Functional Evaluation Research Articles

Midterm functional outcomes of synthetic cartilage implant (SCI) arthroplasty for hallux rigidus

Hallux rigidus is a common degenerative condition of first metatarso-phalangeal joint most commonly affecting patients above 50 years of age. The aim of our study is to evaluate the five-year results of synthetic cartilage implant (Cartiva) arthroplasty for hallux rigidus. A retrospective study of 70 patients who underwent synthetic cartilage implant interpositional arthroplasty were collected and analysed. Patients with Grade 3 to 4 hallux rigidus and who had failed conservative management were included. Patients who had previous forefoot surgery, hallux varus or valgus deformity of more than 250 and neuromuscular disease were excluded. Mean age at the time of operation was 63.4 years (range 42–84 years). The mean follow-up was 62.6 months. The functional evaluation was done using Manchester-Oxford Foot Questionnaire (MOxFQ). EQ-5D and EQVAS.86 patients were matriculated in the study with 70 patients being assessed at five years. The average preoperative MOxFQ score improved from 35.74 (31.44-40.04) to 19.11 (11.31- 26.91) at one year after surgery. The EQ-5D scores improved from preoperative average of 9.40 (8.14-10.66) to 4.26 (2.09-6.43) at one year. The preoperative EQVAS was 61.66 (51.25-72.07) to 71.45 (60.87-82.03 at one year. At five years follow up the average MOxFQ score was 17.6 (9.92-24.38), EQ-5D - 4.8 (2.26- 6.45) and EQVAS – 72.48 (62.40-82.56). Three patients had revision to first MTP fusion due to ongoing pain.Synthetic cartilage implant has demonstrated clinical efficacy and good functional outcomes at the end of five years for the treatment of Hallux rigidus.Level of Clinical Evidence: 4

Hsa_circ_0004194 suppresses colorectal cancer progression via hsa-miR-27a-3p

AimsTo investigate the functional role and the underlying molecular mechanisms associated with hsa_circ_0004194 in the context of colorectal cancer (CRC) and to elucidate its impact on cancer progression. ResultsA notable and statistically significant decrease in the expression levels of hsa_circ_0004194 was observed specifically within CRC tissues when compared to non-tumor colorectal mucosa tissues. Functional evaluations, such as CCK8 assays, plate clone formation analysis, and transwell migration assays, our study revealed hsa_circ_0004194 significantly reduced the activity behavior of CRC cells. This overexpression of hsa_circ_0004194 effectively hindered these key cellular processes, demonstrating its role in suppressing the aggressive behaviors of CRC cells. Additionally, in vivo experiments utilizing mouse xenograft models exhibited that the upregulation of hsa_circ_0004194 significantly attenuated tumor growth, reduced tumor volume, and diminished liver metastasis. Further mechanistic investigation, through the utilization of RNA pull-down and luciferase reporter assays, uncovered that hsa_circ_0004194 sequestered hsa-miR-27a-3p, thereby enhancing retinoic acid X receptor α (RXRα)’ expression which is in CRC cells. Moreover, this circular RNA also impeded the signaling pathway of Wnt/β-catenin. ConclusionOur study is the first to demonstrate that hsa_circ_0004194 exhibits downregulated expression in CRC and functions as a ceRNA by binding to and sequestering hsa-miR-27a-3p, thereby modulating the RXRα/β-catenin signaling pathway to inhibit CRC progression. This discovery suggests that hsa_circ_0004194 holds significant potential as a therapeutic biomarker for patients with CRC.

Clinical and Radiological Outcomes After Isolated Double-Bundle Medial Patellofemoral Ligament Reconstruction: A 5-Year Analysis.

