Structural insights into substrate recognition and translocation of human peroxisomal ABC transporter ALDP.

Dysfunctions of ATP-binding cassette, subfamily D, member 1 (ABCD1) cause X-linked adrenoleukodystrophy, a rare neurodegenerative disease that affects all human tissues. Residing in the peroxisome membrane, ABCD1 plays a role in the translocation of very long-chain fatty acids for their ß-oxidation. Here, the six cryo-electron microscopy structures of ABCD1 in four distinct conformational states were presented. In the transporter dimer, two transmembrane domains form the substrate translocation pathway, and two nucleotide-binding domains form the ATP-binding site that binds and hydrolyzes ATP. The ABCD1 structures provide a starting point for elucidating the substrate recognition and translocation mechanism of ABCD1. Each of the four inward-facing structures of ABCD1 has a vestibule that opens to the cytosol with variable sizes. Hexacosanoic acid (C26:0)-CoA substrate binds to the transmembrane domains (TMDs) and stimulates the ATPase activity of the nucleotide-binding domains (NBDs). W339 from the transmembrane helix 5 (TM5) is essential for binding substrate and stimulating ATP hydrolysis by substrate. ABCD1 has a unique C-terminal coiled-coil domain that negatively modulates the ATPase activity of the NBDs. Furthermore, the structure of ABCD1 in the outward-facing state indicates that ATP molecules pull the two NBDs together and open the TMDs to the peroxisomal lumen for substrate release. The five structures provide a view of the substrate transport cycle and mechanistic implication for disease-causing mutations.

Activities of daily living and its influencing factors for older people with type 2 diabetes mellitus in urban communities of Fuzhou, China.

Background: Type 2 diabetes mellitus (T2DM) is an independent risk factor for functional limitations among the older population. The predicted increase in T2DM cases combined with the ongoing rapidly aging population may further burden the already overloaded healthcare system and aggravate the loss of economic self-sufficiency. This study aimed to investigate the activities of daily living (ADL) and its influencing factors on older people with T2DM, and to provide implications for the development and improvement of community nursing services in the context rapidly aging population in China. Methods: From March 2019 to June 2020, we conducted a cross-sectional questionnaire survey among older T2DM patients in Fuzhou, using a multi-stage cluster sampling approach. Functional status was measured by the Lawton ADL scale. Stata "nptrend" test was used to examine the trend of ordinal variables on ADL. Non-conditional logistic regression was used to identify factors affecting ADL limitations. Results: A total of 2016 questionnaires were received, with a response rate of 96%. 12.4% of participants suffered from varying degrees of functional impairment. ADL limitations increased with age. More comorbidities were associated with a greater risk of developing functional limitations in ADLs. the following sub-groups were more likely to suffer from ADL impairment: those aged 70 and over years (OR = 1.99, 95%CI 1.77-2.56), living in an aged care house or with spouse/children (OR = 2.31, 95%CI 1.25-4.26), low monthly income (OR = 1.49, 95%CI 1.28-1.64), without health insurance (OR = 1.82, 95%CI 1.40-2.40), tight family expenses (OR = 1.95, 95%CI 1.42-2.69), having stroke (OR = 6.70, 95%CI 2.22-20.23) or malignant tumor (OR = 4.45, 95%CI 1.27-15.53), irregular eating habit (OR = 2.55, 95%CI 2.23-2.92), smoking (OR = 1.40, 95%CI 1.22-1.60), sedentary lifestyle (OR = 2.04, 95%CI 1.46-2.85), lack of physical exercise (OR = 1.35, 95%CI 1.19-1.53), sleeping difficulty (OR = 1.25, 95%CI 1.10-1.42), and lack of family support (OR = 1.19, 95%CI 1.10-1.29). Conclusion: Older adults (≥70 years) with T2DM had a high prevalence of functional limitations across a range of daily living tasks, which not only affect individual life of quality but also present a huge burden on the family, health services system, and the whole society. Identified factors associated with ADL limitations may provide useful information for targeted nursing practice and health promotion.

Cardiovascular Effects of High-Frequency Magnetic Seizure Therapy Compared With Electroconvulsive Therapy.

