Single-cell spatial transcriptome reveals cell-type organization in the macaque cortex.

Elucidating the cellular organization of the cerebral cortex is critical for understanding brain structure and function. Using large-scale single-nucleus RNA sequencing and spatial transcriptomic analysis of 143 macaque cortical regions, we obtained a comprehensive atlas of 264 transcriptome-defined cortical cell types and mapped their spatial distribution across the entire cortex. We characterized the cortical layer and region preferences of glutamatergic, GABAergic, and non-neuronal cell types, as well as regional differences in cell-type composition and neighborhood complexity. Notably, we discovered a relationship between the regional distribution of various cell types and the region's hierarchical level in the visual and somatosensory systems. Cross-species comparison of transcriptomic data from human, macaque, and mouse cortices further revealed primate-specific cell types that are enriched in layer 4, with their marker genes expressed in a region-dependent manner. Our data provide a cellular and molecular basis for understanding the evolution, development, aging, and pathogenesis of the primate brain.

LXR agonism for CNS diseases: promises and challenges.

The unfavorable prognosis of many neurological conditions could be attributed to limited tissue regeneration in central nervous system (CNS) and overwhelming inflammation, while liver X receptor (LXR) may regulate both processes due to its pivotal role in cholesterol metabolism and inflammatory response, and thus receives increasing attentions from neuroscientists and clinicians. Here, we summarize the signal transduction of LXR pathway, discuss the therapeutic potentials of LXR agonists based on preclinical data using different disease models, and analyze the dilemma and possible resolutions for clinical translation to encourage further investigations of LXR related therapies in CNS disorders.

scPretrain: multi-task self-supervised learning for cell-type classification.

MOTIVATION: Rapidly generated scRNA-seq datasets enable us to understand cellular differences and the function of each individual cell at single-cell resolution. Cell-type classification, which aims at characterizing and labeling groups of cells according to their gene expression, is one of the most important steps for single-cell analysis. To facilitate the manual curation process, supervised learning methods have been used to automatically classify cells. Most of the existing supervised learning approaches only utilize annotated cells in the training step while ignoring the more abundant unannotated cells. In this article, we proposed scPretrain, a multi-task self-supervised learning approach that jointly considers annotated and unannotated cells for cell-type classification. scPretrain consists of a pre-training step and a fine-tuning step. In the pre-training step, scPretrain uses a multi-task learning framework to train a feature extraction encoder based on each dataset's pseudo-labels, where only unannotated cells are used. In the fine-tuning step, scPretrain fine-tunes this feature extraction encoder using the limited annotated cells in a new dataset. RESULTS: We evaluated scPretrain on 60 diverse datasets from different technologies, species and organs, and obtained a significant improvement on both cell-type classification and cell clustering. Moreover, the representations obtained by scPretrain in the pre-training step also enhanced the performance of conventional classifiers, such as random forest, logistic regression and support-vector machines. scPretrain is able to effectively utilize the massive amount of unlabeled data and be applied to annotating increasingly generated scRNA-seq datasets. AVAILABILITY AND IMPLEMENTATION: The data and code underlying this article are available in scPretrain: Multi-task self-supervised learning for cell type classification, at https://github.com/ruiyi-zhang/scPretrain and https://zenodo.org/record/5802306. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Tunable Gas-Gas Reactions through Nanobubble Pathway.

Combustible gas-gas reactions usually do not occur spontaneously upon mixing without ignition or other triggers to lower the activation energy barrier. Nanobubbles, however, could provide such a possibility in solution under ambient conditions due to high inner pressure and catalytic radicals within their boundary layers. Herein, a tunable gas-gas reaction strategy via bulk nanobubble pathway is developed by tuning the interface charge of one type of bulk nanobubble and promoting its fusion and reaction with another, where the reaction-accompanied size and number concentration change of the bulk nanobubbles and the corresponding thermal effect clearly confirm the occurrence of the nanobubble-based H2 /O2 combustion. In addition, abundant radicals can be detected during the reaction, which is considered to be critical to ignite the gas reaction during the fusion of nanobubbles in water at room temperature. Therefore, the nanobubble-based gas-gas reactions provide a safe and efficient pathway to produce energy and synthesize new matter inaccessible under mild or ambient conditions.

