Integrative multi-omics analysis unveils the connection between transcriptomic characteristics associated with mitochondria and the tumor immune microenvironment in lower-grade gliomas.

Lower-grade gliomas (LGGs) exhibit diverse clinical behaviors and varying immune infiltration levels. Mitochondria have been implicated in numerous cancer pathogenesis and development, including LGGs. However, the precise biological functions of mitochondrial genes in shaping the immune landscape and the prognostic significance of LGGs remain elusive. Utilizing the Mito-Carta3.0 database, we curated a total of 1136 genes implicated in mitochondrial functions. By leveraging the expression profiles of 1136 genes related to mitochondria, we successfully categorized LGGs into four distinctive mitochondria-related transcriptome (MRT) subtypes. Our thorough analysis conclusively demonstrated that these subtypes exhibited marked disparities. To enable a personalized and integrated evaluation of LGG patients, we developed a prognostic signature known as MRT-related prognostic signature (MTRS). MTRS demonstrated correlation with mitochondria-related transcriptome (MRT) subtypes, allowing the assessment of patients' prognosis and immune microenvironment. We conducted a detailed exploration of the single-cell distribution of MTRS in lower-grade gliomas and verified the core genes of MTRS within the spatial transcriptome of these tumors. Furthermore, our study pinpointed MGME1 as the pivotal gene in the model, functioning as an oncogene that exerts influence on cell proliferation and migration capabilities. Our research highlights the importance of mitochondrial transcriptomic features in LGGs, offering paths for tailored therapies.

Brain-targeted ursolic acid nanoparticles for anti-ferroptosis therapy in subarachnoid hemorrhage.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a life -threatening cerebrovascular disease, where early brain injury (EBI) stands as a primary contributor to mortality and unfavorable patient outcomes. Neuronal ferroptosis emerges as a key pathological mechanism underlying EBI in SAH. Targeting ferroptosis for therapeutic intervention in SAH holds significant promise as a treatment strategy. METHODS: SAH model was induced via intravascular puncture and quantitatively assessed the presence of neuronal ferroptosis in the early phase of SAH using FJC staining, Prussian blue staining, as well as malondialdehyde (MDA) and glutathione (GSH) measurements. Hyaluronic acid-coated ursolic acid nanoparticles (HA-PEG-UA NPs) were prepared using the solvent evaporation method. We investigated the in vivo distribution of HA-PEG-UA NPs in SAH model through IVIS and fluorescence observation, and examined their impact on short-term neurological function and cortical neurological injury. Finally, we assessed the effect of UA on the Nrf-2/SLC7A11/GPX4 axis via Western Blot analysis. RESULTS: We successfully developed self-assembled UA NPs with hyaluronic acid to target the increased CD44 expression in the SAH-afflicted brain. The resulting HA-PEG-UA NPs facilitated delivery and enrichment of UA within the SAH-affected region. The targeted delivery of UA to the SAH region can effectively inhibit neuronal ferroptosis, improve neurological deficits, and prognosis in mice. Its mechanism of action is associated with the activation of the Nrf-2/SLC7A11/GPX4 signaling pathway. CONCLUSIONS: Brain-targeted HA-PEG-UA NPs was successfully developed and hold the potential to enhance SAH prognosis by limiting neuronal ferroptosis via modulation of the Nrf-2/SLC7A11/GPX4 signal.

Uncoupling FRUITFULL's functions through modification of a protein motif identified by co-ortholog analysis.

Many plant transcription factors (TFs) are multifunctional and regulate growth and development in more than one tissue. These TFs can generally associate with different protein partners depending on the tissue type, thereby regulating tissue-specific target gene sets. However, how interaction specificity is ensured is still largely unclear. Here, we examine protein-protein interaction specificity using subfunctionalized co-orthologs of the FRUITFULL (FUL) subfamily of MADS-domain TFs. In Arabidopsis, FUL is multifunctional, playing important roles in flowering and fruiting, whereas these functions have partially been divided in the tomato co-orthologs FUL1 and FUL2. By linking protein sequence and function, we discovered a key amino acid motif that determines interaction specificity of MADS-domain TFs, which in Arabidopsis FUL determines the interaction with AGAMOUS and SEPALLATA proteins, linked to the regulation of a subset of targets. This insight offers great opportunities to dissect the biological functions of multifunctional MADS TFs.