There are few studies that have examined clinical and radiological outcomes at 5 years after isolated medial patellofemoral ligament (MPFL) reconstruction. To date, midterm outcomes after isolated double-bundle (DB) MPFL reconstruction are not well known. Isolated DB MPFL reconstruction using a patellar suture anchor technique would lead to improved functional scores and radiological findings, and these improvements would remain stable over the 5-year postoperative period. Case series; Level of evidence, 4. Isolated MPFL reconstruction was performed in patients with recurrent patellar instability between March 2013 and February 2017. Clinical and functional evaluations were performed via an interview using the Kujala, Lysholm, and Tegner scores preoperatively and at 6, 12, 24, and 60 months postoperatively. Radiographs were taken preoperatively, immediately postoperatively, and at 24 and 60 months after surgery. Radiographic assessments included measuring the modified Insall-Salvati ratio, congruence angle, and lateral patellofemoral angle. A total of 31 patients (31 knees) underwent isolated MPFL reconstruction; 4 patients did not complete 5-year follow-up, and thus, 27 patients (27 knees) were enrolled in the study. The mean age at the time of surgery was 22.0 ± 6.4 years (range, 14-32 years). All clinical and functional scores significantly improved in the first 2 years (P < .001), with the mean Kujala, Lysholm, and Tegner scores improving from 52.7 to 90.7, 49.6 to 92.7, and 2.9 to 5.1, respectively. There was no significant difference in scores between 2- and 5-year follow-up. All radiographic parameters significantly improved between preoperatively and immediately postoperatively (P < .001), with mean values for the modified Insall-Salvati ratio, congruence angle, and lateral patellofemoral angle improving from 1.7° to 1.6°, 5.7° to -6.6°, and 3.0° to 5.9°, respectively. No significant differences were observed in radiographic measurements between the postoperative time points. No patients experienced a patellar redislocation or fracture. The prospective analysis of isolated DB MPFL reconstruction at 5-year follow-up showed that clinical and radiological outcomes significantly improved postoperatively and were maintained to 5 years. These midterm results suggest that isolated DB MPFL reconstruction is an effective treatment option for patients with patellar instability.

Functional evaluation after cortical button fixation for distal biceps ruptures – Is there any difference between manual or non-manual workers?

BackgroundThis study aims to compare clinical and functional results after distal biceps tendon repair in manual workers vs. non-manual workers. MethodsThis is a retrospective comparative study which refers to 57 cases with distal biceps tendon rupture, divided in manual workers (24 elbows) and non-manual workers (33), that were treated by a single incision with cortical button and interference screw fixation. Included cases have a minimum of 3 months follow-up, post-operative X-ray and signed informed consent for the investigation. ResultsSupination and flexion strength was higher in manual workers vs. non-manual workers (p-value=0.192 and 0.878, respectively). Nine patients showed loss of range of motion, concerning supination and pronation, and this was correlated to worse functional scores. Functional scores tend to be superior in non-manual workers. Ten patients had heterotopic ossification and 20 patients reported lateral antebrachial cutaneous nerve neuropraxia; one had both. Most of them had a full recovery. ConclusionAccording to clinical evaluation and post-operative scores, the performed surgical procedure provides good to excellent mid-term functional results. Nevertheless, there were not any differences between manual or non-manual workers.

Chitosan-curcumin conjugate prepared by one-step free radical grafting: Characterization, and functional evaluation

Curcumin (Cur) is a naturally hydrophobic polyphenol, and it has a wide range of physiological functions. But the practical application of Cur is constrained by its low water solubility and poor stability. To improve these deficiencies of Cur, a novel Cur derivative (CS-Cur) was prepared by grafting chitosan (CS) with Cur through a one-step reaction of a free radical-mediated redox system. A series of characterizations provided evidence that the grafting of CS with Cur was successful. The obtained CS-Cur showed lower crystallinity and thermal properties than CS and Cur. After grafting, the water solubility of CS-Cur was found to be 9.76±2.45 g/L and greatly improved. Meanwhile, the CS-Cur showed good photothermal stability, antioxidant activity, and photodynamic antibacterial activity in an aqueous solution, and it had good in vitro biosafety. This provides an idea for the design and synthesis of novel highly water-soluble Cur derivatives and also improves the practical application of Cur in aqueous systems.

