Autophagy induction in tumor surrounding cells promotes tumor growth in adult Drosophila intestines.

During tumorigenesis, tumor cells interact intimately with their surrounding cells (microenvironment) for their growth and progression. However, the roles of tumor microenvironment in tumor development and progression are not fully understood. Here, using an established benign tumor model in adult Drosophila intestines, we find that non-cell autonomous autophagy (NAA) is induced in tumor surrounding neighbor cells. Tumor growth can be significantly suppressed by genetic ablation of autophagy induction in tumor neighboring cells, indicating that tumor neighboring cells act as tumor microenvironment to promote tumor growth. Autophagy in tumor neighboring cells is induced downstream of elevated ROS and activated JNK signaling in tumor cells. Interestingly, we find that active transport of nutrients, such as amino acids, from tumor neighboring cells sustains tumor growth, and increasing nutrient availability could significantly restore tumor growth. Together, these data demonstrate that tumor cells take advantage of their surrounding normal neighbor cells as nutrient sources through NAA to meet their high metabolic demand for growth and progression. Thus we provide insights into our understanding of the mechanisms underlying the interaction between tumor cells and their microenvironment in tumor development.

Experimental demonstration of a local active phase compensation method for a phase encoding quantum key distribution system.

An efficient phase stabilization method is required in quantum key distribution (QKD) systems for stability in practical applications. The existing active phase compensation method has limitations in multi-node network applications, especially in network-scale applications based on measurement-device-independent QKD systems. In this study, we propose a local active phase compensation scheme that can realize phase compensation independently for each interferometer node. We performed experimental demonstrations in the BB84 phase encoding system based on a Faraday-Michelson interferometer. The average QBER rates of the system under two different forms of the reference light were found to be 1.9% and 1.6%. This scheme can also be applied to other QKD systems and has potential for application in future quantum communication networks.

A dual-label time-resolved fluorescence immunoassay for screening of osteoporosis based on simultaneous detection of C-terminal telopeptide (ß-CTX) and aminoterminal propeptide (P1NP) of type I procollagen.

Osteoporosis is a disease where increased bone weakness increases the risk of a broken bone. Until a broken bone occurs, there are typically no symptoms. Osteoporosis affects more than 75 million people in the United States, Europe and Japan. The diagnosis of osteoporosis is primarily determined by measuring bone mineral density using dual-energy X-ray absorptiometry, but for men under 50 years of age, premenopausal women should not be made on the basis of densitometric criteria alone. Bone biomarkers are a useful tool in detecting osteoporotic. A two-step dual-label time-resolved fluorescence immunoassay (TRFIA) was developed for the simultaneous detection of serum C-terminal telopeptide (ß-CTX) and amino-terminal propeptide (P1NP) of Type I procollagen in a single run. The performance of this assay was first evaluated using clinical serum samples, and then compared with commercialized kits. The sensitivity of this assay for ß-CTX was 1 ng/L (dynamic range, 0-1000 ng/L), and the sensitivity for P1NP detection was 1 µg/L (dynamic range, 1-1000 µg/L). High correlation coefficients (R) were obtained between the present dual-label TRFIA and commercially available kits (R = 0.99 for ß-CTX and P1NP). The present dual-label TRFIA has high sensitivity, specificity and accuracy in clinical sample analysis. It is a good alternative to the single-label diagnostic methods.

Taste Evaluation of Yellowtail (Seriola Quinqueradiata) Ordinary and Dark Muscle by Metabolic Profiling.

