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Extracellular clustering of amyloid-β (Aβ) and an impaired autophagy lysosomal pathway (ALP) are the hallmark features in the early stages of incurable Alzheimer's disease (AD). There is a pressing need to find or develop new small molecules for diagnostics and therapeutics for the early stages of AD. Herein, we report a small molecule, namely F-SLCOOH, which can bind and detect Aβ 1-42 , Iowa mutation Aβ, Dutch mutation Aβ fibrils and oligomers exhibiting enhanced emission with high affinity. Importantly, F-SLCOOH can readily pass through the blood-brain barrier and shows highly selective binding toward the extracellular Aβ aggregates in real-time in live animal imaging of a 5XFAD mice model. In addition, a high concentration of F-SLCOOH in both brain and plasma of wildtype mice after intraperitoneal administration was found. The ex vivo confocal imaging of hippocampal brain slices indicated excellent colocalization of F-SLCOOH with Aβ positive NU1, 4G8, 6E10 A11 antibodies and THS staining dye, affirming its excellent Aβ specificity and targetability. The molecular docking studies have provided insight into the unique and specific binding of F-SLCOOH with various Aβ species. Importantly, F-SLCOOH exhibits remarkable anti-fibrillation properties against toxic Aβ aggregate formation of Aβ 1-42 , Iowa mutation Aβ, and Dutch mutation Aβ. F-SLCOOH treatment also exerts high neuroprotective functions and promotes autophagy lysosomal biogenesis in neuronal AD cell models. In summary, the present results suggest that F-SLCOOH is a highly promising theranostic agent for diagnosis and therapeutics of AD.

Autophagy impairment is a key factor in Alzheimer's disease (AD) pathogenesis. TFEB (transcription factor EB) and TFE3 (transcription factor binding to IGHM enhancer 3) are nuclear transcription factors that regulate autophagy and lysosomal biogenesis. We previously showed that corynoxine (Cory), a Chinese medicine compound, protects neurons from Parkinson's disease (PD) by activating autophagy. In this study, we investigated the effect of Cory on AD models in vivo and in vitro. We found that Cory improved learning and memory function, increased neuronal autophagy and lysosomal biogenesis, and reduced pathogenic APP-CTFs levels in 5xFAD mice model. Cory activated TFEB/TFE3 by inhibiting AKT/mTOR signaling and stimulating lysosomal calcium release via transient receptor potential mucolipin 1 (TRPML1). Moreover, we demonstrated that TFEB/TFE3 knockdown abolished Cory-induced APP-CTFs degradation in N2aSwedAPP cells. Our findings suggest that Cory promotes TFEB/TFE3-mediated autophagy and alleviates Aβ pathology in AD models., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Sex-specific behaviors are critical for reproduction and species survival. The sex-specifically spliced transcription factor fruitless ( fru ) helps establish male courtship behaviors in invertebrates. Forcing male-specific fru ( fruM ) splicing in Drosophila melanogaster females produces male-typical behaviors while disrupting female-specific behaviors. However, whether fru 's joint role in specifying male and inhibiting female behaviors is conserved across species is unknown. We used CRISPR-Cas9 to force FruM expression in female Drosophila virilis , a species in which males and females produce sex-specific songs . In contrast to D. melanogaster , in which one fruM allele is sufficient to generate male behaviors in females, two alleles are needed in D. virilis females. D. virilis females expressing FruM maintain the ability to sing female-typical song as well as lay eggs, whereas D. melanogaster FruM females cannot lay eggs. These results reveal potential differences in fru function between divergent species and underscore the importance of studying diverse behaviors and species for understanding the genetic basis of sex differences.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the predominant impairment of neurons in the hippocampus and the formation of amyloid plaques, hyperphosphorylated tau protein, and neurofibrillary tangles in the brain. The overexpression of amyloid-β precursor protein (APP) in an AD brain results in the binding of APP intracellular domain (AICD) to Fe65 protein via the C-terminal Fe65-PTB2 interaction, which then triggers the secretion of amyloid-β and the consequent pathogenesis of AD. Apparently, targeting the interaction between APP and Fe65 can offer a promising therapeutic approach for AD. Recently, exosome, a type of extracellular vesicle with diameter around 30-200 nm, has gained much attention as a potential delivery tool for brain diseases, including AD, due to their ability to cross the blood-brain barrier, their efficient uptake by autologous cells, and their ability to be surface-modified with target-specific receptor ligands. Here, the engineering of hippocampus neuron cell-derived exosomes to overexpress Fe65, enabled the development of a novel exosome-based targeted drug delivery system, which carried Corynoxine-B (Cory-B, an autophagy inducer) to the APP overexpressed-neuron cells in the brain of AD mice. The Fe65-engineered HT22 hippocampus neuron cell-derived exosomes (Fe65-EXO) loaded with Cory-B (Fe65-EXO-Cory-B) hijacked the signaling and blocked the natural interaction between Fe65 and APP, enabling APP-targeted delivery of Cory-B. Notably, Fe65-EXO-Cory-B induced autophagy in APP-expressing neuronal cells, leading to amelioration of the cognitive decline and pathogenesis in AD mice, demonstrating the potential of Fe65-EXO-Cory-B as an effective therapeutic intervention for AD., (© 2023. West China Hospital, Sichuan University.)

The autophagy-lysosomal pathway (ALP) is a major cellular machinery involved in the clearance of aggregated proteins in Alzheimer disease (AD). However, ALP is dramatically impaired during AD pathogenesis via accumulation of toxic amyloid beta (Aβ) and phosphorylated-Tau (phospho-Tau) proteins in the brain. Therefore, activation of ALP may prevent the increased production of Aβ and phospho-Tau in AD. Peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor that can activate autophagy, and transcriptionally regulate transcription factor EB (TFEB) which is a key regulator of ALP. This suggests that targeting PPARα, to reduce ALP impairment, could be a viable strategy for AD therapy. In this study, we investigated the anti-AD activity of Caudatin, an active constituent of Cynanchum otophyllum (a traditional Chinese medicinal herb, Qing Yang Shen; QYS). We found that Caudatin can bind to PPARα as a ligand and augment the expression of ALP in microglial cells and in the brain of 3XTg-AD mice model. Moreover, Caudatin could activate PPARα and transcriptionally regulates TFEB-augmented lysosomal degradation of Aβ and phosphor-Tau aggregates in AD cell models. Oral administration of Caudatin decreased AD pathogenesis and ameliorated the cognitive dysfunction in 3XTg-AD mouse model. Conclusively, Caudatin can be a potential AD therapeutic agent via activation of PPARα-dependent ALP., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Bacterial Extracellular Vesicles (BEVs) possess the capability of intracellular interactions with other cells, and, hence, can be utilized as an efficient cargo for worldwide delivery of therapeutic substances such as monoclonal antibodies, proteins, plasmids, siRNA, and small molecules for the treatment of neurodegenerative diseases (NDs). BEVs additionally possess a remarkable capacity for delivering these therapeutics across the blood-brain barrier to treat Alzheimer's disease (AD). This review summarizes the role and advancement of BEVs for NDs, AD, and their treatment. Additionally, it investigates the critical BEV networks in the microbiome-gut-brain axis, their defensive and offensive roles in NDs, and their interaction with NDs. Furthermore, the part of BEVs in the neuroimmune system and their interference with ND, as well as the risk factors made by BEVs in the autophagy-lysosomal pathway and their potential outcomes on ND, are all discussed. To conclude, this review aims to gain a better understanding of the credentials of BEVs in NDs and possibly discover new therapeutic strategies.

Background and Purpose: The insidious onset of Parkinson's disease (PD) makes early diagnosis difficult. Notably, idiopathic rapid eye movement sleep behavior disorder (iRBD) was reported as a prodrome of PD, which may represent a breakthrough for the early diagnosis of PD. However, currently there is no reliable biomarker for PD diagnosis. Considering that α-synuclein (α-Syn) and neuroinflammation are known to develop prior to the onset of clinical symptoms in PD, it was hypothesized that plasma total exosomal α-Syn (t-exo α-Syn), neural-derived exosomal α-Syn (n-exo α-Syn) and exosomal apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) may be potential biomarkers of PD., Methods: In this study, 78 PD patients, 153 probable iRBD patients (pRBD) and 63 healthy controls (HCs) were recruited. α-Syn concentrations were measured using a one-step paramagnetic particle-based chemiluminescence immunoassay, and ASC levels were measured using the Ella system., Results: It was found that t-exo α-Syn was significantly increased in the PD group compared to the pRBD and HC groups (p < 0.0001), whilst n-exo α-Syn levels were significantly increased in both the PD and pRBD groups compared to HCs (p < 0.0001). Furthermore, although no difference was found in ASC levels between the PD and pRBD groups, there was a positive correlation between ASC and α-Syn in exosomes., Conclusions: Our results suggest that both t-exo α-Syn and n-exo α-Syn were elevated in the PD group, whilst only n-exo α-Syn was elevated in the pRBD group. Additionally, the adaptor protein of inflammasome ASC is correlated with α-Syn and may facilitate synucleinopathy., (© 2022 European Academy of Neurology.)

