A randomized, double-blind, positive-controlled, Phase-II clinical trial to evaluate efficacy and safety of Fuke Qianjin capsule in Pakistani patients with pelvic inflammatory disease.

Ethnopharmacological relevance: Pelvic inflammatory disease (PID) is a frequently occurring gynecological disorder mainly caused by the inflammation of a woman's upper genital tract. Generally, antibiotics are used for treating PID, but prolonged use poses potential risks of gut bacterial imbalance, bacterial resistance, super bacteria production, and associated adverse reactions. Traditional Chinese medicine (TCM) has shown unique advantages in various ailments and has received widespread clinical research attention. Fuke Qianjin (FUKE) capsule is an approved National Medical Products Administration (NMPA License No. Z20020024) Chinese herbal prescription that has been widely used individually or in combination with other Western medicines for the treatment of various gynecological inflammatory diseases, including chronic cervicitis, endometritis, and chronic PID. Aim: This clinical trial was designed to assess the safety and efficacy of FUKE capsule in mild-to-moderate symptomatic PID patients. Materials and methods: This phase 2, randomized, double-blind, positive controlled clinical trial was conducted in mild-to-moderate symptomatic PID patients at a single center in Pakistan from 21 September 2021 to 11 March 2022. Eligible female participants were randomly assigned to a test and a control group with a ratio of 1:1. The test group subjects received two metronidazole (METRO) tablets and one doxycycline hyclate (DOXY) simulant at a time, twice daily for 14 days, and two Fuke Qianjin (FUKE) capsules, three times a day after a meal for 28 days. Subjects in the control group received two METRO tablets and one DOXY tablet at a time, twice daily for 14 days, and two FUKE simulant capsules, three times a day after meal for 28 days. The primary efficacy outcome was an improvement in pelvic pain symptoms assessed through a visual analog scale (VAS). The secondary outcomes were the improvement in secondary efficacy symptoms like local physical signs, clinical assessment of leucorrhea and cervical secretions through laboratory examination, and improvement in the maximum area of pelvic effusion assessed through gynecological ultrasound after the treatment. The safety outcomes were assessed through vital signs, laboratory tests, electrocardiogram findings, and adverse events/serious adverse events. Results: A total of 198 subjects with active PID were randomly assigned to a test group (n = 99) and a control group (n = 99). The baseline characteristics of the subjects in the two groups were similar. In the intention-to-treat analysis, the primary efficacy was 84.9% for the test group and 71.6% for the control group, with a statistically significant difference (p = 0.0370; 95% CI -0.2568 to -0.0088). The secondary clinical efficacy was 88.4% for the test group and 82.7% for the control group, with no significant difference (p = 0.2977; 95% CI -0.1632 to 0.0501). The improvement in local physical signs was 95.8% for the test group and 76.9% for the control group, with no significant difference (p = 0.0542; 95% CI -0.3697 to -0.0085). The inter-group non-inferiority comparison showed that the upper limit of the 95% CI was less than 0.15 and thus met the non-inferiority requirements of the test group to the control group. The results of clinical signs of leucorrhea and cervical secretions showed that there was no difference in the rate of improvement between the test and control groups, indicating that FUKE was non-inferior to DOXY. A total of 14 adverse events in eight subjects were observed in the trial, with an incidence rate of 4.7%. Four subjects in each group experienced seven adverse events with 4.5% and 4.8% incidence rates of adverse reactions in the test and control groups, with no statistically significant differences (p = 0.2001). No serious adverse events occurred in the trial. Conclusion: The results of this trial indicate that the test drug (Fuke Qianjin capsule) is non-inferior to the control drug (doxycycline hyclate tablet) in treating mild-to-moderate PID patients with comparable efficacy, safety, and tolerability to the control drug. Clinical Trial Registration: www.clinicaltrials.gov, identifier NCT04723069.

Microenvironment with NIR-Controlled ROS and Mechanical Tensions for Manipulating Cell Activities in Wound Healing.

