Establishment and validation of a nomogram model containing a triglyceride-glucose index and neutrophil-to-high-density lipoprotein ratio for predicting major adverse cardiac events in patients with ST-segment elevation myocardial infarction.

OBJECTIVE: To analyze the predictive value of the triglyceride-glucose (TyG) index and neutrophil-to-high-density lipoprotein ratio (NHR) for in-hospital major adverse cardiac events (MACE) after percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI), and to establish an associated nomogram model. METHODS: In this retrospective study, we collected data from consecutive STEMI patients who underwent PCI from October 2019 to June 2023 at the Second People's Hospital of Hefei and the Second Affiliated Hospital of Anhui Medical University, as training and validation sets. Stepwise regression and multivariate logistic regression analysis were performed to screen independent risk factors, and a nomogram model was constructed and evaluated for its predictive efficacy. RESULTS: The TyG index, NHR, urea, diastolic blood pressure, hypertension, and left ventricular ejection fraction were independent risk factors for in-hospital MACE after PCI, and were used to construct the nomogram model. The C-index of the training and validation sets were 0.799 and 0.753, respectively, suggesting that the model discriminated well. Calibration and clinical decision curves also demonstrated that the nomogram model had good predictive power. CONCLUSION: In STEMI patients, increased TyG index and NHR were closely related to the occurrence of in-hospital MACE after PCI. Our constructed nomogram model has some value for predicting the occurrence of in-hospital MACE in STEMI patients.

Targeted Delivery of Circular Single-Stranded DNA Encoding IL-12 for the Treatment of Triple-Negative Breast Cancer.

Interleukin-12 (IL-12) is a critical cytokine with notable anticancer properties, including enhancing T-cell-mediated cancer cell killing, and curbing tumor angiogenesis. To date, many approaches are evaluated to achieve in situ overexpression of IL-12, minimizing leakage and the ensuing toxicity. Here, it is focused on circular single-stranded DNA (Css DNA), a type of DNA characterized by its unique structure, which could be expressed in mammals. It is discovered that Css DNA can induce sustained luciferase expression for half a year by intramuscular injection and showed effective antitumor results by intratumoral injection. Motivated by these findings, a folate-modified LNP system is now developed for the delivery of Css DNA expressing IL-12 for the therapy of 4T1 triple-negative breast cancer (TNBC). This delivery system effectively activates anti-cancer immune responses, slows tumor growth, significantly prolongs survival in animal models, and prevents tumor recurrence. After 6 months of long-term observation, the elevated level of IL-12 is still detectable in the lymph nodes and serum of the cured mice. This study highlights the long-term sustained expression capacity of Css DNA and its ability to inhibit recurrence, and the potential of tumor-targeted LNPs for Css DNA-based cancer therapy, providing a new insight into gene overexpression strategy.

Drug Repurposing for COVID-19 by Constructing a Comorbidity Network with Central Nervous System Disorders.

In the post-COVID-19 era, treatment options for potential SARS-CoV-2 outbreaks remain limited. An increased incidence of central nervous system (CNS) disorders has been observed in long-term COVID-19 patients. Understanding the shared molecular mechanisms between these conditions may provide new insights for developing effective therapies. This study developed an integrative drug-repurposing framework for COVID-19, leveraging comorbidity data with CNS disorders, network-based modular analysis, and dynamic perturbation analysis to identify potential drug targets and candidates against SARS-CoV-2. We constructed a comorbidity network based on the literature and data collection, including COVID-19-related proteins and genes associated with Alzheimer's disease, Parkinson's disease, multiple sclerosis, and autism spectrum disorder. Functional module detection and annotation identified a module primarily involved in protein synthesis as a key target module, utilizing connectivity map drug perturbation data. Through the construction of a weighted drug-target network and dynamic network-based drug-repurposing analysis, ubiquitin-carboxy-terminal hydrolase L1 emerged as a potential drug target. Molecular dynamics simulations suggested pregnenolone and BRD-K87426499 as two drug candidates for COVID-19. This study introduces a dynamic-perturbation-network-based drug-repurposing approach to identify COVID-19 drug targets and candidates by incorporating the comorbidity conditions of CNS disorders.

Differential network analysis reveals the key role of the ECM-receptor pathway in α-particle-induced malignant transformation.

