High-integrity Pueraria montana var. lobata genome and population analysis revealed the genetic diversity of Pueraria genus.

Pueraria montana var. lobata (P. lobata) is a traditional medicinal plant belonging to the Pueraria genus of Fabaceae family. Pueraria montana var. thomsonii (P. thomsonii) and Pueraria montana var. montana (P. montana) are its related species. However, evolutionary history of the Pueraria genus is still largely unknown. Here, a high-integrity, chromosome-level genome of P. lobata and an improved genome of P. thomsonii were reported. It found evidence for an ancient whole-genome triplication and a recent whole-genome duplication shared with Fabaceae in three Pueraria species. Population genomics of 121 Pueraria accessions demonstrated that P. lobata populations had substantially higher genetic diversity, and P. thomsonii was probably derived from P. lobata by domestication as a subspecies. Selection sweep analysis identified candidate genes in P. thomsonii populations associated with the synthesis of auxin and gibberellin, which potentially play a role in the expansion and starch accumulation of tubers in P. thomsonii. Overall, the findings provide new insights into the evolutionary and domestication history of the Pueraria genome and offer a valuable genomic resource for the genetic improvement of these species.

The active zone protein CLA-1 (Clarinet) bridges two subsynaptic domains to regulate presynaptic sorting of ATG-9.

In neuronal synapses, autophagosome biogenesis is coupled with the activity-dependent synaptic vesicle cycle via ATG-9. How vesicles containing ATG-9 are sorted at the presynapse is unknown. We performed forward genetic screens at single synapses of C. elegans neurons for mutants that disrupt ATG-9 presynaptic localization, and identified the long isoform of the active zone protein CLA-1 (Clarinet; CLA-1 L). We find that disrupting CLA-1 L results in abnormal accumulation of ATG-9-containing vesicles enriched with clathrin. The adaptor protein complexes and proteins at the periactive zone genetically interact with CLA-1 L in ATG-9 sorting. Moreover, the phenotype of the ATG-9 protein in cla-1(L) mutants was not observed for integral synaptic vesicle proteins, suggesting distinct mechanisms that regulate sorting of ATG-9-containing vesicles and synaptic vesicles. Our findings reveal novel roles for active zone proteins in the sorting of ATG-9 and in presynaptic macroautophagy/autophagy.

The active zone protein Clarinet regulates synaptic sorting of ATG-9 and presynaptic autophagy.

Autophagy is essential for cellular homeostasis and function. In neurons, autophagosome biogenesis is temporally and spatially regulated to occur near presynaptic sites, in part via the trafficking of autophagy transmembrane protein ATG-9. The molecules that regulate autophagy by sorting ATG-9 at synapses remain largely unknown. Here, we conduct forward genetic screens at single synapses of C. elegans neurons and identify a role for the long isoform of the active zone protein Clarinet (CLA-1L) in regulating sorting of autophagy protein ATG-9 at synapses, and presynaptic autophagy. We determine that disrupting CLA-1L results in abnormal accumulation of ATG-9 containing vesicles enriched with clathrin. The ATG-9 phenotype in cla-1(L) mutants is not observed for other synaptic vesicle proteins, suggesting distinct mechanisms that regulate sorting of ATG-9-containing vesicles and synaptic vesicles. Through genetic analyses, we uncover the adaptor protein complexes that genetically interact with CLA-1 in ATG-9 sorting. We also determine that CLA-1L extends from the active zone to the periactive zone and genetically interacts with periactive zone proteins in ATG-9 sorting. Our findings reveal novel roles for active zone proteins in the sorting of ATG-9 and in presynaptic autophagy.