The extracellular matrix (ECM) orchestrates cell behavior and tissue regeneration by modulating biochemical and mechanical signals. Manipulating cell-material interactions is crucial for leveraging biomaterials to regulate cell functions. Yet, integrating multiple cues in a single material remains a challenge. Here, near-infrared (NIR)-controlled multifunctional hydrogel platforms, named PIC/CM@NPs, are introduced to dictate fibroblast behavior during wound healing by tuning the matrix oxidative stress and mechanical tensions. PIC/CM@NPs are prepared through cell adhesion-medicated assembly of collagen-like polyisocyanide (PIC) polymers and cell-membrane-coated conjugated polymer nanoparticles (CM@NPs), which closely mimic the fibrous structure and nonlinear mechanics of ECM. Upon NIR stimulation, PIC/CM@NPs composites enhance fibroblast cell proliferation, migration, cytokine production, and myofibroblast activation, crucial for wound closure. Moreover, they exhibit effective and toxin removal antibacterial properties, reducing inflammation. This multifunctional approach accelerates healing by 95%, highlighting the importance of integrating biochemical and biophysical cues in the biomaterial design for advanced tissue regeneration.

Biocontrol activity and potential mechanism of volatile organic compounds from Aspergillus niger strain La2 against pear Valsa canker.

BACKGROUND: Valsa canker caused by Valsa pyri is one of the most destructive diseases of pear, leading to severe yield and economic losses. Volatile organic compounds (VOCs) from endophytes have important roles in the regulation of plant disease. In this study, we investigated the biocontrol activity of the endophytic fungus Aspergillus niger strain La2 and its antagonistic VOCs against pear Valsa canker. RESULTS: Strain La2 exhibited an obvious inhibitory effect against V. pyri. A colonization assay suggested that strain La2 could complete its life cycle on pear twigs. The symptoms of pear Valsa canker were weakened on detached pear twigs after treatment with strain La2. In addition, VOCs from strain La2 also significantly suppressed mycelial growth in V. pyri. Based on the results of headspace solid-phase microextraction/gas chromatography-mass spectrometry analysis, six possible VOCs produced by strain La2 were detected, of which 2,4-di-tert-butylphenol and 4-methyl-1-pentanol were the main antagonistic VOCs in terms of their effect on pear Valsa canker in vitro and in vivo. Further results showed that 4-methyl-1-pentanol could destroy the V. pyri hyphal structure and cell membrane integrity. Importantly, the activities of pear defense-related enzymes (polyphenol oxidase, phenylalanine ammonia lyase and superoxide dismutase) were enhanced after 4-methyl-1-pentanol treatment in pear twigs, suggesting that 4-methyl-1-pentanol might induce a plant disease resistance response. CONCLUSION: Aspergillus niger strain La2 and its VOCs 2,4-di-tert-butylphenol and 4-methyl-1-pentanol have potential as novel biocontrol agents of pear Valsa canker. © 2024 Society of Chemical Industry.

Impact of recombinant human brain natriuretic peptide on emergency dialysis and prognosis in end-stage renal disease patients with type 4 cardiorenal syndrome.

