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Stochastic differential equations (SDE) are a powerful tool to model biological regulatory processes with intrinsic and extrinsic noise. However, numerical simulations of SDE models may be problematic if the values of noise terms are negative and large, which is not realistic for biological systems since the molecular copy numbers or protein concentrations should be non-negative. To address this issue, we propose the composite Patankar-Euler methods to obtain positive simulations of SDE models. A SDE model is separated into three parts, namely, the positive-valued drift terms, negative-valued drift terms, and diffusion terms. We first propose the deterministic Patankar-Euler method to avoid negative solutions generated from the negative-valued drift terms. The stochastic Patankar-Euler method is designed to avoid negative solutions generated from both the negative-valued drift terms and diffusion terms. These Patankar-Euler methods have the strong convergence order of a half. The composite Patankar-Euler methods are the combinations of the explicit Euler method, deterministic Patankar-Euler method, and stochastic Patankar-Euler method. Three SDE system models are used to examine the effectiveness, accuracy, and convergence properties of the composite Patankar-Euler methods. Numerical results suggest that the composite Patankar-Euler methods are effective methods to ensure positive simulations when any appropriate stepsize is used. [ABSTRACT FROM AUTHOR]

Purpose: Adefovir (as dipivoxil) was selected as a probe drug in a previous transporter cocktail phenotyping study to assess renal organic anion transporter 1 (OAT1), with renal clearance (CLR) as the primary parameter describing renal elimination. An approximately 20% higher systemic exposure of adefovir was observed when combined with other cocktail components (metformin, sitagliptin, pitavastatin, and digoxin) compared to sole administration. The present evaluation applied a population pharmacokinetic (popPK) modeling approach to describe adefovir pharmacokinetics as a cocktail component in more detail. Methods: Data from 24 healthy subjects were reanalyzed. After establishing a base model, covariate effects, including the impact of co-administered drugs, were assessed using forward inclusion then backward elimination. Results: A one-compartment model with first-order absorption (including lag time) and a combination of nonlinear renal and linear nonrenal elimination best described the data. A significantly higher apparent bioavailability (73.6% vs. 59.0%) and a lower apparent absorption rate constant (2.29 h−1 vs. 5.18 h−1) were identified in the combined period compared to the sole administration period, while no difference was seen in renal elimination. The population estimate for the Michaelis-Menten constant (Km) of the nonlinear renal elimination was 170 nmol/L, exceeding the observed range of adefovir plasma maximum concentration, while the maximum rate (Vmax) of nonlinear renal elimination was 2.40 µmol/h at the median absolute estimated glomerular filtration rate of 105 mL/min. Conclusion: The popPK modeling approach indicated that the co-administration primarily affected the apparent absorption and/or prodrug conversion of adefovir dipivoxil, resulting in the minor drug-drug interaction observed for adefovir as a victim. However, renal elimination remained unaffected. The high Km value suggests that assessing renal OAT1 activity by CLR has no relevant misspecification error with the cocktail doses used. [ABSTRACT FROM AUTHOR]

Objective Hydroxychloroquine (HCQ) has immunomodulatory, antithrombotic, cardiovascular, antimicrobial, and antineoplastic effects. In this study, we aimed to investigate the antiapoptotic and immunomodulator effects of intraperitoneal HCQ on hypoxic–ischemic (HI) injury in newborn rats. Study Design Wistar albino rats, 7 to 10 days old, were randomly divided into three groups: hypoxic–ischemic encephalopathy (HIE) group, HIE treated with HCQ group, and Sham group. Left common carotid artery ligation and hypoxia model were performed in HIE and HCQ groups. The HCQ group was treated with 80 mg/kg intraperitoneal HCQ every 24 hours for 3 days, while Sham and HIE groups were given physiological saline. After 72 hours, rats were decapitated and brain tissues were stained with hematoxylin and eosin, TUNEL, and IL-1β for histopathological grading and neuronal cell injury. Results Neuronal apoptosis was statistically lower in all neuroanatomical areas in the HCQ group compared with the HIE group. IL-1β-stained areas were similar in both HCQ and HIE groups but significantly higher compared with the Sham group. Histopathological grading scores were found to be lower in the HCQ group on the left parietal cortex and hippocampus region. Conclusion In this study, we have shown for the first time that HCQ treatment decreased apoptosis in HI newborn rat model in both hemispheres. HCQ may be a promising adjuvant therapy in neonatal HIE. Key Points HCQ decreased neuronal apoptosis in the ischemic penumbra of the rat brain. HCQ attenuates hypoxia–ischemia-induced brain injury in neonatal rats. HCQ has no anti-inflammatory effect on HI injury. [ABSTRACT FROM AUTHOR]

Sugar-sweetened beverage (SSB) and fruit juice (FJ) consumption may promote lipid abnormalities in childhood. We examined the association between SSB/FJ intake and lipid levels using electronic health record data for 2816 adolescents. Multivariable logistic regression models treated clinical cutpoints for abnormal lipid levels (triglycerides [TG], high-density lipoprotein (HDL), low-density lipoprotein [LDL], and total cholesterol) as dependent variables. In models not adjusted for adiposity, elevated SSB and FJ consumption was associated with increased odds of having abnormally high TG (SSB: odds ratio [OR] = 1.28 (95% confidence interval [CI] = [1.07-1.52], P =.007); FJ: 1.35 ([1.09-1.69], P =.007)) and abnormally low HDL (SSB: 1.47 ([1.17-1.86], P =.001); FJ: 1.35 ([1.02-1.78], P =.03)). Adjusting for adiposity, a likely mediator of the relationship, attenuated these associations. These findings support the need for identifying unhealthy beverage consumption habits during childhood health care visits as a modifiable behavior associated with cardiometabolic risk. [ABSTRACT FROM AUTHOR]

The incidence and mortality rates of esophageal squamous cell carcinoma (ESCC) have been significantly increasing in China. Indole-3-carbinol (I3C), a naturally occurring component in cruciferous vegetables, is an effective cancer therapy. Yet, its effect and action mechanism in ESCC are still not fully understood. This study explored the role of I3C in ESCC in vitro and in vivo by focusing on the Wnt/β-catenin signaling pathway. MTT and flow cytometry were used to assess cell viability and apoptosis in EC18 and TE1 cells, while wound healing and transwell assays were used to investigate cell migration and invasion in vitro. Expression of β-catenin, c-myc, and cyclin D1 was determined by Western blot; LiCl (an agonist of the canonical Wnt signaling that inhibits GSK3β activity) was used to assess the role of I3C on the Wnt/β-catenin signaling pathway. For in vivo experiments, nude BALB/c mice bearing EC18 xenografts were treated with I3C and/or LiCl. I3C promoted ESCC apoptosis and inhibited cell migration and invasion by downregulating β-catenin, c-myc, and cyclin D1 in vitro and decreased the tumor growth in vivo; this process was reversed by LiCl treatment. In summary, I3C inhibits ESCC malignant behavior by suppressing the Wnt/β-catenin signaling pathway, thus deeming it a promising drug for ESCC treatment. [ABSTRACT FROM AUTHOR]

For more than half a century, biologist Julian Huxley's term, the "Modern Synthesis", has been used as a label for a model of biological evolution where genetic influences are viewed as a principal source of creativity and change. Over the years, as evidence has accumulated that there are many other, far more important factors at work in evolution, theoretical "compromises," such as the so-called "Extended Synthesis", have been proposed. This is no longer tenable. It is time to abandon the Modern Synthesis, and its doppelganger "The Selfish Gene". Here is the case for a new, multi-faceted, open-ended, "inclusive" evolutionary synthesis, where living systems themselves are recognized as purposeful (teleonomic) "agents" and cooperative effects (synergies) of various kinds are seen as all-important influences. • The "Modern Synthesis" in evolution emphasizes a competitive "struggle for existence" among "selfish genes". • Over the years many other sources of evolutionary causation have been identified. • This prompted the proposal for an "extended synthesis". • However, it is now evident that genes play only a minor role in evolution. • It's time to abandon the Modern Synthesis and develop a more "inclusive" synthesis. [ABSTRACT FROM AUTHOR]

Two previously undescribed iridoid glycosides, 6'-O-trans-feruloyl-(4S,6R)-3,4-dihydro-3β-ethoxypaederoside (1) and 6'-O-trans-caffeoyl-(4S,6R)-3,4-dihydro-2'-O-3α-paederoside (2), were isolated from the 90% EtOH extract of the air dried aerial parts of Paederia Foetida. Structural elucidation of all the compounds was performed by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy. The two isolated iridoid glycosides were tested in vivo for their antinociceptive properties. As a result, 2 showed potent antinociceptive effect and its ID50 value (53.4 μmol/kg) was 2-fold less than those of the positive control drugs aspirin and acetaminophen. [ABSTRACT FROM AUTHOR]

Background and Aim: Previous studies have shown promising findings on effectiveness of noisy Galvanic Vestibular Stimulation (nGVS) in various cognitive disorders. The connections of the vestibular system with the hippocampus has been proven. Here we investigated the effect of vestibular galvanic stimulation on the improvement of spatial learning and memory of rats. Methods: Twelve Wistar rats were randomly divided into control and nGVS groups. The nGVS group underwent 30-minute sessions of stimulation at sub-threshold levels for a duration of fourteen days. Following the intervention, both groups underwent assessments of cognitive indices through the Morris water maze task, hippocampal neuronal spike rate by Single-Unit Recording (SUR) and the concentrations of c-fos protein in the hippocampus were measured using ELISA device. Results: The nGVS group exhibited a significant difference compared to the control group in both the time taken to reach the target platform and the percentage of time spent in the goal quarter during the Morris water maze test. The nGVS treatment significantly enhanced spike rate of hippocampal dentate gyrus (p<0.01) compared to the control group. Additionally, c-fos protein concentrations were increased in the nGVS (5.833) than the control group (4.126), (p<0.001). Conclusion: According to the obtained results, nGVS plays a role in improving spatial memory, and a longer duration of intervention is suggested to achieve more obvious improvement results. [ABSTRACT FROM AUTHOR]

