Chemical Comparison and Identification of Xanthine Oxidase Inhibitors of Dioscoreae Hypoglaucae Rhizoma and Dioscoreae Spongiosae Rhizoma by Chemometric Analysis and Spectrum-Effect Relationship.

Dioscoreae hypoglaucae Rhizoma (DH) and Dioscoreae spongiosae Rhizoma (DS) are two similar Chinese herbal medicines derived from the Dioscorea family. DH and DS have been used as medicines in China and other Asian countries for a long time, but study on their phytochemicals and bioactive composition is limited. This present study aimed to compare the chemical compositions of DH and DS, and explore the anti-xanthine oxidase components based on chemometric analysis and spectrum-effect relationship. Firstly, an HPLC method was used to establish the chemical fingerprints of DH and DS samples, and nine common peaks were selected. Then, hierarchical clustering analysis, principal component analysis and orthogonal partial least squares discriminant analysis were employed to compare and discriminate DH and DS samples based on the fingerprints data, and four steroidal saponins compounds (protodioscin, protogracillin, dioscin, gracillin) could be chemical markers responsible for the differences between DH and DS. Meanwhile, the anti-xanthine oxidase activities of these two herbal medicines were evaluated by xanthine oxidase inhibitory assay in vitro. Pearson correlation analysis and partial least squares regression analysis were subsequently used to investigate the spectrum-effect relationship between chemical fingerprints and xanthine oxidase inhibitory activities. The results showed that four steroidal saponins, including protodioscin, protogracillin, methyl protodioscin and pseudoprogracillin could be potential anti-xanthine oxidase compounds in DH and DS. Furthermore, the xanthine oxidase inhibitory activities of the four selected inhibitors were validated by anti-xanthine oxidase inhibitory assessment and molecular docking experiments. The present work provided evidence for understanding of the chemical differences and the discovery of the anti-xanthine oxidase constituent of DH and DS, which could be useful for quality evaluation and bioactive components screening of these two herbal medicines.

SERCA2a: a key protein in the Ca2+ cycle of the heart failure.

Calcium ion (Ca2+) cycle plays a crucial role in the contraction and relaxation of cardiomyocytes. The sarcoplasmic reticulum (SR) acts as an organelle for storing Ca2+, which mediated the release and re-uptake of Ca2+ during contraction and relaxation. Disorders of SR function lead to the dysfunction of Ca2+ cycle and myocardial cell function. The sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) acts as a subtype of SERCA expressed in the heart, which mediates the contraction of cardiomyocytes and Ca2+ in the cytoplasm to re-enter into the SR. The rate of uptake of Ca2+ by the SR determines the rate of myocardial relaxation. The regulation of SERCA2a activity controls the contractility and relaxation of the heart, affecting cardiac function. The expression and activity of SERCA2a are reduced in failing hearts. Gene therapy by increasing the expression of SERCA2a in the heart has been proven effective. In addition, SERCA2a is regulated by a variety of factors, including transmembrane micropeptides, protein kinases, and post-translational modifications (PTMs). In this review, we discuss the regulatory factors of SERCA2a and provide new insights into future treatments and the direction of heart failure research. In addition, gene therapy for SERCA2a has recently emerged as therapeutic option and hence will be discussed in this review.

[Quantitative analysis of fermented aerial part of Bupleurum chinense and prediction of their antimicrobial activity].

