Haploinsufficiency of the Parkinson's disease gene synaptojanin1 is associated with abnormal responses to psychomotor stimulants and mesolimbic dopamine signaling.

The synaptojanin-1 (SYNJ1) gene is known to be important for dopamine-related disorders. Recent evidence has demonstrated that Synj1 deficient mice (Synj1 +/-) have impairments in dopaminergic synaptic vesicular recycling. However, less is known about how Synj1 deficits affect the mesolimbic system, reward processing, and motivated behavior. To examine the role of the Synj1 gene in motivated behavior, we subjected male and female Synj1 +/- and Synj1 +/+ mice to a battery of behavioral tests evaluating hedonic responses, effortful responding, and responses to psychomotor stimulants. We observed that Synj1 +/- mice exhibit few differences in reward processing and motivated behavior, with normal hedonic responses and motivated responding for sucrose. However, male but not female Synj1 +/- demonstrated an attenuated conditioned place preference for cocaine that could not be attributed to deficits in spatial memory. To further understand the dopamine signaling underlying the attenuated response to cocaine in these mutant mice, we recorded nucleus accumbens dopamine in response to cocaine and observed that Synj1 +/- male and female mice took longer to reach peak dopamine release following experimenter-administered cocaine. However, female mice also showed slower decay in accumbens dopamine that appear to be linked to differences in cocaine-induced DAT responses. These findings demonstrate that SYNJ1 deficiencies result in abnormal mesolimbic DA signaling which has not previously been demonstrated. Our work also highlights the need to develop targeted therapeutics capable of restoring deficits in DAT function, which may be effective for reversing the pathologies associated with Synj1 mutations.

Parkinson's disease gene, Synaptojanin1, dysregulates the surface maintenance of the dopamine transporter.

Missense mutations of PARK20/SYNJ1 (synaptojanin1/Synj1) have been linked to complex forms of familial parkinsonism, however, the molecular and cellular changes associated with dopaminergic dysfunction remains unknown. We now report fast depletion of evoked dopamine (DA) and altered maintenance of the axonal dopamine transporter (DAT) in the Synj1+/- neurons. While Synj1 has been traditionally known to facilitate the endocytosis of synaptic vesicles, we demonstrated that axons of cultured Synj1+/- neurons exhibit an increase of total DAT but a reduction of the surface DAT, which could be exacerbated by neuronal activity. We revealed that the loss of surface DAT is specifically associated with the impaired 5'-phosphatase activity of Synj1 and the hyperactive downstream PI(4,5)P2-PKCß pathway. Thus, our findings provided important mechanistic insight for Synj1-regulated DAT trafficking integral to dysfunctional DA signaling in early parkinsonism.

Maternal factor Trim75 contributes to zygotic genome activation program in mouse early embryos.

BACKGROUND: Zygotic genome activation (ZGA) is an important event in the early embryo development, and human embryo developmental arrest has been highly correlated with ZGA failure in clinical studies. Although a few studies have linked maternal factors to mammalian ZGA, more studies are needed to fully elucidate the maternal factors that are involved in ZGA. METHODS AND RESULTS: In this study, we utilized published single-cell RNA sequencing data from a Dux-mediated mouse embryonic stem cell to induce a 2-cell-like transition state and selected potential drivers for the transition according to an RNA velocity analysis. CONCLUSIONS: An overlap of potential candidate markers of 2-cell-like-cells identified in this research with markers generated by various data sets suggests that Trim75 is a potential driver of minor ZGA and may recruit EP300 and establish H3K27ac in the gene body of minor ZGA genes, thereby contributing to mammalian preimplantation embryo development.

Neuroprotective Effects of Leptin on the APP/PS1 Alzheimer's Disease Mouse Model: Role of Microglial and Neuroinflammation.

Background: Microglia are closely linked to Alzheimer's disease (AD) many years ago; however, the pathological mechanisms of AD remain unclear. The purpose of this study was to determine whether leptin affected microglia in the hippocampus of young and aged male APP/PS1 mice. Objective: In a transgenic model of AD, we investigated the association between intraperitoneal injection of leptin and microglia. Methods: We intraperitoneal injection of leptin (1mg/kg) every day for one week and analyzed inflammatory markers in microglia in the hippocampus of adult (6 months) and aged (12 months) APP/PS1 mice. Results: In all leptin treatment group, the brain Aß levels were decrease. We found increased levels of IL-1ß, IL-6 and microglial activation in the hippocampus of adult mice. Using aged mice as an experimental model for chronic neuroinflammation and leptin resistance, the number of Iba-1+ microglia and the levels of IL-1ß/IL-6 in the hippocampus were greatly increased as compared to the adult. But between the leptin treatment and un-treatment, there were no difference. Conclusion: Leptin signaling would regulate the activation of microglia and the release of inflammatory factors, but it is not the only underlying mechanism in the neuroprotective effects of AD pathogenesis.

