A novel GARP humanized mouse model for efficacy assessment of GARP-targeting therapies.

Although breakthroughs have been achieved with immune checkpoint inhibitors (ICI) therapy, some tumors do not respond to those therapies due to primary or acquired resistance. GARP, a type I transmembrane cell surface docking receptor mediating latent transforming growth factor-ß (TGF-ß) and abundantly expressed on regulatory T lymphocytes and platelets, is a potential target to render these tumors responsive to ICI therapy, and enhancing anti-tumor response especially combined with ICI. To facilitate these research efforts, we developed humanized mouse models expressing humanized GARP (hGARP) instead of their mouse counterparts, enabling in vivo assessment of GARP-targeting agents. We created GARP-humanized mice by replacing the mouse Garp gene with its human homolog. Then, comprehensive experiments, including expression analysis, immunophenotyping, functional assessments, and pharmacologic assays, were performed to characterize the mouse model accurately. The Tregs and platelets in the B-hGARP mice (The letter B is the first letter of the company's English name, Biocytogen.) expressed human GARP, without expression of mouse GARP. Similar T, B, NK, DCs, monocytes and macrophages frequencies were identified in the spleen and blood of B-hGARP and WT mice, indicating that the humanization of GARP did not change the distribution of immune cell in these compartments. When combined with anti-PD-1, monoclonal antibodies (mAbs) against GARP/TGF-ß1 complexes demonstrated enhanced in vivo anti-tumor activity compared to monotherapy with either agent. The novel hGARP model serves as a valuable tool for evaluating human GARP-targeting antibodies in immuno-oncology, which may enable preclinical studies to assess and validate new therapeutics targeting GARP. Furthermore, intercrosses of this model with ICI humanized models could facilitate the evaluation of combination therapies.

cTBS over primary motor cortex increased contralateral corticomuscular coupling and interhemispheric functional connection.

Objective.Transcranial magnetic stimulation is a non-invasive brain stimulation technique that changes the activity of the cerebral cortex. Contralesional continuous theta burst stimulation (cTBS) has been proposed and verified beneficial to stroke motor recovery. However, the underlying mechanism is still unclear.Approach.20 healthy right-handed subjects were recruited in this study, receiving real-cTBS over their left primary motor cortex or sham-cTBS. We designed the finger tapping task (FTT) before and after stimulation and recorded the accuracy and reaction time (RT) of the task. The electroencephalogram and surface electromyogram signals were recorded during the left finger pinching task (FPT) before and after stimulation. We calculated cortico-muscular coherence (CMC) in the contralateral hemisphere and cortico-cortical coherence (CCC) in the bilateral hemisphere. The two-way repeated measures analysis of variance was used to analyze the effect of cTBS.Main results.In the FTT, there was a significant main effect of 'time' on RT (F(1, 38) = 24.739,p< 0.001). In the FPT, the results showed that there was a significant interaction effect on the CMC peak and area in the beta band (peak:F(1, 38) = 8.562,p= 0.006; area:F(1, 38) = 5.273,p= 0.027), on the CCC peak in the alpha band (F(1, 38) = 4.815,p= 0.034) and area in the beta band (F(1, 38) = 4.822,p= 0.034). The post hoc tests showed that the CMC peak (W= 20,p= 0.002), the CMC area (W= 13,p= 0.003) and the CCC peak (t= -2.696,p= 0.014) increased significantly after real-cTBS. However, there was no significant decrease or increase after sham-cTBS.Significance.Our study found that cTBS can improve CMC of contralateral hemisphere and CCC of bilateral hemisphere, indicating that cTBS can strengthen cortico-muscular and cortico-cortical coupling.

Human umbilical cord mesenchymal stem cell-derived exosomes attenuate neuroinflammation and oxidative stress through the NRF2/NF-κB/NLRP3 pathway.