The current state of MRI-based radiomics in pituitary adenoma: promising but challenging.

In the clinical diagnosis and treatment of pituitary adenomas, MRI plays a crucial role. However, traditional manual interpretations are plagued by inter-observer variability and limitations in recognizing details. Radiomics, based on MRI, facilitates quantitative analysis by extracting high-throughput data from images. This approach elucidates correlations between imaging features and pituitary tumor characteristics, thereby establishing imaging biomarkers. Recent studies have demonstrated the extensive application of radiomics in differential diagnosis, subtype identification, consistency evaluation, invasiveness assessment, and treatment response in pituitary adenomas. This review succinctly presents the general workflow of radiomics, reviews pertinent literature with a summary table, and provides a comparative analysis with traditional methods. We further elucidate the connections between radiological features and biological findings in the field of pituitary adenoma. While promising, the clinical application of radiomics still has a considerable distance to traverse, considering the issues with reproducibility of imaging features and the significant heterogeneity in pituitary adenoma patients.

AB048. Evidence of effectiveness of neoadjuvant camrelizumab and apatinib in patients with recurrent high-grade gliomas.

BACKGROUND: Recurrent high-grade glioma (HGG) is a challenge with limited treatment options and a poor prognosis. We conducted an open-label phase II study: neoadjuvant camrelizumab and apatinib in patients with recurrent high-grade gliomas (NCT04588987), and interim analysis showed very promising results. We are further searching for evidence of the effectiveness of this strategy. METHODS: Patients with recurrent HGG received neoadjuvant treatment with camrelizumab (intravenous injection 200 mg on day 1) and apatinib (oral 250 mg per day on days 1-7), and 14 days later received surgery for recurrent tumor resection. Sequential therapy began 2 weeks after surgery with the biweekly camrelizumab (200 mg) and 4 weeks after surgery with the daily apatinib (250 mg) until investigator assessed progressive disease or unable to tolerate toxicity. The primary endpoint was overall survival (OS). When patients suspected progress during per-protocol treatment, re-surgery for resection of lesion was done, and the tissue was further examined. RESULTS: Between October 9, 2020, and March 30, 2024, 24 patients were enrolled [19 glioblastomas, one World Health Organization (WHO) grade 4 diffuse astrocytoma, three anaplastic astrocytoma, and one anaplastic oligodendroglioma]. Nineteen patients with interim analysis data, and showed the median progression-free survival (PFS) was 4.8 months [95% confidence interval (CI): 4.4-5.2], the median OS was 12.9 months (95% CI: 9.3-16.4) respectively, with a median follow-up time of 17.5 months (95% CI: 9.0-26.1). There were two patients who suspected progress and received second surgery. One patient showed real tumor progression with active tumor cells. While another patient the histology revealed mainly necrosis with inflammatory cells. Five patients initially showed increased enhancement on magnetic resonance imaging (MRI) but without increased symptoms, and showed continuous improvement when receiving further treatment. CONCLUSIONS: This immuno-target combination neoadjuvant therapy in recurrent HGG demonstrated encouraging efficacy and revealed some evidence of efficacy, and worth to further investigate.

FTO-mediated DSP m6A demethylation promotes an aggressive subtype of growth hormone-secreting pituitary neuroendocrine tumors.