A physics-informed neural network enhanced importance sampling (PINN-IS) for data-free reliability analysis

Reliability analysis of highly sensitive structures is crucial to prevent catastrophic failures and ensure safety. Therefore, these safety-critical systems are to be designed for extremely rare failure events. Accurate statistical quantification of these events associated with a very low probability of occurrence requires millions of evaluations of the limit state function (LSF) involving computationally expensive numerical simulations. Variance reduction techniques like importance sampling (IS) reduce such repetitions to a few thousand. The use of a data-centric metamodel can further cut it down to a few hundred. In data-centric metamodeling approaches, the actual complex numerical analysis is performed at a few points to train the metamodel for approximating the structural response. On the other hand, a physics-informed neural network (PINN) can predict the structural response based on the governing differential equation describing the physics of the problem, without a single evaluation of the complex numerical solver, i.e., data-free. However, the existing PINN models for reliability analysis have been effective only in estimating a large range of failure probabilities (10-1∼10-3). To address this issue, the present study develops a PINN-based data-free reliability analysis for low failure probabilities (<10-5). In doing so, a two-stage PINN integrated with IS (PINN-IS) is proposed. The first stage is employed to approximate the most probable failure point (MPP) appropriately while the second stage enhances the accuracy of LSF predictions at the IS population centred on the approximated MPP. The effectiveness of the proposed approach is numerically illustrated by three structural reliability analysis examples.

Study on the efficacy of posterior cordotomy with partial arytenoidectomy in bilateral vocal fold paralysis

Objective:The aim of this study is to investigate the efficacy of posterior cordotomy with partial arytenoidectomy in bilateral vocal fold paralysis（BVFP）. Methods:Medical records of 37 patients with BVFP were retrospectively collected, and they were all admitted to the Department of Otolaryngology-Head and Neck Surgery, West China Hospital of Sichuan University, from Jan. 2019 to Dec. 2023. Preoperative and postoperative evaluations of respiratory function, voice quality, and swallowing function were conducted. Results:Postoperatively, 32 out of 37 patients achieved significant relief in breathing difficulties. Out of 29 patients with tracheostomy, 26（89.7%） were successfully decannulated. One month postoperative follow-up revealed a decline in voice quality for 33 patients（89.2%）, and 5 cases（13.5%） reported a decrease in swallowing function. However, by three months postoperatively, both voice quality and swallowing function showed significant improvement. Conclusion:Posterior cordotomy with partial arytenoidectomy is an effective surgical method for BVFP, and significantly improve respiratory difficulty despite its impact on voice quality, with no significant impairment to swallowing function, shows significant clinical value.

Clinical Effects of Additional Platelet-Rich Plasma Application to Exercise Therapy in Patients with Subacromial Impingement Syndrome: A Double-Blind Randomized Controlled Trial.