We performed metabolic profiling on yellowtail (Seriola quinqueradiata) muscle to develop an objective taste evaluation method for fish meat. Dark (DM) and ordinary (OM) muscle samples before and after storage were subjected to gas chromatography-mass spectrometry (GC-MS) analysis and taste measurements using an electronic tongue. The metabolites identified by the GC-MS analysis were treated as x variables, and the taste values obtained by the electronic tongue were treated as y variables. The relationships between the metabolites and taste attributes were evaluated by two-way orthogonal projections to latent structures (O2PLS) analysis. The O2PLS analyses were normalized in two ways, unit variance (UV) and pareto (Par) scaling. The O2PLS (UV) analysis produced 3+1+0 models in Autofit and this model was statistically significant with R2Y (0.73) and Q2 (0.52) metrics. In particular, significant correlations were found between DM or OM and metabolite intensity and taste attributes, and strong associations were found between "sourness" and lysine, "irritant" and alanine and phenylalanine, "saltiness" and pantothenic acid, and "umami" and creatinine and histidine. The O2PLS (Par) analysis of DM generated significant predictive models for "acidic bitterness," "irritant," "saltiness," "bitterness," "astringency," and "richness." Among these, only "irritant" was affected by storage. This method was thus effective in evaluating the taste of yellowtail muscle.

Aquaporin-3 Attenuates Oxidative Stress-Induced Nucleus Pulposus Cell Apoptosis Through Regulating the P38 MAPK Pathway.

BACKGROUND/AIMS: Previous studies have shown that oxidative damage is a main contributor to disc nucleus pulposus (NP) cell apoptosis. Aquaporin-3 (AQP-3) facilitates reactive oxygen species (ROS) scavenging and thus alleviates oxidative injury in other cells. This study aims to investigate the role and mechanism of AQP-3 in regulating NP cell apoptosis under oxidative damage. METHODS: Rat NP cells were treated with H2O2 for 48 hours, while control NP cells were free of H2O2. Recombinant AQP-3 lentiviral vectors were used to investigate the effect of enhanced AQP-3 expression levels in NP cells. NP cell apoptosis was assessed by flow cytometry, caspase-3 activity, gene expression of apoptosis-related molecules (Bax, Bcl-2 and caspase-3), and protein expression of cellular apoptosis markers (cleaved PARP and cleaved caspase-3). Additionally, intracellular ROS content and activity of the p38 MAPK pathway were evaluated. RESULTS: Compared with the control NP cells, oxidative damage in the treatment cells significantly increased cell apoptosis ratios and caspase-3 activity, upregulated gene expression of Bax and caspase-3, downregulated gene expression of Bcl-2, and increased protein expression of cleaved PARP and cleaved caspase-3, as well as increased intracellular ROS content and activity of the p38 MAPK pathway. However, AQP-3 overexpression partly alleviated cell apoptosis, decreased intracellular ROS content, and inhibited the p38 MAPK pathway in NP cells under oxidative damage. CONCLUSION: Oxidative damage can significantly downregulate AQP-3 expression. Enhancing AQP-3 expression in NP cells partly attenuates cellular apoptosis through regulating the p38 MAPK pathway under oxidative damage.

Dynamic Compression Promotes the Matrix Synthesis of Nucleus Pulposus Cells Through Up-Regulating N-CDH Expression in a Perfusion Bioreactor Culture.

BACKGROUND/AIMS: An adequate matrix production of nucleus pulposus (NP) cells is an important tissue engineering-based strategy to regenerate degenerative discs. Here, we mainly aimed to investigate the effects and mechanism of mechanical compression (i.e., static compression vs. dynamic compression) on the matrix synthesis of three-dimensional (3D) cultured NP cells in vitro. METHODS: Rat NP cells seeded on small intestinal submucosa (SIS) cryogel scaffolds were cultured in the chambers of a self-developed, mechanically active bioreactor for 10 days. Meanwhile, the NP cells were subjected to compression (static compression or dynamic compression at a 10% scaffold deformation) for 6 hours once per day. Unloaded NP cells were used as controls. The cellular phenotype and matrix biosynthesis of NP cells were investigated by real-time PCR and Western blotting assays. Lentivirus-mediated N-cadherin (N-CDH) knockdown and an inhibitor, LY294002, were used to further investigate the role of N-CDH and the PI3K/Akt pathway in this process. RESULTS: Dynamic compression better maintained the expression of cell-specific markers (keratin-19, FOXF1 and PAX1) and matrix macromolecules (aggrecan and collagen II), as well as N-CDH expression and the activity of the PI3K/Akt pathway, in the 3D-cultured NP cells compared with those expression levels and activity in the cells grown under static compression. Further analysis showed that the N-CDH knockdown significantly down-regulated the expression of NP cell-specific markers and matrix macromolecules and inhibited the activation of the PI3K/Akt pathway under dynamic compression. However, inhibition of the PI3K/Akt pathway had no effects on N-CDH expression but down-regulated the expression of NP cell-specific markers and matrix macromolecules under dynamic compression. CONCLUSION: Dynamic compression increases the matrix synthesis of 3D-cultured NP cells compared with that of the cells under static compression, and the N-CDH-PI3K/Akt pathway is involved in this regulatory process. This study provides a promising strategy to promote the matrix deposition of tissue-engineered NP tissue in vitro prior to clinical transplantation.