AIMS: We investigated whether human umbilical cord mesenchymal stem cell (hUC-MSC)-derived exosomes bear therapeutic potential against lipopolysaccharide (LPS)-induced neuroinflammation. METHODS: Exosomes were isolated from hUC-MSC supernatant by ultra-high-speed centrifugation and characterized by transmission electron microscopy and western blotting. Inflammatory responses were induced by LPS in BV-2 cells, primary microglial cultures, and C57BL/6J mice. H2 O2 was also used to induce inflammation and oxidative stress in BV-2 cells. The effects of hUC-MSC-derived exosomes on inflammatory cytokine expression, oxidative stress, and microglia polarization were studied by immunofluorescence and western blotting. RESULTS: Treatment with hUC-MSC-derived exosomes significantly decreased the LPS- or H2 O2 -induced oxidative stress and expression of pro-inflammatory cytokines (IL-6 and TNF-α) in vitro, while promoting an anti-inflammatory (classical M2) phenotype in an LPS-treated mouse model. Mechanistically, the exosomes increased the NRF2 levels and inhibited the LPS-induced NF-κB p65 phosphorylation and NLRP3 inflammasome activation. In contrast, the reactive oxygen species scavenger NAC and NF-κB inhibitor BAY 11-7082 also inhibited the LPS-induced NLRP3 inflammasome activation and switched to the classical M2 phenotype. Treatment with the NRF2 inhibitor ML385 abolished the anti-inflammatory and anti-oxidative effects of the exosomes. CONCLUSION: hUC-MSC-derived exosomes ameliorated LPS/H2 O2 -induced neuroinflammation and oxidative stress by inhibiting the microglial NRF2/NF-κB/NLRP3 signaling pathway.

A case study on microplastics pollution characteristics in fouling organisms in typical aquaculture bay, China.

Microplastics (MPs) and fouling organisms are prevalent in oceans worldwide. The study aims to investigate the pollution characteristics of MPs in fouling organisms. The study found significant inter-specific differences in the MPs abundance, while the length of MPs is consistent. The average number of MPs in N. exigua is 0.00 ± 0.00. There is a correlation between MPs abundance and weight in sessile group, while gastropods don't. Direct observation has demonstrated that the radulae of N. radula can envelop MPs. Fiber and blue are the predominant forms and colors of MPs found in fouling organisms. It is noteworthy that all film and fragment MPs observed were of a blue hue and had a size limitation of 500 µm. The characteristics of MPs between sessile organisms are more similar than those between gastropods. This study has improved our understanding of the pollution characteristics of MPs in fouling organisms, specifically gastropods.

Eldecalcitol prevents muscle loss and osteoporosis in disuse muscle atrophy via NF-κB signaling in mice.

We investigated the effect of eldecalcitol on disuse muscle atrophy. C57BL/6J male mice aged 6 weeks were randomly assigned to control, tail suspension (TS), and TS-eldecalcitol-treated groups and were injected intraperitoneally twice a week with either vehicle (control and TS) or eldecalcitol at 3.5 or 5 ng for 3 weeks. Grip strength and muscle weights of the gastrocnemius (GAS), tibialis anterior (TA), and soleus (SOL) were determined. Oxidative stress was evaluated by malondialdehyde, superoxide dismutase, glutathione peroxidase, and catalase. Bone microarchitecture was analyzed using microcomputed tomography. The effect of eldecalcitol on C2C12 myoblasts was analyzed by measuring myofibrillar protein MHC and the atrophy markers Atrogin-1 and MuRF-1 using immunofluorescence. The influence of eldecalcitol on NF-κB signaling pathway and vitamin D receptor (VDR) was assessed through immunofluorescence, (co)-immunoprecipitation, and VDR knockdown studies. Eldecalcitol increased grip strength (P < 0.01) and restored muscle loss in GAS, TA, and SOL (P < 0.05 to P < 0.001) induced by TS. An improvement was noted in bone mineral density and bone architecture in the eldecalcitol group. The impaired oxidative defense system was restored by eldecalcitol (P < 0.05 to P < 0.01 vs. TS). Eldecalcitol (10 nM) significantly inhibited the expression of MuRF-1 (P < 0.001) and Atrogin-1 (P < 0.01), increased the diameter of myotubes (P < 0.05), inhibited the expression of P65 and P52 components of NF-κB and P65 nuclear location, thereby inhibiting NF-κB signaling. Eldecalcitol promoted VDR binding to P65 and P52. VDR signaling is required for eldecalcitol-mediated anti-atrophy effects. In conclusion, eldecalcitol exerted its beneficial effects on disuse-induced muscle atrophy via NF-κB inhibition.

Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients.

BACKGROUND: MCL-1 is a prosurvival B-cell lymphoma 2 family protein that plays a critical role in tumor maintenance and survival and can act as a resistance factor to multiple anticancer therapies. Herein, we describe the generation and characterization of the highly potent and selective MCL-1 inhibitor ABBV-467 and present findings from a first-in-human trial that included patients with relapsed/refractory multiple myeloma (NCT04178902). METHODS: Binding of ABBV-467 to human MCL-1 was assessed in multiple cell lines. The ability of ABBV-467 to induce tumor growth inhibition was investigated in xenograft models of human multiple myeloma and acute myelogenous leukemia. The first-in-human study was a multicenter, open-label, dose-escalation study assessing safety, pharmacokinetics, and efficacy of ABBV-467 monotherapy. RESULTS: Here we show that administration of ABBV-467 to MCL-1-dependent tumor cell lines triggers rapid and mechanism-based apoptosis. In vivo, intermittent dosing of ABBV-467 as monotherapy or in combination with venetoclax inhibits the growth of xenografts from human hematologic cancers. Results from a clinical trial evaluating ABBV-467 in patients with multiple myeloma based on these preclinical data indicate that treatment with ABBV-467 can result in disease control (seen in 1 patient), but may also cause increases in cardiac troponin levels in the plasma in some patients (seen in 4 of 8 patients), without other corresponding cardiac findings. CONCLUSIONS: The selectivity of ABBV-467 suggests that treatment-induced troponin release is a consequence of MCL-1 inhibition and therefore may represent a class effect of MCL-1 inhibitors in human patients.

Apoptosis is a type of cell death that removes abnormal cells from the body. Cancer cells can have increased levels of MCL-1, a protein that helps cells survive and prevents apoptosis. ABBV-467 is a new drug that blocks the action of MCL-1 (an MCL-1 inhibitor) and could promote apoptosis. In animal models, ABBV-467 led to cancer cell death and delayed tumor growth. ABBV-467 was also studied in a clinical trial in 8 patients with multiple myeloma, a blood cancer. In 1 patient, ABBV-467 treatment prevented the cancer from getting any worse for 8 months. However, in 4 out of 8 patients ABBV-467 increased the levels of troponin, a protein associated with damage to the heart. This concerning side effect may impact the future development of MCL-1 inhibitors as anticancer drugs.

Proteomic analysis reveals that Polygonatum cyrtonema Hua polysaccharide ameliorates mice muscle atrophy in chemotherapy-induced cachexia.

Polygonatum cyrtonema Hua polysaccharide (PCP) is the main bioactive compound derived from the herb Polygonati Rhizoma, known for its anti-fatigue, antioxidant, immunomodulatory, and anti-inflammatory properties. However, its effectiveness on alleviating chemotherapy-induced muscle atrophy has been unclear. In this study, we utilized proteomic analysis to investigate the effects and mechanisms of PCP on gemcitabine plus cisplatin (GC) induced muscle atrophy in mice. Quality control analysis revealed that the functional PCP, rich in glucose, is a heterogeneous polysaccharide comprised of nine monosaccharides. PCP (64 mg/kg) significantly alleviated body muscle, organ weight loss, and muscle fiber atrophy in chemotherapy-induced cachectic mice. Moreover, PCP suppressed the decrease in serum immunoglobulin levels and the increase in pro-inflammatory factor interleukin-6 (IL-6). Proteomic analysis demonstrated that PCP contributed to the homeostasis of protein metabolism in gastrocnemius muscle. Diacylglycerol kinase (DGKζ) and cathepsin L (CTSL) were identified as primary PCP targets. Furthermore, the IL-6/STAT3/CTSL and DGKζ/FoxO/Atrogin1 signaling pathways were validated. Our findings suggest that PCP exerts an anti-atrophy effect on chemotherapy-induced muscle atrophy by regulating the autophagy-lysosome and ubiquitin-proteasome systems.