Space particle radiation is a major environmental factor in spaceflight, and it is known to cause body damage and even trigger cancer, but with unknown molecular etiologies. To examine these causes, we developed a systems biology approach by focusing on the co-expression network analysis of transcriptomics profiles obtained from single high-dose (SE) and multiple low-dose (ME) α-particle radiation exposures of BEAS-2B human bronchial epithelial cells. First, the differential network and pathway analysis based on the global network and the core modules showed that genes in the ME group had higher enrichment for the extracellular matrix (ECM)-receptor interaction pathway. Then, collagen gene COL1A1 was screened as an important gene in the ME group assessed by network parameters and an expression study of lung adenocarcinoma samples. COL1A1 was found to promote the emergence of the neoplastic characteristics of BEAS-2B cells by both in vitro experimental analyses and in vivo immunohistochemical staining. These findings suggested that the degree of malignant transformation of cells in the ME group was greater than that of the SE, which may be caused by the dysregulation of the ECM-receptor pathway.

Theoretical exploring of potential mechanisms of antithrombotic ingredients in danshen-chishao herb-pair by network pharmacological study, molecular docking and zebrafish models.

BACKGROUND: Salvia miltiorrhiza (Danshen, DS) and Radix Paeoniae Rubra (Chishao, CS) herbal pair (DS-CS) is a famous traditional Chinese combination which has been used as antithrombotic formular for centuries. However, there is still lack of sufficient scientific evidence to illustrate its underlying mechanisms. The purpose of this study is to investigate the antithrombotic effects of DS-CS extract in zebrafish and explore its possible mechanism of action. METHODS: The quality of traditional Chinese medicines DS and CS granules was evaluated using High Performance Liquid Chromatography (HPLC). Subsequently, the therapeutic effect of the DS-CS combination and its components, Salvianolic Acid A (SAA) and Paeoniflorin (PF), in various concentrations on thrombosis was experimentally validated. Moreover, the interaction between DS-CS and the thrombosis disease targets was analyzed through network pharmacology, predicting the potential antithrombotic mechanism of DS-CS. Molecular docking and in vivo zebrafish experiments were conducted to validate the predicted targets, with qRT-PCR utilized for target validation. RESULTS: DS-CS exhibited anti-thrombotic effect in zebrafish with concentrations ranging from 25 to 300 µg/mL. The co-administration of PF and SAA at 25 µg/mL each revealed a synergistic antithrombotic effect exceeding that of individual components when contrasted with PHZ treatment. Protein-protein interaction (PPI) analysis identified key genes, including Albumin (ALB), Proto-oncogene tyro-sine-protein kinase Src (SRC), Matrix metalloproteinase-9 (MMP9), Caspase-3 (CASP3), Epidermal growth factor receptor (EGFR), Fibroblast growth factor 2 (FGF2), Vascular endothelial growth factor receptor 2 (KDR), Matrix metalloprotein-ase-2(MMP2), Thrombin (F2), and Coagulation factor Xa (F10), associated with the antithrombotic action of PF and SAA. Furthermore, KEGG pathway analysis indicated involvement of lipid metabolism and atherosclerosis pathways. Molecular docking revealed strong binding of PF and SAA to pivotal hub genes, such as SRC, EGFR, and F10. The experimental findings demonstrated that DS-CS could upregulate the mRNA expression levels of EGFR while inhibiting F10 and SRC mRNA levels, thereby ameliorating thrombotic conditions. CONCLUSION: This research provided valuable insights into the potential mechanisms underlying the antithrombotic activity of DS-CS. Our findings suggested that PF and SAA could be the key active ingredients responsible for this activity. The antithrombotic effects of DS-CS appeared to be mediated through the regulation of mRNA expression of SRC, EGFR, and F10. These results enhanced our understanding of DS-CS's therapeutic potential and lay the groundwork for future studies to further elucidate its mechanisms of action.

Panax Notoginseng Saponins Regulate Angiogenic Cytokines Through the PI3K/AKT/mTOR Signaling Pathway to Promote Fracture Healing in Ovariectomized Rats.