High-efficiency mechanically assisted alkaline extraction of nanoparticles from biological tissues for spICP-MS analysis.

The widespread use and increased exposure of nanoparticles call for technology to quantify their concentration and size distribution in biological matrices. As ex situ evaluation, facile extraction with high fidelity and efficiency is critical. In this work, single particle inductively coupled plasma mass spectrometry (spICP-MS) was used for nanoparticle number and distribution analysis, where a facile and highly efficient mechanically assisted alkaline digestion has been developed to extract nanoparticles at low alkali concentration. The optimization was performed using chicken tissues in vitro mixed with 30 nm gold nanoparticles, mixture of 30 nm and 60 nm gold nanoparticles, and 45 nm silver nanoparticles, respectively, which is, then, mechanically ground to form tissue homogenate and 2% TMAH is added. The nanoparticles are extracted with a recovery of more than 94% for all the spiked nanoparticle tissue samples. The extraction method has also been attempted to be applied to extract single-sized gold nanoparticles from various organs of mice mixed in vivo with the nanoparticles through intravenous injection, and led to consistent results with acid digestion. Mice injected intravenously with double-sized gold nanoparticle mixture were also studied, further showing that gold nanoparticles of 30 nm and 60 nm have no significant difference in their biodistribution in the same organ. To the best of our knowledge, this is the first attempt for multiple nanoparticles being extracted simultaneously and measured quantitatively from various organs, such as the heart, liver, spleen, lungs, and kidneys. We believe this method is beneficial to the safety assessment and toxicokinetics studies for nanoparticles in tissues.

Tumor microenvironment-responsive BSA nanocarriers for combined chemo/chemodynamic cancer therapy.

Tumor microenvironment (TME), characterized by high glutathione (GSH), high hydrogen peroxide (H2O2) and acidic pH levels, is favorable for the growth, invasion and metastasis of cancer cells. Taking advantage of the specific characteristics of tumors, TME-responsive GCBD NPs are designed to deliver nanoscale coordination polymers (NCPs, GA-Cu) and chemotherapy drugs (doxorubicin, DOX) based on bovine serum albumin (BSA) nanocarriers into cancer cells for combined chemodynamic therapy (CDT) and chemotherapy. In an acidic environment, GCBD NPs could release approximately 90% copper ions, which can not only consume overexpressed GSH to modulate the TME but can also react with endogenous H2O2 in a Fenton-like reaction to achieve the CDT effect. Meanwhile, the released DOX could enter the nucleus of tumor cells and affect their proliferation to achieve efficient chemotherapy. Both in vitro and in vivo experiments showed that GCBD NPs had good biosafety and could effectively inhibit the growth of cancer cells. GCBD NPs are promising as a biocompatible nanoplatform to exploit TME characteristics for combined chemo and chemodynamic therapy, providing a novel strategy to eradicate tumors with high efficiency and specificity.

Lin28B regulates the fate of grafted mesenchymal stem cells and enhances their protective effects against Alzheimer's disease by upregulating IGF-2.

Mesenchymal stem cells (MSCs) transplantation has emerged as a potential therapeutic approach for Alzheimer's disease (AD). However, the poor proliferation capacity and low survival rate of engrafted MSCs in the hostile microenvironment of AD limit their therapeutic efficiency. Lin28B is a conserved RNA-binding protein associated with cell self-renewal and survival. The purpose of the present study was to explore whether lin28B might influence the functions of implanted MSCs and strengthen their neuroprotective potential in AD. A gain-of-function assay was used to upregulate lin28B expression in MSCs by lentiviral transfection. Our in vitro results indicated that lin28B promoted MSCs proliferation and migration, and protected MSCs against Aß1-42-induced cell death by upregulating insulin-like growth factor-2 (IGF-2). Blockage of IGF-2 partially abrogated the above effects of lin28B. After intracerebroventricular injection into amyloid precursor protein/presenilin 1 mice, implanted MSCs were monitored using bioluminescence imaging. We observed that administration of MSCs transfected with lin28B significantly stimulated their proliferation and prolonged cell retention after delivery. Moreover, administration of the transfected MSCs markedly mitigated cognitive deficits, promoted amyloid plaque clearance, decreased the activation of microglia, and reduced neuronal cell death. The data above confirmed our hypothesis that lin28B is a crucial modulator determining the fate of transplanted MSCs by regulating IGF-2-associated pathways and thereby enhancing their protective effects against AD.