Comprehensive transcriptomic analyses identify KDM genes-related subtypes with different TME infiltrates in gastric cancer.

Histone lysine demethylases (KDMs) have been reported in various malignances, which affect transcriptional regulation of tumor suppressor or oncogenes. However, the relationship between KDMs and formation of tumor microenvironment (TME) in gastric cancer (GC) remain unclear and need to be comprehensively analyzed.In the present study, 24 KDMs were obtained and consensus molecular subtyping was performed using the "NMF" method to stratify TCGA-STAD into three clusters. The ssGSEA and CIBERSORT algorithms were employed to assess the relative infiltration levels of various cell types in the TME. The KDM_score was devised to predict patient survival outcomes and responses to both immunotherapy and chemotherapy.Three KDM genes-related molecular subtypes were Figured out in GC with distinctive clinicopathological and prognostic features. Based on the robust KDM genes-related risk_score and nomogram, established in our work, GC patients' clinical outcome can be well predicted. Furthermore, low KDM genes-related risk_score exhibited the more effective response to immunotherapy and chemotherapy.This study characterized three KDM genes-related TME pattern with unique immune infiltration and prognosis by comprehensively analyses of transcriptomic profiling. Risk_score was also built to help clinicians decide personalized anticancer treatment for GC patients, including in prediction of immunotherapy and chemotherapy response for patients.

Symmetrical Contralaterally Controlled Functional Electrical Stimulation Enhanced Cortical Activity and Synchronization of Stroke Survivors.

Contralaterally controlled functional electrical stimulation (CCFES) is a rehabilitation method whose efficacy has been proved in several randomized controlled trials. Symmetrical CCFES (S-CCFES) and asymmetrical CCFES (A-CCFES) are two basic strategies of CCFES. The cortical response can reflect the instant efficacy of CCFES. However, it is still unclear of the difference on cortical responses of these different strategies. Therefore, the aim of the study is to determine what cortical response CCFES may engage. Thirteen stroke survivors were recruited to complete three training sessions with S-CCFES, A-CCFES and unilateral functional electrical stimulation (U-FES), in which the affected arm was stimulated. The electroencephalogram (EEG) signals were recorded during the experiment. The event-related desynchronization (ERD) value of stimulation-induced EEG and phase synchronization index (PSI) for resting EEG were calculated and compared in different tasks. We found that S-CCFES induced significantly stronger ERD at affected MAI(motor area of interest) in alpha-rhythm (8-15Hz), which indicated stronger cortical activity. Meanwhile, S-CCFES also increased intensity of cortical synchronization within the affected hemisphere and between hemispheres, and the significantly increased PSI occurred in a wider area after S-CCFES. Our results suggested that S-CCFES could enhance cortical activity during stimulation and cortical synchronization after stimulation in stroke survivors. S-CCFES seems to have better prospects for stroke recovery.

Enhanced Gradient for Differentiable Architecture Search.

In recent years, neural architecture search (NAS) methods have been proposed for the automatic generation of task-oriented network architecture in image classification. However, the architectures obtained by existing NAS approaches are optimized only for classification performance and do not adapt to devices with limited computational resources. To address this challenge, we propose a neural network architecture search algorithm aiming to simultaneously improve the network performance and reduce the network complexity. The proposed framework automatically builds the network architecture at two stages: block-level search and network-level search. At the stage of block-level search, a gradient-based relaxation method is proposed, using an enhanced gradient to design high-performance and low-complexity blocks. At the stage of network-level search, an evolutionary multiobjective algorithm is utilized to complete the automatic design from blocks to the target network. The experimental results demonstrate that our method outperforms all evaluated hand-crafted networks in image classification, with an error rate of 3.18% on Canadian Institute for Advanced Research (CIFAR10) and an error rate of 19.16% on CIFAR100, both at network parameter size less than 1 M. Obviously, compared with other NAS methods, our method offers a tremendous reduction in designed network architecture parameters.

