The B3 domain-containing transcription factor ZmABI19 coordinates expression of key factors required for maize seed development and grain filling.

Grain filling in maize (Zea mays) is regulated by a group of spatiotemporally synchronized transcription factors (TFs), but the factors that coordinate their expression remain unknown. We used the promoter of the grain filling-specific TF gene Opaque2 (O2) to screen upstream regulatory factors and identified a B3 domain TF, ZmABI19, that directly binds to the O2 promoter for transactivation. zmabi19 mutants displayed developmental defects in the endosperm and embryo, and mature kernels were opaque and reduced in size. The accumulation of zeins, starch and lipids dramatically decreased in zmabi19 mutants. RNA sequencing revealed an alteration of the nutrient reservoir activity and starch and sucrose metabolism in zmabi19 endosperms, and plant phytohormone signal transduction and lipid metabolism in zmabi19 embryos. Chromatin immunoprecipitation followed by sequencing coupled with differential expression analysis identified 106 high-confidence direct ZmABI19 targets. ZmABI19 directly regulates multiple key grain filling TFs including O2, Prolamine-box binding factor 1, ZmbZIP22, NAC130, and Opaque11 in the endosperm and Viviparous1 in the embryo. A number of phytohormone-related genes were also bound and regulated by ZmABI19. Our results demonstrate that ZmABI19 functions as a grain filling initiation regulator. ZmABI19 roles in coupling early endosperm and embryo development are also discussed.

The Regulatory Axis of PD-L1 Isoform 2/TNF/T Cell Proliferation Is Required for the Canonical Immune-Suppressive Effects of PD-L1 Isoform 1 in Liver Cancer.

Despite the well-studied effects of the full-length membrane-locating isoform Iso1 of Programmed Cell Death Protein-Ligand 1 (PD-L1) on immunosuppression, little is known about another membrane-locating isoform, Iso2. While expressional and survival analysis of liver cancer patients indicated that Iso2 plays a tumor-suppressive role, our results also indicated that the tumor-promoting and immune-suppressive effects of Iso1 depended on the positive expression of Iso2. Through mediation analysis, we discovered several downstream genes or pathways of Iso2 and investigated their effects on the Iso1-regulating survival. Among all potential downstream immune factors, Iso2 was inclined to activate the proliferation of T cells by regulating chemokine activity and increasing CD3 levels by promoting TNF expression. Similar results were confirmed in the Mongolian liver cancer cohort, and the Iso2/TNF/T-cell axis was verified in several other cancers in the TCGA cohort. Finally, we demonstrated the promoting effects of Iso2 in terms of producing TNF and increasing T cells both in vitro and in vivo. Our findings illustrate that PD-L1 Iso2 can increase the number of T cells in the tumor microenvironment by elevating TNF levels, which is a necessary part of the tumor-suppressive effects of Iso1 in liver cancer.

Intra-Kernel Reallocation of Proteins in Maize Depends on VP1-Mediated Scutellum Development and Nutrient Assimilation.

During maize (Zea mays) seed development, the endosperm functions as the major organ for storage of photoassimilate, serving to nourish the embryo. α-Zeins and globulins (GLBs) predominantly accumulate in the maize endosperm and embryo, respectively. Here, we show that suppression of α-zeins by RNA interference (αRNAi) in the endosperm results in more GLB1 being synthesized in the embryo, thereby markedly increasing the size and number of protein storage vacuoles. Glb genes are strongly expressed in the middle-to-upper section of the scutellum, cells of which are significantly enlarged by αRNAi induction. Elimination of GLBs caused an apparent reduction in embryo protein level, regardless of whether α-zeins were expressed or suppressed in the endosperm, indicating that GLBs represent the dominant capacity for storage of amino acids allocated from the endosperm. It appears that protein reallocation is mostly regulated at the transcriptional level. Genes differentially expressed between wild-type and αRNAi kernels are mainly involved in sulfur assimilation and nutrient metabolism, and many are transactivated by VIVIPAROUS1 (VP1). In vp1 embryos, misshapen scutellum cells contain notably less cellular content and are unable to respond to αRNAi induction. Our results demonstrate that VP1 is essential for scutellum development and protein reallocation from the endosperm to embryo.

