Redox metabolism maintains the leukemogenic capacity and drug resistance of AML cells.

Rewiring of redox metabolism has a profound impact on tumor development, but how the cellular heterogeneity of redox balance affects leukemogenesis remains unknown. To precisely characterize the dynamic change in redox metabolism in vivo, we developed a bright genetically encoded biosensor for H2O2 (named HyPerion) and tracked the redox state of leukemic cells in situ in a transgenic sensor mouse. A H2O2-low (HyPerion-low) subset of acute myeloid leukemia (AML) cells was enriched with leukemia-initiating cells, which were endowed with high colony-forming ability, potent drug resistance, endosteal rather than vascular localization, and short survival. Significantly high expression of malic enzymes, including ME1/3, accounted for nicotinamide adenine dinucleotide phosphate (NADPH) production and the subsequent low abundance of H2O2. Deletion of malic enzymes decreased the population size of leukemia-initiating cells and impaired their leukemogenic capacity and drug resistance. In summary, by establishing an in vivo redox monitoring tool at single-cell resolution, this work reveals a critical role of redox metabolism in leukemogenesis and a potential therapeutic target.

FvemiR160-FveARF18A-FveAP1/FveFUL module regulates flowering time in woodland strawberry.

Flowering is an indicator of plant transformation from vegetative to reproductive growth. miR160 has been shown to have a significant effect on the growth and development of fruits, leaves, and roots of plants or their stress response to environment, but the participation of miR160 in regulating flowering time in plants is unclear. In this study, we found that two FvemiR160s (FvemiR160a/FvemiR160b) mature sequences in strawberry (Fragaria vesca) were consistent. It was displayed that the miR160 mature sequence is highly conserved in various species, and the miR160 mature sequence formed by the 5' arm of the MIR160 precursor was more conserved. Three FveARFs in woodland strawberry were negatively regulated by FvemiR160a, among which FveARF18A was the most significant. Phylogenetic analysis indicated that FvemiR160 is closely related to apple (Malus domestica), grape (Vitis vinifera), and Arabidopsis thaliana, while FveARF18A is closely related to RcARF18. Subsequently, we demonstrated that FvemiR160a can target cutting FveARF18A to negatively regulate its expression by RLM-5' RACE, cleavage site mutation, and GFP fluorescence assay. Moreover, we observed that FveMIR160a overexpressed plants have advanced flowering, while mFveARF18A overexpressed plants have delayed flowering. We also verified that FveARF18A negatively regulates the expression of FveAP1 and FveFUL by binding their promoters by yeast one-hybrid, LUC, and GUS assay, and FveAP1 and FveFUL transgenic Arabidopsis showed early flowering phenotype. In addition, the expression level of FvemiR160a was decreased obviously while that of FveARF18A was increased obviously by MeJA, GA and IAA. In conclusion, our study reveals the important role of the FvemiR160-FveARF18A-FveAP1/FveFUL module in the flowering process of woodland strawberry and provides a new pathway for studying flowering.

IFN-γ Limits Immunopathogenesis but Delays Fungal Clearance during Pneumocystis Pneumonia.

High levels of IFN-γ are produced in the lung during an adaptive immune response to Pneumocystis, but the effects of this prototypical Th1 cytokine on fungal clearance and immunopathogenesis have not been fully defined. Therefore, Pneumocystis-infected immunodeficient mice were immune reconstituted and administered control or anti-IFN-γ neutralizing Ab to determine how IFN-γ regulates the balance between host defense and immune-mediated lung injury. Mice treated with anti-IFN-γ demonstrated an initial worsening of Pneumocystis pneumonia-related immunopathogenesis, with greater weight loss, heightened lung inflammation, and more severe pulmonary function deficits than control mice. However, IFN-γ neutralization also enhanced macrophage phagocytosis of Pneumocystis and accelerated fungal clearance. When anti-IFN-γ-treated mice were also given IL-4 and IL-13 to promote a Th2-biased lung environment, the accelerated fungal clearance was preserved, but the severity of immunopathogenesis was reduced, and a more rapid recovery was observed. A direct suppressive effect of IFN-γ on macrophages was required but was not solely responsible for delayed fungal clearance, suggesting that IFN-γ acts through multiple mechanisms that likely include modulation of both macrophage and Th polarization. Enhanced Pneumocystis clearance in anti-IFN-γ-treated and IFN-γR-deficient mice was associated with significantly elevated IL-17+ CD4+ T cells and IL-17 protein in the lungs. Furthermore, neutralization of IL-17, but not IL-4, signaling blocked the accelerated fungal clearance observed in anti-IFN-γ-treated mice. Together, these data demonstrate that although IFN-γ delays fungal clearance by suppressing the lung Th17 response, it also serves an important regulatory role that limits immunopathogenesis and preserves pulmonary function.

