Identification of hub genes and key modules in laryngeal squamous cell carcinoma.

Background: Laryngeal squamous cell carcinoma (LSCC) is the prominent cancer in head and neck, which greatly affects life quality of patients. The pathogenesis of LSCC is not clear. Presently, the LSCC treatments include chemotherapy, surgery and radiotherapy; however, these methods have poor efficacy in patients with recurrent and persistent cancer. Therefore, the study identified the hub genes accompanied with LSCC, which may be a potential therapeutic target in the future. Methods: We extracted whole transcriptome high-throughput sequencing (HTS) LSCC data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and calculate differentially expressed genes (DEGs) between LSCC and normal samples using statistical software RStudio. Through weighted gene co-expression network analysis (WGCNA), enrichment examination of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) functions, and examination of protein-protein interaction (PPI) network, we obtained network hub genes and validated the hub genes prognostic value and expression levels of protein. Results: Through analysis of differential gene expression, from the GEO and TCGA databases 2,139 and 2,774 DEGs were obtained, respectively, 13 and 15 modules were screened from TCGA-LSCC and GSE127165 datasets by WGCNA, respectively. The most significant positive and negative correlation modules in the WGCNA and DEG lists were overlapped, and overall 36 co-expressed overlapping genes were retrieved. Through enrichment analysis of GO and KEGG, it was found that the gene functions were highly concentrated in cell junction assembly, basement membrane, extracellular matrix (ECM) structural constituent etc., and the pathways were mainly concentrated in ECM receptor interaction, focal adhesion, small cell lung cancer, and toxoplasmosis. Through analysis of PPI network analysis, 10 network hub genes (SNAI2, ITGA6, LAMB3, LAMC2, CAV1, COL7A1, GJA1, EHF, OAT, and GPT) were obtained. Finally, survival analysis and protein expression validation of these genes confirmed that low OAT expression and high CAV1 expression remarkably influenced the survival of patient's prognosis with LSCC. Conclusions: We recognized the hub genes and key modules nearly associated to LSCC and these genes were validated by survival analysis and the database of Human Protein Atlas (HPA), which is of high importance for unveiling the pathogenesis of LSCC and probing for new precise biological marker and potential therapeutic targets.

Measurable residual disease (MRD)-testing in haematological cancers: A giant leap forward or sideways?

Measurable residual disease (MRD)-testing is used in many haematological cancers to estimate relapse risk and to direct therapy. Sometimes MRD-test results are used for regulatory approval. However, some people including regulators wrongfully believe results of MRD-testing are highly accurate and of proven efficacy in directing therapy. We review MRD-testing technologies and evaluate the accuracy of MRD-testing for predicting relapse and the strength of evidence supporting efficacy of MRD-guided therapy. We show that at the individual level MRD-test results are often an inaccurate relapse predictor. Also, no convincing data indicate that increasing therapy-intensity based on a positive MRD-test reduces relapse risk or improves survival. We caution against adjusting therapy-intensity based solely on results of MRD-testing.

Sirt1 m6A modification-evoked Leydig cell senescence promotes Cd-induced testosterone decline.

Diminished testosterone levels have been documented as a key factor in numerous male health disorders. Both human and animal studies have consistently demonstrated that cadmium (Cd), a pervasive environmental heavy metal, results in decreased testosterone levels. However, the exact mechanism through which Cd interferes with testosterone synthesis remains incompletely elucidated. This research sought to examine the impact of cellular senescence on Cd-suppressed testosterone synthesis. We also investigated the related m6A modification mechanism. The results demonstrated that Cd (100 mg/L) led to a decrease in testosterone levels, along with downregulated expression of testosterone synthase in C57BL/6 N male mice. Furthermore, Cd significantly increased ß-galactosidase staining intensity, senescence-related proteins, and senescence-related secretory phenotypes in mouse testicular Leydig cells. Subsequent investigations revealed that Cd decreased the mRNA and protein levels of NAD-dependent deacetylase Sirtuin-1 (SIRT1) in Leydig cells. Mechanistically, mice treated with resveratrol (50 mg/kg), a specific SIRT1 activator, mitigated Leydig cell senescence and reversed Cd-reduced testosterone levels in mouse testes. These effects were also restored by SIRT1 overexpression in Leydig cells. Additionally, we found that Cd increased the level of methyltransferase enzyme METTL3 and Sirt1 m6A modification in Leydig cells. Mettl3 siRNA effectively restored Cd-enhanced Sirt1 m6A level and reversed Cd-downregulated Sirt1 mRNA expression in Leydig cells. Overall, our findings suggest that Cd exposure inhibits testosterone synthesis via Sirt1 m6A modification-mediated senescence in mouse testes. These results offer an experimental basis for investigating the causes and potential treatments of hypotestosteronemia induced by environmental factors.

