A General Photoactive H-Bonding EDA Complex Model Drives the Selective Hydrothiolation and Hydroxysulfenylation of Carbonyl Activated Alkenes.

Excitation of photoactive electron donor-acceptor (EDA) complexes to generate radical is a promising approach in radical chemistry. In this study, we introduce a new model of H-bonding EDA complexes for the selective hydrothiolation and hydroxysulfenylation of carbonyl-activated alkenes with diverse thiols under visible light conditions. The reliability of this H-bonding EDA complex model has been confirmed by meticulous experimental and theoretical calculations. Mechanistic investigations have revealed the significant influence of the solvent in determining whether the excitation of photoactive H-bonding EDA complex leads to charge transfer (CT) or energy-charge transfer (En-CT), thereby controlling Markovnikov and anti-Markovnikov selectivity. Notably, the Quantum Theory of Atoms in Molecules (QTAIM) analysis clearly shows that the excited state of the C＝O---H-S EDA complex involves closed-shell partially covalent interactions.

Synthetic minority over-sampling technique-enhanced machine learning models for predicting recurrence of postoperative chronic subdural hematoma.

Objective: Chronic subdural hematoma (CSDH) is a neurological condition with high recurrence rates, primarily observed in the elderly population. Although several risk factors have been identified, predicting CSDH recurrence remains a challenge. Given the potential of machine learning (ML) to extract meaningful insights from complex data sets, our study aims to develop and validate ML models capable of accurately predicting postoperative CSDH recurrence. Methods: Data from 447 CSDH patients treated with consecutive burr-hole irrigations at Wenzhou Medical University's First Affiliated Hospital (December 2014-April 2019) were studied. 312 patients formed the development cohort, while 135 comprised the test cohort. The Least Absolute Shrinkage and Selection Operator (LASSO) method was employed to select crucial features associated with recurrence. Eight machine learning algorithms were used to construct prediction models for hematoma recurrence, using demographic, laboratory, and radiological features. The Border-line Synthetic Minority Over-sampling Technique (SMOTE) was applied to address data imbalance, and Shapley Additive Explanation (SHAP) analysis was utilized to improve model visualization and interpretability. Model performance was assessed using metrics such as AUROC, sensitivity, specificity, F1 score, calibration plots, and decision curve analysis (DCA). Results: Our optimized ML models exhibited prediction accuracies ranging from 61.0% to 86.2% for hematoma recurrence in the validation set. Notably, the Random Forest (RF) model surpassed other algorithms, achieving an accuracy of 86.2%. SHAP analysis confirmed these results, highlighting key clinical predictors for CSDH recurrence risk, including age, alanine aminotransferase level, fibrinogen level, thrombin time, and maximum hematoma diameter. The RF model yielded an accuracy of 92.6% with an AUC value of 0.834 in the test dataset. Conclusion: Our findings underscore the efficacy of machine learning algorithms, notably the integration of the RF model with SMOTE, in forecasting the recurrence of postoperative chronic subdural hematoma. Leveraging the RF model, we devised an online calculator that may serve as a pivotal instrument in tailoring therapeutic strategies and implementing timely preventive interventions for high-risk patients.

NeuroD4 converts glioblastoma cells into neuron-like cells through the SLC7A11-GSH-GPX4 antioxidant axis.

