CCT2 is an aggrephagy receptor for clearance of solid protein aggregates.

Protein aggregation is a hallmark of multiple human pathologies. Autophagy selectively degrades protein aggregates via aggrephagy. How selectivity is achieved has been elusive. Here, we identify the chaperonin subunit CCT2 as an autophagy receptor regulating the clearance of aggregation-prone proteins in the cell and the mouse brain. CCT2 associates with aggregation-prone proteins independent of cargo ubiquitination and interacts with autophagosome marker ATG8s through a non-classical VLIR motif. In addition, CCT2 regulates aggrephagy independently of the ubiquitin-binding receptors (P62, NBR1, and TAX1BP1) or chaperone-mediated autophagy. Unlike P62, NBR1, and TAX1BP1, which facilitate the clearance of protein condensates with liquidity, CCT2 specifically promotes the autophagic degradation of protein aggregates with little liquidity (solid aggregates). Furthermore, aggregation-prone protein accumulation induces the functional switch of CCT2 from a chaperone subunit to an autophagy receptor by promoting CCT2 monomer formation, which exposes the VLIR to ATG8s interaction and, therefore, enables the autophagic function.

TOR-mediated Ypt1 phosphorylation regulates autophagy initiation complex assembly.

The regulation of autophagy initiation is a key step in autophagosome biogenesis. However, our understanding of the molecular mechanisms underlying the stepwise assembly of ATG proteins during this process remains incomplete. The Rab GTPase Ypt1/Rab1 is recognized as an essential autophagy regulator. Here, we identify Atg23 and Atg17 as binding partners of Ypt1, with their direct interaction proving crucial for the stepwise assembly of autophagy initiation complexes. Disruption of Ypt1-Atg23 binding results in significantly reduced Atg9 interactions with Atg11, Atg13, and Atg17, thus preventing the recruitment of Atg9 vesicles to the phagophore assembly site (PAS). Likewise, Ypt1-Atg17 binding contributes to the PAS recruitment of Ypt1 and Atg1. Importantly, we found that Ypt1 is phosphorylated by TOR at the Ser174 residue. Converting this residue to alanine blocks Ypt1 phosphorylation by TOR and enhances autophagy. Conversely, the Ypt1S174D phosphorylation mimic impairs both PAS recruitment and activation of Atg1, thus inhibiting subsequent autophagy. Thus, we propose TOR-mediated Ypt1 as a multifunctional assembly factor that controls autophagy initiation via its regulation of the stepwise assembly of ATG proteins.

The calcium-dependent protein kinase CPK16 regulates hypoxia-induced ROS production by phosphorylating the NADPH oxidase RBOHD in Arabidopsis.

Reactive oxygen species (ROS) production is a key event in modulating plant responses to hypoxia and post-hypoxia reoxygenation. However, the molecular mechanism by which hypoxia-associated ROS homeostasis is controlled remains largely unknown. Here, we showed that the calcium-dependent protein kinase CPK16 regulates plant hypoxia tolerance by phosphorylating the plasma membrane-anchored NADPH oxidase RESPIRATORY BURST OXIDASE HOMOLOG D (RBOHD) to regulate ROS production in Arabidopsis (Arabidopsis thaliana). In response to hypoxia or reoxygenation, CPK16 was activated through phosphorylation of its Ser274 residue. The cpk16 knockout mutant displayed enhanced hypoxia tolerance, whereas CPK16-overexpressing (CPK16-OE) lines showed increased sensitivity to hypoxic stress. In agreement with these observations, hypoxia and reoxygenation both induced ROS accumulation in the rosettes of CPK16-OEs more strongly than in rosettes of the cpk16-1 mutant or the wild type. Moreover, CPK16 interacted with and phosphorylated the N terminus of RBOHD at four serine residues (Ser133, Ser148, Ser163, and Ser347) that were necessary for hypoxia- and reoxygenation-induced ROS accumulation. Furthermore, the hypoxia-tolerant phenotype of cpk16-1 was fully abolished in the cpk16 rbohd double mutant. Thus, we have uncovered a regulatory mechanism by which the CPK16-RBOHD module shapes ROS production during hypoxia and reoxygenation in Arabidopsis.

mTORC1-Regulated and HUWE1-Mediated WIPI2 Degradation Controls Autophagy Flux.