Recombinant human brain natriuretic peptide (rhBNP) effects on type 4 cardiorenal syndrome (CRS) and adverse events such as heart failure rehospitalization and all-cause mortality have not been assessed in large-scale research. This study evaluated the impact of rhBNP on emergency dialysis and prognosis in end-stage renal disease (ESRD) patients with type 4 CRS, and the risk factors of emergency dialysis. This retrospective cohort study included patients with type 4 CRS and ESRD admitted for decompensated heart failure between January 2016 and December 2021. Patients were divided into the rhBNP and non-rhBNP cohorts, according to whether they were prescribed rhBNP. The primary outcomes were emergency dialysis at first admission and cardiovascular events within a month after discharge. A total of 77 patients were included in the rhBNP cohort (49 males and 28 females, median age 67) and 79 in the non-rhBNP cohort (47 males and 32 females, median age 68). After adjusting for age, residual renal function, and primary diseases, Cox regression analysis showed that rhBNP was associated with emergency dialysis (HR = 0.633, 95% CI 0.420-0.953) and cardiovascular events (HR = 0.410, 95% CI 0.159-0.958). In addition, multivariate logistic regression analysis showed that estimated glomerular filtration rate (eGFR) (OR = 0.782, 95% CI 0.667-0.917, P = 0.002) and procalcitonin (PCT) levels (OR = 1.788, 95% CI 1.193-2.680, P = 0.005) at the first visit were independent risk factors for emergency dialysis while using rhBNP was a protective factor for emergency dialysis (OR = 0.195, 95% CI 0.084-0.451, P < 0.001). This study suggests that RhBNP can improve cardiac function and reduce the occurrence of emergency dialysis and cardiovascular events in ESRD patients with type 4 CRS.

Exploration of the Biocontrol Activity of Bacillus atrophaeus Strain HF1 against Pear Valsa Canker Caused by Valsa pyri.

Valsa pyri-induced pear Valsa canker is among the most prevalent diseases to impact pear quality and yields. Biocontrol strategies to control plant disease represent an attractive alternative to the application of fungicides. In this study, the potential utility of Bacillus atrophaeus strain HF1 was assessed as a biocontrol agent against pear Valsa canker. Strain HF1 suppressed V. pyri mycelium growth by 61.20% and induced the development of malformed hyphae. Both culture filtrate and volatile organic compounds (VOCs) derived from strain HF1 were able to antagonize V. pyri growth. Treatment with strain HF1-derived culture filtrate or VOCs also induced the destruction of hyphal cell membranes. Headspace mixtures prepared from strain HF1 were analyzed, leading to the identification of 27 potential VOCs. Of the thirteen pure chemicals tested, iberverin, hexanoic acid, and 2-methylvaleraldehyde exhibited the strongest antifungal effects on V. pyri, with respective EC50 values of 0.30, 6.65, and 74.07 µL L-1. Fumigation treatment of pear twigs with each of these three compounds was also sufficient to prevent the development of pear Valsa canker. As such, these results demonstrate that B. atrophaeus strain HF1 and the volatile compounds iberverin, hexanoic acid, and 2-methylvaleraldehyde exhibit promise as novel candidate biocontrol agents against pear Valsa canker.

Efficacy and safety of esketamine for sedation among patients undergoing gastrointestinal endoscopy: a systematic review and meta-analysis.

BACKGROUND: Patients who undergo gastrointestinal endoscopy often require propofol-based sedation combined with analgesics. At present, the efficacy and safety of esketamine as an adjunct to propofol for sedation during endoscopic procedures in patients remains controversial. Moreover, there is no universal agreement regarding the appropriate dose of esketamine supplementation. This study aimed to assess the efficacy and safety of esketamine as an adjunct to propofol for sedation during endoscopic procedures in patients. METHODS: Seven electronic databases and three clinical trial registry platforms were searched and the deadline was February 2023. Randomized controlled trials (RCTs) evaluating the efficacy of esketamine for sedation were included by two reviewers. Data from the eligible studies were combined to calculate the pooled risk ratio or standardized mean difference. RESULTS: Eighteen studies with 1962 esketamine participants were included in the analysis. As an adjunct to propofol, the administration of esketamine reduced the recovery time compared to normal saline (NS). However, there was no significant difference between the opioids group and ketamine group. For propofol dosage, the administration of esketamine required a lower propofol dosage compared to the NS group and opioids group].For complications, the esketamine group had fewer complications compared to the NS group and opioid group in patients, but there were no significant differences between the esketamine group and ketamine group. Notably, the coadministration of esketamine was associated with a higher risk of visual disturbance compared to the NS group. In addition, we used subgroup analysis to investigate whether 0.2-0.5 mg/kg esketamine was effective and tolerable for patients. CONCLUSION: Esketamine as an adjunct to propofol, is an appropriate effective alternative for sedation in participants undergoing gastrointestinal endoscopy. However, considering the possibility of its psychotomimetic effects, esketamine should be used with caution.