N-Cadherin Attenuates High Glucose-Induced Nucleus Pulposus Cell Senescence Through Regulation of the ROS/NF-κB Pathway.

BACKGROUND/AIMS: Diabetes mellitus (DM) is a potential etiology of disc degeneration. N-cadherin (N-CDH) helps maintain the cell viability, cell phenotype and matrix biosynthesis of nucleus pulposus (NP) cells. Here, we mainly aimed to investigate whether N-CDH can attenuate high glucose-induced NP cell senescence and its potential mechanism. METHODS: Rat NP cells were cultured in a base culture medium and base culture medium with a 0.2 M glucose concentration. Recombinant lentiviral vectors were used to enhance N-CDH expression in NP cells. Senescence-associated ß-galactosidase (SA-ß-Gal) activity was measured by SA-ß-Gal staining. NP cell proliferation was evaluated by CCK-8 assay. Telomerase activity and intracellular reactive oxygen species (ROS) content were tested by specific chemical kits according to the manufacturer's instructions. G0/G1 cell cycle arrest was evaluated by flow cytometry. Real-time PCR and Western blotting were used to analyze mRNA and protein expressions of senescence markers (p16 and p53) and matrix macromolecules (aggrecan and collagen II). Additionally, p-NF-κB expression was also analyzed by Western blotting to evaluate NF-κB pathway activity. RESULTS: High glucose significantly decreased N-CDH expression, increased ROS generation and NF-κB pathway activity, and promoted NP cell senescence, which was reflected in the increase in SA-ß-Gal activity and senescence marker (p16 and p53) expression, compared to the control group. High glucose decreased telomerase activity and cell proliferation potency. However, N-CDH overexpression partially attenuated NP cell senescence, decreased ROS content and inhibited the activation of the NF-κB pathway under the high glucose condition. CONCLUSION: High glucose decreases N-CDH expression and promotes NP cell senescence. N-CDH overexpression can attenuate high glucose-induced NP cell senescence through the regulation of the ROS/ NF-κB pathway. This study suggests that N-CDH is a potential therapeutic target to slow DM-mediated disc NP degeneration.

Auricular Vagus Nerve Stimulation Exerts Antiinflammatory Effects and Immune Regulatory Function in a 6-OHDA Model of Parkinson's Disease.