mTORC1, the major homeostatic sensor and responder, regulates cell catabolism mainly by targeting autophagy. Here, we show that mTORC1 directly controls autophagosome formation via phosphorylation of WIPI2, a critical protein in isolation membrane growth and elongation. mTORC1 phosphorylates Ser395 of WIPI2, directing WIPI2 to interact specifically with the E3 ubiquitin ligase HUWE1 for ubiquitination and proteasomal degradation. Physiological or pharmacological inhibition of mTORC1 in cells promotes WIPI2 stabilization, autophagosome formation, and autophagic degradation. In mouse liver, fasting significantly increases the WIPI2 protein level, while silencing HUWE1 enhances autophagy, and introducing WIPI2 improves lipid clearance. Thus, regulation of the intracellular WIPI2 protein level by mTORC1 and HUWE1 is a key determinant of autophagy flux and may coordinate the initiation, progression, and completion of autophagy.

The molecular mechanisms regulating the assembly of the autophagy initiation complex.

The autophagy initiation complex is brought about via a highly ordered and stepwise assembly process. Two crucial signaling molecules, mTORC1 and AMPK, orchestrate this assembly by phosphorylating/dephosphorylating autophagy-related proteins. Activation of Atg1 followed by recruitment of both Atg9 vesicles and the PI3K complex I to the PAS (phagophore assembly site) are particularly crucial steps in its formation. Ypt1, a small Rab GTPase in yeast cells, also plays an essential role in the formation of the autophagy initiation complex through multiple regulatory pathways. In this review, our primary focus is to discuss how signaling molecules initiate the assembly of the autophagy initiation complex, and highlight the significant roles of Ypt1 in this process. We end by addressing issues that need future clarification.

Mec1 regulates PAS recruitment of Atg13 via direct binding with Atg13 during glucose starvation-induced autophagy.

Mec1 is a DNA damage sensor, which performs an essential role in the DNA damage response pathway and glucose starvation-induced autophagy. However, the functions of Mec1 in autophagy remain unclear. In response to glucose starvation, Mec1 forms puncta, which are recruited to mitochondria through the adaptor protein Ggc1. Here, we show that Mec1 puncta also contact the phagophore assembly site (PAS) via direct binding with Atg13. Functional analysis of the Atg13-Mec1 interaction revealed two previously unrecognized protein regions, the Mec1-Binding Region (MBR) on Atg13 and the Atg13-Binding Region (ABR) on Mec1, which mediate their mutual association under glucose starvation conditions. Disruption of the MBR or ABR impairs the recruitment of Mec1 puncta and Atg13 to the PAS, consequently blocking glucose starvation-induced autophagy. Additionally, the MBR and ABR regions are also crucial for DNA damage-induced autophagy. We thus propose that Mec1 regulates glucose starvation-induced autophagy by controlling Atg13 recruitment to the PAS.

Optical single-sideband (OSSB) Raman laser system based on an atomic filter for atom gravimeters.

Phase-modulator-generated laser for Raman transition is widely used in atom gravimeters to simplify a system and improve robustness. However, the induced additional sidebands (ASBs) lead to systematic errors in gravity measurement. This work presents a novel, to our knowledge, method to generate an optical single-sideband (OSSB) laser for Raman transition through phase modulation based on a Faraday anomalous dispersion atomic filter (FADOF). The experimental result indicates that it can reduce the additional sidebands with a signal-to-noise ratio (SNR, the intensity ratio of carrier and unwanted sidebands) of better than 50 dB, and the phase shift caused by ASBs is demonstrated to be effectively suppressed from 358.8 to 2.2 mrad. Furthermore, this system has already been applied on an atom gravimeter to achieve a primary gravity measurement. It shows that the FADOF-based Raman laser system is a new scheme for a compact atom absolute gravimeter.

Biotransformation and disposition characteristics of HSK7653, a novel long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes.

