FLAMES overlaying anti-N-methyl-D-aspartate receptor encephalitis: a case report and literature review.

BACKGROUND: In recent years, simultaneous or sequential occurrence of MOG antibody disease and anti-NMDAR encephalitis in the same patient has been reported with increasing frequency. Scholars refer to the overlapping occurrence of these two disorders as MOG antibody disease and anti-NMDAR encephalitis overlap syndrome (MNOS). Cortical T2-weighted fluid-attenuated inversion recovery (FLAIR) -hyperintense lesions in anti-MOG-associated encephalitis with seizures (FLAMES) is a rare clinical phenotype of MOGAD in which cortical FLAIR high-signal lesions are unilateral, with little spread to the cortex and meninges bilaterally. Although cases of FLAMES have been consistently reported. However, to our knowledge, such cases of FLAMES combined with NMDARE are rare. CASE PRESENTATION: Here, we describe a case of FLAMES combined with anti-NMDARE. The patient was a young male, 29 years old, admitted to our hospital with isolated seizures, whose MRI showed unilateral thalamic and bilateral frontal and parietal leptomeningeal involvement. Since we were unaware of the possibility of bilateral meningo-cortical MOGAD manifestations, the case was initially diagnosed as viral encephalitis and was given antiviral therapy. The diagnosis was not clarified until anti-NMDAR-IgG and MOG-IgG positivity was detected in the cerebrospinal fluid and serum. The patient was then treated with high-dose corticosteroids and his symptoms responded well to the steroids. Therefore, this case expands the clinical spectrum of MNOS overlap syndrome. In addition, we describe the clinical features of MNOS by summarizing the existing literature and exploring the possible mechanisms of its immune response. CONCLUSIONS: Our case serves as a reminder to clinicians that when patients present with atypical clinical manifestations such as seizures, consideration should be given to MNOS and conduct testing for various relevant autoantibodies (including MOG abs) and viruses in both serum and cerebrospinal fluid, as it is easy to misdiagnose the disease as other CNS diseases, such as viral meningoencephalitis. This syndrome exhibits a high responsiveness to steroids, highlighting the critical importance of recognizing the clinical and neuroimaging features of this overlap syndrome for prompt diagnosis and treatment. Furthermore, it enriches the disease spectrum of MNOS.

To Accelerate the Process of Brain Death Determination in China Through the Strategy and Practice of Establishing Demonstration Hospitals.

BACKGROUND: Our objective was to explore whether a brain death determination (BDD) strategy with demonstration hospitals can accelerate the process of BDD in China. METHODS: We proposed the construction standards for the BDD quality control demonstration hospitals (BDDHs). The quality and quantity of BDD cases were then analyzed. RESULTS: A total of 107 BDDHs were established from 2013 to 2022 covering 29 provinces, autonomous regions, and municipalities under jurisdiction of the central government of the Chinese mainland (except Qinghai and Tibet). A total of 1,948 professional and technical personnel from these 107 BDDHs received training in BDD, 107 quality control personnel were trained in the quality control management of BDD, and 1,293 instruments for electroencephalography, short-latency somatosensory evoked potential recordings, and transcranial Doppler imaging were provided for BDD. A total of 6,735 BDD cases were submitted to the quality control center. Among the nine quality control indicators for BDD in these cases, the implementation rate, completion rate, and coincidence rate of apnea testing increased the most, reaching 99%. CONCLUSIONS: The strategy of constructing BDDHs to promote BDD is feasible and reliable. Ensuring quality and quantity is a fundamental element for the rapid and orderly popularization of BDD in China.

ApoE4 associated with severe COVID-19 outcomes via downregulation of ACE2 and imbalanced RAS pathway.

