Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch.

Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.

TRPV4 Channel Signaling in Macrophages Promotes Gastrointestinal Motility via Direct Effects on Smooth Muscle Cells.

Intestinal macrophages are critical for gastrointestinal (GI) homeostasis, but our understanding of their role in regulating intestinal motility is incomplete. Here, we report that CX3C chemokine receptor 1-expressing muscularis macrophages (MMs) were required to maintain normal GI motility. MMs expressed the transient receptor potential vanilloid 4 (TRPV4) channel, which senses thermal, mechanical, and chemical cues. Selective pharmacologic inhibition of TRPV4 or conditional deletion of TRPV4 from macrophages decreased intestinal motility and was sufficient to reverse the GI hypermotility that is associated with chemotherapy treatment. Mechanistically, stimulation of MMs via TRPV4 promoted the release of prostaglandin E2 and elicited colon contraction in a paracrine manner via prostaglandin E receptor signaling in intestinal smooth muscle cells without input from the enteric nervous system. Collectively, our data identify TRPV4-expressing MMs as an essential component required for maintaining normal GI motility and provide potential drug targets for GI motility disorders.

A Bivalent Omicron-Containing Booster Vaccine against Covid-19.

BACKGROUND: The safety and immunogenicity of the bivalent omicron-containing mRNA-1273.214 booster vaccine are not known. METHODS: In this ongoing, phase 2-3 study, we compared the 50-µg bivalent vaccine mRNA-1273.214 (25 µg each of ancestral Wuhan-Hu-1 and omicron B.1.1.529 [BA.1] spike messenger RNAs) with the previously authorized 50-µg mRNA-1273 booster. We administered mRNA-1273.214 or mRNA-1273 as a second booster in adults who had previously received a two-dose (100-µg) primary series and first booster (50-µg) dose of mRNA-1273 (≥3 months earlier). The primary objectives were to assess the safety, reactogenicity, and immunogenicity of mRNA-1273.214 at 28 days after the booster dose. RESULTS: Interim results are presented. Sequential groups of participants received 50 µg of mRNA-1273.214 (437 participants) or mRNA-1273 (377 participants) as a second booster dose. The median time between the first and second boosters was similar for mRNA-1273.214 (136 days) and mRNA-1273 (134 days). In participants with no previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the geometric mean titers of neutralizing antibodies against the omicron BA.1 variant were 2372.4 (95% confidence interval [CI], 2070.6 to 2718.2) after receipt of the mRNA-1273.214 booster and 1473.5 (95% CI, 1270.8 to 1708.4) after receipt of the mRNA-1273 booster. In addition, 50-µg mRNA-1273.214 and 50-µg mRNA-1273 elicited geometric mean titers of 727.4 (95% CI, 632.8 to 836.1) and 492.1 (95% CI, 431.1 to 561.9), respectively, against omicron BA.4 and BA.5 (BA.4/5), and the mRNA-1273.214 booster also elicited higher binding antibody responses against multiple other variants (alpha, beta, gamma, and delta) than the mRNA-1273 booster. Safety and reactogenicity were similar with the two booster vaccines. Vaccine effectiveness was not assessed in this study; in an exploratory analysis, SARS-CoV-2 infection occurred in 11 participants after the mRNA-1273.214 booster and in 9 participants after the mRNA-1273 booster. CONCLUSIONS: The bivalent omicron-containing vaccine mRNA-1273.214 elicited neutralizing antibody responses against omicron that were superior to those with mRNA-1273, without evident safety concerns. (Funded by Moderna; ClinicalTrials.gov number, NCT04927065.).

EVlncRNA-Dpred: improved prediction of experimentally validated lncRNAs by deep learning.