Protective effect of etomidate on cultured retinal ganglion cells with mechanical injury in vitro / 中华眼底病杂志

Objective:To observe the protective effect of etomidate (ET) on cultured retinal ganglion cells (RGC) with mechanical injury in vitro.Methods:New Sprague-Dawley rat RGC was cultured in vitro and identified by double immunofluorescent labeling of Thy1.1 and microtubule associated protein 2. The cultured primary cells were randomly divided into control group, RGC scratch group, ET low dose group (1 μmol/L), ET medium dose group (5 μmol/L) and ET high dose group (10 μmol/L). The RGC mechanical injury model was established by using iris knife to culture cells in RGC scratch group and ET group with different concentration. Seven days after modeling, the RGC survival rate of each group was detected by cell count Kit 8 proliferation assay. The apoptosis rate of RGC was detected by Annexin Ⅴ/propyl iodide double staining. Single factor analysis of variance was used to compare the groups. The pairwise comparison between groups was tested by the least significant difference method.Results:The survival rates of RGC in RGC scratch group, ET low dose group, ET medium dose group and ET high dose group were (72.60±2.97)%, (73.73±1.14)%, (79.19±1.79)% and (83.88±0.94)%, respectively. The RGC apoptosis rates of control group, RGC scratch group, ET low dose group, ET medium dose group and ET high dose group were (5.08±0.17)%, (18.67±1.24)%, (17.96±0.74)%, (15.11±0.56)% and (11.67±1.32)%, respectively. Comparison of RGC survival rate between groups: compared with RGC scratch group, the cell survival rate of ET low-dose group, ET medium-dose group and ET high-dose group was increased, and the difference between RGC scratch group and ET low-dose group was not statistically significant ( P=0.728); the differences between RGC scratch group, ET medium dose group and ET high dose group were statistically significant ( P<0.001); the difference between ET medium dose group and ET high dose group was statistically significant ( P=0.002). Comparison of apoptosis rate of RGC among groups: the apoptosis rate of RGC scratch group was significantly higher than that of control group, the difference was statistically significant ( P<0.001). Compared with RGC scratch group, the apoptosis rate of ET low-dose group, ET medium-dose group and ET high-dose group was decreased, and there was no statistical significance between RGC scratch group and ET low-dose group ( P=0.869). The differences of apoptosis rate between RGC scratch group, ET medium dose group and ET high dose group were statistically significant ( P<0.05). The difference of apoptosis rate between ET medium dose group and ET high dose group was statistically significant ( P=0.007). Conclusion:ET has neuroprotective effect on RGC cultured in vitro with mechanical injury, and the protective effect increases with the increase of ET dose in a certain range.

Clinical efficacy of different anesthesia methods in patients with endovascular treatment for acute anterior circulation ischemic stroke: a meta-analysis / 中华神经科杂志

Objective:To systematically evaluate the efficacy and safety of general anesthesia versus conscious sedation in patients with endovascular therapy for acute ischemic stroke.Methods:Databases, including English databases PubMed, Embase and Cochrane, as well as Chinese databases Wan Fang Data and CNKI, were screened for randomized controlled trials (RCT) of general anesthesia versus conscious sedation on the effect of endovascular treatment for acute anterior circulation ischemic stroke. The searching period was from the establishment of databases to July 14, 2022. Two researchers independently screened literatures, extracted data and evaluated the risk of bias. And meta-analysis was performed using RevMan5.3 software.Results:A total of 7 RCTs involving 923 patients were included, with 461 in the general anesthesia group and 462 in the other. As the meta-analysis showing, general anesthesia could significantly improve the good outcomes (modified Rankin Scale score≤2) at 3 months after endovascular treatment in comparison with conscious sedation ( OR=1.34, 95% CI 1.01-1.78, P=0.04), and significantly increased the rate of successful revascularization ( OR=1.87, 95% CI 1.32-2.65, P<0.001). In addition, there were no statistically significant differences between the two groups in mortality ( OR=0.93, 95% CI 0.66-1.29, P=0.65), symptomatic intracranial hemorrhage ( OR=0.88, 95% CI 0.57-1.35, P=0.55) and intervention-related complications ( OR=0.83, 95% CI 0.50-1.36, P=0.46). However, general anesthesia was associated with higher risk for both 20% reduction in mean arterial pressure ( OR=4.76, 95% CI 1.49-15.19, P=0.008) and pneumonia ( OR=2.58, 95% CI 1.51-4.39, P<0.001). Conclusions:Compared with conscious sedation, endovascular treatment under general anesthesia in patients with acute anterior circulation ischemic stroke may contribute to better outcomes and higher successful revascularization. However, this method will lead to the risk of blood pressure variability and the incidence of pneumonia.

