The GRAS transcription factor CsTL regulates tendril formation in cucumber.

Cucumber (Cucumis sativus, Cs) tendrils are slender vegetative organs that typically require manual removal to ensure orderly growth during greenhouse cultivation. Here, we identified cucumber tendril-less (tl), a Tnt1 retrotransposon-induced insertion mutant lacking tendrils. Map-based cloning identified the mutated gene, CsaV3_3G003590, which we designated as CsTL, which is homologous to Arabidopsis thaliana LATERAL SUPPRESSOR (AtLAS). Knocking out CsTL repressed tendril formation but did not affect branch initiation, whereas overexpression of CsTL resulted in the formation of two or more tendrils in one leaf axil. Although expression of two cucumber genes regulating tendril formation, Tendril (CsTEN) and Unusual Floral Organs (CsUFO), was significantly decreased in CsTL knockout lines, these two genes were not direct downstream targets of CsTL. Instead, CsTL physically interacted with CsTEN, an interaction that further enhanced CsTEN-mediated expression of CsUFO. In Arabidopsis, the CsTL homolog AtLAS acts upstream of REVOLUTA (REV) to regulate branch initiation. Knocking out cucumber CsREV inhibited branch formation without affecting tendril initiation. Furthermore, genomic regions containing CsTL and AtLAS were not syntenic between the cucumber and Arabidopsis genomes, whereas REV orthologs were found on a shared syntenic block. Our results revealed not only that cucumber CsTL possesses a divergent function in promoting tendril formation but also that CsREV retains its conserved function in shoot branching.

Combinatorial transcription factor activities on open chromatin induce embryonic heterogeneity in vertebrates.

During vertebrate gastrulation, mesoderm is induced in pluripotent cells, concomitant with dorsal-ventral patterning and establishing of the dorsal axis. We applied single-cell chromatin accessibility and transcriptome analyses to explore the emergence of cellular heterogeneity during gastrulation in Xenopus tropicalis. Transcriptionally inactive lineage-restricted genes exhibit relatively open chromatin in animal caps, whereas chromatin accessibility in dorsal marginal zone cells more closely reflects transcriptional activity. We characterized single-cell trajectories and identified head and trunk organizer cell clusters in early gastrulae. By integrating chromatin accessibility and transcriptome data, we inferred the activity of transcription factors in single-cell clusters and tested the activity of organizer-expressed transcription factors in animal caps, alone or in combination. The expression profile induced by a combination of Foxb1 and Eomes most closely resembles that observed in the head organizer. Genes induced by Eomes, Otx2, or the Irx3-Otx2 combination are enriched for maternally regulated H3K4me3 modifications, whereas Lhx8-induced genes are marked more frequently by zygotically controlled H3K4me3. Taken together, our results show that transcription factors cooperate in a combinatorial fashion in generally open chromatin to orchestrate zygotic gene expression.

The novel potential therapeutic target PSMP/MSMP promotes acute kidney injury via CCR2.

Acute kidney injury (AKI) is a major worldwide health concern that currently lacks effective medical treatments. PSMP is a damage-induced chemotactic cytokine that acts as a ligand of CCR2 and has an unknown role in AKI. We have observed a significant increase in PSMP levels in the renal tissue, urine, and plasma of patients with AKI. PSMP deficiency improved kidney function and decreased tubular damage and inflammation in AKI mouse models induced by kidney ischemia-reperfusion injury, glycerol, and cisplatin. Single-cell RNA sequencing analysis revealed that Ly6Chi or F4/80lo infiltrated macrophages (IMs) were a major group of proinflammatory macrophages with strong CCR2 expression in AKI. We observed that PSMP deficiency decreased CCR2+Ly6Chi or F4/80lo IMs and inhibited M1 polarization in the AKI mouse model. Moreover, overexpressed human PSMP in the mouse kidney could reverse the attenuation of kidney injury in a CCR2-dependent manner, and this effect could be achieved without CCL2 involvement. Extracellular PSMP played a crucial role, and treatment with a PSMP-neutralizing antibody significantly reduced kidney injury in vivo. Therefore, PSMP might be a therapeutic target for AKI, and its antibody is a promising therapeutic drug for the treatment of AKI.

X-ray Activated Nanoprodrug for Visualization of Cortical Microvascular Alterations and NIR-II Image-Guided Chemo-Radiotherapy of Glioblastoma.