Cell fate and proliferation ability can be transformed through reprogramming technology. Reprogramming glioblastoma cells into neuron-like cells holds great promise for glioblastoma treatment, as it induces their terminal differentiation. NeuroD4 (Neuronal Differentiation 4) is a crucial transcription factor in neuronal development and has the potential to convert astrocytes into functional neurons. In this study, we exclusively employed NeuroD4 to reprogram glioblastoma cells into neuron-like cells. In vivo, the reprogrammed glioblastoma cells demonstrated terminal differentiation, inhibited proliferation, and exited the cell cycle. Additionally, NeuroD4 virus-infected xenografts exhibited smaller sizes compared to the GFP group, and tumor-bearing mice in the GFP+NeuroD4 group experienced prolonged survival. Mechanistically, NeuroD4 overexpression significantly reduced the expression of SLC7A11 and Glutathione peroxidase 4 (GPX4). The ferroptosis inhibitor ferrostatin-1 effectively blocked the NeuroD4-mediated process of neuron reprogramming in glioblastoma. To summarize, our study demonstrates that NeuroD4 overexpression can reprogram glioblastoma cells into neuron-like cells through the SLC7A11-GSH-GPX4 signaling pathway, thus offering a potential novel therapeutic approach for glioblastoma.

Base-promoted one-pot three-component desulphurization cross-coupling access to 4-cyanoimidazole.

A novel, straightforward, and scalable base-mediated one-pot three-component desulphurization cross-coupling strategy is reported for the synthesis of 4-cyanoimidazole derivatives. Over 35 examples are provided and achieved yields exceeding 85%. Notably, the majority of these readily available compounds can be isolated through simple filtration, thereby circumventing the need for laborious column chromatography. Besides, the present protocol can be scaled up to 10 mmol with a yield of 87%, demonstrating promising potential for industrial applications.

GBE1 Promotes Glioma Progression by Enhancing Aerobic Glycolysis through Inhibition of FBP1.

Tumor metabolism characterized by aerobic glycolysis makes the Warburg effect a unique target for tumor therapy. Recent studies have found that glycogen branching enzyme 1 (GBE1) is involved in cancer progression. However, the study of GBE1 in gliomas is limited. We determined by bioinformatics analysis that GBE1 expression is elevated in gliomas and correlates with poor prognoses. In vitro experiments showed that GBE1 knockdown slows glioma cell proliferation, inhibits multiple biological behaviors, and alters glioma cell glycolytic capacity. Furthermore, GBE1 knockdown resulted in the inhibition of the NF-κB pathway as well as elevated expression of fructose-bisphosphatase 1 (FBP1). Further knockdown of elevated FBP1 reversed the inhibitory effect of GBE1 knockdown, restoring glycolytic reserve capacity. Furthermore, GBE1 knockdown suppressed xenograft tumor formation in vivo and conferred a significant survival benefit. Collectively, GBE1 reduces FBP1 expression through the NF-κB pathway, shifting the glucose metabolism pattern of glioma cells to glycolysis and enhancing the Warburg effect to drive glioma progression. These results suggest that GBE1 can be a novel target for glioma in metabolic therapy.

A Reliable Nonhuman Primate Model of Ischemic Stroke with Reproducible Infarct Size and Long-term Sensorimotor Deficits.

A nonhuman primate model of ischemic stroke is considered as an ideal preclinical model to replicate various aspects of human stroke because of their similarity to humans in genetics, neuroanatomy, physiology, and immunology. However, it remains challenging to produce a reliable and reproducible stroke model in nonhuman primates due to high mortality and variable outcomes. Here, we developed a focal cerebral ischemic model induced by topical application of 50% ferric chloride (FeCl3) onto the MCA-M1 segment through a cranial window in the cynomolgus monkeys. We found that FeCl3 rapidly produced a stable intraarterial thrombus that caused complete occlusion of the MCA, leading to the quick decrease of the regional cerebral blood flow in 10 min. A typical cortical infarct was detected 24 hours by magnetic resonance imaging (MRI) and was stable at least for 1 month after surgery. The sensorimotor deficit assessed by nonhuman primate stroke scale was observed at 1 day and up to 3 months after ischemic stroke. No spontaneous revascularization or autolysis of thrombus was observed, and vital signs were not affected. All operated cynomolgus monkeys survived. Our data suggested that FeCl3-induced stroke in nonhuman primates was a replicable and reliable model that is necessary for the correct prediction of the relevance of experimental therapeutic approaches in human beings.