Investigation on the incidence of IRIS in HIV patients with TB infection and its relationship with Th17/Treg, CD4 + T lymphocyte levels / 中国医师杂志

Objective:To investigate the incidence of immune reconstitution inflammatory syndrome (IRIS) in patients with HIV (HIV) and tuberculosis (TB) infection, and analyze the relationship between Th17/Treg cytokines, CD4 + T lymphocytes and IRIS. Methods:HIV patients with TB infection admitted to Public Health Clinical Center of Chengdu from June 2020 to June 2022 were divided into IRIS group (31 cases) and non IRIS group (93 cases) according to whether IRIS occurred after highly active antiretroviral therapy (HAART). The Demography data, clinical data and laboratory indicators of the two groups were compared. Multivariate logistic regression analysis was conducted to investigate the influencing factors of IRIS in HIV patients with TB infection.Results:There was no significant difference in Demography data between the two groups ( P>0.05). There was a statistically significant difference in the history of opportunistic infection between the IRIS group and the non IRIS group (χ 2=5.194, P<0.05). The levels of HIV RNA, interleukin (IL)-17, and IL-23 in the IRIS group were higher than those in the non IRIS group (all P<0.05). The levels of the γ interferon (IFN- γ), the transforming growth factor-β (TGF- β) and baseline CD4 + T lymphocyte count were lower than those in the non IRIS group (all P<0.05). The results of multivariate logistic regression analysis showed that IL-17 ( OR: 1.266, 95% CI: 1.095-1.464), IL-23( OR: 1.384, 95% CI: 1.120-1.710), and TGF- β( OR: 0.589, 95% CI: 0.436-0.797) were influencing factors for the occurrence of IRIS in HIV patients with TB infection (all P<0.05). Conclusions:For patients with high IL-17 levels, high IL-23 levels, and low TGF- β level of HIV complicated with TB infection, clinical prevention and control should be carried out as soon as possible to prevent the occurrence of IRIS.

Scientific and technological innovation drives the development of minimally invasive surgery / 中华消化外科杂志

Scientific and technological innovation is the most important role in driving the development of minimally invasive surgery. After more than 30 years of development, modern mini-mally invasive surgery represented by laparoscopic surgery has gradually matured. Various types of minimally invasive surgeries have been popularized, and the difficulty of surgery has changed from extreme to limit. Surgical equipments and instruments can meet the needs of most clinical operations. The future of minimally invasive surgery has reached a crossroad, and only scientific and technological innovation can promote the development of minimally invasive surgery change lanes and overtake, ushering in new development, new methods, and a new world. For innovation, the most important thing is not knowledge, but vision and ideas. A new technological revolution will inevitably bring about changes in the industry. What changes will be ushered in the operation and treatment of diseases in the future? What will be the breakthrough of minimally invasive surgery? It is worth to wait and see. The authors discuss the development direction of minimally invasive surgery based on the recent application of hot technologies in laparoscopic surgery.

Future of innovation and development of minimally invasive surgical technology and instruments / 中华消化外科杂志

The application of minimally invasive surgery has experienced rapid develop-ment for more than 30 years. The continuous development of minimally invasive technology and instru-ments in the fields of energy platform and imaging equipment has promoted the progress of laparos-copic surgery to be more accurate and secure, and the development of laparoscopic surgery itself has also continuously fed back the innovation of technology and instruments. In recent years, the innovative development of minimally invasive technology and instruments has been more closely combined with the current scientific and technological frontier, leading to the innovative achievements in the fields of robotic surgery, screenless surgery, artificial intelligence, electronic instrument, virtualization and so on. In the new era, surgeons should always keep an eye on the forefront of science and technology, the combination of surgery and technology, application of advanced technology to solve the key problems of current surgery, so as to inject new vitality into the next development of minimally invasive surgery.

