Dual orexin receptor antagonist ameliorates sleep deprivation-induced learning and memory impairment in APP/PS1 mice.

Sleep is considered closely related to cognitive function, and cognitive impairment is the main clinical manifestation of Alzheimer's disease (AD). Sleep disturbance in AD patients is more severe than that in healthy elderly individuals. Additionally, sleep deprivation reportedly increases the activity of the hypothalamic orexin system and the risk of AD. To investigate whether intervention with the orexin system can improve sleep disturbance in AD and its impact on AD pathology. In this study, six-month-old amyloid precursor protein/presenilin 1 mice were subjected to six weeks of chronic sleep deprivation and injected intraperitoneally with almorexant, a dual orexin receptor antagonist (DORA), to investigate the effects and mechanisms of sleep deprivation and almorexant intervention on learning and memory in mice with AD. We found that sleep deprivation aggravated learning and memory impairment and increased brain ß-amyloid (Aß) deposition in mice with AD. The application of almorexant can increase the total sleep time of sleep-deprived mice and reduce cognitive impairment and Aß deposition, which is related to the improvement in Aquaporin-4 polarity. Thus, DORA may be an effective strategy for delaying the progression of AD patients by improving the sleep disturbances.

Reversible Dual Fluorescence-Lifetime Imaging of Mitochondrial GSH and Microviscosity: Real-Time Evaluation of Ferroptosis Status.

Ferroptosis, as a new form of regulated cell death, is implicated in various physiological and pathological processes. Developing a single probe for an independent analysis of multiple analytes related to ferroptosis can provide more accurate information and simplify the detection procedures, but it faces great challenges. In this work, we develop a fluorescent probe for the simultaneous detection of GSH through ratiometric fluorescence response and microviscosity via a fluorescence lifetime model. Based on the reversible Michael addition reaction between GSH and unsaturated C═C bond, the probe responds reversibly to GSH with a ratiometric fluorescence variation and a fast response time (t1/2 = 4.7 s). At the same time, the probe is sensitive to environmental viscosity by changing its fluorescence lifetimes. The probe was applied to monitor the drug-induced ferroptosis process through both the classical Xc-/GSH/GPX4- and DHODH-mediated defense mechanisms. We hope that the probe will provide a useful molecular tool for the real-time live-cell imaging of GSH dynamics, which is benefit to unveiling related physiological and pathological processes.

Pan-cancer analysis of the tumorigenic role of Fanconi anemia complementation group D2 (FANCD2) in human tumors.

Monoubiquitination of FANCD2 is a central step in the activation of the Fanconi anemia (FA) pathway after DNA damage. Defects in the FA pathway centered around FANCD2 not only lead to genomic instability but also induce tumorigenesis. At present, few studies have investigated FANCD2 in tumors, and no pan-cancer research on FANCD2 has been conducted. We conducted a comprehensive analysis of the role of FANCD2 in cancer using public databases and other published studies. Moreover, we evaluated the role of FANCD2 in the proliferation, migration and invasion of lung adenocarcinoma cells through in vitro and in vivo experiments, and explored the role of FANCD2 in cisplatin chemoresistance. We investigated the regulatory effect of FANCD2 on the cell cycle of lung adenocarcinoma cells by flow cytometry, and verified this effect by western blotting. FANCD2 expression is elevated in most TCGA tumors and shows a strong positive correlation with poor prognosis in tumor patients. In addition, FANCD2 expression shows strong correlations with immune infiltration, immune checkpoints, the tumor mutation burden (TMB), and microsatellite instability (MSI), which are immune-related features, suggesting that it may be a potential target of tumor immunotherapy. We further found that FANCD2 significantly promotes the proliferation, invasion, and migration abilities of lung adenocarcinoma cells and that its ability to promote cancer cell proliferation may be achieved by modulating the cell cycle. The findings indicate that FANCD2 is a potential biomarker and therapeutic target in cancer treatment by analyzing the oncogenic role of FANCD2 in different tumors.

4-Octyl itaconate alleviates renal ischemia reperfusion injury by ameliorating endoplasmic reticulum stress via Nrf2 pathway.