The aim of this study was to predict the anti-microbial components in the aerial part of Bupleurum chinense fermented by Lactobacillus plantarum through analyzing the correlation between contents of bioactive components and their inhibitory action for pathogenic bacteria. In this study, the UPLC-MS-MS detection method was established for eight flavonoids(kaempferol-3-O-ß-D-rutinoside, isoquercitrin, quercetin, isorhamnetin, rutin, iridin, quercetin-3-O-ß-L-arabinoside, kaempferol) and DL-3-phenyllactic acid, and the dynamic change of their contents at fermentation course were monitored. Meanwhile, the experiment employed five common no-naquatic pathogenic bacteria(Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Bacillus subtilis), and four common aquatic pathogenic bacteria(Aeruginosa hydrophila, Delayed Edwards, Vibrio alginolyticus, and Vibrio harveyi) to validate in vitro anti-microbial activity of the fermented aerial part of B. chinense at different fermentation time points. Finally, the Pearson correlation analysis was applied to predict the anti-microbial components of the fermented aerial part of B. chinense.The established UPLC-MS-MS method showed a good linearity and the widest linear range was from 0.19 µg·mL~(-1) to 50 µg·mL~(-1). The limit of quantitation and the limit of detection were 0.19-1.56 µg·mL~(-1) and 0.1-0.78 µg·mL~(-1) respectively. During the fermentation within 48 h, the contents of three flavonoids(rutin, quercetin-3-O-ß-L-arabinoside, isoquercitrin) and DL-3-phenyllactic acid from the fermented aerial part of B. chinense increased sharply. In the process of fermentation, the anti-microbial effect of the fermented aerial part of B. chinense on aquatic pathogens was significantly stronger than that on non-aquatic pathogens. Furthermore, Pearson correlation analysis predicted that isoquercitrin, rutin, quercetin-3-O-ß-L-arabinoside and DL-3-phenyllactic acid showed significant correlation with the four aquatic pathogens. This study revealed that the fermented aerial part of B. chinense had a high sensitivity to aquatic pathogens, which may be caused by the increased contents of isoquercitrin, rutin, quercetin-3-O-ß-L-arabinoside and DL-3-phenyllactic acid. In conclusion, this study provides a theoretical basis and new idea for the further development of the large amount of wasteful aerial part of Bupleurum chinense.

The critical role of ASD-related gene CNTNAP3 in regulating synaptic development and social behavior in mice.

Accumulated genetic evidences indicate that the contactin associated protein-like (CNTNAP) family is implicated in autism spectrum disorders (ASD). In this study, we identified genetic mutations in the CNTNAP3 gene from Chinese Han ASD cohorts and Simons Simplex Collections. We found that CNTNAP3 interacted with synaptic adhesion proteins Neuroligin1 and Neuroligin2, as well as scaffolding proteins PSD95 and Gephyrin. Significantly, we found that CNTNAP3 played an opposite role in controlling the development of excitatory and inhibitory synapses in vitro and in vivo, in which ASD mutants exhibited loss-of-function effects. In this study, we showed that the male Cntnap3-null mice exhibited deficits in social interaction， spatial learning and prominent repetitive behaviors. These evidences elucidate the pivotal role of CNTNAP3 in synapse development and social behaviors, providing mechanistic insights into ASD.

Repetitive transcranial magnetic stimulation inhibits Sirt1/MAO-A signaling in the prefrontal cortex in a rat model of depression and cortex-derived astrocytes.

Repetitive transcranial magnetic stimulation (rTMS) is a useful monotherapy for depression or adjunctive therapy for resistant depression. However, the anti-depressive effects of different parameters and the underlying mechanisms remain unclear. Here, we aimed to assess the effect of rTMS with different parameters (1/5/10 Hz, 0.84/1.26 T) on the depressive-like behaviors, 5-hydroxytryptamine (5-HT), 5-HIAA (5-hydroxyindoleacetic acid) and DA and NE levels, and monoamine oxidase A (MAO-A) activity in chronic unpredictable stress-treated rats, along with the expression of sirtuin 1 (Sirt1) and MAO-A in the prefrontal cortex (PFC) and cortex-derived astrocytes from new-born rats. Moreover, the depressive-like behaviors were monitored following the transcranial injection of the Sirt1 inhibitor EX527 (1 mM) daily for 1 week. We found that rTMS treatment (5/10 Hz, 0.84/1.26 T) ameliorated depressive-like behaviors, increased 5-HT, DA and NE levels, decreased the 5-HIAA level and Sirt1 and MAO-A expression, and reduced MAO-A activity in the PFC. The depressive-like behaviors were also ameliorated after the transcranial injection of EX527. Importantly, rTMS (5/10 Hz, 0.84/1.26 T) inhibited Sirt1 and MAO-A expressions in astrocytes and Sirt1 knockdown with short hairpin RNA decreased MAO-A expression in astrocytes. These results suggest that the inhibition of Sirt1/MAO-A expression in astrocytes in the PFC may contribute to the different anti-depressive effects of rTMS with different parameters, and may also provide a novel insight into the mechanisms underlying major depressive disorder.

Multiplexing N-glycan analysis by DNA analyzer.

