A dual-channel fluorescent probe targeting lysosomes for differential detection of Cys/Hcy and GSH: Applications in food, pharmaceutical analysis and bioimaging.

Thiols function as antioxidants in food, prolonging shelf life and enhancing flavor. Moreover, thiols are vital biomolecules involved in enzyme activity, cellular signal transduction, and protein folding among critical biological processes. In this paper, the fluorescent probe PYL-NBD was designed and synthesized, which utilized the fluorescent molecule pyrazoline, the lysosome-targeted morpholine moiety, and the sensing moiety NBD. Probe PYL-NBD was tailored for the recognition of biothiols through single-wavelength excitation, yielding distinct fluorescence emission signals: blue for Cys, Hcy, and GSH; green for Cys, Hcy. Probe PYL-NBD exhibited rapid reaction kinetics (<10 min), distinct fluorescence response signals, and low detection limits (15.7 nM for Cys, 14.4 nM for Hcy, and 12.6 nM for GSH). Probe PYL-NBD enabled quantitative determination of Cys content in food samples and L-cysteine capsules. Furthermore, probe PYL-NBD had been successfully applied for confocal imaging with dual-channel detection of biothiols in various biological specimens, including HeLa cells, zebrafish, tumor sections, and Arabidopsis thaliana.

RNA m5C oxidation by TET2 regulates chromatin state and leukaemogenesis.

Mutation of tet methylcytosine dioxygenase 2 (encoded by TET2) drives myeloid malignancy initiation and progression1-3. TET2 deficiency is known to cause a globally opened chromatin state and activation of genes contributing to aberrant haematopoietic stem cell self-renewal4,5. However, the open chromatin observed in TET2-deficient mouse embryonic stem cells, leukaemic cells and haematopoietic stem and progenitor cells5 is inconsistent with the designated role of DNA 5-methylcytosine oxidation of TET2. Here we show that chromatin-associated retrotransposon RNA 5-methylcytosine (m5C) can be recognized by the methyl-CpG-binding-domain protein MBD6, which guides deubiquitination of nearby monoubiquitinated Lys119 of histone H2A (H2AK119ub) to promote an open chromatin state. TET2 oxidizes m5C and antagonizes this MBD6-dependent H2AK119ub deubiquitination. TET2 depletion thereby leads to globally decreased H2AK119ub, more open chromatin and increased transcription in stem cells. TET2-mutant human leukaemia becomes dependent on this gene activation pathway, with MBD6 depletion selectively blocking proliferation of TET2-mutant leukaemic cells and largely reversing the haematopoiesis defects caused by Tet2 loss in mouse models. Together, our findings reveal a chromatin regulation pathway by TET2 through retrotransposon RNA m5C oxidation and identify the downstream MBD6 protein as a feasible target for developing therapies specific against TET2 mutant malignancies.

Epitranscriptomic m6A modifications during reactivation of HIV-1 latency in CD4+ T cells.