[Development of a multi-residue detection method for 27 typical pharmaceuticals and personal-care products in plants and analysis of their migration patterns in sprouts].

An analytical method based on ultra-performance liquid chromatography-tandem mass spectrometry was developed for the simultaneous determination of 27 pharmaceutical and personal-care product (PPCP) residues in plants. The enrichment and cleanup of PPCPs in plants were achieved using an HLB extraction column, and the separation was performed on a BEH C18 column (100 mm×2.1 mm, 1.7 µm) with 0.1% formic acid water-acetonitrile as the mobile phase via gradient elution. PPCPs were detected with electrospray ionization mass spectrometry in positive-ion multiple-reaction monitoring (MRM) mode. The limits of detection and quantification of the 27 PPCPs in plants were 0.01-0.30 µg/kg and 0.03-0.98 µg/kg, respectively. Good linearities were observed with coefficients of determination (r2) >0.99. The spiked recoveries were between 80.8% and 122.3% with relative standard deviations (RSDs) between 1.0% and 9.9%. The method was subsequently used to study sprouts grown in different concentrations of PPCPs. A total of 10 PPCPs were detected in sprouts grown in medium with a low concentration PPCPs, 13 PPCPs were detected in sprouts grown in medium with a moderate concentration of PPCPs, and 19 PPCPs were detected in sprouts grown in medium with a high concentration of PPCPs. These results showed that plants grown in water bodies contaminated with PPCPs or irrigated with water contaminated with PPCPs absorbed and accumulated these substances and that the amount and type of PPCPs absorbed by plants were closely related to the levels of PPCPs in the external environment. Analysis of the contents of PPCPs in different plant tissues revealed a general distribution of root>stem>leaf. Haemosibutramine showed a tissue distribution of leaf>stem>root, while glibenclamide showed a distribution of root>leaf>stem; these results revealed differences in the distribution of PPCPs in plants. Calculation of the transfer factor (TF) of the PPCPs in plants demonstrated significant differences in the transferability of different PPCPs, with TF=2.34 for haemosibutramine and TF=1.25 for chlorosibutramine. The results showed that among the drugs that migrated in plants, haemonosibutramine and chlorosibutramine had the strongest migration ability in sprouts, followed by nicardipine and chlorpheniramine maleate, and amantadine, N-monodesmethyl sibutramine, carbamazepine and flumequine had the weakest migration ability. Once absorbed, these compounds were transferred to the stems and/or leaves, where they accumulate and cause potential harm by contaminating other plant organs. Therefore, PPCPs such as homosibutramine and chlorosibutramine, which easily migrate in plants, should be given extra attention in future studies. The method is simple in pre-treatment, sensitive and accurate, and can be widely applied to the detection of PPCP residues in plant samples.

TRD-YOLO: A Real-Time, High-Performance Small Traffic Sign Detection Algorithm.

Traffic sign detection is an important part of environment-aware technology and has great potential in the field of intelligent transportation. In recent years, deep learning has been widely used in the field of traffic sign detection, achieving excellent performance. Due to the complex traffic environment, recognizing and detecting traffic signs is still a challenging project. In this paper, a model with global feature extraction capabilities and a multi-branch lightweight detection head is proposed to increase the detection accuracy of small traffic signs. First, a global feature extraction module is proposed to enhance the ability of extracting features and capturing the correlation within the features through self-attention mechanism. Second, a new, lightweight parallel decoupled detection head is proposed to suppress redundant features and separate the output of the regression task from the classification task. Finally, we employ a series of data enhancements to enrich the context of the dataset and improve the robustness of the network. We conducted a large number of experiments to verify the effectiveness of the proposed algorithm. The accuracy of the proposed algorithm is 86.3%, the recall is 82.1%, the mAP@0.5 is 86.5% and the mAP@0.5:0.95 is 65.6% in TT100K dataset, while the number of frames transmitted per second is stable at 73, which meets the requirement of real-time detection.

