A diagnostic signature developed based on the necroptosis-related genes and its association with immune infiltration in osteosarcoma.

Introduction: Osteosarcoma is a bone-derived malignancy that often leads to lung metastasis and death. Material and methods: The RNA-seq data of TARGET-osteosarcoma were collected from TARGET database. GSE16088 and GSE12865 datasets of osteosarcoma x from Gene Expression Database (GEO) were donwloaded. ConsensusClusterPlus was used for molecular subtype classification. Univariate Cox and Lasso regression was employed to develop a risk model. To analyze the regulatory effects of model feature genes on the malignant phenotype of osteosarcoma cell lines, qRT-PCR, Transwell and wound healing assays were performed. The abundance of immune cell infiltration was assessed using MCP-Counter, Gene Set Enrichment Analysis (GSEA), and ESTIMATE. The Tumor Immune Dysfunction and Exclusion (TIDE) software was employed to evaluate immunotherapy and response to conventional chemotherapy drugs. Results: Three clusters (C1, C2 and C3) were classified using 39 necroptosis score-associated genes. In general, C1 and C2 showed better prognosis outcome and lower death rate than C3. Specifically, C2 could benefit more from immunotherapy, while C3 was more sensitive to traditional medicines, and C1 had higher immune cell infiltration. Next, an 8-gene signature and a risk score model were developed, with a low risk score indicating better survival and immune cell infiltration. ROC analysis showed that 1-, 3-, and 5-year overall survival of osteosarcoma could be correctly predicted by the risk score model. Cellular experiments revealed that the model feature gene IFITM3 promoted the osteosarcoma cell migration and invasion. Furthermore, the overall survival of osteosarcoma patients from TARGET and validation datasets can be accurately evaluated using the nomogram model. Conclusions: Our prognostic model developed using necroptosis genes could facilitate the prognostic prediction for patients suffering from osteosarcoma, offering potential osteosarcoma targets.

Targeting NAT10 inhibits osteosarcoma progression via ATF4/ASNS-mediated asparagine biosynthesis.

Despite advances in treatment, the prognosis of patients with osteosarcoma remains unsatisfactory, and searching for potential targets is imperative. Here, we identify N4-acetylcytidine (ac4C) acetyltransferase 10 (NAT10) as a candidate therapeutic target in osteosarcoma through functional screening. NAT10 overexpression is correlated with a poor prognosis, and NAT10 knockout inhibits osteosarcoma progression. Mechanistically, NAT10 enhances mRNA stability of activating transcription factor 4 (ATF4) through ac4C modification. ATF4 induces the transcription of asparagine synthetase (ASNS), which catalyzes asparagine (Asn) biosynthesis, facilitating osteosarcoma progression. Utilizing virtual screening, we identify paliperidone and AG-401 as potential NAT10 inhibitors, and both inhibitors are found to bind to NAT10 proteins. Inhibiting NAT10 suppresses osteosarcoma progression in vivo. Combined treatment using paliperidone and AG-401 produces synergistic inhibition for osteosarcoma in patient-derived xenograft (PDX) models. Our findings demonstrate that NAT10 facilitates osteosarcoma progression through the ATF4/ASNS/Asn axis, and pharmacological inhibition of NAT10 may be a feasible therapeutic approach for osteosarcoma.

Ubiquitination in pyroptosis pathway: A potential therapeutic target for sepsis.

Sepsis remains a significant clinical challenge, causing numerous deaths annually and representing a major global health burden. Pyroptosis, a unique form of programmed cell death characterized by cell lysis and the release of inflammatory mediators, is a crucial factor in the pathogenesis and progression of sepsis, septic shock, and organ dysfunction. Ubiquitination, a key post-translational modification influencing protein fate, has emerged as a promising target for managing various inflammatory conditions, including sepsis. This review integrates the current knowledge on sepsis, pyroptosis, and the ubiquitin system, focusing on the molecular mechanisms of ubiquitination within pyroptotic pathways activated during sepsis. By exploring how modulating ubiquitination can regulate pyroptosis and its associated inflammatory signaling pathways, this review provides insights into potential therapeutic strategies for sepsis, highlighting the need for further research into these complex molecular networks.

Association between various cathepsins and uterine leiomyoma: A Mendelian randomization analysis.