BACKGROUND: Magnetic seizure therapy (MST) is a novel convulsive therapy that has been shown to have antidepressant efficacy comparable to electroconvulsive therapy (ECT) with fewer cognitive side effects. However, the cardiovascular (CVS) effects of high frequency MST in comparison to ECT have not been investigated. MATERIALS AND METHODS: Forty-five patients with depression received 6 treatment sessions of 100 Hz MST versus 6 bifrontal ECT treatments in a nonrandomized comparative clinical design. Data on CVS function including heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and rate pressure product (RPP) were collected at baseline (T0), after the induction of anesthesia but before the electrical stimulation (T1), during convulsion (T2), 2 minutes after cessation of motor seizure (T3), 5 minutes after cessation of motor seizure (T4), and 10 minutes after cessation of motor seizure (T5). Comparisons were made with baseline data and between MST and ECT groups. RESULTS: There were statistically significant elevations in the maximum HR, SBP, DBP, and RPP in patients receiving ECT compared with MST both in the initial and sixth treatments (all P < 0.05). Particularly, at T2, the ECT group had significantly higher HR, SBP, DBP, and RPP than those in MST group both in initial and sixth treatment (all P < 0.001). At the sixth treatment, the ECT group had significantly higher SBP, DBP, and RPP during the treatment than in the MST group (all P < 0.001). LIMITATIONS: The anesthetic choices for this study may limit the generalizability of our findings. The sample size was relatively small. CONCLUSIONS: Compared with ECT, high-frequency MST has fewer CVS side effects and may be a safer option for depression patients with CVS disorders.

Seed oil of Brucea javanica induces apoptosis through the PI3K/Akt signaling pathway in acute lymphocytic leukemia Jurkat cells.

Brucea javanica oil emulsion (BJOE) has been used to treat tumor in China for more than 40 years. However, its components and effectiveness in the treatment of acute lymphocytic leukemia (ALL) and its mechanism of anti-cancer activity remain unknown. In the current study, high-performance liquid chromatography-evaporative light scattering detector (HPLC-ELSD) was used to analyze the components of BJOE. Then, the anti-leukemia effects of BJOE were examined both in vitro and in vivo using ALL Jurkat cells and the p388 mouse leukemia transplant model, respectively. The primary ALL leukemia cells were also used to confirm the anti-leukemia effects of BJOE. The apoptotic-related results indicated that BJOE induced apoptosis in Jurkat cells and were suggestive of intrinsic apoptotic induction. Moreover, BJOE inhibited Akt (protein kinase B) activation and upregulated its downstream targets p53 and FoxO1 (forkhead box gene, group O-1) to initiate apoptosis. The activation of GSK3ß was also involved. Our findings demonstrate that BJOE has anti-leukemia effects on ALL cells and can induce apoptosis in Jurkat cells through the phosphoinositide3-kinase (PI3K) /Akt signaling pathway.

Electroconvulsive therapy is associated with lower readmission rates in patients with schizophrenia.

BACKGROUND: Electroconvulsive therapy is an important somatic treatment for severe mental disorders with established efficacy and safety. However, data on the relationship between ECT and the readmission rate of patients with schizophrenia are scarce. This study will explore the association between the administration of ECT and readmission rates using a machine learning method. METHODS: Inpatient medical records from the year of 2016 in one large psychiatric hospital in Beijing, China, were analyzed using a machine learning algorithm to determine the most important variables affecting readmission of patients with schizophrenia. RESULTS: The medical records of 2131 inpatients with schizophrenia were reviewed. 1099 patients were followed up within 3 months of their index admission (642 ECT cases and 457 non-ECT cases) and 1032 patients were followed up within 6 months (596 ECT cases and 436 non-ECT cases) after discharge. The 3- and 6-month readmission rates in the ECT group (11.37% and 17.94%, respectively) were significantly lower than that of the patients who did not receive ECT (18.79% and 29.36%, respectively, both p < 0.001). The risk of readmission was significantly associated with male sex, older age, being married, having a lower income, a shorter inpatient length of stay, and receiving specific antipsychotic medications including olanzapine, paliperidone, clozapine, and haloperidol during the index admission. In the ECT group, patients who received 9 or more treatments were significantly less likely to be readmitted. CONCLUSION: Receiving ECT may be associated with a lower risk of readmission in patients with schizophrenia.

Does butylphthalide affect on hemodynamics in patients with watershed stroke?: A protocol of systematic review and meta-analysis.