Brain radiomics can reflect the characteristics of brain pathophysiology. However, the value of T1-weighted images, quantitative susceptibility mapping, and R2* mapping in the diagnosis of Parkinson's disease (PD) was underestimated in previous studies. In this prospective study to establish a model for PD diagnosis based on brain imaging information, we collected high-resolution T1-weighted images, R2* mapping, and quantitative susceptibility imaging data from 171 patients with PD and 179 healthy controls recruited from August 2014 to August 2019. According to the inclusion time, 123 PD patients and 121 healthy controls were assigned to train the diagnostic model, while the remaining 106 subjects were assigned to the external validation dataset. We extracted 1408 radiomics features, and then used data-driven feature selection to identify informative features that were significant for discriminating patients with PD from normal controls on the training dataset. The informative features so identified were then used to construct a diagnostic model for PD. The constructed model contained 36 informative radiomics features, mainly representing abnormal subcortical iron distribution (especially in the substantia nigra), structural disorganization (e.g., in the inferior temporal, paracentral, precuneus, insula, and precentral gyri), and texture misalignment in the subcortical nuclei (e.g., caudate, globus pallidus, and thalamus). The predictive accuracy of the established model was 81.1 ± 8.0% in the training dataset. On the external validation dataset, the established model showed predictive accuracy of 78.5 ± 2.1%. In the tests of identifying early and drug-naïve PD patients from healthy controls, the accuracies of the model constructed on the same 36 informative features were 80.3 ± 7.1% and 79.1 ± 6.5%, respectively, while the accuracies were 80.4 ± 6.3% and 82.9 ± 5.8% for diagnosing middle-to-late PD and those receiving drug management, respectively. The accuracies for predicting tremor-dominant and non-tremor-dominant PD were 79.8 ± 6.9% and 79.1 ± 6.5%, respectively. In conclusion, the multiple-tissue-specific brain radiomics model constructed from magnetic resonance imaging has the ability to discriminate PD and exhibits the advantages for improving PD diagnosis., Competing Interests: None

Emerging evidence from Alzheimer's disease (AD) patients suggests that reducing tau pathology can restore cognitive and memory loss. To reduce tau pathology, it is critical to find brain-permeable tau-degrading small molecules that are safe and effective. HDAC6 inhibition has long been considered a safe and effective therapy for tau pathology. Recently, we identified protopine as a dibenzazecine alkaloid with anti-HDAC6 and anti-AD activities. In this study, we synthesized and tested novel protopine derivatives for their pharmacological action against AD. Among them, bromo-protopine (PRO-Br) demonstrated a two-fold increase in anti-HDAC6 activity and improved anti-tau activities compared to the parent compound in both in vitro and in vivo AD models. Furthermore, molecular docking results showed that PRO-Br binds to HDAC6, with a ∆G value of -8.4 kcal/mol and an IC 50 value of 1.51 µM. In neuronal cell lines, PRO-Br reduced pathological tau by inducing chaperone-mediated autophagy (CMA). In 3xTg-AD and P301S tau mice models, PRO-Br specifically decreased the pathogenic hyperphosphorylated tau clumps and led to the restoration of memory functions. In addition, PRO-Br treatment promoted the clearance of pathogenic tau by enhancing the expression of molecular chaperones (HSC70) and lysosomal markers (LAMP2A) via CMA in AD models. Our data strongly suggest that administration of the brain-permeable protopine derivative PRO-Br, could be a viable anti-tau therapeutic strategy for AD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sreenivasmurthy, Iyaswamy, Krishnamoorthi, Reddi, Kammala, Vasudevan, Senapati, Zhu, Su, Liu, Guan, Chua, Cheung, Chen, Zhang, Zhang, Song, Kumar Durairajan and Li.)

Increasing evidence shows that autophagy impairment is involved in the pathogenesis and progression of neurodegenerative diseases including Parkinson's disease (PD). We previously identified a natural alkaloid named corynoxine B (Cory B) as a neuronal autophagy inducer. However, its brain permeability is relatively low, which hinders its potential use in treating PD. Thus we synthesized various derivatives of Cory B to find more potent autophagy inducers with improved brain bioavailability. In this study, we evaluated the autophagy-enhancing effect of CB6 derivative and its neuroprotective action against PD in vitro and in vivo. We showed that CB6 (5-40 μM) dose-dependently accelerated autophagy flux in cultured N2a neural cells through activating the PIK3C3 complex and promoting PI3P production. In MPP + -treated PC12 cells, CB6 inhibited cell apoptosis and increased cell viability by inducing autophagy. In MPTP-induced mouse model of PD, oral administration of CB6 (10, 20 mg· kg -1 ·  d -1 , for 21 days) significantly improved motor dysfunction and prevented the loss of dopaminergic neurons in the striatum and substantia nigra pars compacta. Collectively, compound CB6 is a brain-permeable autophagy enhancer via PIK3C3 complex activation, which may help the prevention or treatment of PD., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Alzheimer's disease (AD) is an age-associated neurodegenerative disease; it is the most common cause of senile dementia. Klotho, a single-pass transmembrane protein primarily generated in the brain and kidney, is active in a variety of metabolic pathways involved in controlling neurodegeneration and ageing. Recently, many studies have found that the upregulation of Klotho can improve pathological cognitive deficits in an AD mice model and have demonstrated that Klotho plays a role in the induction of autophagy, a major contributing factor for AD. Despite the close association between Klotho and neurodegenerative diseases, such as AD, the underlying mechanism by which Klotho contributes to AD remains poorly understood. In this paper, we will introduce the expression, location and structure of Klotho and its biological functions. Specifically, this review is devoted to the correlation of Klotho protein and the AD phenotype, such as the effect of Klotho in upregulating the amyloid-beta clearance and in inducing autophagy for the clearance of toxic proteins, by regulating the autophagy lysosomal pathway (ALP). In summary, the results of multiple studies point out that targeting Klotho would be a potential therapeutic strategy in AD treatment.

Background: Collective evidences have indicated that intracellular accumulation of hyperphosphorylated tau forms neurofibrillary tangles in the brain, which impairs memory, cognition and affects social activities in Alzheimer's disease (AD)., Purpose: To investigate the tau-reducing, and memory-enhancing properties of protopine (PRO), a natural alkaloid isolated from Chinese herbal medicine Corydalis yanhusuo (Yanhusuo in Chinese)., Study Design: By using Histone deacetylase 6 (HDAC6) profiling and immunoprecipitation assays, we assessed that PRO mediated the heat shock protein 90 (HSP90) chaperonic activities for the degradation of pathological tau in AD cell culture models. To study the efficacy of PRO in vivo, we employed 3xTg-AD and P301S tau mice models., Methods: Liquid chromatography/quadrupole time-of-flight mass spectrometry was used to analyze the pharmacokinetic profile of PRO. Seven-month-old 3xTg-AD mice and 1.5-month-old P301S mice were administered PRO (1 and 2.5 mg/kg) orally every day. Morris water maze, contextual fear conditioning and rotarod assays were applied for studying memory functions. Sarkosyl differential centrifugation was used to analyze soluble and insoluble tau. Immunohistochemical analysis were performed to determine tau deposits in AD mice's brain sections. Molecular docking, binding affinity studies and primary cell culture studies were performed to demonstrate the mechanism of action of PRO in silico and in vitro., Results: Our pharmacokinetic profiling demonstrated that PRO significantly entered the brain at a concentration of 289.47 ng/g, and specifically attenuated tau pathology, improved learning and memory functions in both 3xTg-AD and P301S mice. Docking, binding affinity studies, and fluorometric assays demonstrated that PRO directly bound to the catalytic domain 1 (CD1) of HDAC6 and down-regulated its activity. In primary cortical neurons, PRO enhanced acetylation of α-tubulin, indicating HDAC6 inhibition. Meanwhile, PRO promoted the ubiquitination of tau and recruited heat shock protein 70 (HSP70) and heat shock cognate complex 71 (HSC70) for the degradation of pathological tau via the ubiquitin-proteasomal system (UPS)., Conclusion: We identified PRO as a natural HDAC6 inhibitor that attenuated tau pathology and improved memory dysfunctions in AD mice. The findings from this study provides a strong justification for future clinical development of plant-derived protopine as a novel agent for the treatment of tau-related neurodegenerative diseases., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Objective: To improve the clinical management of acute pulmonary embolism caused by antithrombin Ⅲ (AT Ⅲ) deficiency through gene sequence analysis of the SERPINC1 gene. Methods: The diagnosis and treatment of a 33-year-old male patient with chest pain was reviewed. All exon sequences and flanking regions of 7 related genes of thrombophilia were subjected to detection by high-throughput next generation sequencing technology. The gene mutation was inquired in the gene database and the pathogenic probability of the mutant gene was predicted by Mutation Taster software. Results: The patient was diagnosed with acute pulmonary embolism (intermediate-low risk), with the ATⅢ activity less than 50%. Anticoagulation with nadroparin calcium combined with warfarin was administrated, but hemoptysis was aggravated, and then the medication was replaced by anticoagulant of rivaroxaban. In the end, the embolus was gradually absorbed. A heterozygous missense mutation of c.1148T>A (p.L383H) in the SERPINC1 gene was detected. The gene database and Mutation Taster confirmed the mutation as a new pathogenic mutation with the pathogenic probability of 0.999 999 851 200 991. Conclusions: C.1148T>A (p.L383H) is a novel pathogenic mutation in SERPINC1 gene that complements and updates the gene mutation spectrum of hereditary AT Ⅲ deficiency. The new oral anticoagulant rivaroxaban may be used as the first-line treatment for these patients.