Emerging evidence suggests a tentative association between cathepsins and uterine leiomyoma (UL). Previous investigations have predominantly focused on the role of cathepsins in the metastasis and colonization of gynecological malignancies. Still, observational studies may lead to confounding and biases. We employed a bidirectional Mendelian randomization (MR) analysis to elucidate the causative links between various cathepsins and UL. Instrumental variables (IVs) of cathepsins and UL within the European cohort were from extant genome-wide association study datasets. Sensitivity assessments was executed, and the heterogeneity of the findings was meticulously dissected to affirm the solidity of the outcomes. Our findings reveal the association between cathepsin B (CTSB) and an elevated risk of developing UL (all cancers excluded) [Inverse Variance Weighted (IVW) method]: OR = 1.06, 95%CI [1.02, 1.11], P = 0.008895711. Although the association does not persist after multiple testing or Steiger filtering, this finding adds to our understanding of the causal relationship between CTSB of various cathepsins and UL (all cancers excluded) and may herald new therapeutic avenues for individuals affected by this condition.

L-arabinose isomerase from Lactobacillus fermentum C6: Enzymatic characteristics and its recombinant Bacillus subtilis whole cells achieving a significantly increased production of D-tagatose.

L-arabinose isomerase (L-AI) is a functional enzyme for the isomerizing of D-galactose to produce D-tagatose. In this study, L-AI-C6-encoding gene from the probiotic Lactobacillus fermentum C6 was cloned and expressed in Bacillus subtilis WB600 for investigating enzymatic characteristics and bioconverting D-tagatose by means of whole-cell catalysis. Results showed that the engineered B. subtilis WB600-pMA5-LAI achieved a maximum specific activity of L-AI-C6 (232.65 ± 15.54 U/mg protein) under cultivation in LB medium at 28 °C for 40 h. The recombinant L-AI-C6 was purified, and enzymatic characteristics test showed its optimum reaction temperature and pH at 60 °C and 8.0, respectively. In addition, L-AI-C6 exhibited good stability within the pH range of 5.5-9.0. By using B. subtilis WB600-pMA5-LAI cells as whole-cell catalyst, the highest D-tagatose yield reached 42.91 ± 0.28 % with D-galactose as substrate, which was 2.41 times that of L. fermentum C6 (17.79 ± 0.11 %). This suggested that the cloning and heterologous expression of L-AI-C6 was an effective strategy for improving D-tagatose conversion by whole-cell catalysis. In brief, the present study demonstrated that the reaction temperature, pH, and stability of L-AI-C6 from L. fermentum C6 meet the demands of industrial application, and the constructed B. subtilis WB600-pMA5-LAI shows promising potential for the whole-cell biotransformation of D-tagatose.

Structural and spectral properties of Gas-phase FMgn (n = 2-20) clusters based on DFT.

Structure, stability, electronic structure, spectroscopy and chemical bonding properties of a fluorine atom doped gas-phase small to medium-sized magnesium clusters, FMgn (n = 2-20), systematically investigated by CALYPSO software together with density functional theory (DFT). Structural calculations showed that FMgn has a structural diversity which is rarely reported in other magnesium-based clusters before. F atoms were always located in the outer layer of the Mgn host clusters and only two or three Mg atoms surround it. FMg18 was revealed to be supposed to have robust relative stability. Charge transfer and density of states were calculated for analyzing the electronic structure characteristics. Theoretical calculations of IR, Raman and UV-Vis spectra were computed to provide data guidelines for future experimental observations. Finally, the F-Mg and Mg-Mg chemical bonds of the FMgn clusters were analyzed, including the critical bonding points (BCPs) of Laplacian of electron density (Δρ), electron localization function (ELF) and interaction region indicator (IRI). The kind and strength of chemical bonds reveal the mechanism by which the F atom was rapidly stabilized by Mgn (n = 2-20) host clusters.

LNMAC Promotes Cervical Squamous Cell Carcinoma Lymphatic Metastasis via Epigenetic Regulation of FGF2-Induced Lymphangiogenesis.