BACKGROUND: This study will specifically investigate the effect of butylphthalide on hemodynamics in patients with watershed stroke (WS). METHODS: We will search the following databases from their inceptions to the March 1, 2020: Cochrane Library, MEDLINE, EMBASE, PsycINFO, Web of Science, Cumulative Index to Nursing and Allied Health Literature, and China National Knowledge Infrastructure. All relevant randomized controlled trials on exploring the effect of butylphthalide on hemodynamics in patients with WS will be considered for inclusion. No language limitation will be imposed to this study. All study quality will be checked using Cochrane risk of bias tool. RevMan 5.3 software will be utilized for data analysis. RESULTS: This study will summarize the latest evidence to investigate the effect of butylphthalide on hemodynamics in patients with WS. CONCLUSION: Findings from this study will provide theoretical basis of butylphthalide on hemodynamics in patients with WS for clinician and future research. DISSEMINATION AND ETHICS: This study is carried out based on the published data, thus, no ethical approval is required. We will submit this study to a peer-reviewed journal for publication. SYSTEMATIC REVIEW REGISTRATION: INPLASY 202030006.

NLPEI: A Novel Self-Interacting Protein Prediction Model Based on Natural Language Processing and Evolutionary Information.

The study of protein self-interactions (SIPs) can not only reveal the function of proteins at the molecular level, but is also crucial to understand activities such as growth, development, differentiation, and apoptosis, providing an important theoretical basis for exploring the mechanism of major diseases. With the rapid advances in biotechnology, a large number of SIPs have been discovered. However, due to the long period and high cost inherent to biological experiments, the gap between the identification of SIPs and the accumulation of data is growing. Therefore, fast and accurate computational methods are needed to effectively predict SIPs. In this study, we designed a new method, NLPEI, for predicting SIPs based on natural language understanding theory and evolutionary information. Specifically, we first understand the protein sequence as natural language and use natural language processing algorithms to extract its features. Then, we use the Position-Specific Scoring Matrix (PSSM) to represent the evolutionary information of the protein and extract its features through the Stacked Auto-Encoder (SAE) algorithm of deep learning. Finally, we fuse the natural language features of proteins with evolutionary features and make accurate predictions by Extreme Learning Machine (ELM) classifier. In the SIPs gold standard data sets of human and yeast, NLPEI achieved 94.19% and 91.29% prediction accuracy. Compared with different classifier models, different feature models, and other existing methods, NLPEI obtained the best results. These experimental results indicated that NLPEI is an effective tool for predicting SIPs and can provide reliable candidates for biological experiments.

pNNS-Conjugated Chitosan Mediated IGF-1 and miR-140 Overexpression in Articular Chondrocytes Improves Cartilage Repair.

The aim of the present study was to investigate the effects of phosphorylatable nucleus localization signal linked nucleic kinase substrate short peptide (pNNS)-conjugated chitosan (pNNS-CS) mediated miR-140 and IGF-1 in both rabbit chondrocytes and cartilage defects model. pNNS-CS was combined with pBudCE4.1-IGF-1, pBudCE4.1-miR-140, and negative control pBudCE4.1 to form pDNA/pNNS-CS complexes. Then these complexes were transfected into chondrocytes or injected intra-articularly into the knee joints. High levels of IGF-1 and miR-140 expression were detected both in vitro and in vivo. Compared with pBudCE4.1 group, in vitro, the transgenic groups significantly promoted chondrocyte proliferation, increased glycosaminoglycan (GAG) synthesis, and ACAN, COL2A1, and TIMP-1 levels, and reduced the levels of nitric oxide (NO), MMP-13, and ADAMTS-5. In vivo, the exogenous genes enhanced COL2A1, ACAN, and TIMP-1 expression in cartilage and reduced cartilage Mankin score and the contents of NO, IL-1ß, TNF-α, and GAG contents in synovial fluid of rabbits, MMP-13, ADAMTS-5, COL1A2, and COL10A1 levels in cartilage. Double gene combination showed better results than single gene. This study indicate that pNNS-CS is a better gene delivery vehicle in gene therapy for cartilage defects and that miR-140 combination IGF-1 transfection has better biologic effects on cartilage defects.

BGFE: A Deep Learning Model for ncRNA-Protein Interaction Predictions Based on Improved Sequence Information.