According to epidemiologic studies, smoking appears to downregulate the prevalence of Parkinson's disease (PD), possibly due to antiinflammatory mechanisms via activation of α7 nicotinic acetylcholine receptors (α7 nAChRs). This receptor also appears to play a role in T-cell differentiation. Recently, it has become apparent that the innate immune system participates in PD pathogenesis. The aim of this study was to evaluate the effects of auricular vagus nerve stimulation (aVNS) on substantia nigra (SN) dopaminergic neurodegeneration and the associated neuroinflammation and immune responses in a rat PD model. Adult male Wistar rats were unilaterally administered 6-hydroxydopamine (6-OHDA) to the medial forebrain bundle, followed by aVNS treatment after surgery. Following motor behavioral tests, the expression of tyrosine hydroxylase (TH) in the SN and the levels of inflammatory cytokines in the ventral midbrain were evaluated. In addition, changes in the trends of subsets of CD4+ T lymphocytes in the SN were measured by immunofluorescence staining. Western blotting was used to evaluate the α7 nAChR protein level. Compared with 6-OHDA treats rats, aVNS treatment significantly improved motor deficits, increased TH and α7 nAChR expression, and reduced the levels of inflammatory cytokines (tumor necrosis factor-a (TNF-α) and interleukin-1ß (IL-1ß)) (p < 0.05). Additionally, aVNS increased the numbers of regulatory T (Treg) cells while decreasing T helper (Th)17 cells. aVNS exerted neuroprotective effects against dopaminergic damage, possibly by suppressing the evolution of inflammation and modulating innate immune responses. Thus, aVNS may be a potential promising therapy in the future.

A comparative study of the amount of α-synuclein in ischemic stroke and Parkinson's disease.

In the present study, we detected the level of oligomeric form of α-synuclein in the red blood cells of ischemic stroke, Parkinson's disease, and normal people and compared the differences to assess the diagnosis potential of α-synuclein in ischemic stroke patients. 86 ischemic stroke, 100 PD, and 102 healthy cases were enrolled in the present study. Total protein amount in the red blood cells were quantified by BCA assay using spectrophotometer. Levels of oligomeric form of α-synuclein were characterized by a sandwich ELISA. Analysis of correlation analysis and receiver operating characteristic curve were conducted. Significant differences were detected in the levels of oligomeric forms of α-synuclein in different samples' blood cells (P < 0.05); the levels of total protein in (188.1 ± 33.9 mmol/L) healthy people were significantly higher than that of PD (147.7 ± 45.0 mmol/L) and ischemic stroke groups (142.9 ± 43.0 mmol/L) (P < 0.05). There was no correlation between the age of patients and level of α-synuclein (R (2) = 0.216 in ischemic stroke group and -0.104 in PD group) and the receiver operating characteristic curve analysis showed a high sensitivity of α-synuclein in discriminating ischemic stroke (sensitivity was 63.7 % and specificity was 9.6 %) and PD (sensitivity was 44.1 % and specificity was 12.5 %) patients from the controls. The levels of oligomeric form of α-synuclein of red blood cells in ischemic stroke and Parkinson's disease patients were both significant higher than normal people. And the level of oligomeric form α-synuclein showed a potential for diagnosis of ischemic stroke in clinic.

Glatiramer acetate inhibits degradation of collagen II by suppressing the activity of interferon regulatory factor-1.

Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) is considered to be the major one contributing to the process of development of osteoarthritis (OA).Interferon regulatory factor 1 (IRF-1) is an important transcriptional factor accounting for inflammation response induced by TNF-α. The physiological function of IRF-1 in OA is still unknown. In this study, we reported that the expression levels of IRF-1 in OA chondrocytes were significantly higher compared to those in normal chondrocytes, which was reversed by treatment with Glatiramer acetate (GA), a licensed clinical drug for treating patients suffering from multiple sclerosis (MS). We also found that GA is able to attenuate the upregulation of IRF-1 induced by TNF-α. Matrix metalloproteinase13 (MMP-13) is one of the downstream target genes of IRF-1, which can induce the degradation of collagen II. Importantly, our results indicated that GA suppressed the expression of MMP-13 as well as the degradation of collagen II. In addition, GA also suppressed TNF-α-induced production of NO and expression of iNOS. Finally, we found that the inhibition of STAT1 activation played a critical role in the inhibitory effects of GA on the induction of IRF-1 and MMP-13. These data suggest that GA might have a potential effect in therapeutic OA.

Distinctive Pattern of Metal Deposition in Neurologic Wilson Disease: Insights From 7T Susceptibility-Weighted Imaging.