Full-profile pharmacokinetics, anticancer activity and toxicity of an extended release trivalent PEGylated irinotecan prodrug

Irinotecan is an anticancer topoisomerase I inhibitor that acts as a prodrug of the active metabolite, SN-38. Unfortunately, the limited utility of irinotecan is attributed to its pH-dependent stability, short half-life and dose-limiting toxicity. To address this problem, a novel trivalent PEGylated prodrug (PEG-[Irinotecan]3) has been synthesized and its full-profile pharmacokinetics, antitumor activity and toxicity compared with those of irinotecan. The results show that after intravenous administration to rats, PEG-[Irinotecan]3 undergoes stepwise loss of irinotecan to form PEG-[Irinotecan]3‒x (x = 1,2) and PEG-[linker] during which time the released irinotecan undergoes conversion to SN-38. As compared with conventional irinotecan, PEG-[Irinotecan]3 displays extended release of irinotecan and efficient formation of SN-38 with significantly improved AUC and half-life. In a colorectal cancer-bearing model in nude mice, the tumor concentrations of irinotecan and SN-38 produced by PEG-[Irinotecan]3 were respectively 86.2 and 2293 times higher at 48 h than produced by irinotecan. In summary, PEG-[Irinotecan]3 displays superior pharmacokinetic characteristics and antitumor activity with lower toxicity than irinotecan. This supports the view that PEG-[Irinotecan]3 is a superior anticancer drug to irinotecan and it has entered the phase II trial stage.

2,3-Seco and 3-nor guaianolides fromAchillea alpina with antidiabetic activity / 中国天然药物

In this study, we presented the isolation and characterization of eight novel seco-guaianolide sesquiterpenoids (1-8) and two known guaianolide derivatives (9 and 10), from the aerial part of Achillea alpina L.. Compounds 1-3 were identified as guaianolides bearing an oxygen insertion at the 2, 3 position, while compounds 4-8 belonged to a group of special 3-nor guaianolide sesquiterpenoids. The structural elucidation of 1-8, including their absolute configurations, were accomplished by a combination of spectroscopic data analysis and quantum electronic circular dichroism (ECD) calculations. To evaluate the potential antidiabetic activity of compounds 1-10, we investigated their effects on glucose consumption in palmitic acid (PA)-mediated HepG2-insulin resistance (IR) cells. Among the tested compounds, compound 7 demonstrated the most pronounced ability to reverse IR. Moreover, a mechanistic investigation revealed that compound 7 exerted its antidiabetic effect by reducing the production of the pro-inflammatory cytokine IL-1β, which was achieved through the suppression of the NLRP3 pathway.

Analysis of the influence of probe position on quality control test results of dental panoramic radiography equipment / 中国辐射卫生

Objective To quantitatively study the influence of changes in probe position on the quality control test results of dental panoramic radiography and to provide a reference for analyzing the sources of deviations in quality control test results. Methods Eight different models of dental panoramic X-ray machines were selected for this study. The film analysis method was used to determine the position of the central axis of the main beam on the image detector. The position of the probe was accurately controlled through an auxiliary moving device. The tube voltage, radiation output, and half-value layer of the useful beam were measured for positions at the center of the beam; 1 cm upward, downward, left, and right from the center of the beam; and 2 cm upward, downward, left, and right from the center of the beam. Results The tube voltage, radiation output, and half-value layer had a maximum value at the center of the beam, with a decrease in the value as the position deviated from the center. There were significant differences in the probe position sensitivity between different models of dental panoramic radiography equipment. A 2 cm deviation in the probe position resulted in an impact on the measured tube voltage of less than 5.3 kV (5.8%) for less sensitive equipment. A 2 mm deviation in the probe position resulted in an impact on the measured tube voltage of less than 5.4 kV (6.0%) for sensitive equipment. Conclusion The probe position can lead to deviation in the quality control test results of dental panoramic photography. Therefore, determining the position of the central axis of the main beam on the image detector for accurate positioning of the probe is crucial for quality control testing.