Osteoporotic fractures seriously affect the quality of life of the elderly. Panax notoginseng saponins (PNS) have the potential function of preventing osteoporosis. The Phosphatidylinositol 3-kinase (PI3K)/protein kinase (AKT)/mammalian target of rapamycin (mTOR) pathway is involved in the regulation of osteoporosis and has been proven to be related to VEGF secretion and angiogenesis. Therefore, this study aimed to explore the effects of PNS on ovariectomized rats with osteoporotic fracture through the PI3K/AKT/mTOR pathway and angiogenesis-related factors. Female Sprague-Dawley rats were randomly divided into normal control, fracture model, ovariectomized fracture model, low-dose PNS (100 mg/kg/d), and high-dose PNS (200 mg/kg/d). The ovariectomized rat fracture model was established. In low and high dose groups, PNS was administered intraperitoneally. The vascularization of fracture ends was detected in vitro by micro-CT on the 7th, 14th, and 21st day after modeling, and the area and number of blood vessels in the unit field of vision of the callus healing plane were seen by hematoxylin-eosin staining. The expression levels of PI3K, AKT1, mTOR, hypoxia inducible factor-1; VEGF: vascular endothelial growth factor (HIF-1), VEGF, Ang-1, VEGFR2, and angiopoietin like 2 Gene (ANGPTL2) were determined using Western blotting. In the PNS treatment group, the area of cortical bone increased, the area of callus decreased, and the number and area of blood vessels increased significantly when compared with the ovariectomized fracture model group. PNS regulates the PI3K/AKT/mTOR signaling pathway and promotes the expression of vascular-related cytokines (VEGF, Ang-1, VEGFR2, and ANGPTL2) in osteoporotic fractures. PNS may regulate the expression of vascular-related factors through the PI3K/AKT/mTOR pathway and promote the healing of osteoporotic fractures in ovariectomized rats.

Comparative Simulative Analysis and Design of Single-Chain Self-Assembled Protein Cages.

Coiled-coil protein origami (CCPO) is a modular strategy for the de novo design of polypeptide nanostructures. It represents a type of modular design based on pairwise-interacting coiled-coil (CC) units with a single-chain protein programmed to fold into a polyhedral cage. However, the mechanisms underlying the self-assembly of the protein tetrahedron are still not fully understood. In the present study, 18 CCPO cages with three different topologies were modeled in silico. Then, molecular dynamics simulations and CC parameters were calculated to characterize the dynamic properties of protein tetrahedral cages at both the local and global levels. Furthermore, a deformed CC unit was redesigned, and the stability of the new cage was significantly improved.

The Lithofacies of Sandstones Interbedded with Shales: Implication for Organic Matter Accumulation of Triassic Deep Lacustrine Setting, Southern Ordos Basin.

The sandstones interbedded with shales in the lacustrine black shale have great potential to become important targets for oil and gas exploration, but there has been a lack of systematic research regarding their types and genesis. This study focused on the investigation of the Triassic Chang 73 member deep lacustrine sandstone. Eleven lithofacies are identified and classified into three different types of deposits: ash fall and intra- and extra-basinal turbidite deposits. Vitric tuff, pumice-bearing shale, and ash are the main ash fall lithofacies. The presence of reverse grading and a significant concentration of plant fragments/micas suggest extra-basinal turbidite deposits. However, the collapse of deltaic intrabasinal sediments has been well sorted and does not contain plant debris and low-density materials. These three different types of sediments combined with a humid climate are the main causes for the deposition of a large number of sandstone layers in the deep lacustrine environment. Furthermore, the abundant volcanic eruptions are associated with increased organic matter accumulation and promoted the bloom of algae. In addition, the generated oil in the black shales would then migrate and accumulate in the interbedded sandstones. This research provides geological evidence for the prospective prediction of lacustrine shale oil accumulations.

CBD2: A functional biomarker database for colorectal cancer.

The rapidly evolving landscape of biomarkers for colorectal cancer (CRC) necessitates an integrative, updated repository. In response, we constructed the Colorectal Cancer Biomarker Database (CBD), which collected and displayed the curated biomedicine information for 870 CRC biomarkers in the previous study. Building on CBD, we have now developed CBD2, which includes information on 1569 newly reported biomarkers derived from different biological sources (DNA, RNA, protein, and others) and clinical applications (diagnosis, treatment, and prognosis). CBD2 also incorporates information on nonbiomarkers that have been identified as unsuitable for use as biomarkers in CRC. A key new feature of CBD2 is its network analysis function, by which users can investigate the visible and topological network between biomarkers and identify their relevant pathways. CBD2 also allows users to query a series of chemicals, drug combinations, or multiple targets, to enable multidrug, multitarget, multipathway analyses, toward facilitating the design of polypharmacological treatments for CRC. CBD2 is freely available at http://www.eyeseeworld.com/cbd.