BACKGROUND: Growth hormone-secreting pituitary neuroendocrine tumors can be pathologically classified into densely granulated (DGGH) and sparsely granulated types (SGGH). SGGH is more aggressive and associated with a poorer prognosis. While epigenetic regulation is vital in tumorigenesis and progression, the role of N6-methyladenosine (m6A) in aggressive behavior has yet to be elucidated. METHODS: We performed m6A-sequencing on tumor samples from 8 DGGH and 8 SGGH patients, complemented by a suite of assays including ELISA, immuno-histochemistry, -blotting and -fluorescence, qPCR, MeRIP, RIP, and RNA stability experiments, aiming to delineate the influence of m6A on tumor behavior. We further assessed the therapeutic potential of targeted drugs using cell cultures, organoid models, and animal studies. RESULTS: We discovered a significant reduction of m6A levels in SGGH compared to DGGH, with an elevated expression of fat mass and obesity-associated protein (FTO), an m6A demethylase, in SGGH subtype. Series of in vivo and in vitro experiments demonstrated that FTO inhibition in tumor cells robustly diminishes hypoxia resistance, attenuates growth hormone secretion, and augments responsiveness to octreotide. Mechanically, FTO-mediated m6A demethylation destabilizes desmoplakin (DSP) mRNA, mediated by the m6A reader FMR1, leading to prohibited desmosome integrity and enhanced tumor hypoxia tolerance. Targeting the FTO-DSP-SSTR2 axis curtailed growth hormone secretion, therefor sensitizing tumors to octreotide therapy. CONCLUSION: Our study reveals the critical role of FTO in the aggressive growth hormone-secreting pituitary neuroendocrine tumors subtype and suggests FTO may represent a new therapeutic target for refractory/persistent SGGH.

Parathyroid hormone mediates the adverse impact of air pollution exposure on serum 25-hydroxyvitamin D: A nationwide cross-sectional study in China.

BACKGROUND: Maintaining normal levels of 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) is crucial for preserving skeletal health. However, evidence regarding the associations of exposure to air pollution with serum 25(OH)D and PTH were limited and ambiguous. Hence, the objective of this cross-sectional study was to systematically evaluate the association between air pollution [particulate matter ≤ 2.5 µm (PM2.5) and ozone (O3)] exposure and serum 25(OH)D and PTH levels in males aged 50 and above and postmenopausal female. MATERIALS AND METHODS: This study is multicenter, cross-sectional study within the framework of the ongoing China Community-based Cohort of Osteoporosis. The 1-year-average PM2.5 and O3 exposures prior to the baseline survey were estimated using random forest models with relatively high accuracy. Multiple linear regression models were employed to assess the associations between PM2.5 and O3 concentrations with the serum levels of 25(OH)D and PTH. Furthermore, mediation analysis was performed to scrutinize the potential mediating role of PTH in the interplay between PM2.5, O3, and serum 25(OH)D. RESULTS: A total of 13194 participants were included. Our analysis showed that every 10 µg/m3 increase in the 1-year average PM2.5, were associated with -0.32 units (95% CI: 0.48, -0.17) of change in the 25(OH)D and 0.15 units (95% CI: 0.11, 0.19) of change in the PTH, respectively. Every 10 µg/m3 increase in the 1-year average O3, were associated with -0.78 units (95% CI: 1.05, -0.51) of change in the 25(OH)D and 0.50 units (95% CI: 0.43, 0.57) of change in the PTH, respectively. Estimates of the mediation ratio indicated that increased PTH mediated a 50.48% negative correlation between PM2.5 exposure and circulating 25(OH)D level. Increased PTH mediated 69.61% of the negative effects of O3 exposure on circulating 25(OH)D level. CONCLUSIONS: Exposure to PM2.5 and O3 significantly diminished 25(OH)D while elevating PTH levels. Notably, the elevated PTH concentration partially mediates the associations between PM2.5 and O3 exposure and 25(OH)D level.

An oil-in-gel type of organohydrogel loaded with methylprednisolone for the treatment of secondary injuries following spinal cord traumas.