Aims: Endovenous microwave ablation (EMWA) is an endovenous thermoablation (EVTA) system to ablate incompetent truncal veins. Early results suggest that EMWA uses more power than endovenous laser ablation (EVLA) to get the same results. We aimed to define the parameters for EMWA, which give the same tissue ablation as EVLA, using the validated porcine liver model. Methods: EVLA (1470 nm 600 micron radial fibre) treatments were performed at 6 W, 8 W and 10 W, at pullback speeds of 6, 7, 8 and 9 s/cm, giving Linear Endovenous Energy Densities (LEEDs) between 36 - 90 J/cm. Each combination of power and pullback was repeated 5 times. We then used EMWA in the same model. Powers of 35-75 W and pullback speeds of 4-9 s/cm were used (LEEDs 140-675 J/cm). Ablation tracts from both devices were analysed by 2 blinded observers, noting thermal spread and carbonisation. Results: For each commonly used parameter for EVLA, we identified a range of parameters for EMWA that produced similar tissue ablation in the porcine liver model. To keep the pullback speeds within the usual range, powers of 35-75 W were needed with EMWA, with mean EMWA LEEDs 3.9 - 5.8 times higher than EVLA LEEDs. We found the quicker the pullback speed, the higher the multiple of EMWA LEED we needed to get the same effect. Conclusion: We have identified parameters for EMWA that gave equivalent tissue ablation in the porcine liver model to commonly used parameters used for EVLA. These need to be validated clinically, but as the model used has already been validated against clinical outcome in endovenous thermal ablation, there is little reason to suspect that these results would not be valid. As the power during EMWA is higher than EVLA, EVMA LEEDs are approximately 4-6 times higher than EVLA LEEDs to achieve the same thermal effect on the tissues. [ABSTRACT FROM AUTHOR]

Reservoirs exert a profound influence on the cycling of dissolved organic matter (DOM) in inland waters by altering flow regimes. Biological incubations can help to disentangle the role that microbial processing plays in the DOM cycling within reservoirs. However, the complex DOM composition poses a great challenge to the analysis of such data. Here we tested if the interpretable machine learning (ML) methodologies can contribute to capturing the relationships between molecular reactivity and composition. We developed time‐specific ML models based on 7‐day and 30‐day incubations to simulate the biogeochemical processes in the Three Gorges Reservoir over shorter and longer water retention periods, respectively. Results showed that the extended water retention time likely allows the successive microbial degradation of molecules, with stochasticity exerting a non‐negligible effect on the molecular composition at the initial stage of the incubation. This study highlights the potential of ML in enhancing our interpretation of DOM dynamics over time. Plain Language Summary: As a comprehensive man‐made infrastructure, reservoirs significantly influence the chemical composition, reactivity, and turnover time of dissolved organic matter (DOM) within inland waters. However, it remains elusive how DOM molecules respond to microbial processing over different time scales. Besides the well‐recognized predictive power of machine learning (ML) methodologies, we delved into the processes of tuning the ML models to acquire additional interpretability. We used an under‐sampling strategy to improve model performance and simultaneously observed the variations in model performance metrics for different biological reactivity pools over incubations with different durations. We find that shorter incubation periods result in a broader range of molecules disappearing, with a greater contribution of stochasticity, while the longer incubation allows the successive biodegradation of oxygen‐poor compounds, with a greater contribution of directed degradation. As a complement to traditional geochemical methods, we unveiled a novel perspective in understanding the DOM dynamics over time using ML. Key Points: Machine learning (ML) models were built to correlate the molecular composition and biological reactivity at the world's largest reservoirShorter incubations result in a broader range of molecules disappearing, with a greater contribution of stochasticityTuning the ML model contributes to yield additional interpretability beyond its well‐recognized predictive power [ABSTRACT FROM AUTHOR]

Background: Resident microglia- and peripheric macrophage-mediated neuroinflammation plays a predominant role in the occurrence and development of ischemic stroke. Microglia undergo polarization to M1/M2-like phenotype under stress stimulation, which mediates intracellular inflammatory response. β-elemene is a natural sesquiterpene and possesses potent anti-inflammatory activity. This study aimed to investigate the anti-inflammatory efficacy and mechanism of β-elemene in ischemic stroke from the perspective of balancing microglia M1/M2-like polarization. Methods: The middle cerebral artery occlusion (MCAO) model and photothrombotic stroke model were established to explore the regulation effect of β-elemene on the cerebral ischemic injury. The LPS and IFN-γ stimulated BV-2 cells were used to demonstrate the anti-inflammatory effects and potential mechanism of β-elemene regulating M1/M2-like polarization in vitro. Results: In C57BL/6 J mice subjected to MCAO model and photothrombotic stroke model, β-elemene attenuated neurological deficit, reduced the infarction volume and neuroinflammation, thus improving ischemic stroke injury. β-elemene promoted the phenotype transformation of microglia from M1-like to M2-like, which prevented neurons from oxygen and glucose deprivation/reoxygenation (OGD/R) injury by inhibiting inflammatory factor release, thereby reducing neuronal apoptosis. Mechanically, β-elemene prevented the activation of TLR4/NF-κΒ and MAPK signaling pathway and increased AKT/mTOR mediated-autophagy, thereby promoting M2-like polarization of microglia. Conclusions: These results indicated that β-elemene improved cerebral ischemic injury and promoted the transformation of microglia phenotype from M1-like to M2-like, at least in part, through AKT/mTOR-mediated autophagy. This study demonstrated that β-elemene might serve as a promising drug for alleviating ischemic stroke injury. [ABSTRACT FROM AUTHOR]

Background: This study aimed to validate alterations in the gene expression of DNA methylation-related enzymes and global methylation in the peripheral blood mononuclear cell (PBMC) and synovial tissues of animal hip osteoarthritis (OA) models. Methods: Animals were assigned to the control (no treatment), sham (25 µL of sterile saline), and OA (25 µL of sterile saline and 2 mg of monoiodoacetate) groups. Microcomputed tomography scan, histopathological assessment and pain threshold measurement were performed after induction. The mRNA expression of the DNA methylation machinery genes and global DNA methylation in the PBMC and hip synovial tissue were evaluated. Results: The OA group presented with hip joint OA histopathologically and radiologically and decreased pain threshold. The mRNA expression of DNA methyltransferase (Dnmt 3a), ten–eleven translocation (Tet) 1 and Tet 3 in the synovial tissue of the OA group was significantly upregulated. Global DNA methylation in the synovial tissue of the OA group was significantly higher than that of the control and sham groups. Conclusions: The intra-articular administration of monoiodoacetate induced hip joint OA and decreased pain threshold. The DNA methylation machinery in the synovial tissues of hip OA was altered. [ABSTRACT FROM AUTHOR]

Allergic bronchopulmonary aspergillosis and invasive fungal diseases represent distinct infectious entities that cause significant morbidity and mortality. Currently, administered inhaled antifungal therapies are unapproved, have suboptimal efficacy, and are associated with considerable adverse reactions. The emergence of resistant pathogens is also a growing concern. Inhaled antifungal development programs are challenged by inadequate nonclinical infection models, highly heterogenous patient populations, low prevalence rates of fungal diseases, difficulties defining clinical trial enrollment criteria, and lack of robust clinical trial endpoints. On 25 September 2020, the US Food and Drug Administration (FDA) convened a workshop with experts in pulmonary medicine and infectious diseases from academia, industry, and other governmental agencies. Key discussion topics included regulatory incentives to facilitate development of inhaled antifungal drugs and combination inhalational devices, limitations of existing nonclinical models and clinical trial designs, patient perspectives, and industry insights. [ABSTRACT FROM AUTHOR]

Food bioactives exhibit various health-promoting effects and are widely used in functional foods to maintain human health. After oral intake, bioactives undergo complex biological processes before reaching the target organs to exert their biological effects. However, several factors may reduce their bioavailability. Colloidal systems have attracted special attention due to their great potential to improve bioavailability and bioefficiency. Herein, we focus on the importance of in vivo studies of the biological fates of bioactives delivered by colloidal systems. Increasing evidence demonstrates that the construction, composition, and physicochemical properties of the delivery systems significantly influence the in vivo biological fates of bioactives. These results demonstrate the great potential to control the in vivo behavior of food bioactives by designing specific delivery systems. We also compare in vivo and in vitro models used for biological studies of the fate of food bioactives delivered by colloidal systems. Meanwhile, the significance of the gut microbiota, targeted delivery, and personalized nutrition should be carefully considered. This review provides new insight for further studies of food bioactives delivered by colloidal systems, as well as scientific guidance for the reasonable design of personalized nutrition. [ABSTRACT FROM AUTHOR]