Analysis of N-glycan structures has been gaining attentions over the years due to their critical importance to biopharma-based applications and growing roles in biological research. Glycan profiling is also critical to the development of biosimilar drugs. The detailed characterization of N-glycosylation is mandatory because it is a nontemplate driven process and that significantly influences critical properties such as bio-safety and bio-activity. The ability to comprehensively characterize highly complex mixtures of N-glycans has been analytically challenging and stimulating because of the difficulties in both the structure complexity and time-consuming sample pretreatment procedures. CE-LIF is one of the typical techniques for N-glycan analysis due to its high separation efficiency. In this paper, a 16-capillary DNA analyzer was coupled with a magnetic bead glycan purification method to accelerate the sample preparation procedure and therefore increase N-glycan assay throughput. Routinely, the labeling dye used for CE-LIF is 8-aminopyrene-1,3,6-trisulfonic acid, while the typical identification method involves matching migration times with database entries. Two new fluorescent dyes were used to either cross-validate and increase the glycan identification precision or simplify sample preparation steps. Exoglycosidase studies were carried out using neuramididase, galactosidase, and fucosidase to confirm the results of three dye cross-validation. The optimized method combines the parallel separation capacity of multiple-capillary separation with three labeling dyes, magnetic bead assisted preparation, and exoglycosidase treatment to allow rapid and accurate analysis of N-glycans. These new methods provided enough useful structural information to permit N-glycan structure elucidation with only one sample injection.

Peony-Glycyrrhiza Decoction for Antipsychotic-Related Hyperprolactinemia in Women With Schizophrenia: A Randomized Controlled Trial.

OBJECTIVES: An herbal preparation called peony-glycyrrhiza decoction (PGD) may have the potential in reducing antipsychotic-related hyperprolactinemia (hyperPRL). This double-blind, randomized placebo-controlled study aimed to reevaluate the efficacy of PGD against antipsychotic-related hyperPRL. METHODS: Ninety-nine schizophrenic women who were under antipsychotic therapy and had symptomatic hyperPRL were randomly assigned to additional treatment with placebo (n = 50) or PGD (n = 49, 45 g/d) for 16 weeks. The severity of hyperPRL, psychosis, and abnormal involuntary movements was assessed at baseline and weeks 8 and 16 using standard instruments including the Prolactin Related Adverse Event Questionnaire. Blood levels of prolactin (PRL) and related pituitary and sex hormones were measured at the same time points. RESULTS: Peony-glycyrrhiza decoction treatment produced a significantly greater reduction of the Prolactin Related Adverse Event Questionnaire score at weeks 8 and 16 and a greater improvement on abnormal involuntary movements at end point compared with placebo, without altering the severity of psychosis. The group treated with PGD showed significantly higher proportion of having overall improvement on hyperPRL symptoms (χ = 4.010, P = 0.045) and menstrual resumption (χ = 4.549, P = 0.033) at week 8 than placebo. Serum PRL levels were similar in the 2 groups. CONCLUSIONS: Peony-glycyrrhiza decoction is effective in reducing antipsychotic-related hyperPRL and abnormal involuntary movement symptoms, but no reduction in blood PRL concentrations was observed. The underlying mechanisms of PGD's effects need further investigation (trial registration of NCT01852331 at www.clinicaltrials.gov).

Quetiapine Ameliorates Schizophrenia-Like Behaviors and Protects Myelin Integrity in Cuprizone Intoxicated Mice: The Involvement of Notch Signaling Pathway.

BACKGROUND: White matter disturbances and myelin impairment are key features of schizophrenia. The antipsychotic drug quetiapine can promote the maturation of oligodendrocytes, but the molecular mechanisms remain largely unknown. METHODS: The schizophrenia-like behaviors, degrees of demyelination, and levels of Notch signaling molecules in forebrains of adult male C57BL/6 mice were examined after fed with cuprizone (0.2% wt/wt) in the presence or absence of 10mg/kg/d quetiapine for 6 weeks. These parameters were also observed after the transcranial injection of Notch signaling inhibitor MW167 (1mM) daily during the last week of the treatment period. RESULTS: Quetiapine ameliorated the schizophrenia-like behaviors and decreased expression of myelin basic protein and inhibition of Notch signaling molecules, such as Notch1, Hes1, and Hes5, in the forebrain that induced by cuprizone. These beneficial effects of quetiapine were abolished by MW167. CONCLUSIONS: The antipsychotic and myelin protective effects of quetiapine are mediated by Notch signaling in a mouse model of cuprizone-induced demyelination associated with schizophrenia-like behaviors. The Notch pathway might therefore be a novel target for the development of antipsychotic drugs.