BACKGROUND: Recent numerous epidemiology and clinical association studies reported that ApoE polymorphism might be associated with the risk and severity of coronavirus disease 2019 (COVID-19), and yielded inconsistent results. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection relies on its spike protein binding to angiotensin-converting enzyme 2 (ACE2) receptor expressed on host cell membranes. METHODS: A meta-analysis was conducted to clarify the association between ApoE polymorphism and the risk and severity of COVID-19. Multiple protein interaction assays were utilized to investigate the potential molecular link between ApoE and the SARS-CoV-2 primary receptor ACE2, ApoE and spike protein. Immunoblotting and immunofluorescence staining methods were used to access the regulatory effect of different ApoE isoform on ACE2 protein expression. RESULTS: ApoE gene polymorphism (ε4 carrier genotypes VS non-ε4 carrier genotypes) is associated with the increased risk (P = 0.0003, OR = 1.44, 95% CI 1.18-1.76) and progression (P < 0.00001, OR = 1.85, 95% CI 1.50-2.28) of COVID-19. ApoE interacts with both ACE2 and the spike protein but did not show isoform-dependent binding effects. ApoE4 significantly downregulates ACE2 protein expression in vitro and in vivo and subsequently decreases the conversion of Ang II to Ang 1-7. CONCLUSIONS: ApoE4 increases SARS-CoV-2 infectivity in a manner that may not depend on differential interactions with the spike protein or ACE2. Instead, ApoE4 downregulates ACE2 protein expression and subsequently the dysregulation of renin-angiotensin system (RAS) may provide explanation by which ApoE4 exacerbates COVID-19 disease.

Stable isotope characterization of tobacco products: A determination of synthetic or natural nicotine authenticity.

RATIONALE: "Tobacco-free" or synthetic nicotine products have appeared in some markets, increasing potential health risks and regulatory compliance challenges. Currently, there are few reliable methods for the determination of authenticity of natural and synthetic nicotine. Analytical techniques based on stable isotopes have broad application prospects in the traceability and identification of agricultural products. METHODS: Tobacco leaves from four main tobacco production regions in China and different types of tobacco products were extracted with n-hexane and 5% sodium hydroxide to obtain nicotine extracts. Subsequent stable isotope mass spectrometry was performed by analyzing δ2 H, δ13 C, and δ15 N values of nicotine. RESULTS: Firstly, results from a batch of 233 samples indicated stable isotopes were closely related to climate and geographical locations and provide a basis for a determination of the origin of tobacco leaves. In addition, the δ2 H values had significant differences between natural and synthetic nicotine and the results indicate a δ2 H value of -163.0‰ could be the threshold for assessing synthetic and natural nicotine. Finally, a total of 239 results further validated the δ2 H value as a metric for source authentication of commercial tobacco products. CONCLUSIONS: Synthetic (S)-(-)-nicotine could be accurately and quickly identified using the method developed by measuring δ2 H values in a qualitative manner. To our knowledge, this is the first time a stable isotope mass spectrometry technique has been used for distinguishing the source of nicotine. This technique will aid in the accurate identification, labelling, and regulation of synthetic nicotine-based tobacco products.

Analytical strategies in neurotransmitter measurements: A mini literature review.

Neurotransmitters (NTs) are endogenous, polar, low-molecular-weight compounds that play multiple pivotal roles in the central nervous system. NTs are involved in communicating information, responding to stress, regulating motor coordination, and allowing interneuronal communication in living organisms. It is essential to determine the distribution of NTs in brain regions to better understand drug dependence and abuse, neurological disorders, psychological disorders, and aging. Monitoring NT levels is also important in diagnosing and avoiding serious illnesses. We here review chromatography-based analytical techniques, including pretreatment methods (e.g., microdialysis and solid-phase microextraction), as well as detection strategies (e.g., MS and electrochemistry), focusing on developments in these techniques over the past 5 years. We then highlight recent advances in electrochemical and fluorescence imaging methods in vivo and the disadvantages and advantages of such technologies, including high spatiotemporal resolution, polymer specificity, and high sensitivity. Finally, we summarize and compare the complementary advantages of chromatography-based analytical techniques and biosensors and discuss trends in the development of NT detection technologies.

[A Novel Three-minute Game-based Cognitive Risk Screening Tool-WeChat Mini-program-based Design and Large-sample Feasibility Studies].