BACKGROUND AND OBJECTIVES: Noninvasive and accurate biomarkers of neurologic Wilson disease (NWD), a rare inherited disorder, could reduce diagnostic error or delay. Excessive subcortical metal deposition seen on susceptibility imaging has suggested a characteristic pattern in NWD. With submillimeter spatial resolution and increased contrast, 7T susceptibility-weighted imaging (SWI) may enable better visualization of metal deposition in NWD. In this study, we sought to identify a distinctive metal deposition pattern in NWD using 7T SWI and investigate its diagnostic value and underlying pathophysiologic mechanism. METHODS: Patients with WD, healthy participants with monoallelic ATP7B variant(s) on a single chromosome, and health controls (HCs) were recruited. NWD and non-NWD (nNWD) were defined according to the presence or absence of neurologic symptoms during investigation. Patients with other diseases with comparable clinical or imaging manifestations, including early-onset Parkinson disease (EOPD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and neurodegeneration with brain iron accumulation (NBIA), were additionally recruited and assessed for exploratory comparative analysis. All participants underwent 7T T1, T2, and high-resolution SWI scanning. Quantitative susceptibility mapping and principal component analysis were performed to illustrate metal distribution. RESULTS: We identified a linear signal intensity change consisting of a hyperintense strip at the lateral border of the globus pallidus in patients with NWD. We termed this feature "hyperintense globus pallidus rim sign." This feature was detected in 38 of 41 patients with NWD and was negative in all 31 nNWD patients, 15 patients with EOPD, 30 patients with MSA, 15 patients with PSP, and 12 patients with NBIA; 22 monoallelic ATP7B variant carriers; and 41 HC. Its sensitivity to differentiate between NWD and HC was 92.7%, and specificity was 100%. Severity of the hyperintense globus pallidus rim sign measured by a semiquantitative scale was positively correlated with neurologic severity (ρ = 0.682, 95% CI 0.467-0.821, p < 0.001). Patients with NWD showed increased susceptibility in the lenticular nucleus with high regional weights in the lateral globus pallidus and medial putamen. DISCUSSION: The hyperintense globus pallidus rim sign showed high sensitivity and excellent specificity for diagnosis and differential diagnosis of NWD. It is related to a special metal deposition pattern in the lenticular nucleus in NWD and can be considered as a novel neuroimaging biomarker of NWD. CLASSIFICATION OF EVIDENCE: The study provides Class II evidence that the hyperintense globus pallidus rim sign on 7T SWI MRI can accurately diagnose neurologic WD.

Tau-PET imaging in Parkinson's disease: a systematic review and meta-analysis.

Background: Pathological tau accumulates in the cerebral cortex of Parkinson's disease (PD), resulting in cognitive deterioration. Positron emission tomography (PET) can be used for in vivo imaging of tau protein. Therefore, we conducted a systematic review and meta-analysis of tau protein burden in PD cognitive impairment (PDCI), PD dementia (PDD), and other neurodegenerative diseases and explored the potential of the tau PET tracer as a biomarker for the diagnosis of PDCI. Methods: PubMed, Embase, the Cochrane Library, and Web of Science databases were systematically searched for studies published till 1 June 2022 that used PET imaging to detect tau burden in the brains of PD patients. Standardized mean differences (SMDs) of tau tracer uptake were calculated using random effects models. Subgroup analysis based on the type of tau tracers, meta-regression, and sensitivity analysis was conducted. Results: A total of 15 eligible studies were included in the meta-analysis. PDCI patients (n = 109) had a significantly higher tau tracer uptake in the inferior temporal lobe than healthy controls (HCs) (n = 237) and had a higher tau tracer uptake in the entorhinal region than PD with normal cognition (PDNC) patients (n = 61). Compared with progressive supranuclear palsy (PSP) patients (n = 215), PD patients (n = 178) had decreased tau tracer uptake in the midbrain, subthalamic nucleus, globus pallidus, cerebellar deep white matter, thalamus, striatum, substantia nigra, dentate nucleus, red nucleus, putamen, and frontal lobe. Tau tracer uptake values of PD patients (n = 178) were lower than those of patients with Alzheimer's disease (AD) (n = 122) in the frontal lobe and occipital lobe and lower than those in patients with dementia with Lewy bodies (DLB) (n = 55) in the occipital lobe and infratemporal lobe. Conclusion: In vivo imaging studies with PET could reveal region-specific binding patterns of the tau tracer in PD patients and help in the differential diagnosis of PD from other neurodegenerative diseases. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/.