Renal ischemia-reperfusion injury (IRI) is a common clinical complication of multiple severe diseases. Owing to its high mortality and the lack of effective treatment, renal IRI is still an intractable problem for clinicians. Itaconate, which is a metabolite of cis-aconitate, can exert anti-inflammatory and antioxidant roles in many diseases. As a derivative of itaconate with high cell membrane permeability, 4-octyl itaconate (4-OI) could provide a protective effect for various diseases. However, the role of 4-OI in renal IRI is still unclear. Herein, we examined whether 4-OI afforded kidney protection through attenuating endoplasmic reticulum stress (ERS) via nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. To observe the effects of 4-OI on alleviating renal pathologic injury, improving renal dysfunction, decreasing inflammatory cytokines, and reducing oxidative stress, we utilized C57BL/6J mice with bilateral renal pedicle clamped and HK-2 cells with hypoxia/reoxygenation (H/R) exposure in our study. In addition, through western blot assay, we found 4-OI ameliorated renal IRI-induced ERS, and activated Nrf2 pathway. Moreover, Nrf2-knockout (KO) mice and Nrf2 knockdown HK-2 cells were used to validate the role of Nrf2 signaling pathway in 4-OI-mediated alleviation of ERS caused by renal IRI. We demonstrated that 4-OI relieved renal injury and suppressed ERS in wild-type mice, while the therapeutic role was not shown in Nrf2-KO mice. Similarly, 4-OI could exert cytoprotective effect and inhibit ERS in HK-2 cells after H/R, but not in Nrf2 knockdown cells. Our in vivo and in vitro studies revealed that 4-OI protected renal IRI through attenuating ERS via Nrf2 pathway.

Development and validation of a new model for the early diagnosis of tuberculous meningitis in adults based on simple clinical and laboratory parameters.

BACKGROUND: The differential diagnosis between tuberculous meningitis (TBM) and viral meningitis (VM) or bacterial meningitis (BM) remains challenging in clinical practice, particularly in resource-limited settings. This study aimed to establish a diagnostic model that can accurately and early distinguish TBM from both VM and BM in adults based on simple clinical and laboratory parameters. METHODS: Patients diagnosed with TBM or non-TBM (VM or BM) between January 2012 and October 2021 were retrospectively enrolled from the General Hospital (derivation cohort) and Branch Hospital (validation cohort) of Ningxia Medical University. Demographic characteristics, clinical symptoms, concomitant diseases, and cerebrospinal fluid (CSF) parameters were collated. Univariable logistic analysis was performed in the derivation cohort to identify significant variables (P < 0.05). A multivariable logistic regression model was constructed using these variables. We verified the performance including discrimination, calibration, and applicability of the model in both derivation and validation cohorts. RESULTS: A total of 222 patients (70 TBM and 152 non-TBM [75 BM and 77 VM]) and 100 patients (32 TBM and 68 non-TBM [31 BM and 37 VM]) were enrolled as derivation and validation cohorts, respectively. The multivariable logistic regression model showed that disturbance of consciousness for > 5 days, weight loss > 5% of the original weight within 6 months, CSF lymphocyte ratio > 50%, CSF glucose concentration < 2.2 mmol/L, and secondary cerebral infarction were independently correlated with the diagnosis of TBM (P < 0.05). The nomogram model showed excellent discrimination (area under the curve 0.959 vs. 0.962) and great calibration (P-value in the Hosmer-Lemeshow test 0.128 vs. 0.863) in both derivation and validation cohorts. Clinical decision curve analysis showed that the model had good applicability in clinical practice and may benefit the entire population. CONCLUSIONS: This multivariable diagnostic model may help clinicians in the early discrimination of TBM from VM and BM in adults based on simple clinical and laboratory parameters.

Three-dimensional ultrasound-based radiomics nomogram for the prediction of extrathyroidal extension features in papillary thyroid cancer.

Purpose: To develop and validate a three-dimensional ultrasound (3D US) radiomics nomogram for the preoperative prediction of extrathyroidal extension (ETE) in papillary thyroid cancer (PTC). Methods: This retrospective study included 168 patients with surgically proven PTC (non-ETE, n = 90; ETE, n = 78) who were divided into training (n = 117) and validation (n = 51) cohorts by a random stratified sampling strategy. The regions of interest (ROIs) were obtained manually from 3D US images. A larger number of radiomic features were automatically extracted. Finally, a nomogram was built, incorporating the radiomics scores and selected clinical predictors. Receiver operating characteristic (ROC) curves were performed to validate the capability of the nomogram on both the training and validation sets. The nomogram models were compared with conventional US models. The DeLong test was adopted to compare different ROC curves. Results: The area under the receiver operating characteristic curve (AUC) of the radiologist was 0.67 [95% confidence interval (CI), 0.580-0.757] in the training cohort and 0.62 (95% CI, 0.467-0.746) in the validation cohort. Sixteen features from 3D US images were used to build the radiomics signature. The radiomics nomogram, which incorporated the radiomics signature, tumor location, and tumor size showed good calibration and discrimination in the training cohort (AUC, 0.810; 95% CI, 0.727-0.876) and the validation cohort (AUC, 0.798; 95% CI, 0.662-0.897). The result suggested that the diagnostic efficiency of the 3D US-based radiomics nomogram was better than that of the radiologist and it had a favorable discriminate performance with a higher AUC (DeLong test: p < 0.05). Conclusions: The 3D US-based radiomics signature nomogram, a noninvasive preoperative prediction method that incorporates tumor location and tumor size, presented more advantages over radiologist-reported ETE statuses for PTC.