OBJECTIVE: To develop a novel cognitive screening tool for older adults in China. METHODS: "Game-based Cognitive Assessment-3 Minute Version"(G3) was designed and developed based on WeChat mini-program. And its feasibility was analyzed. RESULTS: G3 mini-program contains three one-minute mini digital games and supports users' self-assessment of cognitive functions with instant access to reports. G3 had a good correlation with Montreal Cognitive Assessment Basic (MoCA-B) with Pearson's r =0.611 (P<0.001). Among natural users aged 50 and older (71 179), the G3 initiation and completion rates were 99.55% and 92.28%, respectively. The average time to complete G3 assessments was (278.5±73.73) seconds. CONCLUSIONS: The novel G3 mini-program has good feasibility and usability for older Chinese adults, and can be used for cognitive screening and home self-assessment.

COVID-19 and cognitive impairment: neuroinvasive and blood‒brain barrier dysfunction.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global pandemic. Although COVID-19 was initially described as a respiratory disease, there is growing evidence that SARS-CoV-2 is able to invade the brains of COVID-19 patients and cause cognitive impairment. It has been reported that SARS-CoV-2 may have invasive effects on a variety of cranial nerves, including the olfactory, trigeminal, optic, and vagus nerves, and may spread to other brain regions via infected nerve endings, retrograde transport, and transsynaptic transmission. In addition, the blood-brain barrier (BBB), composed of neurovascular units (NVUs) lining the brain microvasculature, acts as a physical barrier between nerve cells and circulating cells of the immune system and is able to regulate the transfer of substances between the blood and brain parenchyma. Therefore, the BBB may be an important structure for the direct and indirect interaction of SARS-CoV-2 with the brain via the blood circulation. In this review, we assessed the potential involvement of neuroinvasion under the SARS-CoV-2 infection, and the potential impact of BBB disorder under SARS-CoV-2 infection on cognitive impairment.

Mechanistic Studies of an Automated Lipid Nanoparticle Reveal Critical Pharmaceutical Properties Associated with Enhanced mRNA Functional Delivery In Vitro and In Vivo.

Recently, lipid nanoparticles (LNPs) have attracted attention due to their emergent use for COVID-19 mRNA vaccines. The success of LNPs can be attributed to ionizable lipids, which enable functional intracellular delivery. Previously, the authors established an automated high-throughput platform to screen ionizable lipids and identified that the LNPs generated using this automated technique show comparable or increased mRNA functional delivery in vitro as compared to LNPs prepared using traditional microfluidics techniques. In this study, the authors choose one benchmark lipid, DLin-MC3-DMA (MC3), and investigate whether the automated formulation technique can enhance mRNA functional delivery in vivo. Interestingly, a 4.5-fold improvement in mRNA functional delivery in vivo by automated LNPs as compared to LNPs formulated by conventional microfluidics techniques, is observed. Mechanistic studies reveal that particles with large size accommodate more mRNA per LNP, possess more hydrophobic surface, are more hemolytic, bind a larger protein corona, and tend to accumulate more in macropinocytosomes, which may quantitatively benefit mRNA cytosolic delivery. These data suggest that mRNA loading per particle is a critical factor that accounts for the enhanced mRNA functional delivery of automated LNPs. These mechanistic findings provide valuable insight underlying the enhanced mRNA functional delivery to accelerate future mRNA LNP product development.

Fatty alcohol oxidase 3 (FAO3) and FAO4b connect the alcohol- and alkane-forming pathways in Arabidopsis stem wax biosynthesis.

The alcohol- and alkane-forming pathways in cuticular wax biosynthesis are well characterized in Arabidopsis. However, potential interactions between the two pathways remain unclear. Here, we reveal that mutation of CER4, the key gene in the alcohol-forming pathway, also led to a deficiency in the alkane-forming pathway in distal stems. To trace the connection between the two pathways, we characterized two homologs of fatty alcohol oxidase (FAO), FAO3 and FAO4b, which were highly expressed in distal stems and localized to the endoplasmic reticulum. The amounts of waxes from the alkane-forming pathway were significantly decreased in stems of fao4b and much lower in fao3 fao4b plants, indicative of an overlapping function for the two proteins in wax synthesis. Additionally, overexpression of FAO3 and FAO4b in Arabidopsis resulted in a dramatic reduction of primary alcohols and significant increases of aldehydes and related waxes. Moreover, expressing FAO3 or FAO4b led to significantly decreased amounts of C18-C26 alcohols in yeast co-expressing CER4 and FAR1. Collectively, these findings demonstrate that FAO3 and FAO4b are functionally redundant in suppressing accumulation of primary alcohols and contributing to aldehyde production, which provides a missing and long-sought-after link between these two pathways in wax biosynthesis.