ZL006 mitigates anxiety-like behaviors induced by closed head injury through modulation of the neural circuit from the medial prefrontal cortex to amygdala.

Closed head injury is a prevalent form of traumatic brain injury with poorly understood effects on cortical neural circuits. Given the emotional and behavioral impairments linked to closed head injury, it is vital to uncover brain functional deficits and their driving mechanisms. In this study, we employed a robust viral tracing technique to identify the alteration of the neural pathway connecting the medial prefrontal cortex to the basolateral amygdala, and we observed the disruptions in neuronal projections between the medial prefrontal cortex and the basolateral amygdala following closed head injury. Remarkably, our results highlight that ZL006, an inhibitor targeting PSD-95/nNOS interaction, stands out for its ability to selectively reverse these aberrations. Specifically, ZL006 effectively mitigates the disruptions in neuronal projections from the medial prefrontal cortex to basolateral amygdala induced by closed head injury. Furthermore, using chemogenetic approaches, we elucidate that activating the medial prefrontal cortex projections to the basolateral amygdala circuit produces anxiolytic effects, aligning with the therapeutic potential of ZL006. Additionally, ZL006 administration effectively mitigates astrocyte activation, leading to the restoration of medial prefrontal cortex glutamatergic neuron activity. Moreover, in the context of attenuating anxiety-like behaviors through ZL006 treatment, we observe a reduction in closed head injury-induced astrocyte engulfment, which may correlate with the observed decrease in dendritic spine density of medial prefrontal cortex glutamatergic neurons.

Circular RNA ACVR2A promotes the progression of hepatocellular carcinoma through mir-511-5p targeting PI3K-Akt signaling pathway.

Circular RNA (circRNA) is thought to mediate the occurrence and development of human cancer and usually acts as a tiny RNA (miRNA) sponge to regulate downstream gene expression. However, it is not clear whether and how circACVR2A (hsa_circ_0001073) is involved in the progression of HCC. The purpose of this study is to clarify the potential role and molecular mechanism of circACVR2A in regulating the progression of hepatocellular carcinoma cells (HCC). The abundance of related proteins in circACVR2A, microRNA (miR511-5p) and PI3K-Akt signaling pathway was determined by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) or Western blotting. Cell viability, invasion and apoptosis were analyzed by CCK-8, Transwell analysis and Tunel staining, respectively. The interaction between circACVR2A and microRNA was evaluated by double luciferase reporter gene assay. The results showed that circACVR2A was highly expressed in hepatocellular carcinoma cell lines. Our in vivo and in vitro data showed that circACVR2A promoted the proliferation, migration and invasion of HCC. In terms of mechanism, we found that circACVR2A can directly interact with miR511-5p and act as a miRNA sponge to regulate the expression of related proteins in PI3K-Akt signaling pathway.In HCC, circACVR2A can mediate miR-511-5p/mRNA network to activate PI3K signal pathway. This shows that the molecular regulatory network with circACVR2A as the core is a new potential target for diagnosis and treatment of hepatocellular carcinoma.

FUDNC1-dependent mitophagy ameliorate motor neuron death in an amyotrophic lateral sclerosis mouse model.

Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, yet effective treatment is lacking. Moreover, the underlying pathomechanisms of ALS remain unclear, with impaired mitophagy function being increasingly recognized as a contributing factor. FUN14 domain-containing protein 1 (FUNDC1) is an autophagy receptor localized to the outer mitochondrial membrane and a mitochondrial membrane protein that mediates mitophagy and therefore considered as important factor in neurodegenerative diseases. However, its specific role in ALS is not yet clear. Therefore, this study aimed to investigate the regulatory role of FUNDC1 in ALS and determine its regulatory mechanisms. ALS transgenic mice were obtained and maintained under standard conditions. Cell lines were generated by stable transfection with hSOD1G93A or control vectors. Mice received intrathecal injections of AAV9 vectors expressing FUNDC1 or EGFP. Motor function was assessed through behavioral tests, and histological and immunostaining analyses were performed. Colocalization analysis was conducted in transfected cells, and protein expression was evaluated via western blotting. We first observed that FUNDC1 was significantly downregulated in the spinal cord tissues of SOD1G93A mice. FUNDC1 overexpression considerably improved locomotor activity and prolonged survival time in SOD1G93A mice. Mechanistically, reduced expression of FUNDC1 resulted in decreased mitophagy, as indicated by decreased recruitment through LC3 in SOD1G93A mice and cellular models. Consequently, this led to increased mitochondrial accumulation and cell apoptosis, exacerbating the ALS phenotype. Furthermore, we identified transcription factor FOXD3 as an essential upstream factor of FUNDC1, resulting in reduced transcription of FUNDC1 in ALS lesions. This study suggests a novel strategy of targeting FUNDC1-mediated mitophagy for developing therapeutic interventions to mitigate disease progression and improve outcomes for ALS patients.

Molecular Expression and Prognostic Implications of Krüppel-Like Factor 3 (KLF3) in Clear Cell Renal Cell Carcinoma.

A major subtype of renal cancer is clear cell renal cell carcinoma (ccRCC). Krüppel-like factor 3 (KLF3) dysfunction is also revealed leading to poor prognosis in multiple cancer types. However, dysregulation and molecular dynamics of KLF3 underlying ccRCC progression still remains elusive. Here KLF3 gene and protein expressions in ccRCC were explored using data cohorts from The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), Clinical Proteomic Tumor Analysis Consortium (CPTAC) and verified them in our patient cohort. Correlations of KLF3 expression with clinicopathological features, epigenetic modification, and immune microenvironment characteristics were further investigated. KLF3 was significantly down-regulated expressed in ccRCC tissues compared to adjacent normal controls. Adverse pathological parameters and poor prognosis were associated with lower expression of KLF3. Mechanically, KLF3 regulation was mainly attributed to CpG island methylation. KLF3-high expression subgroup was significantly enriched in cell signaling pathways most associated with EMT markers, angiogenesis, inflammatory response, apoptosis, TGF-ß, degradation of ECM, G2M checkpoint, and PI3K-AKT-mTOR. Based on GDSC database, KLF3 upregulation was identified to be associated with higher sensitivities towards PI3K-Akt-mTOR pathway inhibitors such as PI-103, PIK-93, and OSI-027. In addition, patients with down-regulated KLF3 expressions were found more sensitive towards Trametinib, Cetuximab, and Erlotinib. Collectively, our findings suggest that KLF3 may act as a suitable biomarker for prognosis prediction, tumor microenvironment (TME) phenotype identification, thereby helping ccRCC patients to make better therapeutic decisions.

The safety of trastuzumab deruxtecan (DS-8201) with a focus on interstitial lung disease and/or pneumonitis: A systematic review and single-arm meta-analysis.

BACKGROUND: Previous studies involving risk-benefit analysis of trastuzumab deruxtecan (DS-8201) have indicated the benefit of this treatment, although it may increase the risk of interstitial lung disease (ILD) and/or pneumonitis in certain patients. This study aimed to assess the safety of DS-8201. METHODS: A search was done for relevant articles in four electronic databases: PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov. All reports published up until November 2, 2022, were included, and study types were restricted to clinical trials; the last search was then updated to January 10, 2023. We also assessed the quality of the literature with the Cochrane Handbook for Systematic Reviews of Interventions and the Methodological Index for Non-Randomized Studies tool, and then performed a meta-analysis with R version 4.2.1. RESULTS: A total of 1428 patients reported in 13 articles were included in this study. The analysis revealed that the most common all-grade treatment-emergent adverse events (TEAEs) were nausea and fatigue. The most common TEAE of grade 3 or above (grade ≥3) was neutropenia. The incidences of ILD and/or pneumonitis for all-grade and grade ≥3 TEAEs were 12.5% and 2.2%, respectively. CONCLUSIONS: This comprehensive summary of the incidence of TEAEs associated with DS-8201 in clinical trials provides an important guide for clinicians. The most common TEAEs were gastrointestinal reactions and fatigue; meanwhile, the most common grade ≥3 TEAE was hematological toxicity. ILD and/or pneumonitis were specific adverse drug reactions associated with DS-8201, of which physicians should be particularly aware for their higher morbidity and rates of grade ≥3 TEAEs.

