Discovery and directed evolution of C-C bond formation enzymes for the biosynthesis of ß-hydroxy-α-amino acids and derivatives.

ß-Hydroxy-α-amino acids (ß-HAAs) have extensive applications in the pharmaceutical, chemical synthesis, and food industries. The development of synthetic methodologies aimed at producing optically pure ß-HAAs has been driven by practical applications. Among the various synthetic methods, biocatalytic asymmetric synthesis is considered a sustainable approach due to its capacity to generate two stereogenic centers from simple prochiral precursors in a single step. Therefore, extensive efforts have been made in recent years to search for effective enzymes which enable such biotransformation. This review provides an overview on the discovery and engineering of C-C bond formation enzymes for the biocatalytic synthesis of ß-HAAs. We highlight examples where the use of threonine aldolases, threonine transaldolases, serine hydroxymethyltransferases, α-methylserine aldolases, α-methylserine hydroxymethyltransferases, and engineered alanine racemases facilitated the synthesis of ß-HAAs. Additionally, we discuss the potential future advancements and persistent obstacles in the enzymatic synthesis of ß-HAAs.

A Giant Magneto-Superelasticity of 5% Enabled by Introducing Ordered Dislocations in Ni34Co8Cu8Mn36Ga14 Single Crystal.

Elasticity, featured by a recoverable strain, refers to the ability that materials can return to their original shapes after deformation. Typically, the elastic strains of most metals are well-known 0.2%. In shape memory alloys and high entropy alloys, the elastic strains can be several percent, as called superelasticity, which are all triggered by external stresses. A superelasticity induced by magnetic field, termed as magneto-superelasticity, is extremely important for contactless work of materials and for developing brand-new large stroke actuators and high efficiency energy transducers. In magnetic shape memory alloys, the twin boundary motion driven by magnetic field can output a strain of several percent. However, this strain is unrecoverable when removing the magnetic field and hence it is not magneto-superelasticity. Here, a giant magneto-superelasticity of 5% in a Ni34Co8Cu8Mn36Ga14 single crystal is reported by introducing arrays of ordered dislocations to form preferentially oriented martensitic variants during the magnetically induced reverse martensitic transformation. This work provides an opportunity to achieve high performance in functional materials by defect engineering.

The variation of antigenic and histo-blood group binding sites synergistically drive the evolution among chronologically emerging GII.4 noroviruses.

Norovirus, commonly found on shellfish and vegetables, is a foodborne virus with GII.4 as the dominant genotype responsible for widespread outbreaks since 1995. Continuous variation of major capsid protein VP1 can lead to changes in the immunogenicity and host receptor binding ability of norovirus, which is an important evolutionary mechanism. Therefore, analyzing the immunogenicity of VP1 and its binding ability to various HBGAs in GII.4 variants could improve our understanding of the persistent prevalence of GII.4. Here, the results suggest that GII.4 has gradually enhanced its HBGAs binding ability over time for various types of receptors. Variants exhibit significantly stronger immune response to homologous mouse antiserum than heterologous ones, highlighting the importance of variation of antigenic and histo-blood group binding sites in driving the evolution of GII.4. These synergistic forces constantly lead to antigenic drift and changes in receptor binding, resulting in continuous emergence of new variant strains and sustained prevalence.

Protective effect of carbon dots as antioxidants on intestinal inflammation by regulating oxidative stress and gut microbiota in nematodes and mouse models.