Optimization of ear electrodes for SSVEP-based BCI.

Objective.Current ear electrodes often require complex placing or long stimulation durations to achieve good detection of steady-state visual evoked potential (SSVEP). To improve the practicability of ear electrode-based SSVEP-BCI (brain-computer interface) system, we developed a high-performance ear electrode that can be easily placed.Approach.Hydrogel based disposable and replaceable semi-dry electrodes are developed to improve the contact impedance and wear feeling. The best combination of electrodes for SSVEP-BCI application around the ear is optimized by assessing the electrode on volunteers, and the performance of the electrode was compared with that of the occipital electrode.Main results.The developed ear hydrogel electrode can achieve an impedance close to that of the wet electrode. Three combinations of ear electrode groups demonstrate high information transfer rate (ITR) and accuracy in SSVEP-BCI applications. According to the rating of the comprehensive assessment and BCI performance in the online session, the behind-aural electrode is the best electrode combination for recording SSVEP in the ear region. The average preparation time is the shortest, and the average impedance is the lowest. The ITR of the behind-aural electrode based SSVEP-BCI system can reach 37.5 ± 18 bits min-1. The stimulus duration was as low as 3 s compared to 5 s or 10 s in other studies.Significance.The accuracy, ITR, and wear feeling can be improved by introducing a semi-dry ear electrode and optimizing the position and the combination of ear electrode. By providing a better trade-off between performance and convenience, the ear electrode-based SSVEP-BCI promises to be used in daily life.

Ameliorating Osteoarthritis in Mice Using Silver Nanoparticles.

Knee osteoarthritis (KOA) is one of the most commonly encountered degenerative diseases of the joints in people over 45 years of age. Currently, there are not any effective therapeutics for KOA,and the only end-point strategy is total knee arthroplasty (TKA); therefore, KOA is associated with economic burdens and societal costs. The immune inflammatory response is involved in the occurrence and development of KOA. We previously established a mouse model of KOA using type II collagen. Hyperplasia of the synovial tissue was present in the model, alongside a large number of infiltrated inflammatory cells. Silver nanoparticles have substantial anti-inflammatory effects and have been widely used in tumor therapy and surgical drug delivery. Therefore, we evaluated the therapeutic effects of silver nanoparticles in a collagenase II-induced KOA model. The experimental results showed that silver nanoparticles significantly reduced synovial hyperplasia and the infiltration of neutrophils in the synovial tissue. Hence, this work demonstrates the identification of a novel strategy for OA and provides a theoretical basis for preventing the progress of KOA.

Anesthetic drug concentrations and placental transfer rate in fetus between term and preterm infants, twins, and singletons.