Ginsenoside Rb1 protects against diabetes-associated metabolic disorders in Kkay mice by reshaping gut microbiota and fecal metabolic profiles.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax quinquefolius Linn. is one of the most valuable herbal medicine in the world for its broad health benefits, including anti-diabetes. Ginsenoside Rb1, the principal active constituent of Panax quinquefolius Linn., could attenuate insulin resistance and metabolic disorders. The dysfunction of gut microbiota and fecal metabolites plays an important role in the pathogenesis of Type 2 Diabetes mellitus (T2DM). However, whether ginsenoside Rb1's hypoglycemic effect is related to gut microbiota remains elusive. AIM OF THE STUDY: Our study aimed to explore the insulin-sensitizing and anti-diabetic effects of ginsenoside Rb1 as well as the underlying mechanisms. MATERIALS AND METHODS: The T2DM model were established by high fat diet (HFD)-induced Kkay mice. The anti-diabetic effect of ginsenoside Rb1 (200 mg/kg/day) was evaluated by random blood glucose (RBG), fasting blood glucose (FBG), glucose tolerance test (OGTT), serum insulin level, insulin resistance index (HOMA-IR), pancreatic histology analysis, liver indexes, total triglyceride (TG) and total cholesterol (TC). Subsequently, 16S rRNA sequencing and LC-MS-based untargeted metabolomics were applied to characterize the microbiome and metabolites profile in HFD-induced Kkay mice, respectively. Finally, antibiotic treatment was used to validate the potential mechanism of ginsenoside Rb1 by modulating gut microbiota. RESULTS: Our results showed that ginsenoside Rb1 reduced blood glucose, OGTT, serum insulin level, HOMA-IR, liver indexes as well as pancreatic injury. In addition, the ginsenoside Rb1 reversed the gut microbiota dysbiosis in diabetic Kkay mice, as indicated by the elevated abundance of Parasutterella, decreased population of Alistipes, f_Prevotellaceae_unclassified, Odoribacter, Anaeroplasma. Moreover, ginsenoside Rb1 altered free fatty acid (FFA) levels in fecal metabolites, such as decreased the level of α-linolenic acid, 13-OxoODE, oleic acid, 13-HODE, arachidonic acid, palmitic acid, stearic acid, while increased the level of PC (14:0/22:1(13Z)) and PC (16:0/16:0). Notably, ginsenoside Rb1 failed to improve HFD-induced diabetes in Kkay mice with antibiotics intervention. CONCLUSION: These findings suggested that ginsenoside Rb1 may serve as a potential prebiotic agent to modulate specific gut microbes and related metabolites, which play essential roles in diabetes-associated metabolic disorders and insulin resistance.

Lower-Limb Motor Assessment With Corticomuscular Coherence of Multiple Muscles During Ankle Dorsiflexion After Stroke.

Motor impairment after stroke is generally caused by damage to the neural networks that control movement. Corticomuscular coherence (CMC) is a valid method to analyze the functional connectivity of the corticospinal pathway between the cerebral cortex and muscles. However, current studies on CMC in stroke patients only focused on the upper limbs. The functional connectivity between the brain and lower limbs in stroke patients has not been well studied. Therefore, twelve stroke patients and fifteen healthy controls were recruited and their electroencephalogram (EEG) and electromyogram (EMG) of Tibialis Anterior (TA), Lateral Gastrocnemius (LG) and Medial Gastrocnemius (MG) during unilateral static ankle dorsiflexion were recorded. We found the mean beta and gamma CMC values of Cz electrode of stroke patients were significantly lower than those of healthy controls (p < 0.05). The brain topography showed significant coherence in the center of the cerebral cortex in healthy controls, while there was no significant coherence in stroke patients. For clinical assessment, there was a significant positive correlation between CMC and lower limb Fugl-Meyer Assessment (FMA) for Cz-TA in beta band (r = 0.6296, p = 0.0282), Cz-LG in beta band (r = 0.6816, p = 0.0147), and Cz-MG in gamma band (r = 0.6194, p = 0.0317). A multiple linear regression model was established between CMC and lower limb FMA ( R2 = 0.6600 , p = 0.0280). Therefore, CMC between the cerebral cortex and lower limb muscles may be used as a new rehabilitation assessment biomarker in stroke.

