A methodology designed to eliminate mitotic inhibitor action and involving use of pretested fetal calf serum and careful pH and temperature control has been described by which cells from normal human and animal tissue can be maintained in active growth for long periods in vitro without development of aneuploidy. By means of this procedure, it is possible reliably to establish cell cultures from minute skin biopsies which can be taken from any individual. Clones of mammalian cells with chromosomal markers have been isolated by this means from x-irradiated non-irradiated cell cultures. Application of these techniques to chromosome delineation in large numbers of human subjects; determination of chromosomal sex in patients; spontaneuos and induced genetic changes in somatic mammalian cells in vivo and in vitro; comparison of metabolic differences between normal and cancerous cells and other problems have been indicated.
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the synovial membrane, leading to cartilage destruction and bone erosion. Due to the complex pathogenesis of RA and the limitations of current therapies, increasing research attention has been directed towards novel strategies targeting fibroblast-like synoviocytes (FLS), which are key cellular components of the hyperplastic pannus. Recent studies have highlighted the pivotal role of FLS in the initiation and progression of RA, driven by their tumour-like transformation and the secretion of pro-inflammatory mediators, including cytokines, chemokines and matrix metalloproteinases. The aggressive phenotype of RA-FLS is marked by excessive proliferation, resistance to apoptosis, and enhanced migratory and invasive capacities. Consequently, FLS-targeted therapies represent a promising avenue for the development of next-generation RA treatments. The efficacy of such strategies – particularly those aimed at modulating FLS signalling pathways – has been demonstrated in both preclinical and clinical settings, underscoring their therapeutic potential. This review provides an updated overview of the pathogenic mechanisms and functional roles of FLS in RA, with a focus on critical signalling pathways under investigation, including Janus kinase/signal transducer and activator of transcription (JAK/STAT), mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-κB), Notch and interleukin-1 receptor-associated kinase 4 (IRAK4). In addition, we discuss the emerging understanding of FLS-subset-specific contributions to immunometabolism and explore how computational biology is shaping novel targeted therapeutic strategies. A deeper understanding of the molecular and functional heterogeneity of FLS may pave the way for more effective and precise therapeutic interventions in RA.
As a traditional Chinese medicinal herb with a long history, Codonopsis pilosula (CP) has attracted much attention from the medical community in recent years. This review summarizes the research progress of CP in the medical field in the past 5 years. By searching and analyzing the literature, and combining with Cytoscape software, we comprehensively examined the role and mechanism of action of CP in individual application, combination drug application, and the role and mechanism of action of codonopsis pilosula’s active ingredients in a variety of diseases. It also analyzes the medicinal use of CP and its application value in medicine. This review found that CP mainly manifests important roles in several diseases, such as cardiovascular system, nervous system, digestive system, immune system, etc., and regulates the development of many diseases mainly through the mechanisms of inflammation regulation, oxidative stress, immunomodulation and apoptosis. Its rich pharmacological activities and diverse medicinal effects endow CP with broad prospects and application values. This review provides valuable reference and guidance for the further development of CP in traditional Chinese medicine.
Abstract Background Cancer stem-like cells (CSCs) have been extensively researched as the primary drivers of therapy resistance and tumor relapse in patients with breast cancer. However, due to lack of specific molecular markers, increased phenotypic plasticity and no clear clinicopathological features, the assessment of CSCs presence and functionality in solid tumors is challenging. While several potential markers, such as CD24/CD44, have been proposed, the extent to which they truly represent the stem cell potential of tumors or merely provide static snapshots is still a subject of controversy. Recent studies have highlighted the crucial role of the tumor microenvironment (TME) in influencing the CSC phenotype in breast cancer. The interplay between the tumor and TME induces significant changes in the cancer cell phenotype, leading to the acquisition of CSC characteristics, therapeutic resistance, and metastatic spread. Simultaneously, CSCs actively shape their microenvironment by evading immune surveillance and attracting stromal cells that support tumor progression. Methods In this study, we associated in vitro mammosphere formation assays with bulk tumor microarray profiling and deconvolution algorithms to map CSC functionality and the microenvironmental landscape in a large cohort of 125 breast tumors. Results We found that the TME score was a significant factor associated with CSC functionality. CSC-rich tumors were characterized by an immune-suppressed TME, while tumors devoid of CSC potential exhibited high immune infiltration and activation of pathways involved in the immune response. Gene expression analysis revealed IFNG, CXCR5, CD40LG, TBX21 and IL2RG to be associated with the CSC phenotype and also displayed prognostic value for patients with breast cancer. Conclusion These results suggest that the characterization of CSCs content and functionality in tumors can be used as an attractive strategy to fine-tune treatments and guide clinical decisions to improve patients therapy response.