The interactions between ncRNAs and proteins are critical for regulating various cellular processes in organisms, such as gene expression regulations. However, due to limitations, including financial and material consumptions in recent experimental methods for predicting ncRNA and protein interactions, it is essential to propose an innovative and practical approach with convincing performance of prediction accuracy. In this study, based on the protein sequences from a biological perspective, we put forward an effective deep learning method, named BGFE, to predict ncRNA and protein interactions. Protein sequences are represented by bi-gram probability feature extraction method from Position Specific Scoring Matrix (PSSM), and for ncRNA sequences, k-mers sparse matrices are employed to represent them. Furthermore, to extract hidden high-level feature information, a stacked auto-encoder network is employed with the stacked ensemble integration strategy. We evaluate the performance of the proposed method by using three datasets and a five-fold cross-validation after classifying the features through the random forest classifier. The experimental results clearly demonstrate the effectiveness and the prediction accuracy of our approach. In general, the proposed method is helpful for ncRNA and protein interacting predictions and it provides some serviceable guidance in future biological research.

Targeting ALDH2 with disulfiram/copper reverses the resistance of cancer cells to microtubule inhibitors.

Disulfiram (DSF) in combination with copper (Cu) has been reported to override drug resistance in cancer cells, and DSF combined with chemotherapy based on the microtubule inhibitor vinorelbine appears to prolong survival in non-small cell lung cancer patients. Here, we investigated the mechanisms underlying these findings. DSF/Cu reversed the microtubule inhibitor resistance in A549/Taxol and KB/VCR cells in vitro, and had anti-tumor effects in A549/Taxol and KB/VCR xenograft mice. DSF/Cu and DSF reduced the cancer stem cell (CSC) characteristics of drug-resistant A549/Taxol and KB/VCR cells, including sphere formation, colony generation and migration, and DSF/Cu was more effective than DSF alone. DSF/Cu also decreased the aldehyde dehydrogenase (ALDH) activity and the expression of P-gp and stem cell transcription factors in A549/Taxol and KB/VCR cells. Knockdown of ALDH2 attenuated the CSC characteristics of resistant cancer cells and enhanced their sensitivity to Taxol or VCR. Importantly, DSF/Cu treatment inhibited the expression of ALDH2 in vitro and in vivo. Our findings suggest that DSF/Cu reverses microtubule inhibitor resistance in cancer cells by suppressing ALDH2 expression, and Cu improves the activity of DSF.

Effect of Tongxinluo on pulmonary hypertension and pulmonary vascular remodeling in rats exposed to a low pressure hypoxic environment.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongxinluo (TXL), which is a Chinese medicine rooted from traditional used herbs, has been used in clinic to treat cardiovascular and cerebrovascular diseases. However, it remains unknown whether TXL alleviates low pressure hypoxic pulmonary hypertension. AIM OF THE STUDY: Here, we aimed to observe the influence of TXL on pulmonary hypertension in a rat model that exposed to high altitude environment characterized by low pressure hypoxia. MATERIALS AND METHODS: A total of 32 male Sprague-Dawley rats were divided into four groups: control group (normal pressure and normoxia), pulmonary hypertension group (PAH, the parameter is equal to that in altitude 5000m), TXL group (rats living in environment equal to that at altitude of 5000m received TXL treatment), vardenafil group (VDNF, rats living in environment equal to that altitude of 5000m received vardenafil treatment). The high altitude environment was created in chamber by adjusting the inner pressure and oxygen content concomitantly. Before entering the chamber, the TXL group was given TXL (1.2gkg-1d-1) for 28 days, and the VDNF group was given VDNF (0.1gkg-1d-1) for 28 days. After 28 days, the mean pulmonary artery pressure (mPAP) and right ventricular pressure was measured using right heart catheterization. The weight of the right ventricle (RV), left ventricle (LV) and interventricular septum (IVS) was measured, and the right ventricular mass index was calculated. Lung tissue was subjected to hematoxylin and elastic fiber staining, and the medial wall thickness (MT), medial wall cross-sectional area (MA), MT%, and MA% were measured. Proliferative activity within the pulmonary arteries was quantified by Ki67staining. RESULTS: After 28 days, as compared with that in normal control group, animals living in the chamber (PAH group) showed a significant increase in mPAP( 47.5mmHg versus 18mmHg), RV/LV+IVS (0.45 versus 0.21) and MA% (78% versus 44%), respectively. Administration of TXL resulted in a significant decrease of 20mmHg in mPAP, returning of RV/LV+IVS to 0.27, and a 40% reduction in MT% compared with that in PAH group. In the VDNF group, RV/LV+IVS and MT% was 0.268 and 38.77, significantly lower than that in PAH group. While, mPAP increased by 12.5mmHg with treatment by VDNF. In contrast to the PAH group, alpha- Smooth Muscle Actin (α-SMA reduced by 19% in the TXL group (p=0.005) and 16% in the VDNF group (p=0.01). Ki67 expression in the VDNF group was significantly lower than the PAH group (P<0.01). Ki67 expression in the TXL group was significantly lower than the PAH group (P<0.01). Compared with the VDNF group, the indexes above reduced in the TXL group. Our results indicate that TXL significantly reduces pulmonary artery pressure, right ventricular hypertrophy, pulmonary small artery wall thickness, and luminal stenosis. In addition, smooth muscle proliferation markedly decreased and muscular artery decreased. However, TXL was unable to restore parameters to control levels. CONCLUSIONS: The automatic-adjusted low pressure hypoxic chamber was capable of establishing a pulmonary hypertension rat model at an altitude of 5000m. Compared with VDNF, TXL decreased mPAP and right ventricular hypertrophy index (RVHI) in the pulmonary hypertension rat model, and prevented vascular remodeling by reducing small pulmonary artery thickening, smooth muscle thickening and proliferation. Thus, TXL may be a potential treatment for pulmonary hypertension.