Long non-coding RNAs (lncRNAs) played essential roles in nearly every biological process and disease. Many algorithms were developed to distinguish lncRNAs from mRNAs in transcriptomic data and facilitated discoveries of more than 600 000 of lncRNAs. However, only a tiny fraction (<1%) of lncRNA transcripts (~4000) were further validated by low-throughput experiments (EVlncRNAs). Given the cost and labor-intensive nature of experimental validations, it is necessary to develop computational tools to prioritize those potentially functional lncRNAs because many lncRNAs from high-throughput sequencing (HTlncRNAs) could be resulted from transcriptional noises. Here, we employed deep learning algorithms to separate EVlncRNAs from HTlncRNAs and mRNAs. For overcoming the challenge of small datasets, we employed a three-layer deep-learning neural network (DNN) with a K-mer feature as the input and a small convolutional neural network (CNN) with one-hot encoding as the input. Three separate models were trained for human (h), mouse (m) and plant (p), respectively. The final concatenated models (EVlncRNA-Dpred (h), EVlncRNA-Dpred (m) and EVlncRNA-Dpred (p)) provided substantial improvement over a previous model based on support-vector-machines (EVlncRNA-pred). For example, EVlncRNA-Dpred (h) achieved 0.896 for the area under receiver-operating characteristic curve, compared with 0.582 given by sequence-based EVlncRNA-pred model. The models developed here should be useful for screening lncRNA transcripts for experimental validations. EVlncRNA-Dpred is available as a web server at https://www.sdklab-biophysics-dzu.net/EVlncRNA-Dpred/index.html, and the data and source code can be freely available along with the web server.

Splenectomy ameliorates liver cirrhosis by restoring the gut microbiota balance.

BACKGROUND: Dysbiosis of gut microbiota is frequent in liver cirrhosis (LC) patients, and splenectomy (SP) has been reported to improve LC. Herein, we report the effects of SP on gut microbiota, especially on Veillonella parvula, a Gram-negative coccus of the gastrointestinal tract, in LC mice, and the underlying mechanism. METHODS: LC mice models were induced by tail vein injection of concanavalin A (ConA), followed by SP. 16 s rRNA sequencing was conducted to analyze the effects of ConA induction and SP on mouse gut microbiota and the gene expression affected by gut microbiota. LC mice receiving SP were gavaged with Veillonella parvula. Likewise, hepatic stellate cells (HSC) and hepatocytes (HC) were induced with conditioned medium (CM) of Veillonella parvula. RESULTS: SP alleviated LC in mice by restoring gut barrier function and maintaining gut microbiota balance, with Veillonella as the key genus. The Veillonella parvula gavage on LC mice reversed the ameliorative effect of SP. The CM of Veillonella parvula promoted the activation of HSC and the release of IL-6, IL-1ß, and TNF-α. Also, the CM of Veillonella parvula induced HC pyroptosis and the release of ALT and AST. Veillonella parvula represented an imbalance in the gut microbiota, thus enhancing gut-derived endotoxins in the liver with the main target being Tlr4/Nlrp3. Inhibition of Tlr4 blocked Veillonella parvula-induced HC damage, HSC activation, and subsequent LC progression. CONCLUSION: SP-mediated gut microbiota regulation ameliorates ConA-related LC progression by inhibiting Tlr4/Nlrp3 in the liver.

Performance of Metagenomic Next-Generation Sequencing of Cell-Free DNA From Vitreous and Aqueous Humor for Diagnoses of Intraocular Infections.

BACKGROUND: Delayed diagnosis and improper therapy for intraocular infections usually result in poor prognosis. Due to limitations of conventional culture and polymerase chain reaction methods, most causative pathogens cannot be identified from vitreous humor (VH) or aqueous humor (AH) samples with limited volume. METHODS: Patients with suspected intraocular infections were enrolled from January 2019 to August 2021. Metagenomic next-generation sequencing (mNGS) was used to detected causative pathogens. RESULTS: This multicenter prospective study enrolled 488 patients, from whom VH (152) and AH (336) samples were respectively collected and analyzed using mNGS of cell-free DNA (cfDNA). Taking final comprehensive clinical diagnosis as the gold standard, there were 39 patients with indefinite final diagnoses, whereas 288 and 161 patients were diagnosed as definite infectious and noninfectious diseases, respectively. Based on clinical adjudication, the sensitivity (92.2%) and total coincidence rate (81.3%) of mNGS using VH samples were slightly higher than those of mNGS using AH samples (85.4% and 75.4%, respectively). CONCLUSIONS: Using mNGS of cfDNA, an era with clinical experience for more rapid, independent, and impartial diagnosis of bacterial and other intraocular infections can be expected.

Interim report of the reactogenicity and immunogenicity of SARS-CoV-2 XBB-containing vaccines.