The lymph node is the most common site of distant metastasis of cervical squamous cell carcinoma (CSCC), which elicits dismal prognosis and limited efficiency for treatment. Elucidation of the mechanisms underlying CSCC lymphatic metastasis would provide potential therapeutic strategies for nodal metastatic of CSCC. Here, based on in vivo lymphatic metastasis screening model, a circular RNA is identified that is termed as lymph node metastasis associated circRNA (LNMAC), is markedly upregulated in lymphatic metastatic CSCC and correlated with lymph node metastasis. Overexpression of LNMAC dramatically augments the metastatic capability of CSCC cells to the lymph node via inducing lymphangiogenesis. Mechanistically, LNMAC epigenetically upregulates fibroblast growth factor 2 (FGF2) expression by directly associating with histone acacetylase 1 (HDAC1), preventing Importin α6/8-mediated nuclear translocation of HDAC1 and eliciting histone H3K27ac-induced FGF2 transcriptional activation. Treatment with 3F12E7, an anti-FGF2 monoclonal antibody, effectively inhibits LNMAC-induced CSCC lymphatic metastasis. Taken together, these findings indicate that LNMAC plays a crucial role in FGF2-mediated lymphangiogenesis and lymphatic metastasis, highlighting that LNMAC might be a therapeutic target for lymph node metastasis in CSCC patients.

Intuitive eating was associated with anxiety, depression, pregnancy weight and blood glucose in women with gestational diabetes mellitus: a prospective longitudinal study.

Background: Outside of pregnancy, intuitive eating (IE) is associated with lower body weight, blood glucose, and higher positive mood. However, little was known about the relationship between IE and anxiety-depression in the GDM population. Thus, this study aimed to investigate the association of IE with anxiety and depression, pregnancy weight and pregnancy blood glucose in the first and second GDM visit. Methods: Data from 310 pregnant women with GDM from the Fujian Maternal and Child Health Hospital Trial (Approval Number: 2020Y9133) were analyzed. IE was assessed using the Intuitive Eating Scale-2 subscales of Eating for Physiological Reasons rather than Emotional Reasons (EPR), Relying on Hunger and Satiety Cues (RHSC) and Body-Food Choice Consistency (B-FCC). Observations included weight, body mass index (BMI), fasting plasma glucose (FPG) and 2-h postprandial blood glucose; the Hospital Anxiety and Depression Scale (HADS) was used to assess the level of anxiety and depression in pregnant women with GDM. Linear regression analysis was used to assess the correlation between IE and anxiety, depression, pregnancy blood glucose and weight. Results: The cross-sectional analysis showed that the EPR eating behavior was negatively correlated with anxiety and depression, and the B-FCC eating behavior was negatively correlated with depression at both the first and second GDM visit; in addition, the B-FCC eating behavior was associated with lower BMI in the third trimester (all p < 0.05). In longitudinal analyses, the EPR eating behavior in the first visit for GDM predicted lower levels of anxiety and depression in the second GDM visit, whereas the RHSC eating behavior in the first visit for GDM was associated with lower FPG in the second GDM visit (all p < 0.01). Conclusion: These results suggest that practicing intuitive eating may be beneficial and that higher intuitive eating adherence can lead to lower levels of anxiety and depression and more ideal gestational weight and blood glucose values.

Validation of IGA*BSA in Assessing Disease Severity and Response in Patients with Atopic Dermatitis: A Retrospective Cohort Study in China.

Background: Accurate evaluation of atopic dermatitis (AD) severity is crucial to determine and adjust treatment options. Previous studies have found the product of Investigator's Global Assessment (IGA) and affected body surface area (BSA) to be a simple tool, which requires further verification. Objective: To determine the validity of IGA*BSA in assessing the severity of AD across all age, sex, BMI and disease severity groups. Method: We performed a retrospective study of AD using data from a national cohort (China Type II Inflammatory Skin Disease Clinical Research and Standardized Diagnosis and Treatment Project). Results: Overall, 3051 participants were included in the final analysis. IGA*BSA correlated better with objective measures than with subjective measures. IGA*BSA significantly correlated with Eczema Area and Severity Index (EASI) (r = 0.81), which was stronger than either IGA or BSA alone with EASI, regardless of age, sex, Body Mass Index (BMI), and disease severity groups. Besides, IGA*BSA mild, moderate, and severe groups were associated with significantly higher scores of other assessments and had moderate to fair concordance with other assessments severity strata. At follow-up, the concordance of improvement between IGA*BSA 50/75/90 and EASI 50/75/90 was observed (ĸ = 0.65, 0.62, 0.58, respectively). Conclusion: IGA*BSA appears to be a valid objective assessment of AD severity and improvement over time across all age, sex, BMI, and disease severity subgroups in the clinical practice.