Changes and significance of vascular endothelial injury markers in patients with diabetes mellitus and pulmonary thromboembolism.

BACKGROUND: To investigate the changes and clinical significance of vascular endothelial injury markers in type 2 diabetes mellitus (T2DM) complicated with pulmonary embolism (PE). METHODS: This prospective study enrolled patients with T2DM hospitalized in one hospital from January 2021 to June 2022. Soluble thrombomodulin (sTM) (ELISA), von Willebrand factor (vWF) (ELISA), and circulating endothelial cells (CECs) (flow cytometry) were measured. PE was diagnosed by computed tomography pulmonary angiography (CTPA). RESULTS: Thirty participants were enrolled in each group. The plasma levels of sTM (151.22 ± 120.57 vs. 532.93 ± 243.82 vs. 1016.51 ± 218.00 pg/mL, P < 0.001) and vWF (9.63 ± 2.73 vs. 11.50 ± 2.17 vs. 18.02 ± 3.40 ng/mL, P < 0.001) and the percentage of CECs (0.17 ± 0.46 vs. 0.30 ± 0.08 vs. 0.56 ± 0.18%, P < 0.001) gradually increased from the control group to the T2DM group to the T2DM + PE group. sTM (OR = 1.002, 95%CI: 1.002-1.025, P = 0.022) and vWF (OR = 1.168, 95%CI: 1.168-2.916, P = 0.009) were associated with T2DM + PE. sTM > 676.68 pg/mL for the diagnosis of T2DM + PE achieved an AUC of 0.973, while vWF > 13.75 ng/mL achieved an AUC of 0.954. The combination of sTM and vWF above their cutoff points achieved an AUC of 0.993, with 100% sensitivity and 96.7% specificity. CONCLUSIONS: Patients with T2DM show endothelial injury and dysfunction, which were worse in patients with T2DM and PE. High sTM and vWF levels have certain clinical predictive values for screening T2DM accompanied by PE.

Development and Validation of a Radiomics Model Based on 3-Dimensional Endoanal Rectal Ultrasound of Rectal Cancer for Predicting Lymph Node Metastasis.

BACKGROUND: Development of a radiomics model for predicting lymph node metastasis status in rectal cancer patients based on 3-dimensional endoanal rectal ultrasound images. METHODS: This study retrospectively included 79 patients (41 with lymph node metastasis positive and 38 with lymph node metastasis negative) diagnosed with rectal cancer in our hospital from January 2018 to February 2022. The tumor's region of interest is first delineated by radiologists, from which radiomics features are extracted. Radiomics features were then selected by independent samples t-test, correlation coefficient analysis between features, and least absolute shrinkage and regression with selection operator. Finally, a multilayer neural network model is developed using the selected radiomics features, and nested cross-validation is performed on it. These models were validated by assessing their diagnostic performance and comparing the areas under the curve and recall rate curve in the test set. RESULTS: The areas under the curve of radiologist was 0.662 and the F1 score was 0.632. Thirty-four radiomics features were significantly associated with lymph node metastasis (P < .05), and 10 features were finally selected for developing multilayer neural network models. The areas under the curve of the multilayer neural network models were 0.787, 0.761, 0.853, and the mean areas under the curve was 0.800. The F1 scores of the multilayer neural network models were 0.738, 0.740, and 0.818, and the mean F1 score was 0.771. CONCLUSIONS: Radiomics models based on 3-dimensional endoanal rectal ultrasound can be used to identify lymph node metastasis status in rectal cancer patient with good diagnostic performance.

The relationship between home-based physical activity and general well-being among Chinese university students during the COVID-19 pandemic: the mediation effect of self-esteem.