The secondary injuries following traumatic spinal cord injury (SCI) is a multiphasic and complex process that is difficult to treat. Although methylprednisolone (MP) is the only available pharmacological regime for SCI treatment, its efficacy remains controversial due to its very narrow therapeutic time window and safety concerns associated with high dosage. In this study, we have developed an oil-in-gel type of organohydrogel (OHG) in which the binary oleic-water phases coexist, for the local delivery of MP. This new OHG is fabricated by a glycol chitosan/oxidized hyaluronic acid hydrophilic network that is uniformly embedded with a biocompatible oil phase, and it can be effectively loaded with MP or other hydrophobic compounds. In addition to spatiotemporally control MP release, this biodegradable OHG also provides a brain tissue-mimicking scaffold that can promote tissue regeneration. OHG remarkably decreases the therapeutic dose of MP in animals and extends its treatment course over 21 d, thereby timely manipulating microglia/macrophages and their associated with signaling molecules to restore immune homeostasis, leading to a long-term functional improvement in a complete transection SCI rat model. Thus, this OHG represents a new type of gel for clinical treatment of secondary injuries in SCI.

Oblique Lumbar Interbody Fusion Combined with Posterior Percutaneous Pedicle Screw Internal Fixation: Does Variability in Cage Position Influence Clinical Outcomes?

OBJECTIVE: The study investigates how cage positions in oblique lumbar interbody fusion (OLIF) combined with posterior percutaneous pedicle screw internal fixation (PPSF) affect lumbar canal and foraminal decompression and postoperative outcomes, providing guidance for optimal placement and efficacy assessment. METHODS: This investigation assesses radiologic outcomes and follow-up data in relation to cage position variability among 80 patients who underwent L4/5 single-segment OLIF + PPSF from 2018 to 2022. RESULTS: In the study involving 80 participants, the combination of OLIF and PPSF significantly improved lower back and leg symptoms in patients, leading to positive clinical outcomes during follow-up. The intervertebral disk height increased from an average of 8.10 ± 2.79 mm before surgery to 11.75 ± 2.14 mm after surgery (P < 0.001). Additionally, this surgical technique notably increased the FH (P < 0.001) and expanded the DCSA from 68.81 ± 53.89 mmˆ2 before surgery to 102.91 ± 60.46 mmˆ2 after surgery (P < 0.001). Linear results suggest that changes in the position of the cage do not affect spinal imaging parameters. There is no significant difference in the correction of spinal parameters or prognosis whether the cage is back, middle, ahead. CONCLUSIONS: In the OLIF + PPSF procedure, strict requirements for cage position are not necessary to achieve predetermined spinal biomechanical parameters. The practice of repeated fluoroscopy to adjust cage position postimplantation does not provide added clinical benefits to the patient.

Single-cell atlas profiling revealed cellular characteristics and dynamic changes after PD-1 blockade therapy of brain metastases from laryngeal squamous cell carcinoma.

Brain metastasis (BM) in laryngeal squamous cell carcinoma (LSCC) is uncommon but prognosis is poor. Anti-PD-1 immunotherapy benefits some advanced LSCC cases, yet its efficiency is limited by tumor complexity. We analyzed paired metastatic tumor samples from before and after immunotherapy using single-cell RNA sequencing (scRNA-seq), along with a primary LSCC dataset and bulk RNA sequencing. This identified changes post-immunotherapy and revealed differences in single-cell transcriptomes among LSCC, primBM, and neoBM. Our findings show that anti-PD-1 treatment suppresses metastasis-promoting pathways like VEGF and EMT in cancer cells, and alters immune cell functions. Notably, it upregulates T cell activation, leading to CD8 T cell exhaustion from excess heat shock proteins, notably HSPA8. However, CD8 T cell cytotoxic functions improve post-treatment. In myeloid cells, anti-PD-1 therapy enhances antigen presentation and promotes a proinflammatory shift post-metastasis. Additionally, NUPR1 is linked to BM in LSCC, and NEAT1 is a potential metastatic cancer cell cycle participant. Our study provides insights into cancer heterogeneity and the impact of PD-1 immunotherapy on metastasis, aiding precise diagnosis and prognosis.