Protective effects of Radix Pseudostellariae extract against retinal laser injury.

BACKGROUND: This study aimed to analyze the protective effects of a saponin extract from Radix Pseudostellariae (RP) on retinal laser injury based on a retinal photocoagulation model. METHODS: Fifty-eight rabbits were randomly divided into three groups: Group A (saponin extract orally), Group B (physiological saline), and Group C (control). The animals were sacrificed 1 day, 7 days, 14 days, and 30 days after photocoagulation and lesions were evaluated with fundus photography, light microscopy, and electron microscopy. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured, and expression levels of c-fos and Bax genes were also determined. RESULTS: The lesion sizes in Group A were smaller than in Group B. The levels of SOD in Group B were significantly lower than in groups A and C (P<0.001) at all time points. The MDA levels were significantly lower than in groups B and C (P<0.001) at the 1 month point, while the apoptosis rate of Group A was significantly lower than that of Group B at all time points. The expression levels of the c-fos gene in Group B were significantly higher than that in groups A and C, and expression levels of the Bax gene in Group A were significantly lower than that in groups B and C. CONCLUSION: The saponin extract of RP can inhibit oxidative stress, downregulate the levels of c-fos and Bax gene expression, and inhibit apoptosis in the retina after photocoagulation.

Paroxetine up-regulates neurogenesis in hippocampus-derived neural stem cell from fetal rats.

Paroxetine is a widely used antidepressant in clinic. Besides its role in inhibition of serotonin reuptake, resent studies indicate that the increase of hippocampal neurogenesis is also involved in its pharmacology. However, only limited data are available in this regard and its effect on the hippocampus-derived neural stem cell (NSCs) has not been well elucidated. In present study, we utilized hippocampus-derived NSCs from fetal rats to investigate the direct effect of paroxetine on the neurogenesis of NSCs and explore the possible cellular and molecular mechanisms. The results showed that paroxetine not only promoted the proliferation of NSCs, but also promoted NSCs to differentiate into neurons other than glial cells. In addition, the elevated protein levels of phosphorylated ERK1/2, Bcl-2, and brain-derived neurotrophic factor were also observed after paroxetine was administered. Furthermore, the proliferative effect and promotion of NSCs differentiating predominantly into neurons of paroxetine was inhibited by U0126, an ERK1/2 phosphorylation inhibitor. In conclusion, these data indicate that paroxetine can promote neurogenesis of neural stem cells, and this effect might be mediated by ERK1/2 signal pathways.

A mega study of antibiotics contamination in Eastern aquatic ecosystems of China: occurrence, interphase transfer processes, ecotoxicological risks, and source modeling.

Understanding the occurrence, sources, transfer mechanisms, fugacity, and ecotoxicological risks of antibiotics play a pivotal role in improving the sustainability and ecological health of freshwater ecosystems. Therefore, in order to determine the levels of antibiotics, water and sediment samples were collected from multiple Eastern freshwater ecosystems (EFEs) of China, including Luoma Lake (LML), Yuqiao Reservoir (YQR), Songhua Lake (SHL), Dahuofang Reservoir (DHR), and Xiaoxingkai Lake (XKL), and were analyzed using Ultra Performance Liquid Chromatography/Tandem Mass Spectrometry (UPLC-MS/MS). EFEs regions are particularly interesting due to higher urban density, industrialization, and diverse land use in China. The findings revealed that a collective total of 15 antibiotics categorized into four families, which included sulfonamides (SAs), fluoroquinolones (FQs), tetracyclines (TCs), and macrolides (MLs), exhibited high detection frequencies, indicating widespread antibiotic contamination. The pollution levels in the water phase were in the order of LML > DHR > XKL > SHL > YQR. The sum concentration of individual antibiotics for each water body ranged from not detected (ND) to 57.48 ng/L (LML), ND to 12.25 ng/L (YQR), ND to 57.7 ng/L (SHL), ND to 40.50 ng/L (DHR), and ND to 26.30 ng/L (XKL) in the water phase. Similarly, in the sediment phase, the sum concentration of individual antibiotics ranged from ND to 15.35 ng/g, ND to 198.75 ng/g, ND to 1233.34 ng/g, ND to 388.44 ng/g, and ND to 862.19 ng/g, for LML, YQR, SHL, DHR, and XKL, respectively. Interphase fugacity (ffsw) and partition coefficient (Kd) indicated dominant resuspension of antibiotics from sediment to water, causing secondary pollution in EFEs. Two groups of antibiotics, namely MLs (erythromycin, azithromycin, and roxithromycin) and FQs (ofloxacin and enrofloxacin), showed a medium-high level of adsorption tendency on sediment. Source modeling (PMF5.0) identified wastewater treatment plants, sewage, hospitals, aquaculture, and agriculture as the major antibiotic pollution sources in EFEs, contributing between 6% and 80% to different aquatic bodies. Finally, the ecological risk posed by antibiotics ranged from medium to high in EFEs. This study offers valuable insights into the levels, transfer mechanisms, and risks associated with antibiotics in EFEs, enabling the formulation of large-scale policies for pollution control.