Nacre-inspired, strong, tough silk fibroin hydrogels based on biomineralization and the layer-by-layer assembly of ordered silk fabric.

Hydrogels are attractive materials with structures and functional properties similar to biological tissues and widely used in biomedical engineering. However, traditional synthetic hydrogels possess poor mechanical strength, and their applications are limited. Herein, a multidimensional material design method is developed; it includes the in situ gelation of silk fabric and nacre-inspired layer-by-layer assembly, which is used to prepare silk fibroin (SF) hydrogels. The in situ gelation method of silk fabric introduces a directionally ordered fabric network in a silk substrate, considerably enhancing the strength of hydrogels. Based on the nacre structure, the layer-by-layer assembly method enables silk hydrogels to break through the size limit and increase the thickness, realizing the longitudinal extension of the hydrogels. The application of the combined biomineralization and hot pressing method can effectively reduce interface defects and improve the interaction between organic and inorganic interfaces. The multidimensional material design method helps increase the strength (287.78 MPa), toughness (18.43 MJ m-3), and fracture energy (50.58 kJ m-2) of SF hydrogels; these hydrogels can weigh 2000 times their own weight. Therefore, SF hydrogels designed using the aforementioned combined method can realize the combination of strength and toughness and be used in biological tissue engineering and structural materials.

TRPM2 as a conserved gatekeeper determines the vulnerability of DA neurons by mediating ROS sensing and calcium dyshomeostasis.

Different dopaminergic (DA) neuronal subgroups exhibit distinct vulnerability to stress, while the underlying mechanisms are elusive. Here we report that the transient receptor potential melastatin 2 (TRPM2) channel is preferentially expressed in vulnerable DA neuronal subgroups, which correlates positively with aging in Parkinson's Disease (PD) patients. Overexpression of human TRPM2 in the DA neurons of C. elegans resulted in selective death of ADE but not CEP neurons in aged worms. Mechanistically, TRPM2 activation mediates FZO-1/CED-9-dependent mitochondrial hyperfusion and mitochondrial permeability transition (MPT), leading to ADE death. In mice, TRPM2 knockout reduced vulnerable substantia nigra pars compacta (SNc) DA neuronal death induced by stress. Moreover, the TRPM2-mediated vulnerable DA neuronal death pathway is conserved from C. elegans to toxin-treated mice model and PD patient iPSC-derived DA neurons. The vulnerable SNc DA neuronal loss is the major symptom and cause of PD, and therefore the TRPM2-mediated pathway serves as a promising therapeutic target against PD.

The benefit of rhGH therapy in a Chinese child with 12q14 microdeletion syndrome: a case report.

OBJECTIVES: The 12q14 microdeletion syndrome is a rare genetic condition characterized by intrauterine growth restriction, proportionate short stature, failure to thrive, and intellectual disability. Few reports have discussed the therapeutic aspect of patients with 12q14 microdeletion syndrome. Herein, we report the first case of 12q14 microdeletion patient treated with rhGH without growth hormone deficiency. CASE PRESENTATION: The patient presented with feeding difficulties during infancy, failure to thrive, intellectual disability and subtle dysmorphic facial features. The patient first visited the clinic at 5 years and 3 months, his height was 91.4 cm (-4.9 SD) and weight 10.0 kg (-2.86 SD). The growth hormone level was within the normal range. Bone radiological testing revealed no significant abnormalities. Genetic analysis identified a 6.97 Mb deletion at the chromosome 12q14.1-q14.3 region in the proband. Recombinant human growth hormone therapy was initiated, which lasted for 12 months, and the new height was 101.0 cm (-4.0 SD) and weight 12.0 kg (-3.6 SD). CONCLUSIONS: This report first showed that patient with 12q14 microdeletion, although without growth hormone deficiency, can benefit from human growth hormone therapy.