Association of breast milk-derived arachidonic acid-induced infant gut dysbiosis with the onset of atopic dermatitis.

OBJECTIVE: The specific breast milk-derived metabolites that mediate host-microbiota interactions and contribute to the onset of atopic dermatitis (AD) remain unknown and require further investigation. DESIGN: We enrolled 250 mother-infant pairs and collected 978 longitudinal faecal samples from infants from birth to 6 months of age, along with 243 maternal faecal samples for metagenomics. Concurrently, 239 corresponding breast milk samples were analysed for metabolomics. Animal and cellular experiments were conducted to validate the bioinformatics findings. RESULTS: The clinical findings suggested that a decrease in daily breastfeeding duration was associated with a reduced incidence of AD. This observation inspired us to investigate the effects of breast milk-derived fatty acids. We found that high concentrations of arachidonic acid (AA), but not eicosapentaenoic acid (EPA) or docosahexaenoic acid, induced gut dysbiosis in infants. Further investigation revealed that four specific bacteria degraded mannan into mannose, consequently enhancing the mannan-dependent biosynthesis of O-antigen and lipopolysaccharide. Correlation analysis confirmed that in infants with AD, the abundance of Escherichia coli under high AA concentrations was positively correlated with some microbial pathways (eg, 'GDP-mannose-derived O-antigen and lipopolysaccharide biosynthesis'). These findings are consistent with those of the animal studies. Additionally, AA, but not EPA, disrupted the ratio of CD4/CD8 cells, increased skin lesion area and enhanced the proportion of peripheral Th2 cells. It also promoted IgE secretion and the biosynthesis of prostaglandins and leukotrienes in BALB/c mice fed AA following ovalbumin immunostimulation. Moreover, AA significantly increased IL-4 secretion in HaCaT cells costimulated with TNF-α and INF-γ. CONCLUSIONS: This study demonstrates that AA is intimately linked to the onset of AD via gut dysbiosis.

The parasitic lifestyle of an archaeal symbiont.

DPANN archaea are a diverse group of microorganisms characterised by small cells and reduced genomes. To date, all cultivated DPANN archaea are ectosymbionts that require direct cell contact with an archaeal host species for growth and survival. However, these interactions and their impact on the host species are poorly understood. Here, we show that a DPANN archaeon (Candidatus Nanohaloarchaeum antarcticus) engages in parasitic interactions with its host (Halorubrum lacusprofundi) that result in host cell lysis. During these interactions, the nanohaloarchaeon appears to enter, or be engulfed by, the host cell. Our results provide experimental evidence for a predatory-like lifestyle of an archaeon, suggesting that at least some DPANN archaea may have roles in controlling host populations and their ecology.

Whole-genome resequencing reveals genetic diversity and adaptive evolution in Chinese honeybee (Apis cerana cerana) in Guizhou, China.

Introduction: Guizhou Province, characterized by complex and diverse geographic and climatic environments, has rich genetic resources for the Chinese honeybee (Apis cerana cerana) and is one of the main bee-producing areas in China. However, research on the genetic diversity of Chinese honeybee in the Guizhou region is very limited, despite implications for conservation of biodiversity. Methods: In this study, we analyzed the genetic diversity, differentiation, and selection signals based on 116 Chinese honeybees from 12 regions in Guizhou Province using whole-genome sequencing. Results: We identified 1,400,430 high-quality SNPs across all samples. A population structure analysis revealed two independent genetic subgroups of Chinese honeybees in Guizhou, a Yunnan-Guizhou Plateau population in western Guizhou and a hilly-mountainous population in eastern Guizhou. The average nucleotide diversity (Pi) ranged from 0.00138 to 0.00161 and average expected heterozygosity (He) ranged from 0.2592 to 0.2604. The average genetic differentiation index (F ST) for Chinese honeybees in pairwise comparisons of 12 regions ranged from 0.0094 to 0.0293. There was clear genetic differentiation between the western plateau and the eastern hilly mountainous areas of Guizhou; however, F ST values between the eastern and western populations ranged from 0.0170 to 0.0293, indicating a low degree of differentiation. A genome-wide scan revealed a number of genes under selection in the Yunnan-Guizhou Plateau environment. These genes were related to growth and development, reproduction, and cold resistance, and several candidate genes involved in environmental adaptation were identified, including CTR, MAPK, MAST, HSF, and MKKK. Discussion: The results of the present study provide important theoretical bases for the conservation, evaluation, development, and utilization of genetic resources for Chinese honeybees in the Guizhou region and for further investigations of environmental adaptation and underlying mechanisms in the species.