The Maize Imprinted Gene Floury3 Encodes a PLATZ Protein Required for tRNA and 5S rRNA Transcription through Interaction with RNA Polymerase III.

Maize (Zea mays) floury3 (fl3) is a classic semidominant negative mutant that exhibits severe defects in the endosperm but fl3 plants otherwise appear normal. We cloned the fl3 gene and determined that it encodes a PLATZ (plant AT-rich sequence and zinc binding) protein. The mutation in fl3 resulted in an Asn-to-His replacement in the conserved PLATZ domain, creating a dominant allele. Fl3 is specifically expressed in starchy endosperm cells and regulated by genomic imprinting, which leads to the suppressed expression of fl3 when transmitted through the male, perhaps as a consequence the semidominant behavior. Yeast two-hybrid screening and bimolecular luciferase complementation experiments revealed that FL3 interacts with the RNA polymerase III subunit 53 (RPC53) and transcription factor class C 1 (TFC1), two critical factors of the RNA polymerase III (RNAPIII) transcription complex. In the fl3 endosperm, the levels of many tRNAs and 5S rRNA that are transcribed by RNAPIII are significantly reduced, suggesting that the incorrectly folded fl3 protein may impair the function of RNAPIII. The transcriptome is dramatically altered in fl3 mutants, in which the downregulated genes are primarily enriched in pathways related to translation, ribosome, misfolded protein responses, and nutrient reservoir activity. Collectively, these changes may lead to defects in endosperm development and storage reserve filling in fl3 seeds.

Maize endosperm-specific transcription factors O2 and PBF network the regulation of protein and starch synthesis.

The maize endosperm-specific transcription factors opaque2 (O2) and prolamine-box binding factor (PBF) regulate storage protein zein genes. We show that they also control starch synthesis. The starch content in the PbfRNAi and o2 mutants was reduced by ∼5% and 11%, respectively, compared with normal genotypes. In the double-mutant PbfRNAi;o2, starch was decreased by 25%. Transcriptome analysis reveals that >1,000 genes were affected in each of the two mutants and in the double mutant; these genes were mainly enriched in sugar and protein metabolism. Pyruvate orthophosphate dikinase 1 and 2 (PPDKs) and starch synthase III (SSIII) are critical components in the starch biosynthetic enzyme complex. The expression of PPDK1, PPDK2, and SSIII and their protein levels are further reduced in the double mutants as compared with the single mutants. When the promoters of these genes were analyzed, we found a prolamine box and an O2 box that can be additively transactivated by PBF and O2. Starch synthase IIa (SSIIa, encoding another starch synthase for amylopectin) and starch branching enzyme 1 (SBEI, encoding one of the two main starch branching enzymes) are not directly regulated by PBF and O2, but their protein levels are significantly decreased in the o2 mutant and are further decreased in the double mutant, indicating that o2 and PbfRNAi may affect the levels of some other transcription factor(s) or mRNA regulatory factor(s) that in turn would affect the transcript and protein levels of SSIIa and SBEI These findings show that three important traits-nutritional quality, calories, and yield-are linked through the same transcription factors.

Gene duplication confers enhanced expression of 27-kDa γ-zein for endosperm modification in quality protein maize.