AIM: To investigate the metabolism and disposition characteristics of HSK7653 in healthy male Chinese participants. METHODS: A single oral dose of 80 µCi (25 mg) [14C]HSK7653 capsules was administered to six healthy participants, and blood, plasma, urine and faeces were collected. Quantitative and qualitative analysis was conducted to investigate the pharmacokinetics, blood-to-plasma ratio, mass balance and metabolism of HSK7653. RESULTS: The drug was well absorbed and reached a maximum concentration at 1.25 h. The drug-related components (HSK7653 and its metabolites) were eliminated slowly, with a half-life (t1/2) of 111 h. Unchanged HSK7653 contributed to more than 97% of the total radioactivity in all plasma samples. The blood-to-plasma ratio (0.573-0.845) indicated that HSK7653 did not tend to distribute into blood cells. At 504 h postdose, up to 95.9% of the dose was excreted, including 79.8% in urine and 16.1% in faeces. Most of the radioactivity (75.5% dose) in excreta was unchanged HSK7653. In addition, nine metabolites were detected in urine and faeces. The most abundant metabolite was M6-2, a dioxidation product of HSK7653, which accounted for 4.73% and 2.63% of the dose in urine and faeces, respectively. The main metabolic pathways of HSK7653 in vivo included oxidation, pyrrole ring opening and sulphonamide hydrolysation. CONCLUSION: HSK7653 was well absorbed, slightly metabolized and slowly excreted in humans. The high plasma exposure and long t1/2 of HSK7653 may contribute to its long-lasting efficacy as a long-acting dipeptidyl peptidase-4 inhibitor.

Resolvin and lipoxin metabolism network regulated by Hyssopus Cuspidatus Boriss extract in asthmatic mice.

Resolvin (Rv) and lipoxin (Lx) play important regulative roles in the development of several inflammation-related diseases. The dysregulation of their metabolic network is believed to be closely related to the occurrence and development of asthma. The Hyssopus Cuspidatus Boriss extract (SXCF) has long been used as a treatment for asthma, while the mechanism of anti-inflammatory and anti-asthma action targeting Rv and Lx has not been thoroughly investigated. In this study, we aimed to investigate the effects of SXCF on Rv, Lx in ovalbumin (OVA)-sensitized asthmatic mice. The changes of Rv, Lx before and after drug administration were analyzed based on high sensitivity chromatography-multiple response monitoring (UHPLC-MRM) analysis and multivariate statistics. The pathology exploration included behavioral changes of mice, IgE in serum, cytokines in BALF, and lung tissue sections stained with H&E. It was found that SXCF significantly modulated the metabolic disturbance of Rv, Lx due to asthma. Its modulation effect was significantly better than that of dexamethasone and rosmarinic acid which is the first-line clinical medicine and the main component of Hyssopus Cuspidatus Boriss, respectively. SXCF is demonstrated to be a potential anti-asthmatic drug with significant disease-modifying effects on OVA-induced asthma. The modulation of Rv and Lx is a possible underlying mechanism of the SXCF effects.

A novel SPE-LC-MRM strategy for serum demethylzeylasteral quantitation developed with an 18O-labeled internal standard.

Natural bioactive compounds (NBCs) are widely used in clinical treatment. For example, Tripterygium wilfordii Hook f. is commonly known in China as Lei-Gong-Teng which means thunder god vine. This herb is widely distributed in Eastern and Southern China, Korea, and Japan. The natural bioactive compounds of this herb can be extracted and made into tripterygium glycoside tablets. It is one of the most commonly used and effective traditional Chinese herbal medicines against rheumatoid arthritis (RA), nephrotic syndrome (NS), autoimmune hepatis (AIH), and so on. However, many NBCs are difficult to reliably quantify in the serum due to the effects of matrix and RSD. In addition, the targeted compound's internal standard (IS) is rarely sold due to the complex isotope internal standard synthesis pathway. In this study, a new quantitation method for 18O labeling combined with off-line SPE was formulated. We contrasted the recoveries and matrix effects of various separation methods in order to choose the best method. Furthermore, we optimized the conditions for SPE loading and washing. An isotopic internal standard was prepared by the 16O/18O exchanging reaction in order to eliminate the matrix effects. The method's accuracy and precision met the requirements for method validation. The recovery of this method was close to 60%. The relative standard deviation (RSD) of the high-concentration sample was 2%, and the limit of detection (LOD) was 1 ng/mL. This method could be used to analyze the clinical serum concentration of demethylzeylasteral. Sixty samples were collected from 10 patients with diabetes nephropathy. The quantitation results of demethylzeylasteral in patients' serum obtained using this method exhibited a correlation between therapeutic drug monitoring (TDM) and decreased urinary protein. This work may have broad implications for the study of drug metabolism in vivo and the clinical application of low-abundance and difficult-to-quantify NBCs.