Cartilage structure-inspired elastic silk nanofiber network hydrogel for stretchable and high-performance supercapacitors.

Flexible supercapacitors are an important portable energy storage but suffer from low capacitance, inability to stretch, etc. Therefore, flexible supercapacitors must achieve higher capacitance, energy density, and mechanical robustness to expand the applications. Herein, a hydrogel electrode with excellent mechanical strength was created by simulating the collagen fiber network and proteoglycan in cartilage using silk nanofiber (SNF) network and polyvinyl alcohol (PVA). The Young's modulus and breaking strength of the hydrogel electrode increased by 205 % and 91 % compared with PVA hydrogel owing to the enhanced effect of the bionic structure, respectively, which are 1.22 MPa and 1.3 MPa. The fracture energy and fatigue threshold reached 1813.5 J/m2 and 1585.2 J/m2, respectively. The SNF network effectively connected carbon nanotubes (CNTs) and polypyrrole (PPy) in series, affording a capacitance of 13.62 F/cm2 and energy density of 1.2098 mWh/cm2. This capacitance is the highest among currently reported PVA hydrogel capacitors, which can maintain >95.2 % after 3000 charge-discharge cycles. This capacitance Notably, the cartilage-like structure endowed the supercapacitor with high resilience; thus, the capacitance remained >92.1 % under 150 % deformation and >93.35 % after repeated stretching (3000 times), which was far superior to that of other PVA-based supercapacitors. Overall, this effective bionic strategy can endow supercapacitors with ultrahigh capacitance and effectively ensure the mechanical reliability of flexible supercapacitors, which will help expand the applications of supercapacitors.

Synaptojanin1 Modifies Endolysosomal Parameters in Cultured Ventral Midbrain Neurons.

The accumulation of α-synuclein (α-syn)-enriched protein aggregates is thought to arise from dysfunction in degradation systems within the brain. Recently, missense mutations of SYNJ1 encoding the SAC1 and 5'-phosphatase domains have been found in families with hereditary early-onset Parkinsonism. Previous studies showed that Synj1 haploinsufficiency (Synj1+/-) leads to accumulation of the autophagy substrate p62 and pathologic α-syn proteins in the midbrain (MB) and striatum of aged mice. In this study, we aim to investigate the neuronal degradation pathway using the Synj1+/- MB culture from mouse pups of mixed sex as a model. Our data show that GFP-LC3 puncta formation and cumulative mKeima puncta formation are unaltered at baseline in Synj1+/- MB neurons. However, GFP-LAMP1 puncta is reduced with a similar decrease in endogenous proteins, including lysosomal-associated membrane protein (LAMP)1, LAMP2, and LAMP2A. The LAMP1 vesicles are hyperacidified with enhanced enzymatic activity in Synj1+/- MB neurons. Using a combination of light and electron microscopy (EM), we show that endolysosomal changes are primarily associated with a lack of SAC1 activity. Consistently, expressing the SYNJ1 R258Q mutant in N2a cells reduces the lysosome number. Interestingly, the endolysosomal defects in Synj1+/- neurons does not impact the clearance of exogenously expressed wild-type (WT) α-syn; however, the clearance of α-syn A53T was impaired in the axons of Synj1+/- MB neurons. Taken together, our results suggest axonal vulnerability to endolysosomal defects in Synj1-deficient MB neurons.

CT-Based Calculation Model Assists Precise Treatment for Anterior and Posterior Ankle Bony Impingement.