BACKGROUND: Monovalent Omicron XBB.1.5-containing vaccines were approved for Coronavirus disease 2019 (COVID-19) 2023-2024 immunizations. METHODS: This ongoing, open-label, phase 2/3 study evaluated mRNA-1273.815-monovalent (50-µg Omicron XBB.1.5-spike mRNA) and mRNA-1273.231-bivalent (25-µg each Omicron XBB.1.5- and BA.4/BA.5-spike mRNAs))vaccines, administered as 5th doses to adults who previously received a primary series, a 3rd dose of an original mRNA COVID-19 vaccine, and a 4th dose of an Omicron BA.4/BA.5 bivalent vaccine. Interim safety and immunogenicity results 29 days post-vaccination are reported. RESULTS: Participants (randomized 1:1) received 50-µg mRNA-1273.815(n=50) or mRNA-1273.231(n=51); median (interquartile range) months from the prior BA.4/BA.5-bivalent dose were 8.2 (8.1-8.3) and 8.3 (8.1-8.4), respectively. Neutralizing antibody (nAb) increased from pre-booster levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants tested. Day 29 nAb fold-increases from pre-booster levels were numerically higher against XBB.1.5, XBB.1.16, EG.5.1, BA.2.86, and JN.1 than BA.4/BA.5, BQ.1.1 and D614G. The monovalent vaccine also cross-neutralized FL.1.5.1, EG.5.1, BA.2.86, HK.3.1, HV.1 and JN.1 variants in a participant (n=20) subset, 15 days post-vaccination. Reactogenicity was similar to previously reported mRNA-1273 original and bivalent vaccines. CONCLUSIONS: XBB.1.5-containing mRNA-1273 vaccines elicit robust, diverse nAb responses against more recent SARS-CoV-2 variants including JN.1, supporting the XBB.1.5-spike sequence selection for the 2023-2024 COVID-19 vaccine update.

LPS exacerbates TRPV4-mediated itch through the intracellular TLR4-PI3K signalling.

Pruritus is often accompanied with bacterial infections, but the underlying mechanism is not fully understood. Although previous studies revealed that lipopolysaccharides (LPS) could directly activate TRPV4 channel and TRPV4 is involved in the generation of both acute itch and chronic itch, whether and how LPS affects TRPV4-mediated itch sensation remains unclear. Here, we showed that LPS-mediated TRPV4 sensitization exacerbated GSK101-induced scratching behaviour in mice. Moreover, this effect was compromised in TLR4-knockout mice, suggesting LPS acted through a TLR4-dependent mechanism. Mechanistically, LPS enhanced GSK101-evoked calcium influx in mouse ear skin cells and HEK293T cells transfected with TRPV4. Further, LPS sensitized TRPV4 channel through the intracellular TLR4-PI3K-AKT signalling. In summary, our study found a modulatory role of LPS in TRPV4 function and highlighted the TLR4-TRPV4 interaction in itch signal amplification.

Molecular Biological Research on the Pathogenic Mechanism of Retinoblastoma.

Retinoblastoma (RB) is the most common intraocular malignant tumor in children, primarily attributed to the bi-allelic loss of the RB1 gene in the developing retina. Despite significant progress in understanding the basic pathogenesis of RB, comprehensively unravelling the intricate network of genetics and epigenetics underlying RB tumorigenesis remains a major challenge. Conventional clinical treatment options are limited, and despite the continuous identification of genetic loci associated with cancer pathogenesis, the development of targeted therapies lags behind. This review focuses on the reported genomic and epigenomic alterations in retinoblastoma, summarizing potential therapeutic targets for RB and providing insights for research into targeted therapies.

Biocompatible Folic-Acid-Strengthened Ag-Ir Quantum Dot Nanozyme for Cell and Plant Root Imaging of Cysteine/Stress and Multichannel Monitoring of Hg2+ and Dopamine.

