Sludge-derived hydrochar modulates complete nonradical electron transfer in peroxydisulfate activation via pyrrolic-N and carbon defect: Implication for degrading electron-rich ionizable anilines compounds.

Nonradical electron transfer process (ETP) is a promising pathway for pollutant degradation in peroxydisulfate-based advanced oxidation processes (PDS-AOPs). However, there is a critical bottleneck to trigger ETP by sludge-derived hydrochar due to its negatively charged surface, inferior porosity and electrical conductivity. Herein, pyrrolic-N doped and carbon defected sludge-derived hydrochar (SDHC-N) was constructed for PDS activation to degrade anilines ionizable organic compounds (IOC) through complete nonradical ETP oxidation. Degradation of anilines IOC was not only affected by the electron-donating capacity but also proton concentration in solution because of the ionizable amino group (-NH2). Diverse effects including proton favor, insusceptible and inhibition were observed. Impressively, addition of HCO3 with strong proton binding capacity boosted aniline degradation nearly 10 times. Moreover, characterizations and theoretical calculations demonstrated that pyrrolic-N increased electron density and created positively charged surface, profoundly promoting generation of SDHC-N-S2O82-* complexes. More delocalized electrons around carbon defect could enhance electron mobility. This work guides a rational design of sludge-derived hydrochar to mediate nonradical ETP oxidation, and provides insights into the impacts of proton on anilines IOC degradation.

A simple and label-free fluorescent DNA sensor for visual detection of aptamer-based berberine.

The intrinsic fluorescence of berberine is very weak, which can be enhanced by its interaction with specific aptamers. A simple and sensitive DNA sensor for visual detection of berberine has here been established. When using this sensor, there was a good linear relationship between the change in fluorescence intensity of berberine and the concentration of berberine in the range of 16-2000 nM, with a detection limit of 5.1 nM. The change in fluorescence intensity was caused by the addition of aptamers. A detection limit of 170.1 nM was acquired by reading the RGB values of fluorescent images with a smartphone for the quantification of berberine. Common antibiotics did not interfere with the measurement of the berberine concentration. The molecular ion peaks of the complexes formed by the aptamer and berberine could be clearly observed by electrospray ionization mass spectrometry. The UV-vis absorption spectra, circular dichroism spectra, and fluorescence spectra indicated a strong interaction between berberine and the aptamer. The dissociation constant (Kd) between berberine and the aptamer was 1.91 µM. This sensor was both simple and sensitive, requiring only a 21-base oligonucleotide. It realized a visual quantitative analysis with a smartphone. This method could also be used for similar fluorescence visualization determination of aptamer-based drug molecules.

Intensive Cycloalkyl-Fused Pyridines for Aminopyridyl-Zinc-Heteroimidazoles Achieving High Efficiency toward the Ring-Opening Polymerization of Lactides.

The model precatalyst sp3- and sp2-N dinitrogen-coordinated zinc-heteroimidazole has been used as an efficient catalyst for the ring-opening polymerization of cyclic esters. Subsequent to our exceptional active 5,6,7-trihydroquinolin-8-amine-zinc catalysts for the ring-opening polymerization (ROP) of ε-caprolactone, various pyridine-fused cycloalkanones (ring size from five to eight) are developed for the correspondent fused amine-pyridine derivatives and their zinc-heteroimidazole chloride complexes Zn1-Zn8 (LZnCl2) bearing N-diphenylphosphinoethyl pendants. Activated with two equivalents of LiN(SiMe3)2, the title zinc complexes efficiently promote the ROP of L-lactide (L-LA) in situ; among them, Zn4/2Li(NSiMe3)2 catalyzed 500 equivalent L-LA at 80 °C with 92% conversion in 5 min (TOF: 5520 h-1). Under the same conditions, the catalytic efficiency for the ROP of rac-LA by Zn1-Zn8/2Li(NSiMe3)2 was slightly lower than that for L-LA (highest TOF: 4440 h-1). In both cases, cyclooctyl-fused pyridyl-zinc complexes exhibited higher activity than others, while the cycloheptyl-fused zinc complexes showed the lowest activity. The microstructure analysis of the polymers showed they possessed a linear structure capped with CH3O as major and cyclic structure as minor. In this work, all the ligands and zinc complexes were well characterized by 1H/13C/31P NMR, FT-IR spectroscopy as well as elemental analysis.

A novel approach to enhance high optically active L-lactate production from food waste by landfill leachate.