Inflammatory bowel disease (IBD) is a recurrent chronic colitis disease with increasing incidence and prevalence year by year. The single efficacy and significant side effects of traditional IBD treatment drugs have promoted the flourishing development of new drugs. Inspired by many health benefits of carbon dots (CDs) based nanomedicine in biomedical applications, a metal-free carbon dots (CP-CDs) was synthesized from citric acid and polyethylene polyamine to treat colitis. Oxidative stress tests at the cellular and nematode levels demonstrated CP-CDs have good antioxidant effects, while the toxicity of CP-CDs to cells and nematodes is low. CP-CDs were further applied to dextran sodium sulfate (DSS)-induced colitis in mice models, and it was found that CP-CDs can reduce the disease activity index (DAI) score of colon tissue and restore the intestinal barrier. Further, the anti-colitis mechanisms of CP-CDs were explored, one of which is to regulate intestinal oxidative stress in inflammatory mice, further reducing the expression of inflammatory cytokines, and thus alleviating colitis. Notably, 16S rRNA sequence analysis showed that the abundance of beneficial bacteria (Ligilactobacillus and Enterorhabdus) in the intestinal tract increased, while that of harmful bacteria (unclassified_Clostridia_UCG_014) decreased after CP-CDs treatment, indicating that CP-CDs rebalancing the gut microbiota destroyed by DSS is another important mechanism. In short, these non-toxic carbon dots not only have the potential for multi-factor combined relief of colitis but also offer an alternative therapy medicine for patients suffering from IBD.

Minor protopanaxadiol type sapogenins from the alkali hydrolysate of stems-leaves of Panax notoginseng.

Two new protopanaxadiol type sapogenins, (3ß,12ß)-3,12,20-trihydroxydammar-24-en-26-al (1) and (3ß,12ß)-3,12,20-trihydroxydammar-24-en-26-oic acid (2), were isolated from the alkali hydrolysate of stems-leaves of Panax notoginseng, along with seven known analogues (3-9). Their structures were elucidated by spectroscopic analyses and single-crystal X-ray diffraction. Compound 2 and the known sapogenins 5-8 displayed weak to moderate inhibition of NO production in LPS-induced RAW264.7 macrophages with IC50 values from 44.5 to 143.6 µM, respectively.

Dual-emission carbon dots for ratiometric fluorescence sensing of thiabendazole in fruits.

Quantitative determination of pesticides in fruits and vegetables is essential for human healths. Herein, a new dual-emission carbon dots with high fluorescence stability at a pH range of 4-10 and a temperature range of 0-60 °C was synthesized. And a novel ratiometric fluorescence probe was proposed to detect thiabendazole (TBZ) residue with a wide linear range (0-1000 µM) and low detection limit (0.15 µM). The emission at 512 nm exhibited a special "turn-off" fluorescence sensing of TBZ due to internal filter effect, while that at 361 nm barely changed and worked as reference. Furthermore, the ratiometric fluorescence strategy was successfully applied for determining TBZ in fruits with good recoveries (96.73%-111.17 %, 93.29%-120.78 % and 96.28%-100.57 %, respectively). Notably, the constructed ratiometric fluorescence probe had comparable accuracy to HPLC in detecting unknown concentrations of TBZ in pear juice, demonstrating dual-emission carbon dots possess wide and promising applicability for fluorescence sensing pesticides in the future.

A highly efficient open-shell singlet luminescent diradical with strong magnetoluminescence properties.

Developing open-shell singlet (OS) diradicals with high luminescent properties and exceptional single-molecule magnetoluminescence (ML) performance is extremely challenging. Herein, we propose a concept to enhance luminescent efficiency by adjusting the donor conjugation of OS diradicals, thereby achieving a highly luminescent diradical, DR1, with outstanding stability and making it a viable option for use in the emitting layer of organic light-emitting diodes (OLEDs). More importantly, the 0.5 wt%-DR1 doped film demonstrates significant single-molecule magnetoluminescence (ML) properties. A giant ML value of 210% is achieved at a magnetic field of 7 T, showing the great potential of DR1 in magneto-optoelectronic devices.

Establishing a machine learning model for predicting nutritional risk through facial feature recognition.