A Transportable Atomic Gravimeter with Constraint-Structured Active Vibration Isolation.

Many efforts have been taken in recent years to push atomic gravimeters toward practical applications. We demonstrate an atomic gravimeter named NIM-AGRb2 that is transportable and suitable for high-precision gravity measurements. Constraint-structured active vibration isolation (CS-AVI) is used to reduce the ground vibration noise. The constraint structure in CS-AVI ensures that the isolation platform only has vertical translation, with all other degrees of freedom (DoFs) being constrained. Therefore, the stability of active vibration isolation is enhanced. With the implementation of CS-AVI, the sensitivity of NIM-AGRb2 reached as low as 20.5 µGal/Hz1/2. The short-term sensitivity could be further reduced to 10.8 µGal/Hz1/2 in a seismologic observation station. Moreover, we evaluated the system noise of the gravimeter, and the results were consistent with our observations.

Comparison of two methods for tumour-targeting peptide modification of liposomes.

Liposomes decorated with tumour-targeting cell-penetrating peptides can enhance specific drug delivery at the tumour site. The TR peptide, c(RGDfK)-AGYLLGHINLHHLAHL(Aib)HHIL, is pH-sensitive and actively targets tumour cells that overexpress integrin receptor αvß3, such as B16F10 melanoma cells. Liposomes can be modified with the TR peptide by two different methods: utilization of the cysteine residue on TR to link DSPE-PEG2000-Mal contained in the liposome formula (LIPTR) or decoration of TR with a C18 stearyl chain (C18-TR) for direct insertion into the liposomal phospholipid bilayer through electrostatic and hydrophobic interactions (LIPC18-TR). We found that both TR and C18-TR effectively reversed the surface charge of the liposomes when the systems encountered the low pH of the tumour microenvironment, but LIPC18-TR exhibited a greater increase in the charge, which led to higher cellular uptake efficiency. Correspondingly, the IC50 values of PTX-LIPTR and PTX-LIPC18-TR in B16F10 cells in vitro were 2.1-fold and 2.5-fold lower than that of the unmodified PTX-loaded liposomes (PTX-LIP), respectively, in an acidic microenvironment (pH 6.3). In B16F10 tumour-bearing mice, intravenous administration of PTX-LIPTR and PTX-LIPC18-TR (8 mg/kg PTX every other day for a total of 4 injections) caused tumour reduction ratios of 39.4% and 56.1%, respectively, compared to 20.8% after PTX-LIP administration. Thus, we demonstrated that TR peptide modification could improve the antitumour efficiency of liposomal delivery systems, with C18-TR presenting significantly better results. After investigating different modification methods, our data show that selecting an adequate method is vital even when the same molecule is used for decoration.

Mass balance study of [14C]SHR0302, a selective and potent JAK1 inhibitor in humans.

SHR0302, a selective JAK1 inhibitor developed by Jiangsu Hengrui Pharmaceutical Co., was intended for the treatment of rheumatoid arthritis. In this study, we evaluated the pharmacokinetics, mass balance, and metabolism of SHR0302 in six healthy Chinese male subjects after a single 8 mg (80 µCi) oral dose of [14C]SHR0302.SHR0302 was absorbed rapidly (Tmax = 0.505 h), and the average t1/2 of the SHR0302-related components in plasma was approximately 9.18 h. After an oral dose was administered, the average cumulative excretion of the radioactive components was 100.56% ± 1.51%, including 60.95% ± 11.62% in urine and 39.61% ± 10.52% in faeces.A total of 16 metabolites were identified. In plasma, the parent drug SHR0302 accounted for 90.42% of the total plasma radioactivity. In urine, SHR161279 was the main metabolite, accounting for 33.61% of the dose, whereas the parent drug SHR0302 only accounted for 5.1% of the dose. In faeces, the parent drug SHR0302 accounted for 23.73% of the dose, and SHR161279 was the significant metabolite, accounting for 5.67% of the dose. In conclusion, SHR0302-related radioactivity was mainly excreted through urine (60.95%) and secondarily through faeces (39.61%).The metabolic reaction of SHR0302 in the human body is mainly through mono-oxidation and glucuronidation. The main metabolic location of SHR0302 in the human body is the pyrrolopyrimidine ring.

[Transcriptional regulation mechanism of differential accumulation of flavonoids in leaves and roots of Sarcandra glabra based on metabonomics and transcriptomics].

