Integrating somatic mutation profiles with structural deep clustering network for metabolic stratification in pancreatic cancer: a comprehensive analysis of prognostic and genomic landscapes.

Pancreatic cancer is a globally recognized highly aggressive malignancy, posing a significant threat to human health and characterized by pronounced heterogeneity. In recent years, researchers have uncovered that the development and progression of cancer are often attributed to the accumulation of somatic mutations within cells. However, cancer somatic mutation data exhibit characteristics such as high dimensionality and sparsity, which pose new challenges in utilizing these data effectively. In this study, we propagated the discrete somatic mutation data of pancreatic cancer through a network propagation model based on protein-protein interaction networks. This resulted in smoothed somatic mutation profile data that incorporate protein network information. Based on this smoothed mutation profile data, we obtained the activity levels of different metabolic pathways in pancreatic cancer patients. Subsequently, using the activity levels of various metabolic pathways in cancer patients, we employed a deep clustering algorithm to establish biologically and clinically relevant metabolic subtypes of pancreatic cancer. Our study holds scientific significance in classifying pancreatic cancer based on somatic mutation data and may provide a crucial theoretical basis for the diagnosis and immunotherapy of pancreatic cancer patients.

Fluorescence and colorimetric dual-mode multienzyme cascade nanoplatform based on CuNCs/FeMn-ZIF-8/PCN for detection of sarcosine.

It is critical to develop a highly efficient and sensitive method for detecting the biomarker sarcosine (SA) of prostate cancer due to its importance for men's health. In our work, a fluorescence (FL) and colorimetric dual-mode multienzyme cascade nanoplatform for SA detection was designed and constructed. CuNCs/FeMn-ZIF-8/PCN nanocomposites with high FL properties and peroxidase-like activity were successfully prepared by encapsulating copper nanoclusters (CuNCs) into FeMn-ZIF-8 and then loaded onto P-doped graphitic carbon nitride (PCN). Furthermore, the nanocomposites served as carriers for the immobilization of sarcosine oxidase (SOX) to construct a high-efficiency dual-mode multienzyme cascade nanoplatform CuNCs/SOX@FeMn-ZIF-8/PCN for the detection of SA. The intermediate H2O2 generated in the cascade caused the FL quenching of nanocomposites and the discoloration of 3,3',5,5'-tetramethylbenzidin. The linear ranges for SA detection in the dual-mode system were 1-100 µM (FL) and 1-200 µM (colorimetric), with detection limits of 0.34 and 0.59 µM, respectively. This nanoplatform exhibited notable repeatability, specificity, and stability, making it suitable for detecting sarcosine in real human urine samples. Therefore, this dual-mode multienzyme cascade nanoplatform would have a potential applicative prospect for detecting SA and other biomarkers in real clinical samples.

ldi-miR396-LdPMaT1 enhances reactive oxygen species scavenging capacity and promotes drought tolerance in Lilium distichum Nakai autotetraploids.

Drought is a key environmental stress that inhibits plant growth, development, yield and quality. Whole-genome replication is an effective method for breeding drought resistant cultivars. Here, we evaluated the tolerance of Lilium distichum Nakai diploids (2n = 2× = 24) and artificially induced autotetraploids (2n = 4× = 48) to drought simulated by polyethylene glycol (PEG) stress. Autotetraploids showed stronger drought tolerance than diploids, and high-throughput sequencing during PEG stress identified five differentially expressed miRNAs. Transcriptome analysis revealed significantly different reactive oxygen species (ROS)-scavenger expression levels between diploids and autotetraploids, which increased the drought tolerance of autotetraploids. Specifically, we identified ldi-miR396b and its only target gene (LdPMaT1) for further study based on its expression level and ROS-scavenging ability in response to drought stress (DS). Autotetraploids showed higher expression of LdPMaT1 and significantly downregulated expression of ldi-miR396b under DS compared with diploids. Through a short tandem target mimic (STTM) in transgenic lilies, functional studies revealed that miR396b silencing promotes LdPMaT1 expression and the DS response. Under PEG stress, STTM393 transgenic lines showed improved drought resistance mediated by lowered MDA content but exhibited high antioxidant enzyme activity, consistent with the autotetraploid results. Collectively, these findings suggest that ldi-miR396b-LdPMaT1 potentially enhances ROS-scavenging ability, which contributes to improved stress adaptation in autotetraploid lilies.