Three-Dimensional Hounsfield Units Measurement of Pedicle Screw Trajectory for Predicating Screw Loosening in Lumbar Fusion Surgery.

Purpose: Dual-energy X-ray absorptiometry (DXA) is commonly used for evaluation of bone mineral density before spinal surgery, but frequently leads to overestimation in degenerative spinal diseases due to osteoproliferation factors. We introduce a novel method to compare the predictive ability of Hounsfield Units (HU) and DXA methods to predict screw loosening after lumbar interbody fusion surgery in degenerative spinal diseases by measuring HU of pedicle screw trajectory on computed tomography (CT) images preoperatively. Patients and Methods: This retrospective study was conducted on patients who underwent posterior lumbar fusion surgery for degenerative diseases. CT HUs measurement was performed using medical imaging software, including the cancellous region on cross-sections of the vertebral body and three-dimensional pedicle screw trajectory. Receiver operating characteristic (ROC) curve analyses were performed for the risk of pedicle screw loosening in association with the Hounsfield scale and preoperative BMD, and the area under the curve (AUC) and the cutoff values were calculated. Results: A total of 90 patients were enrolled and were divided into loosening (n = 33, 36.7%) and non-loosening groups (n = 57, 63.3%). No significant differences in age, gender, length of fixation and preoperative BMD were found between both groups. The loosening group showed lower CT HU values in the vertebral body and screw trajectory than the non-loosening group. Screw trajectory HU (ST-HU) exhibited a higher AUC value than vertebral body HU (B-HU). The cutoff values of B-HU and ST-HU were 160 and 110 HUs, respectively. Conclusion: Three-dimensional pedicle screw trajectory HU values yields a stronger predictive value than vertebral body HU values and BMD and may provide more guidance for surgery. The risk of screw loosening is significantly increased at ST-HU <110 or B-HU <160 at L5 segment.

CholecTriplet2022: Show me a tool and tell me the triplet - An endoscopic vision challenge for surgical action triplet detection.

Formalizing surgical activities as triplets of the used instruments, actions performed, and target anatomies is becoming a gold standard approach for surgical activity modeling. The benefit is that this formalization helps to obtain a more detailed understanding of tool-tissue interaction which can be used to develop better Artificial Intelligence assistance for image-guided surgery. Earlier efforts and the CholecTriplet challenge introduced in 2021 have put together techniques aimed at recognizing these triplets from surgical footage. Estimating also the spatial locations of the triplets would offer a more precise intraoperative context-aware decision support for computer-assisted intervention. This paper presents the CholecTriplet2022 challenge, which extends surgical action triplet modeling from recognition to detection. It includes weakly-supervised bounding box localization of every visible surgical instrument (or tool), as the key actors, and the modeling of each tool-activity in the form of triplet. The paper describes a baseline method and 10 new deep learning algorithms presented at the challenge to solve the task. It also provides thorough methodological comparisons of the methods, an in-depth analysis of the obtained results across multiple metrics, visual and procedural challenges; their significance, and useful insights for future research directions and applications in surgery.

The Impact of Resource Bricolage on Entrepreneurial Orientation in Start-ups: The Moderating Roles of TMT Heterogeneity and TMT Behavioral Integration.