Uptake and Transport of Different Concentrations of PPCPs by Vegetables.

In many parts of the world, water resources are scarce or even extremely scarce, and the reuse of water resources has become mainstream in today's world. Many regions use treated wastewater for agricultural irrigation, aquaculture, and other activities. However, in recent years, wastewater has been found to contain large amounts of pharmaceuticals and personal care products (PPCPs). Therefore, there is a potential risk of PPCPs being transported in the environment and affecting human health. In this study, we compared the uptake, transport, and accumulation of 27 PPCPs in three types of sprouts (radish, buckwheat, and okra).The bioaccumulation of amantadine, diphenhydramine, chlorpheniramine maleate, sibutramine, hemosibutramine, chlorosibutramine, N-monomethyl sibutramine, N, N-desmethyl sibutramine, and carbamazepine was found to be significantly higher in plants grown for 12 days in media containing 0.5, 5.0, and 50.0 ng/mL PPCPs. With increasing concentration of PPCPs in the culture solution, the amount of PPCPs absorbed by plants and the degree of accumulation also showed an increasing trend. At the same time, it was demonstrated that there was an obvious uptake transfer phenomenon of PPCPs by plants, and the trend of uptake transfer became more and more obvious as the concentration of external environmental pollutants increased. In addition, amantadine, chlorpheniramine maleate, carbamazepine, N, N-desmethyl sibutramine, hemosibutramine, and chlorosibutramine showed more active translocation in some plants (TF > 1.0).

Eldecalcitol prevents muscle loss by suppressing PI3K/AKT/FOXOs pathway in orchiectomized mice.

Elderly male patients are susceptible to develop osteoporosis and sarcopenia, especially those with fragility fractures, hypogonadism, and prostate cancer with androgen deprivation therapy. However, at present, very few treatments are available for men with sarcopenia. Previous preclinical studies in ovariectomized rats have shown the promising effects of eldecalcitol in ameliorating the bone strength and muscle atrophy. We thus investigated the effects of eldecalcitol on androgen-deficient male mice. Six-week-old male mice underwent orchiectomy (ORX) or sham surgery. Mice were randomly divided into 4 groups (n = 12/per group), including 1) sham mice, 2) ORX group, 3) ORX eldecalcitol 30 ng/kg, and 4) ORX eldecalcitol 50 ng/kg. Eldecalcitol increased bone mass and strength of femur in ORX mice. Eldecalcitol 30 ng/kg dose completely rescued ORX-induced muscle weakness. The RT-qPCR showed that eldecalcitol enhanced the mRNA levels of type I and IIa fibers. The expression levels of MuRF1 and Atrogin-1 of gastrocnemius in the eldecalcitol groups were much lower than that of the ORX group. It is assumed that eldecalcitol potentially acts via PI3K/AKT/FOXOs signaling pathway. These findings provide evidence for evaluating eldecalcitol as an investigational treatment for male patients with sarcopenia and osteoporosis.

Nonsingular recursive-structure sliding mode control for high-order nonlinear systems and an application in a wheeled mobile robot.