Free Water MR Imaging of White Matter Microstructural Changes is a Sensitive Marker of Amyloid Positivity in Alzheimer's Disease.

BACKGROUND: Extracellular free water (FW) resulting from white matter degeneration limits the sensitivity of diffusion tensor imaging (DTI) in predicting Alzheimer's disease (AD). PURPOSE: To evaluate the sensitivity of FW-DTI in detecting white matter microstructural changes in AD. To validate the effectiveness of FW-DTI indices to predict amyloid-beta (Aß) positivity in mild cognitive impairment (MCI) subtypes. STUDY TYPE: Retrospective. POPULATION: Thirty-eight Aß-negative cognitively healthy (CH) controls (68.74 ± 8.28 years old, 55% female), 15 Aß-negative MCI patients (MCI-n) (68.87 ± 8.83 years old, 60% female), 29 Aß-positive MCI patients (MCI-p) (73.03 ± 7.05 years old, 52% female), and 29 Aß-positive AD patients (72.93 ± 9.11 years old, 55% female). FIELD STRENGTH/SEQUENCE: 3.0T; DTI, T1 -weighted, T2 -weighted, T2 star-weighted angiography, and Aß PET (18 F-florbetaben or 11 C-PIB). ASSESSMENT: FW-corrected and standard diffusion indices were analyzed using trace-based spatial statistics. Area under the curve (AUC) in distinguishing MCI subtypes were compared using support vector machine (SVM). STATISTICAL TESTS: Chi-squared test, one-way analysis of covariance, general linear regression analyses, nonparametric permutation tests, partial Pearson's correlation, receiver operating characteristic curve analysis, and linear SVM. A P value <0.05 was considered statistically significant. RESULTS: Compared with CH/MCI-n/MCI-p, AD showed significant change in tissue compartment indices of FW-DTI. No difference was found in the FW index among pair-wise group comparisons (the minimum FWE-corrected P = 0.114). There was a significant association between FW-DTI indices and memory and visuospatial function. The SVM classifier with tissue radial diffusivity as an input feature had the best classification performance of MCI subtypes (AUC = 0.91), and the classifying accuracy of FW-DTI was all over 89.89%. DATA CONCLUSION: FW-DTI indices prove to be potential biomarkers of AD. The classification of MCI subtypes based on SVM and FW-DTI indices has good accuracy and could help early diagnosis. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Possible Involvement of Perineuronal Nets in Anti-Depressant Effects of Electroacupuncture in Chronic-Stress-Induced Depression in Rats.

Acupuncture can alleviate depression-like behaviors. However, the neural mechanisms behind the anti-depressive effect remain unknown. Perineuronal net (PNN) abnormalities have been reported in multiple psychiatric disorders. This study investigated the modulation and neural mechanism of PNNs in the anti-depressant process of electroacupuncture (EA) at Baihui (GV20) and Yintang (GV29) points. A rat depression model was induced by chronic unpredicted mild stress (CUMS). The results revealed that CUMS, applied for four weeks, specifically reduces PNNs around parvalbumin (PV). In addition, EA and fluoxetine treatments reverse the decrease in PNNs+ cell density and the ratio of PV and PNN double-positive cells to PV+ neurons in the medial prefrontal cortex (mPFC) after CUMS. Furthermore, EA treatment can reverse the decrease in the protein expression of PNN components (aggrecan and brevican) in the mPFC caused by stress. After EA treatment, the decreased expression of GAD67, GLuA1, and PSD95 in the mPFC induced by CUMS for four weeks was also reversed. PNN degradation in mPFC brain areas potentially interferes with the anti-depressant benefits of EA in rats with depression induced by CUMS. EA treatment did not increase PNNs+ cell density and the ratio of PV and PNN double-positive cells to PV+ neurons after PNNs degradation in the mPFC brain region of rats. This finding indicated that the mechanism of acupuncture's anti-depressant effect may be based on reversing the CUMS-induced decline in PNN expression, the functional impairment of γ-aminobutyric acid (GABA) neurons, and the regulation of excitatory synaptic proteins expression.