OBJECTIVE: Ankle arthroscope is the preferred tool for ankle surgeons to treat ankle impingement. However, there is no relevant report on how to improve the accuracy of arthroscopic osteotomy through preoperative planning. The aims of this study were to investigate a novel method to obtain the bone morphology in anterior and posterior ankle bony impingement through computed tomography (CT) calculation model, use this method to guide surgical decision-making, and compare the postoperative efficacy and actual bone cutting volume with conventional surgery. METHODS: This retrospective cohort study includes 32 consecutive cases with anterior and posterior ankle bony impingement by arthroscopy from January 2017 to December 2019. Mimics software was utilized to calculate the bony morphology and measure the volume of the osteophytes by two trained software engineers. The patients were divided into the precise group (n = 15) and the conventional group (n = 17) according to whether obtain and quantify the osteophytes' morphology with CT based calculation model preoperative. All patients were evaluated clinically using visual analog scale (VAS) score, American Orthopaedic Foot and Ankle Society (AOFAS) score, active dorsiflexion and plantarflexion angle before and after surgery at both 3 months and 12 months postoperatively. We obtained the shape and volume of bone cutting through Boolean calculation. Clinical outcomes and radiological data were compared between the two groups. RESULTS: The VAS score, AOFAS score, active dorsiflexion angle and plantarflexion angle were significantly improved in both groups postoperatively. In comparison of the VAS score, AOFAS score, and active dorsiflexion angle, the precise group were higher than the conventional group in the follow-up at 3 and 12 months postoperatively with statistical difference. The difference between the virtual bone cutting volume and the actual bone cutting volume of the anterior edge of distal tibia in the conventional group and precise group were 244.20 ± 147.66 mm3 and 76.53 ± 168.51 mm3 , respectively, there was statistical difference between the two groups (t = -2.927, p = 0.011). CONCLUSION: Using a novel method of obtaining and quantifying the bony morphology with CT-based calculation model for anterior and posterior ankle bony impingement can help guide surgical decision-making preoperatively and assist precise bone cutting during the operation, which can improve the efficacy and evaluate the accuracy of osteotomy postoperatively.

Cocaine-regulated trafficking of dopamine transporters in cultured neurons revealed by a pH sensitive reporter.

Cocaine acts by inhibiting plasma membrane dopamine transporter (DAT) function and altering its surface expression. The precise manner and mechanism by which cocaine regulates DAT trafficking, especially at neuronal processes, are poorly understood. In this study, we engineered and validated the use of DAT-pHluorin for studying DAT localization and its dynamic trafficking at neuronal processes of cultured mouse midbrain neurons. We demonstrate that unlike neuronal soma and dendrites, which contain a majority of the DATs in weakly acidic intracellular compartments, axonal DATs at both shafts and boutons are primarily (75%) localized to the plasma membrane, whereas large varicosities contain abundant intracellular DAT within acidic intracellular structures. We also demonstrate that cocaine exposure leads to a Synaptojanin1-sensitive DAT internalization process followed by membrane reinsertion that lasts for days. Thus, our study reveals the previously unknown dynamics and molecular regulation for cocaine-regulated DAT trafficking in neuronal processes.

Performance of the clinical assessment scale for autoimmune encephalitis in a pediatric autoimmune encephalitis cohort.

Background: The Clinical Assessment Scale for Autoimmune Encephalitis (CASE), a new scale used for rating the severity of autoimmune encephalitis (AE), has demonstrated good validity and reliability in adults with AE, but there is a shortage of data on its performance in children with AE. This study aimed to assess the reliability and validity of the CASE in a cohort of children with AE. Methods: Forty-seven pediatric inpatients with AE who visited Guizhou Provincial People's Hospital between January 1, 2017, and October 31, 2021, were enrolled in the study. The CASE and mRS scores were obtained through a review of detailed medical records from the Health Information System by two pediatric neurologists. Finally, the performance of the CASE in this pediatric AE cohort was analyzed. Results: The results showed that anti-NMDA receptor encephalitis was the most common (61.70%) type of AE in children. The most common clinical manifestations were language problems (85.1%), psychiatric symptoms (80.9%), and dyskinesia/dystonia (78.7%). The CASE had good item reliability and interevaluator reliability; the Cronbach's alpha value of the total score was 0.825, and the intraclass correlation (ICC) was 0.980. The Cronbach's alpha value by item ranged from 0.16 to 0.406; items 1 and 9 had the lowest and highest Cronbach's alpha values, respectively. The criterion validity between CASE and mRS total scores, as quantified by Pearson correlation, was 0.459, indicating slight to good criterion validity. The area under the curve (AUC) was 0.992 (95% confidence interval: 0.974-1.00). A cutoff value of 14 was selected to determine whether a patient needed admission to the ICU; this cutoff had a sensitivity of 100% and a specificity of 92%. The changes in EEG, MRI, and antibody titers were not related to the severity of AE. A CASE score cutoff of 9 was selected to indicate whether second-line treatment would be needed. Conclusion: The CASE has good reliability and validity in children with AE; however, some items of the CASE may not apply to this population. Thus, an in-depth study of the CASE is needed in children with AE.

The Antibody Assay in Suspected Autoimmune Encephalitis From Positive Rate to Test Strategies.