Despite effective antiretroviral therapy reducing HIV-1 viral loads to undetectable levels, the presence of latently infected CD4+ T cells poses a major barrier to HIV-1 cure. N6-methyladenosine (m6A) modification of viral and cellular RNA has a functional role in regulating HIV-1 infection. m6A modification of HIV-1 RNA can affect its stability, translation, and splicing in cells and suppresses type-I interferon induction in macrophages. However, the function of m6A modification in regulating HIV-1 latency reactivation remains unknown. We used the Jurkat T cell line-derived HIV-1 latency model (J-Lat cells) to investigate changes in m6A levels of cellular RNA in response to latency reversal. We observed a significant increase in m6A levels of total cellular RNA upon reactivation of latent HIV-1 in J-Lat cells. This increase in m6A levels was transient and returned to steady-state levels despite continued high levels of viral gene expression in reactivated cells compared to control cells. Upregulation of m6A levels occurred without significant changes in the protein expression of m6A writers or erasers that add or remove m6A, respectively. Knockdown of m6A writers in J-Lat cells significantly reduced HIV-1 reactivation. Treatment with an m6A writer inhibitor reduced cellular RNA m6A levels, along with a reduction in HIV-1 reactivation. Furthermore, using m6A-specific sequencing, we identified cellular RNAs that are differentially m6A-modified during HIV-1 reactivation in J-Lat cells. Knockdown of identified m6A-modified RNA validates these results with an established primary CD4+ T cell model of HIV-1 latency. These results show the importance of m6A RNA modification in HIV-1 latency reversal. IMPORTANCE: RNA m6A modification is important for regulating gene expression and innate immune responses to HIV-1 infection. However, the functional significance of m6A modification during HIV-1 latency reactivation is unknown. To address this important question, in this study, we used established cellular models of HIV-1 latency, m6A-specific sequencing at single-base resolution, and functional assays. We demonstrate that HIV-1 latency reversal leads to increased levels of cellular m6A modification, correlates with cellular m6A levels, and is dependent on the catalytic activity of the m6A methyltransferase enzyme. We also identified cellular genes that are differentially m6A-modified during HIV-1 reactivation, as well as the sites of m6A within HIV-1 RNA. Our novel findings point toward a significant role for m6A modification in HIV-1 latency reversal.

Structural disruption in subjective cognitive decline and mild cognitive impairment.

Subjective cognitive decline (SCD) marks the initial stage in Alzheimer's disease continuum. Nonetheless, current research findings regarding brain structural changes in the SCD are inconsistent. In this study, 37 SCD patients, 28 mild cognitive impairment (MCI) patients, and 42 healthy controls (HC) were recruited to investigate structural alterations. Morphological and microstructural differences among the three groups were analyzed based on T1- and diffusion-weighted images, correlating them with neuropsychological assessments. Additionally, classification analysis was performed by using support vector machines (SVM) categorize participants into three groups based on MRI features. Both SCD and MCI showed decreased volume in left inferior parietal lobe (IPL) compared to HC, while SCD showed altered morphologies in the right inferior temporal gyrus (ITG), right insula and right amygdala, and microstructures in fiber tracts of the right ITG, lateral occipital cortex (LOC) and insula relative to MCI. Moreover, the volume in the left IPL, right LOC, right amygdala and diffusivity value in fiber tracts of right LOC were significantly correlated with cognitive functions across all subjects. The classification models achieved an accuracy of > 0.7 (AUC = 0.8) in distinguishing the three groups. Our findings suggest that SCD and MCI share similar atrophy in the IPL but show more differences in morphological and microstructural features of cortical-subcortical areas.

YTHDF1 loss in dendritic cells potentiates radiation-induced antitumor immunity via STING-dependent type I IFN production.

RNA N6-methyladenosine (m6A) reader YTHDF1 is implicated in cancer etiology and progression. We discovered that radiotherapy (RT) increased YTHDF1 expression in dendritic cells (DCs) of PBMCs from cancer patients, but not in other immune cells tested. Elevated YTHDF1 expression of DCs was associated with poor outcomes in patients receiving RT. We found that loss of Ythdf1 in DCs enhanced the antitumor effects of ionizing radiation (IR) via increasing the cross-priming capacity of DCs across multiple murine cancer models. Mechanistically, IR upregulated YTHDF1 expression in DCs through STING-IFN-I signaling. YTHDF1 in turn triggered STING degradation by increasing lysosomal cathepsins, thereby reducing IFN-I production. We created a YTHDF1 deletion/inhibition prototype DC vaccine, significantly improving the therapeutic effect of RT and radio-immunotherapy in a murine melanoma model. Our findings reveal a new layer of regulation between YTHDF1/m6A and STING in response to IR, which opens new paths for the development of YTHDF1-targeting therapies.

Low-carbon treatment and remediation of oil sludge in mid-to-high latitude regions: A coupled approach of freeze-thaw and supercritical CO2 extraction.