A bright red fluorescent genetically encoded sensor for lactate imaging.

Lactate plays a crucial role in energy metabolism and greatly impacts protein activities, exerting diverse physiological and pathological effects. Therefore, convenient lactate assays for tracking spatiotemporal dynamics in living cells are desirable. In this paper, we engineered and optimized a red fluorescent protein sensor for l-lactate named FiLa-Red. This indicator exhibited a maximal fluorescence change of 730 % and an apparent dissociation constant (Kd) of approximately 460 µM. By utilizing FiLa-Red and other sensors, we monitored energy metabolism in a multiplex manner by simultaneously tracking lactate and NAD+/NADH abundance in the cytoplasm, nucleus, and mitochondria. The FiLa-Red sensor is expected to be a useful tool for performing metabolic analysis in vitro, in living cells and in vivo.

Grassland degradation affected vegetation carbon density but not soil carbon density.

BACKGROUND: With the profound changes in the global climate, the issue of grassland degradation is becoming increasingly prominent. Grassland degradation poses a severe threat to the carbon cycle and carbon storage within grassland ecosystems. Additionally, it will adversely affect the sustainability of food production. The grassland ecosystem in the northwest region of Liaoning Province, China, is particularly vulnerable due to factors such as erosion from the northern Horqin Sandy Land, persistent arid climate, and issues related to overgrazing and mismanagement of grassland. The degradation issue is especially pronounced in this ecological environment. However, previous research on the carbon density of degraded grasslands in Northeast China has predominantly focused on Inner Mongolia, neglecting the impact on the grasslands in the northwest of Liaoning Province. Therefore, this experiment aims to assess the influence of grassland degradation intensity on the vegetation and soil carbon density in the northwest of Liaoning Province. The objective is to investigate the changes in grassland vegetation and soil carbon density resulting from different degrees of grassland degradation. METHODOLOGY: This study focuses on the carbon density of grasslands at different degrees of degradation in the northwest of Liaoning Province, exploring the variations in vegetation and soil carbon density under different levels of degradation. This experiment employed field sampling techniques to establish 100 × 100 m plots in grasslands exhibiting varying degrees of degradation. Six replications of 100 × 100 m plots per degradation intensity were sampled. Vegetation and soil samples were collected for analysis of carbon density. RESULTS: The results indicate that in the context of grassland degradation, there is a significant reduction in vegetation carbon density. Furthermore, it was found that root carbon density is the primary contributor to vegetation carbon density. In comparison to mildly degraded grasslands, moderately and severely degraded grasslands experience a reduction in vegetation carbon density by 25.6% and 52.6%, respectively. However, with regard to the impact of grassland degradation on soil carbon density, it was observed that while grassland degradation leads to a slight decrease in soil carbon density, there is no significant change in soil carbon density in the short term under the influence of grassland degradation. CONCLUSIONS: Therefore, grassland degradation has exerted a negative impact on aboveground vegetation carbon density, reducing the carbon storage of above-ground vegetation in grasslands. However, there was no significant effect on grassland soil carbon density.

JD-02, a novel Hsp90 inhibitor, induces ROS/SRC axis-dependent cytoprotective autophagy in colorectal cancer cells.

Heat shock protein 90 (Hsp90) is a tumor marker that accelerates cancer growth by disrupting protein homeostasis. However, concerns such as low clinical efficacy and drug resistance continue to be obstacles to the successful marketing of Hsp90 inhibitors. The cytoprotective function of autophagy has been identified as one of the mechanisms by which tumor cells gain resistance to chemotherapy. JD-02 was identified as a new Hsp90 inhibitor that suppressed colorectal cancer (CRC) growth by lowering client protein levels in vivo and in vitro. We found that JD-02 increased cellular autophagy, which inhibited apoptosis. JD-02 enhanced cytoprotective autophagy and regulated apoptotic suppression by increasing intracellular reactive oxygen species and inhibiting SRC protein levels, as demonstrated by quantitative proteomics, bioinformatic analysis, western blotting, and flow cytometry. This effect was reversed by autophagy inhibition. Therefore, due to the synergistic effects of Hsp90 and autophagy inhibitors in efficiently activating apoptotic pathways, they could potentially serve as promising therapeutic options for CRC.

Genetic variation in the aquaporin TONOPLAST INTRINSIC PROTEIN 4;3 modulates maize cold tolerance.