Importance of Morphology of Layered Double Hydroxide in Electrochemical Energy Storage and Catalysis.

The development of nanomaterials for energy storage and conversion has always been important. Layered double hydroxide (LDH) is a promising material due to its high capacity, tunable composition and easy synthesis. In this work, the morphology of NiCo-LDH is tuned with surfactants including sodium dodecyl sulfate (SDS) and cetyltrimethylammonium bromide (CTAB), and investigated the correlation between morphology and electrochemical properties. NiCo-LDH-SDS with a layered structure exhibited a specific capacitance of 1004 C g-1 at 1 A g-1, which is higher than that of the needle-like NiCo-LDH-CTAB (678 C g-1) and the rod-like NiCo-LDH (279 C g-1). Meanwhile, NiCo-LDH-SDS and NiCo-LDH-CTAB showed a reduction of 36 and 19 mV, respectively, in their overpotentials at 10 mA cm-2 compared to NiCo-LDH. Contact angle and adhesive force measurements proved the influence of morphology on the interfacial properties that layered structure is favorable for the timely detachment of the bubbles. Therefore, rational morphology regulation of LDH can effectively alter the gas-liquid-solid interface and thereby accelerate the reaction kinetics. The connections between morphologies, bubbles releasing and electrochemical performance are well established in this work, which can be applied in the investigation of nanomaterials for energy-related activities, especially the ones concerning bubbles releasing processes.

Association between sinus septa and lateral wall thickness with risk of perforation during maxillary sinus lift surgery: A systematic review and meta-analysis.

OBJECTIVE: Sinus membrane perforation is a common complication of sinus lift surgery. This review aimed to examine if anatomical factors such as the presence of septa and lateral wall thickness influence the risk of membrane perforation. METHODS: This study was registered on PROSPERO (CRD42023488259). PubMed, Embase, and Web of Science were searched for relevant studies published up to 26th June 2024. The outcome of interest was the risk of perforation based on presence of septa and lateral wall thickness. Random-effects meta-analysis was conducted with dichotomous data to obtain the odds ratio (OR) of perforation using Review Manager. RESULTS: Ten studies with 1865 patients undergoing 2168 "lateral" sinus lift procedures were included. The total incidence of Schneiderian membrane perforations was 19% (405 cases). Schneiderian membrane perforation was present in 169/425 cases (39.76%) with sinus septa and 184/1492 cases (12.33%) without septa. Meta-analysis showed that septa were significantly associated with an increased risk of perforation (OR: 4.03 95% CI: 1.77, 9.19) with high heterogeneity (I2 = 87%). The certainty of the evidence was very low. Data on lateral wall thickness and risk of perforation was too heterogeneous for a meta-analysis. Studies reported mixed results on the risk of perforation based on lateral wall thickness. CONCLUSIONS: Our results show, with very low-quality evidence, that the presence of septa significantly increases the risk of perforations during maxillary sinus lift surgery. Evidence on the association between lateral wall thickness and a risk of perforations during sinus lift surgery is conflicting, and no clear conclusions can be derived at this stage.

A Real-World Study on the Short-Term Efficacy of Amlodipine in Treating Hypertension Among Inpatients.