Prior studies demonstrate the role of resources in shaping a firm's entrepreneurial orientation from the resource-based view. We expand this line of research by theorising and testing the impact of resource bricolage on entrepreneurial orientation. Based on the data of 295 start-ups, we find that when start-ups face resource constraints, the strategy of resource bricolage has a significant positive effect on entrepreneurial orientation, and the relationship is positively moderated by top management team (TMT) heterogeneity. Meanwhile, the relationship is negatively moderated by TMT behavioral integration. The results are expected to provide theoretical guidance for start-ups to overcome resource constraints and achieve smooth survival and growth.

Distributed Cooperative Quantum Learning for Discrete-Time Multiagent Source Exploration With Information Prompts.

In light of optimization theory and swarm evolutionary schemes, under multiple single-integrator mobile agents equipped with sensors and prompters, this article addresses a discrete-time multiagent source exploration problem with information prompts. Regarding information prompts as constraints on the unknown target, by virtue of penalty function skills (PFSs) and sequential unconstrained minimization techniques (SUMTs), the agents are driven toward the source under the guidance of the control strategy. In two cases of available and unavailable gradient information, a quantum potential well, an average optimal position estimator (AOPE), and a global optimal position estimator (GOPE) are introduced into swarm evolutionary schemes with a periodically oscillating weight, such that distributed cooperative quantum learning (DCQL) policy is proposed as a control strategy under communication restrictions, where AOPE and GOPE are developed relying on distributed consensus theory. In particular, when the gradient is unavailable, we put forth an adaptive generalized Bernstein neural network (AGBNN) to replace it based on excellent properties of Bernstein polynomials and adaptive approaches. Further, a performance analysis for the proposed policy is executed on the convergence and computational complexity, which ensures the accuracy and efficiency of the source exploration in theory. Ultimately, a simulation test is carried out, and the results validate the practicability and effectiveness of the offered method.

Synthesis With Guaranteed Cost and Less Human Intervention for Human-in-the-Loop Control Systems.

This article studies the problem of synthesis with guaranteed cost and less human intervention for linear human-in-the-loop (HiTL) control systems. Initially, the human behaviors are modeled via a hidden controlled Markov process, which not only considers the inference's stochasticity and observation's uncertainty of the human internal state but also takes the control input to human into account. Then, to integrate both models of human and machine as well as their interaction, a hidden controlled Markov jump system (HCMJS) is constructed. With the aid of the stochastic Lyapunov functional together with the bilinear matrix inequality technique, a sufficient condition for the existence of human-assistance controllers is derived on the basis of the HCMJS model, which not only guarantees the stochastic stability of the closed-loop HiTL system but also provides a prescribed upper bound for the quadratic cost function. Moreover, to achieve less human intervention while meeting the desired cost level, an algorithm that mixes the particle swarm optimization and linear matrix inequality technique is proposed to seek a suitable feedback control law to the human and a human-assistance control law to the machine. Finally, the proposed method is applied to a driver-assistance system to verify its effectiveness.

Second dorsal metacarpal artery-based index finger dorsal island flap for the management of thumb defects.

Index finger dorsal island flaps were frequently utilized by hand surgeons to reconstruct thumb defects. However, the blood supply of the traditional index finger dorsal island flap comes from the first dorsal metacarpal artery, which has a smaller diameter, more anatomical variation, and can be injured in conjunction with thumb injuries. Therefore, we design an alternative index finger dorsal island flap based on the second dorsal metacarpal artery to treat thumb skin defects. From August 2015 to October 2018, we used the index finger dorsal island flaps with the second dorsal metacarpal artery to treat 11 patients with thumb skin defects. All the flaps and skin grafts survived completely without complications. At the last follow-up, the mean 2PD of the flap was 6.4 mm (45.5% for excellent, 54.5% for good), the mean ROM of the injured thumbs was 115.9° (72.7% for excellent, 27.3% for good), and the mean cosmetics score was 8.6. Our results demonstrate that the index finger dorsal island flap with the second dorsal metacarpal artery is suitable for the reconstruction of thumb skin defects. The flap has an excellent survival rate and good coverage with satisfactory results and represents a promising treatment for the selected patients. Level of Evidence: Therapeutic, level IV.

Cancer-related stroke: Exploring personalized therapy strategies.