Free thyroxine level is associated with both relapse rate and poor neurofunction in first-attack Neuromyelitis Optica Spectrum Disorder (NMOSD) patients.

BACKGROUND: To investigate whether the serum free thyroxine (FT4) level is a prognostic factor for the first-attack neuromyelitis optica spectrum disorders (NMOSD). METHODS: This retrospective study enrolled 109 patients with first-attack NMOSD. The Expanded Disability Status Scale (EDSS) and the relapse rate were used to evaluate the outcomes. The logistic regression model was used to analyze the independent effects of FT4 on relapse and final EDSS. Kaplan-Meier analysis, scatter plot smoothing method, and two-phase piecewise linear regression model were used to investigate the relationship between the FT4 level and the relapse rate. RESULTS: Multivariate analysis revealed that serum FT4 level might be a risk factor for both final EDSS (ß = 0.17; 95% confidence interval: 0.03-0.32) and the relapse rate (HR = 1.18; 95% confidence interval: 1.05-1.32). Furthermore, 1400 days after the onset, nearly 100% of patients in the high-FT4 group relapsed, while only 40% of the patients in the low-FT4 group relapsed. Finally, we found that the relationship between the FT4 level and the NMOSD relapse rate was nonlinear. The risk of NMOSD relapse increased with the FT4 level up to the inflection point of 12.01 pmol/L (HR = 1.45; 95% confidence interval: 1.06-1.98). When the FT4 level was > 12.01 pmol/L, there was no correlation between the FT4 level and the risk of NMOSD relapse (HR = 1.05; 95% confidence interval: 0.78-1.41). CONCLUSION: Serum FT4 level may be a prognostic indicator for the first-attack in patients with NMOSD. High FT4 levels are associated with poor neurofunctions and a high relapse rate in patients with the first-attack in patients with NMOSD.

p16/Ki67 dual staining improves the detection specificity of high-grade cervical lesions.

AIM: The goal of this study was to analyze the specificity of p16/Ki67 dual staining in the detection of high-grade cervical lesions. METHODS: A total of 223 patients with an average age of 39 years old were enrolled in this study. All samples were analyzed by p16/Ki67 immunocytochemical dual staining, liquid-based cytology and high-risk human papillomavirus (HR-HPV) test. Diagnosis of each patient was verified by histopathological test. RESULTS: The specificity of p16/Ki67 dual staining was 68.33%, which was significantly higher than that of cytology (38.33%) and HR-HPV test (21.67%) (P < 0.05) for CIN2+ detection. p16/Ki67 dual staining had similar sensitivity with HR-HPV test for CIN2+ detection (90.18% vs 93.87%, P = 0.286). In atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) cases, the specificity of p16/Ki67 dual staining was significantly higher than that of HPV test (66.67% vs 3.70%, P < 0.05) and its sensitivity was similar to that of HPV test for CIN2+ detection. The sensitivity and specificity of dual staining for CIN2+ detection in HR-HPV positive women were 90.85% and 70.21%, respectively, which were higher than those of cytology (83.01% and 42.55%) and HPV16/18 test (70.59% and 44.68%). CONCLUSIONS: p16/Ki67 dual staining could improve the specificity of high-grade cervical lesions detection and have similar sensitivity to HPV test for CIN2+ detection. When triaging women with ASC-US or LSIL liquid-based cytology, compared with positive HR-HPV, the specificity of CIN2+ lesion detection was increased by p16/Ki67 dual staining. p16/Ki67 dual staining could reduce colposcopy referrals and avoid excessive diagnosis and treatment.

Inductive biases of neural network modularity in spatial navigation.

The brain may have evolved a modular architecture for daily tasks, with circuits featuring functionally specialized modules that match the task structure. We hypothesize that this architecture enables better learning and generalization than architectures with less specialized modules. To test this, we trained reinforcement learning agents with various neural architectures on a naturalistic navigation task. We found that the modular agent, with an architecture that segregates computations of state representation, value, and action into specialized modules, achieved better learning and generalization. Its learned state representation combines prediction and observation, weighted by their relative uncertainty, akin to recursive Bayesian estimation. This agent's behavior also resembles macaques' behavior more closely. Our results shed light on the possible rationale for the brain's modularity and suggest that artificial systems can use this insight from neuroscience to improve learning and generalization in natural tasks.