Analysis and enhancement of the energy utilization efficiency of corn stover using strain Lsc-8 in a bioelectrochemical system.

The strain Lsc-8 can produce a current density of 33.08 µA cm-2 using carboxymethylcellulose (CMC) as a carbon source in a three-electrode configuration. A co-culture system of strain Lsc-8 and Geobacter sulfurreducens PCA was used to efficiently convert cellulose into electricity to improve the electricity generation capability of microbial fuel cells (MFCs). The maximum current density achieved by the co-culture with CMC was 559 µA cm-2, which was much higher than that of strain Lsc-8 using CMC as the carbon source. The maximum power density reached 492.05 ± 52.63 mW cm-2, which is much higher than that previously reported. Interaction mechanism studies showed that strain Lsc-8 had the ability to secrete riboflavin and convert cellulose into acetic acid, which might be the reason for the high electrical production performance of the co-culture system. In addition, to the best of our knowledge, a co-culture or single bacteria system using agricultural straw as the carbon source to generate electricity has not been reported. In this study, the maximum current density of the three-electrode system inoculated with strain Lsc-8 was 14.56 µA cm-2 with raw corn stover as the sole carbon source. Raw corn stover as a carbon source was also investigated for use in a co-culture system. The maximum current density achieved by the co-culture was 592 µA cm-2. The co-culture system showed a similar electricity generation capability when using raw corn stover and when using CMC. This research shows for the first time that a co-culture or single bacteria system can realize both waste biomass treatment and waste power generation.

Galectin-1 promotes angiogenesis and chondrogenesis during antler regeneration.

BACKGROUND: Deer antlers are the only known mammalian structure that undergoes full regeneration. In addition, it is peculiar because when growing, it contains vascularized cartilage. The differentiation of antler stem cells (ASCs) into chondrocytes while inducing endochondral extension of blood vessels is necessary to form antler vascularized cartilage. Therefore, antlers provide an unparalleled opportunity to investigate chondrogenesis, angiogenesis, and regenerative medicine. A study found that Galectin-1 (GAL-1), which can be used as a marker in some tumors, is highly expressed in ASCs. This intrigued us to investigate what role GAL-1 could play in antler regeneration. METHODS: We measured the expression level of GAL-1 in antler tissues and cells by immunohistochemistry, WB and QPCR. We constructed antlerogenic periosteal cells (APCs, one cell type of ASCs) with the GAL-1 gene knocked out (APCGAL-1-/-) using CRISPR-CAS9 gene editing system. The effect of GAL-1 on angiogenesis was determined by stimulating human umbilical vein endothelial cells (HUVECs) using APCGAL-1-/- conditioned medium or adding exogenous deer GAL-1 protein. The effect of APCGAL-1-/- on chondrogenic differentiation was evaluated compared with the APCs under micro-mass culture. The gene expression pattern of APCGAL-1-/- was analyzed by transcriptome sequencing. RESULTS: Immunohistochemistry revealed that GAL-1 was widely expressed in the antlerogenic periosteum (AP), pedicle periosteum (PP) and antler growth center. Western blot and qRT-PCR analysis using deer cell lines further supports this result. The proliferation, migration, and tube formation assays of human umbilical vein endothelial cells (HUVECs) showed that the proangiogenic activity of APCGAL-1-/- medium was significantly decreased (P < 0.05) compared with the APCs medium. The proangiogenic activity of deer GAL-1 protein was further confirmed by adding exogenous deer GAL-1 protein (P < 0.05). The chondrogenic differentiation ability of APCGAL-1-/- was impeded under micro-mass culture. The terms of GO and KEGG enrichment of the differentially expressed genes (DEGs) of APCGAL-1-/- showed that down-regulated expression of pathways associated with deer antler angiogenesis, osteogenesis and stem cell pluripotency, such as the PI3K-AKT signaling pathway, signaling pathways regulating pluripotency of stem cells and TGF-ß signaling pathway. CONCLUSIONS: Deer GAL-1, has strong angiogenic activity, is widely and highly expressed in deer antler. The APCs can induce angiogenesis by secreting GAL-1. The knockout of GAL-1 gene of APCs damaged its ability to induce angiogenesis and differentiate into chondrocytes. This ability is crucial to the formation of deer antler vascularized cartilage. Moreover, Deer antlers offer a unique model to explore explore how angiogenesis at high levels of GAL-1 expression can be elegantly regulated without becoming cancerous.