This study aimed to investigate the mediating effect of self-esteem on the relationship between home-based physical activity and the general well-being of university students. A web-based questionnaire survey was conducted on 311 Chinese university students using the Physical Activity Rating Scale, Rosenberg Self-Esteem Scale, and General Well-Being Scale. The influence of home-based physical activity on self-esteem and general well-being in Chinese university students was explored using a one-way ANOVA analysis of variance. The mediating model was tested with regression analysis to determine the mediating effects of self-esteem between home-based physical activity and general well-being among Chinese university students during COVID-19. The amount of home-based physical activity had a significant effect on the general well-being (F = 3.46, P < 0.05) and self-esteem (F = 6.99, P < 0.01) of university students. The study found that self-esteem had a full mediation (T = 4.445, P < 0.001) between medium and large amounts of home-based physical activity and general well-being among university students, accounting for 32.5% of the total effect. The study concluded that self-esteem mediated the relationship between home-based physical activity and general well-being in university students during the COVID-19 pandemic. The findings in this study highlight the importance of home-based physical activity in increasing the general well-being of university students during the pandemic.

Interferon-α2a induces CD4+ T cell apoptosis and suppresses Th1/Th17 responses via upregulating IRF1-mediated PDL1 expression in dendritic cells from Behcet's uveitis.

Recombinant interferon-α2a (IFNα2a) has been widely used in the treatment of Behcet's uveitis (BU). However, the mechanism underlying its effects remains poorly understood. In this study, we investigated its effect on dendritic cells (DCs) and CD4+ T cells, which are essential for the development of BU. Our results showed that the expression of PDL1 and IRF1 was significantly decreased in DCs from active BU patients, and IFNα2a could significantly upregulate PDL1 expression in an IRF1-dependent manner. IFNα2a-treated DCs induced CD4+ T cells apoptosis and inhibited the Th1/Th17 immune response in association with reduced secretion of IFN-γ and IL-17. We also found that IFNα2a promoted Th1 cell differentiation and IL-10 secretion by CD4+ T cells. Finally, a comparison of patients before and after IFNα2a therapy revealed that the frequencies of Th1/Th17 cells significantly decreased in association with remission of uveitis after IFNα2a therapy. Collectively, these results show that IFNα2a could exert its effects by modulating the function of DCs and CD4+ T cells in BU.

Correlation Analysis of Molecularly-Defined Cortical Interneuron Populations with Morpho-Electric Properties in Layer V of Mouse Neocortex.

Cortical interneurons can be categorized into distinct populations based on multiple modalities, including molecular signatures and morpho-electrical (M/E) properties. Recently, many transcriptomic signatures based on single-cell RNA-seq have been identified in cortical interneurons. However, whether different interneuron populations defined by transcriptomic signature expressions correspond to distinct M/E subtypes is still unknown. Here, we applied the Patch-PCR approach to simultaneously obtain the M/E properties and messenger RNA (mRNA) expression of >600 interneurons in layer V of the mouse somatosensory cortex (S1). Subsequently, we identified 11 M/E subtypes, 9 neurochemical cell populations (NCs), and 20 transcriptomic cell populations (TCs) in this cortical lamina. Further analysis revealed that cells in many NCs and TCs comprised several M/E types and were difficult to clearly distinguish morpho-electrically. A similar analysis of layer V interneurons of mouse primary visual cortex (V1) and motor cortex (M1) gave results largely comparable to S1. Comparison between S1, V1, and M1 suggested that, compared to V1, S1 interneurons were morpho-electrically more similar to M1. Our study reveals the presence of substantial M/E variations in cortical interneuron populations defined by molecular expression.

Sncg, Mybpc1, and Parm1 Classify subpopulations of VIP-expressing interneurons in layers 2/3 of the somatosensory cortex.

Neocortical vasoactive intestinal polypeptide-expressing (VIP+) interneurons display highly diverse morpho-electrophysiological and molecular properties. To begin to understand the function of VIP+ interneurons in cortical circuits, they must be clearly and comprehensively classified into distinct subpopulations based on specific molecular markers. Here, we utilized patch-clamp RT-PCR (Patch-PCR) to simultaneously obtain the morpho-electric properties and mRNA profiles of 155 VIP+ interneurons in layers 2 and 3 (L2/3) of the mouse somatosensory cortex. Using an unsupervised clustering method, we identified 3 electrophysiological types (E-types) and 2 morphological types (M-types) of VIP+ interneurons. Joint clustering based on the combined electrophysiological and morphological features resulted in 3 morpho-electric types (ME-types). More importantly, we found these 3 ME-types expressed distinct marker genes: ~94% of Sncg+ cells were ME-type 1, 100% of Mybpc1+ cells were ME-type 2, and ~78% of Parm1+ were ME-type 3. By clarifying the properties of subpopulations of cortical L2/3 VIP+ interneurons, this study establishes a basis for future investigations aiming to elucidate their physiological roles.