This paper presents an analytical solution to the model. By solving the system of nonlinear reaction-diffusion equations using Akbari–Ganji's method (AGM), we can derive the semi-analytical expressions for substrate and oxidized and reduced mediator concentrations. These models provide information about enzyme electrode mechanisms and their kinetics. These modeling results can be helpful for sensor design, optimization, and determining how the electrode will react. Further, we studied the effects of many physical and biological parameters on model prediction. The mathematical equations, which are nonlinear partial differential equations, are solved using AGM. Also, we derived the semi-analytical results for concentrations for saturated and unsaturated kinetics. It is verified that the proposed solution is validated by comparing it with numerical solutions. [ABSTRACT FROM AUTHOR]

Background: Fibrosis is a significant pathological feature of chronic skeletal muscle injury, profoundly affecting muscle regeneration. Fibro-adipogenic progenitors (FAPs) have the ability to differentiate into myofibroblasts, acting as a primary source of extracellular matrix (ECM). the process by which FAPs differentiate into myofibroblasts during chronic skeletal muscle injury remains inadequately explored. Method: mouse model with sciatic nerve denervated was constructed and miRNA expression profiles between the mouse model and uninjured mouse were analyzed. qRT/PCR and immunofluorescence elucidated the effect of miR-27b-3p on fibrosis in vivo and in vitro. Dual-luciferase reporter identified the target gene of miR-27b-3p, and finally knocked down or overexpressed the target gene and phosphorylation inhibition of Smad verified the influence of downstream molecules on the abundance of miR-27b-3p and fibrogenic differentiation of FAPs. Result: FAPs derived from a mouse model with sciatic nerves denervated exhibited a progressively worsening fibrotic phenotype over time. Introducing agomiR-27b-3p effectively suppressed fibrosis both in vitro and in vivo. MiR-27b-3p targeted Transforming Growth Factor Beta Receptor 1 (TGF-βR1) and the abundance of miR-27b-3p was negatively regulated by TGF-βR1/Smad. Conclusion: miR-27b-3p targeting the TGF-βR1/Smad pathway is a novel mechanism for regulating fibrogenic differentiation of FAPs. Increasing abundance of miR-27b-3p, suppressing expression of TGF-βR1 and inhibiting phosphorylation of smad3 presented potential strategies for treating fibrosis in chronic skeletal muscle injury. [ABSTRACT FROM AUTHOR]

• Maternal copper deficiency induced growth retardation in offspring. • Maternal copper deficiency caused cardiac dysfunction and liver injury in offspring. • Autophagy is activated by copper deficiency in offspring. Maternal nutritional deficiencies during pregnancy result in birth defects and elevate the risk of cardiovascular diseases and metabolic diseases. Accumulating evidence suggests that deficiency of copper, a fundamental trace element involved in several pivotal physiological processes, promotes the onset of multiple diseases, notably heart and liver diseases. Yet, exploration into the effects of maternal copper deficiency (CuD) on offspring is still limited. In this study, we hypothesized that maternal CuD induced cardiomyopathy and liver injury in offspring through the activation of autophagy. We established a maternal CuD mouse model by feeding pregnant C57BL/6 mice with a CuD diet until the end of the experiment. Echocardiography, histological analysis, western blotting, and quantitative polymerase chain reaction were performed on offspring at postnatal day 14. We found that maternal CuD caused growth retardation and early postnatal death in the offspring. Furthermore, our results revealed that CuD induced cardiac systolic dysfunction, cardiac hypertrophy, hepatic steatosis, and liver injury. Moreover, higher expression of LC3 and lower expression of p62 were observed in the heart tissues and liver tissues of CuD mice compared with the control group, indicating that CuD induced autophagy activation. In conclusion, maternal CuD caused severely deleterious effects on the heart and liver of the offspring via activating autophagy. To explore the effect of dietary maternal CuD on offspring, we established an animal model by feeding pregnant mice with a CuD diet. We found that CuD caused cardiac systolic dysfunction and liver injury. Moreover, we presented the increased LC3 and decreased p62 in CuD mouse heart tissues and liver tissues. These results indicate that CuD causes systolic dysfunction and hepatic steatosis in offspring, which is associated with activation of autophagy. Abbreviations: CuA, copper adequate; CuD, copper deficiency. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: We aimed to investigate the role of apoptosis and its effects on cavernosal smoothmuscle (CSM) function after ischemic priapism (IP) in a rat model. Materials and Methods: Twelve adult Sprague-Dawley rats were assigned into two groups: The priapism and control groups. In all rats, erections were obtained by the vacuum method; however, in the priapism group, erections were maintained with a rubber band for 4 h to mimic priapism. After 14 days following this procedure, penile excision was performed and cavernosal tissues were investigated pharmacologically and histopathologically. Isometric tension changes due to several contractile and relaxant pharmacological agents were investigated with/without nitric oxide synthase (NOS) and guanylate cyclase (GC) inhibition. Results: Isometric contraction and relaxation responses due to the agents applied did not differ between the groups. However, with NOS and GC inhibition, the cavernosal tissues relaxed less in the priapism group than in the controls (p<0.05). Histopathological evaluation of the tissues revealed that the average apoptosis rates were greater in the priapism group than in the controls in both the CSM (60.3% vs. 31.8%) and cavernosal epithelia (40.2% vs. 7%). Conclusion: IP induction caused fibrosis by the apoptotic process in rat CSM. After IP, apoptosis in endothelial tissue was more evident than that in smooth muscle tissue in the corpus cavernosum. IP is likely to affect the NO pathway, resulting in a decrease in the NO-dependent relaxation in the cavernosal tissue. [ABSTRACT FROM AUTHOR]

Specialized pro‐resolving lipid mediators (SPMs) are known for their anti‐inflammatory and pro‐resolving actions. The aim of the present study was to find new functions of the SPM resolvin D1n‐3 DPA (RvD1n‐3 DPA) on oral epithelial cells. As a starting point, we used a dataset obtained by RNA high‐throughput sequencing of oral epithelial cells exposed to TNF‐α and RvD1n‐3 DPA versus TNF‐α alone. GOrilla enrichment analysis showed that the actin cytoskeleton was significantly overrepresented after adjustment for multiple hypothesis testing. As actin, amongst others, is closely related to cell migration, we then explored whether RvD1n‐3 DPA can modulate oral epithelial cell migration. To this end, we used an in vitro cell migration model, including TNF‐α treatment, to mimic an inflammatory cell state. The analysis revealed that RvD1n‐3 DPA increased oral epithelial cell migration in the presence but not in the absence of TNF‐α. Addition of RvD1n‐3 DPA also induced F actin accumulation around the cell nucleus, indicating that RvD1n‐3 DPA potentially can mediate processes of intracellular transport. This indicates that this lipid mediator may be a promising therapeutic candidate in oral mucosal wound healing. [ABSTRACT FROM AUTHOR]

Recent advances in human brain organoid systems have raised serious worries about the possibility that these in vitro 'mini‐brains' could develop sentience, and thus, moral status. This article considers the relative moral status of sentient human brain organoids and research animals, examining whether we have moral reasons to prefer using one over the other. It argues that, contrary to common intuitions, the wellbeing of sentient human brain organoids should not be granted greater moral consideration than the wellbeing of nonhuman research animals. It does so not by denying that typical humans have higher moral status than animals, but instead by arguing that none of the leading justifications for granting humans higher moral status than nonhuman animals apply to brain organoids. Additionally, it argues that there are no good reasons to be more concerned about the well‐being of human brain organoids compared to those generated from other species. [ABSTRACT FROM AUTHOR]

Background: Inhibition of HDAC6 has been proposed as a broadly applicable therapeutic strategy for Charcot–Marie–Tooth disease (CMT). Inhibition of HDAC6 increases the acetylation of proteins important in axonal trafficking, such as α‐tubulin and Miro, and has been shown to be efficacious in several preclinical studies using mouse models of CMT. Aims: Here, we sought to expand on previous preclinical studies by testing the effect of genetic deletion of Hdac6 on mice carrying a humanized knockin allele of Gars1, a model of CMT‐type 2D. Methods: Gars1ΔETAQ mice were bred to an Hdac6 knockout strain, and the resulting offspring were evaluated for clinically relevant outcomes. Results: The genetic deletion of Hdac6 increased α‐tubulin acetylation in the sciatic nerves of both wild‐type and Gars1ΔETAQ mice. However, when tested at 5 weeks of age, the Gars1ΔETAQ mice lacking Hdac6 showed no changes in body weight, muscle atrophy, grip strength or endurance, sciatic motor nerve conduction velocity, compound muscle action potential amplitude, or peripheral nerve histopathology compared to Gars1ΔETAQ mice with intact Hdac6. Interpretation: Our results differ from those of two previous studies that demonstrated the benefit of the HDAC6 inhibitor tubastatin A in mouse models of CMT2D. While we cannot fully explain the different outcomes, our results offer a counterexample to the benefit of inhibiting HDAC6 in CMT2D, suggesting additional research is necessary. [ABSTRACT FROM AUTHOR]