Fusion imaging versus ultrasound-guided percutaneous thermal ablation of liver cancer: a meta-analysis.

BACKGROUND: Ultrasound-guided percutaneous thermal ablation has become an alternative treatment for small hepatocellular carcinoma (HCC). Recent evidence suggests that fusion imaging (FI) may improve the feasibility and efficacy of thermal ablation for HCC, while the clinical evidence remains limited. PURPOSE: To compare FI versus ultrasound-guided thermal ablation for HCC. MATERIAL AND METHODS: Relevant cohort or randomized controlled trials were found by searching Medline, Web of Science, Cochrane Library, and Embase. The pooling of results was performed using a random-effects model incorporating heterogeneity. RESULTS: In this meta-analysis, 15 studies involving 1472 patients (1831 tumors) for FI-guided ablation and 1380 patients (1864 tumors) for ultrasound-guided ablation were included. Pooled results showed that compared to conventional HCC ablation guided by ultrasound, the FI-guided procedure showed a similar technique efficacy rate (risk ratio [RR] = 1.01, 95% confidence interval [CI] = 1.00-1.02, P = 0.25; I2 = 30%). However, FI-guided tumor ablation was associated with a lower incidence of overall complications (RR = 0.70, 95% CI = 0.50-0.97, P = 0.03; I2 = 0%). Moreover, patients receiving FI-guided tumor ablation had a lower risk of local tumor progression during follow-up than those with ultrasound-guided ablation (RR = 0.61, 95% CI = 0.47-0.78, P < 0.001; I2 = 13%). Subgroup analysis according to FI strategy, imaging techniques in controls, and tumor diameter showed consistent results (p for subgroup difference all >0.05). CONCLUSION: FI-guided thermal ablation may be more effective and safer than ultrasound-guided ablation for patients with HCC.

Design, Synthesis, Biological Evaluation and Molecular Docking Studies of Quercetin-Linker-H2 S Donor Conjugates for the Treatment of Diabetes and Wound Healing.

Based on the use of quercetin for treating diabetes and H2 S for promoting wound healing, a series of three quercetin-linker-H2 S donor conjugates was designed, synthesized and characterized by 1 H-NMR, 13 C-NMR and MS. Meanwhile, in vitro evaluation of these compounds was also researched by IR-HepG2 treatment experiment, MTT assay, scratch test and tubule formation experiment. The three compounds could be used to treat insulin resistance induced by high glucose and promote the proliferation of human umbilical vein endothelial cells, wound healing, and the formation of tubules in vitro under a high-glucose environment. Our results illustrate that these compounds could be used to treat diabetes and promote wound healing at the same time. Furthermore, molecular docking study results of the compounds were consistent with the evaluated biological activity. In vivo research of compounds is underway.

Competitive fluorescent immunoassay for the ultrasensitive determination of amyloid beta peptide1-42 based on Ag@SiO2@N, S-GQD nanocomposites.

A competitive fluorescent immunoassay is described for the ultrasensitive determination of amyloid beta peptide1-42 (Aß1-42), a biomarker for early diagnosis of Alzheimer's disease. N, S-doped graphene quantum dots (N, S-GQDs) were freely assembled on the surface of Ag@SiO2 nanoparticles to obtain a composite (Ag@SiO2@N, S-GQD nanocomposite), which was successfully prepared and characterized. By theoretical study, the optical properties of nanocomposites are improved compared with GQDs, due to the advantages of combining N, S co-doping and metal-enhanced fluorescence (MEF) effect of Ag NPs. In addition, Aß1-42 was modified by Ag@SiO2@N, S-GQDs to prepare a probe with high photoluminescence properties (Ag@SiO2@N, S-GQDs-Aß1-42). In the presence of Aß1-42, a competitive reaction towards anti-Aß1-42 fixed on the ELISA plate was proceeded between Aß1-42 and Ag@SiO2@N, S-GQDs-Aß1-42 by specific capture of antigen-antibody. The emission peak of Ag@SiO2@N, S-GQDs-Aß1-42 (400 nm emission) was used for the quantitative determination of Aß1-42. Under the optimal conditions, the fluorescent immunoassay exhibited a linear range of 0.32 pg·mL-1-5 ng·mL-1 with a detection limit of 0.098 pg·mL-1. The results show that the immunoassay has good analytical ability and can provide a new method for the clinical determination of Aß1-42.