Cold stress is a major abiotic stress that threatens maize (Zea mays L.) production worldwide. Understanding the molecular mechanisms underlying cold tolerance is crucial for breeding resilient maize varieties. Tonoplast intrinsic proteins (TIPs) are a subfamily of aquaporins in plants. Here, we report that TIP family proteins are involved in maize cold tolerance. The expression of most TIP genes was responsive to cold stress. Overexpressing TIP2;1, TIP3;2 or TIP4;3 reduced the cold tolerance of maize seedlings, while loss-of-function mutants of TIP4;3 exhibited enhanced cold tolerance. Candidate gene-based association analysis revealed that a 328-bp transposon insertion in the promoter region of TIP4;3 was strongly associated with maize cold tolerance. This transposon insertion conferred cold tolerance by repressing TIP4;3 expression through increased methylation of its promoter region. Moreover, TIP4;3 was found to suppress stomatal closure and facilitate reactive oxygen species (ROS) accumulation under cold stress, thereby inhibiting the expression of cold-responsive genes, including DEHYDRATION-RESPONSIVE ELEMENT BINDING FACTOR 1 (DREB1) genes and a subset of peroxidase genes, ultimately attenuating maize cold tolerance. This study thus elucidates the mechanism underlying TIP-mediated cold tolerance and identifies a favourable TIP4;3 allele as a potential genetic resource for breeding cold-tolerant maize varieties.

FveDREB1B improves cold tolerance of woodland strawberry by positively regulating FveSCL23 and FveCHS.

Cold stress has seriously inhibited the growth and development of strawberry during production. CBF/DREB1 is a key central transcription factor regulating plant cold tolerance, but its regulatory mechanisms are varied in different plants. Especially in strawberry, the molecular mechanism of CBF/DREB1 regulating cold tolerance is still unclear. In this study, we found that FveDREB1B was most significantly induced by cold stress in CBF/DREB1 family of diploid woodland strawberry. FveDREB1B was localized to the nucleus, and DREB1B sequences were highly conserved in diploid and octoploid strawberry, and even similar in Rosaceae. And FveDREB1B overexpressed strawberry plants showed delayed flowering and increased cold tolerance, while FveDREB1B silenced plants showed early flowering and decreased cold tolerance. Under cold stress, FveDREB1B activated FveSCL23 expression by directly binding to its promoter. Meanwhile, FveDREB1B and FveSCL23 interacted with FveDELLA, respectively. In addition, we also found that FveDREB1B promoted anthocyanin accumulation in strawberry leaves by directly activating FveCHS expression after cold treatment and recovery to 25°C. DREB1B genes were also detected to be highly expressed in cold-tolerant strawberry resources 'Fragaria mandschurica' and 'Fragaria nipponica'. In conclusion, our study reveals the molecular mechanism of FveDREB1B-FveSCL23-FveDELLA module and FveDREB1B-FveCHS module to enhance the cold tolerance of woodland strawberry. It provides a new idea for improving the cold tolerance of cultivated strawberry and evaluating the cold tolerance of strawberry germplasm resources.

Single-cell transcriptome landscape elucidates the cellular and developmental responses to tomato chlorosis virus infection in tomato leaf.

Plant viral diseases compromise the growth and yield of the crop globally, and they tend to be more serious under extreme temperatures and drought climate changes. Currently, regulatory dynamics during plant development and in response to virus infection at the plant cell level remain largely unknown. In this study, single-cell RNA sequencing on 23 226 individual cells from healthy and tomato chlorosis virus-infected leaves was established. The specific expression and epigenetic landscape of each cell type during the viral infection stage were depicted. Notably, the mesophyll cells showed a rapid function transition in virus-infected leaves, which is consistent with the pathological changes such as thinner leaves and decreased chloroplast lamella in virus-infected samples. Interestingly, the F-box protein SKIP2 was identified to play a pivotal role in chlorophyll maintenance during virus infection in tomato plants. Knockout of the SlSKIP2 showed a greener leaf state before and after virus infection. Moreover, we further demonstrated that SlSKIP2 was located in the cytomembrane and nucleus and directly regulated by ERF4. In conclusion, with detailed insights into the plant responses to viral infections at the cellular level, our study provides a genetic framework and gene reference in plant-virus interaction and breeding in the future research.

Research on the mitigation of redeposition defects on the fused silica surface during wet etching process.