To boost the enzyme-like activity, biological compatibility, and antiaggregation effect of noble-metal-based nanozymes, folic-acid-strengthened Ag-Ir quantum dots (FA@Ag-Ir QDs) were developed. Not only did FA@Ag-Ir QDs exhibit excellent synergistic-enhancement peroxidase-like activity, high stability, and low toxicity, but they could also promote the lateral root propagation of Arabidopsis thaliana. Especially, ultratrace cysteine or Hg2+ could exclusively strengthen or deteriorate the inherent fluorescence property with an obvious "turn-on" or "turn-off" effect, and dopamine could alter the peroxidase-like activity with a clear hypochromic effect from blue to colorless. Under optimized conditions, FA@Ag-Ir QDs were successfully applied for the turn-on fluorescence imaging of cysteine or the stress response in cells and plant roots, the turn-off fluorescence monitoring of toxic Hg2+, or the visual detection of dopamine in aqueous, beverage, serum, or medical samples with low detection limits and satisfactory recoveries. The selective recognition mechanisms for FA@Ag-Ir QDs toward cysteine, Hg2+, and dopamine were illustrated. This work will offer insights into constructing some efficient nanozyme sensors for multichannel environmental analyses, especially for the prediagnosis of cysteine-related diseases or stress responses in organisms.

OsAlR3 regulates aluminum tolerance through promoting the secretion of organic acids and the expression of antioxidant genes in rice.

In acidic soils, aluminum (Al) toxicity inhibits the growth and development of plant roots and affects nutrient and water absorption, leading to reduced yield and quality. Therefore, it is crucial to investigate and identify candidate genes for Al tolerance and elucidate their physiological and molecular mechanisms under Al stress. In this study, we identified a new gene OsAlR3 regulating Al tolerance, and analyzed its mechanism from physiological, transcriptional and metabolic levels. Compared with the WT, malondialdehyde (MDA) and hydrogen peroxide (H2O2) content were significantly increased, superoxide dismutase (SOD) activity and citric acid (CA) content were significantly decreased in the osalr3 mutant lines when exposed to Al stress. Under Al stress, the osalr3 exhibited decreased expression of antioxidant-related genes and lower organic acid content compared with WT. Integrated transcriptome and metabolome analysis showed the phenylpropanoid biosynthetic pathway plays an important role in OsAlR3-mediated Al tolerance. Exogenous CA and oxalic acid (OA) could increase total root length and enhance the antioxidant capacity in the mutant lines under Al stress. Conclusively, we found a new gene OsAlR3 that positively regulates Al tolerance by promoting the chelation of Al ions through the secretion of organic acids, and increasing the expression of antioxidant genes.

Effects of sleep deprivation on language-related brain functional connectivity: differences by gender and age.

Sleep deprivation (SD) negatively affects many cognitive functions, such as language performance. However, what remains unclear is whether and how SD affects the language-related brain network based on gender and age differences. The current study of 86 healthy adults used resting-state functional magnetic resonance imaging (rs-fMRI) to measure language-related functional connectivity after full sleep or partial SD. Gender and age differences in functional connectivity were assessed across four linguistic aspects: phonetics, morphology, semantics, and syntax. The results showed that SD can affect the connectivity status of language-related brain networks, especially syntax-related networks. Furthermore, the influence of SD on the functional connectivity in language-related networks differed between male and female groups, and between younger and older groups. Specifically, there were gender differences in the temporal association cortex and age differences in the parietal association cortex, during full sleep versus partial SD. These findings highlight changes in the brain's functional connectivity in response to SD as a potential source of gender and age differences in brain function.

Realizing High Thermoelectric Properties in Bi2S3 Bulk via Band Engineering and Nanorods Compositing.

Bismuth sulfide is a promising thermoelectric material because of its low cost and toxicity; however, its low electrical conductivity limits its thermoelectric properties. In this study, Bi2S3+x wt% HfCl4 (x = 0, 0.25, 0.5, 0.75, and 1.0) bulk samples are fabricated using a combination of melting and spark plasma sintering. The microstructures, electronic structures, and thermoelectric properties of the composites are characterized. The results of electronic structure calculations show that doping with HfCl4 produces an impurity energy level that narrows the bandgap and allows the Fermi energy level to enter the conduction band, leading to a favorable increase in carrier concentration. By regulating the HfCl4 doping concentration, the electrical conductivity of the 0.75 wt% doped sample reaches 253 Scm-1 at 423 K and its maximum ZT value is 0.47 at 673 K. Moreover, the sample is compounded with Bi2S3 nanorods prepared by the hydrothermal method, reducing thermal conductivity by 30% due to the introduction of additional interfaces and pores. This resulted in a final ZT value of 0.61 at 673 K, which is approximately eight times higher than that of pure Bi2S3. This step-by-step optimization approach provides a valuable methodology for enhancing the performance of other thermoelectric material systems.