Selective Delivery of Tofacitinib Citrate to Hair Follicles Using Lipid-Coated Calcium Carbonate Nanocarrier Controls Chemotherapy-Induced Alopecia Areata.

Chemotherapy-induced alopecia (CIA) is one of the common side effects in cancer treatment. The psychological distress caused by hair loss may cause patients to discontinue chemotherapy, affecting the efficacy of the treatment. The JAK inhibitor, Tofacitinib citrate (TFC), showed huge potential in therapeutic applications for treating baldness, but the systemic adverse effects of oral administration and low absorption rate at the target site limited its widespread application in alopecia. To overcome these problems, we designed phospholipid-calcium carbonate hybrid nanoparticles (PL/ACC NPs) for a topical application to target deliver TFC. The results proved that PL/ACC-TFC NPs showed excellent pH sensitivity and transdermal penetration in vitro. PL/ACC NPs offered an efficient follicular targeting approach to deliver TFC in a Cyclophosphamide (CYP)-induced alopecia areata mouse model. Compared to the topical application of TFC solution, PL/ACC-TFC NPs significantly inhibited apoptosis of mouse hair follicles and accelerated hair growth. These findings support that PL/ACC-TFC NPs has the potential for topical application in preventing and mitigating CYP-induced Alopecia areata.

The effect of episodic foresight on intertemporal decision-making: the role of future self-continuity and perceived control.

To investigate the mechanism of episodic foresight of different valences on intertemporal decision-making, this study examined the mediating role of future self-continuity in the influence of episodic foresight on intertemporal decision-making and the moderating role of perceived control in two experiments. The results found that (1) future self-continuity mediated the effect of episodic foresight on individuals' intertemporal decision-making; and (2) perceived control moderated the indirect effect of episodic foresight on intertemporal decision-making through future self-continuity. Under low perceived control, individuals with positive episodic foresight had stronger future self-continuity and preferred future options, while individuals with negative episodic foresight had lower future self-continuity. In contrast, under high perceived control, individuals with different episodic foresight potencies did not show significant differences in their future self-continuity levels, but all showed higher levels and tended to choose the delayed option when faced with an intertemporal choice. From the perspective of the self-cognition, this study provided new insights into the relationship between episodic foresight and intertemporal decision-making and the psychological mechanisms of intertemporal decision-making.

Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Diffuse Alveolar Hemorrhage Associated with Systemic Lupus Erythematosus in Mice by Promoting M2 Macrophage Polarization via the microRNA-146a-5p/NOTCH1 Axis.