Increasing evidence suggests that genetic factors play a key role in the development of Parkinson's disease (PD). The variant rs11240572 in the PARK16 gene locus is strongly associated with PD. However, its effect on the pathogenesis of PD is yet to be clarified. The objective of the study was to explore the effect of the PARK16 rs11240572 variant on brain structure in PD patients. A total of 51 PD patients were enrolled in the study and genotyped for the rs11240572 variant. Clinical assessments and MRI scans were conducted across all participants. Voxel-based morphometry (VBM) was used to investigate gray matter volume (GMV) of the whole brain between these two groups. Correlation analysis was performed to identify the relationships between GMV and clinical features. There were 17 rs11240572-A variant carriers and 34 non-carriers, with no significant demographic differences between these two groups. Compared with non-carriers, rs11240572-A carriers showed increased GMV in the left caudate nucleus and putamen, but decreased GMV in the left superior temporal gyrus and supramarginal gyrus. In non-carriers, left basal ganglia GMV was positively correlated with UPDRS III (r = 0.365, p = 0.034) and bradykinesia (r = 0.352, p = 0.042), but negatively correlated with MMSE (r =  - 0.344, p = 0.047), while in carriers negative correlation between basal ganglia GMV and MMSE was also observed (r =  - 0.666, p = 0.004). Moreover, the GMV of left temporoparietal cortex was positively associated with cognitive function in both groups (carriers, r = 0.692, p = 0.002; non-carriers, r = 0.879, p < 0.001). When reducing the sample size of non-carriers to the level of the carrier sample, similar correlations were observed in both groups. Our study showed that the PARK16 rs11240572 variant affects the brain structure of patients with PD, especially in the basal ganglia and temporoparietal cortex. This indicated that this variant might play an important role in the pathogenesis of PD., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease. Deposition of amyloid β plaques (Aβ) and neurofibrillary tangles (NFTs) is the key pathological hallmark of AD. Accumulating evidence suggest that impairment of autophagy-lysosomal pathway (ALP) plays key roles in AD pathology., Purpose: The present study aims to assess the neuroprotective effects of Qingyangshen (QYS), a Chinese herbal medicine, in AD cellular and animal models and to determine its underlying mechanisms involving ALP regulation., Methods: QYS extract was prepared and its chemical components were characterized by LC/MS. Then the pharmacokinetics and acute toxicity of QYS extract were evaluated. The neuroprotective effects of QYS extract were determined in 3XTg AD mice, by using a series of behavioral tests and biochemical assays, and the mechanisms were examined in vitro., Results: Oral administration of QYS extract improved learning and spatial memory, reduced carboxy-terminal fragments (CTFs), amyloid precursor protein (APP), Aβ and Tau aggregates, and inhibited microgliosis and astrocytosis in the brains of 3XTg mice. Mechanistically, QYS extract increased the expression of PPARα and TFEB, and promoted ALP both in vivo and in vitro., Conclusion: QYS attenuates AD pathology, and improves cognitive function in 3XTg mice, which may be mediated by activation of PPARα-TFEB pathway and the subsequent ALP enhancement. Therefore, QYS may be a promising herbal material for further anti-AD drug discovery., (Copyright © 2021. Published by Elsevier GmbH.)

Host-microbiota interactions are vital for diverse pathophysiological events and may be targeted for innovative therapeutics. Nuclear receptors (NRs) are versatile host sensors of microbial signals that coordinate diverse environmental cues with local and remote adaptions. Harnessing NR-mediated sensory machinery could provide an alternative lynchpin for gut microbiota-oriented drug discovery strategy., Competing Interests: Declaration of Interests The authors declare no conflict of interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To investigate the prevalence of Spirometra mansoni infections in hosts in Jiangsu Province, so as to provide the scientific basis for the management of sparganosis mansoni., Methods: From 2018 to 2019, nine counties (cities, districts) were randomly selected from Jiangsu Province as the survey sites, and 100 healthy individuals were randomly selected to perform the serological test of S. mansoni infections and the detection of S. mansoni eggs. The procercoids were detected in the intermediate host Cyclops , and the S. mansoni eggs were identified in the stool samples of the definitive hosts cats and dogs., Results: The prevalence of S. mansoni human infections was 0 (0/900) in the 9 survey sites of Jiangsu Province, and the sero-prevalence of the specific IgG antibody against S. mansoni was 1.22% (11/900). The positive rate of procercoids was 0.33% (3/900) in Cyclops . In addition, the S. mansoni egg-positive rate was 1.48% (2/135) in cats and dogs., Conclusions: Sparganosis mansoni is prevalent in Jiangsu Province. Health education pertaining to the damages of sparganosis mansoni and the route of S. mansoni infections should be improved.

Objective: To observe the effect of ginger-partitioned moxibustion on digestive tract reaction, quality of life and white blood cell count after chemotherapy in advanced malignant bone tumors patients., Methods: A total of 64 patients were randomly divided into an observation group and a control group, 32 cases in each group. Both groups were treated with adriamycin combined with cisplatin (AP) chemotherapy. The patients in the control group were treated by tropisetron hydrochloride intravenous on preventing the vomiting 1 h before receiving chemotherapy. On the basis of the control group, the patients in the observation group were treated with ginger-partitioned moxibustion at Neiguan (PC 6), Zusanli (ST 36), Shenque (CV 8), and Zhongwan (CV 12) 2 h after chemotherapy, once a day, 30 min each time. The course of chemotherapy, ginger-partitioned moxibustion and tropisetron hydrochloride intravenous was 5 days. The digestive tract reaction rating, quality of life score and white blood cell count were compared 1 d before chemotherapy, 2 d after chemotherapy and 7 d after chemotherapy between the two groups., Results: The number of 0 grade in digestive tract reaction 2 d and 7 d after chemotherapy in the observation group was significantly higher than that in the control group ( P <0.05), and the number of Ⅲ、Ⅳ grade was lower than that in the control group ( P <0.05). The quality of life scores of both groups 2 d after chemotherapy were lower than those before chemotherapy ( P <0.05), and there was no significant difference between the two groups ( P >0.05). The quality of life score of the control group 7 d after chemotherapy was lower than that before chemotherapy ( P <0.05), the quality of life score of the observation group was not statistically different from that before chemotherapy ( P >0.05), and the quality of life score in the observation group was higher than that in the control group ( P <0.05). The white blood cell count 2 d after chemotherapy in both groups was lower than before treatment ( P <0.05), and there was no significant difference between the two groups ( P >0.05). Seven days after chemotherapy, the white blood cell count in the control group was lower than that before chemotherapy ( P <0.05), while there was no significant difference in the observation group compared with before chemotherapy ( P >0.05), and the white blood cell count in the observation group was higher than that in the control group ( P <0.05)., Conclusion: Ginger-partitioned moxibustion can prevent and treat vomiting after chemotherapy in advanced malignant bone tumors, and improve the quality of life and white blood cell count of patients.

Background: Excessive aggregation of α-synuclein is the key pathophysiological feature of Parkinson's disease (PD). Rapid eye movement sleep behavior disorder (RBD) is also associated with synucleinopathies and considered as a powerful predictor of PD. Growing evidence suggests the diminished clearance of α-synuclein may be partly attributable to poor interstitial fluid drainage, which can be reflected by magnetic resonance imaging (MRI)-visible enlarged perivascular space (EPVS). However, the effect of MRI-visible EPVS on iRBD and PD, and their correlation with clinical characteristics remain unclear., Objective: To evaluate the clinical and neuroimaging significance of MRI-visible EPVS in iRBD and PD patients., Methods: We enrolled 33 iRBD patients, 82 PD (with and without RBD) patients, and 35 healthy controls (HCs), who underwent clinical evaluation and 3.0 Tesla MRI. Two neurologists assessed MRI-visible EPVS in centrum semiovale (CSO), basal ganglia (BG), substantia nigra (SN), and brainstem (BS). Independent risk factors for iRBD and PD were investigated using multivariable logistic regression analysis. Spearman analysis was used to test the correlation of MRI-visible EPVS with clinical characteristics of patients., Results: iRBD patients had significantly higher EPVS burdens (CSO, BG, SN, and BS) than PD patients. Higher CSO-EPVS and BS-EPVS burdens were independent risk factors for iRBD. Furthermore, higher CSO-EPVS and SN-EPVS burdens were positively correlated with the severity of clinical symptom in iRBD patients, and higher BG-EPVS burden was positively correlated with the severity of cognitive impairment in PD patients., Conclusion: iRBD and PD patients have different MRI-visible EPVS burdens, which may be related with a compensatory mechanism in glymphatic system. Lower MRI-visible EPVS burden in PD patients may be a manifestation of severe brain waste drainage dysfunction. These findings shed light on the pathophysiologic relationship between iRBD and PD with respect to neuroimaging marker of PD., (Copyright © 2020 Si, Gu, Song, Zhou, Fang, Jin, Wu, Gao, Guo, Guan, Xu, Yin, Yan, Zhang and Pu.)