Catalytic Reversible (De)hydrogenation To Rotate a Chemically Fueled Molecular Switch.

We report here the development of a rotating molecular switch based on metal-catalyzed reversible (de)-hydrogenation. Under an argon atmosphere, acceptorless dehydrogenation induces a switch from an alcohol to a ketone, while reversing to a hydrogen pressure switches back the system to the alcohol. Based on a tolane scaffold, such reversible (de)-hydrogenation enables 180° rotation. The absence of waste accumulation in a switch relying on chemical stimuli is of great significance and could potentially be applied to the design of efficient complex molecular machines.

Catalysis Driven Six-Step Synthesis of Apratoxin A Key Polyketide Fragment.

Apratoxin A is a potent anticancer natural product whose key polyketide fragment constitutes a considerable challenge for organic synthesis, with five prior syntheses requiring 12 to 20 steps for its preparation. By combining different redox-economical catalytic stereoselective transformations, the key polyketide fragment could be rapidly prepared. Followed by a site-selective protection of the diol, this strategy enables the preparation of the apratoxin A fragment in only six steps, representing the shortest route to this polyketide.

Impact of Helicobacter pylori Infection and Outcome of Anti-Helicobacter pylori Therapy in Patients with Reflux Laryngopharyngitis.

Objectives: This study was designed to explore the relationship between Helicobacter pylori (Hp) infection and reflux laryngopharyngitis (RLP) and to evaluate the outcome of anti-Hp therapy in improving RLP symptoms. Methods: A total of 410 patients with RLP were enrolled and tested for Hp infection. The association of Hp infection with reflux symptom index (RSI) and reflux finding score (RFS) was determined. Hp-positive patients received either a proton pump inhibitor (PPI) omeprazole alone (control group) or a combination regimen (experimental group) consisting of omeprazole, mosapride citrate, amoxicillin, and clarithromycin. Therapeutic outcomes were compared 4 weeks later. Results: Of the 410 participants, 290 were Hp-positive and 120 Hp-negative. Both RSI and RFS were significantly higher in Hp-positive patients than in Hp-negative patients. Hp infection status was positively correlated with RSI (P < 0.05) and RFS (P < 0.05). The overall response rate was higher in the experimental group than in the control group. Both the groups had a significant reduction in RSI and RFS after therapy, with a greater improvement in the experimental group (P < 0.05). Conclusion: Our findings establish a link between Hp infection and RLP. Anti-Hp therapy improves RSI and RFS in RLP patients. Therefore, Hp eradication drugs may be added to the PPI-based regimen in the treatment of RLP.

The mutation spectrum of Parkinson-disease-related genes in early-onset Parkinson's disease in ethnic Chinese.

BACKGROUND AND PURPOSE: Recent genetic progress has shown many causative/risk genes linked to Parkinson's disease (PD), mainly in patients of European ancestry. The study aimed to investigate the PD-related genes and determine the mutational spectrum of early-onset PD in ethnic Chinese. METHODS: In this study, whole-exome sequencing and/or gene dosage analysis were performed in 704 early-onset PD (EOPD) patients (onset age ≤45 years) and 1866 controls. Twenty-six PD-related genes and 20 other genes linked to neurodegenerative and lysosome diseases were analysed. RESULTS: Eighty-two (11.6%, 82/704) EOPD patients carrying rare pathogenic/likely pathogenic variants in PD-related genes were identified. The mutation frequency in autosomal recessive inheritance EOPD (42.9%, 27/63) was much higher than that in autosomal dominant inheritance EOPD (0.9%, 12/110) or sporadic EOPD (8.1%, 43/531). Bi-allelic mutations in PRKN were the most frequent, accounting for 5.1% of EOPD cases. Three common pathogenic variants, p.A53V in SNCA, p.G284R in PRKN and p.P53Afs*38 in CHCHD2, occur exclusively in Asians. The putative damaging variants from GBA, PRKN, DJ1, PLA2G6 and GCH1 contributed to the collective risk for EOPD. Notably, the protein-truncating variants in CHCHD2 were enriched in EOPD, especially for p.P53Afs*38, which was also found in three patients from an independent cohort of patients with late-onset PD (n = 1300). Functional experiments confirmed that truncated CHCHD2 variants cause loss of function and are linked to mitochondrial dysfunction. CONCLUSIONS: Our study reveals that the genetic spectrum of EOPD in Chinese, which may help develop genetic scanning strategies, provided more evidence supporting CHCHD2 in PD.