Synthetic fibrous hydrogels as a platform to decipher cell-matrix mechanical interactions.

Cells continuously sense external forces from their microenvironment, the extracellular matrix (ECM). In turn, they generate contractile forces, which stiffen and remodel this matrix. Although this bidirectional mechanical exchange is crucial for many cell functions, it remains poorly understood. Key challenges are that the majority of available matrices for such studies, either natural or synthetic, are difficult to control or lack biological relevance. Here, we use a synthetic, yet highly biomimetic hydrogel based on polyisocyanide (PIC) polymers to investigate the effects of the fibrous architecture and the nonlinear mechanics on cell-matrix interactions. Live-cell rheology was combined with advanced microscopy-based approaches to understand the mechanisms behind cell-induced matrix stiffening and plastic remodeling. We demonstrate how cell-mediated fiber remodeling and the propagation of fiber displacements are modulated by adjusting the biological and mechanical properties of this material. Moreover, we validate the biological relevance of our results by demonstrating that cellular tractions in PIC gels develop analogously to those in the natural ECM. This study highlights the potential of PIC gels to disentangle complex bidirectional cell-matrix interactions and to improve the design of materials for mechanobiology studies.

Fast reconstruction method of three-dimension model based on dual RGB-D cameras for peanut plant.

BACKGROUND: Plant shape and structure are important factors in peanut breeding research. Constructing a three-dimension (3D) model can provide an effective digital tool for comprehensive and quantitative analysis of peanut plant structure. Fast and accurate are always the goals of the plant 3D model reconstruction research. RESULTS: We proposed a 3D reconstruction method based on dual RGB-D cameras for the peanut plant 3D model quickly and accurately. The two Kinect v2 were mirror symmetry placed on both sides of the peanut plant, and the point cloud data obtained were filtered twice to remove noise interference. After rotation and translation based on the corresponding geometric relationship, the point cloud acquired by the two Kinect v2 was converted to the same coordinate system and spliced into the 3D structure of the peanut plant. The experiment was conducted at various growth stages based on twenty potted peanuts. The plant traits' height, width, length, and volume were calculated through the reconstructed 3D models, and manual measurement was also carried out during the experiment processing. The accuracy of the 3D model was evaluated through a synthetic coefficient, which was generated by calculating the average accuracy of the four traits. The test result showed that the average accuracy of the reconstructed peanut plant 3D model by this method is 93.42%. A comparative experiment with the iterative closest point (ICP) algorithm, a widely used 3D modeling algorithm, was additionally implemented to test the rapidity of this method. The test result shows that the proposed method is 2.54 times faster with approximated accuracy compared to the ICP method. CONCLUSIONS: The reconstruction method for the 3D model of the peanut plant described in this paper is capable of rapidly and accurately establishing a 3D model of the peanut plant while also meeting the modeling requirements for other species' breeding processes. This study offers a potential tool to further explore the 3D model for improving traits and agronomic qualities of plants.

Research on the Structure Design and Mechanical Properties of Performance Optimized Multi-Axial Geogrid.

In order to solve the problem of low transverse tensile strength of triaxial geogrid, a kind of performance-optimized multi-axial geogrid (POMG) that can bear larger transverse loads was designed. Firstly, the forming equipment and process of POMG are designed. Secondly, through the test of formability and mechanical properties, the POMG with good formability and mechanical properties is obtained, and the average tensile strength of POMG with circular and semicircular holes is the highest, reaching more than 16 KN/m. Finally, the feasibility of the process is further verified by numerical simulation, and the shape distribution and stress-strain law of POMG during the forming process are obtained, which provides further guidance for the actual production.