Exercise therapy (ET) is the main and initial treatment modality for treating subacromial impingement syndrome (SIS). The isolated or combined use of platelet-rich plasma (PRP) applications in treating SIS is increasing and promising. A comparison was made on the effectiveness of ET alone and in combination with PRP on pain, functionality, and quality of life (QoL) in patients with SIS. The purposes of this study were to (1) investigate the possible positive effects of PRP injections combined with ET in treating SIS on pain, functionality, and QoL and (2) propose an alternative treatment protocol. It was hypothesized that the group receiving PRP applications in addition to ET would have a better QoL due to less pain and higher functionality 6 months after treatment. Randomized controlled trial; Level of evidence, 2. Volunteer patients diagnosed with SIS were included based on history and physical examination findings. All participants underwent magnetic resonance imaging to confirm the diagnosis and exclude possible accompanying pathologies. The patients were randomly divided into 2 groups. The first group underwent ET at home for 8 weeks (ET group), and the second group received the same ET program and an additional 2 PRP injections, at the beginning of the study and the end of the fourth week (PRP group). Patients were evaluated initially and 6 months after the treatment using the visual analog scale (VAS) for pain score, Constant-Murley Score (CMS), and the 36-Item Short Form Health Survey (SF-36). The Kolmogorov-Smirnov test determined the conformity of the data to a normal distribution, chi-square analysis was used to compare categorical variables between groups, and the Mann-Whitney U test was used to compare continuous and intergroup variables. Intragroup changes before and after treatment were evaluated with the Wilcoxon signed-rank test. P < .05 was considered statistically significant. A total of 67 patients were initially enrolled; 5 were excluded and 6 were lost to follow-up (1 because of a COVID diagnosis). Thus, 56 patients (56 shoulders) were included for analysis. There were 28 patients in the ET group and 28 patients in the PRP group. There were no statistical differences between groups regarding participant characteristics and clinical evaluations before treatment. A statistically significant improvement was observed in pain (VAS subgroups), functionality (CMS subgroups), and QoL (SF-36 subgroups) evaluations of patients in both the ET and the PRP groups compared with before the treatment and 6 months after treatment (P < .05). At the 6-month posttreatment evaluation, the PRP group was statistically significantly superior to isolated ET in terms of VAS rest (P = .001) and night (P = .004) scores. This superiority was also in favor of the PRP group in flexion strength (P = .001), abduction strength (P = .046), and abduction degree (P = .041) measurements. There was no significant difference between ET and PRP groups regarding VAS activity, CMS, and SF-36 scores (P > .05) at 6 months. Our study showed that both isolated ET and additional PRP application to ET are effective methods in SIS treatment regarding pain, function, and QoL. Combining ET with PRP was superior in reducing pain and improving abduction degree and strength.

Functional evaluation of TMEM176B and its predictive role for severe respiratory viral infection through integrated analysis of single-cell and bulk RNA-sequencing.

Transmembrane protein 176B (TMEM176B), localized mainly on the endosomal membrane, has been reported as an immune regulatory factor in malignant diseases. However, the biological function of this molecule remains undetermined during respiratory viral infections. To investigate the functions and prognostic value of this gene, six gene sets were selected from the Gene Expression Omnibus database for research. First, the function of TMEM176B and its co-expressed genes were evaluated at different levels (cell, peripheral blood, lung tissue). Afterwards, a machine learning algorithm was utilized to analyze the relationship between TMEM176B and its interacting genes with prognosis. After importance evaluation and variable screening, a prognostic model was established. Finally, the reliability of the model was further verified through external data sets. In vitro experiments were conducted to validate the function of TMEM176B. TMEM176B and its co-expressed genes are involved in multiple processes such as inflammasome activation, myeloid immune cell development, and immune cell infiltration. Machine learning further screened 27 interacting gene modules including TMEM176B as prognostic models for severe respiratory viral infections, with the area under the ROC curve (AUCs) of 0.986 and 0.905 in derivation and external validation sets, respectively. We further confirmed that viral load as well as NLRP3 activation and cell death were significantly enhanced in TMEM176B-/- THP-1-differentiated macrophages via in vitro experiments. Our study revealed that TMEM176B is involved in a wide range of biological functions in respiratory viral infections and has potential prognostic value, which is expected to bring new insights into the clinical management of severe respiratory viral infection hosts.