Background: Oral squamous cell carcinoma (OSCC), a form of head and neck squamous cell carcinoma (HNSCC) has a poor 5-year survival rate. OSCC patients are often treated with cisplatin but resistance to chemotherapy is often observed. This makes it important identification of alternative therapeutic targets which will result in more favorable outcome in OSCC patients. The plant homeodomain (PHD)-containing protein Inhibitor of Growth family of tumor suppressor proteins (p33ING1b) has been indicated as a tumor suppressor in different cancers including OSCC. This protein has been shown to function by modulating transcriptional activity of p53; however, the exact mechanism(s) are not well defined., Methods: Expression of total and acetylated p53 and p33ING1b protein was determined in OSCC cell lines YD-9, YD-8, and YD-38 by immunoblot analysis. Effect of modulation of p33ING1b protein expression on acetylation of p53 and cell proliferation was determined by immunoblot and MTT assay. Effect of modulation of p33ING1b protein expression on transactivation of p53 was assessed by heterologous promoter-based reporter and chromatin immunoprecipitation. Effect of modulation of expression of p33ING1b on SIR2 mRNA and protein was determined by quantitative real-time PCR and immunoblot analyses. Impact of modulation of p33ING1b alone or in combination with SIR2 on chemosensitivity of YD-9 and YD-8 cells to cisplatin was determined in time and dose-dependent cell proliferation assays., Results: Here, using a panel of OSCC cell lines with wild type or mutant p53, we show that p33ING1b expression is correlated to acetylation of p53 at lysine 382 residue. Increased acetylation of p53 following overexpression of p33ING1b was associated with increased expression of the pro-apoptotic proteins BAX, p21, and cleaved-Caspase 3, and decreased cell proliferation. Reporter assays with p21 and BAX promoters showed that p33ING1b expression levels directly correlated to promoter activity of these 2 genes. Chromatin immunoprecipitation assay showed that transcriptional regulation of p21 and BAX by acetylated p53 is dependent on expression level of p33ING1b. Differential acetylation of p53 following modulation of p33ING1b expression was indirect. Expression of p33ING1b was found to be inversely correlated to the NAD-dependent deacetylase silent information regulator 2 (SIR2). SIR2 was transcriptionally regulated by p33ING1b. Relative expression of p33ING1b was found to dictate chemosensitivity of OSCC cell lines to cisplatin treatment. Concomitant overexpression of p33ING1b and knockdown of SIR2 had a synergistic effect on chemosensitivity of OSCC cell lines to cisplatin, compared to either overexpression of p33ING1b or knockdown of SIR2 alone., Conclusions: The results from the current study thus elucidate that p33ING1b regulates p53 acetylation irrespective of p53 mutation and subsequent transactivation by transcriptional regulation of SIR2 expression. The results also indicate that p33ING1b and SIR2 are potentially attractive therapeutic targets., Competing Interests: Competing InterestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Objective: To observe the effect of ginger-partitioned moxibustion intervention on gastrointestinal reaction, the quality of life, the counts of blood platelet (PLT) and white blood cells (WBC) after chemotherapy in lung cancer patients., Methods: The lung cancer patients treated with chemotherapy were randomized into observation group (30 cases) and control group (30 cases). In the control group, the intravenous injection with Tropisetron(5 mg) was given 1 h before chemotherapy. In the observation group, in addition to the same treatment as the control group, 2 hours after chemotherapy, ginger-partitioned moxibustion was applied to bilateral Zusanli (ST36), bilateral Neiguan (PC6) and bilateral Tianshu (ST25) for 20 min each time. The treatments were conducted once daily for 3 days. Separately, 2 days before chemotherapy, 24 h and 7 days after chemotherapy, the gastrointestinal reaction score and the score of the quality of life, the PLT and WBC counts were observed in the two groups., Results: The effective rate of the gastrointestinal reaction degree in the observation group were higher than those in the control group 24 h and 7 days after chemotherapy ( P <0.05). Twenty-four hours after chemotherapy, the score of the quality of life, the PLT and WBC counts were lower as compared with those before the treatment in both groups respectively( P <0.05). Seven days after chemotherapy, the score of the quality of life, the PLT and WBC counts in the observation group were higher than those in the control group ( P <0.05)., Conclusion: The ginger-partitioned moxibustion achieves the definite clinical effect of the prevention of nausea and vomiting induced by chemotherapy in lung cancer. This therapy is simple in operation, high in safety, absent in obvious adverse reactions and high in patient's compliance.

Objective: To understand the status of child health services by primary medical institutions in less developed areas in Sichuan province and provide evidence for the development of health policy for poverty alleviation. Methods: Annual child health records in the primary medical institutions selected through multistage stratified sampling in 21 prefectures in Sichuan were extracted during 2014-2018. Field survey and telephone interview were used to evaluate the performance of child health services provided and the child guardian's satisfaction degree. Sample descriptive statistics, pair sample t -test, χ (2) test, trend χ (2) test, Pearson correlation analysis were used for statistical analysis. Results: Except child system management rate, the other indicators reflecting the status of child health service in less developed areas in Sichuan were on rise ( P <0.05), and close to average level of whole province in 2018. Except child system management rate, the other indicators reflecting the status of child health management in less developed counties were lower than those in developed counties in Sichuan, most differences were significant ( P <0.05). Except child health management rate of traditional Chinese medicine, the other indicators reflecting the status of child health management in less developed counties were higher than those in poverty-stricken counties in Sichuan, most differences were not significant ( P ≥0.05). Except child systematic management rate, the gap in indicators reflecting child health service status between less developed area and developed area was in reduction, some difference were significant ( P <0.05). The child guardian satisfaction degree was associated with true child health management rates ( r =0.947, P =0.015), and child health management rate of traditional Chinese medicine ( r =0.996, P <0.001). Conclusions: Some achievements have been made in child health services provided by primary medical institutions in less developed areas in Sichuan. To achieve the 2020 poverty alleviation goal, it is necessary to take measures to increase input and improve service level.

Aims: Cognitive impairment is a common symptom in the trajectory of Parkinson's disease (PD). However, the pathological underpinning is not fully known. We aimed to explore the critical structural alterations in the process of cognitive decline and its relationships with the dopaminergic deficit and the level of related cerebrospinal fluid (CSF) proteins., Methods: Ninety-four patients with PD and 32 controls were included in this study. Neuropsychological tests were performed at baseline and after 28 months to identify which patients had normal cognition and which ones developed PD-MCI after follow-up ("converters"). Gray matter atrophy was assessed in cross-sectional and longitudinal analyses, respectively. The associations between altered GMV with dopamine transporter (DAT) results and the level of CSF proteins were assessed., Results: Among the 94 patients with normal cognition at baseline, 24 (mean age, 63.1 years) developed PD-MCI after 28 months of follow-up, and 70 (mean age, 62.3 years) remained nonconverters. The converters showed significant right temporal atrophy at baseline and extensive atrophy in temporal lobe at follow-up. Progressive bilateral frontal lobe atrophy was found in the converters. Baseline right temporal atrophy was correlated with the striatal dopaminergic degeneration in the converters. No correlation was found between the right temporal atrophy and the alterations of CSF proteins., Conclusion: Early atrophy in temporal lobes and progressive atrophy in frontal lobes might be a biomarker for developing multidomain impairment of cognition and converting to PD-MCI. Furthermore, cognition-related temporal atrophy might be associated with dopaminergic deficit reflected by DAT scan but independent of CSF proteins in patients with PD who convert to PD-MCI., (© 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Objective: To observe the effect of acupuncture in different time on nausea and vomiting induced by chemotherapy of lung cancer., Methods: A total of 150 patients with chemotherapy for lung cancer were randomized into a No.1 observation group, a No.2 observation group and a control group, 50 cases in each one. Excluded the dropped-off cases, finally, there were 49 cases in the No.1 observation group, 44 cases in the No.2 observation group and 47 cases in the control group. In the control group, 30 min before chemotherapy, the slow intravenous injection with tropisetron hydrochloride was used, 5 mg each time, once a day for 3 days. In the No.1 observation group, 30 min before chemotherapy, the slow intravenous injection with tropisetron hydrochloride was given combined with acupuncture. The acupoints selected were Zusanli (ST 36), Zhongwan (CV 12) and Neiguan (PC 6). The needles were retained for 30 min. The treatment was given once a day for 3 days totally. In the No.2 observation group, 30 min before chemotherapy, the slow intravenous injection with tropisetron hydrochloride was used, and 30 min after chemotherapy, acupuncture treatment was exerted. The acupoints and needling method were same as those in the No.1 observation group. Before and after treatment, the digestive reaction score, Karnofsky performance status scale (KPS) score and white blood cell count were all observed in the three groups. Additionally, the therapeutic effect and adverse reaction were observed and the therapeutic effect was compared among the treatment with acupuncture in different time., Results: On the 2nd day of chemotherapy, the effective rates were 85.7% (42/49) and 75.0% (33/44) in the No.1 observation group and the No.2 observation group respectively, both higher obviously than 68.1% (32/47) in the control group ( P <0.05), and the effective rate in the No.1 observation group was higher obviously than the No.2 observation group ( P <0.05). On the 3rd day of chemotherapy, the effective rates were 81.6% (40/49) and 61.4% (27/44) in the No.1 observation group and the No.2 observation group respectively, both higher obviously than 57.5% (27/47) in the control group ( P <0.05), and the effective rate in the No.1 observation group was higher obviously than the No.2 observation group ( P <0.05). Compared before treatment, the KPS scores after treatment were obviously lower in the three groups ( P <0.05), and the decreased value of KPS score in the No.1 observation group was much lower than the control group and the No.2 observation group ( P <0.05). After 3-day chemotherapy, the white blood cell count was all reduced in each group, but the decreased value was not different statistically among the groups ( P >0.05)., Conclusion: Acupuncture combined with the slow intravenous injection with tropisetron hydrochloride achieve the satisfactory effect of prevention and treatment for vomiting induced by chemotherapy of lung cancer. The acupuncture intervention before chemotherapy greatly improves the effect on the nausea and vomiting induced by chemotherapy of lung cancer.