Systemic lupus erythematosus (SLE)-associated diffuse alveolar hemorrhage (DAH) is a rare but extremely harmful condition. The current study sought to dissect the mechanisms underlying the effects of human umbilical cord mesenchymal stem cell (HUCMSC)-derived exosomes on M2 macrophage polarization in SLE-associated DAH via the microRNA (miR)-146a-5p/NOTCH1 axis. A DAH mouse model was established using pristane. Exosomes were isolated from HUCMSCs transfected or untransfected with the miR-146a-5p antagonist or agonist and their NCs and then injected into DAH mice. Additionally, miR-146a-5p was overexpressed in macrophages. Expression of miR-146a-5p, NOTCH1, M1 macrophage markers, and M2 macrophage markers was measured in mice and macrophages, and inflammatory factor levels were detected. Mouse lung injuries were evaluated, so was the binding of miR-146a-5p to NOTCH1. Rescue experiments were conducted in mice and macrophages using NOTCH1 shRNA and pcDNA3.1-NOTCH1, respectively. NOTCH1 expression was enhanced in DAH mice. HUCMSC-derived exosomes reduced NOTCH1 expression, bleeding, inflammation, and M1 macrophage polarization but elevated M2 macrophage polarization in lung tissues of DAH mice. Mechanistically, NOTCH1 is negatively targeted by miR-146a-5p. miR-146a-5p overexpression diminished M1 marker and inflammatory factor levels but enhanced M2 marker levels in macrophages, which was nullified by NOTCH1 overexpression. HUCMSC-derived exosomes with miR-146a-5p inhibition increased NOTCH1 expression, worsened bleeding and inflammation, and augmented M1 macrophage polarization while decreasing M2 macrophage polarization in lung tissues of DAH mice, which was abrogated by silencing NOTCH1. HUCMSC-derived exosomes diminished NOTCH1 expression to accelerate M2 macrophage polarization via delivery of miR-146a-5p, thus alleviating SLE-associated DAH in mice.

sRAGE Inhibits the Mucus Hypersecretion in a Mouse Model with Neutrophilic Asthma.

BACKGROUND: Neutrophilic asthma (NA) may result in irreversible airflow limitations. Soluble advanced glycosylation receptor (sRAGE) has been shown to be associated with neutrophilic airway inflammation. However, the association between sRAGE and mucus hypersecretion in NA remains unknown. This study aims to assess the function of sRAGE on mucus hypersecretion. METHODS: A NA mouse model was established and treated with adeno-associated virus 9 (AAV9)-sRAGE and inhibitors. Collagen deposition and goblet cell hyperplasia in the lungs were evaluated by periodic acid-Schiff (PAS) and Masson staining. sRAGE and mucin levels in bronchoalveolar lavage fluid were measured by ELISA. Pathway molecule expression levels were determined by RT-qPCR and western blotting. RESULTS: The results showed that the NA mouse model exhibited airway mucus hypersecretion. Mice can be effectively transfected by AAV9-sRAGE via tail-vein injection and intranasal drip. AAV9-sRAGE increased the sRAGE levels but it inhibited the collagen deposition, the PAS score, as well as the expression of MUC5AC and MUC5B. Inhibitors of high-mobility group protein 1 (HMGB1), receptor for advanced glycation end product (RAGE) and phosphatidylinositol 3-kinase (PI3K) suppressed the MUC5AC levels in NA mice as well as in cultured HMGB1-induced human bronchial epithelial cells. Furthermore, the phospho- extracellular signal-regulated kinase (ERK) protein in NA was increased while the sRAGE intervention inhibited this elevation. CONCLUSIONS: These results suggest that sRAGE may be a potential target for the treatment of mucus hypersecretion in NA.

A New 7-Azaindole Structure Analog: Molecular Docking, Synthesis and Preliminary Biological Activity in Vitro for Anticancer.

In this work, a series of 7-azaindole analogs were designed by the bioisosteric principle based on the pharmacodynamic parent nucleus. Moreover, 5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyrimidin-2-amine (compound P1) with the strongest interaction with colony-stimulating factor 1 receptor (CSF-1R) was screened by molecular docking. Compound P1 was successfully prepared by the six-step reaction with HPLC purity of 99.26 % and characterized by 1 H-NMR and ESI-MS spectra. In vitro bioactivity study showed that compound P1 appeared the cytotoxicity to MCF-7 and A549 cells, especially to HOS cells (IC50 =88.79±8.07 nM), while it had lower toxicity to normal L929 cells (IC50 =140.49±8.03 µM). In addition, compound P1 could induce HOS cell death by apoptosis and blocking the G0/G1 phase at nanomolar concentrations. The obtained results indicated that compound P1 might be a promising candidate compound for anticancer drug.

Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in Patients With Extensive-Stage Small Cell Lung Cancer: The ASTRUM-005 Randomized Clinical Trial.