Objective: The aim of this study was to analyze the positive rate and test strategies of suspected autoimmune encephalitis (SAE) based on an antibody assay. Methods: Patients who were diagnosed with suspected autoimmune encephalitis in Guizhou Province between June 1, 2020, and June 30, 2021 and who had anti-neuronal autoantibodies detected by Guizhou KingMed Diagnostics Group Co., Ltd. were included in this study. The positive rate and the test strategies were analyzed based on the results of the anti-neuronal antibody assay. Results: A total of 263 patients with SAE were included, 58.2% (153/263) of whom were males, with a median age of 33 years (1-84 years). 84% (221/263) of all patients completed both serum and CSF tests. A total of 46.0% (121/263) of SAE patients received the AE-6 examination package. The antibody-positive rate was 9.9% (26/263) in the current cohort, with an observed incidence of antibody positive of 0.2 in 100,000 (26/11,570,000, 95% CI: 0.15-0.30), and the estimated incidence was 0.9 in 100,000 (95% CI: 0.84-0.95) of the total population. A total of 9 different anti-neuronal antibodies were detected. Anti-NMDAR antibody was the most common antibody in 46.2% (12/26) of subjects, 70.0% (7/10) of whom were children, followed by anti-Caspr2 antibody in 30.8% (8/26); the remaining 7 antibodies were detected in 23.1% (6/26) of the population. There were no obvious differences among age, sex or season in the positive rate of anti-neuronal antibodies. The cost of antibody testing per capita was $439.30 (SD±$195.10). The total cost of AE-14 was the highest at $48.016.81 (41.56%) among all examination packages. Conclusions: This study described the positive rate associated with AE-related anti-neuronal antibodies and test strategies in the current cohort, which provides a basis for clinicians in clinical practice.

Air-Stable 2D Cr5 Te8 Nanosheets with Thickness-Tunable Ferromagnetism.

2D magnetic materials have aroused widespread research interest owing to their promising application in spintronic devices. However, exploring new kinds of 2D magnetic materials with better stability and realizing their batch synthesis remain challenging. Herein, the synthesis of air-stable 2D Cr5 Te8 ultrathin crystals with tunable thickness via tube-in-tube chemical vapor deposition (CVD) growth technology is reported. The importance of tube-in-tube CVD growth, which can significantly suppress the equilibrium shift to the decomposition direction and facilitate that to the synthesis reaction direction, for the synthesis of high-quality Cr5 Te8 with accurate composition, is highlighted. By precisely adjusting the growth temperature, the thickness of Cr5 Te8 nanosheets is tuned from ≈1.2 nm to tens of nanometers, with the morphology changing from triangles to hexagons. Furthermore, magneto-optical Kerr effect measurements reveal that the Cr5 Te8 nanosheet is ferromagnetic with strong out-of-plane spin polarization. The Curie temperature exhibits a monotonic increase from 100 to 160 K as the Cr5 Te8 thickness increases from 10 to 30 nm and no apparent variation in surface roughness or magnetic properties after months of exposure to air. This study provides a robust method for the controllable synthesis of high-quality 2D ferromagnetic materials, which will facilitate research progress in spintronics.

Mini-review: Synaptojanin 1 and its implications in membrane trafficking.

This mini-review aims to summarize a growing body of literature on synaptojanin 1 (Synj1), a phosphoinositide phosphatase that was initially known to have a prominent role in synaptic vesicle recycling. Synj1 is coded by the SYNJ1 gene, whose mutations and variants are associated with an increasing number of neurological disorders. To better understand the mechanistic role of Synj1 in disease pathogenesis, we review details of phosphoinositide signaling pathways and the reported involvement of Synj1 in membrane trafficking with a specific focus on Parkinson's disease (PD). Recent studies have tremendously advanced our understanding of Synj1 protein structure and function while broadening our view of how Synj1 regulates synaptic membrane trafficking and endosomal trafficking in various organisms and cell types. A growing body of evidence points to inefficient membrane trafficking as key pathogenic mechanisms in neurodegenerative diseases associated with abnormal Synj1 expression. Despite significant progress made in the field, the mechanism by which Synj1 connects to trafficking, signaling, and pathogenesis is lacking and remains to be addressed.

Urgency in Improving Child Health Care Workers' Awareness and Knowledge of ASD: Findings From a Cross-Sectional Study in Southwest China.