TTC3-Mediated Protein Quality Control, A Potential Mechanism for Cognitive Impairment.

The tetrapeptide repeat domain 3 (TTC3) gene falls within Down's syndrome (DS) critical region. Cognitive impairment is a common phenotype of DS and Alzheimer's disease (AD), and overexpression of TTC3 can accelerate cognitive decline, but the specific mechanism is unknown. The TTC3-mediated protein quality control (PQC) mechanism, similar to the PQC system, is divided into three parts: it acts as a cochaperone to assist proteins in folding correctly; it acts as an E3 ubiquitin ligase (E3s) involved in protein degradation processes through the ubiquitin-proteasome system (UPS); and it may also eventually cause autophagy by affecting mitochondrial function. Thus, this article reviews the research progress on the structure, function, and metabolism of TTC3, including the recent research progress on TTC3 in DS and AD; the role of TTC3 in cognitive impairment through PQC in combination with the abovementioned attributes of TTC3; and the potential targets of TTC3 in the treatment of such diseases.

Synergistic effects of Rapamycin and Fluorouracil to treat a gastric tumor in a PTEN conditional deletion mouse model.

The tumor suppressor gene phosphatase and tensin homolog (PTEN) in PI3K/Akt/mTOR pathway is essential in inhibiting tumor growth and metastasis. However, whether the mutation of PTEN gene could induce tumorigenesis and impact the treatment of gastric cancer is still unclear. The purpose of the study was to investigate the combined treatment of gastric tumorigenesis using Rapamycin and Fluorouracil (5-Fu) through interfering with the Akt/mTOR pathway in a mouse model with PTEN conditional deletion. Three groups of mice were exposed for 5 days to Rapamycin and 5-Fu separately and together. The gene expression of the Akt/mTOR pathway, the protein expression of caspase-3 and p-Akt, p-S6K and p-4EBP1, and the pathological changes in stomachs were analyzed. Our study demonstrates that the conditional PTEN deletion in the cells of glandular stomach induces hyperplastic gastric tumors in mice. The combined Rapamycin administration with 5-Fu resulted in better outcomes than their separate administration for the treatment of gastric cancer by inhibiting the mTOR signal pathway. Our study indicates that Rapamycin has a synergistic interaction with chemotherapeutic 5-Fu, and demonstrates a potential therapeutic combination treatment on glandular stomach tumor with PTEN functional absence or aberrantly activated Akt/mTOR pathway. It provides important insights into the inhibition of the Akt/mTOR pathway in gastric cancer clinical therapy.

Dl-3-n-butylphthalide promotes neurite outgrowth of primary cortical neurons by Sonic Hedgehog signaling via upregulating Gap43.

Neurite outgrowth is the basis for wiring during the development of the nervous system. Dl-3-n-butylphthalide (NBP) has been recognized as a promising treatment to improve behavioral, neurological and cognitive outcomes in ischemic stroke. However, little is known about the effect and mechanism of NBP on the neurite outgrowth. In this study, we used different methods to investigate the potential effects of NBP on the neurite extension and plasticity of immature and mature primary cortical neurons and explored the underlying mechanisms. Our results demonstrated that in immature and mature cortical neurons, NBP promoted the neurite length and intersections, increased neuritic arborization, elevated numbers of neurite branch and terminal points and improved neurite complexity and plasticity of neuronal development processes. Besides, our data revealed that NBP promoted neurite extension and branching partly by activating Shh signaling pathway via increasing Gap43 expression both in immature and mature primary cortical neurons. The present study provided new insights into the contribution of NBP in neuronal plasticity and unveiled a novel pathway to induce Gap43 expression in primary cortical neurons.