The maize opaque2 (o2) mutant has a high nutritional value but it develops a chalky endosperm that limits its practical use. Genetic selection for o2 modifiers can convert the normally chalky endosperm of the mutant into a hard, vitreous phenotype, yielding what is known as quality protein maize (QPM). Previous studies have shown that enhanced expression of 27-kDa γ-zein in QPM is essential for endosperm modification. Taking advantage of genome-wide association study analysis of a natural population, linkage mapping analysis of a recombinant inbred line population, and map-based cloning, we identified a quantitative trait locus (qγ27) affecting expression of 27-kDa γ-zein. qγ27 was mapped to the same region as the major o2 modifier (o2 modifier1) on chromosome 7 near the 27-kDa γ-zein locus. qγ27 resulted from a 15.26-kb duplication at the 27-kDa γ-zein locus, which increases the level of gene expression. This duplication occurred before maize domestication; however, the gene structure of qγ27 appears to be unstable and the DNA rearrangement frequently occurs at this locus. Because enhanced expression of 27-kDa γ-zein is critical for endosperm modification in QPM, qγ27 is expected to be under artificial selection. This discovery provides a useful molecular marker that can be used to accelerate QPM breeding.

A proprietary herbal medicine (5-Ling Granule) for Tourette syndrome: a randomized controlled trial.

BACKGROUND: Tourette syndrome (TS) is a common tic disorder in children and adolescents. There is preliminary evidence that herbal medicine may possess the potential to treat tics. The purpose of this study was to formally evaluate the efficacy and safety of 5-Ling Granule (5-LGr), a proprietary polyherbal product, for the treatment of patients with TS in comparison with tiapride and placebo. METHODS: In this multisite, double-blind, double-dummy, randomized, placebo-controlled trial, 603 patients with TS aged 5-18 years were randomly assigned to treatment with placebo (n = 117), tiapride (n = 123, 200-400 mg/day) or 5-LGr (n = 363, 15-22.5 g/day) for 8 weeks. The primary outcome was measured using the Yale Global Tic Severity Scale (YGTSS) and its subscales, total tic Score (TTS) and tic-related impairment. Incidence of adverse events was compared among the three groups. RESULTS: While tics of all patients were reduced over time, 5-LGr and tiapride treatment produced significantly greater improvement on the YGTSS overall scale and subscale for TTS and impairment at endpoint than the placebo. Seventy-four percentage of patients in the 5-LGr arm and 68.3% in the tiapride arm had clinical response and these rates of response were significantly higher than those on placebo (44.0%, p < .001). The incidence of overall adverse events was significantly fewer for patients on placebo and 5-LGr compared to tiapride (11.2% and 13.8% vs. 26.0%, p = .002); in particular physical tiredness, dizziness and sleep disturbance. CONCLUSIONS: The clinical efficacy of 5-LGr is comparable to tiapride in reducing tics. Its safety profile is better than tiapride. 5-LGr can be considered a safe and effective therapy for TS (Trial registration: www.clinicaltrials.gov: NCT01501695).

Widespread application of apomixis in agriculture requires further study of natural apomicts.

Apomixis, or asexual reproduction through seeds, is frequent in nature but does not exist in any major crop species, yet the phenomenon has captivated researchers for decades given its potential for clonal seed production and plant breeding. A discussion on whether this field will benefit from the continued study of natural apomicts is warranted given the recent outstanding progress in engineering apomixis. Here, we summarize what is known about its genetic control and the status of applying synthetic apomixis in agriculture. We argue there is still much to be learned from natural apomicts, and learning from them is necessary to improve on current progress and guarantee the effective application of apomixis beyond the few genera it has shown promise in so far. Specifically, we stress the value of studying the repeated evolution of natural apomicts in a phylogenetic and comparative -omics context. Finally, we identify outstanding questions in the field and discuss how technological advancements can be used to help close these knowledge gaps. In particular, genomic resources are lacking for apomicts, and this must be remedied for widespread use of apomixis in agriculture.

Plasma exchange as an effective treatment for cytokine release syndrome following T cell receptor­engineered T cell immunotherapy: A case report.