BACKGROUND: Cancer and ischemic stroke are two common diseases that threaten human health and have become the main causes of death in the world. It is estimated that one-in-ten patients with ischemic stroke have concomitant cancer, and this incidence is expected to increase as improvements in medical technology extends the life expectancy of cancer patients. DISCUSSION: Cancer-related stroke (CRS) refers to unexplained ischemic stroke in patients with active cancer that cannot be explained by current stroke mechanisms. Available evidence suggests that CRS accounts for 5-10% of embolic stroke of undetermined source (ESUS). Although the incidence of CRS is gradually increasing, its underlying pathogenesis remains unclear. Also, there is no consensus on acute treatment and secondary prevention of stroke. CONCLUSION: In this review, we retrospectively analyzed the incidence, mechanisms of CRS, its potential as a new stroke subtype, options for acute treatment, secondary prevention strategies, and disease progression, with the aim of attempting to explore personalized therapy strategies.

Babao Dan Alleviates 5-Fluorouracil-Induced Intestinal Damage via Wnt/ß-Catenin Pathway.

OBJECTIVE: To evaluate the protective function of Babao Dan (BBD) on 5-flurouracil (5-FU)-induced intestinal mucositis (IM) and uncover the underlying mechanism. METHODS: A total of 18 male mice were randomly divided into 3 groups by a random number table, including control, 5-FU and 5-FU combined BBD groups, 6 mice in each group. A single intraperitoneal injection of 5-FU (150 mg/kg) was performed in 5-FU and 5-FU combined BBD groups on day 0. Mice in 5-FU combined BBD group were gavaged with BBD (250 mg/kg) daily from day 1 to 6. Mice in the control group were gavaged with saline solution for 6 days. The body weight and diarrhea index of mice were recorded daily. On the 7th day, the blood from the heart of mice was collected to analyze the proportional changes of immunological cells, and the mice were subsequently euthanized by mild anesthesia with 2% pentobarbital sodium. Colorectal lengths and villus heights were measured. Intestinal-cellular apoptosis and proliferation were evaluated by Tunel assay and immunohistochemical staining of proliferating cell nuclear antigen, respectively. Immunohistochemistry and Western blot were performed to investigate the expressions of components in Wnt/ß-catenin pathway (Wnt3, LRP5, ß-catenin, c-Myc, LRG5 and CD44). RESULTS: BBD obviously alleviated 5-FU-induced body weight loss and diarrhea, and reversed the decrease in the number of white blood cells, including monocyte, granulocyte and lymphocyte, and platelet (P<0.01). The shortening of colon caused by 5-FU was also reversed by BBD (P<0.01). Moreover, BBD inhibited apoptosis and promoted proliferation in jejunum tissues so as to reduce the intestinal mucosal damage and improve the integrity of villus and crypts. Mechanically, the expression levels of Wnt/ß -catenin mediators such as Wnt3, LRP5, ß-catenin were upregulated by BBD, activating the transcription of c-Myc, LRG5 and CD44 (P<0.01). CONCLUSIONS: BBD attenuates the adverse effects induced by 5-FU via Wnt/ß-catenin pathway, suggesting it may act as a potential agent against chemotherapy-induced intestinal mucositis.

Nanomechanical analysis of insulinoma cells after glucose and capsaicin stimulation using atomic force microscopy.

AIM: Glucose stimulates insulin secretion from pancreatic islet ß cells by altering ion channel activity and membrane potential in the ß cells. TRPV1 channel is expressed in the ß cells and capsaicin induces insulin secretion similarly to glucose. This study aims to investigate the biophysical properties of the ß cells upon stimulation of membrane channels using an atomic force microscopic (AFM) nanoindentation system. METHODS: ATCC insulinoma cell line was used. Cell stiffness, a marker of reorganization of cell membrane and cytoskeleton due to ion channel activation, was measured in real time using an integrated AFM nanoindentation system. Cell height that represented structural changes was simultaneously recorded along with cell stiffness. RESULTS: After administration of glucose (16, 20 and 40 mmol/L), the cell stiffness was markedly increased in a dose-dependent manner, whereas cell height was changed in an opposite way. Lower concentrations of capsaicin (1.67 × 10(-9) and 1.67 × 10(-8) mol/L) increased the cell stiffness without altering cell height. In contrast, higher concentrations of capsaicin (1.67 × 10(-6) and 1.67 × 10(-7) mol/L) had no effect on the cell physical properties. CONCLUSION: A unique bio-nanomechanical signature was identified for characterizing biophysical properties of insulinoma cells upon general or specific activation of membrane channels. This study may deepen our understanding of stimulus-secretion coupling of pancreatic islet cells that leads to insulin secretion.