This study aims to explore the molecular regulation mechanism of the differential accumulation of flavonoids in the leaves and roots of Sarcandra glabra. Liquid chromatography-mass spectrometry(LC-MS) and high-throughput transcriptome sequencing(RNA-seq) were employed to screen out the flavonoid-related differential metabolites and differentially expressed genes(DEGs) encoding key metabolic enzymes. Eight DEGs were randomly selected for qRT-PCR verification. The results showed that a total of 37 flavonoid-related differential metabolites between the leaves and roots of S. glabra were obtained, including pinocembrin, phlorizin, na-ringenin, kaempferol, leucocyanidin, and 5-O-caffeoylshikimic acid. The transcriptome analysis predicted 36 DEGs associated with flavonoids in the leaves and roots of S. glabra, including 2 genes in the PAL pathway, 3 genes in the 4CL pathway, 2 genes in the CHS pathway, 4 genes in the CHI pathway, 2 genes in the FLS pathway, 1 gene in the DFR pathway, 1 gene in the CYP73A pathway, 1 gene in the CYP75B1 pathway, 3 genes in the PGT1 pathway, 6 genes in the HCT pathway, 2 genes in the C3'H pathway, 1 gene in the CCOAOMT pathway, 1 gene in the ANR pathway, 1 gene in the LAR pathway, 2 genes in the 3AT pathway, 1 gene in the BZ1 pathway, 2 genes in the IFTM7 pathway, and 1 gene in the CYP81E9 pathway. Six transcription factors, including C2H2, bHLH, and bZIP, were involved in regulating the differential accumulation of flavonoids in the leaves and roots of S. glabra. The qRT-PCR results showed that the up-or down-regulated expression of the 8 randomly selected enzyme genes involved in flavonoid synthesis in the leaves and roots of S. glabra was consistent with the transcriptome sequencing results. This study preliminarily analyzed the transcriptional regulation mechanism of differential accumulation of flavonoids in the leaves and roots of S. glabra, laying a foundation for further elucidating the regulatory effects of key enzyme genes and corresponding transcription factors on the accumulation of flavonoids in S. glabra.

Frontoparietal paired associative stimulation versus single-site stimulation for generalized anxiety disorder: a pilot rTMS study.

BACKGROUND: At present, the use of repetitive transcranial magnetic stimulation (rTMS) for generalized anxiety disorder (GAD) is limited to single-site interventions. We investigated whether dual-site frontoparietal stimulation delivered using cortical-cortical paired associative stimulation (ccPAS) had stronger clinical efficacy than single-site stimulation in patients with GAD. METHODS: We randomized 50 patients with GAD to 1 Hz rTMS (10 sessions) using 1 of the following protocols: single-site stimulation over the right dorsolateral prefrontal cortex (dlPFC; 1500 pulses per session); single-site stimulation over the right posterior parietal cortex (PPC; 1500 pulses per session); repetitive dual-site ccPAS (rds-ccPAS) over the right dlPFC and right PPC with 1500 pulses per session (rd-ccPAS-1500); or rds-ccPAS over the right dlPFC and right PPC with 750 pulses per session (rd-ccPAS-750). Both rds-ccPAS treatments used a between-site interval of 100 ms. RESULTS: Clinical scores for anxiety, depression and insomnia were reduced in all 4 groups after treatment. We found greater improvements in anxiety symptoms in the rds-ccPAS-1500 group compared to the rds-ccPAS-750 and single-site groups. We found greater improvements in depression symptoms and insomnia in the rds-PAS-1500 group compared to the single-site groups. The rds-ccPAS-1500 group also showed significant or trend-level improvements in anxiety symptoms and insomnia at 10-day and 1-month followup. More patients responded to treatment with rds-ccPAS-1500 than with single-site stimulation. The between-group differences in response rates persisted to the 3-month follow-up. Treatment using rds-ccPAS with a between-site interval of 100 ms induced a more significant improvement than the between-site interval of 50 ms we evaluated in a previous study. LIMITATIONS: These results need to be replicated in a larger sample using sham control and equal-pulse single-site stimulation. CONCLUSION: Frontoparietal rds-ccPAS may be a better treatment option for GAD.

Measuring functional connectivity in patients with strabismus using stationary functional magnetic resonance imaging: a resting-state network study.