Importance: Programmed cell death ligand 1 inhibitors combined with chemotherapy has changed the approach to first-line treatment in patients with extensive-stage small cell lung cancer (SCLC). It remained unknown whether adding a programmed cell death 1 (PD-1) inhibitor to chemotherapy provided similar or better benefits in patients with extensive-stage SCLC, which would add evidence on the efficacy of checkpoint inhibitors in the treatment of extensive-stage SCLC. Objective: To evaluate the efficacy and adverse event profile of the PD-1 inhibitor serplulimab plus chemotherapy compared with placebo plus chemotherapy as first-line treatment in patients with extensive-stage SCLC. Design, Setting, and Participants: This international, double-blind, phase 3 randomized clinical trial (ASTRUM-005) enrolled patients at 114 hospital sites in 6 countries between September 12, 2019, and April 27, 2021. Of 894 patients who were screened, 585 with extensive-stage SCLC who had not previously received systemic therapy were randomized. Patients were followed up through October 22, 2021. Interventions: Patients were randomized 2:1 to receive either 4.5 mg/kg of serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 12 weeks. Main Outcomes and Measures: The primary outcome was overall survival (prespecified significance threshold at the interim analysis, 2-sided P < .012). There were 13 secondary outcomes, including progression-free survival and adverse events. Results: Among the 585 patients who were randomized (mean age, 61.1 [SD, 8.67] years; 104 [17.8%] women), 246 (42.1%) completed the trial and 465 (79.5%) discontinued study treatment. All patients received study treatment and were included in the primary analyses. As of the data cutoff (October 22, 2021) for this interim analysis, the median duration of follow-up was 12.3 months (range, 0.2-24.8 months). The median overall survival was significantly longer in the serplulimab group (15.4 months [95% CI, 13.3 months-not evaluable]) than in the placebo group (10.9 months [95% CI, 10.0-14.3 months]) (hazard ratio, 0.63 [95% CI, 0.49-0.82]; P < .001). The median progression-free survival (assessed by an independent radiology review committee) also was longer in the serplulimab group (5.7 months [95% CI, 5.5-6.9 months]) than in the placebo group (4.3 months [95% CI, 4.2-4.5 months]) (hazard ratio, 0.48 [95% CI, 0.38-0.59]). Treatment-related adverse events that were grade 3 or higher occurred in 129 patients (33.2%) in the serplulimab group and in 54 patients (27.6%) in the placebo group. Conclusions and Relevance: Among patients with previously untreated extensive-stage SCLC, serplulimab plus chemotherapy significantly improved overall survival compared with chemotherapy alone, supporting the use of serplulimab plus chemotherapy as the first-line treatment for this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT04063163.

Update on the association between alpha-synuclein and tau with mitochondrial dysfunction: Implications for Parkinson's disease.

The critical role of mitochondrial dysfunction in the pathological mechanisms of neurodegenerative disorders, particularly Parkinson's disease (PD), is well established. Compelling evidence indicates that Parkinson's proteins (e.g., α-synuclein, Parkin, PINK1, DJ-1, and LRRK2) are associated with mitochondrial dysfunction and oxidative stress in PD. Significantly, there is a possible central role of alpha-synuclein (α-Syn) in the occurrence of mitochondrial dysfunction and oxidative stress by the mediation of different signaling pathways. Also, tau, traditionally considered as the main component of neurofibrillary tangles, aggregates and amplifies the neurotoxic effects on mitochondria by interacting with α-Syn. Moreover, oxidative stress caused by mitochondrial dysfunction favors assembly of both α-Syn and tau and also plays a key role in the formation of protein aggregates. In this review, we provide an overview of the relationship between these two pathological proteins and mitochondrial dysfunction in PD, and also summarize the underlying mechanisms in the interplay of α-Syn aggregation and phosphorylated tau targeting the mitochondria, to find new strategies to prevent PD processing.

Integrated metabolome and transcriptome analysis of the anthocyanin biosynthetic pathway in relation to color mutation in miniature roses.