Oxidative DNA damage pathogenically links to some major diseases. This study aimed to comprehensively assess the association between serum total cholesterol (TC) and oxidative DNA damage based on propensity score matching (PSM) method. A total of 407 participants chronically exposed to arsenic via drinking water from China were enrolled. Oxidative DNA damage was determined with urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG). Serum TC was classified into favourable TC (FTC, TC <5.18 mmol/L) and unfavourable TC (NFTC, TC ≥5.18 mmol/L) categories. Multivariable generalised linear regression model was applied to examine the association. Of 407 participants, 125 pairs with FTC and NFTC subjects were matched using PSM. Urinary 8-OHdG/creatinine levels in NFTC were significantly higher than those in FTC category ( p  = .002). As compared to the counterparts, additional adjusted log-transformed 8-OHdG/creatinine increase was observed in NFTC for unmatched ( β  = 0.12, p  = .052) and matched ( β  = 0.17, p  < .001) participants, respectively. We also detected obviously increased log-transformed urinary 8-OHdG/creatinine with per interquartile range raise of serum TC either in unmatched ( β  = 0.10, p  = .007) or matched ( β  = 0.16, p  = .003) subjects. In conclusion, serum TC was independently associated with oxidative DNA damage. Our findings provided new insights on the health promotion of lipids relevant to the early warning of diseases due to oxidative DNA damage.

Objective: To investigate the pathological escalation after cervical cone resection in postmenopausal women, and analyze the related influencing factors. Methods: A retrospective cohort study was conducted at the Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University between July 2013 and January 2015. Seven hundred and fifty cases of cervical cone-cut were enrolled in this study, 129 cases of them were postmenopausal women, and 621 were premenopausal women. All results of patients' liquid-based thin-layer cytology (TCT) , HPV test, colposcopy and biopsy pathology, cervical cone resection and postoperative pathological examination were collected. Then the compliance with the pathological examination results after colposcopic cervical biopsy and cervical cone resection, and the related factors affecting the pathological escalation after cervical cone resection were analyzed. The pathological escalation of patients with different menopausal conditions after cervical cone resection was also analyzed. Results: (1) Of the 750 patients, there were 329 patients had the same pathological examination results after colposcopic cervical biopsy and cervical cone resection, which accounted for 43.9% (329/750) . And 216 cases demonstrated pathological escalation after cervical cone resection, which accounted for 28.8% (216/750) . The results of TCT examination and menopause were significantly correlated with the pathological escalation after cervical cone resection ( P <0.05) . However, the condition of HPV infection was unrelated to pathological escalation after cervical cone resection ( P >0.05) . (2) Compared with the different results of TCT examination [including non-intrusive load monitoring (NILM) , atypical squamous cell of undetermined signification (ASCUS) , low-grade squamous intraepithelial lesion (LSIL) , high-grade squamous intraepithelial lesion (HSIL) ], the ratio of pathological escalation after cervical cone resection was not statistically significant difference between postmenopausal and non-menopausal patients ( P >0.05) . The proportion of pathological escalation of patients with >5 years of menopause was significantly higher than that of patients with menopause time ≤5 years (40.3% vs 27.7%, OR =1.8, 95% CI : 1.1-2.8, P =0.029) . Among them, when the result of TCT examination was LSIL, the rate of pathological escalation in patients > 5 years of menopause was significantly higher than that in menopause time ≤5 years (6/10 vs 26.3%, OR =4.2, 95% CI : 1.1-15.8, P =0.033) . While the results of TCT examination were NILM, ASCUS or HSIL showed there was no statistically significant difference between two groups ( P >0.05) . (3) Among the 143 cases, of which the result of TCT examination was LSIL, 9 cases of the pathological examination results after cervical resection were escalated to cervical cancer, which accounted for 6.3% (9/143) . Among 10 cases of menopause time >5 years, 2 cases (2/10) of the pathological examination results after cervical cone resection were escalated to cervical cancer. Among 133 cases with menopause time ≤ 5 years, 7 cases (5.3%) were upgraded to cervical cancer after cervical cone resection. The ratio of pathological escalation to cancer in postmenopausal patients with >5 years was higher than that of menopause time ≤5 years. Due to the data volume limitation, the comparison was not statistically significant difference (χ 2 =0.460, P >0.05) . Conclusions: In postmenopausal women, especially when menopausal time is > 5 years, the proportion of pathological escalation after cervical cone resection following colposcopic cervical biopsy is increased. And the pathological escalation after cervical cone resection is significantly correlated with the results of TCT examination and menopausal status. Therefore, doctors should treat the colposcopic biopsy pathological results with caution during clinic. Depending on TCT results, loop electrosurgical excision procedure (LEEP) sampling could be administrated directly in case of avoid missing diagnosis.

P-glycoprotein affects the transport of numerous drugs including chemotherapeutic drugs vincristine sulfate (VCR) and docetaxel (DTX), and is one of the main causes for multidrug resistance. Our previous studies have shown that oxypeucedanin (OPD) can enhance the intestinal transit of puerarin and VCR. However, the underlying mechanism is unclear. This study investigated the potential mechanism by which OPD improves P-gp-mediated drug transport. Molecular docking was performed to predict the binding force between OPD and P-gp and the contribution of OPD on P-gp activity. We observed the effect of OPD on the transport of VCR in MDCK-MDR1 cell monolayer and also measured the plasma pharmacokinetic parameters of DTX in the presence and absence of OPD by LC-MS/MS. Moreover, we further investigated the reversal mechanism of OPD on P-gp-mediated drug transport by determining the intracellular accumulation of Rhodamine-123 (Rh123) and P-gp ATPase activity as well as protein expression and mRNA level of P-gp. Our molecular docking results revealed that the binding force between OPD and P-gp was much lower than that between P-gp and verapamil (a P-gp substrate). The transport study in vitro indicated that OPD increased the flux of VCR across MDCK-MDR1 cell monolayer. The in vivo pharmacokinetic parameters data showed OPD increased the absorption of DTX. OPD activated P-gp ATPase activity and enhanced intracellular accumulation of Rh123 in MDCK-MDR1 cells. Western blotting and qRT-PCR outcomes indicated that OPD suppressed P-gp protein expression as well as downregulated P-gp mRNA level. Thus, OPD reverse P-gp-mediated drug transport via inhibition of P-gp activity and P-gp protein expression as well as downregulation of P-gp mRNA level. Our results suggest that OPD could reverse P-gp-mediated drug resistance in tumor cells.