Effects of nitrogen addition and Bothriochloa ischaemum and Lespedeza davurica mixture on plant chlorophyll fluorescence and community production in semi-arid grassland.

Background: Grass-legume mixture can effectively improve productivity and stimulate overyielding in artificial grasslands, but may be N-limited in semi-arid regions. This study investigated the effects of N addition on chlorophyll fluorescence and production in the grass-legume mixtures community. Methods: An N addition experiment was conducted in the Bothriochloa ischaemum and Lespedeza davurica mixture community, with seven mixture ratios (B0L10, B2L8, B4L6, B5L5, B6L4, B8L2, and B10L0) according to the sowing abundance of B.ischaemum and L.davurica and four N addition levels, N0, N25, N50, and N75 (0,25,50,75kgNhm-2 a-1), respectively. We analyzed the response of chlorophyll fluorescence parameters of the two species, the rapid light-response curves of chlorophyll fluorescence, as well as aboveground biomass (AGB) and overyielding. Results: Our results showed that the two species showed different photosynthetic strategies, with L.davurica having significantly higher initial fluorescence (Fo), effective photochemical quantum yield of PSII (ΦPSII), and coefficient of photochemical fluorescence quenching (qP) than B. ischaemum, consisting with results of rapid light-response curves. N addition and mixture ratio both had significant effects on chlorophyll fluorescence and AGB (p<0.001). The ΦPSII and qP of L.davurica were significantly lowest in B5L5 and B6L4 under N addition, and the effect of N varied with mixture ratio. The photosynthetic efficiency of B. ischaemum was higher in mixture than in monoculture (B10L0), and ΦPSII was significantly higher in N50 than in N25 and N50 at mixture communities except at B5L5. The community AGB was significantly higher in mixture communities than in two monocultures and highest at B6L4. In the same mixture ratio, the AGB was highest under the N50. The overyielding effects were significantly highest under the N75 and B6L4 treatments, mainly attributed to L.davurica. The partial least squares path models demonstrated that adding N increased soil nutrient content, and complementary utilization by B.ischaemum and L.davurica increased the photosynthetic efficiency. However, as the different photosynthetic strategies of these two species, the effect on AGB was offset, and the mixture ratio's effects were larger than N. Our results proposed the B6L4 and N50 treatments were the optimal combination, with the highest AGB and overyielding, moderate grass-legume ratio, optimal community structure, and forage values.

Innovation and evaluation of vocational pharmaceutical education system under the 1 + X certificate system in China.

BACKGROUND AND OBJECTIVES: The 1 + X certificate system, introduced in China in 2019, integrates academic credentials with vocational skill certificates to meet the heightened demand for skilled talents in the growing economy. This study aims to innovate and evaluate the vocational pharmaceutical education system under the 1 + X certificate framework, specifically addressing the gap between theoretical education and workplace requirements. MATERIALS AND METHODS: A retrospective observational approach analyzed 490 pharmacy students over two academic years. The 2021 cohort underwent 1 + X integrated education, while the 2020 cohort followed conventional education. We collaborated closely with industry partners to identify and compile typical job competencies, formulating work projects aligned with industry demands. Combining the skill level standards and assessment content of "1+X Pharmaceutical Purchasing and Sales" and "1+X Pharmaceutical Preparation", we revised the course standards, incorporating typical work projects into the 2021 pharmacy professional teaching curriculum. This constituted the fundamental content of the 1 + X education reform. Statistical analysis compared course scores and 1 + X certificate examination performance. RESULTS: The 2021 cohort, under the 1 + X educational model, demonstrated higher average scores in pharmacy courses, with significant improvements in pharmacology (1 + X vs. Traditional education: 58.40 ± 14.20 vs. 53.44 ± 14.67), clinical pharmacotherapy (72.74 ± 10.28 vs. 63.15 ± 11.03), and pharmaceutical distribution and marketing (79.34 ± 10.96 vs. 67.50 ± 15.82). 1 + X certificate pass rates and satisfaction with the model were also higher than the 2020 cohort. CONCLUSION: The 1 + X certificate system is useful for developing talent in Chinese vocational education, effectively integrating assessments with industry standards. Future research should aim at evaluating long-term outcomes and improving quantitative skills assessments for enhanced effectiveness.