Introduction: Postoperative atrial fibrillation (POAF) is common following open heart surgery, and is associated with significant morbidity. Medications used for ventricular rate control of POAF may not be effective in controlling rapid ventricular rates during the postoperative period because of increased sympathetic tone. The purpose of this study was to develop nonpharmacologic rate control of POAF by atrioventricular node (AVN) fat pad stimulation using clinically available temporary pacing wires in the canine sterile pericarditis model. Methods: We studied 10 sterile pericarditis dogs in the closed‐chest state on postoperative days 1−3. The AVN fat pad stimulation (amplitude 2–15 mA; frequency 20 Hz; pulse width 0.03–0.2 ms) was performed during sustained POAF (>5 min). We measured ventricular rate and inefficient ventricular contractions during sustained POAF and compared it with and without AVN fat pad stimulation. Also, the parameters of AVN fat pad stimulation to achieve a rate control of POAF were measured over the postoperative days. Results: Eleven episodes of sustained POAF were induced in 5/10 sterile pericarditis dogs in the closed‐chest state on postoperative days 1−2. During POAF, the AVN fat pad stimulation decreased the ventricular rate from 178 ± 52 bpm to 100 ± 8 bpm in nine episodes. Nonpharmacologic rate control therapy successfully controlled the ventricular rate and eliminated inefficient ventricular contractions during POAF for the duration of the AVN fat pad stimulation. The AVN fat pad stimulation output remained relatively stable over the postoperative days. Conclusion: During sustained POAF, nonpharmacologic rate control by AVN fat pad stimulation effectively and safely controlled rapid ventricular rates throughout the postoperative period. [ABSTRACT FROM AUTHOR]

Objective The aim of the study is to investigate the therapeutic effects of astaxanthin (AST) and resveratrol (RVT) on multiorgan damage in an animal model of the supraceliac aortic ischemia-reperfusion (I/R). Methods In this study, 28 rats (n = 7/group), 200 to 250 g in weight, were randomized to four groups (1: Sham, 2: Control + I/R, 3: AST + I/R, and 4: RVT + I/R). Following the abdominal incision, aortic dissection was performed in the sham group without injury. Other groups underwent I/R injury via supraceliac aortic clamping (20 minutes) and reperfusion. The rats were administered olive oil (3 mL/kg) orally for 2 weeks before and 1 week after the laparotomy. Additionally, oral AST (10 mg/kg) or RVT (50 mg/kg) was given to the study groups. All rats were sacrificed on the 3rd week of the experiment after blood samples were taken for analysis. Multiple rat tissues were removed. Results We found that RVT increased total antioxidant status (TAS) and superoxide dismutase (SOD) levels, and decreased total oxidant status (TOS), oxidative stress index (OSI), myeloperoxidase (MPO), and malondialdehyde (MDA) levels, while AST increased the levels of TAS, decreased TNF-α, MDA, TOS, and OSI (p <0.05). Pathological investigations of the rat tissues revealed that both AST and RVT ameliorated tissue damage and apoptosis. Conclusion Our study suggests that AST and RVT might show therapeutic effects against oxidative tissue damage and apoptosis in an animal model of aortic I/R. Further studies are required. Key Points Major congenital heart diseases are at high risk of multiorgan damage. Re-establishment of blood flow may result in ischemia-reperfusion (I/R) injury. Astaxanthin and resveratrol may have therapeutic effects against I/R injury. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although sodium-glucose cotransporter-2 inhibitors have been shown to improve cardiovascular outcomes in general, little is presently known about any sex-specific changes that may result from this therapy. We sought to investigate and quantify potential sex-specific changes seen with the sodium-glucose cotransporter-2 inhibitor canagliflozin (CAN) in a swine model of chronic myocardial ischemia. STUDY DESIGN: Eighteen Yorkshire swine underwent left thoracotomy with placement of an ameroid constrictor. Two weeks postop, swine were assigned to receive either control (F = 5 and M = 5) or CAN 300 mg daily (F = 4 and M = 4). After 5 weeks of therapy, swine underwent myocardial functional measurements, and myocardial tissue was sent for proteomic analysis. RESULTS: Functional measurements showed increased cardiac output, stroke volume, ejection fraction, and ischemic myocardial flow at rest in male swine treated with CAN compared with control male swine (all p < 0.05). The female swine treated with CAN had no change in cardiac function as compared with control female swine. Proteomic analysis demonstrated 6 upregulated and 97 downregulated proteins in the CAN female group compared with the control female group. Pathway analysis showed decreases in proteins in the tricarboxylic acidic cycle. The CAN male group had 639 upregulated and 172 downregulated proteins compared with control male group. Pathway analysis showed increases in pathways related to cellular metabolism and decreases in pathways relevant to the development of cardiomyopathy and to oxidative phosphorylation. CONCLUSIONS: Male swine treated with CAN had significant improvements in cardiac function that were not observed in female swine treated with CAN. Moreover, CAN treatment in male swine was associated with significantly more changes in protein expression than in female swine treated with CAN. The increased proteomic changes seen in the CAN male group likely contributed to the more robust changes in cardiac function seen in male swine treated with CAN. [ABSTRACT FROM AUTHOR]

Aim: Using network pharmacology and experimental validation to explore the therapeutic efficacy and mechanism of curcumin (Cur) in periodontitis treatment. Materials and Methods: Network pharmacology was utilized to predict target gene interactions of Cur‐Periodontitis. Molecular docking was used to investigate the binding affinity of Cur for the predicted targets. A mouse model with ligature‐induced periodontitis (LIP) was used to verify the therapeutic effect of Cur. Microcomputed tomography (micro‐CT) was used to evaluate alveolar bone resorption, while western blotting, haematoxylin–eosin staining and immunohistochemistry were used to analyse the change in immunopathology. SYTOX Green staining was used to assess the in vitro effect of Cur in a mouse bone marrow‐isolated neutrophil model exposed to lipopolysaccharide. Results: Network pharmacology identified 114 potential target genes. Enrichment analysis showed that Cur can modulate the production of neutrophil extracellular traps (NETs). Molecular docking experiments suggested that Cur effectively binds to neutrophil elastase (ELANE), peptidylarginine deiminase 4 (PAD4) and cathepsin G, three enzymes involved in NETs. In LIP mice, Cur alleviated alveolar bone resorption and reduced the expression of ELANE and PAD4 in a time‐dependent but dose‐independent manner. Cur can directly inhibit NET formation in the cell model. Conclusions: Our research suggested that Cur may alleviate experimental periodontitis by inhibiting NET formation. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effect of subgingival delivery of progranulin (PGRN)/gelatin methacryloyl (GelMA) complex as an adjunct to scaling and root planing (SRP) on an experimental periodontitis dog model with Class II furcation involvement (FI). Materials and Methods: A Class II FI model was established, and the defects were divided into four treatment groups: (a) no treatment (control); (b) SRP; (c) SRP + GelMA; (d) SRP + PGRN/GelMA. Eight weeks after treatment, periodontal parameters were recorded, gingival crevicular fluid and gingival tissue were collected for ELISA and RT‐qPCR, respectively, and mandibular tissue blocks were collected for micro computed tomography (micro‐CT) scanning and hematoxylin and eosin (H&E) staining. Results: The SRP + PGRN/GelMA group showed significant improvement in all periodontal parameters compared with those in the other groups. The expression of markers related to M1 macrophage and Th17 cell significantly decreased, and the expression of markers related to M2 macrophage and Treg cell significantly increased in the SRP + PGRN/GelMA group compared with those in the other groups. The volume, quality and area of new bone and the length of new cementum in the root furcation defects of the PGRN/GelMA group were significantly increased compared to those in the other groups. Conclusions: Subgingival delivery of the PGRN/GelMA complex could be a promising non‐surgical adjunctive therapy for anti‐inflammation, immunomodulation and periodontal regeneration. [ABSTRACT FROM AUTHOR]

Interstitial high-dose-rate brachytherapy (HDR-BT) is an effective therapy modality for patients with localized prostate carcinoma. The objectives of the study were to optimise the therapy regime variables using two models: response surface methodology (RSM) and artificial neural network (ANN). Thirty-one studies with 5651 patients were included (2078 patients presented as low-risk, 3077 patients with intermediate-risk, and 496 patients with high-risk). A comparison of these therapy schedules was carried out using an effective biologically effective dose (BED ef) that was calculated assuming the number of treatment days and dose (D) per day. The modelling and optimization of therapy parameters (BED ef and risk level) in order to obtain the maximum biochemical free survival (BFS) were carried out by the RSM and ANN models. An optimal treatment schedule (BFS = 97%) for patients presented with low-risk biochemical recurrence would be D = 26 Gy applied in one application, 2 fractions at least 6 h apart, within an overall treatment time of 1 day (BED ef = 251 Gy) by the RSM and ANN model. For patients presented with intermediate- or high-risk an optimal treatment regime (BFS = 94% and 90%, respectively) would be D = 38 Gy applied in one application, 4 fractions at least 6 h apart, with an overall treatment time of 2 days (BED ef = 279 Gy) by the RSM and ANN models. The RSM and ANN models determine almost the same optimal values for the set of predicted therapy parameters that make a feasible selection of an optimal treatment regime. • HDR-BT is an effective therapy modality for patients with localised prostate carcinoma. • Optimisation of HDR-BT regime variables was carried out by the RSM and ANN models. • The RSM and ANN models determined almost the same optimal values. [ABSTRACT FROM AUTHOR]