Biocontrol activity and action mechanism of Paenibacillus polymyxa strain Nl4 against pear Valsa canker caused by Valsa pyri.

Pear Valsa canker caused by Valsa pyri is among the most destructive diseases of pear, which causes significant economic loss. The present study was developed to explore the biocontrol efficiency and underlying antagonistic mechanism of Paenibacillus polymyxa strain Nl4 against V. pyri. P. polymyxa strain Nl4, one of the 120 different endophytic bacterial strains from pear branches, exhibited strong inhibitory effects against the mycelial growth of V. pyri and caused hyphal malformation. Culture filtrate derived from strain Nl4 was able to effectively suppress mycelial growth of V. pyri, and was found to exhibit strong protease, cellulase and ß-1, 3-glucanase activity. Through re-isolation assay, strain Nl4 was confirmed to be capable of colonizing and surviving in pear branch. Treatment with strain NI4 effectively protected against pear Valsa canker symptoms on detached pear twigs inoculated with V. pyri. Moreover, strain Nl4 promoted enhanced plant growth probably through the solubilization of phosphorus. Comparative transcriptomic analyses revealed that strain NI4 was able to suppress V. pyri growth in large part through the regulation of the expression of membrane- and energy metabolism-related genes in this pathogen. Further transcriptomic analyses of pear trees indicated that strain NI4 inoculation was associated with changes in the expression of genes associated with secondary metabolite biosynthesis, signal transduction, and cutin, suberine, and wax biosynthesis. Together, these data highlighted P. polymyxa strain Nl4 as a promising biocontrol agent against pear Valsa canker and investigated the possible mechanisms of strain Nl4 on control of this devastating disease.

Toward Tissue-Like Material Properties: Inducing In Situ Adaptive Behavior in Fibrous Hydrogels.

The materials properties of biological tissues are unique. Nature is able to spatially and temporally manipulate (mechanical) properties while maintaining responsiveness toward a variety of cues; all without majorly changing the material's composition. Artificial mimics, synthetic or biomaterial-based are far less advanced and poorly reproduce the natural cell microenvironment. A viable strategy to generate materials with advanced properties combines different materials into nanocomposites. This work describes nanocomposites of a synthetic fibrous hydrogel, based on polyisocyanide (PIC), that is noncovalently linked to a responsive cross-linker. The introduction of the cross-linker transforms the PIC gel from a static fibrous extracellular matrix mimic to a highly dynamic material that maintains biocompatibility, as demonstrated by in situ modification of the (non)linear mechanical properties and efficient self-healing properties. Key in the material design is cross-linking at the fibrillar level using nanoparticles, which, simultaneously may be used to introduce more advanced properties.

Polyisocyanide hydrogels with tunable nonlinear elasticity mediate liver carcinoma cell functional response.

Hepatocellular carcinoma development is closely related to the changes in tissue mechanics induced by excess collagen deposition and crosslinking, which leads to liver fibrosis and malignant progression. The role of matrix stiffness has been widely assessed using various linearly elastic materials. However, the liver, like many soft tissues, also exhibits nonlinear elasticity by strain-stiffening, allowing cells to mechanically interact with their micromilieus which has attracted much attention in cellular processes recently. Here, we use a biomimetic hydrogel grafting of GRGDS peptide with tunable nonlinear mechanical properties, polyisocyanides (PIC), to investigate the influence of strain-stiffening on HepG2 liver cancer cell behavior by tuning PIC polymer length. Compared to short PIC polymer with lower critical stress, PIC hydrogels composed of long polymer with higher critical stress promote the motility and invasiveness of HepG2 cells, and induce more actin stress fibers and higher expression level of mechanotransducer YAP and its nuclear translocation. Strikingly, the expression of calcium-activated potassium channel KCa3.1, an important biomarker in hepatocellular carcinoma, is also affected by the mechanical property of PIC hydrogels. It was also shown that downregulating the KCa3.1 channel can be achieved by inhibiting the formation of actin fibers. Our findings imply that the strain-stiffening property of PIC hydrogels affects the expression of KCa3.1 potassium channel via mediating cytoskeletal stress fiber formation, and ultimately influences the liver carcinoma cell functional response. STATEMENT OF SIGNIFICANCE: The effect of nonlinear elasticity by strain-stiffening, is assessed in HepG2 liver cancer cell behavior by using a biomimetic hydrogel with tunable mechanical properties, polyisocyanides (PIC). PIC gels with higher critical stress promote the motility and invasiveness of HepG2 cells and induce upregulated expression levels of KCa3.1 potassium channel and YAP, but which can be suppressed by inhibiting the formation of actin fibers. Our findings imply that the strain-stiffening property of PIC gels influences the expression of KCa3.1 potassium channel via mediating cytoskeletal stress fiber formation and, ultimately affects the liver carcinoma cell functional response.