Objective: This study aims to determine the drug concentration of etomidate, remifentanil, and rocuronium bromide for general anesthesia in fetus as well as the placental transport rate between term and preterm delivery, twins, and singleton. Study design: Sixty parturients with 72 fetuses undergoing cesarean section under general anesthesia were included. According to whether the fetus was a twin or premature, parturients were divided into Group I (term singleton), Group II (premature singleton), Group III (term twins), and Group IV (premature twins). The preoperative demographic characteristics and laboratory examination of parturients, hemodynamic indicators, the Apgar score of neonates at 1, 5, and 10 min after delivery and at specific assigned values, umbilical artery blood gas analysis results, neonatal weight, and resuscitative measures were recorded. Anesthetic drug concentrations in maternal arterial (MA), umbilical arterial (UA), and umbilical venous (UV) blood were detected by Ultra Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS). Result: No significant differences were observed in the concentrations of etomidate, remifentanil, and rocuronium bromide in MA, UV, and UA blood, or in the UV/MA and UA/UV ratios between term and preterm infants, twins, and singletons. Moreover, there was no variation in the anesthetic drug concentration among each pair of twins. Additionally, no correlation was found between the neonatal weight and the plasma concentrations of anesthetic drugs in UV and UA blood, except for remifentanil in UA blood. Conclusion: Preterm or twin deliveries do not affect the neonatal concentration of etomidate, remifentanil, and rocuronium bromide used in general anesthesia for cesarean sections. Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR2100046547.

Microstructural and functional impairment of the basal ganglia in Wilson's disease: a multimodal neuroimaging study.

Objectives: Magnetic susceptibility changes in brain MRI of Wilson's disease (WD) patients have been described in subcortical nuclei especially the basal ganglia. The objectives of this study were to investigate its relationship with other microstructural and functional alterations of the subcortical nuclei and the diagnostic utility of these MRI-related metrics. Methods: A total of 22 WD patients and 20 healthy controls (HCs) underwent 3.0T multimodal MRI scanning. Susceptibility, volume, diffusion microstructural indices and whole-brain functional connectivity of the putamen (PU), globus pallidus (GP), caudate nucleus (CN), and thalamus (TH) were analyzed. Receiver operating curve (ROC) was applied to evaluate the diagnostic value of the imaging data. Correlation analysis was performed to explore the connection between susceptibility change and microstructure and functional impairment of WD and screen for neuroimaging biomarkers of disease severity. Results: Wilson's disease patients demonstrated increased susceptibility in the PU, GP, and TH, and widespread atrophy and microstructural impairments in the PU, GP, CN, and TH. Functional connectivity decreased within the basal ganglia and increased between the PU and cortex. The ROC model showed higher diagnostic value of isotropic volume fraction (ISOVF, in the neurite orientation dispersion and density imaging model) compared with susceptibility. Severity of neurological symptoms was correlated with volume and ISOVF. Susceptibility was positively correlated with ISOVF in GP. Conclusion: Microstructural impairment of the basal ganglia is related to excessive metal accumulation in WD. Brain atrophy and microstructural impairments are useful neuroimaging biomarkers for the neurological impairment of WD.

Research Progress on the Flexibility of an Implantable Neural Microelectrode.

Neural microelectrode is the important bridge of information exchange between the human body and machines. By recording and transmitting nerve signals with electrodes, people can control the external machines. At the same time, using electrodes to electrically stimulate nerve tissue, people with long-term brain diseases will be safely and reliably treated. Young's modulus of the traditional rigid electrode probe is not matched well with that of biological tissue, and tissue immune rejection is easy to generate, resulting in the electrode not being able to achieve long-term safety and reliable working. In recent years, the choice of flexible materials and design of electrode structures can achieve modulus matching between electrode and biological tissue, and tissue damage is decreased. This review discusses nerve microelectrodes based on flexible electrode materials and substrate materials. Simultaneously, different structural designs of neural microelectrodes are reviewed. However, flexible electrode probes are difficult to implant into the brain. Only with the aid of certain auxiliary devices, can the implant be safe and reliable. The implantation method of the nerve microelectrode is also reviewed.

Derlin-1 and TER94/VCP/p97 are required for intestinal homeostasis.