Objective: To evaluate the levels of awareness and knowledge of ASD among child health care workers in China, we conducted a cross-sectional, questionnaire-based study to assess the participants' awareness and knowledge of ASD. Methods: A total of 159 child health care workers from Southwest China participated in the survey and filled out the questionnaire.Descriptive analysis was conducted on the five parts of the questionnaire, including general knowledge, symptomology, screening and diagnosis, and intervention and treatment. Univariate analysis was used to assess impacts of the participants' basic demographic characteristics on the questionnaire scores. Multivariate analysis was used to analyze association of the participants' basic demographic characteristics and the questionnaire scores. Results: Less than 15% of the participants knew that ASD is a developmental, congenital and genetic disorder. Few participants knew that the symptoms include language disorder (38.4%) and social dysfunction (29.6%). A minority of the participants knew the diagnostic criteria (22.6%) and the age for early screening (14.5%). A total of 23.9% of the participants agreed that there are no effective drugs to treat ASD, and 6.3% agreed that ASD is incurable. A number of years in practice of ≥10 (OR = 0.3249, 95% CI: 0.1080-0.9189) was the main factor related to a high questionnaire score. Conclusions: Most participants had relatively low levels of awareness and knowledge of ASD, especially in terms of general knowledge as well as knowledge of intervention and treatment. Working for more than 10 years was a significant predictor of higher levels of awareness and knowledge of ASD. ASD-related training and knowledge dissemination are crucial for the early diagnosis and intervention of ASD. Child health care workers' awareness and knowledge of ASD needs to be improved to help build public awareness about ASD.

Comparative effects of pollen limitation, floral traits and pollinators on reproductive success of Hedysarum scoparium Fisch. et Mey. in different habitats.

BACKGROUND: Reproduction in most flowering plants may be limited because of the decreased visitation or activity of pollinators in fragmented habitats. Hedysarum scoparium Fisch. et Mey. is an arid region shrub with ecological importance. We explored the pollen limitation and seed set of Hedysarum scoparium in fragmented and restored environments, and examined whether pollen limitation is a significant limiting factor for seed set. We also compared floral traits and pollinator visitation between both habitats, and we determined the difference of floral traits and pollinators influenced reproductive success in Hedysarum scoparium. RESULTS: Our results indicated that supplementation with pollen significantly increased seed set per flower, which is pollen-limited in this species. Furthermore, there was greater seed set of the hand cross-pollination group in the restored habitat compared to the fragmented environment. More visits by Apis mellifera were recorded in the restored habitats, which may explain the difference in seed production between the fragmented and restored habitats. CONCLUSIONS: In this study, a positive association between pollinator visitation frequency and open flower number was observed. The findings of this study are important for experimentally quantifying the effects of floral traits and pollinators on plant reproductive success in different habitats.

Synaptojanin1 deficiency upregulates basal autophagosome formation in astrocytes.

Macroautophagy dysregulation is implicated in multiple neurological disorders, such as Parkinson's disease. While autophagy pathways are heavily researched in heterologous cells and neurons, regulation of autophagy in the astrocyte, the most abundant cell type in the mammalian brain, is less well understood. Missense mutations in the Synj1 gene encoding Synaptojanin1 (Synj1), a neuron-enriched lipid phosphatase, have been linked to Parkinsonism with seizures. Our previous study showed that the Synj1 haploinsufficient (Synj1+/-) mouse exhibits age-dependent autophagy impairment in multiple brain regions. Here, we used cultured astrocytes from Synj1-deficient mice to investigate its role in astrocyte autophagy. We report that Synj1 is expressed in low levels in astrocytes and represses basal autophagosome formation. We demonstrate using cellular imaging that Synj1-deficient astrocytes exhibit hyperactive autophagosome formation, represented by an increase in the size and number of GFP-microtubule-associated protein 1A/1B-light chain 3 structures. Interestingly, Synj1 deficiency is also associated with an impairment in stress-induced autophagy clearance. We show, for the first time, that the Parkinsonism-associated R839C mutation impacts autophagy in astrocytes. The impact of this mutation on the phosphatase function of Synj1 resulted in elevated basal autophagosome formation that mimics Synj1 deletion. We found that the membrane expression of the astrocyte-specific glucose transporter GluT-1 was reduced in Synj1-deficient astrocytes. Consistently, AMP-activated protein kinase activity was elevated, suggesting altered glucose sensing in Synj1-deficient astrocytes. Expressing exogenous GluT-1 in Synj1-deficient astrocytes reversed the autophagy impairment, supporting a role for Synj1 in regulating astrocyte autophagy via disrupting glucose-sensing pathways. Thus, our work suggests a novel mechanism for Synj1-related Parkinsonism involving astrocyte dysfunction.