The permeability of the highly selective blood-brain barrier (BBB) to anticancer drugs and the difficulties in defining deep tumor boundaries often reduce the effectiveness of glioma treatment. Thus, exploring the combination of multiple treatment modalities under the guidance of second-generation near-infrared (NIR-II) window fluorescence (FL) imaging is considered a strategic approach in glioma theranostics. Herein, a hybrid X-ray-activated nanoprodrug was developed to precisely visualize the structural features of glioma microvasculature and delineate the boundary of glioma for synergistic chemo-radiotherapy. The nanoprodrug comprised down-converted nanoparticle (DCNP) coated with X-ray sensitive poly(Se-Se/DOX-co-acrylic acid) and targeted Angiopep-2 peptide (DCNP@P(Se-DOX)@ANG). Because of its ultrasmall size and the presence of DOX, the nanoprodrug could easily cross BBB to precisely monitor and localize glioblastoma via intracranial NIR-II FL imaging and synergistically administer antiglioblastoma chemo-radiotherapy through specific X-ray-induced DOX release and radiosensitization. This study provides a novel and effective strategy for glioblastoma imaging and chemo-radiotherapy.

Macrophage GIT1 promotes oligodendrocyte precursor cell differentiation and remyelination after spinal cord injury.

Spinal cord injury (SCI) can result in severe motor and sensory deficits, for which currently no effective cure exists. The pathological process underlying this injury is extremely complex and involves many cell types in the central nervous system. In this study, we have uncovered a novel function for macrophage G protein-coupled receptor kinase-interactor 1 (GIT1) in promoting remyelination and functional repair after SCI. Using GIT1flox/flox Lyz2-Cre (GIT1 CKO) mice, we identified that GIT1 deficiency in macrophages led to an increased generation of tumor necrosis factor-alpha (TNFα), reduced proportion of mature oligodendrocytes (mOLs), impaired remyelination, and compromised functional recovery in vivo. These effects in GIT1 CKO mice were reversed with the administration of soluble TNF inhibitor. Moreover, bone marrow transplantation from GIT1 CWT mice reversed adverse outcomes in GIT1 CKO mice, further indicating the role of macrophage GIT1 in modulating spinal cord injury repair. Our in vitro experiments showed that macrophage GIT1 plays a critical role in secreting TNFα and influences the differentiation of oligodendrocyte precursor cells (OPCs) after stimulation with myelin debris. Collectively, our data uncovered a new role of macrophage GIT1 in regulating the transformation of OPCs into mOLs, essential for functional remyelination after SCI, suggesting that macrophage GIT1 could be a promising treatment target of SCI.

A Treg-related riskscore model may improve the prognosis evaluation of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) poses a significant health challenge. This study aims to investigate the prognostic value of a regulatory T cell (Treg)-related gene signature in CRC. METHODS: We extracted the gene expression and clinical data on CRC from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The gene module related to Treg was identified by weighted gene co-expression network analysis (WGCNA). The genes in the significant module were filtered by univariate Cox, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis. A riskscore model was established in terms of the key Treg-related genes. The reliability of this riskscore model was validated using the external GEO dataset. The association of riskscore with clinical features, mutation patterns and signaling pathways was explored. RESULTS: Genes in the blue module showed the strongest association with Tregs. After a series of filtering cycles, seven Treg-related key genes, GDE1, GSR, HSPB1, AOC2, TBX19, TAMM41 and TIGD6, were selected to construct a riskscore model. This model performed well in evaluating the patients' survival in TCGA cohort, and was further affirmed by the GSE17536 validation cohort. For precise evaluation of the patients' survival, we established a nomogram in light of riskscore and clinical factors. Patients in different risk groups had distinct clinical features, mutation patterns and signaling pathway activities. The expression of five key genes was significantly associated with Treg infiltration in the CRC samples. CONCLUSION: We established a useful riskscore model in light of seven Treg-related genes. This model may contribute to the prognosis evaluation, direct tailored treatment, and hopefully improve clinical outcomes of the CRC patients.

Enhanced Alkaline Hydrogen Evolution Reaction through Lanthanide-Modified Rhodium Intermetallic Catalysts.