Evaluation of Neonatal Cerebral Circulation Under Hypoxic Ischemic Risk Factors Based on Quantitative Analysis of Cerebral Veins with Magnetic Resonance Susceptibility Weighted Imaging.

PURPOSE: To observe the regulation of cerebral circulation in vivo based on image segmentation algorithms for deep learning in medical imaging to automatically detect and quantify the neonatal deep medullary veins (DMVs) on susceptibility weighted imaging (SWI) images. To evaluate early cerebral circulation self-rescue for neonates undergoing risk of cerebral hypoxia-ischaemia in vivo. METHODS: SWI images and clinical data of 317 neonates with or without risk of cerebral hypoxia-ischaemia were analyzed. Quantitative parameters showing the number, width, and curvature of DMVs were obtained using an image segmentation algorithm. RESULTS: The number of DMVs was greater in males than in females (p < 0.01), and in term than in preterm infants (p = 0.001). The width of DMVs was greater in term than in preterm infants (p < 0.01), in low-risk than in high-risk group (p < 0.01), and in neonates without intracranial extracerebral haemorrhage (ICECH) than with ICECH (p < 0.05). The curvature of DMVs was greater in term than in preterm infants (P < 0.05). The width of both bilateral thalamic veins and anterior caudate nucleus veins were positively correlated with the number of DMVs; the width of bilateral thalamic veins was positively correlated with the width of DMVs. CONCLUSION: The DMVs quantification based on image segmentation algorithm may provide more detailed and stable quantitative information in neonate. SWI vein quantification may be an observable indicator for in vivo assessment of cerebral circulation self-regulation in neonatal hypoxic-ischemic brain injury.

No association between hepatitis C virus infection and risk of colorectal cancer: a systematic review and meta-analysis of cohort studies.

Background and aim: There is still uncertainty regarding whether hepatitis C virus (HCV) infection is associated with colorectal cancer (CRC). This study aims to investigate the potential association between HCV infection and CRC through a systematic review and meta-analysis of cohort studies. Methods: PubMed, Embase, and Web of Science were systematically searched from the beginning of their inception to October 2023 to find relevant cohort studies on the association between HCV infection and CRC risk. The random-effect, generic inverse variance method was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC outcome among individuals with HCV infection. We also performed subgroup and sensitivity analysis. Results: A total of 8 cohort studies involving 1,939,164 participants were included in this meta-analysis. The result from the meta-analysis suggested that there was no statistically significant association between HCV and the risk of developing CRC (HR = 0.99, 95% CI: 0.82-1.88, p = 0.88) with low statistical heterogeneity (I2 = 28%, p = 0.20). Subgroup analyses that were conducted based on study design, diagnosis of HCV infection, and publication year yielded similar results. Analyses of subgroups based on study areas revealed that there was no significant association between HCV infection and CRC risk in Asia (n = 2, HR = 0.96, 95% CI: 0.71-1.29, p = 0.79; I2 = 26%), Europe (n = 3, HR = 1.06, 95% CI: 0.83-1.37, p = 0.63; I2 = 0%), and North America (n = 2, HR = 1.10, 95% CI: 0.87-1.38, p = 0.44; I2 = 0%); however, a negative correlation was found in Oceania (n = 1, HR = 0.43, 95% CI: 0.22-0.84, p = 0.01). Sensitivity analysis further reinforce the stability of our conclusion. Conclusion: Our cohort-based meta-analysis showed insufficient evidence to support the association between HCV infection and an increased risk of CRC. To gain a clearer insight into the potential association between these two conditions, it would be beneficial to conduct large, well-designed, high-quality prospective cohort studies that consider different ethnic populations and potential confounding factors.Systematic review registration: PROSPERO, identifier [CRD42023472688], https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023472688.

Exploring the Molecular Characteristics and Role of PDGFB in Testis and Epididymis Development of Tibetan Sheep.