Machine learning for improving high-dimensional proxy confounder adjustment in healthcare database studies: An overview of the current literature.

PURPOSE: Supplementing investigator-specified variables with large numbers of empirically identified features that collectively serve as 'proxies' for unspecified or unmeasured factors can often improve confounding control in studies utilizing administrative healthcare databases. Consequently, there has been a recent focus on the development of data-driven methods for high-dimensional proxy confounder adjustment in pharmacoepidemiologic research. In this paper, we survey current approaches and recent advancements for high-dimensional proxy confounder adjustment in healthcare database studies. METHODS: We discuss considerations underpinning three areas for high-dimensional proxy confounder adjustment: (1) feature generation-transforming raw data into covariates (or features) to be used for proxy adjustment; (2) covariate prioritization, selection, and adjustment; and (3) diagnostic assessment. We discuss challenges and avenues of future development within each area. RESULTS: There is a large literature on methods for high-dimensional confounder prioritization/selection, but relatively little has been written on best practices for feature generation and diagnostic assessment. Consequently, these areas have particular limitations and challenges. CONCLUSIONS: There is a growing body of evidence showing that machine-learning algorithms for high-dimensional proxy-confounder adjustment can supplement investigator-specified variables to improve confounding control compared to adjustment based on investigator-specified variables alone. However, more research is needed on best practices for feature generation and diagnostic assessment when applying methods for high-dimensional proxy confounder adjustment in pharmacoepidemiologic studies.

The Preparation of Biomineralized PIC/HA Hybrid Composites with Strain-Stiffening and the Effect on MC3T3-E1 Cells.

The development of biomimetic extracellular matrix (ECM) with fibrous structure and complex nonlinear mechanics has been attracting intensive attention over the past decades both in material science and tissue engineering. Polyisocyanopeptide (PIC) hydrogels are a class of fully synthetic materials that can mimic biogels, such as fibrin and collagen, in nearly all aspects, particularly the micron-sized gel network and the strong strain-stiffening behavior in the biological regime. Here, a biomimetic PIC/hydroxyapatite (HA) hybrid composite through an enzymatic biomineralization strategy is constructed. HA biominerals grew on PIC bundles in situ catalyzed by the embedded alkaline phosphatase (ALP), which further crosslinked the gel networks and reinforced the mechanical property of PIC hydrogels. Significantly, PIC/HA composites exhibited ultra-responsive nonlinear mechanics with higher sensitivity to mechanical stress compared with those without biomineralization. As a consequence, the presence of HA can provide cell adhesion sites for PIC gels and induce osteogenic differentiation of pre-osteoblasts by virtue of the changes in mechanical properties. With these outstanding properties, therefore, PIC/HA composites present promising prospects in bone tissue engineering as biomimetic ECM.

An Improved DeepLab v3+ Deep Learning Network Applied to the Segmentation of Grape Leaf Black Rot Spots.