Construction of Harmonious of Doctor-patient Relationship under the Influence of "Internet+Healthcare" / 中国医学伦理学

Under the background of "Internet+Healthcare", the iterative development and large-scale application of new technologies have brought great impact on doctor-patient relationship, and promoted the harmonious development of doctor-patient relationship to a certain extent. By analyzing the impact of "Internet+Healthcare" on doctor-patient relationship, this paper proposed to deepen the patient-centered doctor-patient relationship model, enhance the efficiency of doctor-patient communication and improve communication channels between doctors and patients, strengthen the supervision of internet medical information, and call on new media to actively promote the development of doctor-patient relationship.

Progress on genome-wide association studies on mosaic chromosomal alterations / 中华流行病学杂志

Mosaic chromosomal alteration (mCA) is referred to as large-scale somatic mutations on chromosomes, which results in diverse karyotypes in body. The mCA is regarded as one of the phenotypes of aging. Studies have revealed its associations with many chronic diseases such as hematopoietic cancers and cardiovascular diseases, but its genetic basis (e.g. genetic susceptibility variants) is still under-investigated. This paper reviews GWAS studies for mCA on autosomal chromosomes and sex chromosomes [mosaic loss of the Y chromosome (mLOY) and mosaic loss of the X chromosome (mLOX)] based on large population, respectively. Most of the genetic susceptibility loci found in studies for autosomal mCA were associated with copy-neutral loss of heterozygosity. The study of sex chromosome mCA focused on mosaic loss mutations. The number of genetic susceptibility loci for mLOY was high (up to 156), but it was relatively less for mLOX.

Epidemiological distribution characteristics of peripheral blood mosaic chromosomal alteration in adults from 10 regions of China / 中华流行病学杂志

Objective: To describe the epidemiological distribution characteristics of peripheral blood mosaic chromosomal alteration (mCA) in community adults aged 30-79 years in 10 regions of China. Methods: A total of 100 297 participants with complete baseline information (demographic characteristics, lifestyle, physical examination, etc.) and genotyping data of blood-derived DNA in ten regions of the China Kadoorie Biobank study were included. The mCAs were detected with the Mosaic Chromosomal Alterations pipeline, and logistic regression models were used to compare the differences in the detection rate of mCAs in different regions and populations. Results: A total of 5 810 mCA carriers were detected, with the detection rate of 5.8%. The standardized detection rate was 5.1%. The baseline detection rate of mCA increased with age, which were 3.4%, 5.0%, and 9.4% in those aged 30-, 51-, and >60 years, respectively (trend test P<0.001). A more significant proportion of mCAs were found in men (8.0%) than women (4.0%), as well as in urban areas (6.4%) than in rural areas (5.3%), the difference was significant (P<0.001). After adjusting for age and gender, the detection rate of mCA was higher in current smokers or people quitting smoking due to illness and people with low physical activity level, and the mCA detection rate was lower in obesy people (5.3%) than that in people with normal body weight (5.9%) (P=0.006). Conclusions: The detection rate of mCAs varied with region and population in community adults aged 30-79 years in 10 regions of China. The study results might contribute to the molecular identification of aging populations and guide precision prevention of age-related diseases such as cancers.