Purpose: Hospitalized hypertensive patients rely on blood pressure medication, yet there is limited research on the sole use of amlodipine, despite its proven efficacy in protecting target organs and reducing mortality. This study aims to identify key indicators influencing the efficacy of amlodipine, thereby enhancing treatment outcomes. Patients and Methods: In this multicenter retrospective study, 870 hospitalized patients with primary hypertension exclusively received amlodipine for the first 5 days after admission, and their medical records contained comprehensive blood pressure records. They were categorized into success (n=479) and failure (n=391) groups based on average blood pressure control efficacy. Predictive models were constructed using six machine learning algorithms. Evaluation metrics encompassed the area under the curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). SHapley Additive exPlanations (SHAP) analysis assessed feature contributions to efficacy. Results: All six machine learning models demonstrated superior predictive performance. Following variable reduction, the model predicting amlodipine efficacy was reconstructed using these algorithms, with the light gradient boosting machine (LightGBM) model achieving the highest overall performance (AUC = 0.803). Notably, amlodipine showed enhanced efficacy in patients with low platelet distribution width (PDW) values, as well as high hematocrit (HCT) and thrombin time (TT) values. Conclusion: This study utilized machine learning to predict amlodipine's effectiveness in hypertension treatment, pinpointing key factors: HCT, PDW, and TT levels. Lower PDW, along with higher HCT and TT, correlated with enhanced treatment outcomes. This facilitates personalized treatment, particularly for hospitalized hypertensive patients undergoing amlodipine monotherapy.

Correlation of internalized stigma with self-esteem, social support and coping styles in patients with rheumatoid arthritis: A cross-sectional study.

AIM: To understand the status of internalized stigma in patients with rheumatoid arthritis (RA) and explore its relationship with self-esteem, social support, and coping style. METHODS: This cross-sectional study selected patients with RA who visited the Rheumatology and Immunology Department of a tertiary hospital from May 2022 to May 2023. The Chinese versions of the Internalized Stigma of Mental Illness Scale-Rheumatoid Arthritis (ISMI-RA), Social Support Rating Scale, Rosenberg Self-Esteem Scale, and Medical Coping Style Questionnaire were administered to assess the internalized stigma, social support, self-esteem, and coping styles, respectively. The Pearson correlation test or Spearman rank correlation was then used to analyze the correlation between these measures. RESULTS: Overall, 69.5% participants reported high level of internalized stigma. The average age of the 174 participants was 52.67 ± 12.24 years, with 87.36 per cent female patients. The mean ISMI-RA score was 54.49 ± 9.62, and the ISMI-RA subscale with the highest average score was alienation. The Pearson's correlations show that internalized stigma was positively associated with the coping styles of avoidance (r = .212, p < .01) and acceptance (r = .560, p < .01), and that internalized stigma was negatively associated with the coping styles of confrontation (r = -.479, p < .01), social support (r = -.570, p < .01), and self-esteem(r = -.512, p < .05). CONCLUSION: The high level of internalized stigma in RA patients suggests that we should develop interventions to improve patients' self-esteem, encourage them to adopt positive coping styles, and gain more social support for them, so as to alleviate their internalized stigma.

Electrooxidative 1,3-Oxo/Carboamination of Arylcyclopropanes.

Herein, the work demonstrates an electrochemically paired electrolysis approach facilitating the efficient achievement of the electrooxidative 1,3-oxo/carboamination of arylcyclopropanes under mild conditions. The formation of 1,3-arylamination of arylcyclopropanes involves commercially available amine redox mediators through a radical-radical process. In addition, the successful execution of ß-amino ketones also occurs under atmospheric conditions. The control experiments supported the existence of key benzylic radical intermediates in the reaction pathway.

Can we reach consensus on the dominant sulfate formation pathway in China's haze?

Atmospheric sulfate aerosols contribute significantly to air pollution and climate change. Sulfate formation mechanisms during winter haze events in northern China have recently received considerable attention, with more than 10 studies published in high-impact journals. However, the conclusions from in-field measurements, laboratory studies, and numerical simulations are inconsistent and even contradictory. Here, we propose a physically based yet simple method to clarify the debate on the dominant sulfate formation pathway. Based on the hazes evolving in the synoptic scale, first, a characteristic sulfate formation rate is derived using the Eulerian mass conservation equation constrained by in situ observations. Then, this characteristic value is treated as a guideline to determine the dominant sulfate formation pathway with a 0D chemical box model. Our observation-derived results establish a linkage between studies from laboratory experiments and chemical transport model simulations. A convergent understanding could therefore be reached on sulfate formation mechanisms in China's wintertime haze. This method is universal and can be applied to various haze conditions and different secondary products.

Adipose tissue in older individuals: a contributing factor to sarcopenia.