Design of highly efficient electrocatalysts for alkaline hydrogen evolution reaction (HER) is of paramount importance for water electrolysis, but still a considerable challenge because of the slow HER kinetics in alkaline environments. Alloying is recognized as an effective strategy to enhance the catalytic properties. Lanthanides (Ln) are recognized as an electronic and structural regulator, attributed to their unique 4f electron behavior and the phenomenon known as lanthanide contraction. Here, a new class of Rh3Ln intermetallics (IMs) are synthesized using the sodium vapor reduction method. The alloying process induced an upshift of the d-band center and electron transfer from Ln to Rh, resulting in optimized adsorption and dissociation energies for H2O molecules. Consequently, Rh3Tb IMs exhibited outstanding HER activity in both alkaline environments and seawater, displaying an overpotential of only 19 mV at 10 mA cm-2 and a Tafel slope of 22.2 mV dec-1. Remarkably, the current density of Rh3Tb IMs at 100 mV overpotential is 8.6 and 5.7 times higher than that of Rh/C and commercial Pt/C, respectively. This work introduces a novel approach to the rational design of HER electrocatalysis and sheds light on the role of lanthanides in electrocatalyst systems.

Enhanced Alkaline Hydrogen Evolution Reaction via Electronic Structure Regulation: Activating PtRh with Rare Earth Tm Alloying.

Developing high-performance electrocatalysts for alkaline hydrogen evolution reaction (HER) is crucial for producing green hydrogen, yet it remains challenging due to the sluggish kinetics in alkaline environments. Pt is located near the peak of HER volcano plot, owing to its exceptional performance in hydrogen adsorption and desorption, and Rh plays an important role in H2O dissociation. Lanthanides (Ln) are commonly used to modulate the electronic structure of materials and further influence the adsorption/desorption of reactants, intermediates, and products, and noble metal-Ln alloys are recognized as effective platforms where Ln elements regulate the catalytic properties of noble metals. Here Pt1.5Rh1.5Tm alloy is synthesized using the sodium vapor reduction method. This alloy demonstrates superior catalytic activity, being 4.4 and 6.6 times more effective than Pt/C and Rh/C, respectively. Density Functional Theory (DFT) calculations reveal that the upshift of d-band center and the charge transfer induced by alloying promote adsorption and dissociation of H2O, making Pt1.5Rh1.5Tm alloy more favorable for the alkaline HER reaction, both kinetically and thermodynamically.

Rice microRNA156/529-SQUAMOSA PROMOTER BINDING PROTEIN-LIKE7/14/17 modules regulate defenses against bacteria.

Rice (Oryza sativa L.) microRNA156/529-SQUAMOSA PROMOTER BINDING PROTEIN-LIKE7/14/17 (miR156/529-SPL7/14/17) modules have pleiotropic effects on many biological pathways. OsSPL7/14 can interact with DELLA protein SLENDER RICE1 (SLR1) to modulate gibberellin acid (GA) signal transduction against the bacterial pathogen Xanthomonas oryzae pv. oryzae. However, whether the miR156/529-OsSPL7/14/17 modules also regulate resistance against other pathogens is unclear. Notably, OsSPL7/14/17 functioning as transcriptional activators, their target genes, and the corresponding downstream signaling pathways remain largely unexplored. Here, we demonstrate that miR156/529 play negative roles in plant immunity and that miR156/529-regulated OsSPL7/14/17 confer broad-spectrum resistance against 2 devastating bacterial pathogens. Three OsSPL7/14/17 proteins directly bind to the promoters of rice Allene Oxide Synthase 2 (OsAOS2) and NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 (OsNPR1) and activate their transcription, regulating jasmonic acid (JA) accumulation and the salicylic acid (SA) signaling pathway, respectively. Overexpression of OsAOS2 or OsNPR1 impairs the susceptibility of the osspl7/14/17 triple mutant. Exogenous application of JA enhances resistance of the osspl7/14/17 triple mutant and the miR156 overexpressing plants. In addition, genetic evidence confirms that bacterial pathogen-activated miR156/529 negatively regulate pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) responses, such as pattern recognition receptor Xa3/Xa26-initiated PTI. Our findings demonstrate that bacterial pathogens modulate miR156/529-OsSPL7/14/17 modules to suppress OsAOS2-catalyzed JA accumulation and the OsNPR1-promoted SA signaling pathway, facilitating pathogen infection. The uncovered miR156/529-OsSPL7/14/17-OsAOS2/OsNPR1 regulatory network provides a potential strategy to genetically improve rice disease resistance.

