte interface. Subsequently, we delve into the latest advancements and strategies dedicated to overcoming these challenges, with designated sections on cathode and anode interface design. In the end, we share our insights into the advancements and opportunities for interface design in realizing the full potential of LLZO‐based SSLBs, ultimately contributing to the development of safe and high‐performance energy storage solutions.

Abstract Pneumatic artificial muscles can move continuously under the power support of air pumps, and their flexibility also provides the possibility for applications in complex environments. However, in order to achieve operation in confined spaces, the miniaturization of artificial muscles becomes crucial. Since external attachment devices greatly hinder the miniaturization and use of artificial muscles, we propose a light-driven approach to get rid of these limitations. In this study, we report a miniaturized fiber-reinforced artificial muscle based on mold editing, capable of bending and axial elongation using gas-liquid conversion in visible light. The minimum volume of the artificial muscle prepared using this method was 15.7 mm3 (d = 2 mm, l = 5 mm), which was smaller than those of other fiber-reinforced pneumatic actuators. This research can promote the development of non-tethered pneumatic actuators for rescue and exploration, and create the possibility of miniaturization of actuators.

Pseudostellaria heterophylla (Miq.) Pax, a highly valued Chinese medicinal plant, is experiencing a notable decline in yield and quality due to viral diseases, particularly caused those by TuMV and BBWV2. Currently, the absence of a quantitative detection method for these viruses in P. heterophylla impedes the accurate diagnosis. The development of an accurate quantitative detection method is thus essential for effectively managing viral diseases in this plant. In this study, singleplex and duplex TaqMan qPCR were developed for the detection of the two viruses, based on two viral cloning vectors. Concurrently, the levels of both viruses were examined in the main produced regions of P. heterophylla. Furthermore, the levels of BBWV2 were examined during its infection of P. heterophylla. The optimal singleplex qPCR employed 0.1 μM of hydrolysis probe and 0.1 μM of primer for TuMV, while 0.2 μM of hydrolysis probe and 0.1 μM of primer were utilised for BBWV2. In contrast, the duplex qPCR employed the use of 0.1 μM of the upstream/downstream primer from each primer pair, with 0.2 μM of the respective hydrolysis probes. The 95% limit of detection (LOD) for singleplex qPCR was 734 copies for TuMV and 20 copies for BBWV2, while the 95% LOD for duplex qPCR was 945 copies for TuMV and 47 copies for BBWV2. Furthermore, the intra- and inter-assay coefficients of variation were found to be less than 1.2% for both singleplex and duplex qPCR. Of the P. heterophylla sampled 60 sites, 96% were found to be infected by one of two viruses. The levels of BBWV2 in N. benthamiana and P. heterophylla demonstrated an initial increase, followed by a subsequent decrease. The TaqMan qPCR methods provide a technical foundation for the monitoring of virus infections in P. heterophylla.

Abstract Current approaches in myocardial infarction treatment are limited by low cellular oxidative stress resistance, reducing the long-term survival of therapeutic cells. Here we develop a liquid-crystal substrate with unique surface properties and mechanical responsiveness to produce size-controllable cardiospheres that undergo pyroptosis to improve cellular bioactivities and resistance to oxidative stress. We perform RNA sequencing and study cell metabolism to reveal increased metabolic levels and improved mitochondrial function in the preconditioned cardiospheres. We test therapeutic outcomes in a rat model of myocardial infarction to show that cardiospheres improve long-term cardiac function, promote angiogenesis and reduce cardiac remodeling during the 3-month observation. Overall, this study presents a promising and effective system for preparing a large quantity of functional cardiospheres, showcasing potential for clinical application.

Abstract Objective This systematic review aimed to analyse the effect of early weight bearing versus late weight bearing on rehabilitation outcomes after ankle fractures, which primarily include ankle function scores, time to return to work/daily life and complication rates. Methods The China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, China Science and Technology Journal, Web of Science, PubMed, Embase and Cochrane Library databases were searched. The focus was on identifying randomised controlled trials centred on early weight‐bearing interventions for post‐operative ankle fracture rehabilitation. All databases were searched for eligible studies published within the period from database inception to 20 June 2023. The eligible studies were screened according to the inclusion criteria. Study quality was evaluated using the methodology recommended by the Cochrane Handbook for the Systematic Evaluation of Interventions. Two authors independently performed the literature search and data extraction. Eligible studies were subjected to meta‐analyses using Review Manager 5.3. Based on the time points at which post‐operative ankle function was reported in the studies included in this paper, we decided to perform a meta‐analysis of ankle function scores at 6 weeks post‐operatively, 12 weeks post‐operatively, 24–26 weeks post‐operatively and 1 year post‐operatively. Results A total of 11 papers, comprising 862 patients, were included. Meta‐analysis indicated that patients receiving early weight‐bearing interventions, which referred to weight‐bearing for 6 weeks post‐operatively, experienced enhancements in ankle function scores (Olerud–Molander score, AOFAS score or Baird–Jackson score) at various post‐operative milestones: 6 weeks (SMD = 0.69, 95% CI: 0.49–0.88 and p 0.05). Conclusion The results showed that early weight bearing is effective in improving ankle function among post‐operative ankle fracture patients and allows patients to return to daily life earlier. Significantly, the safety profile of early weight bearing remains favourable, with no higher risk of complications than late weight bearing.