Sarcopenia is a geriatric syndrome characterized by a functional decline in muscle. The prevalence of sarcopenia increases with natural aging, becoming a serious health problem among elderly individuals. Therefore, understanding the pathology of sarcopenia is critical for inhibiting age-related alterations and promoting health and longevity in elderly individuals. The development of sarcopenia may be influenced by interactions between visceral and subcutaneous adipose tissue and skeletal muscle, particularly under conditions of chronic low-grade inflammation and metabolic dysfunction. This hypothesis is supported by the following observations: (i) accumulation of senescent cells in both adipose tissue and skeletal muscle with age; (ii) gut dysbiosis, characterized by an imbalance in gut microbial communities as the main trigger for inflammation, sarcopenia, and aged adipose tissue; and (iii) microbial dysbiosis, which could impact the onset or progression of a senescent state. Moreover, adipose tissue acts as an endocrine organ, releasing molecules that participate in intricate communication networks between organs. Our discussion focuses on novel adipokines and their role in regulating adipose tissue and muscle, particularly those influenced by aging and obesity, emphasizing their contributions to disease development. On the basis of these findings, we propose that age-related adipose tissue and sarcopenia are disorders characterized by chronic inflammation and metabolic dysregulation. Finally, we explore new potential therapeutic strategies involving specialized proresolving mediator (SPM) G protein-coupled receptor (GPCR) agonists, non-SPM GPCR agonists, transient receptor potential (TRP) channels, antidiabetic drugs in conjunction with probiotics and prebiotics, and compounds designed to target senescent cells and mitigate their pro-inflammatory activity.

High expression of EBP is an adverse prognostic factor for de novo acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disease, for which identifying reliable prognostic markers is critical for accurate clinical prognosis and treatment optimization. The inhibition of emopamil-binding protein gene (EBP) expression has been demonstrated to induce cancer cell death via depleting downstream sterols. Nevertheless, no comprehensive studies have been conducted specifically in tumors, including AML. METHOD: Herein, survival analyses were performed on the dataset obtained from The Cancer Genome Atlas (TCGA). Besides, the EBP levels were quantified using real-time qPCR in a cohort of 120 AML patients, and the value of EBP was further assessed using our clinical data. RESULTS: Patients with high EBP expression had worse overall survival (OS) and event-free survival (EFS) than patients with low EBP expression, both in the TCGA dataset and our clinical data. Additionally, white blood cell (WBC) counts were higher in patients with high EBP expression (P = 0.032). Moreover, in patients with intermediate-risk AML, it was discovered that elevated EBP expression was linked to a worse EFS (P = 0.038). Multivariate analysis demonstrated that high EBP expression was an independent prognostic factor in AML patients and was associated with a shorter OS and EFS (OS: P = 0.041; EFS: P = 0.017). Furthermore, the data revealed that transplantation in the high-EBP group led to an improvement in survival (OS: P = 0.001; EFS: P = 0.001). The same benefit was also observed in intermediate-risk AML patients (OS: P = 0.026; EFS: P = 0.026). CONCLUSION: Collectively, our findings indicated that high expression of EBP in AML patients was an adverse prognostic factor, but transplantation had the otential to alleviate its negative effects.

Analysis of ion transport properties of Glycine max HKT transporters and identifying a regulation of GmHKT1;1 by the non-functional GmHKT1;4.

The HKT transporter plays an important role for plants in response to salt stress, but the transport property of the soybean HKT transporters at the molecular level is still unclear. Here, using Xenopus oocyte as a heterologous expression system and two-electrode voltage-clamp technique, we identified four HKT transporters, GmHKT1;1, GmHKT1;2, GmHKT1;3, and GmHKT1;4, which all belong to type I subfamily, but having distinct ion transport properties. While GmHKT1;1, GmHKT1;2 and GmHKT1;3 function as Na+ transporters, GmHKT1;1 is less selective against K+ than the two other transporters. Astonishingly, GmHKT1;4, which lacks transmembrane segments and has no ion permeability, is significantly expressed, and its gene expression pattern is different from the other three GmHKTs under salt stress. Interestingly, GmHKT1;4 reduced the Na+/K+ currents mediated by GmHKT1;1. Further study showed that the transport ability of GmHKT1;1 regulated by GmHKT1;4 was related to the structural differences in the first intracellular domain and the fourth repeat domain. Overall, we have identified one unique GmHKT member, GmHKT1;4, which modulates the Na+ and K+ transport ability of GmHKT1;1 via direct interaction. Thus, we have revealed a new type of HKTs interaction model for altering their ion transport properties.