Genome-wide association study identified candidate genes for egg production traits in the Longyan Shan-ma duck.

Egg production is an important economic trait in layer ducks and understanding the genetics basis is important for their breeding. In this study, a genome-wide association study (GWAS) for egg production traits in 303 female Longyan Shan-ma ducks was performed based on a genotyping-by-sequencing strategy. Sixty-two single nucleotide polymorphisms (SNPs) associated with egg weight traits were identified (P < 9.48 × 10-5), including 8 SNPs at 5% linkage disequilibrium (LD)-based Bonferroni-corrected genome-wide significance level (P < 4.74 × 10-6). One hundred and nineteen SNPs were associated with egg number traits (P < 9.48 × 10-5), including 13 SNPs with 5% LD-based Bonferroni-corrected genome-wide significance (P < 4.74 × 10-6). These SNPs annotated 146 target genes which contained known candidate genes for egg production traits, such as prolactin and prolactin releasing hormone receptor. This study identified that these associated genes were significantly enriched in egg production-related pathways (P < 0.05), such as the oxytocin signaling, MAPK signaling, and calcium signaling pathways. It was notable that 18 genes were differentially expressed in ovarian tissues between higher and lower egg production in Shan-ma ducks. The identified potential candidate genes and pathways provide insight into the genetic basis underlying the egg production trait of layer ducks.

Cyclin L1 participates in Adriamycin resistance and progression of osteosarcoma via PI3K/AKT-mTOR pathway.

Chemoresistance is a common and thorny problem in the treatment of osteosarcoma (OS), which obstructs the response of relapse or metastasis of OS to chemotherapy and leads to the unfavorable prognosis of OS patients. Cyclin L1 (CCNL1) is a non-canonical cyclin that plays an important role in the regulation of tumor cell proliferation and lymph node metastasis. In this work, we explored the impact of CCNL1 expression levels on proliferation, migration, and Adriamycin (ADM) resistance in OS and related mechanisms. We found that CCNL1 expression levels were significantly associated with clinical prognosis of patients with OS and CCNL1 could promote OS proliferation and migration. In addition, we also revealed that cellular CCNL1 was significantly increased in ADM-resistant OS cells and promoted ADM resistance. The PI3K/AKT-mTOR pathway is involved in CCNL1-mediated ADM resistance in OS. In summary, CCNL1 is involved in the progression of ADM resistance and OS through the PI3K/AKT-mTOR pathway, which will provide a new clue to the mechanism of ADM resistance and a potential target for the treatment of ADM-resistant OS.

Injectable ultrasonic sensor for wireless monitoring of intracranial signals.

Direct and precise monitoring of intracranial physiology holds immense importance in delineating injuries, prognostication and averting disease1. Wired clinical instruments that use percutaneous leads are accurate but are susceptible to infection, patient mobility constraints and potential surgical complications during removal2. Wireless implantable devices provide greater operational freedom but include issues such as limited detection range, poor degradation and difficulty in size reduction in the human body3. Here we present an injectable, bioresorbable and wireless metastructured hydrogel (metagel) sensor for ultrasonic monitoring of intracranial signals. The metagel sensors are cubes 2 × 2 × 2 mm3 in size that encompass both biodegradable and stimulus-responsive hydrogels and periodically aligned air columns with a specific acoustic reflection spectrum. Implanted into intracranial space with a puncture needle, the metagel deforms in response to physiological environmental changes, causing peak frequency shifts of reflected ultrasound waves that can be wirelessly measured by an external ultrasound probe. The metagel sensor can independently detect intracranial pressure, temperature, pH and flow rate, realize a detection depth of 10 cm and almost fully degrade within 18 weeks. Animal experiments on rats and pigs indicate promising multiparametric sensing performances on a par with conventional non-resorbable wired clinical benchmarks.

NSUN4 mediated RNA 5-methylcytosine promotes the malignant progression of glioma through improving the CDC42 mRNA stabilization.