Green insurance (GI), as an innovative product integrating environmental protection and the financial sector, not only contributes to improving regional environmental quality (EQ) but also enhances corporate environmental risk management and awareness, driving the flourishing development of green finance and the environmental protection industry. Therefore, understanding the relationship between GI and EQ is crucial. This article delves into the mechanisms through which GI influences EQ, proposing a hypothesis that suggests an inverted “U” shape impact. Subsequently, based on panel data from 30 provinces in China spanning from 2000 to 2021, nonlinear regression models and threshold regression models were constructed to test the hypothesis. The research findings indicate: (1) Results from the fixed-effects regression model demonstrate that the impact of GI on China’s EQ follows an inverted “U” shape. (2) Results from the threshold regression model also reveal an inverted “U” shape impact of GI on China’s EQ, with a threshold value of 2.196. (3) Economic level and industrial structure exhibit significant inhibitory effects on EQ improvement. Technological level and environmental regulations demonstrate notable promotional effects. Population size shows no significant impact on EQ improvement. The study identifies a nonlinear effect of GI on EQ improvement, surpassing existing linear effect research, deepening the understanding of its impact on EQ, and contributing to the enhancement of regional EQ.

Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1–BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination–deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.

Abstract Background In addition to specifically inducing tumor cell apoptosis, recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has also been reported to influence the cancer immune microenvironment; however, its underlying effects and mechanisms remain unclear. Investigating the immunomodulatory effects and mechanisms of recombinant TRAIL in the tumor microenvironment (TME) may provide an important perspective and facilitate the exploration of novel TRAIL strategies for tumor therapy. Methods Immunocompetent mice with different tumors were treated with three doses of recombinant TRAIL, and then the tumors were collected for immunological detection and mechanistic investigation. Methodological approaches include flow cytometry analysis and single-cell sequencing. Results In an immunocompetent mouse model, recombinant soluble mouse TRAIL (smTRAIL) had dose-related immunomodulatory effects. The optimal dose of smTRAIL (2 mg/kg) activated innate immune cells and CD8+ T cells, whereas higher doses of smTRAIL (8 mg/kg) promoted the formation of a tumor-promoting immune microenvironment to counteract the apoptotic effects on tumor cells. The higher doses of smTRAIL treatment promoted M2-like macrophage recruitment and polarization and increased the production of protumor inflammatory cytokines, such as IL-10, which deepened the suppression of natural killer (NK) cells and CD8+ T cells in the tumor microenvironment. By constructing an HU-HSC-NPG.GM3 humanized immune system mouse model, we further verified the immunomodulatory effects induced by recombinant soluble human TRAIL (shTRAIL) and found that combinational administration of shTRAIL and trabectedin, a macrophage-targeting drug, could remodel the tumor immune microenvironment, further enhance antitumor immunity, and strikingly improve antitumor effects. Conclusion Our results highlight the immunomodulatory role of recombinant TRAIL and suggest promising therapeutic strategies for clinical application. Graphical Abstract

Objective Pumping tests are an important method for determining the hydrogeological parameters of aquifers and evaluating groundwater resources. For the analysis of single-well pumping tests, existing models assume that the well diameter remains constant with depth and that the aquifer is either unconfined or confined. They do not consider situations where the well diameter varies or when multiple aquifers are encountered. Methods In this study, we developed a steady-state mixed-well flow model to account for a pumping well with a variable diameter that penetrates multiple aquifers with the assumption of horizontal flow within the aquifers. The analytical solutions for the relation between pumping discharge and drawdown were derived. This study explores the methodology of using single-well steady-state pumping tests with variable-diameter wells to obtain aquifer parameters. Additionally, accurate solutions for the equivalent radius of a confined aquifer segment and alternative radius calculation formulas are proposed. Results The mixed-well flow model was applied to analyze pumping tests near the Zihe River. Based on the data from three stepped pumping tests, a parabolic relationship between pumping discharge Qw and drawdown sw was established.The model predicted a pumping discharge of 4 093.8 m3/d when the maximum drawdown sw was 25 m. The hydraulic conductivity of the unconfined aquifer was estimated to be 1.88 m/d, and the hydraulic conductivity of the confined aquifer was estimated as 0.43 m/d, with a relative error of less than 5%. Conclusion The mixed-well model serves as a theoretical foundation for predicting water yield from pumping wells in multiple aquifers system. However, it is important to acknowledge that the model's applicability is constrained by certain assumptions. In situations where rivers fully penetrate aquifers, there is a possibility of overestimating the hydraulic conductivity. On the other hand, when rivers only partially penetrate aquifers, the analytical solution may underestimate the hydraulic conductivity.

Low temperature storage is widely used in the storage and transportation of postharvest fruits and vegetables. However, the negative effects of chilling injury (CI) on certain fruits and vegetables cannot be ignored. Therefore, efficient CI prevention technologies were used for reducing CI. This paper expounds the mechanisms of CI, common symptoms of CI and its impacts on the quality of fruits and vegetables, and summarizes the application of CI prevention technology. CI control methods are mainly classified into physical treatments (hot shock, near-freezing storage, high relative humidity storage, light-proof storage, and electromagnetic field), chemical treatments (melatonin, 1-methylcyclopropene, astragalus polysaccharides, γ-aminobutyric acid, 24-epibrassinolide, methyl jasmonate, trisodium phosphate, glycine betaine, and salicylic acid, etc.), coating treatments (sodium alginate, chitosan, carboxymethyl cellulose and aloe vera gel, etc.) and their combined treatments. These treatments have enhanced antioxidant activity, enzyme activity, membrane system integrity, and energy levels, thereby reducing the CI of fruits and vegetables.