The oil sludge produced while extracting large oil and gas fields in the middle and high latitude regions has caused serious pollution to the surrounding soil. The key to solving this problem in the future is to unify the remediation of soil and the treatment of oil sludge. This study uses supercritical carbon dioxide(scCO2) technology to construct a low-carbon method, providing a new approach to achieve this goal. The study determines the optimal extraction conditions for black calcareous soil with 15% oil content to be 55 °C, 25 MPa, and 90 min through single factor and response surface experiments. Experiments on the scCO2 extraction coupled with freeze-thaw cycles show that oil sludge with a water content of 10% can improve the extraction efficiency of scCO2 by about 2.69% after less than five freeze-thaw cycles. The study also compares the extraction efficiency of the four soils, with a difference of 6.03% observed under the same conditions. Additionally, we analyze the impact of the extraction process on changes in the properties of the oil and soil in the oil sludge. Comprehensive tests, including scanning electron microscope (SEM), nutrient detection, X-ray powder diffractometer (XRD), fourier transform infrared spectroscopy (FTIR), and Gas Chromatography (GC), have been conducted. Results show that standalone scCO2 extraction can remove up to 98.2% of petroleum hydrocarbons from the oil sludge, while simultaneously causing small changes to the soil microstructure and the crystal structure of the oil sludge. Furthermore, this process does not lead to a significant depletion of key nutrients or the generation of new pollutants.

Bacterial co-infection in COVID-19: a call to stay vigilant.

Co-infection with diverse bacteria is commonly seen in patients infected with the novel coronavirus, SARS-CoV-2. This type of co-infection significantly impacts the occurrence and development of novel coronavirus infection. Bacterial co-pathogens are typically identified in the respiratory system and blood culture, which complicates the diagnosis, treatment, and prognosis of COVID-19, and even exacerbates the severity of disease symptoms and increases mortality rates. However, the status and impact of bacterial co-infections during the COVID-19 pandemic have not been properly studied. Recently, the amount of literature on the co-infection of SARS-CoV-2 and bacteria has gradually increased, enabling a comprehensive discussion on this type of co-infection. In this study, we focus on bacterial infections in the respiratory system and blood of patients with COVID-19 because these infection types significantly affect the severity and mortality of COVID-19. Furthermore, the progression of COVID-19 has markedly elevated the antimicrobial resistance among specific bacteria, such as Klebsiella pneumoniae, in clinical settings including intensive care units (ICUs). Grasping these resistance patterns is pivotal for the optimal utilization and stewardship of antibiotics, including fluoroquinolones. Our study offers insights into these aspects and serves as a fundamental basis for devising effective therapeutic strategies. We primarily sourced our articles from PubMed, ScienceDirect, Scopus, and Google Scholar. We queried these databases using specific search terms related to COVID-19 and its co-infections with bacteria or fungi, and selectively chose relevant articles for inclusion in our review.

Boosted H2O2 utilization and selective hydroxyl radical generation for water decontamination: Synergistic roles of dual active sites in H2O2 activation.

H2O2 as a green oxidant plays a crucial role in numerous green chemical reactions. However, how to improve its activation and utilization efficiency as well as regulate the distribution of ROS remains a pressing challenge. In this work, a sulfur quantum dots (SQDs) modified zero-valent iron (SQDs@ZVI) was delicately designed and prepared, whose iron sites can coordinate with strongly electronegative sulfur atoms to construct highly reactive Fe-S dual active sites, for high-efficient selective H2O2 activation and utilization with potent •OH production. Experimental tests, in situ FTIR/Raman spectra and theoretical calculations demonstrated that SQDs modulates the local coordination structure and electronic density of iron centers, thus effectively enhancing its Fenton reactivity and promoting the rate-limiting H2O2 adsorption and subsequent barrierless dissociation of peroxyl bonds into •OH via the formation of bridged S-O-O-Fe complexes. Consequently, substantial generated surface-bound •OH induced by the highly reactive Fe-S dual sites enabled excellent degradation of miscellaneous organic pollutants over a broad pH range (3.0-9.0). The developed device-scale Fenton filter realized durable performance (up to 200 h), verifying the vast potential of SQDs@ZVI with diatomic sites for practical application. This work presents a promising strategy to construct metal-nonmetal diatomic active sites toward boosting selective activation and effective utilization of H2O2, which may inspire the design of efficient heterogeneous Fenton reaction for water decontamination.