Background: Malnutrition affects many worldwide, necessitating accurate and timely nutritional risk assessment. This study aims to develop and validate a machine learning model using facial feature recognition for predicting nutritional risk. This innovative approach seeks to offer a non-invasive, efficient method for early identification and intervention, ultimately improving health outcomes. Methods: We gathered medical examination data and facial images from 949 patients across multiple hospitals to predict nutritional status. In this multicenter investigation, facial images underwent preprocessing via face alignment and cropping. Orbital fat pads were isolated using the U-net model, with the histogram of oriented gradient (HOG) method employed for feature extraction. Standardized HOG features were subjected to principal component analysis (PCA) for dimensionality reduction. A support vector machine (SVM) classification model was utilized for NRS-2002 detection. Our approach established a non-linear mapping between facial features and NRS-2002 nutritional risk scores, providing an innovative method for evaluating patient nutritional status. Results: In context of orbital fat pad area segmentation with U-net model, the averaged dice coefficient is 88.3%. Our experimental results show that the proposed method to predict NRS-2002 scores achieves an accuracy of 73.1%. We also grouped the samples by gender, age, and the location of the hospital where the data were collected to evaluate the classification accuracy in different subsets. The classification accuracy rate for the elderly group was 85%, while the non-elderly group exhibited a classification accuracy rate of 71.1%; Furthermore, the classification accuracy rate for males and females were 69.2 and 78.6%, respectively. Hospitals located in remote areas, such as Tibet and Yunnan, yielded a classification accuracy rate of 76.5% for collected patient samples, whereas hospitals in non-remote areas achieved a classification accuracy rate of 71.1%. Conclusion: The attained accuracy rate of 73.1% holds significant implications for the feasibility of the method. While not impeccable, this level of accuracy highlights the potential for further improvements. The development of this algorithm has the potential to revolutionize nutritional risk assessment by providing healthcare professionals and individuals with a non-invasive, cost-effective, and easily accessible tool.

Synthesis, properties and mechanism of carbon dots-based nano-antibacterial materials.

Antibiotics play an important role in the treatment of diseases, but bacterial resistance caused by their widespread and unreasonable use has become an urgent problem in clinical treatment. With the rapid advancement of nanoscience and nanotechnology, the development of nanomedicine has been transformed into a new approach to the problem of bacterial resistance. As a new type of carbon-based nanomaterial, carbon dots (CDs) have attracted the interest of antibacterial researchers due to their ease of preparation, amphiphilicity, facile surface functionalization, and excellent optical properties, among other properties. This article reviewed the synthesis methods and properties of various CDs and their composites in order to highlight the advancements in the field of CDs-based antibacterial agents. Then we focused on the relationship between the principal properties of CDs and the antibacterial mechanism, including the following: (1) the physical damage caused by the small size, amphiphilicity, and surface charge of CDs. (2) Photogenerated electron transfer characteristics of CDs that produce reactive oxygen species (ROS) in themselves or in other compounds. The ability of ROS to oxidize can lead to the lipid peroxidation of cell membranes, as well as damage proteins and DNA. (3) The nano-enzyme properties of CDs can catalyze reactions that generate ROS. (4) Synergistic antibacterial effect of CDs and antibiotics or other nanocomposites. Finally, we look forward to the challenges that CDs-based nanocomposites face in practical antibacterial applications and propose corresponding solutions to further expand the application potential of nanomaterials in the treatment of infectious diseases, particularly drug-resistant bacterial infections.

Continuous-Wave Lasing in Perovskite LEDs with an Integrated Distributed Feedback Resonator.

Realization of electrically pumped laser diodes based on solution-processed semiconductors is a long-standing challenge. Metal halide perovskites have shown great potential toward this goal due to their excellent optoelectronic properties. Continuous-wave (CW) optically pumped lasing in a real electroluminescent device represents a key step to current-injection laser diodes, but it has not yet been realized. This is mainly due to the challenge of incorporating a resonant cavity into an efficient light-emitting diode (LED) able to sustain intensive carrier injection. Here, CW lasing is reported in an efficient perovskite LED with an integrated distributed feedback resonator, which shows a low lasing threshold of 220 W cm-2 at 110 K. Importantly, the LED works well at a current density of 330 A cm-2 , indicating the carrier injection rate already exceeds the threshold of optically pumping. The results suggest that electrically pumped perovskite laser diodes can be achieved once the Joule heating issue is overcome.