Prior nasal delivery of antagomiR-122 prevents radiation-induced brain injury.

Radiation-induced brain injury is a major adverse event in head and neck tumor treatment, influencing the quality of life for the more than 50% of patients who undergo radiation therapy and experience long-term survival. However, no effective treatments are available for these patients, and preventative drugs and effective drug-delivery methods must be developed. Based on our results, miR-122-5p was upregulated in the mouse radiation-induced brain injury (RBI) model and patients with nasopharyngeal carcinoma (NPC) who received radiation therapy. Intranasal administration of a single antagomiR-122-5p dose before irradiation effectively alleviated radiation-induced cognitive impairment, neuronal injury, and neuroinflammation in the mouse RBI model. Results further indicated that miR-122-5p inhibition in microglia reduced the levels of proinflammatory cytokines and enhanced the phagocytic function to protect against radiation-induced neuronal injury in cell models. Further, we profiled transcriptome data and verified that Tensin 1 (TNS1) may be the target of miR-122-5p in RBI. In summary, our results reveal a distinct role for miR-122-5p in regulating neuroinflammation in RBI, indicating that a non-invasive strategy for intranasal miR-122-5p administration may be an attractive therapeutic target in RBI, providing new insights for clinical trials. Further systematic safety assessment, optimization of drug administration, and clarity of mechanism will accelerate the process into clinical practice.

Pharmacokinetics, tissue distribution, plasma protein binding rate and excretion of sinoacutine following intravenous administration in female and male Sprague-Dawley rats.

Sinoacutine is a natural isoquinoline alkaloid isolated from traditional Chinese medicine Stephanina yunnanensis H. S. Lo. Our aim was to study the pharmacokinetic characteristics of sinoacutine, which is essential during the development of new drugs.In this study, an accurate, sensitive, and efficient liquid chromatography (HPLC) method was developed and applied to evaluate the pharmacokinetics, tissue distribution, plasma protein binding rate, and excretion after intravenous injection of sinoacutine in rats.The pharmacokinetic parameters of sinoacutine were accorded with a two-compartment model in rats, and the AUC0-t in female was greater than that in male. Sinoacutine could be detected in heart, liver, spleen, lung, kidney, and brain, and the content in liver and kidney was relatively high. Meanwhile, it had a high plasma protein binding rate of 79.16%. Excretion of sinoacutine through faeces and urine was low, and the average excretion rate was 9.96%. There were gender differences in blood drug concentration, tissue distribution, and excretion significantly (p < 0.05).In summary, this study lays a foundation for elucidating the pharmacokinetic rule of sinoacutine and the data can provide a reliable scientific resource for further research.

Poly I:C Exacerbates Airway Inflammation and Remodeling in Cigarette Smoke-Exposed Mice.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disorder characterized by chronic inflammation and airway remodeling. Cigarette smoke (CS) and respiratory viruses are major causes of COPD development and exacerbation, but the mechanisms of these compounding factors on inflammation and pathological changes in airway structure still need further investigation. PURPOSE: This work aimed to investigate the effects and mechanisms of Poly I:C on pathological changes in CS-induced COPD mice, such as airway inflammation and remodeling. METHODS: From 1 to 8 weeks, the mice were exposed to CS, Poly I:C, or a combination of both. To compare the pathological changes among different groups over time, the mice were sacrificed at week 4, 8, 16, and 24, then the lungs were harvested to measure pulmonary pathology, inflammatory cytokines, and airway remodeling. RESULTS: Our data revealed that the fundamental characteristics of COPD, such as pulmonary pathological damage, the release of inflammatory mediators, and the remodeling of airway walls, were observed at week 8 in CS-exposed mice and these pathological changes persisted to week 16. Compared with the CS group, the pathological changes, including decreased lung function, inflammatory cell infiltration, alveolar destruction, and airway wall thickening, were weaker in the Poly I:C group. These pathological changes were observed at week 8 and persisted to week 16 in Poly I:C-induced mice. Furthermore, Poly I:C exacerbated lung tissue damage in CS-induced COPD mice. The decreased lung function, airway inflammation and remodeling were observed in the combined group at week 4, and these pathological changes persisted to week 24. Our research indicated that Poly I:C enhanced the expression of p-P38, p-JNK and p-NF-κB in CS-exposed mice. CONCLUSION: Poly I:C could promote airway inflammation and remodeling in CS-induced COPD mice probably by NF-κB and MAPK signaling.