Yigong Powder regulates CXCL12/CXCR4 signaling to reduce glutamate release and prevent cognitive decline in mouse model of aging / 中国中药杂志

This study aims to explore the effect of preventive administration of Yigong Powder on the learning and memory abilities of the mouse model of aging induced by D-galactose and decipher the underlying mechanism, so as to provide a basis for the application of Yigong Powder in the prevention and treatment of cognitive decline. Forty KM mice were randomized into control, model, donepezil(1.5 mg·kg~(-1)), and high-dose(7.5 g·kg~(-1)) and low-dose(3.75 g·kg~(-1)) Yigong Powder groups. The mice in other groups except the control group were injected with D-galactose(200 g·kg~(-1)) at the back of the neck for the modeling of aging. At the same time, the mice were administrated with corresponding drugs by gavage for one month. Morris water maze was used to examine the learning and memory abilities of the mice. Hematoxylin-eosin staining was employed to observe the pathological and morphological changes of the hippocampus. The immunofluorescence assay was employed to detect the expression of ionized calcium-binding adapter molecule 1(IBA1), glial fibrillary acidic protein(GFAP), chemokine C-X-C-motif ligand 12(CXCL12), chemokine C-X-C-motif receptor 4(CXCR4) in the hippocampus and observe the positional relationship between IBA1, GFAP, and CXCR4. Western blot was employed to determine the protein levels of extracellular regulated kinase(ERK), p-ERK, and tumor necrosis factor receptor 1(TNFR1). Enzyme-linked immunosorbent assay was employed to measure the levels of glutamate and tumor necrosis factor(TNF-α) in the brain tissue and the level of TNF-α in the serum and spleen. Yigong Powder significantly shortened the escape latency, increased the times crossing platforms, and prolonged the cumulative time in quadrants of the aging mice. It alleviated the nerve cell disarrangement, increased intercellular space, and cell degeneration or death in the hippocampus and reduced the pathology score of the damaged nerve. Moreover, Yigong Powder reduced the positive area of IBA1 and GFAP, reduced the levels of TNF-α in the brain tissue, serum, and spleen, and decreased spleen index. Furthermore, Yigong Powder decreased the average fluorescence intensity of CXCL12 and CXCR4, reduced CXCR4-positive astrocytes and microglia, down-regulated the protein levels of p-ERK/ERK and TNFR1, and lowered the level of glutamate in the brain tissue. This study showed that the preventive administration of Yigong Powder can ameliorate the learning and memory decline of the D-galactose-induced aging mice by regulating the immune function of the spleen and the CXCL12/CXCR4 signaling in the brain to reduce glutamate release. However, the mechanism of Yigong San in preventing and treating dementia via regulating spleen and stomach function remains to be studied.

An Anterior Cingulate Cortex-to-Midbrain Projection Controls Chronic Itch in Mice / 神经科学通报·英文版

Itch is an unpleasant sensation that provokes the desire to scratch. While acute itch serves as a protective system to warn the body of external irritating agents, chronic itch is a debilitating but poorly-treated clinical disease leading to repetitive scratching and skin lesions. However, the neural mechanisms underlying the pathophysiology of chronic itch remain mysterious. Here, we identified a cell type-dependent role of the anterior cingulate cortex (ACC) in controlling chronic itch-related excessive scratching behaviors in mice. Moreover, we delineated a neural circuit originating from excitatory neurons of the ACC to the ventral tegmental area (VTA) that was critically involved in chronic itch. Furthermore, we demonstrate that the ACC→VTA circuit also selectively modulated histaminergic acute itch. Finally, the ACC neurons were shown to predominantly innervate the non-dopaminergic neurons of the VTA. Taken together, our findings uncover a cortex-midbrain circuit for chronic itch-evoked scratching behaviors and shed novel insights on therapeutic intervention.

Standard Process for Palliative Sedation in Peking Union Medical College Hospital / 中国医学科学院学报

End-stage patients experience unbearable pain because of refractory symptoms.Palliative sedation is a form of palliative care which relieves patients' agony by lowering their consciousness.Standard palliative sedation can help patients die with dignity.It is distinct from euthanasia and does not alter the survival of patients.Sufficient palliative care is the premise of palliative sedation.Repeated and detailed clinical evaluation,as well as multidisciplinary involvement,is necessary for the standardized implementation of palliative sedation.Here,we proposed the standard process and specifications of palliative sedation in Peking Union Medical College Hospital.Furthermore,we reported a case of palliative sedation for an advanced cancer patient with refractory delirium and living pain to demonstrate its application in clinical practice.

l-Cysteine modified metal-organic framework as a chiral stationary phase for enantioseparation by capillary electrochromatography.