CCNK Gene Deficiency Influences Neural Progenitor Cells Via Wnt5a Signaling in CCNK-Related Syndrome.

OBJECTIVE: Rare variants of CCNK (cyclin K) give rise to a syndrome with intellectual disability. The purpose of this study was to describe the genotype-phenotype spectrum of CCNK-related syndrome and the underlying molecular mechanisms of pathogenesis. METHODS: We identified a number of de novo CCNK variants in unrelated patients. We generated patient-induced pluripotent stem cells (iPSCs) and neural progenitor cells (NPCs) as disease models. In addition, we constructed NPC-specific Ccnk knockout (KO) mice and performed molecular and morphological analyses. RESULTS: We identified 2 new patients harboring CCNK missense variants and followed-up 3 previous reported patients, which constitute the largest patient population analysis of the disease. We demonstrate that both the patient-derived NPC models and the Ccnk KO mouse displayed deficient NPC proliferation and enhanced apoptotic cell death. RNA sequencing analyses of these NPC models uncovered transcriptomic signatures unique to CCNK-related syndrome, revealing significant changes in genes, including WNT5A, critical for progenitor proliferation and cell death. Further, to confirm WNT5A's role, we conducted rescue experiments using NPC and mouse models. We found that a Wnt5a inhibitor significantly increased proliferation and reduced apoptosis in NPCs derived from patients with CCNK-related syndrome and NPCs in the developing cortex of Ccnk KO mice. INTERPRETATION: We discussed the genotype-phenotype relationship of CCNK-related syndrome. Importantly, we demonstrated that CCNK plays critical roles in NPC proliferation and NPC apoptosis in vivo and in vitro. Together, our study highlights that Wnt5a may serve as a promising therapeutic target for the disease intervention. ANN NEUROL 2023;94:1136-1154.

De novo CLPTM1 variants with reduced GABAA R current response in patients with epilepsy.

OBJECTIVE: To investigate the clinical features and potential pathogenesis mechanism of de novo CLPTM1 variants associated with epilepsy. METHODS: Identify de novo genetic variants associated with epilepsy by reanalyzing trio-based whole-exome sequencing data. We analyzed the clinical characteristics of patients with these variants and performed functional in vitro studies in cells expressing mutant complementary DNA for these variants using whole-cell voltage-clamp current recordings and outside-out patch-clamp recordings from transiently transfected human embryonic kidney (HEK) cells. RESULTS: Two de novo missense variants related to epilepsy were identified in the CLPTM1 gene. Functional studies indicated that CLPTM1-p.R454H and CLPTM1-p.R568Q variants reduced the γ-aminobutyric acid A receptor (GABAA R) current response amplitude recorded under voltage clamp compared to the wild-type receptors. These variants also reduced the charge transfer and altered the time course of desensitization and deactivation following rapid removal of GABA. The surface expression of the GABAA R γ2 subunit from the CLPTM1-p.R568Q group was significantly reduced compared to CLPTM1-WT. SIGNIFICANCE: This is the first report of functionally relevant variants within the CLPTM1 gene. Patch-clamp recordings showed that these de novo CLPTM1 variants reduce GABAA R currents and charge transfer, which should promote excitation and hypersynchronous activity. This study may provide insights into the molecular mechanisms of the CLPTM1 variants underlying the patients' phenotypes, as well as for exploring potential therapeutic targets for epilepsy.

Application of comprehensive unit-based safety program model to improve chemotherapy-induced nausea and vomiting in patients with ovarian cancer: a retrospective study.