Cognitive impairment caused by hypoxia: from clinical evidences to molecular mechanisms.

Hypoxia is a state of reduced oxygen supply and excessive oxygen consumption. According to the duration of hypoxic period, it can be classified as acute and chronic hypoxia. Both acute and chronic hypoxia could induce abundant neurological deficits. Although there have been significant advances in the pathophysiological injuries, few studies have focused on the cognitive dysfunction. In this review, we focused on the clinical evidences and molecular mechanisms of cognitive impairment under acute and chronic hypoxia. Hypoxia can impair several cognitive domains such as attention, learning and memory, procession speed and executive function, which are similar in acute and chronic hypoxia. The severity of cognitive deficit correlates with the duration and degree of hypoxia. Recovery can be achieved after acute hypoxia, while sequelae or even dementia can be observed after chronic hypoxia, perhaps due to the different molecular mechanisms. Cardiopulmonary compensatory response, glycolysis, oxidative stress, calcium overload, adenosine, mitochondrial disruption, inflammation and excitotoxicity contribute to the molecular mechanisms of cognitive deficit after acute hypoxia. During the chronic stage of hypoxia, different adaptive responses, impaired neurovascular coupling, apoptosis, transcription factors-mediated inflammation, as well as Aß accumulation and tau phosphorylation account for the neurocognitive deficit. Moreover, brain structural changes with hippocampus and cortex atrophy, ventricle enlargement, senile plaque and neurofibrillary tangle deposition can be observed under chronic hypoxia rather than acute hypoxia.

Novel mutation of SIK1 gene causing a mild form of pediatric epilepsy in a Chinese patient.

Developmental and Epileptic Encephalopathy (DEE) is a group of disorders affecting children at early stages of infancy, which is characterized by frequent seizures, epileptiform activity on EEG, and developmental delayor regression. Developmental and epileptic encephalopathy-30 (DEE30) is a severe neurologic disorder characterized by onset of refractory seizures soon after birth or in the first months of life. Which was recently found to be caused by heterozygous mutations in the salt-inducible kinase SIK1. In this study, we investigated a patient with early onset epilepsy. DNA sequencing of the whole coding region revealed a de novel heterozygous nucleotide substitution (c.880G > A) causing a missense mutation (p.A294T). This mutation was classified as variant of unknown significance (VUS) by American College of Medical Genetics and Genomics (ACMG). To further investigate the pathogenicity and pathogenesis of this mutation, we established a human neuroblastoma cell line (SH-SY5Y) stably-expressing wild type SIK1 and A294T mutant, and compared the transcriptome and metabolomics profiles. We presented a pediatric patient suffering from infantile onset epilepsy. Early EEG showed a boundary dysfunction of activity and MRI scan of the brain was normal. The patient responded well to single anti-epileptic drug treatment. Whole-exome sequencing found a missense mutation of SIK1 gene (c.880G > A chr21: 43,420,326 p. A294T). Dysregulated transcriptome and metabolome in cell models expressing WT and MUT SIK1 confirmed the pathogenicity of the mutation. Specifically, we found MEF2C target genes, certain epilepsy causing genes and metabolites are dysregulated by SIK1 mutation. We found MEF2C target genes, certain epilepsy causing genes and metabolites are dysregulated by SIK1 mutation. Our finding further expanded the disease spectrum and provided novel mechanistic insights of DEE30.

Tyrosine-Reactive Cross-Linker for Probing Protein Three-Dimensional Structures.