T-cell receptor-engineered T-cell (TCR-T) immunotherapy is a promising approach for the treatment of solid tumors. However, TCR-T therapy can result in severe cytokine release syndrome (CRS), thus limiting its therapeutic application. The present study reported the case of a patient with TCR-T-related CRS, which was treated successfully with plasma exchange (PE). A 35-year-old male patient, who was diagnosed with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) with lung metastases, was enrolled in a clinical trial for hepatitis B virus surface antigen-specific TCR-expressing autologous T-cell therapy for HBV-related HCC after failing multiple lines of targeted immunotherapy and local treatments. Therefore, TCR-Ts were infused after peripheral blood mononuclear cell collection, engineering and lymphodepletion chemotherapy. However, following engineered T-cell reinfusion, the patient developed a fever, hypotension, edema, multiple serous effusion and acute kidney injury, and was consequently diagnosed with grade 3 CRS and transferred to the Intensive Care Unit. The patient received three daily PE sessions (3,000 ml of fresh frozen plasma per session), renal replacement therapy, tocilizumab and 1,000 mg pulse methylprednisolone for 3 days. Following treatment, the patient's hemodynamic condition was stabilized and the C-reactive protein, ferritin and IL-6 levels were markedly reduced. During follow-up, a stable disease state was exhibited by the liver cancer and lung metastatic lesions. To the best of our knowledge, this is the first case reporting PE as a treatment approach for managing CRS following TCR-T therapy for solid tumors. The present study demonstrated that blood purification treatments, such as PE, which target inflammatory mediators and restore the balance between pro- and anti-inflammatory cytokines, could be a notable component in managing severe CRS associated with engineered T-cell treatment. However, additional clinical and translational studies are needed to further understand the mechanisms of T-cell immunotherapy to treat patients with solid tumors.

Association between Dietary Acid Load and Chronic Kidney Disease in the Chinese Population: A Comprehensive Analysis of the China Health and Nutrition Survey (2009).

BACKGROUND: Dietary acid load (DAL) is closely related to several chronic diseases. However, the link between DAL and chronic kidney disease (CKD) remains scarce and without data from the Chinese populations whose diet is quite different from people in Western countries. METHODS: This study evaluated DAL by potential renal acid load (PRAL) and net endogenous acid production (NEAP). We clarified the relationship between DAL and CKD by logistic regression analysis based on data from the China Health and Nutrition Survey (CHNS). RESULTS: The final analysis included 7699 individuals, of whom 811 (11.44%) were CKD patients. Although there was no notable link between PRAL and CKD, higher NEAP levels were independently correlated with CKD. As NEAP values rise, so does CKD prevalence. This trend remains highly significant even after adjustments. In subgroup analyses, the relationship between NEAP and CKD was more consistent in the elderly and subjects with a waistline of less than 82 cm and those without diabetes and heart disease. RCS analysis further confirmed the clear linear relationship between the OR of CKD and NEAP score. CONCLUSIONS: This study highlighted that higher NEAP was positively correlated with the risk of CKD.

Immune-inflammatory markers and clinical characteristics as predictors of the depth of response and prognosis of patients with PD-L1 ≥50% metastatic non-small cell lung cancer receiving first-line immunotherapy.

BACKGROUND: Patients with programmed cell death-ligand 1 (PD-L1) ≥50% metastatic non-small cell lung cancer (NSCLC) treated with first-line immunotherapy showed heterogeneous tumor responses. In this study, we investigated the clinical and immune-inflammatory markers distinguishing patients with metastatic NSCLC achieving high depth of tumor response (HDPR) from those with non-high depth of response (NHDPR). The impact of clinical features on the prognosis of patients with PD-L1 ≥50% were further clarified. METHODS: The clinical characteristics and immune-inflammatory markers of 17 patients with PD-L1 ≥50% metastatic NSCLC at Beijing Tiantan Hospital between July 2020 and December 2023 were retrospectively analyzed. RESULTS: Among the 17 patients, seven (41.2%) patients achieved HDPR (range: -50%, -72%) and 10 (58.8%) patients achieved NHDPR (range: -13%, -45%). Below normal CD4 + T lymphocytes/CD8 + T lymphocytes (CD4/CD8) ratio (p = 0.01) and oncogenes and/or tumor suppressor gene mutations (TP53/KRAS/EGFR) (p = 0.001) were found enriched for NHDPR compared with HDPR. With a median follow-up of 26.0 months (range: 17.2-34.8 months), the median progression-free survival (PFS) following first-line immunotherapy and overall survival (OS) were 9.0 months (95% CI: 5.0-13.0) and not reached (NR), respectively. The neutrophil-to-lymphocyte ratio (NLR) was identified as an independent prognostic factor on first-line PFS. Patients with an NLR ≥4 exhibited a shorter median PFS (7.0 months vs. NR; p = 0.033; 95% CI: 1.2-80.2) than those with an NLR <4 following first-line immunotherapy. CONCLUSIONS: Among patients with PD-L1 ≥50% metastatic NSCLC who received first-line immunotherapy, a lower CD4/CD8 ratio and the presence of genes mutations showed a diminished tumor response and a higher NLR ratio exhibited a worse median PFS.