BACKGROUND: To explore the effect of intervention programs constructed under the guidance of the comprehensive unit-based safety program (CUSP) model on chemotherapy-induced nausea and vomiting (CINV) in patients with ovarian cancer. METHOD: According to the time of admission, 90 ovarian cancer chemotherapy patients in the first affiliated Hospital of Anhui Medical University from June 2019 to September 2020 were divided into an intervention group and a control group with 45 cases each. Both groups of patients received routine intervention, and the intervention group implemented the CUSP program on this basis. The intervention lasted 8 months. Before and after the intervention, the patients in the ward were used the Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool, the Functional Living Index-Emesis (FLIE), and the Hospital Anxiety and Depression Scale (HADS) for the effect evaluation. RESULTS: After the intervention, the degree of nausea and vomiting frequency in the intervention group were significantly lower than that in the control group, especially the degree of nausea in the delayed phase (P < 0.05). The score of the functional living index-emesis in the intervention group was significantly higher than that in the control group (P < 0.05), and the anxiety and depression in the intervention group were significantly relieved compared to the control group (P < 0.05). CONCLUSION: The intervention program guided by the CUSP model can significantly alleviate patients' nausea and vomiting, improve the quality of life, and relieve anxiety and depression. The CUSP model is suitable for clinical practice and has guiding significance for clinical work.

Superresolution live-cell imaging reveals that the localization of TMEM106B to filopodia in oligodendrocytes is compromised by the hypomyelination-related D252N mutation.

Hypomyelination leukodystrophies constitute a group of heritable white matter disorders exhibiting defective myelin development. Initially identified as a lysosomal protein, the TMEM106B D252N mutant has recently been associated with hypomyelination. However, how lysosomal TMEM106B facilitates myelination and how the D252N mutation disrupts that process are poorly understood. We used superresolution Hessian structured illumination microscopy (Hessian-SIM) and spinning disc-confocal structured illumination microscopy (SD-SIM) to find that the wild-type TMEM106B protein is targeted to the plasma membrane, filopodia, and lysosomes in human oligodendrocytes. The D252N mutation reduces the size of lysosomes in oligodendrocytes and compromises lysosome changes upon starvation stress. Most importantly, we detected reductions in the length and number of filopodia in cells expressing the D252N mutant. PLP1 is the most abundant myelin protein that almost entirely colocalizes with TMEM106B, and coexpressing PLP1 with the D252N mutant readily rescues the lysosome and filopodia phenotypes of cells. Therefore, interactions between TMEM106B and PLP1 on the plasma membrane are essential for filopodia formation and myelination in oligodendrocytes, which may be sustained by the delivery of these proteins from lysosomes via exocytosis.

Maternal and perinatal outcomes of low-dose aspirin plus low-molecular-weight heparin therapy on antiphospholipid antibody-positive pregnant women with chronic hypertension.

Objectives: Positive antiphospholipid antibodies (aPLs) and chronic hypertension (CH) in pregnancy are important causes of maternal and neonatal morbidity and mortality. However, there are no relevant studies on the treatment of aPL-positive pregnant women with CH. This study aimed to determine the effect of low-dose aspirin (LDA) plus low-molecular-weight heparin (LMWH) on maternal and perinatal outcomes in persistently aPL-positive pregnant women with CH. Methods: This study was performed at the First Affiliated Hospital of Dalian Medical University in Liaoning, China, from January 2018 to December 2021. Pregnant women diagnosed CH and persistently positive aPL who had no autoimmune disease such as systemic lupus erythematosus, antiphospholipid syndrome were recruited and divided into control group (LDA and LWMH were not used), LDA group (LDA was used) and LDA plus LMWH group (both LDA and LMWH were used) according to whether they use LDA and/or LMWH. A total of 81 patients were enrolled, including 40 patients in the control group, 19 patients in the LDA group, and 22 patients in the LDA plus LMWH group. The maternal and perinatal outcomes of LDA plus LMWH therapy were analysed. Results: Compared with control group, the rate of severe preeclampsia in LDA group (65.00% vs. 31.58%, p = 0.016) and LDA plus LMWH group (65.00% vs. 36.36%, p = 0.030) had a statistically significant reduction. Compared with control group, the rate of fetal loss in LDA group (35.00% vs. 10.53%, p = 0.014) and LDA plus LMWH group (35.00% vs. 0.00%, p = 0.002) had a statistically significant reduction. Compared with control group, the rate of live birth in LDA group (65.00% vs. 89.74%, p = 0.048) and LDA plus LMWH group (65.00% vs. 100.00%, p = 0.002) had a statistically significant increased. Compared withcontrol group, the incidence of early-onset preeclampsia (47.50% vs. 36.84%, p = 0.008) and early-onset severe preeclampsia (47.50% vs. 13.64%, p = 0.001) in the LDA plus LMWH group decreased and were statistically different. Furthermore, we also found that LDA or LDA plus LMWH hadn't increase the rate of blood loss and placental abruption. Conclusion: Both LDA and LDA combined with LMWH could decrease the incidence of severe preeclampsia, decrease the rate of foetal loss, increase the rate of live birth. However, LDA plus LWMH could reduce and delay the onset of severe preeclampsia, prolong the gestational age and increase the rate of full-term delivery, improve the maternal and perinatal outcomes.