Samuel G. Jacobson, Artur V. Cideciyan, Allen C. Ho
et al.
Summary: Signaling of vision to the brain starts with the retinal phototransduction cascade which converts visible light from the environment into chemical changes. Vision impairment results when mutations inactivate proteins of the phototransduction cascade. A severe monogenically inherited blindness, Leber congenital amaurosis (LCA), is caused by mutations in the GUCY2D gene, leading to a molecular defect in the production of cyclic GMP, the second messenger of phototransduction. We studied two patients with GUCY2D-LCA who were undergoing gene augmentation therapy. Both patients had large deficits in rod photoreceptor-based night vision before intervention. Within days of therapy, rod vision in both patients changed dramatically; improvements in visual function and functional vision in these hyper-responding patients reached more than 3 log10 units (1000-fold), nearing healthy rod vision. Quick activation of the complex molecular pathways from retinal photoreceptor to visual cortex and behavior is thus possible in patients even after being disabled and dormant for decades.
BackgroundAspartate aminotransferase-to-alanine transaminase ratio (AST/ALT) has been reported affect the risk of type 2 diabetes (T2DM), but it is uncertain if it has relationship with gestational diabetes mellitus (GDM).ObjectivesOur study aimed to investigate the association between AST/ALT ratio in the first trimester and the risk of subsequent development of GDM.MethodThis prospective cohort study enrolling 870 pregnant women, 204 pregnant women with missing data or liver diseases were excluded, 666 pregnant women were included in this study containing 94 GDM women. Blood samples were collected in the first trimester. Univariate analysis and multivariate logistic regression were used to evaluate the association between AST/ALT and GDM. Nomogram was established based on the results of multivariate logistic analysis. Receiver Operating Characteristic (ROC) curves and calibration curves were used to evaluate the predictive ability of this nomogram model for GDM. Decision curve analysis (DCA) was used to examine the clinical net benefit of predictive model.ResultsAST/ALT ratio (RR:0.228; 95% CI:0.107-0.488) was associated with lower risk of GDM after adjusting for confounding factors. Indicators used in nomogram including AST/ALT, maternal age, preBMI, waist circumference, glucose, triglycerides, high density lipoprotein cholesterol and parity. The area under the ROC curve (AUC) value of this predictive model was 0.778, 95% CI (0.724, 0.832). Calibration curves for GDM probabilities showed acceptable agreement between nomogram predictions and observations. The DCA curve demonstrated a good positive net benefit in the predictive model.ConclusionsThe early AST/ALT level of pregnant women negatively correlated with the risk of GDM. The nomogram including AST/ALT at early pregnancy shows good predictive ability for the occurrence of GDM.
Diseases of the endocrine glands. Clinical endocrinology
Summary: How organisms cope with coldness and high pressure in the hadal zone remains poorly understood. Here, we sequenced and assembled the genome of hadal sea cucumber Paelopatides sp. Yap with high quality and explored its potential mechanisms for deep-sea adaptation. First, the expansion of ACOX1 for rate-limiting enzyme in the DHA synthesis pathway, increased DHA content in the phospholipid bilayer, and positive selection of EPT1 may maintain cell membrane fluidity. Second, three genes for translation initiation factors and two for ribosomal proteins underwent expansion, and three ribosomal protein genes were positively selected, which may ameliorate the protein synthesis inhibition or ribosome dissociation in the hadal zone. Third, expansion and positive selection of genes associated with stalled replication fork recovery and DNA repair suggest improvements in DNA protection. This is the first genome sequence of a hadal invertebrate. Our results provide insights into the genetic adaptations used by invertebrate in deep oceans.
Mateus Neri Oliveira Reis, Luciana Cristina Vitorino, Lucas Loram Lourenço
et al.