5-Methylcytosine (m5C) methylation is a significant post-transcriptional modification that play a crucial role in the development and progression of numerous cancers. Whereas the functions and molecular mechanisms underlying m5C methylation in gliomas remain unclear. This study dedicated to explore changes of m5C levels and the clinical significance of the m5C writer NSUN4 in gliomas. We found that high m5C levels were negatively related to prognosis of patients with glioma. Moreover, gain- and loss-of-function experiments revealed the role of NSUN4 in enhancing m5C modification of mRNA to promote the malignant progression of glioma. Mechanistically speaking, NSUN4-mediated m5C alterations regulated ALYREF binding to CDC42 mRNA, thereby impacting the mRNA stability of CDC42. We also demonstrated that CDC42 promoted glioma proliferation, migration, and invasion by activating the PI3K-AKT pathway. Additionally, rescue experiments proved that CDC42 overexpression weaken the inhibitory effect of NSUN4 knockdown on the malignant progression of gliomas in vitro and in vivo. Our findings elucidated that NSUN4-mediated high m5C levels promote ALYREF binding to CDC42 mRNA and regulate its stability, thereby driving the malignant progression of glioma. This provides theoretical support for targeted the treatment of gliomas.

Zero-profile implant system versus novel plate systems after ACDF for comparison of sagittal balance parameters and clinical efficacy analysis.

BACKGROUND: The zero-profile implant system (Zero-P) and conventional plates have been widely used in anterior cervical discectomy and fusion (ACDF) to treat cervical spondylosis. The purpose of this study was to compare the effects of the application of Zero-P and new conventional plates (ZEVO, Skyline) in ACDF on the sagittal imaging parameters of cervical spondylosis patients and to analyze their clinical efficacy. METHODS: We conducted a retrospective study on 119 cervical spondylosis patients from January 2018 to December 2021, comparing outcomes between those receiving the Zero-P device (n = 63) and those receiving a novel conventional plate (n = 56, including 46 ZEVO and 10 Skyline plates) through ACDF. Cervical sagittal alignment was assessed pre- and postoperatively via lateral radiographs. The Japanese Orthopedic Association (JOA), Neck Disability Index (NDI), and visual analog scale (VAS) scores were recorded at baseline, after surgery, and at the 2-year follow-up to evaluate patient recovery and intervention success. RESULTS: There were significant differences in the postoperative C0-C2 Cobb angle and postoperative sagittal segmental angle (SSA) between patients in the novel conventional plate group and those in the Zero-P group (P < 0.05). Postoperatively, there were significant changes in the C2‒C7 Cobb angle, C0‒C2 Cobb angle, SSA, and average surgical disc height (ASDH) compared to the preoperative values in both patient groups (P < 0.05). Dysphagia in the immediate postoperative period was lower in the Zero-P group than in the new conventional plate group (0% in the Zero-P group, 7.14% in the novel conventional plate group, P = 0.046), and the symptoms disappeared within 2 years in both groups. There was no statistically significant difference between the two groups in terms of complications of adjacent spondylolisthesis (ASD) at 2 years postoperatively (3.17% in the Zero-P group, 8.93% in the novel conventional plate group; P = 0.252). According to the subgroup analysis, there were significant differences in the postoperative C2‒C7 Cobb angle, C0‒C2 Cobb angle, T1 slope, and ASDH between the ZEVO group and the Skyline group (P < 0.05). Compared with the preoperative scores, the JOA, NDI, and VAS scores of all groups significantly improved at the 2-year follow-up (P < 0.01). According to the subgroup analysis, the immediate postoperative NDI and VAS scores of the ZEVO group were significantly better than those of the Skyline group (P < 0.05). CONCLUSION: In ACDF, both novel conventional plates and Zero-P can improve sagittal parameters and related scale scores. Compared to the Zero-P plate, the novel conventional plate has a greater advantage in correcting the curvature of the surgical segment, but the Zero-P plate is less likely to produce postoperative dysphagia.