Lyophilizable Stem Cell-Hybrid Liposome with Long-Term Stability and High Targeting Capacity.

The hybridization of liposome with stem cell membranes is an emerging technology to prepare the nanovehicle with the capacity of disease-responsive targeting. However, the long-term storage of this hybrid liposome has received limited attention in the literature, which is essential for its potential applicability in the clinic. Therefore, the preservation of long-term activity of stem cell-hybrid liposome using freeze-drying is investigated in the present study. Mesenchymal stem cell-hybrid liposome is synthesized and its feasibility for freeze-drying under different conditions is examined. Results reveal that pre-freezing the hybrid liposome at -20 °C in Tris buffer solution (pH 7.4) containing 10% trehalose can well preserve the liposomal structure for at least three months. Notably, major membrane proteins on the hybrid liposome are protected in this formulation and CXCR4-associated targeting capacity is maintained both in vitro and in vivo. Consequently, the hybrid liposome stored for three months demonstrates a comparable tumor inhibition as the fresh-prepared one. The present study provides the first insights into the long-term storage of stem cell hybrid liposome using lyophilization, which may make an important step forward in enhancing the long-term stability of these promising biomimetic nanovehicle and ease the logistics and the freeze-storage in the potential clinical applications.

The 3-Dimensional Intelligent Structured Light Technique: A New Registration Method in Stereotactic Neurosurgery.

BACKGROUND AND OBJECTIVES: Surface-based facial scanning registration emerged as an essential registration method in the robot-assisted neuronavigation surgery, providing a marker-free way to align a patient's facial surface with the imaging data. The 3-dimensional (3D) structured light was developed as an advanced registration method based on surface-based facial scanning registration. We aspire to introduce the 3D structured light as a new registration method in the procedure of the robot-assisted neurosurgery and assess the accuracy, efficiency, and safety of this method by analyzing the relative operative results. METHODS: We analyzed the results of 47 patients who underwent Ommaya reservoir implantation (n = 17) and stereotactic biopsy (n = 30) assisted by 3D structured light at our hospital from January 2022 to May 2023. The accuracy and additional operative results were analyzed. RESULTS: For the Ommaya reservoir implantation, the target point error was 3.2 ± 2.2 mm and the entry point error was 3.3 ± 2.4 mm, while the operation duration was 35.8 ± 8.3 minutes. For the stereotactic biopsy, the target point error was 2.3 ± 1.3 mm and the entry point error was 2.7 ± 1.2 mm, while the operation duration was 24.5 ± 6.3 minutes. CONCLUSION: The 3D structured light technique reduces the patients' discomfort and offers the advantage of a simpler procedure, which can improve the clinical efficiency with the sufficient accuracy and safety to meet the clinical requirements of the puncture and navigation.

Discovery and engineering of ChCas12b for precise genome editing.