Considering a scenario where there is a low availability and increasing costs of fertilizers in the global agricultural market, as well as a finitude of important natural resources, such as phosphorus (P), this study tested the effect of the inoculation of rhizospheric or endophytic microorganisms isolated from <i>Hymenaea courbaril</i> and <i>Butia purpurascens</i> on the growth promotion of <i>Glycine max</i> (L.) Merr. The tests were conducted in a controlled greenhouse system, and the effects of biofertilization were evaluated using the following parameters: dry biomass, nutritional content, and photochemical and photosynthetic performance of plants. Seed biopriming was performed with four bacterial and four fungal isolates, and the results were compared to those of seeds treated with the commercial product Biomaphos<sup>®</sup>. Overall, microbial inoculation had a positive effect on biomass accumulation in <i>G. max</i>, especially in strains PA12 (<i>Paenibacillus alvei</i>), SC5 (<i>Bacillus cereus</i>), and SC15 (<i>Penicillium sheari</i>). The non-inoculated control plants accumulated less nutrients, both in the whole plant and aerial part, and had reduced chlorophyll index and low photosynthetic rate (<i>A</i>) and photochemical efficiency. Strains PA12 (<i>P. alvei</i>), SC5 (<i>B. cereus</i>), and 328EF (<i>Codinaeopsis</i> sp.) stood out in the optimization of nutrient concentration, transpiration rate, and stomatal conductance. Plants inoculated with the bacterial strains PA12 (<i>P. alvei</i>) and SC5 (<i>B. cereus</i>) and with the fungal strains 328EF (<i>Codinaeopsis</i> sp.) and SC15 (<i>P. sheari</i>) showed the closest pattern to that observed in plants treated with Biomaphos<sup>®</sup>, with the same trend of direction of the means associated with chlorophyll index, (<i>A</i>), dry mass, and concentration of important nutrients such as N, P, and Mg. We recommend the use of these isolates in field tests to validate these strains for the production of biological inoculants as part of the portfolio of bioinputs available for <i>G. max</i>.
Among Chinese soft-shelled turtles, <i>Pelodiscus sinensis</i>, males have a richer nutritional value and higher market price than females. All-male offspring were obtained by 17β-estradiol (E2). However, the molecular mechanisms of E2 inducing sexual reversal remain unclear. In this study, we cloned estrogen nuclear receptors (ERs) from <i>P. sinensis</i> and investigated their expression profiles. We examined the responses of ERα and ERβ after treatment with different concentrations of 1.0, 5.0, and 10 mg/mL E2. ERs showed abundant expressions in the adult gonad, <i>ERα</i> for ovary, and <i>ERβ</i> for testis. E2 can up-regulate the expression of <i>ERα</i>, which showed a remarkable increase while the promotion of <i>ERβ</i> was unobvious. They reached a high level at stage 17 after the treatment of E2, genes of the female-related genes <i>Rspo1</i>, <i>Wnt4</i>, β-catenin, <i>Foxl2</i>, <i>Cyp19a1,</i> and <i>Sox3</i> exhibited a significant raise at stage 17 with the increase in the concentration of E2 while the male-related genes <i>Sox9</i>, <i>Dmrt1</i>, and <i>Amh</i> were significantly inhibited. Our study cloned the full length of ERs and analyzed their structures and expressions, laying a foundation for the further study of the effect of estrogen on sex determination.
Murtaza S Nagree, Tania C Felizardo, Mary L Faber
et al.
Abstract T cells are the current choice for many cell therapy applications. They are relatively easy to access, expand in culture, and genetically modify. Rapamycin‐conditioning ex vivo reprograms T cells, increasing their memory properties and capacity for survival, while reducing inflammatory potential and the amount of preparative conditioning required for engraftment. Rapamycin‐conditioned T cells have been tested in patients and deemed to be safe to administer in numerous settings, with reduced occurrence of infusion‐related adverse events. We demonstrate that ex vivo lentivirus‐modified, rapamycin‐conditioned CD4+ T cells can also act as next‐generation cellular delivery vehicles—that is, “micropharmacies”—to disseminate corrective enzymes for multiple lysosomal storage disorders. We evaluated the therapeutic potential of this treatment platform for Fabry, Gaucher, Farber, and Pompe diseases in vitro and in vivo. For example, such micropharmacies expressing α‐galactosidase A for treatment of Fabry disease were transplanted in mice where they provided functional enzyme in key affected tissues such as kidney and heart, facilitating clearance of pathogenic substrate after a single administration.