Background: Skeletal craniofacial morphology can be influenced by changes in masticatory muscle function, which may also change the functional profile of the muscles. Objectives: To investigate the effects of age and functional demands on the expression of Myosin Heavy‐Chain (MyHC) isoforms in representative jaw‐closing and jaw‐opening muscles, namely the masseter and digastric muscles respectively. Methods: Eighty‐four male Wistar rats were divided into four age groups, namely an immature (n = 12; 4‐week‐old), early adult (n = 24; 16‐week‐old), adult (n = 24; 26‐week‐old) and mature adult (n = 24; 38‐week‐old) group. The three adult groups were divided into two subgroups each based on diet consistency; a control group fed a standard (hard) diet, and an experimental group fed a soft diet. Rats were sacrificed, and masseter and digastric muscles dissected. Real‐time quantitative polymerase chain reaction was used to compare the mRNA transcripts of the MyHC isoforms—Myh7 (MyHC‐I), Myh2 (MyHC‐IIa), Myh4 (MyHC‐IIb) and Myh1 (MyHC‐IIx)—of deep masseter and digastric muscles. Results: In the masseter muscle, hypofunction increases Myh1 (26, 38 weeks; p <.0001) but decreases Myh4 (26 weeks; p =.046) and Myh2 (26 weeks; p <.0001) expression in adult rats. In the digastric muscle, hypofunction increases Myh1 expression in the mature adult rats (38 weeks; p <.0001), while Myh2 expression decreases in adult rats (26 weeks; p =.021) as does Myh4 (26 weeks; p =.001). Myh7 expression is increased in the digastric muscle of mature adult rats subjected to hypofunction (38 weeks; p = <.0001), while it is very weakly expressed in the masseter. Conclusion: In jaw‐opening and jaw‐closing muscles, differences in myosin expression between hard‐ and soft‐diet‐fed rats become evident in adulthood, suggesting that long‐term alteration of jaw function is associated with changes in the expression of MyHC isoforms and potential fibre remodelling. This may give insight into the role of function on masticatory muscles and the resultant craniofacial morphology. [ABSTRACT FROM AUTHOR]

Background: Mandibular reconstruction patients often suffer abnormalities in the mandibular kinematics. In silico simulations, such as musculoskeletal modelling, can be used to predict post‐operative mandibular kinematics. It is important to validate the mandibular musculoskeletal model and analyse the factors influencing its accuracy. Objectives: To investigate the jaw opening‐closing movements after mandibular reconstruction, as predicted by the subject‐specific musculoskeletal model, and the factors influencing its accuracy. Methods: Ten mandibular reconstruction patients were enrolled in this study. Cone‐beam computed tomography images, mandibular movements, and surface electromyogram signals were recorded preoperatively. A subject‐specific mandibular musculoskeletal model was established to predict surgical outcomes using patient‐averaged muscle parameter changes as model inputs. Jaw bone geometry was replaced by surgical planning results, and the muscle insertion sites were registered based on the non‐rigid iterative closest point method. The predicted jaw kinematic data were validated based on 6‐month post‐operative measurements. Correlations between the prediction accuracy and patient characteristics (age, pathology and surgical scope) were further analysed. Results: The root mean square error (RMSE) for lower incisor displacement was 31.4%, and the error for peak magnitude of jaw opening was 4.9 mm. Age, post‐operative infection and radiotherapy influenced the prediction accuracy. The amount of masseter detachment showed little correlation with jaw opening. Conclusion: The mandibular musculoskeletal model successfully predicted short‐range jaw opening functions after mandibular reconstruction. It provides a novel surgical planning method to predict the risk of developing trismus. [ABSTRACT FROM AUTHOR]

Background: Obstructive sleep apnoea (OSA) is an independent risk factor for cardiovascular diseases. We aimed to investigate the role of nuclear factor‐kappa B (NF‐κB) in the changes of cardiac structures in OSA rabbits treated by mandibular advancement device (MAD). Methods: Eighteen male New Zealand white rabbits aged 6 months were randomly divided into three groups: control group, group OSA and group MAD. Hyaluronate gel was injected into the soft palate of the rabbits in group OSA and group MAD to induce OSA. The cone beam computer tomography (CBCT) of the upper airway and polysomnography (PSG) was performed to ensure successful modelling. CBCT and PSG were applied again to detect the effects of MAD treatment. All animals were induced to sleep in a supine position for 4–6 h a day for 8 weeks. Then the levels of NF‐κB, Interleukin 6 (IL‐6), Interleukin 10 (IL‐10) and the proportion of myocardial fibrosis (MF) were detected. Results: The higher activation of NF‐κB, IL‐6 and IL‐10 were found in the OSA group than in the control group, leading to the increase of collagen fibres compared with the control group. Furthermore, the apnoea‐hypopnea index (AHI) was positively correlated with the above factors. There were no significant differences between group MAD and the control group. Conclusion: The NF‐κB pathway was activated in the myocardium of OSA rabbits, which accelerated the development of MF. Early application of MAD could reduce the activation of NF‐κB in the myocardium and prevent the development of MF. [ABSTRACT FROM AUTHOR]

This study investigated the effects of ghrelin on oxidative stress, working memory, inflammatory parameters, and neuron degeneration. TBI was produced with the weight-drop technique. Rats in the G+TBI and TBI+G groups received ghrelin for 7 or 2 days, respectively. The control group received saline. On the 8th day of the study, the brain and blood tissue were taken under anesthesia. A significant increase in brain GSH-PX, MDA, IL-1β, TGF-β1, and IL-8 levels and a significant decrease in CAT levels were found in the TBI group compared to the control. Serum MDA, GSH, IL-1β, and IL-8 levels were increased with TBI. Ghrelin treatment after TBI significantly increased the serum GSH, CAT, GSH-PX, and brain GSH and CAT levels, while it significantly decreased the serum MDA, IL-1β, and brain MDA, TGF-β1, and IL-8 levels. Histological evaluations revealed that ghrelin treatment led to a reduction in inflammation, while also significantly ameliorating TBI-induced neuron damage and vascular injuries. Immunohistochemistry staining showed that GFAP staining intensity was significantly increased in the cortex and hippocampus in TBI, and GFAP immunoreactivity was decreased with ghrelin treatment. The results from this study suggested that ghrelin may have curative effects on TBI. [ABSTRACT FROM AUTHOR]

Since 2013, Flanders has introduced a screening programme for colorectal cancer for all citizens aged between 50 and 74 years. The objective of this study was to assess the cost-utility of an expansion of the colorectal cancer screening policy in Flanders (Belgium) and to place these findings in the international context. Cost-utility analysis using high-detail data about screening participation, screening results, and epidemiological data, a Markov cohort model has been constructed to study long-term costs and effects. A cost-utility analysis was performed as a three-way comparison between current, expanded (from age 45 years), and no screening scenarios, from a societal and healthcare perspective. Robustness was assessed by both one-way and probabilistic sensitivity analyses. Analyses show that both current and expanded screening result in quality-adjusted life years (QALY) gains and are mostly cost-saving. Overall, 97.5% of Incremental Cost-Effectiveness Ratios (ICERs) remained well below € 2000 per QALY for all comparisons. Parameters related to the colonoscopy that follows a positive test result such as compliance and cost are especially impactful on the cost-effectiveness. Screening participation and screening costs have remained comparatively stable, making colorectal cancer screening a cost-effective (dominant) policy. Expanding the screen age to 45 years is also cost-effective (dominant) compared with current screening, albeit with a slimmer margin. [ABSTRACT FROM AUTHOR]

Background: Endoscopic submucosal dissection (ESD) requires high endoscopic technical skills, and trainees should develop effective training methods. In collaboration with KOTOBUKI Medical, we developed the G-Master, which is a non-animal training model that can simulate various parts of gastric ESD. We aimed to clarify the usefulness of the G-Master for inexperienced ESD trainees. Methods: We collected data from the first 5 gastric ESD cases conducted by 15 inexperienced ESD trainees at 5 participating centers between 2018 and 2022. The participants were divided into two groups: the G-Master training and non-G-Master training groups. Outcome measurements, such as procedural speed, perforation rate, self-completion rate, and en bloc resection rate, were compared between the two groups retrospectively. Results: A total of 75 gastric ESD cases were included in this study. The G-Master training group included 25 cases performed by 5 trainees, whereas the non-G-Master training group included 50 cases performed by 10 trainees. The median procedural speed for all cases was significantly faster in the G-Master training group than in the non-G-Master training group. Moreover, the procedural speed was linearly improved from the initial to the last cases in the lower location in the G-Master training group compared with the non-G-Master training group. In addition, although there was no significant difference, the G-Master training group showed lower rates of perforation and a lesser need to transition to expert operators than the non-G-Master training group. Conclusion: The G-Master could improve the ESD skills of inexperienced ESD trainees. [ABSTRACT FROM AUTHOR]

Complex chromosomal rearrangements (CCRs) are often observed in clinical samples from patients with cancer and congenital diseases but are difficult to induce experimentally. Here, we report the first success in establishing animal models for CCRs. Mutation in Recql5 , a crucial member of the DNA helicase RecQ family involved in DNA replication, transcription, and repair, enabled CRISPR/Cas9-mediated CCRs, establishing a mouse model containing triple fusion genes and megabase-sized inversions. Some of these structural features of individual chromosomal rearrangements use template switching and microhomology-mediated break-induced replication mechanisms and are reminiscent of the newly described phenomenon "chromoanasynthesis." These data show that Recql5 mutant mice could be a powerful tool to analyze the pathogenesis of CCRs (particularly chromoanasynthesis) whose underlying mechanisms are poorly understood. The Recql5 mutants generated in this study are to be deposited at key animal research facilities, thereby making them accessible for future research on CCRs. [ABSTRACT FROM AUTHOR]