Constructing and validating a predictive nomogram for osteoporosis risk among Chinese single-center male population using the systemic immune-inflammation index.

Osteoporosis (OP) is a bone metabolism disease that is associated with inflammatory pathological mechanism. Nonetheless, rare studies have investigated the diagnostic effectiveness of immune-inflammation index in the male population. Therefore, it is interesting to achieve early diagnosis of OP in male population based on the inflammatory makers from blood routine examination. We developed a prediction model based on a training dataset of 826 Chinese male patients through a retrospective study, and the data was collected from January 2022 to May 2023. All participants underwent the dual-energy X-ray absorptiometry (DXEA) and blood routine examination. Inflammatory markers such as systemic immune-inflammation index (SII) and platelet-to-lymphocyte ratio (PLR) was calculated and recorded. We utilized the least absolute shrinkage and selection operator (LASSO) regression model to optimize feature selection. Multivariable logistic regression analysis was applied to construct a predicting model incorporating the feature selected in the LASSO model. This predictive model was displayed as a nomogram. Receiver operating characteristic (ROC) curve, C-index, calibration curve, and clinical decision curve analysis (DCA) to evaluate model performance. Internal validation was test by the bootstrapping method. This study was approved by the Ethic Committee of the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine (Ethic No. JY2023012) and conducted in accordance with the relevant guidelines and regulations. The predictive factors included in the prediction model were age, BMI, cardiovascular diseases, cerebrovascular diseases, neuropathy, thyroid diseases, fracture history, SII, PLR, C-reactive protein (CRP). The model displayed well discrimination with a C-index of 0.822 (95% confidence interval: 0.798-0.846) and good calibration. Internal validation showed a high C-index value of 0.805. Decision curve analysis (DCA) showed that when the threshold probability was between 3 and 76%, the nomogram had a good clinical value. This nomogram can effectively predict the incidence of OP in male population based on SII and PLR, which would help clinicians rapidly and conveniently diagnose OP with men in the future.

SARS-CoV-2 Omicron Variants Show Attenuated Neurovirulence Compared with the Wild-Type Strain in Elderly Human Brain Spheroids.

Infection with severe acute respiratory syndrome coronavirus 2 Omicron variants still causes neurological complications in elderly individuals. However, whether and how aging brains are affected by Omicron variants in terms of neuroinvasiveness and neurovirulence are unknown. Here, we utilize resected paracarcinoma brain tissue from elderly individuals to generate primary brain spheroids (BSs) for investigating the replication capability of live wild-type (WT) strain and Omicron (BA.1/BA.2), as well as the mechanisms underlying their neurobiological effects. We find that both WT and Omicron BA.1/BA.2 are able to enter BSs but weakly replicate. There is no difference between Omicron BA.1/BA.2 and WT strains in neurotropism in aging BSs. However, Omicron BA.1/BA.2 exhibits ameliorating neurological damage. Transcriptional profiling indicates that Omicron BA.1/BA.2 induces a lower neuroinflammatory response than WT strain in elderly BSs, suggesting a mechanistic explanation for their attenuated neuropathogenicity. Moreover, we find that both Omicron BA.1/BA.2 and WT strain infections disrupt neural network activity associated with neurodegenerative disorders by causing neuron degeneration and amyloid-ß deposition in elderly BSs. These results uncover Omicron-specific mechanisms and cellular immune responses associated with severe acute respiratory syndrome coronavirus 2-induced neurological complications.

Cysteine and glycine-rich protein 2 is crucial for maintaining the malignant phenotypes of gliomas through its action on Notch signalling cascade.