GRAS family member LATERAL SUPPRESSOR regulates the initiation and morphogenesis of watermelon lateral organs.

The lateral organs of watermelon (Citrullus lanatus), including lobed leaves, branches, flowers, and tendrils, together determine plant architecture and yield. However, the genetic controls underlying lateral organ initiation and morphogenesis remain unclear. Here, we found that knocking out the homologous gene of shoot branching regulator LATERAL SUPPRESSOR in watermelon (ClLs) repressed the initiation of branches, flowers, and tendrils and led to developing round leaves, indicating that ClLs undergoes functional expansion compared with its homologs in Arabidopsis (Arabidopsis thaliana), rice (Oryza sativa), and tomato (Solanum lycopersicum). Using ClLs as the bait to screen against the cDNA library of watermelon, we identified several ClLs-interacting candidate proteins, including TENDRIL (ClTEN), PINOID (ClPID), and APETALA1 (ClAP1). Protein-protein interaction assays further demonstrated that ClLs could directly interact with ClTEN, ClPID, and ClAP1. The mRNA in situ hybridization assay revealed that the transcriptional patterns of ClLs overlapped with those of ClTEN, ClPID, and ClAP1 in the axillary meristems and leaf primordia. Mutants of ClTEN, ClPID, and ClAP1 generated by the CRISPR/Cas9 gene editing system lacked tendrils, developed round leaves, and displayed floral diapause, respectively, and all these phenotypes could be observed in ClLs knockout lines. Our findings indicate that ClLs acts as lateral organ identity protein by forming complexes with ClTEN, ClPID, and ClAP1, providing several gene targets for transforming the architecture of watermelon.

A modified nucleoside O6-methyl-2'-deoxyguanosine-5'-triphosphate exhibits anti-glioblastoma activity in a caspase-independent manner.

Resistance to temozolomide (TMZ), the frontline chemotherapeutic agent for glioblastoma (GBM), has emerged as a formidable obstacle, underscoring the imperative to identify alternative therapeutic strategies to improve patient outcomes. In this study, we comprehensively evaluated a novel agent, O6-methyl-2'-deoxyguanosine-5'-triphosphate (O6-methyl-dGTP) for its anti-GBM activity both in vitro and in vivo. Notably, O6-methyl-dGTP exhibited pronounced cytotoxicity against GBM cells, including those resistant to TMZ and overexpressing O6-methylguanine-DNA methyltransferase (MGMT). Mechanistic investigations revealed that O6-methyl-dGTP could be incorporated into genomic DNA, disrupting nucleotide pools balance, and inducing replication stress, resulting in S-phase arrest and DNA damage. The compound exerted its anti-tumor properties through the activation of AIF-mediated apoptosis and the parthanatos pathway. In vivo studies using U251 and Ln229 cell xenografts supported the robust tumor-inhibitory capacity of O6-methyl-dGTP. In an orthotopic transplantation model with U87MG cells, O6-methyl-dGTP showcased marginally superior tumor-suppressive activity compared to TMZ. In summary, our research, for the first time, underscores the potential of O6-methyl-dGTP as an effective candidate against GBM, laying a robust scientific groundwork for its potential clinical adoption in GBM treatment regimens.

Efficient biodegradation of chlorobenzene via monooxygenation pathways by Pandoraea sp. XJJ-1 with high potential for groundwater bioremediation.

Chlorobenzene (CB), extensively used in industrial processes, has emerged as a significant contaminant in soil and groundwater. The eco-friendly and cost-effective microbial remediation has been increasingly favored to address this environmental challenge. In this study, a degrading bacterium was isolated from CB-contaminated soil at a pesticide plant, identified as Pandoraea sp. XJJ-1 (CCTCC M 2021057). This strain completely degraded 100 mg·L-1 CB and showed extensive degradability across a range of pH (5.0-9.0), temperature (10-37 °C), and CB concentrations (100-600 mg·L-1). Notably, the degradation efficiency was 85.2% at 15 °C, and the strain could also degrade six other aromatic hydrocarbons, including benzene, toluene, ethylbenzene, and xylene (o-, m-, p-). The metabolic pathway of CB was inferred using ultraperformance liquid chromatography, gas chromatography-mass spectrometry, and genomic analysis. In strain XJJ-1, CB was metabolized to o-chlorophenol and 3-chloroxychol by CB monooxygenase, followed by ortho-cleavage by the action of 3-chlorocatechol 1,2-dioxygenase. Moreover, the presence of the chlorobenzene monooxygenation pathway metabolism in strain XJJ-1 is reported for the first time in Pandoraea. As a bacterium with low-temperature resistance and composite pollutant degradation capacity, strain XJJ-1 has the potential application prospects in the in-situ bioremediation of CB-contaminated sites.