BACKGROUND: Strabismus (STR) is a common eye disease characterized by abnormal eye movements and stereo vision. Neuroimaging studies have revealed that STR patients have impaired functional connectivity (FC) in the visual cortex and sensorimotor cortex. PURPOSE: To investigate alterations in FC and connections within and between subnetworks of the visual network (VN), sensorimotor network (SMN), and default mode network (DMN) in patients with STR. MATERIAL AND METHODS: A total of 32 patients with STR (24 men, 8 women) and 32 age- and sex-matched healthy controls (HCs) (24 men, 8 women) were recruited. Participants underwent resting-state functional magnetic resonance imaging scans. The resting-state network (RSN) was examined by independent component analysis, and differences in RSN FC between STR and HC groups were evaluated with the t test. Functional network connectivity (FNC) analysis was performed for the three RSNs. RESULTS: Compared to the HC group, the STR group showed increased FC in the VN and SMN (voxel-level P < 0.01; two-tailed Gaussian random field correction; cluster-level P < 0.05). There were no significant alterations in DMN FC between the two groups. FNC analysis of connections in the RSN revealed that one of the three connections in the VN was reduced, but no connectivity changes were observed in the SMN or DMN. FNC analysis of the connection between two RSNs showed that two had increased and one had a decreased connection value. CONCLUSION: The VN, SMN, and DMN are reorganized in patients with STR compared to HCs, providing novel insight into the neural substrates of STR.

Investigation of changes in activity and function in acute unilateral open globe injury-associated brain regions based on percent amplitude of fluctuation method: a resting-state functional MRI study.

BACKGROUND: Open globe injury (OGI) is a serious condition that can lead to visual impairment and lifelong sequelae, brain activity of some brain regions would change in patients with OGI. PURPOSE: To evaluate changes in brain activity associated with unilateral OGI by resting-state functional magnetic resonance imaging (rs-fMRI) and analysis of percentage amplitude of fluctuation (PerAF). MATERIAL AND METHODS: A total of 22 patients with OGI (12 men, 10 women) and 22 healthy controls (HCs) matched for sex, age, and body weight were enrolled. All patients underwent rs-fMRI scans. Brain activity in the relevant brain regions was assessed with the PerAF method. The ability of PerAF to distinguish patients with OGI from HCs was assessed by receiver operating characteristic (ROC) curve analysis. We also examined the relationship between Hospital Anxiety and Depression Scale (HADS) scores and PerAF signals by Pearson's correlation analysis. RESULTS: PerAF values in amygdala_R and Frontal_Inf_Orb_L/Frontal_Inf_Oper_L were increased whereas that in Cerebellum Anterior Lobe/Cerebelum_8_L was decreased in patients with OGI compared to HCs. The areas under the ROC curve showed that these brain regions could distinguish between patients with OGI and HCs. The PerAF value of amygdala_R was positively correlated with HADS scores. CONCLUSION: Changes in PerAF in the amygdala_R, Frontal_inferior_Orb_L/Frontal_Inf_Oper_L, and Cerebellum Anterior Lobe/Cerebelum_8_L in patients with OGI may be related to an increased risk of developing psychiatric disorders such as anxiety and depression. PerAF can be used to investigate the neural basis of complications associated with OGI and monitor disease progression.

Abnormal fractional amplitude of low-frequency fluctuations in MOG-lgG optic neuritis patients: a resting-state functional MRI study.

Optic neuritis (ON) is a general term for inflammation of any part of the optic nerve resulting from demyelination or infection. The number of patients with MOG-lgG antibody-related optic neuritis is increasing recently. Our study uses the fractional amplitude of low-frequency fluctuation (fALFF) method to compare the activity of specific brain regions in MOG-lgG ON patients and healthy controls (HCs). We selected a total of 21 MOG-lgG ON patients and 21 HCs were included in the study. All subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI). The independent-samples t-test was used to compare demographic data and average fALFF values between groups. The specificity and sensitivity of fALFF values for distinguishing between MOG-lgG ON patients and HCs were evaluated by receiver operating characteristic (ROC) curve analysis. Pearson's correlation analysis was used to analyze the relationship between fALFF values and clinical characteristics in MOG-lgG ON patients. Our results showed that fALFF values of the right cerebellum and left middle cingulum were lower whereas those of bilateral inferior temporal lobes, right gyrus rectus, and the left superior and right middle frontal lobes of MOG-lgG ON patients were higher than those of HCs (P < 0.05). The average fALFF value of the left superior frontal lobe in MOG-lgG ON patients was positively correlated with Hospital Anxiety and Depression Scale score (HADS) (r = 0.6004; P < 0.05) and duration of MOG-lgG ON (r = 6487; P < 0.05). Thus, patients with MOG-lgG ON have abnormal activity in the brain regions related to vision. Changes in fALFF value can reflect functional sequelae of MOG-lgG ON, including abnormal anxiety or depressive emotional changes.