Discriminating fingerprints of chronic neuropathic pain following spinal cord injury using artificial neural networks and mass spectrometry analysis of female mice serum

Spinal cord injury (SCI) often leads to central neuropathic pain, a condition associated with significant morbidity and is challenging in terms of the clinical management. Despite extensive efforts, identifying effective biomarkers for neuropathic pain remains elusive. Here we propose a novel approach combining matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with artificial neural networks (ANNs) to discriminate between mass spectral profiles associated with chronic neuropathic pain induced by SCI in female mice. Functional evaluations revealed persistent chronic neuropathic pain following mild SCI as well as minor locomotor disruptions, confirming the value of collecting serum samples. Mass spectra analysis revealed distinct profiles between chronic SCI and sham controls. On applying ANNs, 100% success was achieved in distinguishing between the two groups through the intensities of m/z peaks. Additionally, the ANNs also successfully discriminated between chronic and acute SCI phases. When reflexive pain response data was integrated with mass spectra, there was no improvement in the classification. These findings offer insights into neuropathic pain pathophysiology and underscore the potential of MALDI-TOF MS coupled with ANNs as a diagnostic tool for chronic neuropathic pain, potentially guiding attempts to discover biomarkers and develop treatments.

Intractability results for integration in tensor product spaces

We prove lower bounds on the worst-case error of numerical integration in tensor product spaces. The information complexity is the minimal number N of function evaluations that is necessary such that the N-th minimal error is less than a factor ε times the initial error, i.e., the error for N=0, where ε belongs to (0,1). We are interested to which extent the information complexity depends on the number d of variables of the integrands. If the information complexity grows exponentially fast in d, then the integration problem is said to suffer from the curse of dimensionality.Under the assumption of the existence of a worst-case function for the uni-variate problem, we present two methods for providing lower bounds on the information complexity. The first method is based on a suitable decomposition of the worst-case function and can be seen as a generalization of the method of decomposable reproducing kernels. The second method, although only applicable for positive quadrature rules, does not require a suitable decomposition of the worst-case function. Rather, it is based on a spline approximation of the worst-case function and can be used for analytic functions. Several applications of both methods are presented.

A Robust and Optimal Iterative Algorithm Employing a Weight Function for Solving Nonlinear Equations with Dynamics and Applications

This study introduces a novel, iterative algorithm that achieves fourth-order convergence for solving nonlinear equations. Satisfying the Kung–Traub conjecture, the proposed technique achieves an optimal order of four with an efficiency index (I) of 1.587, requiring three function evaluations. An analysis of convergence is presented to show the optimal fourth-order convergence. To verify the theoretical results, in-depth numerical comparisons are presented for both real and complex domains. The proposed algorithm is specifically examined on a variety of polynomial functions, and it is shown by the efficient and accurate results that it outperforms many existing algorithms in terms of speed and accuracy. The study not only explores the proposed method’s convergence properties, computational efficiency, and stability but also introduces a novel perspective by considering the count of black points as an indicator of a method’s divergence. By analyzing the mean number of iterations necessary for methods to converge within a cycle and measuring CPU time in seconds, this research provides a holistic assessment of both the efficiency and speed of iterative methods. Notably, the analysis of basins of attraction illustrates that our proposed method has larger sets of initial points that yield convergence.

Study design and procedures in the incontinence post robot-assisted radical prostatectomy: anatomical and functional causes (IPA) - a prospective observational clinical trial.

To describe the study design and procedures of the incontinence post robot- assisted radical prostatectomy, anatomical and functional causes (IPA) trial. This trial aims to identify and study patient and procedure specific factors leading to urinary incontinence post robot-assisted laparoscopic radical prostatectomy (RALP). The IPA study is a prospective, multicentre, open non-randomised surgical trial, including patients prior to RALP and registered on-line (ISRCTN67297115). IPA is administered from the Department of Urology at Sahlgrenska University Hospital, Gothenburg, Sweden. Patients undergo an anatomical and functional evaluation using magnetic resonance imaging (MRI), urodynamics including cystometry, pressure-flow and urethral pressure profile, and dynamic transrectal ultrasound prior to and 3 months after RALP. The incontinence data are gathered using patient reported outcome measure questionnaires. The primary endpoint is incontinence at 3 months after RALP, defined as need of any pad. The secondary endpoints are incontinence 12 months post RALP defined as need of any pad, and 3- and 12-months post RALP, defined as use of more than a safety pad. Until October 2023, 207 patients have been included of the stipulated 1,000, with an increasing rate of accrual. Out of these patients,187 have had a pre- and post-operative MRI and 177 have undergone pre- and post-operative urodynamics. The design of the IPA study, together with promising accrual and coming multicentre inclusion, will hopefully result in the identification, and deeper understanding, of the various risk-factors for post-RALP incontinence. This could improve information and decision making regarding adequate treatment for patients with prostate cancer.