The study was aimed to establish a liquid chromatography-tandem mass spectrometric method for the determination of the docetaxel concentration in rat plasma, and study the effect of coumarin constituents (imperatorin, isoimperatorin and oxypeucedanin) in Angelica dahurica on pharmacokinetics of docetaxel.Plasma was precipitated with acetonitrile and determined by LC-MS method with Paclitaxel as an internal standard. The specificity, linearity, range, accuracy, precision and stability of the method were suitable for the determination of docetaxel in plasma.Six sprague-dawley rats in each group received intragastric administration of docetaxel (50 mg•kg⁻¹), oxypeucedanin (8 mg•kg⁻¹) combined with docetaxel (50 mg•kg⁻¹), imperatorin (15 mg•kg⁻¹) combined with docetaxel (50 mg•kg⁻¹), and isoimperatorin(15 mg•kg⁻¹) combined with docetaxel (50 mg•kg⁻¹).Their drug plasma concentration was determined by LC-MS with Paclitaxel as an internal standard to draw plasma concentration-time curve, and the phamacokinetic parameters were calculated by DAS 2.0. The results showed that the phamacokinetic parameters of docetaxel all had notable changes when combined with imperatorin, isoimperatorin, and oxypeucedanin, respectively. The phamacokinetic parameters AUC and Cmax were significantly increased, indicating that coumarin constituents in Angelica dahurica could promote the oral bioavailability of docetaxel, and their effects were in the following order: oxypeucedanin> isoimperatorin> imperatorin., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

To study the correlation of four properties of traditional Chinese medicine and the function of reversing multidrug resistance (MDR) of tumor cells, with 580 herbs in Chinese Pharmacopoeia 2015 version as the research objects. CNKI, CBA, Wanfang, VIP, and PubMed were searched to screen the documents related to the reversal of MDR for collection, summarizing and analysis. The results of the research showed that a total of 114 species Chinese herbs had been reported to be associated with reversal of MDR in tumor cells. Among 15 Chinese herbs with heat nature, 7 herbs had the function of reversing MDR in tumor cells, accounting for 46.7%. Among the 48 herbs with cool nature, 12 herbs had the function of reversing MDR, accounting for 25%. Among the 211 herbs with cold nature, 46 herbs had the function of reversing MDR, accounting for 21.8%. Among the 179 herbs with warm nature, 34 herbs had the function of reversing MDR, accounting for 19%. Among the 127 herbs with neutral nature, 15 herbs had the function of reversing MDR, accounting for 11.8%. Through the analysis on the relationship between four properties of 114 kinds of traditional Chinese medicines and reversing multidrug resistance of tumor cells, this paper speculated that there was a certain correlation between four properties of traditional Chinese medicine and the function of reversing multidrug resistance of tumor cells., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

P-glycoprotein (P-gp) affects the transport of many drugs; including puerarin and vincristine. Our previous study demonstrated that imperatorin increased the intestinal absorption of puerarin and vincristine by inhibiting P-gp-mediated drug efflux. However; the underlying mechanism was not known. The present study investigated the mechanism by which imperatorin promotes P-gp-mediated drug transport. We used molecular docking to predict the binding force between imperatorin and P-gp and the effect of imperatorin on P-gp activity. P-gp efflux activity and P-gp ATPase activity were measured using a rhodamine 123 (Rh-123) accumulation assay and a Pgp-Glo™ assay; respectively. The fluorescent probe 1,6-diphenyl-1,3,5-hexatriene (DPH) was used to assess cellular membrane fluidity in MDCK-MDR1 cells. Western blotting was used to analyze the effect of imperatorin on P-gp expression; and P-gp mRNA levels were assessed by qRT-PCR. Molecular docking results demonstrated that the binding force between imperatorin and P-gp was much weaker than the force between P-gp and verapamil (a P-gp substrate). Imperatorin activated P-gp ATPase activity; which had a role in the inhibition of P-gp activity. Imperatorin promoted Rh-123 accumulation in MDCK-MDR1 cells and decreased cellular membrane fluidity. Western blotting demonstrated that imperatorin inhibited P-gp expression; and qRT-PCR revealed that imperatorin down-regulated P-gp (MDR1) gene expression. Imperatorin decreased P-gp-mediated drug efflux by inhibiting P-gp activity and the expression of P-gp mRNA and protein. Our results suggest that imperatorin could down-regulate P-gp expression to overcome multidrug resistance in tumors.

Learning and memory formation in Drosophila rely on a network of neurons in the mushroom bodies (MBs). Whereas numerous studies have delineated roles for individual cell types within this network in aspects of learning or memory, whether or not these cells can also be distinguished by the genes they express remains unresolved. In addition, the changes in gene expression that accompany long-term memory formation within the MBs have not yet been studied by neuron type. Here, we address both issues by performing RNA sequencing on single cell types (harvested via patch pipets) within the MB. We discover that the expression of genes that encode cell surface receptors is sufficient to identify cell types and that a subset of these genes, required for sensory transduction in peripheral sensory neurons, is not only expressed within individual neurons of the MB in the central brain, but is also critical for memory formation., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Brains are optimized for processing ethologically relevant sensory signals. However, few studies have characterized the neural coding mechanisms that underlie the transformation from natural sensory information to behavior. Here, we focus on acoustic communication in Drosophila melanogaster and use computational modeling to link natural courtship song, neuronal codes, and female behavioral responses to song. We show that melanogaster females are sensitive to long timescale song structure (on the order of tens of seconds). From intracellular recordings, we generate models that recapitulate neural responses to acoustic stimuli. We link these neural codes with female behavior by generating model neural responses to natural courtship song. Using a simple decoder, we predict female behavioral responses to the same song stimuli with high accuracy. Our modeling approach reveals how long timescale song features are represented by the Drosophila brain and how neural representations can be decoded to generate behavioral selectivity for acoustic communication signals., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A bacterial strain YHl that used p-tert-Butylcatechol (TBC) as the sole carbon and energy source was isolated from the activated sludge of the wastewater treatment plant of a chemical factory. The strain was identified as Pseudomonas corrugate by morphological characteristics, physiological and biochemical properties, BIOLOG and the 16S rDNA sequence analysis. The degration rate of TBC was above 82% with an initial concentration of 500 mg.L-1 at 24-36°C and an initial pH of 7. 0-10. 0. Through single-factor experiments of its degradation characteristics of strain YH1, the results showed that its optimal additional carbon and nitrogen sources were sucrose and tryptone, the optimal temperature was 30°C, the optimal initial pH was 7. 0, and the optimal inoculation volume was 2%. In order to improve the TBC degradation rate, the concentrations of sucrose and tryptone and initial pH were identified as the main factors by Placket-Burman Assay. Then these factors reached their optimal region by Steepest Ascent. Finally, the optimal levels of those main factors were further optimized using Box-Behnken design and response surface analysis. The optimal conditions were as follows: sucrose concentration 3% (ρ), tryptone concentration 1. 44% (ρ), TBC concentration 400 mg.L-1, initial pH value 8. 12, inoculation amount 2. 97% (φ), temperature 30°C, training time 96 h. Under the optimal conditions mentioned above, the TBC degradation rate reached 98. 21%. Enzymology analysis and localization experiments showed that the TBC-degrading enzymes were intracellular proteins and the synthesis of catechol 1,2-dioxygenase (C12O) could be induced by TBC. Through design of specific PCR primers for the degrading enzymes, the gene encoding the catechol 1,2-dioxygenase was amplified from YHL. It was found that genes encoding TBC-degrading enzyme were located on plasmids by the plasmid detection and elimination experiments. In addition, YH1 was tolerant to high concentration of NaCl and many kinds of heavy metal ions, and resistant to multiple antibiotics. This paper provided some information for the effective treatment of complex industrial wastewater.

Objective and Design: Cigarette smoke (CS)-induced inflammation is critical in chronic obstructive pulmonary disease (COPD). However, the role of acetylation at histone 3 lysine 9 (H3K9) in COPD inflammation remains unclear. The present study assessed the effect of acetylation of H3K9 on transcription both in rat lungs and in macrophages., Methods: Sprague-Dawley rats were exposed to CS for either 6 or 12 weeks and rat lungs were collected. Rat macrophages were subjected to 20 % cigarette smoke extract (CSE) for 48 h., Results: CS increased MCP-1 and IL-8 expressions at both mRNA and protein levels in rat lungs after 6 and 12 weeks; increased TNF-α and MMP9 expressions at both levels were noted only after 12 weeks. CSE increased these genes expression in macrophages after 48 h exposure. Increased abundance of acetylated H3K9 protein in rat lungs and in macrophages were associated with decreased expression of histone deacetylase-1(HDAC1). Chromatin immunoprecipitation demonstrated increased level of acetylated H3K9 on promoter regions of these genes both in vivo and in vitro. Knockdown of HDAC1 increased these genes mRNA expression., Conclusions: CS increased H3K9 acetylation and subsequently altered the expression of pro-inflammatory mediators and protease genes through HDAC1 depression in CS-induced rat lungs and in macrophages.

Objective: To understand the situation of intestinal nematode infections and assess the preventive effects, so as to provide the evidence for formulating the further measures of prevention., Methods: Five villages from 5 townships of different geographical locations were selected and 500 residents of each village were surveyed. The eggs of intestinal nematodes were detected by the Kato-Katz technique, and 50 students and 50 residents per village were investigated by questionnaires about health education., Results: Among 3 011 people detected, 17 persons were infected with intestinal nematodes and the total infection rate was 0.56%. The rates of Ascaris lumbricoides, hookworm, Trichuris trichiura, Enterobius vermicularis, and Trichostrongylus were 0.10%, 0.33%, 0.03%, 0.03% and 0.07%, respectively. The awareness rate of health knowledge was 97.80% and the formation rate of health behavior was 97.00%., Conclusion: The infection rates of intestinal nematodes, the awareness rate of health knowledge and the formation rate of health behavior in the population of Hongze County have achieved the criteria of effective control of intestinal parasitic diseases.