CSMD3 Deficiency Leads to Motor Impairments and Autism-Like Behaviors via Dysfunction of Cerebellar Purkinje Cells in Mice.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with highly heritable heterogeneity. Mutations of CUB and sushi multiple domains 3 (CSMD3) gene have been reported in individuals with ASD. However, the underlying mechanisms of CSMD3 for the onset of ASD remain unexplored. Here, using male CSMD3 knock-out (CSMD3 -/-) mice, we found that genetic deletion of CSMD3 produced core autistic-like symptoms (social interaction deficits, restricted interests, and repetitive and stereotyped behaviors) and motor dysfunction in mice, indicating that the CSMD3 gene can be considered as a candidate for ASD. Moreover, we discovered that the ablation of CSMD3 in mice led to abnormal cerebellar Purkinje cell (PC) morphology in Crus I/II lobules, including aberrant developmental dendritogenesis and spinogenesis of PCs. Furthermore, combining in vivo fiber photometry calcium imaging and ex vivo electrophysiological recordings, we showed that the CSMD3 -/- mice exhibited an increased neuronal activity (calcium fluorescence signals) in PCs of Crus I/II lobules in response to movement activity, as well as an enhanced intrinsic excitability of PCs and an increase of excitatory rather than inhibitory synaptic input to the PCs, and an impaired long-term depression at the parallel fiber-PC synapse. These results suggest that CSMD3 plays an important role in the development of cerebellar PCs. Loss of CSMD3 causes abnormal PC morphology and dysfunction in the cerebellum, which may underlie the pathogenesis of motor deficits and core autistic-like symptoms in CSMD3 -/- mice. Our findings provide novel insight into the pathophysiological mechanisms by which CSMD3 mutations cause impairments in cerebellar function that may contribute to ASD.SIGNIFICANCE STATEMENT Autism spectrum disorder (ASD) is a neurodevelopmental disorder with highly heritable heterogeneity. Advances in genomic analysis have contributed to numerous candidate genes for the risk of ASD. Recently, a novel giant gene CSMD3 encoding a protein with CUB and sushi multiple domains (CSMDs) has been identified as a candidate gene for ASD. However, the underlying mechanisms of CSMD3 for the onset of ASD remain largely unknown. Here, we unravel that loss of CSMD3 results in abnormal morphology, increased intrinsic excitabilities, and impaired synaptic plasticity in cerebellar PCs, subsequently leading to motor deficits and ASD-like behaviors in mice. These results provide novel insight into the pathophysiological mechanisms by which CSMD3 mutations cause impairments in cerebellar function that may contribute to ASD.

Indirect Bandgap Emission of the Metal Halide Perovskite FAPbI3 at Low Temperatures.

In this work, we provide a picture of the band structure of FAPbI3 by investigating low-temperature spin-related photophysics. When the temperature is lower than 120 K, two photoluminescence peaks can be observed. The lifetime of the newly emerged low-energy emission is much longer than that of the original high-energy one by two orders of magnitude. We propose that Rashba effect-caused spin-dependent band splitting is the reason for the emergence of the low-energy emission and verify this using the magneto-optical measurements.