The rise of baobab trees in Madagascar.

The baobab trees (genus Adansonia) have attracted tremendous attention because of their striking shape and distinctive relationships with fauna1. These spectacular trees have also influenced human culture, inspiring innumerable arts, folklore and traditions. Here we sequenced genomes of all eight extant baobab species and argue that Madagascar should be considered the centre of origin for the extant lineages, a key issue in their evolutionary history2,3. Integrated genomic and ecological analyses revealed the reticulate evolution of baobabs, which eventually led to the species diversity seen today. Past population dynamics of Malagasy baobabs may have been influenced by both interspecific competition and the geological history of the island, especially changes in local sea levels. We propose that further attention should be paid to the conservation status of Malagasy baobabs, especially of Adansonia suarezensis and Adansonia grandidieri, and that intensive monitoring of populations of Adansonia za is required, given its propensity for negatively impacting the critically endangered Adansonia perrieri.

Primulaweiliei (Primulaceae), a new species from Hubei, Central China.

In this study, we describe and illustrate a new species, Primulaweiliei L.S.Yang, Z.K.Wu & G.W.Hu, from the Shennongjia Forestry District, Hubei Province in Central China. It is morphologically assigned to Primulasect.Aleuritia based on its dwarf and hairless habit, long petiole, fruits longer than calyx and covered by farina on the scape. This new species is similar to P.gemmifera and P.munroisubsp.yargongensis in the same section, but it can be distinguished by its smaller calyxes, homostylous flowers, corolla tube throat without annular appendage and only 1-2 flowers in each inflorescence. Based on the assessment conducted according to the IUCN Red List criteria, we propose that P.weiliei be classified as a Critically Endangered (CR) species.

AEG-1 as a Novel Therapeutic Target in Colon Cancer: A Study from Silencing AEG-1 in BALB/c Mice to Large Data Analysis.

BACKGROUND: Astrocyte elevated gene-1 (AEG-1) is overexpressed in various malignancies. Exostosin-1 (EXT-1), a tumor suppressor, is an intermediate for malignant tumors. Understanding the mechanism behind the interaction between AEG-1 and EXT-1 may provide insights into colon cancer metastasis. METHODS: AOM/DSS was used to induce tumor in BALB/c mice. Using an in vivo-jetPEI transfection reagent, transient transfection of AEG-1 and EXT-1 siRNAs were achieved. Histological scoring, immunohistochemical staining, and gene expression studies were performed from excised tissues. Data from the Cancer Genomic Atlas and GEO databases were obtained to identify the expression status of AEG-1 and itsassociation with the survival. RESULTS: In BALB/c mice, the AOM+DSS treated mice developed necrotic, inflammatory and dysplastic changes in the colon with definite clinical symptoms such as loss of goblet cells, colon shortening, and collagen deposition. Administration of AEG-1 siRNA resulted in a substantial decrease in the disease activity index. Mice treated with EXT-1 siRNA showed diffusely reduced goblet cells. In vivo investigations revealed that PTCH-1 activity was influenced by upstream gene AEG-1, which in turn may affect EXT-1 activity. Data from The Cancer Genomic Atlas and GEO databases confirmed the upregulation of AEG-1 and downregulation of EXT-1 in cancer patients. CONCLUSIONS: This study revealed that AEG-1 silencing might alter EXT-1 expression indirectly through PTCH-1, influencing cell-ECM interactions, and decreasing dysplastic changes, proliferation and invasion.

Design of a novel gamma camera with large field of view for 16N diagnosis in the primary loop of nuclear reactor.