Objectives: Summarize the progress and hot topic evolution of non-coding RNAs (ncRNAs) research in esophageal squamous cell carcinoma (ESCC) in recent years and predict future research directions.Methods: Relevant articles from the Web of Science until 31 October 2023 were obtained. Bibliometric analysis of included articles was performed using software (VOSviewer, CiteSpace, and Bibliometrix). The volume and citation of publications, as well as the country, institution, author, journal, keywords of the articles were used as variables to analyze the research trends and hot spot evolution.Results: 1,118 literature from 2008 to 2023 were retrieved from database, with 25 countries/regions, 793 institutions, 5,426 authors, 261 journals involved. Global cooperation was centered on China, Japan, and the United States. Zhengzhou University, an institution from China, had the highest publication. The most prolific author was Guo Wei, and the most prolific journal was Oncology Letters. Analysis of keywords revealed that the research in this field revolved around the role of ncRNAs in the occurrence, development, diagnosis, treatment, and prognosis of ESCC, mainly including micro RNAs, long non-coding RNAs, and then circular RNAs.Conclusion: Overall, research on ncRNAs in ESCC remains strong. Previous research has mainly focused on the basic research, with a focus on the mechanism of ncRNAs in the occurrence, development, diagnosis, treatment, and prognosis of ESCC. Combining current research with emerging disciplines to further explore its mechanisms of action or shifting the focus of research from preclinical research to clinical research based on diagnosis, treatment, and prognosis, will be the main breakthrough in this field in the future.

ObjectivesThe acupoint LR3 (Taichong) is frequently utilized in clinical acupuncture. However, its underlying neural mechanisms remain not fully elucidated, with speculations suggesting its close association with specific brain activity patterns.MethodsA comprehensive literature search was undertaken across several online databases, such as PubMed, Web of Science, Embase, Cochrane Library, CNKI (China National Knowledge Infrastructure), Wanfang Database, VIP Database, and the Chinese Biomedical Database. Two independent researchers handled the study selection, quality assessment, and data extraction processes. Using the seed-based d-mapping meta-analysis approach, we evaluated the brain regions activated by LR3 acupuncture in healthy subjects. Subsequent subgroup analysis was stratified by fMRI types, and regression analyses were performed considering the duration of acupuncture, depth of needle insertion, and needle diameter. The identified active brain regions were then intricately projected onto large-scale functional networks.ResultsA total of 10 studies met the criteria for inclusion, encompassing 319 healthy right-handed participants. The meta-analysis indicates that acupuncture at the LR3 activates regions such as the right postcentral gyrus, left thalamus, left middle frontal gyrus, and right superior frontal gyrus. Additionally, meta-regression analysis highlights that increased acupuncture duration correlates with progressively intensified activation of the right superior frontal gyrus. Subgroup analysis posits that variations in the type of fMRI employed might account for heterogeneity in the pooled results. Concurrently, functional network analysis identifies the primary activated regions as aligning with the Basal ganglia network, Auditory network, Left executive control network, Posterior salience network, Right executive control network, and Sensorimotor networks.ConclusionAcupuncture at the LR3 in healthy subjects selectively activates brain regions linked to pain perception, emotional processing, and linguistic functions. Extending the needle retention duration intensifies the activation of the right superior frontal gyrus. These findings enrich our comprehension of the neurobiological underpinnings of acupuncture’s role in pain mitigation and emotional regulation.

Abstract Background Reducing preventable adverse maternal and offspring outcomes is a global priority. The causes of adverse maternal and fetal outcomes are complex with multidimensional influencing factors. In addition, the Covid-19 epidemic has had a significant psychological and physical impact on people. China is now stepping into the post-epidemic era. We are curious about the psychological and physical situation of maternity in China at this stage. Therefore, we plan to initiate a prospective longitudinal study to investigate the multidimensional influences and mechanisms that affect maternal and offspring health. Method We will recruit eligible pregnant women at Renmin Hospital of Hubei Province, China. The expected sample size is 1490. We will assess socio-demographics, Covid-19 related information, social capital, sleep, mental health and medical records, including clinical examination and biochemical tests. Eligible pregnant women will be enrolled in the study with less than 14 weeks of gestation. Participants will receive a total of nine follow-up visits between mid-pregnancy and one year postpartum. The offspring will be followed up at birth, 6 weeks, 3 months, 6 months and one year. In addition, a qualitative study will be conducted to understand the underlying causes that affect maternal and offspring health outcomes. Discussion This is the first longitudinal study of maternity in Wuhan, Hubei Province which integrates physical, psychological and social capital dimensions. Wuhan is the first city to be affected by Covid-19 in China. As China moves into the post-epidemic era, this study will provide us with a better understanding of the long-term impact of the epidemic on maternal and offspring health outcomes. We will implement a range of rigorous measures to enhance participants’ retention rate and ensure the quality of data. The study will provide empirical results for maternal health in the post-epidemic era.

Abstract Small GTPases including Ras, Rho, Rab, Arf, and Ran are omnipresent molecular switches in regulating key cellular functions. Their dysregulation is a therapeutic target for tumors, neurodegeneration, cardiomyopathies, and infection. However, small GTPases have been historically recognized as “undruggable”. Targeting KRAS, one of the most frequently mutated oncogenes, has only come into reality in the last decade due to the development of breakthrough strategies such as fragment-based screening, covalent ligands, macromolecule inhibitors, and PROTACs. Two KRASG12C covalent inhibitors have obtained accelerated approval for treating KRASG12C mutant lung cancer, and allele-specific hotspot mutations on G12D/S/R have been demonstrated as viable targets. New methods of targeting KRAS are quickly evolving, including transcription, immunogenic neoepitopes, and combinatory targeting with immunotherapy. Nevertheless, the vast majority of small GTPases and hotspot mutations remain elusive, and clinical resistance to G12C inhibitors poses new challenges. In this article, we summarize diversified biological functions, shared structural properties, and complex regulatory mechanisms of small GTPases and their relationships with human diseases. Furthermore, we review the status of drug discovery for targeting small GTPases and the most recent strategic progress focused on targeting KRAS. The discovery of new regulatory mechanisms and development of targeting approaches will together promote drug discovery for small GTPases.