TRAF2 associates with cullin neddylation complex assembly.

Cullin-based RING ligases (CRLs) comprise the largest family of ubiquitin E3 ligases. CRL activity is tightly regulated by cullin neddylation, which has been associated with various diseases. Although inhibitors of CRLs neddylation have been reported, there is a lack of small molecules that can selectively target individual cullins. Here, we identified a natural product, liquidambaric acid (LDA), with relatively selective inhibition properties against cullin (Cul) 2 neddylation, and found that its target, Tumor Necrosis Factor receptor-associated factor 2 (TRAF2) was required for the activity. TRAF2 associates with the Cul2 neddylation complex and regulates the machinery assembly, especially that of E2 (UBC12) and E3 (RBX1) enzymes. In addition, we demonstrated that by intervention of the associations between TRAF2 and the neddylation machinery, LDA disturbed NEDD8 transfer from E1 to E2, therefore blocking Cul2 neddylation. Taken together, we show that TRAF2 plays a positive role in neddylation cascades, and we have identified a small molecule capable of selective modulation of cullin neddylation.

Progress in the study of pentraxin-3(PTX-3) as a biomarker for sepsis.

Sepsis is a intricate pathological process characterized by life-threatening organ dysfunction resulting from a dysregulated host response to infection. It stands as a prominent cause of mortality among critically ill patients globally. The pivotal focus in sepsis management lies in the early identification and prompt administration of antimicrobial agents. Owing to the constraints of current diagnostic methodologies, marked by insufficient sensitivity and delayed outcomes, extensive research has been undertaken to ascertain novel biomarkers for sepsis. In this review, we provide an overview discussing the latest advancements in the study of PTX-3 as a biomarker for sepsis. We acknowledge pivotal discoveries from preceding research and engage in discourse regarding the challenges and limitations confronted by PTX-3 as a sepsis biomarker.

Self-Assembling Nanoparticle Hemagglutinin Influenza Vaccines Induce High Antibody Response.

As a highly pathogenic avian virus, H5 influenza poses a serious threat to livestock, the poultry industry, and public health security. Hemagglutinin (HA) is both the dominant epitope and the main target of influenza-neutralizing antibodies. Here, we designed a nanoparticle hemagglutinin influenza vaccine to improve the immunogenicity of the influenza vaccine. In this study, HA5 subtype influenza virus was used as the candidate antigen and was combined with the artificially designed double-branch scaffold protein I53_dn5 A and B. A structurally correct and bioactive trimer HA5-I53_dn5B/Y98F was obtained through secretion and purification using an insect baculovirus expression system; I53_dn5A was obtained by purification using a prokaryotic expression system. HA5-I53_dn5B/Y98F and I53_dn5A self-assembled into spherical nanoparticles (HA5-I53_dn5) in vitro with a diameter of about 45 nm. Immunization and serum test results showed that both HA5-I53_dn5B/Y98F and HA5-I53_dn5 could induce HA5-specific antibodies; however, the immunogenicity of HA5-I53_dn5 was better than that of HA5-I53_dn5B/Y98F. Groups treated with HA5-I53_dn5B and HA5-I53_dn5 nanoparticles produced IgG antibody titers that were not statistically different from those of the nanoparticle-containing adjuvant group. This production of trimerized HA5-I53_dn5B and HA5-I53_dn5 nanoparticles using baculovirus expression provides a reference for the development of novel, safe, and efficient influenza vaccines.

Quercetin Modulates Ferroptosis via the SIRT1/Nrf-2/HO-1 Pathway and Attenuates Cartilage Destruction in an Osteoarthritis Rat Model.