The rate at which beneficial alleles fix in a population depends on the probability of and time to fixation of such alleles. Both of these quantities can be significantly impacted by population subdivision and limited gene flow. Here, we investigate how limited dispersal influences the rate of fixation of beneficial de novo mutations, as well as fixation time from standing genetic variation. We investigate this for a population structured according to the island model of dispersal allowing us to use the diffusion approximation, which we complement with simulations. We find that fixation may take on average fewer generations under limited dispersal than under panmixia when selection is moderate. This is especially the case if adaptation occurs from de novo recessive mutations, and dispersal is not too limited (such that approximately F ST < 0.2 ⁠). The reason is that mildly limited dispersal leads to only a moderate increase in effective population size (which slows down fixation), but is sufficient to cause a relative excess of homozygosity due to inbreeding, thereby exposing rare recessive alleles to selection (which accelerates fixation). We also explore the effect of metapopulation dynamics through local extinction followed by recolonization, finding that such dynamics always accelerate fixation from standing genetic variation, while de novo mutations show faster fixation interspersed with longer waiting times. Finally, we discuss the implications of our results for the detection of sweeps, suggesting that limited dispersal mitigates the expected differences between the genetic signatures of sweeps involving recessive and dominant alleles. [ABSTRACT FROM AUTHOR]

Purpose: The association between birth order and adverse perinatal outcomes has been well studied in twin pregnancies. However, little is known about the differences in immediate perinatal outcomes as well as long‐term hospitalization of the offspring in triplet pregnancies according to their birth order. As such, we aimed to assess the differences in immediate perinatal outcomes and long‐term hospitalizations among triplets by their birth order. Methods: In a retrospective hospital‐based cohort study, immediate perinatal outcomes and long‐term hospitalizations were compared among triplet siblings according to their birth order. Deliveries occurred between the years 1991 and 2021 in a tertiary medical center. The study groups were followed until 18 years of age for cardiovascular, respiratory, neurological, and infection‐related hospitalizations. Generalized estimation equation (GEE) models were used to control for confounders. Kaplan–Meier survival curves were used to compare cumulative long‐term hospitalization incidences and Cox proportional hazards models were performed to control for confounders. Results: The study included 117 triplet deliveries. Rates of small for gestational age (SGA) infants increased linearly by birth order (6.0%, 7.7%, and 15.4% for the first, second, and third siblings, respectively; p‐value for trends = 0.035). Using a GEE model controlling for maternal age, being born third in a triplet pregnancy was independently associated with SGA (third vs. first sibling, adjusted OR 3.0, 95% CI 1.38–6.59, p = 0.005). No significant differences in cardiovascular, respiratory, neurological, and infection‐related hospitalizations were noted among the first, second, and third siblings. Likewise, using Kaplan–Meier survival analyses, no significant differences in the cumulative incidence of long‐term pediatric hospitalizations were noted between the siblings. In Cox proportional hazards models, controlling for weight and gender, birth order in a triplet pregnancy did not exhibit an association with long‐term hospitalizations of the offspring. Conclusion: Despite the association between birth order and SGA, birth order in triplets does not seem to have an impact on the risk for long‐term offspring hospitalization. [ABSTRACT FROM AUTHOR]

Spiking Neural P Systems (SNP) are well-established computing models that take inspiration from spikes between biological neurons; these models have been widely used for both theoretical studies and practical applications. Virus machines (VMs) are an emerging computing paradigm inspired by viral transmission and replication. In this work, a novel extension of VMs inspired by SNPs is presented, called Virus Machines with Host Excitation (VMHEs). In addition, the universality and explicit results between SNPs and VMHEs are compared in both generating and computing mode. The VMHEs defined in this work are shown to be more efficient than SNPs, requiring fewer memory units (hosts in VMHEs and neurons in SNPs) in several tasks, such as a universal machine, which was constructed with 18 hosts less than the 84 neurons in SNPs, and less than other spiking models discussed in the work. [ABSTRACT FROM AUTHOR]

The aim of this study was to use a combination of physiologically based pharmacokinetic (PBPK) modeling and urinary glucose excretion (UGE) modeling to predict the time profiles of pharmacokinetics (PK) and UGE for the sodium‐glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMP). Additionally, the study aims to explore the compensatory effect of SGLT1 in renal glucose reabsorption (RGR) when SGLT2 is inhibited. The PBPK‐UGE model was developed using physicochemical and biochemical properties, renal physiological parameters, binding kinetics, glucose, and Na+ reabsorption kinetics by SGLT1/2. For area under the plasma concentration‐time curve, maximum plasma concentration, and cumulative EMP excretion in urine, the predicted values fell within a range of 0.5‐2.0 when compared to observed data. Additionally, the simulated UGE data also matched well with the clinical data, further validating the accuracy of the model. According to the simulations, SGLT1 and SGLT2 contributed approximately 13% and 87%, respectively, to RGR in the absence of EMP. However, in the presence of EMP at doses of 2.5 and 10 mg, the contribution of SGLT1 to RGR significantly increased to approximately 76%‐82% and 89%‐93%, respectively, in patients with type 2 diabetes mellitus. Furthermore, the model supported the understanding that the compensatory effect of SGLT1 is the underlying mechanism behind the moderate inhibition observed in total RGR. The PBPK‐UGE model has the capability to accurately predict the PK and UGE time profiles in humans. Furthermore, it provides a comprehensive analysis of the specific contributions of SGLT1 and SGLT2 to RGR in the presence or absence of EMP. [ABSTRACT FROM AUTHOR]

Purpose: This study examined the acute and long-term effects of nandrolone decanoate (ND) on fractional synthetic rates (FSR). Methods: Male C57BL/6 mice were randomized into ND (n = 20) or sham (n = 20) groups. ND injections (10 g⋅kg-1⋅wk-1) started at 7 months of ages and continued for 6 wk. Ten animals from each group were randomly separated and examined 1 wk following drug cessation. The remaining animals were examined at 16 months of age. Animals were injected IP with 1.5 mL of deuterated water 24 h before euthanasia. The kidney, liver, heart, gastrocnemius, and soleus were extracted. Samples were analyzed for deuterated alanine enrichment in the bound protein and intracellular fraction by liquid chromatography tandem mass spectrometry to measure estimated FSR (fraction/day (F/D)) of mixed tissue. Results: One-way ANOVA, with treatment and age as fixed factors, indicated that kidney FSR was greater (P = 0.027) in ND (0.41 ± 0.02 F/D) than sham (0.36 ± 0.014F/D) and higher (P = 0.003) in young (0.42 ± 0.2 F/D) than old (0.35 ± 0.01 F/D). Liver and heart FSR values were greater (P ≤ 0.001) in young (0.79 ± 0.06 F/D and 0.13 ± 0.01 F/D, respectively) compared with old (0.40 ± 0.01 F/D and 0.09 ± 0.01 F/D, respectively), but not between ND and sham. Gastrocnemius FSR was (P ≤ 0.001) greater in young (0.06 ± 0.01 F/D) compared with old (0.03 ± 0.002 F/D), and greater (P = 0.006) in ND (0.05 ± 0.01 F/D) compared with sham (0.04 ± 0.003 F/D). Soleus FSR rates were greater (P = 0.050) in young (0.13 ± 0.01 F/D) compared with old (0.11 ± 0.003 F/D), but not between ND (0.12 ± 0.01 F/D) and sham (0.12 ± 0.01 F/D). Old animals who had received ND displayed elevated FSR in the gastrocnemius (P = 0.054) and soleus (P = 0.024). Conclusions: ND use in young adult animals appeared to maintain long-term elevations in FSR in muscle during aging. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to investigate 12 wk of simple and complex voluntary wheel running on Alzheimer's disease (AD), associated biomarkers, and behaviors. Methods: Sixty male Wistar rats were randomly divided into six groups: healthy control (Con-Sed), AD only (AD-Sed), simple wheel control (SWC), complex wheel control (CWC), simple wheel AD (SWAD), and complex wheel AD (CWAD). Novelty-suppressed feeding test and the Morris water maze test were used to evaluate depression and memory, respectively. Ki67 was measured in the hippocampus, whereas interleukin (IL)-1β and neural/glial antigen 2 (NG2) were measured in both the hippocampus and the prefrontal cortex. One-way ANOVA with Tukey's post hoc test was performed. Results: AD-Sed group had significantly lower special memory (P < 0.001) compared with Con-Sed. Simple and complex wheel running attenuated these deficits in the SWAD and CWAD groups, respectively (P < 0.001). Only the CWAD group had significantly improved novelty-suppressed feeding test time compared with AD-Sed (P < 0.001), equivalent to the healthy wheel running groups. AD-Sed has significantly higher hippocampal concentrations of Ki67 (P = 0.01) compared with the Con-Sed. Both SWAD and CWAD had significantly reduced Ki67 with similar concentrations compared with the SWC and CWC groups (P > 0.05). AD-Sed animals also presented with significantly higher hippocampal and prefrontal cortex concentrations of IL-1β compared with Con-Sed (P < 0.001). SWAD and CWAD had no effect in changing these concentrations. Complex wheel running significantly increased NG2 in the healthy control and AD models, whereas simple wheel running significantly increased NG2 in the AD model. Conclusions: The results of our study suggest that complex wheel running might be more advantageous in promoting memory and neuroplasticity while reducing depression that is associated with AD. [ABSTRACT FROM AUTHOR]