Effects of low-frequency pulsed electrical stimulation at the common peroneal nerve on chronic refractory wounds of the lower limb: A randomized controlled trial.

Background and aims: Electrical stimulation (ES) has been shown to substantially enhance the quality of life by alleviating pain in patients with chronic wounds. This study aimed to observe the effects of low-frequency pulsed wearable ES at the common peroneal nerve on chronic refractory wounds of the lower limb. Methods: Forty-eight participants were randomly divided into control group (n = 24) and treatment group (n = 24) in this study. The control group received standard wound care (SWC) exclusively, whereas the treatment group was administered both SWC and the wearable low-frequency ES targeting the common peroneal nerve. Measurements of wound area, pain intensity, wound status, and quality of life scores were systematically recorded both before and after 4 weeks treatment. Results: After 4 weeks of intervention, the percentage area reduction was significantly higher in the treatment group compared to the control group (Z = -3.9, p < 0.001), and the healing rate of the treatment group was significantly higher than that of the control group (33% vs. 4%). Moreover, the visual Analog Scale for Pain score (ß = -0.65, p = 0.019), the Bates-Jensen Wound Assessment Tool score (p < 0.05), and the questionnaire on quality of life with chronic wounds (Wound-Qol) score (ß = -4.23, p = 0.003) were significantly decreased in the patients in the treatment group compared to the control group. Conclusion: The wearable low-frequency pulsed ES at the common peroneal nerve for the treatment of chronic refractory wounds showed significant improvement and were far superior compared to SWC. Future research should broaden its scope to include a diverse range of wound types and benefit from collaboration across multiple research centers.

Adsorption-desorption mechanisms and migration behavior of fluchlordiniliprole in four different soils under varied conditions.

Utilizing infrared spectroscopy coupled with batch equilibrium methods, the adsorption and desorption characteristics of the novel Insecticide fluchlordiniliprole were assessed in four different soil types. It was found that fluchlordiniliprole's adsorption and desorption in these soils were consistent with the Freundlich isotherm, exhibiting adsorption capacities (KF-ads) ranging from 8.436 to 36.269. Temperature fluctuations, encompassing both high and low extremes, impaired the ability of soil to adsorb fluchlordiniliprole. In addition, adsorption dynamics were modulated by several other factors, including soil pH, ionic strength, amendments (e.g., biochar and humic substances), and the presence of various surfactants and microplastics. Although capable of leaching, fluchlordiniliprole exhibited weak mobility in most soils. Therefore, it appears that fluchlordiniliprole seems to pose a threat to surface soil and aquatic biota, but a minimal threat to groundwater. SYNOPSIS STATEMENT: This research examines the dynamics of fluchlordiniliprole in soil, an will aid in maintaining ecological safety and managing agricultural pesticides. The study's comprehensive analysis of adsorption, desorption, and soil migration patterns significantly contributes to our understanding of pesticide interactions with diverse soil types. The results of this study will enable the development of environmentally responsible agricultural practices.

Epitranscriptomic reader YTHDF2 regulates SEK1(MAP2K4)-JNK-cJUN inflammatory signaling in astrocytes during neurotoxic stress.

As the most abundant glial cells in the central nervous system (CNS), astrocytes dynamically respond to neurotoxic stress, however, the key molecular regulators controlling the inflammatory status of these sentinels during neurotoxic stress are many and complex. Herein, we demonstrate that the m6A epitranscriptomic mRNA modification tightly regulates the pro-inflammatory functions of astrocytes. Specifically, the astrocytic neurotoxic stressor, manganese (Mn), downregulated the m6A reader YTHDF2 in human and mouse astrocyte cultures and in the mouse brain. Functionally, YTHDF2 knockdown augmented, while its overexpression dampened, the neurotoxic stress-induced proinflammatory response, suggesting YTHDF2 serves as a key upstream regulator of inflammatory responses in astrocytes. Mechanistically, YTHDF2 RIP-sequencing identified MAP2K4 (MKK4; SEK1) mRNA as a YTHDF2 target influencing inflammatory signaling. Our target validation revealed that Mn-exposed astrocytes mediate proinflammatory responses by activating the phosphorylation of SEK1, JNK, and cJUN signaling. Collectively, YTHDF2 serves as a key upstream 'molecular switch' controlling SEK1(MAP2K4)-JNK-cJUN proinflammatory signaling in astrocytes.