Advances in lung ischemia/reperfusion injury: unraveling the role of innate immunity.

BACKGROUND: Lung ischemia/reperfusion injury (LIRI) is a common occurrence in clinical practice and represents a significant complication following pulmonary transplantation and various diseases. At the core of pulmonary ischemia/reperfusion injury lies sterile inflammation, where the innate immune response plays a pivotal role. This review aims to investigate recent advancements in comprehending the role of innate immunity in LIRI. METHODS: A computer-based online search was performed using the PubMed database and Web of Science database for published articles concerning lung ischemia/reperfusion injury, cell death, damage-associated molecular pattern molecules (DAMPs), innate immune cells, innate immunity, inflammation. RESULTS: During the process of lung ischemia/reperfusion, cellular injury even death can occur. When cells are injured or undergo cell death, endogenous ligands known as DAMPs are released. These molecules can be recognized and bound by pattern recognition receptors (PRRs), leading to the recruitment and activation of innate immune cells. Subsequently, a cascade of inflammatory responses is triggered, ultimately exacerbating pulmonary injury. These steps are complex and interrelated rather than being in a linear relationship. In recent years, significant progress has been made in understanding the immunological mechanisms of LIRI, involving novel types of cell death, the ability of receptors other than PRRs to recognize DAMPs, and a more detailed mechanism of action of innate immune cells in ischemia/reperfusion injury (IRI), laying the groundwork for the development of novel diagnostic and therapeutic approaches. CONCLUSIONS: Various immune components of the innate immune system play critical roles in lung injury after ischemia/reperfusion. Preventing cell death and the release of DAMPs, interrupting DAMPs receptor interactions, disrupting intracellular inflammatory signaling pathways, and minimizing immune cell recruitment are essential for lung protection in LIRI.

Three-Component Construction of Mesoporous Metal-Organic Frameworks and Their Incorporation into Solid Polymer Electrolytes for Li-Ion Conduction.

Solid electrolytes with high ionic conductivity and satisfactory electrochemical stability are essential for the development of solid-state batteries. However, current strategies, including polymer (and polymer-based composite) electrolytes, still face challenges in meeting the bar set by real operations. We seek to improve the Li-ion conduction of the electrolytes by incorporating mesoporous metal-organic frameworks (MOFs) into the polymer matrix. Specifically, MOFs with pores larger than 3.0 nm are constructed by three-component reactions that involve the construction of both coordinative and dynamic imine linkages. The MOFs allow polymer penetration and amorphization and efficient lithium salt dissociation in the confined channels. Numerous metal sites and organic functionalities in the MOF backbone further assist the ion migration by providing strong interactions with the fluorinated polymer and the Li+. Remarkable ionic conductivity (0.95 mS cm-1) and a large lithium transference number (0.64) are achieved. Overall, the study fully utilizes both the MOF structural units with atomic precision and the encompassed space at the mesoscale for solid-state electrolyte development.

Macrophage migration inhibitory factor reversed senescent phenotype in human chondrocytes in vitro.

BACKGROUND: The senescence of chondrocytes, which is closely linked to the development of osteoarthritis (OA), has been found to be influenced by the inflammatory environment of joint cavity. However, there remains a lack of comprehensive understanding regarding the specific mechanisms through which cytokine impacts chondrocytes senescence. PURPOSE: To investigate the effects of MIF on the chondrocytes senescence and explore the underlying mechanism. METHODS: Human cytokine array and ELISA were used for the level of MIF in synovium fluid. CCK-8 was used for chondrocytes viability. IF, WB, SA-ß-gal staining and flow cytometry were used for the chondrogenic, apoptotic and senescent phenotype of chondrocytes. RESULTS: The level of MIF was significantly increased in OA patients. MIF significantly reversed the senescent phenotype induced by LPS pretreatment in human chondrocytes. MIF significantly enhanced the expression of Col II, SOX9, and ACAN in LPS pre-treated human chondrocytes. Furthermore, MIF significantly inhibited the apoptosis of LPS-induced senescent chondrocytes. CONCLUSION: Increased level of MIF in osteoarthritic joint cavity might effectively suppress the senescent phenotype and simultaneously improve the chondrogenic phenotype in chondrocytes, the underlying mechanism was likely to be independent of apoptosis.