Metabolite Profiling and Identification of Sweet/Bitter Taste Compounds in the Growth of Cyclocarya Paliurus Leaves Using Multiplatform Metabolomics.

Cyclocarya paliurus tea, also known as "sweet tea", an herbal tea with Cyclocarya paliurus leaves as raw material, is famous for its unique nutritional benefits and flavor. However, due to the unique "bittersweet" of Cyclocarya paliurus tea, it is still unable to fully satisfy consumers' high-quality taste experience and satisfaction. Therefore, this study aimed to explore metabolites in Cyclocarya paliurus leaves during their growth period, particularly composition and variation of sweet and bitter taste compounds, by combining multi-platform metabolomics analysis with an electronic tongue system and molecular docking simulation technology. The results indicated that there were significant differences in the contents of total phenols, flavonoids, polysaccharides, and saponins in C. paliurus leaves in different growing months. A total of 575 secondary metabolites were identified as potential active metabolites related to sweet/bitter taste using nontargeted metabolomics based on UHPLC-MS/MS analysis. Moreover, molecular docking technology was utilized to study interactions between the candidate metabolites and the sweet receptors T1R2/T1R3 and the bitter receptors T2R4/T2R14. Six key compounds with high sweetness and low bitterness were successfully identified by using computational simulation analysis, including cis-anethole, gluconic acid, beta-D-Sedoheptulose, asparagine, proline, and citrulline, which may serve as candidates for taste modification in Cyclocarya paliurus leaves. These findings provide a new perspective for understanding the sweet and bitter taste characteristics that contribute to the distinctive sensory quality of Cyclocarya paliurus leaves.

The NRF2-CARM1 axis links glucose sensing to transcriptional and epigenetic regulation of the pentose phosphate pathway in gastric cancer.

Cancer cells autonomously alter metabolic pathways in response to dynamic nutrient conditions in the microenvironment to maintain cell survival and proliferation. A better understanding of these adaptive alterations may reveal the vulnerabilities of cancer cells. Here, we demonstrate that coactivator-associated arginine methyltransferase 1 (CARM1) is frequently overexpressed in gastric cancer and predicts poor prognosis of patients with this cancer. Gastric cancer cells sense a reduced extracellular glucose content, leading to activation of nuclear factor erythroid 2-related factor 2 (NRF2). Subsequently, NRF2 mediates the classic antioxidant pathway to eliminate the accumulation of reactive oxygen species induced by low glucose. We found that NRF2 binds to the CARM1 promoter, upregulating its expression and triggering CARM1-mediated hypermethylation of histone H3 methylated at R arginine 17 (H3R17me2) in the glucose-6-phosphate dehydrogenase gene body. The upregulation of this dehydrogenase, driven by the H3R17me2 modification, redirects glucose carbon flux toward the pentose phosphate pathway. This redirection contributes to nucleotide synthesis (yielding nucleotide precursors, such as ribose-5-phosphate) and redox homeostasis and ultimately facilitates cancer cell survival and growth. NRF2 or CARM1 knockdown results in decreased H3R17me2a accompanied by the reduction of glucose-6-phosphate dehydrogenase under low glucose conditions. Collectively, this study reveals a significant role of CARM1 in regulating the tumor metabolic switch and identifies CARM1 as a potential therapeutic target for gastric cancer treatment.

Turtling: a time-aware neural topic model on NIH grant data.