Platelet-derived growth factor B (PDGFB), as an important cellular growth factor, is widely involved in the regulation of cellular events such as cell growth, proliferation, and differentiation. Although important, the expression characteristics and biological functions in the mammalian reproductive system remain poorly understood. In this study, the PDGFB gene of Tibetan sheep was cloned by RT-PCR, and its molecular characteristics were analyzed. Subsequently, the expression of the PDGFB gene in the testes and epididymides (caput, corpus, and cauda) of Tibetan sheep at different developmental stages (3 months, 1 year, and 3 years) was examined by qRT-PCR and immunofluorescence staining. A bioinformatic analysis of the cloned sequences revealed that the CDS region of the Tibetan sheep PDGFB gene is 726 bp in length and encodes 241 amino acids with high homology to other mammals, particularly goats and antelopes. With the increase in age, PDGFB expression showed an overall trend of first decreasing and then increasing in the testis and epididymis tissues of Tibetan sheep, and the PDGFB mRNA expression at 3 months of age was extremely significantly higher than that at 1 and 3 years of age (p < 0.05). The PDGFB protein is mainly distributed in testicular red blood cells and Leydig cells in Tibetan sheep at all stages of development, as well as red blood cells in the blood vessel, principal cells, and the pseudostratified columnar ciliated epithelial cells of each epididymal duct epithelium. In addition, PDGFB protein expression was also detected in the spermatocytes of the 3-month-old group, spermatids of the 1-year-old group, spermatozoa and interstitial cells of the 3-year-old group, and loose connective tissue in the epididymal duct space in each developmental period. The above results suggest that the PDGFB gene, as an evolutionarily conserved gene, may play multiple roles in the development and functional maintenance of testicular cells (such as red blood cells, Leydig cells, and germ cells) and epididymal cells (such as red blood cells, principal cells, and ciliated epithelial cells) during testicular and epididymal development, which lays a foundation for the further exploration of the mechanisms by which the PDGFB gene influences spermatogenesis in Tibetan sheep.

Incidence and clinical analysis of asymptomatic intracranial hemorrhage in neonates with cerebral hypoxic-ischaemic risk based on multisequence MR images.

The incidence and clinical distribution of intracranial haemorrhage (ICH) in neonates at risk of cerebral hypoxia-ischaemia have not been reported in specific studies. Based on conventional magnetic resonance imaging (MRI) versus susceptibility weighted imaging (SWI), this study aimed to analyse the occurrence of asymptomatic ICH in newborns with or without risk of cerebral hypoxia-ischaemia and to accumulate objective data for clinical evaluations of high-risk neonates and corresponding response strategies. 317 newborns were included. MRI revealed that the overall incidence of ICH was 59.31%. The most common subtype was intracranial extracerebral haemorrhage (ICECH) which included subarachnoid haemorrhage (SAH) and subdural haemorrhage (SDH). ICECH accounted for 92.02% of ICH. The positive detection rate of ICECH by SWI was significantly higher than that by T1WI. The incidence of total ICH, ICECH and SAH was greater among children who were delivered vaginally than among those who underwent caesarean delivery. Asymptomatic neonatal ICH may be a common complication of the neonatal birth process, and SWI may improve the detection rate. Transvaginal delivery and a weight greater than 2500 g were associated with a high incidence of ICECH in neonates. The impact of neonatal cerebral hypoxia-ischaemia risk factors on the occurrence of asymptomatic ICH may be negligible.

ACE2: the node connecting the lung cancer and COVID-19.

Angiotensin-converting Enzyme 2 (ACE2) collaborates with Angiotensin (Ang) 1-7 and Mas receptors to establish the ACE2-Ang (1-7)-Mas receptor axis. ACE2 impacts lung function and can cause lung injury due to its inflammatory effects. Additionally, ACE2 contributes to pulmonary vasculature dysfunction, resulting in pulmonary hypertension. In addition, ACE2 is a receptor for coronavirus entry into host cells, leading to coronavirus infection. Lung cancer, one of the most common respiratory diseases worldwide, has a high rate of infection. Elevated levels of ACE2 in lung cancer patients, which increase the risk of SARS-CoV-2 infection and severe disease, have been demonstrated in clinical studies and by molecular mechanisms. The association between lung cancer and SARS-CoV-2 is closely linked to ACE2. This review examines the basic pathophysiological role of ACE2 in the lung, the long-term effects of SARS-CoV-2 infection on lung function, the development of pulmonary fibrosis, chronic inflammation in long-term COVID patients, and the clinical research and mechanisms underlying the increased susceptibility of lung cancer patients to the virus. Possible mechanisms of lung cancer in SARS-CoV-2-infected individuals and the potential role of ACE2 in this process are also explored in this review. The role of ACE2 as a therapeutic target in the novel coronavirus infection process is also summarized. This will help to inform prevention and treatment of long-term pulmonary complications in patients.