Objective: Migraine, a prevalent and debilitating disease, involves complex pathophysiology possibly including inflammation and heightened pain sensitivity. The current study utilized the complete Freund's adjuvant (CFA) model of inflammation, with onabotulinumtoxinA (BoNT/A) as a treatment of interest due to its use in clinical migraine management. Using an animal model, the study sought to investigate the role of BoNT/A in modulating CFA‐induced inflammation, alterations in pain sensitivity, and the regulation of calcitonin gene–related peptide (CGRP) release. Further, we aimed to assess the changes in SNAP‐25 through western blot analysis to gain insights into the mechanistic action of BoNT/A. Methods: BoNT/A or control was administered subcutaneously at the periorbital region of rats 3 days before the induction of inflammation using CFA. Periorbital mechanical sensitivity was assessed post‐inflammation, and alterations in CGRP release were evaluated. Changes in SNAP‐25 levels were determined using western blot analysis. Results: Upon CFA‐induced inflammation, there was a marked increase in periorbital mechanical sensitivity, with the inflammation side showing increased sensitivity compared to other periorbital areas. BoNT/A did decrease the withdrawal thresholds in the electronic von Frey test. Despite not being able to observe differences in pain thresholds or CGRP release, BoNT/A reduced baseline release under CFA inflamed conditions. Analysis of SNAP‐25 levels in the trigeminal ganglion revealed both intact and cleaved forms that were notably elevated in BoNT/A‐treated animals. These findings, derived from western blot analysis, suggest an effect on neurotransmitter release. Conclusion: Our investigation highlights the role of BoNT/A in reducing baseline CGRP in the context of inflammation and its involvement in SNAP‐25 cleavage. In contrast, BoNT/A did not appear to alter facial pain sensitivity induced by inflammation, suggesting that mechanisms other than baseline CGRP could be implicated in the elevated thresholds in the CFA model. Plain Language Summary: Migraine is often linked to increased pain sensitivity and potential inflammation, and treatments targeting these symptoms are crucial for improving the quality of life for those with migraine. Our research investigated the impact of onabotulinumtoxinA (BoNT/A) on migraine‐related conditions in a laboratory animal model, focusing on its effect on pain sensitivity and calcitonin gene‐related peptide (CGRP), a peptide associated with migraine, and we discovered that while BoNT/A does not significantly alter pain sensitivity, it reduced the baseline release of CGRP when inflammation was present, shedding light on its potential role in treating migraine. The reduction in CGRP release in inflamed conditions suggests that BoNT/A might be beneficial in managing migraine by targeting specific aspects of the condition, such as inflammation‐related peptide release. [ABSTRACT FROM AUTHOR]

This work investigates the dynamics of discrete reaction-diffusion Gierer-Meinhardt system as mathematical models of biological pattern formation. We study the system's local asymptotic behaviour with and without the diffusion once developing the discrete integer variant of the well-known Gierer-Meinhardt model and proving that the model has a unique equilibrium. The requirements for the steady-state solution's local and global stability are found with the help of relevant approaches and the Lyapunov technique. Two large biological models and simulations are used throughout the work to validate the utility of the suggested technique. [ABSTRACT FROM AUTHOR]

Aims: Evidence is accumulating of the therapeutic benefits of mesenchymal stromal cells (MSCs) in diabetes‐related conditions. We have identified a novel population of stromal cells within islets of Langerhans – islet stellate cells (ISCs) – which have a similar morphology to MSCs. In this study we characterize mouse ISCs and compare their morphology and function to MSCs to determine whether ISCs may also have therapeutic potential in diabetes. Methods: ISCs isolated from mouse islets were compared to mouse bone marrow MSCs by analysis of cell morphology; expression of cell‐surface markers and extracellular matrix (ECM) components; proliferation; apoptosis; paracrine activity; and differentiation into adipocytes, chondrocytes and osteocytes. We also assessed the effects of co‐culture with ISCs or MSCs on the insulin secretory capacity of islet beta cells. Results: Although morphological similar, ISCs were functionally distinct from MSCs. Thus, ISCs were less proliferative and more apoptotic; they had different expression levels of important paracrine factors; and they were less efficient at differentiation down multiple lineages. Co‐culture of mouse islets with ISCs enhanced glucose induced insulin secretion more effectively than co‐culture with MSCs. Conclusions: ISCs are a specific sub‐type of islet‐derived stromal cells that possess biological behaviors distinct from MSCs. The enhanced beneficial effects of ISCs on islet beta cell function suggests that they may offer a therapeutic target for enhancing beta cell functional survival in diabetes. [ABSTRACT FROM AUTHOR]

Simple Summary: Most cancer patients are older and have concomitant diseases because the incidence of most cancer types increases with age. This leads to patients taking a variety of medications that can cause drug-related problems (DRPs). DRPs can cause harm, including increased illness, avoidable hospital stays, and even death. Common DRPs are drug–drug interactions, not taking medication as prescribed, and adverse drug reactions. In our study, we aimed to assess these medication risks in hospitalized cancer patients and to identify factors that influence their health-related quality of life (HRQOL) as a patient-relevant outcome. The results of the pharmacist-led medication reviews show that DRPs are common in hospitalized cancer patients. Therefore, patient questionnaires about therapy-related symptoms could improve the detection of DRPs. While drug-related factors had no effect on HRQOL during the hospital stay, our analysis revealed other influencing factors, such as relapse status of the cancer disease and length of hospital stay. Background: We aimed to assess medication risks and determine factors influencing the health-related quality of life (HRQOL) in cancer inpatients. Methods: A retrospective analysis was conducted to identify drug-related problems (DRPs) based on medication reviews, including patient-reported outcomes (PROs). Multiple linear regression analyses were performed to identify sociodemographic, disease-related, and drug therapy-related factors influencing changes from hospital admission to discharge in the scales of the EORTC QLQ-C30 questionnaire. Results: A total of 162 inpatients with various hematological and solid cancer diseases was analyzed. Patients received a mean of 11.6 drugs and 92.6% of patients exhibited polymedication resulting in a mean of 4.0 DRPs per patient. Based on PRO data, 21.5% of DRPs were identified. Multiple linear regression models described the variance of the changes in global HRQOL and physical function in a weak-to-moderate way. While drug therapy-related factors had no influence, relapse status and duration of hospital stay were identified as significant covariates for global HRQOL and physical function, respectively. Conclusion: This analysis describes underlying DRPs in a German cancer inpatient population. PROs provided valuable information for performing medication reviews. The multiple linear regression models for global HRQOL and physical function provided explanations for changes during hospital stay. [ABSTRACT FROM AUTHOR]

Simple Summary: The United States is suffering from an epidemic associated with infections with the Human Papilloma Virus (HPV) that are responsible for the development of head and neck squamous cell carcinoma (HNSCC). Our study aims to characterize immune profiles, and the oral microbiota in oropharyngeal tumors associated with anti-PD-1 treatment response in a preclinical murine model for HPV+ oropharyngeal cancer. We confirmed 16 immune markers and specific bacteria in the oral cavity that differentiate between treatment responders and non-responders, which may be used as potential biomarkers for PD-1 blockade response. The United States is suffering from an epidemic associated with high-risk strains of the Human Papillomavirus (HPV) predominantly responsible for the development of head and neck squamous cell carcinoma (HNSCC). Treatment with immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand PD-L1 has shown poor efficacy in HNSCC patients, observing only a 20–30% response. Therefore, biological marker identification associated with PD-1 blockade response is important to improve prognosis and define novel therapeutics for HNSCC patients. Therapy response was associated with increased frequencies of activated CD27+T cells, activated CD79a+ B cells, antigen-presenting CD74+ dendritic and B cells, and PD-L1+ and PD-L2+ myeloid-derived suppressor cells (MDSCs). The oral microbiota composition differed significantly in mice bearing tongue tumors and treated with anti-PD-1. A higher abundance of Allobaculum, Blautia, Faecalibacterium, Dorea, or Roseburia was associated with response to the therapy. However, an increase in Enterococcus was attributed to tongue tumor-bearing non-responding mice. Our findings indicate that differences in immune phenotypes, protein expression, and bacterial abundance occur as mice develop tongue tumors and are treated with anti-PD-1. These results may have a clinical impact as specific bacteria and immune phenotype could serve as biomarkers for treatment response in HNSCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Chronic inflammation is one of the major risk factors for colorectal cancer development. This study aims to determine the effect of genetic mutations on inflammation-induced colon tumor cell heterogeneity and differentiation. Using single-cell approaches, we found that the addition of BRAFV600E to Apc mutant mice (BLM) increased colon epithelial tumor differentiation. Additionally, we found that BLM epithelial tumors had increased expression of revival colon stem cell (RevCSC) markers and reduced WNT signaling compared to Apc mutant epithelial tumors (Min). In contrast, the loss of Msh2 in Min mice (MSH2KO) increased epithelial tumor stem cell populations with increased WNT signaling compared to Min epithelial tumor. We also identified additional potential regulators of BLM epithelial tumor differentiation such as CDX2 and NDRG1. Genetic mutations and chronic inflammation of the colon contribute to the development of colorectal cancer (CRC). Using a murine model of inflammation-induced colon tumorigenesis, we determined how genetic mutations alter colon tumor cell differentiation. Inflammation induced by enterotoxigenic Bacteroides fragilis (ETBF) colonization of multiple intestinal neoplasia (MinApcΔ716/+) mice triggers loss of heterozygosity of Apc causing colon tumor formation. Here, we report that the addition of BRAFV600E mutation (BRAFF-V600ELgr5tm1(Cre/ERT2)CleMinApcΔ716/+, BLM) or knocking out Msh2 (Msh2LoxP/LoxPVil1-creMinApcΔ716/+, MSH2KO) in the Min model altered colon tumor differentiation. Using single-cell RNA sequencing, we uncovered the differences between BLM, Min, and MSH2KO tumors at a single-cell resolution. BLM tumors showed an increase in differentiated tumor epithelial cell lineages and a reduction in the tumor stem cell population. Interestingly, the tumor stem cell population of BLM tumors had revival colon stem cell characteristics with low WNT signaling and an increase in RevCSC marker gene expression. In contrast, MSH2KO tumors were characterized by an increased tumor stem cell population that had higher WNT signaling activity compared to Min tumors. Furthermore, overall BLM tumors had higher expression of transcription factors that drive differentiation, such as Cdx2, than Min tumors. Using RNA velocity, we identified additional potential regulators of BLM tumor differentiation such as NDRG1. The role of CDX2 and NDRG1 as putative regulators for BLM tumor cell differentiation was verified using organoids derived from BLM tumors. Our results demonstrate the critical connections between genetic mutations and cell differentiation in inflammation-induced colon tumorigenesis. Understanding such roles will deepen our understanding of inflammation-associated colon cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Mutation of the SMARCB1 gene can cause one of the most aggressive and lethal cancers of early childhood and infancy, malignant rhabdoid tumor (MRT). Despite the standard multimodal therapy (resection, conventional chemotherapy, and radiotherapy), the outlook for young children with MRT is poor. For infants, the disease can also preclude the use of radiotherapy. Numerous experimental treatments explore epigenetic mechanisms, but the DNA damage response has not yet been extensively evaluated as a therapeutic approach for MRT. We report a new therapeutic strategy for SMARCB1-deficient MRTs, combining PARP1 inhibition and DNA damage induction. The observed synergy between the PEGylated PARP1 inhibitor talazoparib (PEG~TLZ) and the DNA alkylating agent temozolomide (TMZ) may lead to improved therapeutic strategies for patients with this challenging cancer. We identified a new potential biomarker of response to PEG~TLZ+TMZ, O6-methylguanine methyltransferase (MGMT), and uncovered dysregulated signaling pathways involved in the response. Additionally, we elucidated the pro-survival role of SMARCB1 loss in MRT cells. Malignant rhabdoid tumors (MRTs) are among the most aggressive and treatment-resistant malignancies affecting infants, originating in the kidney, brain, liver, and soft tissues. The 5-year event-free survival rate for these cancers is a mere 20%. In nearly all cases of MRT, the SMARCB1 gene (occasionally SMARCA4)—a pivotal component of the SWI/SNF chromatin remodeling complex—is homozygously deleted, although the precise etiology of these tumors remains unknown. While young patients with localized MRT generally show improved outcomes, especially those who are older and have early-stage disease, the overall prognosis remains poor despite optimal standard treatments. This highlights the urgent need for more effective treatment strategies. We investigated the antitumor activity of a PARP1 inhibitor (talazoparib, TLZ) combined with a DNA alkylating agent (temozolomide, TMZ) in MRT xenograft models. PARP1 is a widely targeted molecule in cancer treatment and, beyond its role in DNA repair, it participates in transcriptional regulation by recruiting chromatin remodeling complexes to modulate DNA accessibility for RNA polymerases. To widen the therapeutic window of the drug combination, we employed PEGylated TLZ (PEG~TLZ), which has been reported to reduce systemic toxicity through slow drug release. Remarkably, our findings indicate that five out of six MRT xenografts exhibited an objective response to PEG~TLZ+TMZ therapy. Significantly, the loss of SMARCB1 was found to confer a protective effect, correlating with higher expression levels of DNA damage and repair proteins in SMARCB1-deficient MRT cells. Additionally, we identified MGMT as a potential biomarker indicative of in vivo MRT response to PEG~TLZ+TMZ therapy. Moreover, our analysis revealed alterations in signaling pathways associated with the observed antitumor efficacy. This study presents a novel and efficacious therapeutic approach for MRT, along with a promising candidate biomarker for predicting tumor response. [ABSTRACT FROM AUTHOR]