A new kind of chiral zirconium based metal-organic framework, l-Cys-PCN-222, was synthesized using l-cysteine (l-Cys) as a chiral modifier by a solvent-assisted ligand incorporation approach and utilized as the chiral stationary phase in the capillary electrochromatography system. l-Cys-PCN-222 was characterized by X-ray diffraction, thermogravimetric analysis, X-ray photoelectron spectroscopy, Fourier-transform infrared spectra, nitrogen adsorption/desorption, circular dichroism spectrum, zeta-potential and so on. The results revealed that l-Cys-PCN-222 had the advantages of good crystallinity, high specific surface area (1818 m2 g-1), thermal stability and chiral recognition performance. Meanwhile, the l-Cys-PCN-222-bonded open-tubular column was prepared using l-Cys-PCN-222 particles as the solid phase by 'thiol-ene' click chemistry reaction and characterized by scanning electron microscopy, which proved the successful bonding of l-Cys-PCN-222 to the column inner wall. Finally, the stability, reproducibility and chiral separation performance of the l-Cys-PCN-222-bonded OT column were measured. Relative standard deviations (RSD) of the column efficiencies for run-to-run, day-to-day, column-to-column and runs were 1.39-6.62%, and did not obviously change after 200 runs. The enantiomeric separation of 17 kinds of chiral compounds including acidic, neutral and basic amino acids, imidazolinone and aryloxyphenoxypropionic pesticides, and fluoroquinolones were achieved in the l-Cys-PCN-222-bonded OT column. These results demonstrated that the chiral separation system of the chiral metal-organic frameworks (CMOFs) coupled with capillary electrochromatography has good application prospects.

Presynaptic autophagy is coupled to the synaptic vesicle cycle via ATG-9.

Autophagy is a cellular degradation pathway essential for neuronal health and function. Autophagosome biogenesis occurs at synapses, is locally regulated, and increases in response to neuronal activity. The mechanisms that couple autophagosome biogenesis to synaptic activity remain unknown. In this study, we determine that trafficking of ATG-9, the only transmembrane protein in the core autophagy pathway, links the synaptic vesicle cycle with autophagy. ATG-9-positive vesicles in C. elegans are generated from the trans-Golgi network via AP-3-dependent budding and delivered to presynaptic sites. At presynaptic sites, ATG-9 undergoes exo-endocytosis in an activity-dependent manner. Mutations that disrupt endocytosis, including a lesion in synaptojanin 1 associated with Parkinson's disease, result in abnormal ATG-9 accumulation at clathrin-rich synaptic foci and defects in activity-induced presynaptic autophagy. Our findings uncover regulated key steps of ATG-9 trafficking at presynaptic sites and provide evidence that ATG-9 exo-endocytosis couples autophagosome biogenesis at presynaptic sites with the activity-dependent synaptic vesicle cycle.

New eudesmane sesquiterpenoids from Atractylodis Macrocephalae Rhizoma and their inhibitory activities against SREBPs / 中国中药杂志

Three sesquiterpenoids were isolated and purified from the 95% ethanol extract of Atractylodis Macrocephalae Rhizoma by column chromatography on silica gel, Sephadex LH-20, ODS, and high-performance liquid chromatography(HPLC). Their chemical structures were identified on the basis of spectroscopic analysis and physiochemical properties as(7Z)-8β,13-diacetoxy-eudesma-4(15),7(11)-diene(1), 7-oxo-7,8-secoeudesma-4(15),11-dien-8-oic acid(2), and guai-10(14)-en-11-ol(3). Compounds 1 and 2 are new compounds and compound 3 was obtained from Compositae family for the first time. Compounds 1, 2, and 3 showed weak inhibitory activities against sterol regulatory element-binding proteins(SREBPs).