USING THE BACKFIX METHOD TO REHABILITATE ATHLETES’ INJURY IN TRIPLE JUMP – A CASE STUDY

The triple jump is a complex athletic event where performance relies on a combination of speed, strength, and advanced technique in executing the three phases that form the biomechanics of the event. Due to the specific forces exerted on the athlete's musculoskeletal system, along with potential weaknesses in physical training, athletes are at risk of injury. This case study presents the original approach used to rehabilitate and prevent new injuries usually experienced by the Romanian athlete G.R.C., a 25-year-old European junior vice-champion in the triple jump. He sought treatment at the MediSport SRL clinic for multiple chronic and acute injuries that were limiting his performance. Comprehensive clinical and functional evaluations revealed all these limitations, prompting an integrated approach to his rehabilitation and training program. After the kinesitherapy program consisting of 18 sessions focused on functional musculoskeletal balancing using an electronic dynamometer, a key component of the BackFix system and method, important improvements were observed in core stability, static balance, and posture. Additionally, muscle strength in the previously deficient areas increased, pain disappeared in all affected regions, and recovery time after competitive effort improved, laying the foundation for optimal performance in the 2024 summer season. The successful use of the BackFix method leads us to recommend it as an alternative to other traditional training and recovery methods, while also encouraging further research into its application in the triple jump and other sports branches.

A novel directional simulation method for estimating failure possibility

Failure possibility plays a crucial role in assessing the safety level of structures under fuzzy uncertainty. However, the traditional fuzzy simulation method suffers from computational inefficiency as it requires a large number of samples for accurate estimation. To address this issue, a directional simulation method is proposed to improve the efficiency of estimating failure possibility. The directional simulation method reformulates the failure possibility estimation into two key steps: the generation of direction samples and the estimation of conditional failure possibility under each direction sample in the polar coordinate system of the standard fuzzy space. To ensure direction uniformity, these direction samples are generated by adopting a good lattice point set based on stratified sampling on the unit hypercube. The conditional failure possibility under each direction sample is estimated by solving the minimum root of a nonlinear equation. The proposed method effectively reduces the dimensionality of the fuzzy input and greatly improves the computational efficiency. To further enhance efficiency, an adaptive Kriging model is embedded into the directional simulation method to reduce the number of performance function evaluations. Four examples are performed to illustrate the accuracy and efficiency of the proposed method. The results highlight the superiority of the directional simulation method over the traditional fuzzy simulation method, offering substantial improvements in computational efficiency while maintaining high estimation accuracy.

Causal effect of psoriasis on aortic valve stenosis: a two-sample Mendelian randomization study.