Purpose – This study aims to evaluate the characteristics of climate change in Yunnan minority areas and identify an effective path to promote sustainable livelihoods based on climate change. Design/methodology/approach – Taking Yunnan Province as an example, based on the expansion of the traditional sustainable livelihood framework, the authors constructed a system dynamics (SD) model of sustainable livelihood from the six subsystems of natural, physical, financial, social, human and cultural and tested the accuracy and effectiveness of the model with data from Cangyuan County. By adjusting these parameters, five development paths are designed to simulate the future situation of the livelihood system and determine the optimal path. Findings – Climate change has exacerbated the vulnerability of people’s livelihoods. In future, each of the five development paths will be advantageous for promoting sustainable livelihoods. However, compared with Path I (maintaining the status quo), Path III (path of giving priority to culture) and Path IV (path of giving priority to economic development) have more obvious advantages. Path II (path of giving priority to people’s lives) gradually increases the development rate by promoting people’s endogenous motivation, and Path V (path of coordinated development) is better than the other paths because of its more balanced consideration. Originality/value – The analytical framework of sustainable livelihoods based on the characteristics of minority areas is broadened. By constructing a SD model of the livelihood system, the limitations of traditional static analysis have been overcome and a development path for promoting sustainable livelihoods through simulation is proposed. This study offers a theoretical framework and reference method for livelihood research against the backdrop of climate change and a decision-making basis for enhancing climate adaptability and realizing sustainable livelihoods.

The ORB (Oriented fast and rotated brief, ORB) algorithm is limited by its inability to extract feature points or extract only a small number of feature points when a fixed threshold is used in complex lighting conditions. To address this issue, this paper proposes a method that combines image enhancement with truncated adaptive threshold to improve the ORB feature extraction algorithm. Firstly, the original image is converted to grayscale. Secondly, the image is enhanced by applying Gaussian filtering for noise reduction, truncated adaptive gamma brightness adjustment, and unsharp masking operation. Then, the enhanced image is segmented into subregions of a specified size, and an improved truncated OTUS method is employed to calculate the adaptive threshold for each subregion. Finally, ORB feature points are extracted by utilizing the adaptive threshold. Experimental results show that the improved ORB algorithm can significantly increase the number of feature points in complex lighting conditions, with good accuracy, real-time performance, and robustness.

Objective Our objective was to explore the national traditional Chinese medicine by studying master Diangui Li's medication experience in treating atrophic gastritis (AG) concomitant with Helicobacter pylori (Hp) infection based on data mining, and to provide the reference for the clinical treatment of relevant diseases.

Abstract Recovery of skin function remains a significant clinical challenge for deep burns owing to the severe scar formation and poor appendage regeneration, and stem cell therapy has shown great potential for injured tissue regeneration. Here, a cell‐free therapy system for deep burn skin was explored using mesenchymal stem cell paracrine proteins (MSC‐PP) and polyethylene glycol (PEG) temperature‐sensitive hydrogels. A three‐dimensional (3D) dynamic culture system for MSCs' large‐scale expansion was established using a porous gelatin microcarrier crosslinked with hyaluronic acid (PGM‐HA), and the purified MSC‐PP from culture supernatant was characterized by mass spectrometric analysis. The results showed the 3D dynamic culture system regulated MSCs cell cycle, reduced apoptosis, and decreased lactic acid content, and the MSC‐PP produced in 3D group can promote cell proliferation, migration, and adhesion. The MSC‐PP + PEG system maintained stable release in 28 days of observation in vitro. The in vivo therapeutic efficacy was investigated in the rabbit's third‐degree burn model, and saline, PEG, MSC‐PP, and MSC‐PP + PEG treatments groups were set. The in vivo results showed that the MSC‐PP + PEG group significantly improved wound healing, inhibited scar formation, and facilitated skin appendage regeneration. In conclusion, the MSC‐PP + PEG sustained‐release system provides a potentially effective treatment for deep burn skin healing.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease that poses a significant challenge to medical professionals due to its increasing incidence and prevalence coupled with the limited understanding of its underlying molecular mechanisms. In this study, we employed a novel approach by integrating five expression datasets from bulk tissue with single-cell datasets; they underwent pseudotime trajectory analysis, switch gene selection, and cell communication analysis. Utilizing the prognostic information derived from the GSE47460 dataset, we identified 22 differentially expressed switch genes that were correlated with clinical indicators as important genes. Among these genes, we found that the midkine (MDK) gene has the potential to serve as a marker of Idiopathic pulmonary fibrosis because its cellular communicating genes are differentially expressed in the epithelial cells. We then utilized midkine and its cellular communication-related genes to calculate the midkine score. Machine learning models were further constructed through midkine and related genes to predict Idiopathic pulmonary fibrosis disease through the bulk gene expression datasets. The midkine score demonstrated a correlation with clinical indexes, and the machine learning model achieved an AUC of 0.94 and 0.86 in the Idiopathic pulmonary fibrosis classification task based on lung tissue samples and peripheral blood mononuclear cell samples, respectively. Our findings offer valuable insights into the pathogenesis of Idiopathic pulmonary fibrosis, providing new therapeutic directions and target genes for further investigation.