Overexpression of NT3P75-2 gene modified bone marrow mesenchymal stem cells supernatant promotes neurological function recovery in ICH rats.

Intracerebral hemorrhage (ICH) is an acute cerebrovascular disease with high mortality and long-term disability rates. Stem cell transplantation and neurotrophic factor therapy have shown great potential in ICH. It has been established that mutated NT3 (NT3P75 - 2) can enhance the positive biological functions of NT3 by decreasing its affinity to the P75-2 receptor. The present study aimed to explore whether NT3P75-2 could further improve neurological recovery after ICH. First, we constructed three stable BMSC cell lines (GFP, GFP-NT3 overexpressed and GFP-NT3P75 - 2 overexpressed) by lentivirus infection. Next, rats were injected with fresh supernatants of these three cell lines on days 1 (24 h) and 3 (72 h) post-ICH induction. Behavioral evaluations were conducted to assess the neurological recovery of ICH rats. We further evaluated changes in microglia activation, neuron survival and proliferation of neural stem cells. Compared with the GFP group and the GFP-NT3 group, animals in the GFP-NT3P75 - 2 group exhibited better motor function improvements and milder neuroinflammation response. Meanwhile, overexpression of NT3P75 - 2 significantly decreased neuronal apoptosis and increased number of SOX2 - positive cells. Taken together, our study demonstrated that early administration of NT3P75 - 2 enriched BMMSC supernatants significantly enhanced neuro-functional recovery after ICH by regulating neuroinflammation response, neuronal survival and increasing neural stem cell number, providing a new therapeutic strategy and direction for early treatment of ICH.

Conventional craniotomy versus conservative treatment in patients with minor spontaneous intracerebral hemorrhage in the basal ganglia.

BACKGROUND: The treatment for spontaneous intracerebral hemorrhage (ICH) is still controversial, especially for hematomas in the basal ganglia. A retrospective case-control study with propensity score matching was performed to compare the outcomes of conventional craniotomy and conservative treatment for patients with minor ICH in the basal ganglia. METHODS: We retrospectively collected the data of consecutive patients with minor basal ganglia hemorrhage from January 2018 to August 2019. We compared clinical outcomes of two groups using propensity score matching. The extended Glasgow outcome scale obtained by phone interviews based on questionnaires at a 12-month follow-up was used as the primary outcome measure. According to a previous prognosis algorithm, patients were divided into good and poor prognosis groups to obtain a dichotomized (favorable or unfavorable) outcome as the primary outcome. Secondary outcomes included hospitalized complications, mortality, and modified Rankin score at 12 months. RESULTS: A total of 54 patients were analyzed, and the baseline characteristics of patients in the surgery and conservative treatment groups were well matched. The primary favorable outcome at 12 months was significantly higher in the conservative treatment group than in the surgery group (81% vs 44%; OR 1.833, 95% CI 1.159-2.900; P=0.005). The incidence of pneumonia in the surgery group was significantly higher than that in the conservative treatment group (P=0.005). CONCLUSIONS: It is not recommended to undertake conventional craniotomy for patients with a minor hematoma (25-40 ml) in the basal ganglia. An open craniotomy might induce worse long-term functional outcomes than the conservative treatment.

Hydrophosphorylation of electron-deficient alkenes and alkynes mediated by convergent paired electrolysis.

A straightforward and practical strategy for hydrophosphorylation of electron-deficient alkenes and alkynes to access γ-ketophosphine oxides, enabled by a convergent paired electrolysis (CPE) in the absence of a metal, base, and redox reagent, has been described. Mechanistic studies have revealed that the diarylphosphane oxides play the dual role of a phosphorus radical precursor and hydrogen donor in this transformation.

An electrochemical gram-scale protocol for pyridylation of inert N-heterocycles with cyanopyridines.