BACKGROUND: Roses are famous ornamental plants worldwide. Floral coloration is one of the most prominent traits in roses and is mainly regulated through the anthocyanin biosynthetic pathway. In this study, we investigated the key genes and metabolites of the anthocyanin biosynthetic pathway involved in color mutation in miniature roses. A comparative metabolome and transcriptome analysis was carried out on the Neptune King rose and its color mutant, Queen rose, at the blooming stage. Neptune King rose has light pink colored petals while Queen rose has deep pink colored petals. RESULT: A total of 190 flavonoid-related metabolites and 38,551 unique genes were identified. The contents of 45 flavonoid-related metabolites, and the expression of 15 genes participating in the flavonoid pathway, varied significantly between the two cultivars. Seven anthocyanins (cyanidin 3-O-glucosyl-malonylglucoside, cyanidin O-syringic acid, cyanidin 3-O-rutinoside, cyanidin 3-O-galactoside, cyanidin 3-O-glucoside, peonidin 3-O-glucoside chloride, and pelargonidin 3-O-glucoside) were found to be the major metabolites, with higher abundance in the Queen rose. Thirteen anthocyanin biosynthetic related genes showed an upregulation trend in the mutant flower, which may favor the higher levels of anthocyanins in the mutant. Besides, eight TRANSPARENT TESTA 12 genes were found upregulated in Queen rose, probably contributing to a high vacuolar sequestration of anthocyanins. Thirty transcription factors, including two MYB and one bHLH, were differentially expressed between the two cultivars. CONCLUSIONS: This study provides important insights into major genes and metabolites of the anthocyanin biosynthetic pathway modulating flower coloration in miniature rose. The results will be conducive for manipulating the anthocyanin pathways in order to engineer novel miniature rose cultivars with specific colors.

Transcriptomics and targeted metabolomics reveal the regulatory network of Lilium davidii var. unicolor during bulb dormancy release.

MAIN CONCLUSION: Through combined analysis of the transcriptome and targeted metabolome of lily bulbs, the possible molecular mechanism of dormancy release was revealed. Regulation of bulb dormancy is critical for ensuring annual production and high-quality cultivation. The application of low temperatures is the most effective method for breaking bulb dormancy, but the molecular mechanism underlying this response is unclear. Herein, targeted metabolome and transcriptome analyses were performed on Lilium davidii var. unicolor bulbs stored for 0, 50, and 100 days at 4 °C. Dormancy release mainly depended on the accumulation of gibberellins GA4 and GA7, which are synthesized by the non-13-hydroxylation pathway, rather than GA3, and ABA was degraded in the process. The contents of nonbioactive GA9, GA15, and GA24, the precursors of GA4 synthesis, increased with bulb dormancy release. Altogether, 113,252 unique transcripts were de novo assembled through high-throughput transcriptome sequences, and 639 genes were continuously differentially expressed. Energy sources during carbohydrate metabolism mainly depend on glycolysis and the pentose phosphate pathway. Screening of transcription factor families involved in bulb dormancy release showed that MYB, WRKY, NAC, and TCP members were significantly correlated with the targeted metabolome. Coexpression analysis further confirmed that ABI5, PYL8, PYL4, and PP2C, which are vital ABA signaling elements, regulated GA3ox and GA20ox in the GA4 biosynthesis pathway, and XERICO may be involved in the regulation of ABA and GA4 signaling through the ubiquitination pathway. WRKY32, WRKY71, DAM14, NAC8, ICE1, bHLH93, and TCP15 also participated in the ABA/GA4 regulatory network, and ICE1 may be the key factor linking temperature signals and hormone metabolism. These results will help to reveal the bulb dormancy molecular mechanism and develop new strategies for high-quality bulb production.

Iron-Catalyzed Oxidative Amination of Benzylic C(sp3)-H Bonds with Anilines.

Iron-catalyzed oxidative amination of benzylic C(sp3)-H bonds with anilines bearing electron-withdrawing groups (EWGs) or electron-donating groups (EDGs) is realized based on simple variations of N-substituents on imidazolium cations in novel ionic Fe(III) complexes. The structural modification of the imidazolium cation resulted in regulation of the redox potential and the catalytic performance of the iron metal center. Using DTBP as oxidant, [HItBu][FeBr4] showed the highest catalytic activity for anilines bearing EWGs, while [HIPym][FeBr4] was more efficient for EDG-substituted anilines. This work provides alternative access to benzylamines with the advantages of both a wide substrate scope and iron catalysis.