Tanshinone IIA regulates CCl4 induced liver fibrosis in C57BL/6J mice via the PI3K/Akt and Nrf2/HO-1 signaling pathways.

Chronic liver diseases caused by various factors may develop into liver fibrosis (LF). Early stage of LF could be reversible. Tanshinone IIA (Tan IIA), an extract from Salvia miltiorrhiza, has been reported to be hepatoprotective. However, the potential targets and mechanism of Tan IIA in the treatment of LF are still unclear. Our study aims at the anti-LF mechanism of Tan IIA through network pharmacological analysis combined with LF-related experiments. Serum biochemical indicators and histopathological examination showed that Tan IIA could ameliorate the process of LF in the CCl4 -induced mouse model. Western blot and immunohistochemical assays showed that Tan IIA decreased the expression of Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositide 3-kinases/protein kinase B (PI3K/Akt), and nuclear factor erythroid 2-related factor/heme oxygenase-1 (Nrf2/HO-1). Compared with the model group, the Tan IIA groups increased the decreased superoxide dismutase activity and glutathione content, while decreasing the increased malondialdehyde content. These results indicate that Tan IIA may play an antioxidant role by inhibiting the expression of KRAS, PI3K/Akt, and Nrf2/HO-1 to ameliorate the progression of LF, which to some extent explains the pharmacological mechanism of Tan IIA in LF. In conclusion, our study demonstrates that Tan IIA could regulate LF via PI3K/Akt and Nrf2/HO-1 signaling pathways. It may be an effective therapeutic compound for the treatment of LF.

CCR2 is a potential therapeutic target in peri-implantitis.

AIM: CCR2 (C-C chemokine receptor type 2) plays a crucial role in inflammatory and bone metabolic diseases; however, its role in peri-implantitis remains unclear. This study aimed to explore whether CCR2 contributes to peri-implantitis and the treatment effects of cenicriviroc (CVC) on peri-implant inflammation and bone resorption. MATERIALS AND METHODS: The expression of CCR2 was studied using clinical tissue analysis and an in vivo peri-implantitis model. The role of CCR2 in promoting inflammation and bone resorption in peri-implantitis was evaluated in Ccr2-/- mice and wild-type mice. The effect of CVC on peri-implantitis was evaluated using systemic and local dosage forms. RESULTS: Human peri-implantitis tissues showed increased CCR2 and CCL2 levels, which were positively correlated with bone loss around the implants. Knocking out Ccr2 in an experimental model of peri-implantitis resulted in decreased monocyte and macrophage infiltration, reduced pro-inflammatory cytokine generation and impaired osteoclast activity, leading to reduced inflammation and bone loss around the implants. Treatment with CVC ameliorated bone loss in experimental peri-implantitis. CONCLUSIONS: CCR2 may be a potential target for peri-implantitis treatment by harnessing the immune-inflammatory response to modulate the local inflammation and osteoclast activity.

Construction and Validation of Novel Ferroptosis-related Risk Score Signature and Prognostic Prediction Nomogram for Patients with Colorectal Cancer.