Motivation: Recent initiatives for federal grant transparency allow direct knowledge extraction from large volumes of grant texts, serving as a powerful alternative to traditional surveys. However, its computational modeling is challenging as grants are usually multifaceted with constantly evolving topics. Results: We propose Turtling, a time-aware neural topic model with three unique characteristics. First, Turtling employs pretrained biomedical word embedding to extract research topics. Second, it leverages a probabilistic time-series model to allow smooth and coherent topic evolution. Lastly, Turtling leverages additional topic diversity loss and funding institute classification loss to improve topic quality and facilitate funding institute prediction. We apply Turtling on publicly available NIH grant text and show that it significantly outperforms other methods on topic quality metrics. We also demonstrate that Turtling can provide insights into research topic evolution by detecting topic trends across decades. In summary, Turtling may be a valuable tool for grant text analysis. Availability and implementation: Turtling is freely available as an open-source software at https://github.com/aicb-ZhangLabs/Turtling.

Prominent elevation of extracellular matrix molecules in intracerebral hemorrhage.

Background: Intracerebral hemorrhage (ICH) is the predominant type of hemorrhagic stroke with high mortality and disability. In other neurological conditions, the deposition of extracellular matrix (ECM) molecules is a prominent obstacle for regenerative processes and an enhancer of neuroinflammation. Whether ECM molecules alter in composition after ICH, and which ECM members may inhibit repair, remain largely unknown in hemorrhagic stroke. Methods: The collagenase-induced ICH mouse model and an autopsied human ICH specimen were investigated for expression of ECM members by immunofluorescence microscopy. Confocal image z-stacks were analyzed with Imaris 3D to assess the association of immune cells and ECM molecules. Sections from a mouse model of multiple sclerosis were used as disease and staining controls. Tissue culture was employed to examine the roles of ECM members on oligodendrocyte precursor cells (OPCs). Results: Among the lectican chondroitin sulfate proteoglycan (CSPG) members, neurocan but not aggrecan, versican-V1 and versican-V2 was prominently expressed in perihematomal tissue and lesion core compared to the contralateral area in murine ICH. Fibrinogen, fibronectin and heparan sulfate proteoglycan (HSPG) were also elevated after murine ICH while thrombospondin and tenascin-C was not. Confocal microscopy with Imaris 3D rendering co-localized neurocan, fibrinogen, fibronectin and HSPG molecules to Iba1+ microglia/macrophages or GFAP+ astrocytes. Marked differentiation from the multiple sclerosis model was observed, the latter with high versican-V1 and negligible neurocan. In culture, purified neurocan inhibited adhesion and process outgrowth of OPCs, which are early steps in myelination in vivo. The prominent expression of neurocan in murine ICH was corroborated in human ICH sections. Conclusion: ICH caused distinct alterations in ECM molecules. Among CSPG members, neurocan was selectively upregulated in both murine and human ICH. In tissue culture, neurocan impeded the properties of oligodendrocyte lineage cells. Alterations to the ECM in ICH may adversely affect reparative outcomes after stroke.

Enhancing the oxygen reduction activity by constructing nanocluster-scaled Fe2O3/Cu interfaces.

Interface engineering is a promising strategy to enhance the catalytic performance of electrocatalysts for the oxygen reduction reaction (ORR). However, it is still a challenge to modulate the size into a suitable range (e.g., nanocluster-scale) to make the most of the interface. Moreover, the explicit mechanism of the interface for enhancing catalytic performance is still elusive. Herein, a model catalyst (FeCu@NC) loaded with nanocluster-scaled Fe2O3/Cu interfaces was prepared by modulating the metal components of the precursor to explore the enhancement of interface engineering for the ORR. Benefiting from the synergistic effect of the strong interfacial coupling effects of Fe2O3/Cu and optimized microstructure, FeCu@NC exhibited superior ORR activity and zinc-air battery performance. Experimental and theoretical calculations revealed that the presence of the Fe2O3/Cu interface breaks the traditional cognition to endow the Cu atoms (intrinsically inferior for the ORR) with a slight positive charge, which serves as the active sites for the ORR. This study provides a novel insight into the design of advanced electrocatalysts for the ORR by interface engineering.

Enhanced liver X receptor signalling reduces brain injury and promotes tissue regeneration following experimental intracerebral haemorrhage: roles of microglia/macrophages.