Altered CD226/TIGIT expressions were associated with NK phenotypes in primary antiphospholipid syndrome and affected by IL-4/JAK pathway.

Natural killer (NK) cells were reported to be involved in the pathogenesis of primary antiphospholipid syndrome (pAPS). Immunosuppressive receptor T-cell immunoreceptor with Ig and ITIM domains (TIGIT) and activating receptor cluster of differentiation 226 (CD226) are specifically expressed on NK cells with competitive functions. This study aims to investigate the expression diversities of CD226/TIGIT on NK subsets and their associations with NK subsets activation phenotypes and potential clinical significance, furthermore, to explore potential cause for CD226/TIGIT expression diversities in pAPS. We comparatively assessed the changes of CD56brightNK, CD56dimNK, and NK-like cells in 70 pAPS patients compared with control groups, including systemic lupus erythematosus, asymptomatic antiphospholipid antibodies carriers (asymp-aPLs carriers), and healthy controls and their expression diversities of CD226/TIGIT by flow cytometry. CD25, CD69, CD107α expression, and interferon gamma (IFN-γ) secretion levels of NK subsets were detected to determine the potential association of CD226/TIGIT expression with NK subsets phenotypes. CD226/TIGIT expression levels were compared among different subgroups divided by aPLs status. Moreover, in vitro cultures were conducted to explore the potential mechanisms of CD226/TIGIT expression imbalance. CD56brightNK and CD3+CD56+NK-like cells were significantly increased while CD56dimNK cells were obviously decreased in pAPS, and CD56brightNK and NK-like cells exhibited significantly higher CD226 but lower TIGIT expressions. CD226+CD56brightNK and TIGIT-CD56brightNK cells show higher CD69 expression and IFN-γ secretion capacity, and CD226+NK-like and TIGIT-NK-like cells showed higher expressions of CD25 and CD69 but lower apoptosis rate than CD226- and TIGIT+CD56brightNK/NK-like cells, respectively. The imbalanced CD226/TIGIT expressions were most significant in aPLs triple-positive group. Imbalanced expressions of CD226/TIGIT on CD56brightNK and NK-like cells were aggravated after interleukin-4 (IL-4) stimulation and recovered after tofacitinib blocking. Our data revealed significant imbalanced CD226/TIGIT expressions on NK subsets in pAPS, which closely associated with NK subsets phenotypes and more complicated autoantibody status. CD226/TIGIT imbalanced may be affected by IL-4/Janus Kinase (JAK) pathway activation.

Endothelium-specific deletion of p62 causes organ fibrosis and cardiac dysfunction.

BACKGROUND: The autophagy adapter SQSTM1/p62 is crucial for maintaining homeostasis in various organs and cells due to its protein-protein interaction domains and involvement in diverse physiological and pathological processes. Vascular endothelium cells play a unique role in vascular biology and contribute to vascular health. METHODS: Using the Cre-loxP system, we generated mice with endothelium cell-specific knockout of p62 mediated by Tek (Tek receptor tyrosine kinase)-cre to investigate the essential role of p62 in the endothelium. In vitro, we employed protein mass spectrometry and IPA to identify differentially expressed proteins upon knockdown of p62. Immunoprecipitation assays were conducted to demonstrate the interaction between p62 and FN1 or LAMC2 in human umbilical vein endothelium cells (HUVECs). Additionally, we identified the degradation pathway of FN1 and LAMC2 using the autophagy inhibitor 3-methyladenine (3-MA) or proteasome inhibitor MG132. Finally, the results of immunoprecipitation demonstrated that the interaction between p62 and LAMC2 was abolished in the PB1 truncation group of p62, while the interaction between p62 and FN1 was abolished in the UBA truncation group of p62. RESULTS: Our findings revealed that p62 Endo mice exhibited heart, lung, and kidney fibrosis compared to littermate controls, accompanied by severe cardiac dysfunction. Immunoprecipitation assays provided evidence of p62 acting as an autophagy adapter in the autophagy-lysosome pathway for FN1 and LAMC2 degradation respectively through PB1 and UBA domain with these proteins rather than proteasome system. CONCLUSIONS: Our study demonstrates that defects in p62 within endothelium cells induce multi-organ fibrosis and cardiac dysfunction in mice. Our findings indicate that FN1 and LAMC2, as markers of (EndoMT), have detrimental effects on HUVECs and elucidate the autophagy-lysosome degradation mechanism of FN1 and LAMC2.