This work investigates the problem of fast tracking control for a class of high-order nonlinear systems subject to the matched disturbances. More particularly, a novel practical fixed-time disturbance observer is first presented by using a smooth hyperbolic tangent function. Then, a new nonsingular recursive-structure sliding mode surface is proposed based on the terminal sliding mode surface. With the reconstructed information deriving from the designed disturbance observer, a nonsingular recursive-structure sliding mode based finite-time tracking control approach incorporating with a new adaptive law is proposed to ensure the tracking errors converge to a small region of the origin in finite time. The finite-time stability of the closed-loop tracking control system driven by the proposed control scheme is analyzed and proved utilizing Lyapunov theory. And also, the proposed generalized control approach is applied to a mobile robotic experimental platform to achieve accurate trajectory tracking on the uneven ground. Finally, the numerical simulation and comparative experiment results demonstrate the effectiveness and superiority of the proposed approach.

The development of template-based facial expression perception from 6 to 15 years of age.

When perceiving emotional facial expressions, adults use a template-matching strategy, comparing the perceived face with a stored representation. A rejection of unnaturally exaggerated faces is characteristic of this strategy because the exaggerated expressions do not match the stored template. In contrast, a rule-based perceptual strategy (e.g., wide eyes indicate surprise) would be more tolerant of exaggeration. The current study uses exaggeration tolerance to test the expression perception strategies of children from 6 to 15 years of age. In Experiment 1, 62 (38 male) participants viewed pairs of happy or sad faces varying in exaggeration and selected the face that looked closest to how a happy (or sad) person really looks. With age, children became less likely to choose the more exaggerated expression. In Experiment 2, this result was replicated with each of the six basic emotions. Sixty-six children (26 male, 50 Caucasian, 10 mixed-race, four Indian, two unidentified) from 6 to 15 years of age completed the same experimental tasks as Experiment 1 for all six emotions. Again, with age children became less likely to choose the more exaggerated face. The results from both experiments suggest that the development of an adult-like template-matching strategy lasts into adolescence. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The Crystallisation, Microphase Separation and Mechanical Properties of the Mixture of Ether-Based TPU with Different Ester-Based TPUs.

The difference in compatibility at the molecular level can lead to a change of microphase separation structure of thermoplastic polyurethanes blend systems, which will improve their thermal and mechanical properties. In this study, TDI-polyester based TPU was blended with MDI-polyether-based TPU and MDI-polyester based TPU, with different ratios. In the blend system, the obvious reduction of the melting temperature of the high-temperature TDI-polyester based TPU component indicates its hard segments can be mutually integrated with the other component. For TDI-polyester based TPU/MDI-polyether based TPU blends, their similar hard segment ratio and similar chemical structure of the soft segment give the molecular chains of the two components better compatibility. The aggregation structure of the two kinds of chains can rearrange at the molecular level which makes the hard domains mutually integrate to form a new phase separation structure with larger phase region distance. As a result, the yield strength of this blend increased by almost 143% when the elongation at break was only reduced by 12%. In contrast, the other group of blends still partly maintain their respective micro domains, forming a weak interface and leading to a decreased of elongation at break.

Mst2 Overexpression Inhibits Thyroid Carcinoma Growth and Metastasis by Disrupting Mitochondrial Fitness and Endoplasmic Reticulum Homeostasis.

Although the incidence of thyroid carcinoma has increased over the past several decades, it has an excellent prognosis and overall 5-year survival, with a stable mortality rate, except in cases with advanced stages or rare malignant tumor types. Biomarkers have emerged as effective targets of molecular therapy against thyroid carcinoma due to their rapid and convenient detection; however, there has been little clinical application. Macrophage stimulating 2 (Mst2) is a proapoptotic protein with implications in carcinogenesis and metastasis. We found that Mst2 overexpression-induced endoplasmic reticulum (ER) stress in MDA-T32 thyroid carcinoma cells, accompanied by elevated caspase-12 activity, increased apoptotic rate, and reduced cell viability. In addition, Mst2 overexpression contributed to mitochondrial damage, as evidenced by increased mitochondrial oxidative stress and activated the mitochondrial apoptotic pathway. Inhibition of the JNK pathway abolished these effects. These results show Mst2 to be a novel tumor suppressor that induces mitochondrial dysfunction and ER stress via the JNK pathway. Thus, Mst2 could potentially serve as a biomarker for developing targeted therapy against thyroid carcinoma.