Background: Colorectal cancer (CRC) has a high morbidity and mortality. Ferroptosis is a phenomenon in which metabolism and cell death are closely related. The role of ferroptosis-related genes in the progression of CRC is still not clear. Therefore, we screened and validated the ferroptosis-related genes which could determine the prevalence, risk and prognosis of patients with CRC. Methods: We firstly screened differentially expressed ferroptosis-related genes by The Cancer Genome Atlas (TCGA) database. Then, these genes were used to construct a risk-score model using the least absolute shrinkage and selection operator (LASSO) regression algorithm. The function and prognosis of the ferroptosis-related genes were confirmed using multi-omics analysis. The gene expression results were validated using publicly available databases and qPCR. We also used publicly available data and ferroptosis-related genes to construct a prognostic prediction nomogram. Results: A total of 24 differential expressed genes associated with ferroptosis were screened in this study. A three-gene risk score model was then established based on these 24 genes and GPX3, CDKN2A and SLC7A11 were selected. The significant prognostic value of this novel three-gene signature was also assessed. Furthermore, we conducted RT-qPCR analysis on cell lines and tissues, and validated the high expression of CDKN2A, GPX3 and low expression of SLC7A11 in CRC cells. The observed mRNA expression of GPX3, CDKN2A and SLC7A11 was consistent with the predicted outcomes. Besides, eight variables including selected ferroptosis related genes were included to establish the prognostic prediction nomogram for patients with CRC. The calibration plots showed favorable consistency between the prediction of the nomogram and actual observations. Also, the time-dependent AUC (>0.7) indicated satisfactory discriminative ability of the nomogram. Conclusions: The present study constructed and validated a novel ferroptosis-related three-gene risk score signature and a prognostic prediction nomogram for patients with CRC. Also, we screened and validated the ferroptosis-related genes GPX3, CDKN2A, and SLC7A11 which could serve as novel biomarkers for patients with CRC.

Relationships of tumor differentiation and immune infiltration in gastric cancers revealed by single-cell RNA-seq analyses.

Gastric cancers are highly heterogeneous malignant tumors. To reveal the relationship between differentiation status of cancer cells and tumor immune microenvironments in gastric cancer, single-cell RNA-sequencing was performed on normal mucosa tissue, differentiated gastric cancer (DGC) tissue, poorly differentiated gastric cancer (PDGC) tissue and neuroendocrine carcinoma (NEC) tissue sampled from surgically resected gastric cancer specimens. We identified the signature genes for both DGC and PDGC, and found that signature genes of PDGC strongly enriched in the epithelial-mesenchymal transition (EMT) program. Furthermore, we found that DGC tends to be immune-rich type whereas PDGC tends to be immune-poor type defined according to the density of tumor-infiltrating CD8+ T cells. Additionally, interferon alpha and gamma responding genes were specifically expressed in the immune-rich malignant cells compared with immune-poor malignant cells. Through analyzing the mixed adenoneuroendocrine carcinoma, we identified intermediate state malignant cells during the trans-differentiation process from DGC to NEC, which showed double-negative expressions of both DGC marker genes and NEC marker genes. Interferon-related pathways were gradually downregulated along the DGC to NEC trans-differentiation path, which was accompanied by reduced CD8+ cytotoxic T-cell infiltration. In summary, molecular features of both malignant cells and immune microenvironment cells of DGC, PDGC and NEC were systematically revealed, which may partially explain the strong tumor heterogeneities of gastric cancer. Especially along the DGC to NEC trans-differentiation path, immune-evasion was gradually enhanced with the decreasing activities of interferon pathway responses in malignant cells.

Advancements in investigating the role of cerebral small vein loss in Alzheimer's disease-related pathological changes.

Alzheimer's disease (AD) is the prevailing type of dementia in the elderly, yet a comprehensive comprehension of its precise underlying mechanisms remains elusive. The investigation of the involvement of cerebral small veins in the advancement of AD has yet to be sufficiently explored in previous studies, primarily due to constraints associated with pathological staining techniques. However, recent research has provided valuable insights into multiple pathophysiological occurrences concerning cerebral small veins in AD, which may manifest sequentially, concurrently, or in a self-perpetuating manner. These events are presumed to be among the initial processes in the disease's progression. The impact of cerebral small vein loss on amyloid beta (Aß) clearance through the glial lymphatic system is noteworthy. There exists a potential interdependence between collagen deposition and Aß deposition in cerebral small veins. The compromised functionality of cerebral small veins can result in decreased cerebral perfusion pressure, potentially leading to cerebral tissue ischemia and edema. Additionally, the reduction of cerebral small veins may facilitate the infiltration of inflammatory factors into the brain parenchyma, thereby eliciting neuroinflammatory responses. Susceptibility-weighted imaging (SWI) is a valuable modality for the efficient assessment of cerebral small veins, precisely the deep medullary vein (DMV), and holds promise for the identification of precise and reliable imaging biomarkers for AD. This review presents a comprehensive overview of the current advancements and obstacles to the impairment of cerebral small veins in AD. Additionally, we emphasize future research avenues and the importance of conducting further investigations in this domain.