Many clustered regularly interspaced short palindromic repeat and CRISPR-associated protein 12b (CRISPR-Cas12b) nucleases have been computationally identified, yet their potential for genome editing remains largely unexplored. In this study, we conducted a GFP-activation assay screening 13 Cas12b nucleases for mammalian genome editing, identifying five active candidates. Candidatus hydrogenedentes Cas12b (ChCas12b) was found to recognize a straightforward WTN (W = T or A) proto-spacer adjacent motif (PAM), thereby dramatically expanding the targeting scope. Upon optimization of the single guide RNA (sgRNA) scaffold, ChCas12b exhibited activity comparable to SpCas9 across a panel of nine endogenous loci. Additionally, we identified nine mutations enhancing ChCas12b specificity. More importantly, we demonstrated that both ChCas12b and its high-fidelity variant, ChCas12b-D496A, enabled allele-specific disruption of genes harboring single nucleotide polymorphisms (SNPs). These data position ChCas12b and its high-fidelity counterparts as promising tools for both fundamental research and therapeutic applications.

FBN1 knockout promotes cervical artery dissection by inducing N-glycosylation alternation of extracellular matrix proteins in rat VSMCs.

FBN1 mutation promotes the degeneration of microfibril structures and extracellular matrix (ECM) integrity in the tunica media of the aorta in Marfan syndrome. However, whether FBN1 modulates cervical artery dissection (CAD) development and the potential molecular mechanisms of abnormal FBN1 in CAD remains elusive. In this study, FBN1 deficiency participated in the development of CAD and influenced the proliferation, apoptosis, and migration of vascular smooth muscle cells. FBN1 knockout induced alternations in mRNA levels of the transcriptome, protein expression of the proteome, and abundance of N-glycosylation of the N-glycoproteome. Comprehensive analysis of multiple omics showed up-regulation in mRNA levels of ECM proteins; yet, both the ECM protein levels and relative abundance of N-glycosylation were decreased. Moreover, we performed in vivo experiments to confirm the altered glycosylation of proteins in vascular smooth muscle cells. In conclusion, FBN1 deletion in vascular smooth muscle cells can result in altered N-glycosylation of ECM protein, which were critical for the stability of ECM and the process of CAD. This may open the way for a novel therapeutic strategy to treat people with CAD.

Thyroid transcription factor 1 (TTF-1) negativity as a predictor of unfavorable response to EGFR-TKI therapy in advanced lung adenocarcinoma patients with EGFR mutations.

BACKGROUND: The absence of thyroid transcription factor 1 (TTF-1) is associated with a lower frequency of epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma (LUAD). The aim of this study was to assess the impact of TTF-1 expression on the clinical response to EGFR-tyrosine kinase inhibitor (TKI) treatment in patients with advanced LUAD. METHODS: The data of patients with advanced LUAD who were admitted to the Beijing Tiantan Hospital and Peking University Cancer Hospital (China) between April 2009 and May 2023 was retrospectively analyzed. RESULTS: A total of 227 patients diagnosed with advanced LUAD were included, of which 28.2% (64/227) had TTF-1-negative adenocarcinoma, while 54.6% (124/227) harbored EGFR mutations. Negative TTF-1 expression significantly correlated with male sex (68.8% vs. 42.3%, p < 0.001), history of heavy smoking (57.8% vs. 36.2%, p = 0.003), poorly differentiated tumors (86.5% vs. 43.2%, p < 0.001), and lower frequency of EGFR mutations (26.6% vs. 65.6%, p < 0.001) compared with TTF-1 positivity. Multivariable logistic regression showed that low prevalence of EGFR mutations (p < 0.001) and male sex (p = 0.006) were independent predictive factors for the negative expression of TTF-1. Patients lacking TTF-1 also exhibited worse overall response rate (ORR; 23.5% vs. 54.2%, p = 0.019), disease control rate (DCR; 58.8% vs. 89.7%, p = 0.003), and median progression-free survival (PFS; 2.9 vs. 11.6 months, p < 0.001) following treatment with EGFR-TKIs compared to the TTF-1-positive patients with EGFR mutations. CONCLUSIONS: Patients with TTF-1-negative and EGFR-mutant LUAD show a diminished response to EGFR-TKIs.