Epidemiological studies have suggested a potential connection between psoriasis and an increased risk of aortic valve stenosis (AS), though the impact of psoriasis on AS progression remains uncertain. The study aims to investigate the causal relationship between psoriasis and AS using Mendelian randomization (MR) analysis, as well as to uncover potential mechanisms underlying this association. A two-sample MR analysis was conducted using publicly available summary statistics from genome-wide association studies (GWAS) of psoriasis and AS. Cis-eQTL and significant genes were identified for each causal single-nucleotide polymorphisms (SNPs), followed by pathway enrichment and protein-protein interaction (PPI) analysis for functional evaluation. Hub genes were pinpointed by Cytospace. The transcriptional profile of AS population was acquired, and interconnected genes networks were clustered using Molecular Complex Detection (MCODE). Our results demonstrate a significant causal relationship between psoriasis and AS, with a genetic predisposition to psoriasis associated with a higher AS risk (odds ratio: 1.46). Pathway and PPI analyses unveiled 15 hub genes, including HLA-C, HLA-B, ISG15, IFIT3, and MX2, along with immune-related pathways linking psoriasis and AS. Moreover, the transcriptional profiling of the AS database highlighted the significant involvement of adaptive immune cells in AS development. Notably, among the 15 hub genes, ISG15, MX2, OAS3, OASL, IFI6, and EPSTI1 exhibited higher expression in the AS population. Our study provides compelling evidence supporting a causal relationship between psoriasis and AS. Furthermore, the identified hub genes and immune-related pathways may play an important role in the development of both diseases.

Insights into flavor quality and metabolites profiles of fresh cheese with different probiotics by SPME-GC-MS and untargeted metabolomics

In this study, fresh cheeses produced with four novel probiotics (Lactobacillus casei PB-LC39, Lactobacillus rhamnosus PB-LR76, Lactobacillus helveticus HH-LH17, and Lactobacillus plantarum HH-LP56) were named as LC, LR, LH, and LP, respectively. SPME-GC-MS and untargeted metabolomics were used to compare and analyze the flavor quality, metabolites and metabolic pathways of LC, LR, LH and LP, and the potential function of differential metabolites was emphasized. The results demonstrated that the incorporation of probiotics resulted in a significant increase in the number of volatile flavor compounds and varying flavor profiles within the cheese. Especially LC, exhibited aromas reminiscent of wine, fruit and rose, and displayed the most favorable flavor qualities among all probiotic cheeses. The results of differential metabolite screening and metabolic pathway demonstrated that probiotic cheese could result in the production of 146–192 differential metabolites, mainly carbohydrates, proteins and acids. Arginine biosynthesis was a key differential metabolite pathway made by probiotics. The LC, LR, LH, and LP groups contained 22, 27, 23, and 24 functional metabolites, including L-carnitine, naringenin, and turanose et al., which might confer anti-inflammatory and improve lipid metabolism functions. These findings provide a theoretical basis for the further functional evaluation and development of probiotic cheese.

Development of a multi-analysis model using an epithelial-fibroblast co-culture system as an alternative to animal testing.

The evaluation of respiratory chemical substances has been mostly performed in animal tests (OECD TG 403, TG 412, TG 413, etc.). However, there have been ongoing discussions about the limited use of these inhalation toxicity tests due to differences in the anatomical structure of the respiratory tract, difficulty in exposure, laborious processes, and ethical reasons. Alternative animal testing methods that mimic in vivo testing are required. Therefore, in this study, we established a co-culture system composed of differentiated epithelial cells under an air-liquid interface (ALI) system in the apical part and fibroblasts in the basal part. This system was designed to mimic the wound-healing mechanism in the respiratory system. In addition, we developed a multi-analysis system that simultaneously performs toxicological and functional evaluations. Several individual assays were used sequentially in a multi-analysis model for pulmonary toxicity. Briefly, cytokine analysis, histology, and cilia motility were measured in the apical part, and cell migration and gel contraction assay were performed by exposing MRC-5 cells to the basal culture. First, human airway epithelial cells from bronchial (hAECB) were cultured under air-liquid interface (ALI) system conditions and validated pseudostratified epithelium by detecting differentiation-related epithelial markers using Transepithelial Electrical Resistance (TEER) measurement, Hematoxylin and Eosin (H&E) staining, and immunocytochemistry (ICC) staining. Afterward, the co-culture cells exposed to Transforming growth factor-beta 1 (TGF-β1), a key mediator of pulmonary fibrosis, induced significant toxicological responses such as cytotoxicity, cell migration, and gel contraction, which are wound-healing markers. In addition, cilia motility in epithelial cells was significantly decreased compared to control. Therefore, the multi-analysis model with a 3D epithelial-fibroblast co-culture system is expected to be useful in predicting pulmonary toxicity as a simple and efficient high-throughput screening method and as an alternative to animal testing.