Cross-linking mass spectrometry (XL-MS) has made significant progress in understanding the structure of protein and elucidating architectures of larger protein complexes. Current XL-MS applications are limited to targeting lysine, glutamic acid, aspartic acid, and cysteine residues. There remains a need for the development of novel cross-linkers enabling selective targeting of other amino acid residues in proteins. Here, a novel simple cross-linker, namely, [4,4'-(disulfanediylbis(ethane-2,1-diyl)) bis(1,2,4-triazolidine-3,5-dione)] (DBB), has been designed, synthesized, and characterized. This cross-linker can react selectively with tyrosine residues in protein through the electrochemical click reaction. The DBB cross-links produced the characteristic peptides before and after electrochemical reduction, thus permitting the simplified data analysis and accurate identification for the cross-linked products. This is the first time a cross-linker is developed for targeting tyrosine residues on protein without using photoirradiation or a metal catalyst. This strategy might potentially be used as a complementary tool for XL-MS to probe protein 3D structures, protein complexes, and protein-protein interaction.

Two plastidic glycolate/glycerate translocator 1 isoforms function together to transport photorespiratory glycolate and glycerate in rice chloroplasts.

The photorespiratory pathway is highly compartmentalized. As such, metabolite shuttles between organelles are critical to ensure efficient photorespiratory carbon flux. Arabidopsis plastidic glycolate/glycerate translocator 1 (PLGG1) has been reported as a key chloroplastic glycolate/glycerate transporter. Two homologous genes, OsPLGG1a and OsPLGG1b, have been identified in the rice genome, although their distinct functions and relationships remain unknown. Herein, our analysis of exogenous expression in oocytes and yeast shows that both OsPLGG1a and OsPLGG1b have the ability to transport glycolate and glycerate. Furthermore, we demonstrate in planta that the perturbation of OsPLGG1a or OsPLGG1b expression leads to extensive accumulation of photorespiratory metabolites, especially glycolate and glycerate. Under ambient CO2 conditions, loss-of-function osplgg1a or osplgg1b mutant plants exhibited significant decreases in photosynthesis efficiency, starch accumulation, plant height, and crop productivity. These morphological defects were almost entirely recovered when the mutant plants were grown under elevated CO2 conditions. In contrast to osplgg1a, osplgg1b mutant alleles produced a mild photorespiratory phenotype and had reduced accumulation of photorespiratory metabolites. Subcellular localization analysis showed that OsPLGG1a and OsPLGG1b are located in the inner and outer membranes of the chloroplast envelope, respectively. In vitro and in vivo experiments revealed that OsPLGG1a and OsPLGG1b have a direct interaction. Our results indicate that both OsPLGG1a and OsPLGG1b are chloroplastic glycolate/glycerate transporters required for photorespiratory metabolism and plant growth, and that they may function as a singular complex.

Dysfunction of the SNARE complex in neurological and psychiatric disorders.

The communication between neurons constitutes the basis of all neural activities, and synaptic vesicle exocytosis is the fundamental biological event that mediates most communication between neurons in the central nervous system. The SNARE complex is the core component of the protein machinery that facilitates the fusion of synaptic vesicles with presynaptic terminals and thereby the release of neurotransmitters. In synapses, each release event is dependent on the assembly of the SNARE complex. In recent years, basic research on the SNARE complex has provided a clearer understanding of the mechanism underlying the formation of the SNARE complex and its role in vesicle formation. Emerging evidence indicates that abnormal expression or dysfunction of the SNARE complex in synapse physiology might contribute to abnormal neurotransmission and ultimately to synaptic dysfunction. Clinical research using postmortem tissues suggests that SNARE complex dysfunction is correlated with various neurological diseases, and some basic research has also confirmed the important role of the SNARE complex in the pathology of these diseases. Genetic and pharmacogenetic studies suggest that the SNARE complex and individual proteins might represent important molecular targets in neurological disease. In this review, we summarize the recent progress toward understanding the SNARE complex in regulating membrane fusion events and provide an update of the recent discoveries from clinical and basic research on the SNARE complex in neurodegenerative, neuropsychiatric, and neurodevelopmental diseases.