TRPC6 Knockout Alleviates Renal Fibrosis through PI3K/AKT/GSK3B Pathway.

OBJECTIVE: Renal fibrosis is the ultimate pathway of various forms of acute and chronic kidney damage. Notably, the knockout of transient receptor potential channel 6 (TRPC6) has shown promise in alleviating renal fibrosis. However, the regulatory impact of TRPC6 on renal fibrosis remains unclear. METHODS: In vivo, TRPC6 knockout (TRPC6-/-) mice and age-matched 129 SvEv (WT) mice underwent unilateral renal ischemia-reperfusion (uIR) injury surgery on the left renal pedicle or sham operation. Kidneys and serum were collected on days 7, 14, 21, and 28 after euthanasia. In vitro, primary tubular epithelial cells (PTECs) were isolated from TRPC6-/- and WT mice, followed by treatment with transforming growth factor ß1 (TGFß1) for 72 h. The anti-fibrotic effect of TRPC6-/- and the underlying mechanisms were assessed through hematoxylin-eosin staining, Masson staining, immunostaining, qRT-PCR, and Western blotting. RESULTS: Increased TRPC6 expression was observed in uIR mice and PTECs treated with TGFß1. TRPC6-/- alleviated renal fibrosis by reducing the expression of fibrotic markers (Col-1, α-SMA, and vimentin), as well as decreasing the apoptosis and inflammation of PTECs during fibrotic progression both in vivo and in vitro. Additionally, we found that the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase 3 beta (GSK3ß) signaling pathway, a pivotal player in renal fibrosis, was down-regulated following TRPC6 deletion. CONCLUSION: These results suggest that the ablation of TRPC6 may mitigate renal fibrosis by inhibiting the apoptosis and inflammation of PTECs through down-regulation of the PI3K/AKT/GSK3ß pathway. Targeting TRPC6 could be a novel therapeutic strategy for preventing chronic kidney disease.

Ultrastructural insights into cellular organization, energy storage and ribosomal dynamics of an ammonia-oxidizing archaeon from oligotrophic oceans.

Introduction: Nitrososphaeria, formerly known as Thaumarchaeota, constitute a diverse and widespread group of ammonia-oxidizing archaea (AOA) inhabiting ubiquitously in marine and terrestrial environments, playing a pivotal role in global nitrogen cycling. Despite their importance in Earth's ecosystems, the cellular organization of AOA remains largely unexplored, leading to a significant unanswered question of how the machinery of these organisms underpins metabolic functions. Methods: In this study, we combined spherical-chromatic-aberration-corrected cryo-electron tomography (cryo-ET), scanning transmission electron microscopy (STEM), and energy dispersive X-ray spectroscopy (EDS) to unveil the cellular organization and elemental composition of Nitrosopumilus maritimus SCM1, a representative member of marine Nitrososphaeria. Results and Discussion: Our tomograms show the native ultrastructural morphology of SCM1 and one to several dense storage granules in the cytoplasm. STEM-EDS analysis identifies two types of storage granules: one type is possibly composed of polyphosphate and the other polyhydroxyalkanoate. With precise measurements using cryo-ET, we observed low quantity and density of ribosomes in SCM1 cells, which are in alignment with the documented slow growth of AOA in laboratory cultures. Collectively, these findings provide visual evidence supporting the resilience of AOA in the vast oligotrophic marine environment.

GPX4, ferroptosis, and diseases.

GPX4 (Glutathione peroxidase 4) serves as a crucial intracellular regulatory factor, participating in various physiological processes and playing a significant role in maintaining the redox homeostasis within the body. Ferroptosis, a form of iron-dependent non-apoptotic cell death, has gained considerable attention in recent years due to its involvement in multiple pathological processes. GPX4 is closely associated with ferroptosis and functions as the primary inhibitor of this process. Together, GPX4 and ferroptosis contribute to the pathophysiology of several diseases, including sepsis, nervous system diseases, ischemia reperfusion injury, cardiovascular diseases, and cancer. This review comprehensively explores the regulatory roles and impacts of GPX4 and ferroptosis in the development and progression of these diseases, with the aim of providing insights for identifying potential therapeutic strategies in the future.