The laser-induced damage of ultraviolet fused silica optics is a critical factor that limits the performance enhancement of high-power laser facility. Currently, wet etching technology based on hydrofluoric acid (HF) can effectively eliminate absorbing impurities and subsurface defects, thereby significantly enhancing the damage resistance of fused silica optics. However, with an increase in the operating fluence, the redeposition defects generated during wet etching gradually become the primary bottleneck that restricts its performance improvement. The composition and morphology of redeposition defects were initially identified in this study, followed by an elucidation of their formation mechanism. A mitigation strategy was then proposed, which combines a reduction in the generation of precipitation with an acceleration of the precipitation dissolution process. Additionally, we systematically investigated the influence of various process parameters such as extrinsic impurity, etching depth, and megasonic excitation on the mitigation of deposition defects. Furthermore, a novel multiple-step dynamic etching method was developed. Through comprehensive characterization techniques, it has been confirmed that this new etching process not only effectively mitigate redeposition defects under low fluence conditions but also exhibits significant inhibition effects on high fluence precursors. Consequently, it significantly enhances the laser damage resistance performance of fused silica optics.

A Three-Dimensional Non-Fullerene Acceptor with Contorted Hexabenzocoronene and Perylenediimide for Organic Solar Cells.

Although fullerene derivatives such as [6,6]-phenyl-C61/C71-butyric acid methyl ester (PC61BM/PC71BM) have dominated the the photoactive acceptor materials in bulk heterojunction organic solar cells (OSCs) for decades, they have several drawbacks such as weak absorption, limited structural tunability, prone to aggregation, and high costs of production. Constructing non-fullerene small molecules with three-dimensional (3D) molecular geometry is one of the strategies to replace fullerenes in OSCs. In this study, a 3D molecule, contorted hexa-cata-hexabenzocoronene tetra perylenediimide (HBC-4-PDI), was designed and synthesized. HBC-4-PDI shows a wide and strong light absorption in the whole UV-vis region as well as suitable energy levels as an acceptor for OSCs. More importantly, the 3D construction effectively reduced the self-aggregation of c-HBC, leading to an appropriate scale phase separation of the blend film morphology in OSCs. A preliminary power conversion efficiency of 2.70 % with a champion open-circuit voltage of 1.06 V was obtained in OSCs with HBC-4-PDI as the acceptor, which was the highest among the previously reported OSCs based on c-HBC derivatives. The results indicated that HBC-4-PDI may serve as a good non-fullerene acceptor for OSCs.

GLO1 regulates hepatocellular carcinoma proliferation and migration through the cell cycle pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor characterized by a high mortality rate. The occurrence and progression of HCC are linked to oxidative stress. Glyoxalase-1 (GLO1) plays an important role in regulating oxidative stress, yet the underlying mechanism remains unclear. GLO1 may serve as a prognostic biomarker and therapeutic target for HCC. METHODS: Based on TCGA database hepatocellular carcinoma samples, we conducted a bioinformatics analysis to explore the correlation between GLO1 expression and HCC cell proliferation and viability. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that differentially expressed genes (DEGs) were mainly enriched in the cell cycle pathway. We analyzed the relationships between GLO1 and 24 genes enriched in the cell cycle pathway using a protein-protein interaction (PPI) network. Finally, experimental validation was performed to assess GLO1's impact on the distribution of cells at different cell cycle stages and on the proliferation and migration of HCC cells. RESULTS: Our study demonstrated that GLO1 was overexpressed in HCC tissues and was associated with a poor prognosis. Data analysis indicated that overexpression of GLO1 activated the cell cycle pathway and positively correlated with expression of the majority of key cell cycle genes. Experimental validation showed that GLO1 expression affects the number of HCC cells in G2 and S phases and regulates HCC cell proliferation and migration. CONCLUSIONS: GLO1 represents a promising therapeutic target for HCC, providing valuable insights into its role in the viability and proliferation of HCC cells.

Acromegalic Rat Model Presented Cognitive Impairments and Tau Hyperphosphorylation in the Hippocampus.