Simple Summary: Inconsistent engraftment of luciferase-expressing tumors, especially GL261 Red-FLuc, has been reported in the recent literature. However, techniques to improve tumor take have not been described. Our study aimed to optimize two luciferase-expressing mouse glioblastoma models, GL261 Red-FLuc and TRP-mCherry-FLuc, which revealed differences in tumor development and characteristics. While the features of each tumor were distinct, with GL261 Red-FLuc tumors showing high mitotic activity and vascularization and TRP-mCherry-FLuc tumors displaying necrosis and invasiveness, each exhibited features reminiscent of patients with glioblastoma. Furthermore, we developed a method for high-throughput sample analysis by quantifying the luciferase-positive tumor volume using artificial intelligence. Our findings provide valuable insights for researchers using similar models, emphasizing the need to consider tumor engraftment for robust preclinical research. Glioblastoma (GBM) is the most aggressive brain cancer. To model GBM in research, orthotopic brain tumor models, including syngeneic models like GL261 and genetically engineered mouse models like TRP, are used. In longitudinal studies, tumor growth and the treatment response are typically tracked with in vivo imaging, including bioluminescence imaging (BLI), which is quick, cost-effective, and easily quantifiable. However, BLI requires luciferase-tagged cells, and recent studies indicate that the luciferase gene can elicit an immune response, leading to tumor rejection and experimental variation. We sought to optimize the engraftment of two luciferase-expressing GBM models, GL261 Red-FLuc and TRP-mCherry-FLuc, showing differences in tumor take, with GL261 Red-FLuc cells requiring immunocompromised mice for 100% engraftment. Immunohistochemistry and MRI revealed distinct tumor characteristics: GL261 Red-FLuc tumors were well-demarcated with densely packed cells, high mitotic activity, and vascularization. In contrast, TRP-mCherry-FLuc tumors were large, invasive, and necrotic, with perivascular invasion. Quantifying the tumor volume using the HALO® AI analysis platform yielded results comparable to manual measurements, providing a standardized and efficient approach for the reliable, high-throughput analysis of luciferase-expressing tumors. Our study highlights the importance of considering tumor engraftment when using luciferase-expressing GBM models, providing insights for preclinical research design. [ABSTRACT FROM AUTHOR]

Objective: The specific role of fibroblast‐like synoviocytes (FLSs) in the pathogenesis of rheumatoid arthritis (RA) is still not fully elucidated. This study aimed to explore the molecular mechanisms of epigenetic pathways, including three epigenetic factors, microRNA (miRNA)‐22 (MIR22), ten‐eleven translocation methylcytosine dioxygenase 3 (TET3), and MT‐RNR2 like 2 (MTRNR2L2), in RA‐FLSs. Methods: The expression of MIR22, TET3, and MTRNR2L2 in the synovium of patients with RA and arthritic mice were determined by fluorescence in situ hybridization, quantitative polymerase chain reaction (qPCR), immunohistochemistry, and Western blot. Mir22−/− and Tet3+/− mice were used to establish a collagen antibody–induced arthritis (CAIA) model. Mir22 angomir and Tet3 small interfering RNA (siRNA) were used to illustrate the therapeutic effects on arthritis using a collagen‐induced (CIA) model. Bioinformatics, luciferase reporter assay, 5‐hydroxymethylcytosine (5hmC) dot blotting, chromatin immunoprecipitation–qPCR, and hydroxymethylated DNA immunoprecipitation were conducted to show the direct repression of MIR22 on the TET3 and transcriptional activation of TET3 on MTRNR2L2. Results: The Mir22−/− CAIA model and RA‐FLS–related in vitro experiments demonstrated the inhibitory effect of MIR22 on inflammation. MIR22 can directly inhibit the translation of TET3 in RA‐FLSs by binding to its 3′ untranslated region in TET3. The Tet3+/− mice–established CAIA model showed less severe symptoms of arthritis in vivo. In vitro experiments further confirmed the proinflammatory effect of TET3 in RA. In addition, the CIA model was used to validate the therapeutic effects of Mir22 angomir and Tet3 siRNA. Finally, TET3 exerts its proinflammatory effect by promoting 5hmC production in the promoter of its target MTRNR2L2 in RA‐FLSs. Conclusion: The key role of the MIR22‐TET3‐MTRNR2L2 pathway in RA‐FLSs provided an experimental basis for further studies into the pathogenesis and related targets of RA from the perspective of FLSs. [ABSTRACT FROM AUTHOR]

Background: To investigate the effect and underlying mechanism of umbilical cord blood-mononuclear cells (UCB-MNCs) in treating knee osteoarthritis (KOA) in rabbits. Methods: A rabbit KOA model was prepared by anterior cruciate ligament transection (ACLT). Fifty New Zealand white rabbits were randomly divided into the control group, model group, sodium hyaluronate (SH) group, platelet-rich plasma (PRP) group and UCB-MNC group. Knee injections were performed once a week for five consecutive weeks. The gross view of the knee joint, morphology of knee cartilage and structural changes in the knee joint were observed on CT scans, and graded by the Lequesne MG behavioral score and the Mankin score. TNF-α and IL-1β levels in the synovial fluid of the knee were measured by the enzyme-linked immunosorbent assay (ELISA). Expression levels of MMP-13 and COL-II in the knee cartilage were detected by Western blotting and qRT-PCR. Results: The Lequesne MG behavioral score and the Mankin score were significantly higher in the model group than those in the control group (P < 0.05). Rabbits in the SH, PRP and UCB-MNC groups had sequentially lower scores than those in the model group. Imaging features of KOA were more pronounced in the model group than in the remaining groups. CB-MNC significantly relieved KOA, compared to SH and PRP. Significantly higher levels of TNF-α and IL-1β in the synovial fluid of the knee, and up-regulated MMP-13 and down-regulated COL-II in the knee cartilage were detected in the model group than in the control group. These changes were significantly reversed by the treatment with SH, PRP and UCB-MNCs, especially UCB-MNCs. Conclusion: Injections of UCB-MNCs into knees protect the articular cartilage and hinder the progression of KOA in rabbits by improving the local microenvironment at knee joints. [ABSTRACT FROM AUTHOR]