High Targeting Specificity toward Pulmonary Inflammation Using Mesenchymal Stem Cell-Hybrid Nanovehicle for an Efficient Inflammation Intervention.

Pulmonary inflammation is one of the most reported tissue inflammations in clinic. Successful suppression of inflammation is vital to prevent further inevitably fatal lung degeneration. Glucocorticoid hormone, such as methylprednisolone (MP), is the most applied strategy to control the inflammatory progression yet faces the challenge of systemic side effects caused by the requirement of large-dosage and frequent administration. Highly efficient delivery of MP specifically targeted to inflammatory lung sites may overcome this challenge. Therefore, the present study develops an inflammation-targeted biomimetic nanovehicle, which hybridizes the cell membrane of mesenchymal stem cell with liposome, named as MSCsome. This hybrid nanovehicle shows the ability of high targeting specificity toward inflamed lung cells, due to both the good lung endothelium penetration and the high uptake by inflamed lung cells. Consequently, a single-dose administration of this MP-loaded hybrid nanovehicle achieves a prominent treatment of lipopolysaccharide-induced lung inflammation, and negligible treatment-induced side effects are observed. The present study provides a powerful inflammation-targeted nanovehicle using biomimetic strategy to solve the current challenges of targeted inflammation intervention.

The prognostic value of cancer stage-associated genes in clear cell renal cell carcinoma.

OBJECTIVES: Clear cell renal cell carcinoma (ccRCC) is a highly prevalent subtype of malignant renal tumor, but unfortunately, the survival rate remains unsatisfactory. The aim of the present study is to explore genomic features that are correlated with cancer stage, allowing for the identification of subgroups of ccRCC patients with high risk of unfavorable outcomes and enabling prompt intervention and treatment. METHODS: We compared the gene expression levels across ccRCC patients with diverse cancer stages from The Cancer Genome Atlas (TCGA) database, which revealed characteristic genes associated with tumor stage. We then extracted prognostic genes and used least absolute shrinkage selection operator (LASSO) regression to select four genes for feature extraction and the construction of a prognostic risk model. RESULTS: We have identified a total of 171 differentially expressed genes (DEGs) that are closely linked to the tumor stage of ccRCC through difference analysis. A prognostic risk model constructed based on the expression levels of ZIC2, TFAP2A-AS1, ITPKA, and SLC16A12 holds significant prognostic value in ccRCC. The results of the functional enrichment analysis imply that the DEGs are mainly involved in the regulation of immune-related signaling pathways, and therefore may have a significant function in immune system regulation of ccRCC. CONCLUSIONS: Our study has successfully identified significant DEGs between high- and low-staging groups of ccRCC using bioinformatics methods. The construction of a prognostic risk model based on the expression levels of ZIC2, TFAP2A-AS1, ITPKA, and SLC16A12 has displayed promising prognostic significance, indicating its valuable potential for clinical application.

Efficient intervention for pulmonary fibrosis via mitochondrial transfer promoted by mitochondrial biogenesis.

The use of exogenous mitochondria to replenish damaged mitochondria has been proposed as a strategy for the treatment of pulmonary fibrosis. However, the success of this strategy is partially restricted by the difficulty of supplying sufficient mitochondria to diseased cells. Herein, we report the generation of high-powered mesenchymal stem cells with promoted mitochondrial biogenesis and facilitated mitochondrial transfer to injured lung cells by the sequential treatment of pioglitazone and iron oxide nanoparticles. This highly efficient mitochondrial transfer is shown to not only restore mitochondrial homeostasis but also reactivate inhibited mitophagy, consequently recovering impaired cellular functions. We perform studies in mouse to show that these high-powered mesenchymal stem cells successfully mitigate fibrotic progression in a progressive fibrosis model, which was further verified in a humanized multicellular lung spheroid model. The present findings provide a potential strategy to overcome the current limitations in mitochondrial replenishment therapy, thereby promoting therapeutic applications for fibrotic intervention.