Preparation of Cu/Cu2O/BC and Its Performance in Adsorption-Photocatalytic Degradation of Methyl Orange in Water.

In this study, we prepared a low-cost novel Cu/Cu2O/BC nanocomposite visible-light photocatalyst by the impregnation method using CuSO4·5H2O and rice husk biochar (BC) as raw materials and Na2S2O4 as a single reductant to improve the stability and dispersion of the Cu/Cu2O nanoparticles, in order to solve their aggregation tendency during photocatalysis. The morphology and structure of the Cu/Cu2O/BC were characterized using various analytical and spectroscopic techniques. The photocatalytic effect and cyclic stability of the synthesized photocatalyst on methyl orange (MO) removal were investigated under visible light radiation and various parameter conditions, including the mass ratio of BC to Cu/Cu2O, initial MO concentration, pH, temperature, and catalyst dosage. The results show that the synthesized Cu/Cu2O/BC nanocomposite composed of Cu/Cu2O spherical particles was loaded on the BC carrier, which has better stability and dispersion. The best adsorption-photocatalytic effect of the Cu/Cu2O/BC is exhibited when the mass ratio of BC to Cu/Cu2O is 0.2. A total of 100 mg of Cu/Cu2O/BC can remove 95% of the MO and 88.26% of the COD in the aqueous solution at pH = 6, T = 25 °C, and an initial MO concentration of 100 mg/L. After five cycles of degradation, the MO degradation rate in the sample can still remain at 78.41%. Both the quasi-secondary kinetic model and the Langmuir isothermal adsorption model describe the adsorption process. Additionally, the thermodynamic analysis demonstrates that the photocatalytic process follows the quasi-primary kinetic model and that the removal process is of spontaneous heat absorption. The photocatalyst described in this paper offers a cost-effective, easily prepared, and visible-light-responsive solution for water pollution treatment.

m6A mRNA methylation in brown fat regulates systemic insulin sensitivity via an inter-organ prostaglandin signaling axis independent of UCP1.

Brown adipose tissue (BAT) regulates systemic metabolism by releasing signaling lipids. N6-methyladenosine (m6A) is the most prevalent and abundant post-transcriptional mRNA modification and has been reported to regulate BAT adipogenesis and energy expenditure. Here, we demonstrate that the absence of m6A methyltransferase-like 14 (METTL14) modifies the BAT secretome to improve systemic insulin sensitivity independent of UCP1. Using lipidomics, we identify prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a) as BAT-secreted insulin sensitizers. PGE2 and PGF2a inversely correlate with insulin sensitivity in humans and protect mice from high-fat-diet-induced insulin resistance by suppressing specific AKT phosphatases. Mechanistically, METTL14-mediated m6A promotes the decay of PTGES2 and CBR1, the genes encoding PGE2 and PGF2a biosynthesis enzymes, in brown adipocytes via YTHDF2/3. Consistently, BAT-specific knockdown of Ptges2 or Cbr1 reverses the insulin-sensitizing effects in M14KO mice. Overall, these findings reveal a novel biological mechanism through which m6A-dependent regulation of the BAT secretome regulates systemic insulin sensitivity.

m6A mRNA methylation by METTL14 regulates early pancreatic cell differentiation.