[Clinical features of diffuse large B-cell lymphoma in head and neck].

Objective:To investigate the clinical features of diffuse large B-cell lymphoma （DLBCL） of head and neck. Methods:A retrospective study was conducted among patients with DLBCL in the Department of otolaryngology and head and neck surgery of the Second Affiliated Hospital of Xi'an Jiaotong University from July 2011 to September 2021. The disease location, clinical manifestations, diagnosis, treatment and prognosis of DLBCL patients in head and neck were analyzed retrospectively. Results:Oropharynx（27 cases, including 25 cases in tonsil）, neck（29 cases）, nasopharynx and nasal cavity （7 cases）were included in 63 cases of DLBCL in head and neck. Pharyngalgia, pharyngeal foreign body sensation and dysphagia were the most common manifestations of oropharyngeal DLBCL, while nasal obstruction, runny nose and hyposmia were the initial manifestations of nasal and nasopharyngeal DLBCL.Under the NBI endoscopy, locally uplifted neoplasm with rough surface mucosa was observed in 34 cases DLBCL patients of oropharynx, nasopharynx and nasal cavity. Among them, 16 cases were covered with yellow-white and patchy pseudomembrane on the surface of the neoplasm, and 5 cases were detected with abnormal new vessels, including 3 cases of tonsils, 1 case of root of tongue, and 1 case of nasopharynx. Painless progressive lymphadenectasis was the common manifestation of DLBCL in head and neck, and the maximum diameter（[21.3±6.7]mm） of neck lymph nodes in the same side of DLBCL was significantly larger than that in the opposite side（[16.0±7.2]mm, P=0.009）. Sixty-three cases of DLBCL in head and neck, including 27 cases of germinal center type（GCB）, 33 cases of nongerminal center type（non-GCB）, and 3 cases of non-specific DLBCL, were confirmed the diagnosis by needle biopsy（33 cases, 52.4%） and surgical resection（30 cases, 47.6%）. The imaging features of DLBCL in head and neck were mostly showed as local soft tissue masses with uniform density and uneven enhancement, and the surrounding structures were often compressed and displaced. All the patients were treated with standard R-CHOP chemotherapy regimens, and overall survival was longer in normal LDH, and overall survival of the patients at low risk of IPI was longer than those at medium-high or high risk of IPI（PLDH=0.011, PIPI=0.022, P<0.05）. Conclusion:DLBCL mainly occurs in oropharynx, especially the unilateral tonsil. When flake yellow-white pseudomembrane adhesion and abnormal neovessels on the surface of the mass are detected under endoscopy, and the ultrasound suggested multiple enlarged lymph nodes in the neck with large iplateral lymph nodes, the possibility of DLBCL should be considered. Surgical resection could be performed for diagnosis if necessary, and early diagnosis would have a better prognosis.

Enantioselective Synthesis of Acyclic Stereotriads Featuring Fluorinated Tetrasubstituted Stereocenters.

Elaboration of enantioenriched complex acyclic stereotriads represents a challenge for modern synthesis even more when fluorinated tetrasubstituted stereocenters are targeted. We have been able to develop a simple strategy in a sequence of two unprecedented steps combining a diastereoselective aldol-Tishchenko reaction and an enantioselective organocatalyzed kinetic resolution. The aldol-Tishchenko reaction directly generates a large panel of acyclic 1,3-diols possessing a fluorinated tetrasubstituted stereocenter by condensation of fluorinated ketones with aldehydes under very mild basic conditions. The anti 1,3-diols featuring three contiguous stereogenic centers are generated with excellent diastereocontrol (typically >99 : 1 dr). Depending upon the precursors both diastereomers of stereotriads are accessible through this flexible reaction. Furthermore, from the obtained racemic scaffolds, development of an organocatalyzed kinetic resolution enabled to generate the desired enantioenriched stereotriads with excellent selectivity (typically er >95 : 5).

Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population.

BACKGROUND: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. METHODS: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. FINDINGS: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. CONCLUSIONS: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.