The assessment of the concentration and distribution of l6N, derived from 16O in the cooling water exposed to neutron irradiation, is essential for ensuring radiation safety during nuclear reactor operation. The imaging method allows for the visualization of the intensity distribution of these l6N by capturing gamma-rays emitted during their decay process. However, the existing gamma camera is exclusively compatible with gamma-rays below 2 MeV. In this paper, a novel gamma camera featuring a thick double-conical penumbra aperture, a pixelated Lu1.8Y0.2SiO5:Ce scintillator array, and a position-sensitive photomultiplier tube is proposed to address this limitation. This innovative design offers a large field of view (FOV) and is suitable for high energy extended gamma source imaging. The optimization of key parameters of the camera was conducted, and a FOV of 60° and an angular resolution of up to 4.57° were achieved. Imaging simulations, including a simplified model of the primary loop of the pressurized-water reactor by GEANT4 code and image reconstruction using the expectation maximum algorithm, demonstrated that the proposed gamma camera could obtain a satisfactory spatial resolution for diagnosing the distribution of 16N in the primary loop of a nuclear reactor.

Development of Injectable Thermosensitive Nanocomposite Hydrogel for Ratiometric Drug Delivery to Treat Drug Resistant Chondrosarcoma In Vivo.

Chondrosarcoma(CS), a prevalent primary malignant bone tumor, frequently exhibits chemotherapy resistance attributed to upregulated anti-apoptosis pathways such as the Bcl-2 family. In this manuscript, a new strategy is presented to augment chemosensitivity and mitigate systemic toxicity by harnessing a nano-enabled drug delivery hydrogel platform. The platform utilizes "PLGA-PEG-PLGA", an amphiphilic triblock copolymer combining hydrophilic polyethylene glycol (PEG) and hydrophobic polylactide glycolide (PLGA) blocks, renowned for its properties conducive to crafting a biodegradable, temperature-sensitive hydrogel. This platform is tailored to encapsulate a ratiometrically designed dual-loaded liposomes containing a first-line chemo option for CS, Doxorubicin (Dox), plus a calculated amount of small molecule inhibitor for anti-apoptotic Bcl-2 pathway, ABT-737. In vitro and in vivo evaluations demonstrate successful Bcl-2 suppression, resulting in the restoration of Dox sensitivity, evident through impeded tumor growth and amplified necrosis rates at the tumor site. This delivery system showcases remarkable thermal responsiveness, injectability, and biodegradability, all finely aligned with the clinical demands of CS treatment. Collectively, this study introduces a transformative avenue for tackling drug resistance in CS chemotherapy, offering significant clinical potential.

SPARC Stabilizes ApoE to Induce Cholesterol-Dependent Invasion and Sorafenib Resistance in Hepatocellular Carcinoma.

Dysregulation of cholesterol homeostasis is implicated in the development and progression of hepatocellular carcinoma (HCC) that is characterized by intrahepatic and early extrahepatic metastases. A better understanding of the underlying mechanisms regulating cholesterol metabolism in HCC could help identify strategies to circumvent the aggressive phenotype. Here, we found that high expression of intracellular SPARC (secreted protein acidic and rich in cysteine) was significantly associated with elevated cholesterol levels and an enhanced invasive phenotype in HCC. SPARC potentiated cholesterol accumulation in HCC cells during tumor progression by stabilizing the ApoE protein. Mechanistically, SPARC competitively bound to ApoE, impairing its interaction with the E3 ligase tripartite motif containing 21 (TRIM21) and preventing its ubiquitylation and subsequent degradation. ApoE accumulation led to cholesterol enrichment in HCC cells, stimulating PI3K-AKT signaling and inducing epithelial-mesenchymal transition (EMT). Importantly, sorafenib-resistant HCC cells were characterized by increased expression of intracellular SPARC, elevated cholesterol levels, and enhanced invasive capacity. Inhibiting SPARC expression or reducing cholesterol levels enhanced the sensitivity of HCC cells to sorafenib treatment. Together, these findings unveil interplay between SPARC and cholesterol homeostasis. Targeting SPARC-triggered cholesterol-dependent oncogenic signaling is a potential therapeutic strategy for advanced HCC. SIGNIFICANCE: Intracellular SPARC boosts cholesterol availability to fuel invasion and drug resistance in hepatocellular carcinoma, providing a rational approach to improve the treatment of advanced liver cancer.

Ethnobotanical study of traditional medicinal plants used by the local Gamo people in Boreda Abaya District, Gamo Zone, southern Ethiopia.