Qin-Yu-Qing-Chang decoction reshapes colonic metabolism by activating PPAR-γ signaling to inhibit facultative anaerobes against DSS-induced colitis

BackgroundQin-Yu-Qing-Chang decoction (QYQC), an herbal formula from China, is extensively employed to manage ulcerative colitis (UC) and exhibits potential benefits for colonic function. Nevertheless, the fundamental molecular mechanisms of QYQC remain largely uncharted.MethodsThe primary constituents of QYQC were determined utilizing UHPLC-MS/MS analysis and the effectiveness of QYQC was assessed in a mouse model of colitis induced by dextran sulfate sodium. Evaluations of colon inflammatory responses and mucosal barrier function were thoroughly assessed. RNA sequencing, molecular docking, colonic energy metabolism, and 16S rRNA sequencing analysis were applied to uncover the complex mechanisms of QYQC in treating UC. Detect the signal transduction of the peroxisome proliferator-activated receptor-γ (PPAR-γ) both in the nucleus and cytoplasm. Furthermore, a PPAR-γ antagonist was strategically utilized to confirm the functional targets that QYQC exerts.ResultsUtilizing UHPLC-MS/MS, the principal constituents of the nine traditional Chinese medicinal herbs comprising QYQC were systematically identified. QYQC treatment substantially ameliorated colitis in mice, as evidenced by the improvement in symptoms and the reduction in colonic pathological injuries. Besides, QYQC treatment mitigated the inflammatory response and improved mucosal barrier function. Furthermore, QYQC enhanced the mitochondria citrate cycle (TCA cycle) by triggering PPAR-γ signaling and increasing the proportion of PPAR-γ entering the nucleus. This prevented the unconstrained expansion of facultative anaerobes, particularly pathogenic Escherichia coli (E. coli, family Enterobacteriaceae) and thus improved colitis. Results of molecular docking indicated that the representative chemical components of QYQC including Baicalin, Paeoniflorin, Mollugin, and Imperatorin bound well with PPAR-γ. The impact of QYQC on colitis was diminished in the presence of a PPAR-γ antagonist.ConclusionsIn summary, QYQC ameliorates UC by activating PPAR-γ signaling and increasing the proportion of PPAR-γ entering the nucleus, which enhances the energy metabolism of intestinal epithelial cells and thereby preventing the uncontrolled proliferation of facultative anaerobes.

Large language models as surrogate models in evolutionary algorithms: A preliminary study

Large Language Models (LLMs) have demonstrated remarkable advancements across diverse domains, manifesting considerable capabilities in evolutionary computation, notably in generating new solutions and automating algorithm design. Surrogate-assisted selection plays a pivotal role in evolutionary algorithms (EAs), especially in addressing expensive optimization problems by reducing the number of real function evaluations. However, whether LLMs can serve as surrogate models remains an unknown. In this study, we propose a novel surrogate model based purely on LLM inference capabilities, eliminating the need for training. Specifically, we formulate model-assisted selection as a classification problem or a regression problem, utilizing LLMs to directly evaluate the quality of new solutions based on historical data. This involves predicting whether a solution is good or bad, or approximating its value. This approach is then integrated into EAs, termed LLM-assisted EA (LAEA). Detailed experiments compared the visualization results of 2D data from 9 mainstream LLMs, as well as their performance on 5-10 dimensional problems. The experimental results demonstrate that LLMs have significant potential as surrogate models in evolutionary computation, achieving performance comparable to traditional surrogate models only using inference. This work offers new insights into the application of LLMs in evolutionary computation. Code is available at: https://github.com/hhyqhh/LAEA.git.