Asp-containing actinomycin and tetracyclic chromophoric analogues from the Streptomyces sp. strain S22.

Three novel actinomycins, actimomycin S (1), neo-actinomycins C and D (2 and 3), and one new benzo[d]oxazole alkaloid (4) were isolated from the Streptomyces sp. strain S22, along with three known congeners F9 (5), X2 (6) and X0ß (7) and 2-acetylamino-3-hydroxyl-4-methyl-benzoic acid methyl ester (8). The structures of the new products were elucidated by spectroscopic methods, and the absolute configuration of amino acid residues was determined by Marfey's analysis. Actinomycin S contains an aspartic acid (Asp) residue in the ß-peptidolactone ring. This is the first report of an Asp residue within an actinomycin-type natural product. Notably, neo-actinomycins C and D feature a rare tetracyclic 5H-oxazolo[4,5-b]phenoxazine chromophore. Among these, neo-actinomycin D, with an unprecedented molecular formula, represents the highest molecular weight member in the actinomycin family. Actinomycins 1-3 exhibited antimicrobial activity against multiple resistant "ESKAPE" pathogens with MIC values ranging from 1.25 to 80.0 µg mL-1. In addition, 1-3 showed potent cytotoxic activities against the HepG2 liver carcinoma cell line with IC50 values of 0.10, 0.32, and 0.024 µM, respectively. Furthermore, 1 inhibited cell proliferation by inducing G0-G1 phase arrest in the cell cycle.

A Highly Stable Organic Luminescent Diradical.

It is very challenging to obtain stable room-temperature luminescent open-shell singlet diradicals. Herein we report the first stable Müller's hydrocarbon TTM-PhTTM with luminescent properties. Variable-temperature electron paramagnetic resonance spectroscopy measurements and theoretical calculations show that TTM-PhTTM has an open-shell singlet ground state with a diradical character of 90 %. Because of a small singlet-triplet energy gap, the open-shell singlet ground state can be thermally excited to a triplet state. TTM-PhTTM shows room-temperature deep-red emission in various solutions. Unusually high stability of TTM-PhTTM was also observed owing to effective steric hindrance and spin delocalization. Our results are beneficial to the rational design and discovery of more stable luminescent diradical materials.

Human-induced pluripotent stem cell-derived cerebral organoid of leukoencephalopathy with vanishing white matter.

INTRODUCTION: Leukoencephalopathy with vanishing white matter (VWM) is a rare autosomal recessive leukoencephalopathy resulting from mutations in EIF2B1-5, which encode subunits of eukaryotic translation initiation factor 2B (eIF2B). Studies have found that eIF2B mutation has a certain influence on embryonic brain development. So far, the effect of the eIF2B mutations on the dynamic process of brain development is not fully understood yet. AIMS: Three-dimensional brain organoid technology has promoted the study of human nervous system developmental diseases in recent years, providing a potential platform for elucidating the pathological mechanism of neurodevelopmental diseases. In this study, we aimed to investigate the effects of eIF2B mutation on the differentiation and development of different nerve cells during dynamic brain development process using 3D brain organoids. RESULTS: We constructed eIF2B mutant and wild-type brain organoid model with induced pluripotent stem cell (iPSC). Compared with the wild type, the mutant brain organoids were significantly smaller, accompanied by increase in apoptosis, which might be resulted from overactivation of unfolded protein response (UPR). Neuronal development was delayed in early stage, but with normal superficial neuronal differentiation in later stage. eIF2B mutations resulted in immature astrocytes with increased expression of GFAPδ, nestin, and αB-crystallin, and there were increased oligodendrocyte progenitor cells, decreased mature oligodendrocytes, and sparse myelin in mutant cerebral organoids in the later stage. CONCLUSION: we constructed the first eIF2B mutant cerebral organoids to explore the dynamic brain development process, which provides a platform for further research on the specific pathogenesis of VWM.