BACKGROUND: Medicinal plants have been used for centuries and are still relied upon by over 80% of the Ethiopian population. The people of Gamo, southern Ethiopia, have a rich cultural and traditional lifestyle with a long history of using plant resources for various uses including traditional herbal medicine. However, their traditional knowledge of traditional medicinal plants in Boreda Abaya District has not been explored Ethnobotanically yet, despite preserving diverse indigenous traditional medicinal plants. Hence, the study aimed to document and analyze traditional medicinal plants and associated traditional knowledge and practices used by local people. MATERIALS AND METHODS: Quantitative ethnobotanical data were collected via semi-structured interviews, face-to-face conversations, group discussions, and guided field trips between September 2022 and February 2023. In total, 92 informants participated, of which 25 were key informants. Quantitative data indices (informant consensus factor-ICF-and use report-Ur) were computed by MS Excel spreadsheet software. Scientific names of medicinal plants were checked via World Flora Online. RESULTS: In the present study, we recorded 188 traditional medicinal plant species belonging to 163 genera and 73 plant families. Lamiaceae (16 species), Asteraceae (16 species), Fabaceae (11 species), and Euphorbiaceae (8 species) contributed highest number of species and were found to be predominant family in the area. Leaves and seeds were most frequently used plant parts, and pounding (46%) was the main method to prepare remedies. The sudden sickness disease category scored the highest consensus (ICF: 0.35), followed by blood and circulatory-related disease categories (ICF: 0.33). The highest number of plant taxa (61 species) used to treat dermal disease has a 71-use report score, while fewer plant taxa (21 species) were utilized to treat genitourinary system-related disease category, having 25 use reports. Ocimum lamiifolium (Ur:56) and Moringa stenopetala (Ur:51) are widely used species and received highest use report value. CONCLUSION: Gamo people possess extensive traditional knowledge of ethnomedicine. The region's vegetation hosts diverse medicinal species, but deforestation, agriculture, and droughts threaten them. Local conservation practices require scientific support, prioritizing species having higher use reports (Ur), and in-depth investigations of promising species for drug development are essential.

Projected impacts of climate change on the habitat of Xerophyta species in Africa.

Climate change poses a serious long-term threat to biodiversity. To effectively reduce biodiversity loss, conservationists need to have a thorough understanding of the preferred habitats of species and the variables that affect their distribution. Therefore, predicting the impact of climate change on species-appropriate habitats may help mitigate the potential threats to biodiversity distribution. Xerophyta, a monocotyledonous genus of the family Velloziaceae is native to mainland Africa, Madagascar, and the Arabian Peninsula. The key drivers of Xerophyta habitat distribution and preference are unknown. Using 308 species occurrence data and eight environmental variables, the MaxEnt model was used to determine the potential distribution of six Xerophyta species in Africa under past, current and future climate change scenarios. The results showed that the models had a good predictive ability (Area Under the Curve and True Skill Statistics values for all SDMs were more than 0.902), indicating high accuracy in forecasting the potential geographic distribution of Xerophyta species. The main bioclimatic variables that impacted potential distributions of most Xerophyta species were mean temperature of the driest quarter (Bio9) and precipitation of the warmest quarter (Bio18). According to our models, tropical Africa has zones of moderate and high suitability for Xerophyta taxa, which is consistent with the majority of documented species localities. The habitat suitability of the existing range of the Xerophyta species varied based on the climate scenario, with most species experiencing a range loss greater than the range gain regardless of the climate scenario. The projected spatiotemporal patterns of Xerophyta species help guide recommendations for conservation efforts.

Genetic screen identified PRMT5 as a neuroprotection target against cerebral ischemia.

Epigenetic regulators present novel opportunities for both ischemic stroke research and therapeutic interventions. While previous work has implicated that they may provide neuroprotection by potentially influencing coordinated sets of genes and pathways, most of them remain largely uncharacterized in ischemic conditions. In this study, we used the oxygen-glucose deprivation (OGD) model in the immortalized mouse hippocampal neuronal cell line HT-22 and carried out an RNAi screen on epigenetic regulators. PRMT5 was identified as a novel negative regulator of neuronal cell survival after OGD, which presented a phenotype of translocation from the cytosol to the nucleus upon oxygen and energy depletion both in vitro and in vivo. PRMT5 bound to the chromatin and a large number of promoter regions to repress downstream gene expression. Silencing Prmt5 significantly dampened the OGD-induced changes for a large-scale of genes, and gene ontology analysis showed that PRMT5-target genes were highly enriched for Hedgehog signaling. Encouraged by the above observation, mice were treated with middle cerebral artery occlusion with the PRMT5 inhibitor EPZ015666 and found that PRMT5 inhibition sustains protection against neuronal death in vivo. Together, these findings revealed a novel epigenetic mechanism of PRMT5 in cerebral ischemia and uncovered a potential target for neuroprotection.