A new porous MOF with two uncommon metal-carboxylate-pyrazolate clusters and high CO2/N2 selectivity.

By a less-exploited strategy, a stable framework was constructed by using 4,4'-biphenyldicarboxylic acid (H2bpdc) and methyl-functionalized 3,3',5,5'-tetramethyl-4,4'-bipyrazole (H2bpz) coligands, revealing a new (6,8)-connected net based on two extremely rare trinuclear and tetranuclear metal-carboxylate-pyrazolate clusters. The framework is very porous and possesses not only high CO2 loadings but also very high CO2/N2 selectivities at 308 and 313 K because of the polar pore surface decorated by clusters, pyrazolyl units, and confined cages with methyl groups dangling. Importantly, GCMC simulation identified two favorable CO2 sorption sites located sequentially near Co3(pz)3 and Co3(CO2)2(pz) motifs of the tetranuclear cluster, and the multipoint framework-CO2 interactions were distinguished. The framework also displays remarkable stability toward water and organic solvents.

[Effects of maternal exposure to nano-alumina during pregnancy on neurodevelopment in offspring mice].

OBJECTIVE: To observe the effects of maternal exposure to nano-alumina during pregnancy on the neurodevelopment in offspring mice. METHODS: Female ICR mice began to be exposed to nano-alumina 10 d before mating, and the nano-alumina exposure lasted till offspring mice were born. All the female mice were randomly divided into 5 groups: solvent control group (saline), nano-carbon group (11.76 mg/ml), micro-alumina group (50 mg/ml), 50 nm alumina group (50 mg/ml), and 13 nm alumina group (50 mg/ml). All the mice were treated by nasal drip (10 µl/time) 3 times daily till offspring mice were born. Physiological indices, reflex and sensory function test, endurance test, Morris water maze test, positioning and navigation test, and open field test were used to evaluate the neurodevelopment of newborn mice. RESULTS: On day 28, the body weight of 13 nm alumina group (16.73±4.04 g) was significantly lower than that of solvent control group (20.45±2.50 g) (P<0.01); the 13 nm alumina group had significantly delayed time to ear opening compared with the solvent control group (4.91±0.78 d vs 4.45±0.50 d, P<0.01); compared with the solvent control group, the nano-carbon group, micro-alumina group, 50 nm alumina group, and 13 nm alumina group had significantly delayed time to eruption of teeth (10.05±0.23 d vs 10.32±0.48 d, 10.75±0.45 d, 10.32±0.47 d, and 10.79±0.49 d, P<0.05 or P<0.01). On days 4 and 7 after birth, compared with the solvent control group, other groups had significantly decreased proportions of mice which passed the cliff avoidance test (P < 0.05 or P < 0.01). On days 12 and 14 after birth, compared with the solvent control group, the nano-carbon group, 50 nm alumina group, and 13 nm alumina group had significantly reduced pre-suspension time in the endurance test (P < 0.05 or P < 0.01). The Morris water maze and positioning and navigation tests showed that the 13 nm alumina group had a significantly increased 5 d incubation period compared with the solvent control group (P < 0.05); compared with the solvent control group, other groups had significantly reduced numbers of platform crossings (P < 0.05 or P < 0.01). The open field test showed that the nano-carbon group and 13 nm alumina group had reduced numbers of rearings compared with the solvent control group (P < 0.05); compared with the solvent control group, other groups had significantly reduced numbers of modifications (P < 0.01). CONCLUSION: Maternal exposure to nano-alumina (13 nm) during pregnancy has inhibitory effects on the physical development and early behavioral development in newborn mice and can also inhibit the learning and memory abilities and adaptability to new environment in offspring mice. The neurodevelopmental toxicity of nano-alumina to newborn mice increases as the particle sizes of nano-alumina decrease, which has been demonstrated by the endurance test and number of rearings.