The common method for evaluating the extent of grape disease is to classify the disease spots according to the area. The prerequisite for this operation is to accurately segment the disease spots. This paper presents an improved DeepLab v3+ deep learning network for the segmentation of grapevine leaf black rot spots. The ResNet101 network is used as the backbone network of DeepLab v3+, and a channel attention module is inserted into the residual module. Moreover, a feature fusion branch based on a feature pyramid network is added to the DeepLab v3+ encoder, which fuses feature maps of different levels. Test set TS1 from Plant Village and test set TS2 from an orchard field were used for testing to verify the segmentation performance of the method. In the test set TS1, the improved DeepLab v3+ had 0.848, 0.881, and 0.918 on the mean intersection over union (mIOU), recall, and F1-score evaluation indicators, respectively, which was 3.0, 2.3, and 1.7% greater than the original DeepLab v3+. In the test set TS2, the improved DeepLab v3+ improved the evaluation indicators mIOU, recall, and F1-score by 3.3, 2.5, and 1.9%, respectively. The test results show that the improved DeepLab v3+ has better segmentation performance. It is more suitable for the segmentation of grape leaf black rot spots and can be used as an effective tool for grape disease grade assessment.

Occurrence and Detection of Carbendazim Resistance in Botryosphaeria dothidea from Apple Orchards in China.

Botryosphaeria dothidea causes white rot, which is among the most devastating diseases affecting apple crops globally. In this study, we assessed B. dothidea resistance to carbendazim by collecting samples from warts on the infected branches of apple trees or from fruits exhibiting evidence of white rot. All samples were collected from different orchards in nine provinces of China in 2018 and 2019. In total, 440 B. dothidea isolates were evaluated, of which 19 isolates from three provinces were found to exhibit carbendazim resistance. We additionally explored the fitness and resistance stability of these isolates, revealing that they were no less fit than carbendazim-sensitive isolates in terms of pathogenicity, sporulation, and mycelial growth and that the observed carbendazim resistance was stable. Sequencing of the ß-tubulin gene in carbendazim-resistant isolates showed the presence of a substitution at codon 198 (GAG to GCG) that results in an alanine substitution in place of glutamic acid (E198A) in all 19 resistant isolates. A loop-mediated isothermal amplification (LAMP) method was then developed to rapidly and specifically identify this E198A mutation. This LAMP method offers value as a tool for rapidly detecting carbendazim-resistant isolates bearing this E198A mutation and can thus be used for the widespread monitoring of apple crops to detect and control the development of such resistance.

Framework for the synthesis of non-randomised studies and randomised controlled trials: a guidance on conducting a systematic review and meta-analysis for healthcare decision making.

INTRODUCTION: High-quality randomised controlled trials (RCTs) provide the most reliable evidence on the comparative efficacy of new medicines. However, non-randomised studies (NRS) are increasingly recognised as a source of insights into the real-world performance of novel therapeutic products, particularly when traditional RCTs are impractical or lack generalisability. This means there is a growing need for synthesising evidence from RCTs and NRS in healthcare decision making, particularly given recent developments such as innovative study designs, digital technologies and linked databases across countries. Crucially, however, no formal framework exists to guide the integration of these data types. OBJECTIVES AND METHODS: To address this gap, we used a mixed methods approach (review of existing guidance, methodological papers, Delphi survey) to develop guidance for researchers and healthcare decision-makers on when and how to best combine evidence from NRS and RCTs to improve transparency and build confidence in the resulting summary effect estimates. RESULTS: Our framework comprises seven steps on guiding the integration and interpretation of evidence from NRS and RCTs and we offer recommendations on the most appropriate statistical approaches based on three main analytical scenarios in healthcare decision making (specifically, 'high-bar evidence' when RCTs are the preferred source of evidence, 'medium,' and 'low' when NRS is the main source of inference). CONCLUSION: Our framework augments existing guidance on assessing the quality of NRS and their compatibility with RCTs for evidence synthesis, while also highlighting potential challenges in implementing it. This manuscript received endorsement from the International Society for Pharmacoepidemiology.