INTRODUCTION: Acromegaly patients, in addition to the most prominent physical and endocrine changes, also exhibit a higher risk of cognitive dysfunction. However, the reasons and mechanisms underlying cognitive impairments in acromegaly patients remain unknown. METHODS: Acromegalic rats were induced by subcutaneous injection of tumor cells, with continuous monitoring of the body weight and hormones to confirm the occurrence of acromegaly. Behavioral assessments, including open field test, novel object recognition test, and Barnes maze test, were conducted to evaluate the animals' cognitive function. Western blotting, immunohistochemistry, and immunofluorescence techniques were employed to examine changes in the hippocampal tau protein, Aß, and associated signaling pathways. RESULTS: The tumor cells secreting growth hormone increased the secretion of growth hormone, resulting in changes in body size and endocrine functions, thus causing acromegaly. The acromegaly model showed deficiencies in working memory and spatial memory. Hyperphosphorylation of tau protein was observed in the hippocampus of the acromegaly model, but no Aß deposition was observed. The acromegaly model exhibits hippocampal growth hormone (GH) resistance, decreased expression of GH receptors, and subsequently reduced expression activity of the PI3K-Akt-GSK3ß signaling pathway, which is responsible for the hyperphosphorylation of tau protein. CONCLUSION: The prolonged elevation of GH and insulin-like growth factor 1 caused by acromegaly may lead to abnormalities in the SD rat's PI3K-Akt-GSK3ß signaling pathway, subsequently resulting in hyperphosphorylation of the hippocampal tau protein and cognitive impairment.

Efficacy of Recombinant Human Parathyroid Hormone 1-34 and Vitamin K2 Combination Therapy in Postmenopausal Osteoporosis.

This study aimed to assess the efficacy and safety of a combined recombinant human parathyroid hormone 1-34 [rhPTH (1-34)] and vitamin K2 therapy versus vitamin K2 alone in the treatment of postmenopausal osteoporosis. A total of 77 postmenopausal osteoporosis patients were randomly divided into two groups. Patients in one group received vitamin K2 alone, while patients in the other group received a combination of rhPTH (1-34) and vitamin K2. Bone mineral density (BMD), electrolyte levels, pain scores, bone metabolism levels, and adverse drug reactions were compared pre- and post-treatment. Both two treatments improved BMD, blood calcium concentrations, pain scores, and increased osteocalcin and osteoprotegerin levels. Notably, the combined rhPTH (1-34) and vitamin K2 treatment demonstrated superior efficacy in improving BMD and bone metabolism markers. Furthermore, there was no significant difference in the incidence of adverse reactions between the two groups, indicating the safety of the combined treatment. In summary, the combined therapy of rhPTH (1-34) and vitamin K2 exhibited more potent efficacy in the treatment of postmenopausal osteoporosis, more effectively enhancing BMD and bone metabolism markers than vitamin K2 alone, without a significant increase in adverse reactions.

Precise treatment of pelvic fracture urethral injury associated with urethrorectal fistula.

OBJECTIVE: To evaluate the effect of a new strategy of transperineal anastomotic urethroplasty (TAU) with proximal transection in treating pelvic fracture urethral injury (PFUI) associated with urethrorectal fistula (URF). PATIENTS AND METHODS: A retrospective review of all patients treated by TAU with proximal transection and fistula repair for PFUI associated with URF was performed between August 2013 and July 2022. Information on demographics, peri-operative variables, and postoperative follow-up outcomes was collected. Successful surgery was defined as restoration of a uniform urethral calibre using flexible cystoscopy (third postoperative month) without strictures or leakage, with no further interventions required. Functional outcomes, including erectile function (assessed using the five-item International Index of Erectile Function) and urinary continence, were assessed. RESULTS: Forty patients diagnosed with PFUI associated with URF and treated by TAU with proximal transection and rectal fistula repair were enrolled. Six patients (15.0%) had a history of failed urethral reconstruction. The mean stenosis length and fistula diameter were 2.9 cm and 1.2 cm, respectively. All patients underwent faecal diversion before urethroplasty. After a median (range) follow-up of 45 (3-115) months, the final success rate was 90.0% (36/40). Postoperative complications included haematoma in three patients, epididymo-orchitis in three, wound infection in one, wound bleeding in one, delayed wound healing in three, and wound numbness in three. The overall incidence of postoperative erectile dysfunction reached 75.0%, with a median (range) score of 9 (0-19). Normal continence was achieved in 31 patients (77.5%). Occasional incontinence without the need for urinal pads occurred in eight patients, whereas one patient required urinal pads. CONCLUSIONS: Transperineal anastomotic urethroplasty with proximal transection is a precise and effective surgical strategy for treating PFUI associated with URF. This strategy ensures a high success rate and improves surgical efficiency.