Osteoarthritis (OA) is the most common joint disease, causing symptoms such as joint pain, swelling, and deformity, which severely affect patients' quality of life. Despite advances in medical treatment, OA management remains challenging, necessitating the development of safe and effective drugs. Quercetin (QUE), a natural flavonoid widely found in fruits and vegetables, shows promise due to its broad range of pharmacological effects, particularly in various degenerative diseases. However, its role in preventing OA progression and its underlying mechanisms remain unclear. In this study, we demonstrated that QUE has a protective effect against OA development both in vivo and in vitro, and we elucidated the underlying molecular mechanisms. In vitro, QUE inhibited the expression of IL-1ß-induced chondrocyte matrix metalloproteinases (MMP3 and MMP13) and inflammatory mediators such as INOS and COX-2. It also promoted the expression of collagen II, thereby preventing the extracellular matrix (ECM). Mechanistically, QUE exerts its protective effect on chondrocytes by activating the SIRT1/Nrf-2/HO-1 and inhibiting chondrocyte ferroptosis. Similarly, in an OA rat model induced by anterior cruciate ligament transection (ACLT), QUE treatment improved articular cartilage damage, reduced joint pain, and normalized abnormal subchondral bone remodeling. QUE also reduced serum IL-1ß, TNF-α, MMP3, CTX-II, and COMP, thereby slowing the progression of OA. QUE exerts chondroprotective effects by inhibiting chondrocyte oxidative damage and ferroptosis through the SIRT1/Nrf-2/HO-1 pathway, effectively alleviating OA progression in rats.

Ultrasound molecular imaging for early detection of acute renal ischemia-reperfusion injury.

Background: Microcirculatory perfusion disorder and inflammatory response are critical links in acute kidney injury (AKI). We aim to construct anti-vascular cell adhesion molecule-1(VCAM-1) targeted microbubbles (TM) to monitor renal microcirculatory perfusion and inflammatory response. Methods: TM carrying VCAM-1 polypeptide was constructed by biological coupling. The binding ability of TM to human umbilical vein endothelial cells (HUVECs) was detected. Bilateral renal ischemia-reperfusion injury (IRI) models of mice were established to evaluate microcirculatory perfusion and inflammatory response using TM. Thirty-six mice were randomly divided into six groups according to the different reperfusion time (0.5, 2, 6, 12, and 24 h) and sham-operated group (Sham group). The correlation of TM imaging with serum and histopathological biomarkers was investigated. Results: TM has advantages such as uniform distribution, regular shape, high stability, and good biosafety. TM could bind specifically to VCAM-1 molecule expressed by tumor necrosis factor-alpha (TNF-α)-treated HUVECs. In the renal IRI-AKI model, the area under the curve (AUC) of TM significantly decreased both in the renal cortical and medullary after 2 h of reperfusion compared with the Sham group (p < 0.05). Normalized intensity difference (NID) of TM at different reperfusion time was all higher than that of blank microbubbles (BM) and the Sham group (p < 0.05). Ultrasound molecular imaging of TM could detect AKI early before commonly used renal function markers, histopathological biomarkers, and BM imaging. AUC of TM was negatively correlated with serum creatinine (Scr), blood urea nitrogen (BUN), and Cystatin C (Cys-C) levels, and NID of TM was linearly correlated with VCAM-1, TNF-α, and interleukin-6 (IL-6) expression (p < 0.05). Conclusions: Ultrasound molecular imaging based on TM carrying VCAM-1 polypeptide can accurately evaluate the changes in renal microcirculatory perfusion and inflammatory response, which might be a promising modality for early diagnosis of AKI.

The development of 177Lu-DOTA-CC-PSMA following a unified "Click Chemistry" protocol of synthesizing metal nuclide-conjugated radiopharmaceuticals.