Global burden of hip fracture: The Global Burden of Disease Study.

This study is the first to measure global burden of hip fracture in patients aged 55 years and older across 204 countries and territories from 1990 to 2019. Our study further proved that the global burden of hip fracture is still large. Hip fractures among males are perhaps underestimated, and older adults should be given more attention. PURPOSE: Hip fracture is a tremendous universal public health challenge, but no updated comprehensive and comparable assessment of hip fracture incidence and burden exists for most of the world in older adults. METHODS: Using data from the Global Burden of Diseases (GBD) 2019, we estimated the number and rates of the incidence, prevalence, and years lived with disability (YLD) of hip fracture across 204 countries and territories in patients aged 55 years and older from 1990 to 2019. RESULTS: In 2019, the incidence, prevalence, and YLDs rates of hip fracture in patients aged 55 years and older were 681.35 (95% UI 508.36-892.27) per 100000 population, 1191.39 (95% UI 1083.80-1301.52) per 100000 population, and 130.78 (95% UI 92.26-175.30) per 100000 population. During the three decades, the incidence among people aged below 60 years showed a downward trend, whereas it showed a rapid upward trend among older adults. All the numbers and rates of hip fractures among females were higher than those among males and increased with age, with the highest number and rate in the highest age group. Notably, the male to female ratio of the incidence for people aged over 55 years increased from 0.577 in 1990 to 0.612 in 2019. Falls were the leading cause among both sexes and in all age groups. CONCLUSIONS: The incidence and the number of hip fractures among patients aged 55 years and older increased over the past three decades, indicating that the global burden of hip fracture is still large. Hip fractures among males are perhaps underestimated, and older adults should be given more attention.

Electrochemical detection of myoglobin using an ultrasensitive label-free sensor derived from cubic-ZIF67@Au-rGOF-NH2 composite of MOF and GOF.

Markers of myocardial injury, such as myoglobin (Mb), are substances swiftly released into the peripheral bloodstream upon myocardial cell injury or altered cardiac activity. During the onset of acute myocardial infarction, patients experience a significant surge in serum Mb levels. Given this, precise detection of Mb is essential, necessitating the development of innovative assays to optimize detection capabilities. This study introduces the synthesis of a three-dimensional hierarchical nanocomposite, Cubic-ZIF67@Au-rGOF-NH2, utilizing aminated reduced graphene oxide and zeolite imidazolium ester framework-67 (ZIF67) as foundational structures. Notably, this novel material, applied in a label-free electrochemical immunosensor, presents a groundbreaking approach for detecting myocardial injury markers. Experimental outcomes revealed ZIF67 and AuNPs exhibit enhanced affinity and growth on the 3D-rGOF-NH2 matrix, thus amplifying electrical conductivity while preserving the inherent electrochemical attributes of ZIF67. As a result, the Cubic-ZIF67@Au-rGOF-NH2 label-free electrochemical immunosensor exhibited a broad detection range and high sensitivity for Mb. The derived standard curve was ΔIp = 16.67552lgC+275.245 (R = 0.993) with a detection threshold of 3.47 fg/ml. Moreover, recoveries of standards spiked into samples ranged between 96.3% and 108.7%. Importantly, the devised immunosensor retained notable selectivity against non-target proteins, proving its potential clinical utility based on exemplary sample analysis performance.

Suppression of DNMT1 combined with ATM or ATR inhibitor as a therapeutic combination of acute myeloid leukemia.

The potential treatment option of targeting DNA methyltransferase 1 (DNMT1) has been explored, but further investigation is required to assess the efficacy of combination therapy in acute myeloid leukemia (AML). In this study, bioinformatics and online databases were utilized to select the combined therapeutic targets. The potential kinases associated with DNMT1-related genes in AML were analyzed using the Cancer Genome Atlas (TCGA) database and X2K Appyter (Expression2Kinases) database. In-vitro evaluations were conducted to assess the synergistic effects between DNMT1 and ATR/ATM in five AML cell lines (MOLM-16, NB-4, HEL 92.1.7, HEL, EOL-1). In our study, ATR and ATM are primarily the kinases associated with DNMT1-related genes in AML. We observed a significant upregulation of DNMT1, ATR, and ATM expression in AML tissues and cell lines. The five AML cell lines demonstrated sensitivity to monotherapy with GSK-368, AZD-1390, or AZD-6738 (EC50 value ranges from 5.461 to 7.349 nM, 5.821 to 10.120 nM, and 7.618 to 10.100 nM, respectively). A considerable synergistic effect was observed in AML cell lines when combining GSK-368 and AZD-1390, GSK-368 and AZD-6738, or AZD-1390 and AZD-6738, resulting in induced cell apoptosis and inhibited cell growth. DNMT1, ATM, and ATR possess potential as therapeutic targets for AML. Both individual targeting and combination targeting of these molecules have been confirmed as promising therapeutic approaches for AML.