Adult stem cells are critical for the maintenance of residential tissue homeostasis and functions. However, the roles of cellular protein homeostasis maintenance in stem cell proliferation and tissue homeostasis are not fully understood. Here, we find that Derlin-1 and TER94/VCP/p97, components of the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway, restrain intestinal stem cell proliferation to maintain intestinal homeostasis in adult Drosophila. Depleting any of them results in increased stem cell proliferation and midgut homeostasis disruption. Derlin-1 is specifically localized in the ER of progenitors, and its C-terminus is required for its function. Interestingly, we find that increased stem cell proliferation is resulted from elevated ROS levels and activated JNK signaling in Derlin-1- or TER94-deficient progenitors. Further removal of reactive oxygen species (ROS) or inhibition of JNK signaling almost completely suppresses increased stem cell proliferation. Together, these data demonstrate that the ERAD pathway is critical for stem cell proliferation and tissue homeostasis. Thus, we provide insights into our understanding of the mechanisms underlying cellular protein homeostasis maintenance (ER protein quality control) in tissue homeostasis and tumor development.

Auxilin regulates intestinal stem cell proliferation through EGFR.

Adult tissue homeostasis is maintained by residential stem cells. The proliferation and differentiation of adult stem cells must be tightly balanced to avoid excessive proliferation or premature differentiation. However, how stem cell proliferation is properly controlled remains elusive. Here, we find that auxilin (Aux) restricts intestinal stem cell (ISC) proliferation mainly through EGFR signaling. aux depletion leads to excessive ISC proliferation and midgut homeostasis disruption, which is unlikely caused by defective Notch signaling. Aux is expressed in multiple types of intestinal cells. Interestingly, aux depletion causes a dramatic increase in EGFR signaling, with a strong accumulation of EGFR at the plasma membrane and an increased expression of EGFR ligands in response to tissue stress. Furthermore, Aux co-localizes and associates with EGFR. Finally, blocking EGFR signaling completely suppresses the defects caused by aux depletion. Together, these data demonstrate that Aux mainly safeguards EGFR activation to keep a proper ISC proliferation rate to maintain midgut homeostasis.

Exosome transportation-mediated immunosuppression relief through cascade amplification for enhanced apoptotic body vaccination.

Cancer vaccines represent the most promising strategies in the battle against cancers. Eliciting a robust therapeutic effect with vaccines, however, remains a challenge owing to the weak immunogenicity of autologous tumor antigens and highly immunosuppressive microenvironment. In the present study, we constructed CpG oligodeoxyribonucleotide (CpG ODN)-loaded cancer cell apoptotic bodies (Abs) as cancer vaccines for enhanced immunotherapy through cascade amplification-mediated immunosuppression relief. Abs that contain an abundant source of tumor-specific neoantigens and other tumor-associated antigens (TAAs) can be regarded as vaccines with higher immunogenicity. The de novo synthesized Abs-CpG could target and polarize macrophages to improve the immunosuppressive microenvironment. More importantly, we found that the effect of immunosuppression relief was cascade amplified, which was mediated by M1 macrophage-derived exosome transportation. Our results showed that CpG ODN polarized macrophages to M1 type and produced a large amount of TNF-α, which then activated cell division control protein 42 (Cdc42). Interestingly, we found that exosomes from M1 macrophages delivered Cdc42 and CpG to adjacent macrophages and further enhanced the phagocytosis of adjacent macrophages by positive feedback. Through cascade amplification induced by Abs-CpG with macrophage exosomes, the immunogenicity and immunosuppressive microenvironment were greatly improved, which then enhanced the performance of cancer vaccine therapy. Thus, we propose that a strategy of combining the Abs-based vaccine platform with the immunomodulatory approach represents the next generation of cancer immunotherapy. STATEMENT OF SIGNIFICANCE: 1. We discovered a relieving strategy for tumor immunosuppressive microenvironment: Abs-CpG polarized macrophages to M1 type, and M1 macrophage-derived exosomes delivered Cdc42 and CpG to adjacent macrophages, which then further enhanced the phagocytosis of adjacent macrophages by positive feedback. Through cascade amplification induced by the transfer of macrophage exosomes, the immunogenicity and immunosuppressive microenvironment were greatly improved. 2. As a vaccine, Abs contained both tumor-specific neoantigens and other tumor-associated antigens with higher immunogenicity and high clinical transformability.