BACKGROUND: Currently, the synthesis pathway of metal nuclide-labeled radiopharmaceuticals is mainly divided into two steps: first, connecting the chelator with the target molecule, and second, labeling the metal nuclide to the chelator. However, the second step of the reaction to label the metal nuclide requires high temperature (90-100 °C), which tends to denature and inactivate the target molecule, leading to loss of biological activities, especially the targeting ability. A feasible solution may be the click chemistry labeling method, which consists of reacting a metal nuclide with a chelating agent to generate an intermediate and then synthesizing a radiopharmaceutical agent via the click chemistry intermediate and the target molecule-alkyne compound. In this study, through the click chemistry of 177Lu-DOTA-N3 with prostate-specific membrane antigen (PSMA)-alkyne compound, 177Lu-labeled PSMA-targeted molecular probe was synthesized and evaluated for its potential to be cleared from the bloodstream and rapidly distributed to tissues and organs, achieving a high target/non-target ratio. 177Lu-PSMA-617 was utilized as an analogue for comparison in terms of synthesizing efficiency and PSMA-targeting ability. RESULTS: A novel 177Lu-labeled PSMA radioligand was successfully synthesized through the click chemistry of 177Lu-DOTA-N3 with PSMA-alkyne compound, and abbreviated as 177Lu-DOTA-CC-PSMA, achieving a radiochemical yield of 77.07% ± 0.03% (n = 6) and a radiochemical purity of 97.62% ± 1.49% (n = 6) when purified by SepPak C18 column. Notably, 177Lu-DOTA-CC-PSMA was characterized as a hydrophilic compound that exhibited stability at room temperature and commendable pharmacokinetic properties, such as the superior uptake (19.75 ± 3.02%ID/g at 0.5 h) and retention (9.14 ± 3.16%ID/g at 24 h) within xenografts of 22Rv1 tumor-bearing mice. SPECT/CT imaging indicated that radioactivity in both kidneys and bladder was essentially eliminated after 24 h, while 177Lu-DOTA-CC-PSMA was further enriched and retained in PSMA-expressing tumors, resulting in the high target/non-target ratio. CONCLUSION: This study demonstrated the potential of click chemistry to unify the synthesis of metal radiopharmaceuticals, and 177Lu-DOTA-CC-PSMA was found for rapid clearance and appropriate chemical stability as a PSMA-targeted radioligand.

Transcriptomic profiling and discovery of key transcription factors involved in adventitious roots formation from root cuttings of mulberry.

ARs plays a crucial role in plant morphogenesis and development. The limited and inefficient rooting of scions poses a significant challenge to the efficiency and quality of clonal propagation of forest trees in silvicultural practices. Building on previous research conducted by our team, we found that applying IBA at a concentration of 1000 mg/L significantly enhanced mulberry rooting. This study aims to uncover the molecular mechanisms underlying this effect by analyzing RNA sequencing data from mulberry phloem before and after treatment with IBA over time intervals of 10, 20, 30, and 40 days. We identified 5226 DEGs, which were then classified into GO terms and KEGG pathways, showing significant enrichment in hormone signaling processes. Using WGCNA, we identified eight co-expression modules, two of which were significantly correlated with the IBA treatment. Additionally, 18 transcription factors that potentially facilitate ARs formation in mulberry were identified, and an exploratory analysis on the cis-regulatory elements associated with these transcription factors was conducted. The findings of this study provide a comprehensive understanding of the mechanisms of ARs in mulberry and offer theoretical support for the discovery and utilization of exceptional genetic resources within the species.

Metabolic engineering combined with site-directed saturated mutations of α-keto acid decarboxylase for efficient production of 6-aminocaproic acid and 1,6-hexamethylenediamine.

6-Aminocaproic acid (6ACA) and 1,6-hexamethylenediamine (HMDA) are key precursors for nylon synthesis, and both are produced using petroleum-based chemical processes. However, the utilization of bio-based raw materials for biological production of monomers is crucial for nylon industry. In this study, we demonstrated that metabolic engineering of Escherichia coli and selected mutations of α-keto acid decarboxylase successfully synthesized 6ACA and HMDA. An artificial iterative cycle from l-lysine to chain-extended α-ketoacids was introduced into Escherichia coli BL21 (DE3). Then, the extended α-ketoacids were decarboxylated and oxidized for 6ACA production. Overexpression of catalase (KatE) combined with the site-directed mutations of α-isopropylmalate synthase (LeuA) contributed synergistic enhancement effect on synthesis of 6ACA, resulting in a 1.3-fold increase in 6ACA titer. Selected mutations in α-keto acid decarboxylase (KivD) improved its specificity and 170.00 ± 5.57 mg/L of 6ACA with a yield of 0.13 mol/mol (6ACA/ l-lysine hydrochloride) was achieved by shake flask cultivation of the engineered strain with the KivD# (F381Y/V461I). Meanwhile, the engineered E. coli could accumulate 84.67 ± 4.04 mg/L of HMDA with a yield of 0.08 mol/mol (HMDA/ l-lysine hydrochloride) by replacing aldehyde dehydrogenase with bi-aminotransferases. This achievement marks a significant advancement in the biological synthesis of 6-carbon compounds, since the biosynthetic pathways of HMDA are rarely identified.