N6-methyladenosine (m6A) is the most abundant chemical modification in mRNA and plays important roles in human and mouse embryonic stem cell pluripotency, maintenance, and differentiation. We have recently reported that m6A is involved in the postnatal control of ß-cell function in physiological states and in type 1 and 2 diabetes. However, the precise mechanisms by which m6A acts to regulate the development of human and mouse pancreas are unexplored. Here, we show that the m6A landscape is dynamic during human pancreas development, and that METTL14, one of the m6A writer complex proteins, is essential for the early differentiation of both human and mouse pancreatic cells.

Proton vs Electron: The Dual Role of Redox-Inactive Metal Ions in Permanganate Oxidation Kinetics.

Redox-inactive metal-ion-driven modulation of the oxidation behavior of high-valent metal-oxo complex has garnered significant interest in biological and chemical synthesis; however, their role in permanganate (Mn(VII)) oxidation for the removal of organic pollutants has been largely neglected. Here, we uncover the impact of six metal ions (i.e., Ca2+, Mg2+, Ni2+, Zn2+, Al3+, and Sc3+) presenting in water environments on Mn(VII) activity. These ions uniformly boost the electron and oxygen transfer capabilities of Mn(VII) while impeding proton transfer, as evidenced by electrochemical tests, thioanisole probe analysis, and the kinetic isotope effect. The observed effects are intricately linked to the Lewis acidity of the metal ions. Further mechanistic insights reveal that Mn(VII) can interact with metal ions without direct reduction. Such interactions modify the electronic configuration of Mn(VII) and create an acidic microenvironment, thus increasing its electrophilicity and the energy barrier for the abstraction of proton from organic substrates. More importantly, the efficacy of Mn(VII) in removing phenolic pollutants is regulated by these ions through changing the driving force for proton and electron transfer, i.e., facilitated at pH > 4.5 and inhibited at lower pH. The contribution of active Mn intermediates is also discussed to reveal the oxidative mechanism of the metal ion/Mn(VII) system. These findings not only facilitate the rational design of Mn(VII) oxidation conditions in the presence of metal ions for water decontamination but also offer an alternative paradigm for enhancing electrophilic oxidation.

Modular enantioselective assembly of multi-substituted boron-stereogenic BODIPYs.

Boron dipyrromethenes (BODIPYs) are some of the most popular and indispensable tetracoordinate boron compounds and have found widespread applications owing to their excellent spectroscopic and photophysical properties. BODIPYs possessing boron-stereogenic centres are scarce, and strategies for the synthesis of enantioenriched boron-stereogenic BODIPYs with structural diversity remain underdeveloped. In theory, the BODIPY core skeleton has several sites that could be decorated with different substituents. However, due to the lack of general and efficient asymmetric synthetic methods, this potential diversity of chiral BODIPYs has not been exploited. Here we demonstrate a modular enantioselective assembly of multi-substituted boron-stereogenic BODIPYs in high efficiency with excellent enantioselectivities. Key to the success is the Pd-catalysed desymmetric Suzuki cross-coupling, enabling the precise discrimination of the two α C-Cl bonds of the designed prochiral BODIPY scaffold, giving access to a wide range of highly functionalized boron-stereogenic BODIPYs. Derivatizations, photophysical properties and applications in chiral recognition of the obtained optical BODIPYs are further explored.

Efficacy and safety of standard BEACOPP regimen versus ABVD regimen for treatment of advanced Hodgkin's lymphoma.

INTRODUCTION: The current treatment regimens for Hodgkin's lymphoma (HL) are associated with high incidences of adverse events. PURPOSE: This study aimed to compare the efficacy and safety of doxorubicin + bleomycin + vincristine + dacarbazine (ABVD) and standard bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisone (BEACOPP) chemotherapy in the treatment of advanced stage HL. METHODS: This multicenter, randomized, parallel, open, positive control noninferiority trial was conducted from 2016 to 2019 and comprised 93 subjects who were randomized in a 1:1 ratio between the treatment (BEACOPP; n = 44) and control (ABVD; n = 49) groups. RESULTS: The primary efficacy endpoint of this trial was the objective response rate (ORR) after eight cycles of chemotherapy, which was 100.00% (36/36) in the treatment group and 95.74% (45/49) in the control group. The incidence of adverse reactions was 100% in both groups. Significant differences (P < 0.05) in the incidences of grade 3 (39/44 [88.64%] vs. 23/49 [46.94%]) and grade 4 (27/44 [61.36%] vs. 8/49 [16.94%]) adverse events were observed between the treatment and control groups, respectively. However, most of these reactions were manageable, with no serious consequences, and were reversible after discontinuation of the treatment. CONCLUSION: Both regimens had a similar ORR and were associated with a high number of adverse events. The ABVD regimen was better tolerated and safer than the standard BEACOPP regimen. This study indicates that the standard BEACOPP regimen may be considered as a treatment option for patients with advanced HL.