Cell-matrix reciprocity in 3D culture models with nonlinear elasticity.

Three-dimensional (3D) matrix models using hydrogels are powerful tools to understand and predict cell behavior. The interactions between the cell and its matrix, however is highly complex: the matrix has a profound effect on basic cell functions but simultaneously, cells are able to actively manipulate the matrix properties. This (mechano)reciprocity between cells and the extracellular matrix (ECM) is central in regulating tissue functions and it is fundamentally important to broadly consider the biomechanical properties of the in vivo ECM when designing in vitro matrix models. This manuscript discusses two commonly used biopolymer networks, i.e. collagen and fibrin gels, and one synthetic polymer network, polyisocyanide gel (PIC), which all possess the characteristic nonlinear mechanics in the biological stress regime. We start from the structure of the materials, then address the uses, advantages, and limitations of each material, to provide a guideline for tissue engineers and biophysicists in utilizing current materials and also designing new materials for 3D cell culture purposes.

Photothermal Conjugated Polymer Nanoparticles for Suppressing Breast Tumor Growth by Regulating TRPA1 Ion Channels.

Cancer cells survive by relying on oxidative stress defense against the accumulation of reactive oxygen species (ROS) during tumor formation. ROS-sensitive TRPA1 ion channels are overexpressed in breast cancer cells and induce a large influx of Ca2+ which upregulates the anti-apoptotic pathway to lead breast cancer cells to produce oxidative stress defense and enhance the resistance to ROS related chemotherapy. Targeting and inhibiting the TRPA1 ion channels are critical for breaking down the oxidative stress defense system and overcoming cellular resistance. Here, near-infrared (NIR) light-responsive conjugated polymer nanoparticles are designed and prepared to promote apoptosis of breast cancer cells, reduce cell drug resistance and suppress tumor growth through the remote and precise regulation of TRPA1 ion channels. Upon 808 nm laser irradiation, the nanoparticles block the formation of Ca2+ /CaM complex and regulate the content of MCL-1 protein. Especially, the nanoparticles overcome drug resistance of cancer cells, therefore accelerating apoptosis of cancer cells and suppressing tumor growth in mice. Compared with carboplatin, the volume of tumor induced by NPs-H decreases by 54.1%. This work provides a strategy to disrupt the oxidative stress defense system and downregulate the antiapoptotic signaling pathway in cancer cells.

Biocontrol activity of Bacillus halotolerans strain Pl7 against Botryosphaeria dothidea causing apple postharvest decay and potential mechanisms.

Apple ring rot, one of the most common apple postharvest diseases during storage, is caused by Botryosphaeria dothidea. Fungicide application is the most widely used method to control this disease, but the increasing environmental and food safety concerns greatly limit their use. The present study aimed to examine the biocontrol activity and underlying action mechanism of Bacillus halotolerans strain Pl7 against B. dothidea. The results revealed that B. halotolerans strain Pl7 exhibited strong inhibitory activity against B. dothidea by 69% in vitro. The culture filtrate of strain Pl7 possessed cellulase, ß-1, 3-glucanase, protease activity and mediated the antifungal activity against B. dothidea. Further analysis demonstrated that culture filtrate of strain Pl7 could cause cell membrane permeabilization of B. dothidea. Apple fruit suffering from ring rot induced by a carbendazim (CBZ)-sensitive or -resistant B. dothidea isolate was much suppressed after being treated with strain Pl7, maintaining postharvest quality. The ability of strain Pl7 to swiftly colonize and thrive in apple fruit wounds was demonstrated by a re-isolation assay. Additional transcriptome studies of untreated and treated apple fruit with strain Pl7 revealed that strain Pl7 mostly changed the expression of genes functioning in plant secondary metabolite biosynthesis and plant-pathogen interaction. In light of these outcomes, the underlying antagonistic mechanism was investigated, and B. halotolerans strain Pl7 was identified as a promsing microbial biocontrol agent against apple postharvest decay.