Background: During August 2011-February 2012, an outbreak of type Π circulating vaccine-derived poliovirus (cVDPVs) occurred in Sichuan Province, China., Methods: A field investigation of the outbreak was conducted to characterize outbreak isolates and to guide emergency response. Sequence analysis of poliovirus capsid protein VP1 was performed to determine the viral propagation, and a coverage survey was carried out for risk assessment., Results: One clinical compatible polio case and three VDPV cases were determined in Ngawa County, Ngawa Tibetan and Qiang Autonomous Prefecture, Sichuan Province. Case patients were unimmunized children, 0.8-1 years old. Genetic sequencing showed that the isolates diverged from the VP1 region of the type Π Sabin strain by 5-12 nucleotides (nt) and shared the same 5 nt VP1 substitutions, which indicate single lineage of cVDPVs. Of the 7 acute flaccid paralysis cases (all>6 months) reported in Ngawa Prefecture in 2011, 4 (57.1%) cases (including 2 polio cases) did not receive oral attenuated poliovirus vaccine. Supplementary immunization activities (SIAs) were conducted in February-May, 2012, and the strain has not been isolated since., Conclusion: High coverage of routine immunization should be maintained among children until WPV transmission is globally eradicated. Risk assessments should be conducted regularly to pinpoint high risk areas or subpopulations, with SIAs developed if necessary.

Cigarette smoke has been shown to cause chronic inflammation of the lungs, eventually leading to chronic obstructive pulmonary disease (COPD). Additionally, recent studies have suggested that mesenchymal stem cells (MSCs) can mediate local inflammatory responses in the lungs. Thus, the aim of the present study was to test the effects of rat MSCs (rMSCs) on inflammation of the lungs and destructive pulmonary function induced by cigarette smoke in rats. Rats were exposed to cigarette smoke for 7 weeks. rMSCs were cultured in vitro and infused intratracheally into cigarette smoke-exposed rats. The total and differential cell counts in the bronchoalveolar lavage fluid (BALF), histological changes, pro-inflammatory cytokines, transforming growth factor-β1 (TGF-β1) expression, and pulmonary function were evaluated. Additionally, human peripheral blood mononuclear cells and human MSCs were cocultured in vitro to detect cytokines and TGF-β1 levels. We found that rMSC administration resulted in downregulation of pro-inflammatory cytokines in the lungs while increasing TGF-β1 expression, reducing total inflammatory cell numbers in the BALF, and improving pulmonary histopathology and airflow obstruction. Coculture revealed that human MSCs mediated an anti-inflammatory effect partly via upregulation of TGF-β1. These findings suggested that MSCs may have therapeutic potential in cigarette smoke-induced inflammation and airflow obstruction, partly via upregulation of TGF-β1.

Pannexin1 (Panx1) is a subtype of the newly discovered gap junction proteins named Pannexin(s). Panx1 is widely expressed in the nervous system, cardiovascular system, etc and can form non-selective and large conductance hemichannel. It has been demonstrated that various conditions can regulate Panx1 open and affect the body's physiological function via macromolecular substance (for instance, ATP) releasing. This review gives a detailed introduction to the main distribution of Panxl, summarizes the open and inhibition condition of Panx1, and finally, prospects directions of future research.

Progressive pulmonary inflammation and emphysema have been implicated in the progression of chronic obstructive pulmonary disease (COPD), while current pharmacological treatments are not effective. Transplantation of bone marrow mesenchymal stem cells (MSCs) has been identified as one such possible strategy for treatment of lung diseases including acute lung injury (ALI) and pulmonary fibrosis. However, their role in COPD still requires further investigation. The aim of this study is to test the effect of administration of rat MSCs (rMSCs) on emphysema and pulmonary function. To accomplish this study, the rats were exposed to cigarette smoke (CS) for 11 weeks, followed by administration of rMSCs into the lungs. Here we show that rMSCs infusion mediates a down-regulation of pro-inflammatory mediators (TNF-α, IL-1β, MCP-1, and IL-6) and proteases (MMP9 and MMP12) in lung, an up-regulation of vascular endothelial growth factor (VEGF), VEGF receptor 2, and transforming growth factor (TGFβ-1), while reducing pulmonary cell apoptosis. More importantly, rMSCs administration improves emphysema and destructive pulmonary function induced by CS exposure. In vitro co-culture system study of human umbilical endothelial vein cells (EA.hy926) and human MSCs (hMSCs) provides the evidence that hMSCs mediates an anti-apoptosis effect, which partly depends on an up-regulation of VEGF. These findings suggest that MSCs have a therapeutic potential in emphysematous rats by suppressing the inflammatory response, excessive protease expression, and cell apoptosis, as well as up-regulating VEGF, VEGF receptor 2, and TGFβ-1., (Copyright © 2012 Wiley Periodicals, Inc.)

A field experiment was conducted at the Yuzhou Experimental Base of Henan Province to study the effects of different application rates (0, 30, 60, and 90 kg x hm(-2)) of water-retaining agent (WRA) on the root physiological characteristics, biomass, and grain yield of two winter wheat cultivars Zhengmai-9694 and Aikang-58, aimed to probe into the action mechanisms of WRA on the root system of winter wheat at its different growth stages. The application of WRA decreased the root membrane permeability and soluble sugar content, and increased the root vigor. After the application of WRA, the Zhengmai-9694 at its different growth stages had a greater decrement of root membrane permeability, compared with Aikang-58. In all treatments except 90 kg x hm(-2) of WRA, the root vigor of Aikang-58 was obviously higher than that of Zhengmai-9694. At booting and grain-filling stages, the root soluble sugar content of Zhengmai-9694 decreased much more than that of Aikang-58. In the whole growth period of the two cultivars, their root membrane permeability and soluble sugar content were the lowest in treatment 60 kg x hm(-2) of WRA, and no significant differences were observed between treatments 60 and 90 kg x hm(-2) of WRA. The root vigor of Zhengmai-9694 increased remarkably with the increasing rate of WRA application, while that of Aikang-58 was the highest in treatment 60 kg x hm(-2) of WRA. The application of WRA also increased root biomass, and at jointing and booting stages, the root biomass of Aikang-58 was much higher than that of Zhengmai-9694. However, at grain-filling stage, the biomass of Aikang-58 in treatments 60 and 90 kg x hm(-2) of WRA was lower than that of Zhengmai-9694. Treatment 60 kg x hm(-2) of WRA had the highest grain yield of the two cultivars. It was concluded that WRA had more significant effects on Zhengmai-9694 than on Aikang-58, and applying 60 kg x hm(-2) of WRA could obtain the best effect.

An investigation was made at a hilly upland in western Henan Province to understand the effects of water-retaining agent (0, 45, and 60 kg x hm(-2)), straw mulching (3000 and 6000 kg x hm(-2)), and plastic mulching (thickness < 0.005 mm) on winter wheat growth, soil moisture and nutrition conditions, and precipitation use. All the three measures promoted winter wheat growth, enhanced grain yield and precipitation use efficiency, and improved soil moisture and nutritional regimes. These positive effects were more obvious when the straw- or plastic mulching was combined with the use of water-retaining agent. Comparing with the control, all the measures increased the soil moisture content at different growth stages by 0.1%-6.5%. Plastic film mulching had the best water-retention effect before jointing stage, whereas water-retaining agent showed its best effect after jointing stage. Soil moisture content was the lowest at flowering and grain-filling stages. Land cover increased the grain yield by 2.6%-20.1%. The yield increment was the greatest (14.2%-20.1%) by the combined use of straw mulching and water-retaining agent, followed by plastic mulching combined with water-retaining agent (11.9% on average). Land cover also improved the precipitation use efficiency (0.4-3.2 kg x mm(-1) x hm(-2)) in a similar trend as the grain yield. This study showed that land cover and water-retaining agent improved soil moisture and nutrition conditions and precipitation utilization, which in turn, promoted the tillering of winter wheat, and increased the grain number per ear and the 1000-grain mass.

We report that an intrauterine contraceptive device (IUCD) embedded within intrauterine tumour (submucous myoma) in a postmenopausal woman was misdiagnosed, definitively diagnosed and successfully removed with hysteroscopic resection. Hysteroscopy and hysteroscopic resection of the submucous myoma with IUCD should be reserved as a minimally invasive, safe and reliable treatment method, and can avoid a laparotomy and hysterotomy. This is believed to be the first reported case of such an occurrence.