Poly-ß-cyclodextrin strengthen Pr6O11 porous oxidase mimic for dual-channel visual recognition of bioactive cysteine and Fe2.

To conveniently monitor bioactive cysteine (Cys) and Fe2+ in practice, a kind of poly-ß-cyclodextrin strengthen praseodymium oxide (Pr6O11) porous oxidase mimic (p-ß-CD@Pr6O11) was constructed by virtue of the strong coordination between nano Pr6O11 and poly-ß-cyclodextrin substrate. After its microstructure and physicochemical property were characterized in detail, it was noted that porous p-ß-CD@Pr6O11 exhibited excellent enzyme-like catalytic activity to accelerate the oxidation of 3,3',5,5,'-tetramethylbanzidine (TMB) and 2,2'-azinobis (3-ethylbenzo-thiazoline-6-sulfonic acid) ammonium salt (ABTS) with significant color-enhancement effect in the air. Based on the signal amplification, trace Cys could exclusively deteriorate the UV-vis absorbance at 653 nm of p-ß-CD@Pr6O11-TMB and Fe2+ alter the one at 729 nm of p-ß-CD@Pr6O11-ABTS with visual color changes. Under the optimized conditions, the proposed p-ß-CD@Pr6O11-TMB and p-ß-CD@Pr6O11-ABTS systems were successfully applied for dual-channel monitoring of Cys in Cys capsules and fetal bovine serum and Fe2+ in agricultural products with quite low detection limits, i.e., 7.8×10-9 mol·L-1 for Cys and 6.93×10-8 mol·L-1 (S/N=3) for Fe2+, respectively. The synergetic-enhancement detection mechanisms to Cys and Fe2+ were also proposed.

HOXC6-mediated transcriptional activation of ENO2 promotes oral squamous cell carcinoma progression through the Warburg effect.

Oral squamous cell carcinoma (OSCC) requires an in-depth exploration of its molecular mechanisms. The Warburg effect, along with the oncogenes enolase 2 (ENO2) and homeobox C6 (HOXC6), plays a central role in cancer. However, the specific interaction between ENO2 and HOXC6 in driving the Warburg effect and OSCC progression remains poorly understood. Through differential gene expression analysis in head and neck squamous cell carcinomas using Gene Expression Profiling Interactive Analysis, we identified upregulated ENO2 in OSCC. Silencing ENO2 in OSCC cells revealed its involvement in migration, invasion, and aerobic glycolysis of OSCC cells. Further exploration of ENO2's regulatory network identified HOXC6 as a potential transcriptional regulator. Subsequently, HOXC6 was silenced in OSCC cells, and expressions of ENO2 were assessed to validate its relationship with ENO2. Chromatin Immunoprecipitation and luciferase assays were utilized to investigate the direct transcriptional activation of ENO2 by HOXC6. A rescue assay co-overexpressing ENO2 and silencing HOXC6 in OSCC cells affirmed HOXC6's role in ENO2-associated glycolysis. High ENO2 expression in OSCC was validated through quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry analyses, which correlated with poor patient survival. Functional assays demonstrated that ENO2 silencing inhibited glycolysis and attenuated the aggressiveness of OSCC cells. In vivo studies confirmed the oncogenic role of ENO2 in OSCC growth. Notably, HOXC6 exhibited a positive correlation with ENO2 expression in clinical samples. Mechanistically, HOXC6 was identified as a direct transcriptional activator of ENO2, orchestrating the Warburg effect in OSCC cells. This study reveals the intricate link between HOXC6-mediated ENO2 transcriptional activation and the Warburg effect in OSCC, offering a potential therapeutic target for treating OSCC patients.