Here, we present a protocol to decyanopyridate inert N-heterocycles access to N-fused heterocycles via the mechanism of dual proton-coupled electron transfer (PCET). We describe a detailed guide to performing an electrochemical gram-scale protocol for decyanopyridation of inert N-heterocycles. The desired pyridylated quinolone is synthesized in a 5.0 mmol scale with a yield of 76%. The protocol is limited to cyanopyridines. For complete details on the use and execution of this protocol, please refer to Niu et al. (2022).

PTBP1 knockdown promotes neural differentiation of glioblastoma cells through UNC5B receptor.

Rationale: Cell reprogramming technology is utilized to prevent cancer progression by transforming cells into terminally differentiated, non-proliferating states. Polypyrimidine tract binding protein 1 (PTBP1) is an RNA binding protein required for the growth of neurons and may directly transform multiple normal human cells into functioning neurons in vitro and in vivo when expressed at low levels. As a result, we identified it as a key to inhibiting cancer cell proliferation by boosting glioblastoma cell neural differentiation. Methods: Immunocytofluorescence (ICF) targeting TUJ1, MAP2, KI67, and EdU were utilized to evaluate glioblastoma cell reprogramming under PTBP1 knockdown or other conditions. PTBP1 and other target genes were detected using Western blotting and qRT-PCR. Activating protein phosphatase 2A (PP2A) and RhoA were detected using specific kits. CCK8 assays were employed to detect cell viability. Bioluminescence, immunohistofluorescence (IHF), and Kaplan-Meier survival analyses were utilized to demonstrate the in vivo reprogramming efficiency of PTBP1 knockdown in U87 murine glioblastoma model. In this study, RNA-seq technology was used to examine the intrinsic pathway. Results: The expression of TUJ1 and MAP2 neural markers, as well as the absence of KI67 and EdU proliferative markers in U251, U87, and KNS89 cells, indicated that glioblastoma cell reprogramming was successful. In vivo, U87 growth generated xenografts was substantially shrank due to PTBP1 knockdown induced neural differentiation, and these tumor-bearing mice had a prolonged survival time. Following RNA-seq, ten potential downstream genes were eliminated. Lentiviral interference and inhibitors blocking tests demonstrated that UNC5B receptor and its downstream signaling were essential in the neural differentiation process mediated by PTBP1 knockdown in glioblastoma cells. Conclusions: Our results indicate that PTBP1 knockdown promotes neural differentiation of glioblastoma cells via UNC5B receptor, consequently suppressing cancer cell proliferation in vitro and in vivo, providing a promising and feasible approach for glioblastoma treatment.

Electrochemical ammonium-cation-assisted pyridylation of inert N-heterocycles via dual-proton-coupled electron transfer.

A straightforward and practical strategy for pyridylation of inert N-heterocycles, enabled by ammonium cation and electrochemical, has been described. This protocol gives access to various N-fused heterocycles and bidentate nitrogen ligand compounds, through dual-proton-coupled electron transfer (PCET) and radical cross-coupling in the absence of exogenous metal and redox reagent. It features broad substrate scope, wide functional group tolerance, and easy gram-scale synthesis. Various experiments and density functional theory (DFT) calculation results show the mechanism of dual PCET followed by radical cross-coupling is the preferred pathway. Moreover, ammonium salt plays the dual role of protonation reagent and electrolyte in this conversion, and the resulting product 9-(pyridin-4-yl)acridine compound can be used for fluorescence recognition of Fe2+ and Pd2+ with high sensitivity.

In vivo reprogramming of NG2 glia enables adult neurogenesis and functional recovery following spinal cord injury.