Cysteine and glycine-rich protein 2 (CSRP2) is expressed differently in numerous cancers and plays a key role in carcinogenesis. However, the role of CSRP2 in glioma is unknown. This study sought to determine the expression profile and clinical significance of CSRP2 in glioma and explore its biological functions and mechanisms via lentivirus-mediated CSRP2 silencing experiments. Increased CSRP2 was frequently observed in gliomas, which was associated with clinicopathological characteristics and an unfavourable prognosis. Decreasing CSRP2 led to the suppression of malignant proliferation, metastasis and stemness in glioma cells while causing hypersensitivity to chemotherapeutic drugs. Mechanistic investigations revealed that CSRP2 plays a role in mediating the Notch signalling cascade. Silencing CSRP2 decreased the levels of Notch1, cleaved Notch1, HES1 and HEY1, suppressing the Notch signalling cascade. Reactivation of Notch markedly diminished the tumour-inhibiting effects of CSRP2 silencing on the malignant phenotypes of glioma cells. Notably, CSRP2-silencing glioma cells exhibited reduced potential in the formation of xenografts in nude mice in vivo, which was associated with an impaired Notch signalling cascade. These results showed that CSRP2 is overexpressed in glioma and has a crucial role in sustaining the malignant phenotypes of glioma, suggesting that targeting CSRP2 could be a promising strategy for glioma treatment.

The mechanistic view of non-coding RNAs as a regulator of inflammatory pathogenesis of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor and non-motor symptoms. Emerging evidence suggests that inflammation plays a crucial role in the pathogenesis of PD, with the NLRP3 inflammasome implicated as a key mediator. Nfon-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have recently garnered attention for their regulatory roles in various biological processes, including inflammation. This review aims to provide a mechanistic insight into how ncRNAs function as regulators of inflammatory pathways in PD, with a specific focus on the NLRP3 inflammasome. We discuss the dysregulation of miRNAs and lncRNAs in PD pathogenesis and their impact on neuroinflammation through modulation of NLRP3 activation, cytokine production, and microglial activation. Additionally, we explore the crosstalk between ncRNAs, alpha-synuclein pathology, and mitochondrial dysfunction, further elucidating the intricate network underlying PD-associated inflammation. Understanding the mechanistic roles of ncRNAs in regulating inflammatory pathways may offer novel therapeutic targets for the treatment of PD and provide insights into the broader implications of ncRNA-mediated regulation in neuroinflammatory diseases.

RNA sequencing-based approaches to identifying disulfidptosis-related diagnostic clusters and immune landscapes in osteoporosis.

Disulfidptosis, a newly recognized cell death triggered by disulfide stress, has garnered attention for its potential role in osteoporosis (OP) pathogenesis. Although sulfide-related proteins are reported to regulate the balance of bone metabolism in OP, the precise involvement of disulfidptosis regulators remains elusive. Herein, leveraging the GSE56815 dataset, we conducted an analysis to delineate disulfidptosis-associated diagnostic clusters and immune landscapes in OP. Subsequently, vertebral bone tissues obtained from OP patients and controls were subjected to RNA sequencing (RNA-seq) for the validation of key disulfidptosis gene expression. Our analysis unveiled seven significant disulfidptosis regulators, including FLNA, ACTB, PRDX1, SLC7A11, NUBPL, OXSM, and RAC1, distinguishing OP samples from controls. Furthermore, employing a random forest model, we identified four diagnostic disulfidptosis regulators including FLNA, SLC7A11, NUBPL, and RAC1 potentially predictive of OP risk. A nomogram model integrating these four regulators was constructed and validated using the GSE35956 dataset, demonstrating promising utility in clinical decision-making, as affirmed by decision curve analysis. Subsequent consensus clustering analysis stratified OP samples into two different disulfidptosis subgroups (clusters A and B) using significant disulfidptosis regulators, with cluster B exhibiting higher disulfidptosis scores and implicating monocyte immunity, closely linked to osteoclastogenesis. Notably, RNA-seq analysis corroborated the expression patterns of two disulfidptosis modulators, PRDX1 and OXSM, consistent with bioinformatics predictions. Collectively, our study sheds light on disulfidptosis patterns, offering potential markers and immunotherapeutic avenues for future OP management.