An organocatalytic asymmetric sequential allylic alkylation-cyclization of Morita-Baylis-Hillman carbonates and 3-hydroxyoxindoles.

The first organocatalytic asymmetric sequential allylic alkylation-cyclization of Morita-Baylis-Hillman carbonates and 3-hydroxyoxindoles has been developed to afford spirooxindoles bearing α-methylene-γ-butyrolactone motifs in 25-85% yield, 60-94% ee and up to >20 : 1 diastereoselectivity.

A 3D porous metal-organic framework containing nanotubes based on multiple helices.

Combining Co2 clusters with mixed H2bpdc and H2bpz ligands creates an unprecedented 3-fold interpenetrated 5-connected porous framework, which possesses the fascinating double-walled nanotubes structure assembled from nonuple and triple helices, and exhibits gas sorption properties.

A polar tetrazolyl-carboxyl microporous Zn(II)-MOF: sorption and luminescent properties.

A Zn(II)-MOF [Zn(2)(tzba)(DMF)]·0.5DMF (1) (H(2)tzba = 4-(1H-tetrazol-5-yl) benzoic acid, DMF = N,N'-dimethylformamide) has been solvothermally synthesized and characterized. 1 is a three-dimensional (3D) microporous framework possessing an unusual multi-nodal (3,3,6)- or (4,4,4,4)-connected topological net. The small-sized pores, open metal sites, phenyl π systems and tetrazolyl groups of tzba(2-) decorating the pore with high polarity enable 1 to attract strongly for CO(2), which leads to high sorption heat for CO(2) and significant selectivities for CO(2) over H(2) and N(2). In addition, 1 and desolvated 1' display strong and weak blue luminescence in solid state, respectively, being mainly related to the framework vibration due to the residing and releasing of DMF molecules in the channel.

Direct asymmetric vinylogous Mannich reaction of 3,4-dihalofuran-2(5H)-one with aldimine catalyzed by quinine.

The direct asymmetric vinylogous Mannich reaction of 3,4-dihalofuran-2(5H)-one with aldimine catalyzed by quinine was first reported, and γ-butenolides have been obtained in excellent yield (up to 98%) and enantioselectivities (up to 95% ee). The synthetic applications of this protocol are demonstrated in the preparations of γ-substituted amino butyrolactones and vicinal amino alcohols.

Organocatalytic stereocontrolled synthesis of 3,3'-pyrrolidinyl spirooxindoles by [3+2] annulation of isocyanoesters with methyleneindolinones.

A stereoselective [3+2] cycloaddition of isocyanoesters to methyleneindolinones catalyzed by a quinine-based thiourea-tertiary amine has been successfully developed. Just by tuning the protecting groups on substrates, a variety of optically enriched 3,3'-pyrrolidinyl spirooxindole diastereomers could be obtained in excellent enantioselectivities (up to 99% ee).

Asymmetric Michael addition of α-substituted isocyanoacetates with maleimides catalyzed by chiral tertiary amine thiourea.

A highly diastereoselective and enantioselective Michael addition of α-substituted isocyanoacetates with maleimides catalyzed by bifunctional tertiary amine thioureas has been developed. Various chiral succinimide derivatives bearing adjacent quaternary and tertiary stereocenters were prepared in excellent yields (up to 98%), diastereoselectivities (up to 99:1), and enantioselectivities (up to 98% ee). The synthetic utility of chiral succinimide derivatives is also demonstrated in the preparation of h5-HT(1d) receptor agonist motifs.