IntroductionBreast cancer remains a significant global health challenge, accounting for 2.3 million new cases in 2020 and ranking as the most prevalent cancer by incidence and the fourth in cancer-related mortality worldwide. In China, breast cancer also rapidly increases incidence and burden. The research of exosomes in breast cancer has attracted more and more attention and has a rapid development. Recognizing the pivotal role of exosomes in breast cancer research, we have undertaken a comprehensive scientometric analysis of pertinent scholarly articles published over the past decade to elucidate the current research landscape for researchers.MethodsIn this study, we gathered all pertinent publications from the Web of Science. Biblioshiny (a web interface for Bibliometrix), VOSviewer software, and CiteSpace software were used to analyze the information on publications, including global trends, countries, institutions, journals, authors, keywords, and citations.ResultsA total of 1,239 articles and 625 review articles were retrieved. The annual global publication output has an increased trend in recent decades overall. China contributed the most articles. The publications of the USA had the most total link strength. Nanjing Medical University had the most total link strength. The most relevant source was the International Journal of Molecular Sciences. Tang JH contributed the most articles and had the highest H-index, G-index, and total link strength. The most cited document was “Tumor exosome integrins determine organotropic metastasis”, with 2730 citations. The basic themes included “exosomes”, “expression”, “cells”, “identification”, “biomarkers”, and “serum”. The keyword “membrane vesicle” had the strongest bursts. The keywords “target”, “biology”, “suppressor cell”, “molecular mechanism”, “tumor progression”, “inhibitor”, and “model” appeared as prominent focal points in current research and active areas of exploration.ConclusionOver the past decade, exosome research in breast cancer has undergone a discernible evolution, shifting from broader investigations of exosome roles to focused exploration of specific pathways relevant to breast cancer. Notably, the emphasis has extended to the clinical application of exosomes as biomarkers and potential therapeutic agents in breast cancer treatment.

The transcriptome complexity and splicing patterns in male and female cattle are ambiguous, presenting a substantial obstacle to genomic selection programs that seek to improve productivity, disease resistance, and reproduction in cattle. A comparative transcriptomic analysis using Oxford Nanopore Technologies (ONT) was conducted in bovine testes (TESTs), ovaries (OVAs), muscles (MUSCs), and livers (LIVs). An average of 5,144,769 full-length reads were obtained from each sample. The TESTs were found to have the greatest number of alternative polyadenylation (APA) events involved in processes such as sperm flagellum development and fertilization in male reproduction. In total, 438 differentially expressed transcripts (DETs) were identified in the LIVs in a comparison of females vs. males, and 214 DETs were identified in the MUSCs between females and males. Additionally, 14,735, 36,347, and 33,885 DETs were detected in MUSC vs. LIV, MUSC vs. TEST, and OVA vs. TEST comparisons, respectively, revealing the complexity of the TEST. Gene Set Enrichment Analysis (GSEA) showed that these DETs were mainly involved in the “spermatogenesis”, “flagellated sperm motility”, “spermatid development”, “reproduction”, “reproductive process”, and “microtubule-based movement” KEGG pathways. Additional studies are necessary to further characterize the transcriptome in different cell types, developmental stages, and physiological conditions in bovines and ascertain the functions of the novel transcripts.

Abstract Background Fear of childbirth (FOC) is a common psychological problem in Chinese pregnant women. FOC can influence both maternal health and infants’ wellness. Special assessment tools for FOC in Mandarin Chinese are currently lacking. The aim of this study was to evaluate the psychometric properties of the Mandarin Chinese of the Wijma Delivery Expectancy/Experience Questionnaire Version A (W-DEQ-A). Methods We recruited 364 Chinese pregnant women from April 2021 to July 2021. Translation and cultural adaptation, as well as reliability and validity testing were conducted. Analyses included the content validity, structural validity, criterion-related validity, convergent validity and reliability. The content validity indices were used to assess the content validity of the tool. The structural validity was tested through exploratory factor analysis and confirmatory factor analysis. The Cronbach’s alpha coefficient was used to evaluate the reliability of the W-DEQ-A Chinese version. Results The Chinese translation showed excellent similarities and equivalence to the original version, with the satisfactory content validity. Factor analysis indicated 5 factors, accounting for 57% of the total variance. Both criterion-related validity and convergent validity proved to be acceptable. The reliability was tested with a Cronbach’s alpha coefficient of 0.911 for the total scale. Conclusion The W-DEQ-A Chinese version is a reliable and valid tool to identify FOC in Mandarin Chinese-speaking populations.

Objective To compare the non-synonymous single nucleotide polymorphisms of the carrier protein of branched-chain amino acid transport system Ⅱ (TP0265) of Treponema pallidum (Tp) in Guangdong clinical strain (GD1) with the standard strain of Nichols in the United States and Treponema spp. Methods GD1 was serially subcultured in rabbit testis for obtaining Tp bacterial suspension. GD1 DNA was extracted and the concentration of GD1 genome was quantitatively detected by TP0574 qPCR. GD1 DNA was detected by TP0548 PCR and genotyping system. PCR detection by TP0265 Multiple sequence alignment analysis was performed between GD1 TP0265 and nsSNPs of American Nichols standard strain and Treponema globe. Results The sequencing results of TP0548 were confirmed to be f subtype by BioEdit multiple sequence alignment. Compared with the American Nichols strain, it was found that GD1 had a G175A mutation at the TP0265 base, resulting in the mutation of proline (P) at position 230 of the TP0265 protein to leucine (L). Compared with different Treponema species in the global Treponema genus, except for Nichols, Dal-1 and Nichols Houston in the United States, the TP0265 mutation was found. Conclusion There is a TP0265 nsSNPs mutation in GD1, which involves a wide range of Treponema species worldwide.