Objective: To study the role of phosphorylation of c-Jun NH2-terminal kinase (JNK) in asthmatic airway remodeling and to explore the effect of glucocorticoids on IL-1beta, JNK and airway remodeling., Methods: Forty-eight 4 - 6 week old male SD rats were randomly divided into 4 groups with 12 rats in each group: the control group, the asthma group, the budesonide (BUD) group, and the dexamethasone (DXM) group. The asthma airway remodeling models were made by intra-peritoneal injection of ovalbumin (OVA) on days 1 and 8 and inhalation of OVA every other day for 12 weeks since day 15. The BUD group underwent inhalation of BUD 30 min before every inhalation; the DXM group received intra-peritoneal injection of DXM 30 min before every inhalation; while the control group received normal saline instead of OVA. The histopathology and ultrastructural changes of pulmonary tissues were observed by light microscope and transmission electron microscope (TEM). The total bronchial wall thickness (Wat) and the airway smooth muscle thickness (Wam) were measured by image analysis system. The concentrations of IL-1beta in serum and BALF were tested by sandwich ELISA. The protein expressions of P-JNK and P-c-Jun were detected by immunohistochemistry technique. Lung tissue extracts were analyzed for phosphorylation of JNK by Western blot. Linear correlation analysis was used to evaluate correlations between Wat and P-JNK protein (mA), Wam and P-JNK protein (mA), P-JNK protein (mA) and levels of IL-1beta in serum, P-JNK protein (mA) and levels of IL-1beta in BALF., Results: In the asthma group, HE-staining showed inflammatory cell infiltration around bronchi and mucous gland hyperplasia. TEM examination showed airway smooth muscle and collagen fiber proliferation, and widening of intercellular distance. The Wat and Wam of the asthma group were significantly higher than those of the control group, while the thickness of airway wall in the glucocorticoid intervention groups became significantly decreased. The concentrations of IL-1beta in serum and BALF of the asthma group [(81 +/- 4) ng/L, (331 +/- 15) ng/L] were significantly higher than those of the control group [(53 +/- 6) ng/L, (130 +/- 9) ng/L] (t = -8.62 and t = -24.10, both P < 0.01). Mean absorbance values (by immunohistochemistry) of P-JNK and P-c-Jun in the asthma group were significantly higher than those of the control group, and the mean absorbance values of P-JNK and P-c-Jun in the BUD and DXM groups were significantly lower than those of the asthma group, but higher than those of the control group (F = 223.59 and F = 76.53, both P < 0.01). Absorbance (by Western blot) of P-JNK in the control, asthma, BUD, and DXM groups were (1.00 +/- 0.00), (1.66 +/- 0.16), (1.18 +/- 0.12), and (1.29 +/- 0.14), respectively; that of the asthma group was significantly higher than that of the control group, while absorbance of P-JNK in the BUD and the DXM groups were significantly lower than that of the asthma group, but higher than that of the control group (F = 17.84, P < 0.05). Strong positive correlations were found between Wat or Wam and P-JNK (mA) (r = 0.700 and r = 0.769, P < 0.01, respectively, n = 48). Strong positive correlations were also found between P-JNK (mA) and concentration of IL-1beta in serum or BALF (r = 0.689 and r = 0.805, P < 0.01, respectively, n = 48)., Conclusion: Phosphorylation of JNK is closely related to asthma airway remodeling. Glucocorticoids can inhibit phosphorylation of JNK, one mechanism of which may be down-regulation of IL-beta expression.

Vaccination is the important measure to improve the immunity level and prevent infectious disease. To ensure the safety injection in the vaccination is important. Because the consciousness of the safety injection continuously strengthens, Various safety injection devices emerged and continuously developed. AD suringe and the needle collecting device has renovated for 3 generation so far. This thesis summaried and discussed the research and development of the safety injection device in the vaccination.

Objective: To understand the changes of hepatitis B infection rates, before and after the hepatitis B vaccine was included into EPI, and to evaluate the effect of immunization which would lead to the development of a more appropriate hepatitis B control strategy., Methods: Seroepidemiologic method, with multi-section random sampling method were chosen. 14 sites from 8 counties were involved. 2-4 ml of the vein blood was drawn from all the individuals engaged in the study including 3806 samples. HBsAg, anti-HBs, anti-HBc of the samples were tested with ELISA., Results: Standardized positive rates of HBsAg and HBsAb were found as 7.05% and 29.77% respectively with the overall infection rate of HBV as 40.30%. The hepatitis B vaccine coverage of the children under 15 years was 70.73% and the positive rates for both HBsAg and anti-HBs were 2.62% and 56.68%, respectively. The coverage of hepatitis B vaccine among children under 3 years was 83.44% and the positive rates of both HBsAg and anti-HBs were 1.47% and 67.69% respectively, hepatitis B vaccine coverage of children under 3 years was 85.77%, with positive rates of HBsAg and anti-HBs as 1.78% and 75.44% respectively., Conclusion: Results from our study revealed that since the introduction of hepatitis B vaccination, the prevalence rates of HBsAg and HBV infection had an obvious decline, especially in children aged under 15 years of old, suggesting that some changes had occurred in the epidemic characteristics of hepatitis B in Sichuan.

Objective: To study the role of c-Jun N-terminal kinase (JNK) signal transduction pathway in the course of asthma airway remodeling, to explore whether IL-1beta participates in asthma airway remodeling mediated by JNK signal transduction pathway., Methods: Totally 72 male Sprague-Dawlay rats (6 - 8 weeks old, weighing about 120 g) were randomly divided into control groups (36 rats) and asthma groups (36 rats). The rats were sensitized for inducing asthma by intraperitoneal injection of ovalbumin and AL(OH)3 and were repeatedly exposed to aerosolized ovalbumin for 4, 8, 12 weeks (A4, A8, or A12 group), each had 12 rats, and correspondingly control rats were intraperitoneally injected with 0.9% NaCl, then were repeatedly exposed to 0.9% NaCl for 4, 8, 12 weeks (C4, C8, or C12 group), each had 12 rats. The ultrastructural changes of pulmonary tissues were observed by transmission electron microscope (TEM). The total bronchial wall thickness (Wat) and the airway smooth muscle thickness (Wam) were measured by an image analysis system. The concentrations of IL-1beta in serum and bronchoalveolar lavage fluid (BALF) were tested by a "sandwich" ELISA. The protein expressions of P-JNK and P-c-Jun were detected by immunohistochemical technique. Lung tissue extracts were analyzed for phosphorylation of JNK by Western blotting. Linear correlation analysis showed the correlation between Wat and P-JNK protein, Wam and P-JNK protein, levels of IL-1beta in serum and P-JNK protein, levels of IL-1beta in BALF and P-JNK protein., Results: In asthma groups, TEM showed alveolar septal proliferation and alveolus type II epithelial cells swelling. Wat and Wam in all asthma groups were significantly higher than those in corresponding control groups (P < 0.01, respectively), and compared with group A4 and group A8, Wat and Wam of group A12 significantly increased (P < 0.01). The concentrations of IL-1beta in serum and BALF of asthma groups were all significantly higher than those of the corresponding control groups (P < 0.01, respectively), and compared with group A4 and group A8, the concentrations of IL-1beta in BALF of group A12 significantly increased (P < 0.01 or P < 0.05), but the levels of IL-1beta in serum were not significantly different among them (P > 0.05). Mean absorbance values (by immunohistochemistry) of P-JNK and P-c-Jun in asthma groups were significantly higher than those in corresponding control groups (P < 0.01, respectively), and compared with group A4 and group A8, those of group A12 significantly increased (P < 0.01 or P < 0.05). The absorbance (by Western Blot) of P-JNK in A4, A8, A12 group was significantly higher than that in C4, C8, C12 groups (P < 0.01, respectively), and compared with group A4, that of P-JNK of A12 significantly increased (P < 0.01), and compared with group A8, there was no significant difference (P > 0.05). Strong positive correlations were found between Wat or Wam and P-JNK (r = 0.823 and r = 0.818, P < 0.01, respectively, n = 68) and between P-JNK and concentration of IL-1beta in serum or BALF (r = 0.717 and r = 0.803, P < 0.01, respectively, n = 68)., Conclusions: The expression of P-JNK and its downstream P-c-Jun in rats of asthma airway remodeling is increased, which implicates that JNK signal transduction pathway plays an important role in the course of asthma airway remodeling. IL-1beta participates in asthma airway remodeling possibly partly through activating JNK signal transduction pathway.

Members of the Ras superfamily of small GTPases and the heterotrimeric G protein gamma subunit are methylated on their carboxy-terminal cysteine residues by isoprenylcysteine methyltransferase. In Dictyostelium discoideum, small GTPase methylation occurs seconds after stimulation of starving cells by cAMP and returns quickly to basal levels, suggesting an important role in cAMP-dependent signaling. Deleting the isoprenylcysteine methyltransferase-encoding gene causes dramatic defects. Starving mutant cells do not propagate cAMP waves in a sustained manner, and they do not aggregate. Motility is rescued when cells are pulsed with exogenous cAMP, or coplated with wild-type cells, but the rescued cells exhibit altered polarity. cAMP-pulsed methyltransferase-deficient cells that have aggregated fail to differentiate, but mutant cells plated in a wild-type background are able to do so. Localization of and signaling by RasG is altered in the mutant. Localization of the heterotrimeric Ggamma protein subunit was normal, but signaling was altered in mutant cells. These data indicate that isoprenylcysteine methylation is required for intercellular signaling and development in Dictyostelium.