BACKGROUND: Inflammation-exacerbated secondary brain injury and limited tissue regeneration are barriers to favourable prognosis after intracerebral haemorrhage (ICH). As a regulator of inflammation and lipid metabolism, Liver X receptor (LXR) has the potential to alter microglia/macrophage (M/M) phenotype, and assist tissue repair by promoting cholesterol efflux and recycling from phagocytes. To support potential clinical translation, the benefits of enhanced LXR signalling are examined in experimental ICH. METHODS: Collagenase-induced ICH mice were treated with the LXR agonist GW3965 or vehicle. Behavioural tests were conducted at multiple time points. Lesion and haematoma volume, and other brain parameters were assessed using multimodal MRI with T2-weighted, diffusion tensor imaging and dynamic contrast-enhanced MRI sequences. The fixed brain cryosections were stained and confocal microscopy was applied to detect LXR downstream genes, M/M phenotype, lipid/cholesterol-laden phagocytes, oligodendrocyte lineage cells and neural stem cells. Western blot and real-time qPCR were also used. CX3CR1CreER: Rosa26iDTR mice were employed for M/M-depletion experiments. RESULTS: GW3965 treatment reduced lesion volume and white matter injury, and promoted haematoma clearance. Treated mice upregulated LXR downstream genes including ABCA1 and Apolipoprotein E, and had reduced density of M/M that apparently shifted from proinflammatory interleukin-1ß+ to Arginase1+CD206+ regulatory phenotype. Fewer cholesterol crystal or myelin debris-laden phagocytes were observed in GW3965 mice. LXR activation increased the number of Olig2+PDGFRα+ precursors and Olig2+CC1+ mature oligodendrocytes in perihaematomal regions, and elevated SOX2+ or nestin+ neural stem cells in lesion and subventricular zone. MRI results supported better lesion recovery by GW3965, and this was corroborated by return to pre-ICH values of functional rotarod activity. The therapeutic effects of GW3965 were abrogated by M/M depletion in CX3CR1CreER: Rosa26iDTR mice. CONCLUSIONS: LXR agonism using GW3965 reduced brain injury, promoted beneficial properties of M/M and facilitated tissue repair correspondent with enhanced cholesterol recycling.

Obesity in acute ischaemic stroke patients treated with intravenous thrombolysis therapy.

OBJECTIVES: This article aimed to analyze the relationship between obesity and the efficacy of acute ischaemic stroke patients treated with IVT. BACKGROUND: Stroke causes morbidity and mortality in large numbers of individuals annually. Intravenous thrombolysis (IVT)with recombinant tissue plasminogen activator (r-tPA) is currently the only approved by the FDA for treatment of acute ischaemic stroke. Researchers have focused on studying the mechanisms associated with ischaemic stroke. Obesity is an established vascular risk factor with increasing prevalence and a huge impact on public health worldwide. It is an independent predictor for ischaemic stroke with a 4% risk increase for each unit augmentation in body mass index (BMI). Therefore, obese patients will constitute an increasing subgroup of candidates for IVT. However, its impact on prognosis in acute ischaemic stroke patients with intravenous thrombolysis did not reach a consensus conclusion. METHODS: Systematic literature search of PUBMED databases published before August 2020, was performed to identify studies addressing the role of obesity in acute ischaemic stroke patients treated with IVT. Studies included randomized clinical trials, observational studies, guideline statements, and review articles. CONCLUSIONS: Obesity may be related to long-term prognosis of large group of AIS patients treated with IVT. It depends on the scale of clinical study samples, follow-up time, and evaluation criteria.

Case Report: Identification of a novel LYN::LINC01900 transcript with promyelocytic phenotype and TP53 mutation in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a malignant disease of myeloid hematopoietic stem/progenitor cells characterized by the abnormal proliferation of primitive and naive random cells in the bone marrow and peripheral blood. Acute promyelocytic leukemia (APL) is a type (AML-M3) of AML. Most patients with APL have the characteristic chromosomal translocation t(15; 17)(q22; q12), forming PML::RARA fusion. The occurrence and progression of AML are often accompanied by the emergence of gene fusions such as PML::RARA, CBFß::MYH11, and RUNX1::RUNX1T1, among others. Gene fusions are the main molecular biological abnormalities in acute leukemia, and all fusion genes act as crucial oncogenic factors in leukemia. Herein, we report the first case of LYN::LINC01900 fusion transcript in AML with a promyelocytic phenotype and TP53 mutation. Further studies should address whether new protein products may result from this fusion, as well as the biological function of these new products in disease occurrence and progression.