Adult neurogenesis plays critical roles in maintaining brain homeostasis and responding to neurogenic insults. However, the adult mammalian spinal cord lacks an intrinsic capacity for neurogenesis. Here we show that spinal cord injury (SCI) unveils a latent neurogenic potential of NG2+ glial cells, which can be exploited to produce new neurons and promote functional recovery after SCI. Although endogenous SOX2 is required for SCI-induced transient reprogramming, ectopic SOX2 expression is necessary and sufficient to unleash the full neurogenic potential of NG2 glia. Ectopic SOX2-induced neurogenesis proceeds through an expandable ASCL1+ progenitor stage and generates excitatory and inhibitory propriospinal neurons, which make synaptic connections with ascending and descending spinal pathways. Importantly, SOX2-mediated reprogramming of NG2 glia reduces glial scarring and promotes functional recovery after SCI. These results reveal a latent neurogenic potential of somatic glial cells, which can be leveraged for regenerative medicine.

Oridonin interrupts cellular bioenergetics to suppress glioma cell growth by down-regulating PCK2.

We aim to evaluate the tumor metabolic suppressive activity of Oridonin (extract of Rabdosia rubescens) in glioma and elucidate its potential mechanism. Effects of Oridonin on U251/U87 cells were determined by CCK8, RTCA, colony formation, flow cytometry, wound healing, and Transwell assay. Xenograft tumor model to evaluate the effect of Oridonin on glioma cells in vivo. Cellular bioenergetics were measured by Seahorse. RNA-seq was performed to screen potential biological pathways in Oridonin treated cells. Bioinformatics analysis of PCK2 in glioma was performed based on TCGA/CGGA. Endogenous PCK2 was knocked-down by lentivirus packaged shRNA. We found Oridonin significantly inhibited cell growth in U251/U87 in vitro and in vivo. Both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were decreased in Oridonin-treated U251/U87 cells. Oridonin treatment led to PCK2 down-regulation. Additionally, PCK2 was up-regulated in higher grade glioma and correlated with poor outcomes. Furthermore, PCK2 depletion significantly inhibited cell growth and decreased OCR/ECAR in U251/U87 which coincided with the effects of Oridonin. Therefore, we evaluated the potent anti-tumor property of Oridonin in glioma. Importantly, we demonstrated that PCK2 might be a novel target of Oridonin on glioma by inducing energy crisis and increasing oxidative stress.

Electroreductive C3 Pyridylation of Quinoxalin-2(1H)-ones: An Effective Way to Access Bidentate Nitrogen Ligands.

The construction of functional N-containing active biomolecules and bidentate nitrogen ligands by electroreductive pyridylation of N-heteroaromatics is an eye-catching task and challenge. A simple and practical electroreductive-induced C3 pyridylation of quinoxalin-2(1H)-ones with readily available cyanopyridines is reported. More than 36 examples are supplied, and the reaction performed in >95% yield. The present protocol provides a convenient, efficient, and gram-scale synthesis strategy for a series of new types of potential bidentate nitrogen ligands.

Prospects of Directly Reprogrammed Adult Human Neurons for Neurodegenerative Disease Modeling and Drug Discovery: iN vs. iPSCs Models.

A reliable disease model is critical to the study of specific disease mechanisms as well as for the discovery and development of new drugs. Despite providing crucial insights into the mechanisms of neurodegenerative diseases, translation of this information to develop therapeutics in clinical trials have been unsuccessful. Reprogramming technology to convert adult somatic cells to induced Pluripotent Stem Cells (iPSCs) or directly reprogramming adult somatic cells to induced Neurons (iN), has allowed for the creation of better models to understand the molecular mechanisms and design of new drugs. In recent times, iPSC technology has been commonly used for modeling neurodegenerative diseases and drug discovery. However, several technological challenges have limited the application of iN. As evidence suggests, iN for the modeling of neurodegenerative disorders is advantageous compared to those derived from iPSCs. In this review, we will compare iPSCs and iN models for neurodegenerative diseases and their potential applications in the future.

Elevated blood urea nitrogen is associated with recurrence of post-operative chronic subdural hematoma.