Optimal Sagittal Insertion Depth and Direction of Femoral Intramedullary Rod in Total Knee Arthroplasty in Chinese Osteoarthritis Patients.

OBJECTIVE: To identify the optimal femoral intramedullary rod insertion depth and direction on the sagittal plane in total knee arthroplasty (TKA) of Chinese osteoarthritis (OA) patients. METHODS: From January to December 2019, CT data were collected for 85 consecutive entire lower extremity Chinese OA patients. A three-dimensional method was used to simulate intramedullary rod penetration. The intramedullary rods were inserted toward the anterior (TA), center (TC), and posterior (TP) of the femoral canal, respectively. Four penetration depths of 150, 200, 250, and 300 mm from the joint line were set. The intersection angle was measured between the simulated intramedullary rod and the mechanical axis of the femur (FMA) on the sagittal plane. RESULTS: Our study included 85 Chinese OA patients: 46 women, with a mean age of 65.7 ± 8.4 years (range, 51-85 years) and 39 men, with a mean age of 65.6 ± 8.1 years (range, 46-86 years). The intersection angle between the FMA and the femoral anatomical axis was smaller in men, 2.4° ± 1.6° (range, 0°-4.8°), than in women, 3.5° ± 2.3° (range, 0.7º-8.2°), with a significant statistical difference (P < 0.01). In the comparison of the intersection angle between the simulated intramedullary rod and the FMA, there was no statistical difference between TA200 and TC200 in women (P > 0.05). The proportions were up to 91% and 96% of TA200 at 0°-3° and 0°-5° intervals, respectively, but just 63% and 78% in TC200. In TA150, 76% of intersection angles were greater than 5°. Only approximately 60% in TA250 and TA300 were within the 0°-5° interval and 40% were less than 0°. Only 57% of intersection angles in TC150 were in the 0°-3° interval. TC250, TC300, and TP150 were mostly below 0°. In men, there were statistical differences between all groups. All intersection angles were greater than 5° in TA150. TA200 and TA250 were mostly greater than 5° (87% and 59%, respectively) and 72% of intersection angles were within 0°-5° interval in TA300. TC150 had 92% of intersection angles within the 0°-5° interval but only 62% between the 0° and 3° interval. In the TC200, up to 90% and 97% were within 0°-3° and 0°-5° intervals, respectively. TC300, TP150, and TP200 were mostly below 0°. CONCLUSION: We described an innovative method for rapidly, simply, and accurately identifying the sagittal insertion depth and direction of the femoral intramedullary rod in TKA, which can optimize the position of the femoral prosthetic component on the sagittal plane in TKA.

Synj1 haploinsufficiency causes dopamine neuron vulnerability and alpha-synuclein accumulation in mice.

Synaptojanin1 (synj1) is a phosphoinositide phosphatase with dual SAC1 and 5'-phosphatase enzymatic activities in regulating phospholipid signaling. The brain-enriched isoform has been shown to participate in synaptic vesicle (SV) recycling. More recently, recessive human mutations were identified in the two phosphatase domains of SYNJ1, including R258Q, R459P and R839C, which are linked to rare forms of early-onset Parkinsonism. We now demonstrate that Synj1 heterozygous deletion (Synj1+/-), which is associated with an impaired 5'-phosphatase activity, also leads to Parkinson's disease (PD)-like pathologies in mice. We report that male Synj1+/- mice display age-dependent motor function abnormalities as well as alpha-synuclein accumulation, impaired autophagy and dopaminergic terminal degeneration. Synj1+/- mice contain elevated 5'-phosphatase substrate, PI(4,5)P2, particularly in the midbrain neurons. Moreover, pharmacological elevation of membrane PI(4,5)P2 in cultured neurons impairs SV endocytosis, specifically in midbrain neurons, and further exacerbates SV trafficking defects in Synj1+/- midbrain neurons. We demonstrate down-regulation of SYNJ1 transcript in a subset of sporadic PD brains, implicating a potential role of Synj1 deficiency in the decline of dopaminergic function during aging.