miR-107-5p ameliorates neurological damage, oxidative stress, and immune responses in mice with Alzheimer's disease by suppressing the Toll-like receptor 4 (TLR4)/nuclear factor-kappaB(NF-κB) pathway.

Alzheimer's disease (AD) is a progressively debilitating neurodegenerative condition primarily affecting the elderly. Emerging research suggests that microRNAs (miRNAs) play a role in the development of AD. This study investigates the impact of miR-107-5p on neurological damage, oxidative stress, and immune responses in AD. We utilized APP/PS1 mice as AD mouse models and C57BL/6 J mice as controls. AD mice received treatment with agomir miR-107-5p (to overexpress miR-107-5p) or BAY11-7082 (an NF-κB pathway inhibitor). We evaluated learning and memory abilities through the Morris water maze test. Histopathological changes, hippocampal neuron distribution, and apoptosis were assessed using hematoxylin-eosin, Nissl, and TUNEL staining. Reactive oxygen species (ROS) levels, amyloid-Aß (Aß1-40/42) contents, and inflammatory factors (TNF-α, IL-6, IL-1ß) in hippocampal tissues were measured using ROS kits and enzyme-linked immunosorbent assay (ELISA). Microglial activation in hippocampal tissues was observed under a fluorescence microscope. miR-107-5p's binding to TLR4 was predicted via the TargetScan database and confirmed through a dual-luciferase assay. miR-107-5p expression, along with TLR4, APOE, and TREM2 in hippocampal tissue homogenate, and NF-κB p65 protein expression in the nucleus and cytoplasm were assessed via RT-qPCR and Western blot. Overexpression of miR-107-5p ameliorated hippocampal neurological damage, oxidative stress, and immune responses. This was evidenced by improved enhanced learning/memory abilities, reduced Aß1-40 and Aß1-42 levels, diminished neuronal injuries, decreased ROS and TNF-α, IL-6, and IL-1ß levels, increased APOE and TREM2 levels, and suppressed microglial activation. miR-107-5p directly targeted and inhibited TLR4 expression, leading to reduced nuclear translocation of NF-κB p65 in the NF-κB pathway. Inhibition of the NF-κB pathway similarly improved neurological damage, oxidative stress, and immune response in AD mice. miR-107-5p exerts its beneficial effects by suppressing the TLR4/NF-κB pathway, ultimately ameliorating neurological damage, oxidative stress, and immune responses in AD mice.

Brain connectomics improve prediction of 1-year decreased quality of life in breast cancer: A multi-voxel pattern analysis.

PURPOSE: Whether brain connectomics can predict 1-year decreased Quality of Life (QoL) in patients with breast cancer are unclear. A longitudinal study was utilized to explore their prediction abilities with a multi-center sample. METHODS: 232 breast cancer patients were consecutively enrolled and 214 completed the 1-year QoL assessment (92.2%). Resting state functional magnetic resonance imaging was collected before the treatment and a multivoxel pattern analysis (MVPA) was performed to differentiate whole-brain resting-state connectivity patterns. Net Reclassification Improvement (NRI) as well as Integrated Discrimination Improvement (IDI) were calculated to estimate the incremental value of brain connectomics over conventional risk factors. RESULTS: Paracingulate Gyrus, Superior Frontal Gyrus and Frontal Pole were three significant brain areas. Brain connectomics yielded 7.8-17.2% of AUC improvement in predicting 1-year decreased QoL. The NRI and IDI ranged from 20.27 to 54.05%, 13.21-33.34% respectively. CONCLUSION: Brain connectomics contribute to a more accurate prediction of 1-year decreased QoL in breast cancer. Significant brain areas in the prefrontal lobe could be used as potential intervention targets (i.e., Cognitive Behavioral Group Therapy) to improve long-term QoL outcomes in breast cancer.