Summary: Background: The ability to accurately identify the absolute risk of neurosyphilis diagnosis for patients with syphilis would allow preventative and therapeutic interventions to be delivered to patients at high-risk, sparing patients at low-risk from unnecessary care. We aimed to develop, validate, and evaluate the clinical utility of simplified clinical diagnostic models for neurosyphilis diagnosis in HIV-negative patients with syphilis. Methods: We searched PubMed, China National Knowledge Infrastructure and UpToDate for publications about neurosyphilis diagnostic guidelines in English or Chinese from database inception until March 15, 2023. We developed and validated machine learning models with a uniform set of predictors based on six authoritative diagnostic guidelines across four continents to predict neurosyphilis using routinely collected data from real-world clinical practice in China and the United States (through the Dermatology Hospital of Southern Medical University in Guangzhou [659 recruited between August 2012 and March 2022, treated as Development cohort], the Beijing Youan Hospital of Capital Medical University in Beijng [480 recruited between December 2013 and April 2021, treated as External cohort 1], the Zhongshan Hospital of Xiamen University in Xiamen [493 recruited between November 2005 and November 2021, treated as External cohort 2] from China, and University of Washington School of Medicine in Seattle [16 recruited between September 2002 and April 2014, treated as External cohort 3] from United States). We included all these patients with syphilis into our analysis, and no patients were further excluded. We trained eXtreme gradient boosting (XGBoost) models to predict the diagnostic outcome of neurosyphilis according to each diagnostic guideline in two scenarios, respectively. Model performance was measured through both internal and external validation in terms of discrimination and calibration, and clinical utility was evaluated using decision curve analysis. Findings: The final simplified clinical diagnostic models included neurological symptoms, cerebrospinal fluid (CSF) protein, CSF white blood cell, and CSF venereal disease research laboratory test/rapid plasma reagin. The models showed good calibration with rescaled Brier score of 0.99 (95% CI 0.98–1.00) and excellent discrimination (the minimum value of area under the receiver operating characteristic curve, 0.84; 95% CI 0.81–0.88) when externally validated. Decision curve analysis demonstrated that the models were useful across a range of neurosyphilis probability thresholds between 0.33 and 0.66 compared to the alternatives of managing all patients with syphilis as if they do or do not have neurosyphilis. Interpretation: The simplified clinical diagnostic models comprised of readily available data show good performance, are generalisable across clinical settings, and have clinical utility over a broad range of probability thresholds. The models with a uniform set of predictors can simplify the sophisticated clinical diagnosis of neurosyphilis, and guide decisions on delivery of neurosyphilis health-care, ultimately, support accurate diagnosis and necessary treatment. Funding: The Natural Science Foundation of China General Program, Health Appropriate Technology Promotion Project of Guangdong Medical Research Foundation, Department of Science and technology of Guangdong Province Xinjiang Rural Science and Technology（Special Commissioner）Project, Southern Medical University Clinical Research Nursery Garden Project, Beijing Municipal Administration of Hospitals Incubating Program.

Abstract Introduction Several low‐ and middle‐income countries (LMICs) are preparing to introduce long‐acting pre‐exposure prophylaxis (LAP). Amid multiple pre‐exposure prophylaxis (PrEP) options and constrained funding, decision‐makers could benefit from systematic implementation planning and aligned costs. We reviewed national costed implementation plans (CIPs) to describe relevant implementation inputs and activities (domains) for informing the costed rollout of LAP. We assessed how primary costing evidence aligned with those domains. Methods We conducted a rapid review of CIPs for oral PrEP and family planning (FP) to develop a consensus of implementation domains, and a scoping review across nine electronic databases for publications on PrEP costing in LMICs between January 2010 and June 2022. We extracted cost data and assessed alignment with the implementation domains and the Global Health Costing Consortium principles. Results We identified 15 implementation domains from four national PrEP plans and FP‐CIP template; only six were in all sources. We included 66 full‐text manuscripts, 10 reported LAP, 13 (20%) were primary cost studies‐representing seven countries, and none of the 13 included LAP. The 13 primary cost studies included PrEP commodities (n = 12), human resources (n = 11), indirect costs (n = 11), other commodities (n = 10), demand creation (n = 9) and counselling (n = 9). Few studies costed integration into non‐HIV services (n = 5), above site costs (n = 3), supply chains and logistics (n = 3) or policy and planning (n = 2), and none included the costs of target setting, health information system adaptations or implementation research. Cost units and outcomes were variable (e.g. average per person‐year). Discussion LAP planning will require updating HIV prevention policies, technical assistance for logistical and clinical support, expanding beyond HIV platforms, setting PrEP achievement targets overall and disaggregated by method, extensive supply chain and logistics planning and support, as well as updating health information systems to monitor multiple PrEP methods with different visit schedules. The 15 implementation domains were variable in reviewed studies. PrEP primary cost and budget data are necessary for new product introduction and should match implementation plans with financing. Conclusions As PrEP services expand to include LAP, decision‐makers need a framework, tools and a process to support countries in planning the systematic rollout and costing for LAP.

In this study, we investigate the synergistic effect of gemcitabine (Gem) and a novel DNA vaccine in the treatment of pancreatic cancer in mice and explore the anti-tumor mechanism of this combination therapy. Fibroblast activation protein α-expressing cancer-associated fibroblasts (FAPα+ CAFs), a dominant component of the tumor microenvironment (TME), have been shown to modulate the extracellular matrix (ECM) to promote the growth, invasion, and metastasis of pancreatic cancer (PC). Therefore, FAPα+ CAFs may be an ideal target for the treatment of PC. However, treatments that solely target FAPα+ CAFs do not directly affect tumor cells. We recently constructed a novel chimeric DNA vaccine (OsFS) against human FAPα and survivin, which simultaneously targets FAPα+ CAFs and tumor cells. In Panc02 tumor-bearing mice, OsFS vaccination not only reduced the proportion of immunosuppressive cells but also promoted the recruitment of tumor-infiltrating lymphocytes, which remodeled the TME to support anti-tumor immune responses. Furthermore, after depletion of regulatory T cells (Tregs) by metronomic low-dose Gem therapy, the anti-tumor effects of OsFS were enhanced. Taken together, our results indicate that the combination of the FAPα/survivin co-targeting DNA vaccine and low-dose Gem may be an effective therapy for PC.