BACKGROUND: Chronic subdural hematoma (CSDH) is fundamentally treatable with about a 2-31% recurrence rate. Recently, there has been renewed interest in the association between Blood Urea Nitrogen (BUN) and intracranial lesion. Therefore, this paper attempts to show the relationship between BUN and CSDH recurrence. METHODS: A total of 653 CSDH cases with Burr-hole Irrigation (BHI) were enrolled from December 2014 to April 2019. The analyzed parameters included age, gender, comorbidities, laboratory investigations, medication use and hematoma location. The cases were divided into recurrence and non-recurrence groups while postoperative BUN concentration was further separated into quartiles (Q1 ≤ 4.0 mmol/L, 4.0 < Q2 ≤ 4.9 mmol/L, 4.9 < Q3 ≤ 6.4 mmol/L, Q4 > 6.4 mmol/L). Restricted cubic spline regressions and logistic regression models were performed to estimate the effect of BUN on CSDH recurrence. RESULTS: CSDH recurrence was observed in 96 (14.7%) cases. Significant distinctions were found between recurrence and non-recurrence groups in postoperative BUN quartiles of cases (P = 0.003). After adjusting for the potential confounders, the odds ratio of recurrence was 3.069 (95%CI =1.488-6.330, p = 0.002) for the highest quartile of BUN compared with the lowest quartile. In multiple-adjusted spline regression, a high BUN level visually showed a significantly high OR value of recurrence risk. CONCLUSIONS: Elevated BUN at post-operation is significantly associated with the recurrence of CSDH, and it is indicated that high levels of serum BUN after evacuation may serve as a risk factor for CSDH recurrence.

Electrochemical-Induced Transfer Hydrogenation of Imidazopyridines with Secondary Amine as Hydrogen Donor.

Electrochemical-induced transfer hydrogenation (TH) of N-heteroaromatic to construct biologically active functional molecule is an appealing and yet challenging task. We report herein the first selective transfer hydrogenation of imidazopyridine derivatives with secondary amines as the hydrogen donors under electrochemical conditions. The successful conversion of cathode transfer hydrogenation depends on the solvation effect. Importantly, such electrochemical-induced transfer hydrogenation can be easily amplified with excellent efficiency.

Distribution pattern of invasion-related bio-markers in head Marjolin's ulcer.

Marjolin's ulcer (MU) is a rare and aggressive cutaneous malignancy that typically presented in an area of traumatized or chronically inflamed skin and particularly in burn scars. Among them, the MU in the scalp with extensive invasion of the skull is exceptional and severe. The principle of management for MU is to obtain an early diagnosis and perform prompt surgical interventions. The invasive capacity of MU may vary among different sites of the scalp, which may require different therapeutic strategies for surgical excision. However, no clear evidence has been provided to determine the invasion ability of MU at different regions of the lesion as a surgical guidance. In present study, a 41-year-old female with a 40-year history of scalp ulceration has been examined. After resection of the MU lesion, hematoxylin and eosin (H&E) staining was performed to confirm the pathology of the cutaneous malignancy after surgical excision. Furthermore, reverse transcription-quantitative PCR experiment was performed out to determine the expression levels of invasion-associated biomarkers at different sites of the scalp affected by MU. Pathological analysis with H&E staining indicated a differentiated squamous cell carcinoma with invasion of the skull. The invasion-associated biomarkers were highly expressed in the core region compared to the middle region as well as the edge of MU tissue. Taken together, the present study suggests that the expression pattern of invasion-associated biomarkers varies between different regions of the MU lesion. High expression levels in the core region of MU indicates that the resection of the center area may be critical for the successful surgical treatment of MU.

New Measures for the Coronavirus Disease 2019 Response: A Lesson From the Wenzhou Experience.

As the outbreak of coronavirus disease 2019 (COVID-19) has spread globally, determining how to prevent the spread is of paramount importance. We reported the effectiveness of different responses of 4 affected cities in preventing the COVID-19 spread. We expect the Wenzhou anti-COVID-19 measures may provide information for cities around the world that are experiencing this epidemic.