Altered functional connectivity of primary visual cortex in adults with strabismus and amblyopia: a resting-state fMRI study.

Functional connectivity of the primary visual cortex was explored with resting functional magnetic resonance imaging among adults with strabismus and amblyopia and healthy controls. We used the two-sample test and receiver operating characteristic curves to investigate the differences in mean functional connectivity values between the groups with strabismus and amblyopia and healthy controls. Compared with healthy controls, functional connectivity values in the left Brodmann areas 17, including bilateral lingual/angular gyri, were reduced in groups with strabismus and amblyopia. Moreover, functional connectivity values in the right Brodmann area 17, including left cuneus, right inferior occipital gyrus, and left inferior parietal lobule, were reduced in adults with strabismus and amblyopia. Our findings indicate that functional connectivity abnormalities exist between the primary visual cortex and other regions. This may be the basis of the pathological mechanism of visual dysfunction and stereovision disorders in adults with strabismus and amblyopia.

[Antidepressant effect and molecular mechanism of notoginsenoside R_1 based on network pharmacology and animal experiments].

To provide experimental basis and theoretical guidance for further research on the molecular mechanism of notoginsenoside R_1(NGR_1) in the treatment of depression, the present study analyzed the potential mechanism of NGR_1 in the treatment of depression through network pharmacology and verified it by molecular docking and animal experiments. PharmMapper, SwissTargetPrediction, and GeneCards were used to predict the related targets of both NGR_1 and depression to obtain the potential targets of NGR_1 in the treatment of depression. The database for annotation, visualization and integrated discovery(DAVID) was used for GO functional annotation and KEGG pathway enrichment analysis to screen the possible mechanisms of NGR_1 exerting antidepressant effect. Cytoscape 3.9.0 was adopted to construct a protein-protein interaction(PPI) network, and the topological analysis was performed to obtain the core targets. The binding activity of NGR_1 to core targets was tested by molecular docking. The depression model was prepared by injecting lipopolysaccharide(LPS) into the lateral ventricle in mice, and intervened with NGR_1. The antidepressant effect of NGR_1 was detected by behavioral tests and RT-qPCR. The results showed that by network pharmacology, 56 common targets of NGR_1 and depression were predicted, and GO enrichment analysis determined 13 related biological processes, mainly involving G protein-coupled receptor signaling pathway, positive regulation of transcription from RNA polymerase Ⅱ promoter, cytokine-mediated signaling pathway, gene expression, apoptosis, cell proliferation, and signal transduction. In addition, KEGG pathway enrichment analysis identified ten potential pathways, including neuroactive ligand-receptor interaction signaling pathway, lipid and atherosclerosis signaling pathway, cAMP signaling pathway, PI3 K-AKT signaling pathway, and lipid and atherosclerosis signaling pathway. PPI analysis revealed that the core targets included CASP3, VEGFA, IGF1, STAT3, MAPK1, PPARG, MTOR, MAPK14, NR3 C1 and AR, and molecular docking demonstrated that NGR_1 had desirable binding activity to these target proteins. In animal experiments, the results showed that NGR_1 improved the disease behavior of depressed mice, significantly inhibited the neuroinflammatory response(reducing the mRNA expression of Iba-1, TNF-α, IL-1ß, and IL-6), and regulated the mRNA expression of lipid and atherosclerosis signaling pathway-related targets(CASP3, STAT3, MAPK1 and MAPK14). This indicated that the antidepressant mechanism of NGR_1 may be related to the regulation of lipid and atherosclerosis signaling pathway. In conclusion, network pharmacology was used to reveal the core targets and pathways of NGR_1, and some of them were verified in animal experiments, which provided the basis for in-depth exploration on the mechanism of NGR_1 in the treatment of depression.