Abstract Background Progressive neuronal death is the key pathological feature of Alzheimer’s disease (AD). However, the molecular mechanisms underlying the neuronal death in AD patients have not been fully elucidated. Necroptosis reportedly activates and induces neuronal death in patients with Alzheimer’s disease (AD); however, the main mediators and mechanisms underlying necroptosis induction in AD remain elusive. Methods The function of hyperphosphorylated tau (pTau) in inducing necroptosis in neuronal cell was examined using Western blotting, RT-PCR and flow cytometry. Tau-induced inflammation was identified via RNA sequencing and transwell assay. Pharmacological methods and CRISPR–Cas9 technology were used to verify the role of necrosome proteins in pTau-stimulated neuronal death and inflammation. TauP301S model mice were treated with Nec-1 s to evaluate the role of necroptosis in tau pathology. Results Hyperphosphorylated tau could induce necroptosis in neuronal cells by promoting the formation of the RIPK1/RIPK3/MLKL necrosome. In addition, pTau significantly stimulated cell-autonomous overexpression of cytokines and chemokines via the intracellular nuclear factor kappa B (NF-κB) signaling pathway. Importantly, the RIPK1/RIPK3/MLKL axis was essential for the pTau-mediated NF-κB activation and cytokine storm. Furthermore, necroptosis stimulation, NF-κB activation, and cytokine induction have been detected in TauP301S mice and blocking necroptosis markedly ameliorated behavioral defects and excessive neuroinflammation in AD mice. Conclusions Our study, for the first time, revealed that pTau contributes to neuronal death by inducing necroptosis and inflammation, mediated by activating the RIPK1/RIPK3/MLKL and NF-κB pathways, thereby delineating the hierarchical molecular network of neuronal necroptosis induction in AD.

One of the major functions of the accessory protein Vif of human immunodeficiency virus type 1 (HIV-1) is to induce the degradation of APOBEC3 (A3) family proteins by recruiting a Cullin5-ElonginB/C-CBFβ E3 ubiquitin ligase complex to facilitate viral replication. Therefore, the interactions between Vif and the E3 complex proteins are promising targets for the development of novel anti-HIV-1 drugs. Here, peptides are designed for the Vif-CBFβ interaction based on the sequences of Vif mutants with higher affinity for CBFβ screened by a yeast surface display platform. We identified two peptides, VMP-63 and VMP-108, that could reduce the infectivity of HIV-1 produced from A3G-positive cells with IC50 values of 49.4 μM and 55.1 μM, respectively. They protected intracellular A3G from Vif-mediated degradation in HEK293T cells, consequently increasing A3G encapsulation into the progeny virions. The peptides could rapidly enter cells after addition to HEK293T cells and competitively inhibit the binding of Vif to CBFβ. Homology modeling analysis demonstrated the binding advantages of VMP-63 and VMP-108 with CBFβ over their corresponding wild-type peptides. However, only VMP-108 effectively restricted long-term HIV-1 replication and protected A3 functions in non-permissive T lymphocytes. Our findings suggest that competitive Vif-derived peptides targeting the Vif-CBFβ interaction are promising for the development of novel therapeutic strategies for acquired immune deficiency syndrome.

Abstract Rotary voice coil actuator (RVCA) is mainly used for reciprocating drive of small inertia loads in a limited range of angle, which is widely used in aerospace and other fields. Thermal resistance is one of the most important parameters of RVCAs, which is directly related to the steady‐state temperature rising and operation reliability. Because the thermal resistance cannot be measured directly, the analytical method is usually used to calculate the thermal resistance of the RVCA. However, due to the particularity of the thermal circuit calculation, the calculation is complicated and the result is not accurate. It is not conducive for engineering applications of this kind of actuator. In this paper, a series of rotary voice coil motor is selected as the research object. Through analytical calculation and thermal simulation, a more accurate thermal resistance calculation correction model and thermal resistance value of RVCAs are obtained, and the accuracy of the estimation results is verified by experiments. On this basis, the effective volume of the coil frame of the RVCA is selected as the variable, and the concise variation law of the series thermal resistance data is obtained. This paper provides a fast and accurate estimation method for the thermal resistance of RVCA, which has an important reference value for expanding the engineering applications of RVCAs.

Abstract Background The deep sea harbors the majority of the microbial biomass in the ocean and is a key site for organic matter (OM) remineralization and storage in the biosphere. Microbial metabolism in the deep ocean is greatly controlled by the generally depleted but periodically fluctuating supply of OM. Currently, little is known about metabolic potentials of dominant deep-sea microbes to cope with the variable OM inputs, especially for those living in the hadal trenches—the deepest part of the ocean. Results In this study, we report the first extensive examination of the metabolic potentials of hadal sediment Chloroflexi, a dominant phylum in hadal trenches and the global deep ocean. In total, 62 metagenome-assembled-genomes (MAGs) were reconstructed from nine metagenomic datasets derived from sediments of the Mariana Trench. These MAGs represent six novel species, four novel genera, one novel family, and one novel order within the classes Anaerolineae and Dehalococcoidia. Fragment recruitment showed that these MAGs are globally distributed in deep-sea waters and surface sediments, and transcriptomic analysis indicated their in situ activities. Metabolic reconstruction showed that hadal Chloroflexi mainly had a heterotrophic lifestyle, with the potential to degrade a wide range of organic carbon, sulfur, and halogenated compounds. Our results revealed for the first time that hadal Chloroflexi harbor pathways for the complete hydrolytic or oxidative degradation of various recalcitrant OM, including aromatic compounds (e.g., benzoate), polyaromatic hydrocarbons (e.g., fluorene), polychlorobiphenyl (e.g., 4-chlorobiphenyl), and organochlorine compounds (e.g., chloroalkanes, chlorocyclohexane). Moreover, these organisms showed the potential to synthesize energy storage compounds (e.g., trehalose) and had regulatory modules to respond to changes in nutrient conditions. These metabolic traits suggest that Chloroflexi may follow a “feast-or-famine” metabolic strategy, i.e., preferentially consume labile OM and store the energy intracellularly under OM-rich conditions, and utilize the stored energy or degrade recalcitrant OM for survival under OM-limited condition. Conclusion This study expands the current knowledge on metabolic strategies in deep-ocean Chlorolfexi and highlights their significance in deep-sea carbon, sulfur, and halogen cycles. The metabolic plasticity likely provides Chloroflexi with advantages for survival under variable and heterogenic OM inputs in the deep ocean. Video Abstract