A lysosome-targeted fluorescent probe for thiol detection in drug analysis and multiple biological systems.

Biothiols, characterized by their unique sulfhydryl (-SH) groups, possess excellent antioxidant properties, effectively neutralizing the damage to cellular structures caused by reactive oxygen species (ROS) in living organisms. Additionally, lysosomes play a crucial role in decomposing damaged biomolecules through the action of their internal enzymes, regulating the cellular redox state, and mitigating oxidative stress. To facilitate rapid monitoring of intracellular biothiols, particularly within lysosomes, we constructed a lysosome-targeted biothiol fluorescent probe, PHL-DNP, in this study. PHL-DNP exhibited excellent photophysical properties in an aqueous test system, including strong fluorescence enhancement response, excellent selectivity, and low detection limits (Cys 16.5 nM, Hcy 16.8 nM, GSH 21.3 nM, Cap 26.6 nM). These attributes enabled easy and efficient qualification of Cys on test strips and accurate determination of the effective content of captopril tablets. Notably, PHL-DNP demonstrated low cytotoxicity and precise lysosomal targeting. Through bioimaging, PHL-DNP not only monitored changes in biothiol levels under oxidative stress but also assessed biothiols in complex biological systems such as live HeLa cells, zebrafish, tumor tissue sections, and radish roots. This provides a promising tool for quantitative analysis of biothiols, disease marker detection, and drug testing.

Characterizing Relationships between T-cell Inflammation and Outcomes in Patients with High-Risk Neuroblastoma According to Mesenchymal and Adrenergic Signatures.

Recent insights have identified adrenergic (ADRN) and mesenchymal (MES) cell lineages as distinct biologic cell types and T-cell inflammation as a prognostic marker in neuroblastoma. We hypothesized that elucidating unique and overlapping aspects of these biologic features could serve as novel biomarkers for informing ongoing efforts to improve therapeutic approaches for children with high-risk neuroblastoma. We identified lineage-specific, single-stranded super-enhancers to define ADRN and MES specific genes. Publicly available RNA-seq of diagnostic tumor biopsies was used in Discovery and Validation cohorts. Each tumor was assigned a relative MES score and T-cell inflammation (TCI) score. Survival was assessed using the Kaplan-Meier method, and differences were assessed by the log-rank test. Inflammation scores were correlated with MES scores and anticorrelated with MYCN-amplification in both cohorts. Among patients with high-risk, ADRN tumors, those with TCI tumors had superior overall survival to those with non-inflamed tumors. A similar, but nonsignificant, trend was observed in the Validation cohort. Conversely, there was no difference according to TCI status in the MES cohort in either the Discover or Validation cohorts. High-inflammation scores were correlated with improved survival in some patients with high-risk, ADRN but not MES neuroblastoma. Our findings bolster support for further developing T-cell-based and immunotherapy-based approaches for children with high-risk neuroblastoma of varying MES and ADRN expression. SIGNIFICANCE: Adrenergic (ADRN) and mesenchymal (MES) lineages are distinct biologic cell types in neuroblastoma. We defined ADRN and MES specific genes and found that high-risk, ADRN tumors harboring elevated T-cell inflammation signatures had superior overall survival. Our findings bolster support for further developing immunotherapy-based approaches for children with high-risk neuroblastoma.