The dynamic visual acuity test (DVAT) is a functional evaluation tool for the impairment and compensation of the vestibular system, which could reflect the Vestibulo-ocular reflex (VOR) function. We present an overview of DVAT research, displaying recent advances in test methods, application, and influencing factors; and discussing the clinical value of DVAT to provide a reference for clinical application. There are two primary types of DVAT: dynamic-object DVAT and static-object DVAT. For the latter, in addition to the traditional bedside DVAT, there are numerous other approaches, including Computerized DVAT (cDVAT), DVAT on a treadmill, DVAT on a rotary, head thrust DVA (htDVA) and functional head impulse testing (fHIT), gaze shift dynamic visual acuity with walking (gsDVA), translational dynamic visual acuity test (tDVAT), pediatric DVAT. The results of DAVT are affected by subject [occupation, static visual acuity (SVA), age, eyeglass lenses], testing methods, caffeine, and alcohol. DVAT has numerous clinical applications, such as screening for vestibular impairment, assessing vestibular rehabilitation, predicting fall risk, and evaluating ophthalmology-related disorders, vestibular disorders, and central system disorders.

Muscle contraction increases the level of reactive oxygen species (ROS), which has been acknowledged as key signaling entities in muscle remodeling and to underlie the healthy adaptation of skeletal muscle. ROS inevitably endows damage to various cellular molecules including DNA. DNA damage ought to be repaired to ensure genome integrity; yet, how DNA repair byproducts affect muscle adaptation remains elusive. Here, we showed that exercise elicited the generation of 8-oxo-7,8-dihydroguanine (8-oxoG), that was primarily found in mitochondrial genome of myofibers. Upon exercise, TA muscle's 8-oxoG excision capacity markedly enhanced, and in the interstitial fluid of TA muscle from the post-exercise mice, the level of free 8-oxoG base was significantly increased. Addition of 8-oxoG to myoblasts triggered myogenic differentiation via activating Ras-MEK-MyoD signal axis. 8-Oxoguanine DNA glycosylase1 (OGG1) silencing from cells or Ogg1 KO from mice decreased Ras activation, ERK phosphorylation, MyoD transcriptional activation, myogenic regulatory factors gene (MRFs) expression. In reconstruction experiments, exogenously added 8-oxoG base enhanced the expression of MRFs and accelerated the recovery of the injured skeletal muscle. Collectively, these data not only suggest that DNA repair metabolite 8-oxoG function as a signal entity for muscle remodeling and contribute to exercise-induced adaptation of skeletal muscle, but also raised the potential for utilizing 8-oxoG in clinical treatment to skeletal muscle damage-related disorders.

Mobile robots are widely used in medicine, agriculture, home furnishing, and industry. Simultaneous localization and mapping (SLAM) is the working basis of mobile robots, so it is extremely necessary and meaningful for making researches on SLAM technology. SLAM technology involves robot mechanism kinematics, logic, mathematics, perceptual detection, and other fields. However, it faces the problem of classifying the technical content, which leads to diverse technical frameworks of SLAM. Among all sorts of SLAM, visual SLAM (V-SLAM) has become the key academic research due to its advantages of low price, easy installation, and simple algorithm model. Firstly, we illustrate the superiority of V-SLAM by comparing it with other localization techniques. Secondly, we sort out some open-source V-SLAM algorithms and compare their real-time performance, robustness, and innovation. Then, we analyze the frameworks, mathematical models, and related basic theoretical knowledge of V-SLAM. Meanwhile, we review the related works from four aspects: visual odometry, back-end optimization, loop closure detection, and mapping. Finally, we prospect the future development trend and make a foundation for researchers to expand works in the future. All in all, this paper classifies each module of V-SLAM in detail and provides better readability to readers. This is undoubtedly the most comprehensive review of V-SLAM recently.

This article presents the fire Smith method, which integrates the plate model and the Smith method, to analyze the impact of fire temperature and extent on the buckling strength of frigates. This investigation focused on the frigate’s buckling strength and how it is affected by a fire, achieved by modifying both deck temperature and area. Leveraging the principle of oxygen consumption, a coefficient “D” was introduced to account for fire temperature and region variations. This enabled the characterization of buckling strength under varying temperature and regional conditions through 64 simulations conducted on a frigate model. The outcomes revealed that the disparity between simulation results and the fire Smith method remained below 10%, establishing a solid basis for engineering assessment. As the high-temperature area decreased and necessitated less oxygen, the ultimate strength initiated a decline. However, upon reaching a certain threshold temperature, the ultimate strength stabilized. Conversely, expansive high-temperature zones caused a decline in ultimate strength, coupled with an increased oxygen requirement. Under consistent oxygen consumption conditions, the rate of ultimate strength reduction intensified. Consequently, these divergent characteristics of ultimate strength in various high-temperature areas underscored that minimizing the expansive fire high-temperature zones can significantly enhance the ship’s fire resistance, safeguarding its structural integrity.