The recycling of food waste (FW) through anaerobic fermentation into lactic acid (LA), with two isomers L-LA and D-LA, aligns with the principles of a bio-based circular economy. However, FW fermentation is often limited by competing pathways, acidification inhibition, and trace metals deficiency. This study investigates the introduction of landfill leachate, containing buffering agents (ammonia) and trace metals, into FW fermentation. Various dosages of landfill leachate, ranging from 90 (LN-90) to 450 mg/L (LN-450) based on inclusive ammonia calculation, were employed. Results showed that LA production peaked at 43.65 ± 0.57 g COD/L in LN-180 on day 6, with a high optical activity of L-LA at 92.40 ± 1.15 %. Fermentation pathway analysis revealed that landfill leachate amendment enhances hydrolysis (as evidenced by increased activity of amylase, α-glucosidase, and protease) and glycolysis (resulting in enhanced utilization of carbohydrates and glucose). The inclusive ammonia in leachate plays a crucial role as a buffer, maintaining optimal pH conditions (5-7), thereby reducing volatile fatty acid production and thus intensifying LA orientations. The increased activity of L-lactate dehydrogenase (L-LA generation) and decreased NAD-independent lactate dehydrogenase (LA consumption) in properly dosed leachate further explained the high accumulation of L-LA. Dominance of lactic acid bacteria, including Streptococcus, Enterococcus, Klebsiella, Bifidobacterium, Bavariicoccus, and Lacticaseibacillus, accounted for 91.08% (LN-90), while inhibitory effects were observed in LN-450 (4.45%). Functional gene analysis further supported the enhanced glycolysis, L-lactate dehydrogenase, and nitrogen assimilation. Finally, a network analysis indicates a beneficial effect on the genus Enterococcus and Klebsiella by landfill leachate addition. This study demonstrates the efficiency of utilizing landfill leachate to enhance LA recycling from FW fermentation, aligning with the concept of circular economy by transforming waste into valuable resources.

Factors influencing the Central Nervous System (CNS) distribution of the ATR inhibitor elimusertib (BAY1895344): Implications for the treatment of CNS tumors.

Glioblastoma (GBM) is a disease of the whole brain, with infiltrative tumor cells protected by an intact BBB. GBM has a poor prognosis despite aggressive treatment, in part due to lack of adequate drug permeability at the BBB. Standard of care GBM therapies include radiation and cytotoxic chemotherapy that lead to DNA damage. Subsequent activation of DNA damage response (DDR) pathways can induce resistance. Various DDR inhibitors, targeting the key regulators of these pathways such as ataxia telangiectasia mutated and Rad3-related (ATR), are being explored as radio- and chemo-sensitizers. Elimusertib, a novel ATR kinase inhibitor, can prevent repair of damaged DNA, increasing efficacy of DNA damaging cytotoxic therapies. Robust synergy was observed in vitro when elimusertib was combined with the DNA-damaging agent, temozolomide, however, we did not observe improvement with this combination in in vivo efficacy studies in GBM orthotopic tumor-bearing mice. This in vitro - in vivo disconnect was explored to understand factors influencing CNS distribution of elimusertib and reasons for lack of efficacy. We observed that elimusertib is rapidly cleared from systemic circulation in mice and would not maintain adequate exposure in the CNS for efficacious combination therapy with temozolomide. CNS distribution of elimusertib is partially limited by P-gp efflux at the BBB, and high binding to CNS tissues leads to low levels of pharmacologically active (unbound) drug in the brain. Acknowledging the potential for inter-species differences in pharmacokinetics, these data suggest that clinical translation of elimusertib in combination with temozolomide for treatment of GBM may be limited. Significance Statement This study examined the disconnect between the in vitro synergy and in vivo efficacy of elimusertib/temozolomide combination therapy by exploring systemic and CNS distributional pharmacokinetics. Results indicate that the lack of improvement in in vivo efficacy in GBM PDX models could be attributed to inadequate exposure of pharmacologically active drug concentrations in the CNS. These observations can guide further exploration of elimusertib for the treatment of GBM, or other CNS tumors.

COPD-Like Phenotypes in TBC-Treated Mice Can be Effectively Alleviated via Estrogen Supplement.

Tris(2,3-dibromopropyl) isocyanurate (TBC), recognized as an endocrine disruptor, can cause inflammatory injury to the lung tissue of mice. To investigate the specific respiratory effects of TBC, male C57BL/6J mice were administered a daily dose of 20 mg/kg of TBC over 14 days. Postexposure, these mice developed chronic obstructive pulmonary disease (COPD)-like symptoms characterized by inflammatory lung damage and functional impairment. In light of the antiestrogenic properties of TBC, we administrated estradiol (E2) to investigate its potential protective role against TBC-induced damage and found that the coexposure of E2 notably mitigated the COPD-like phenotypes. Immunohistochemical analysis revealed that TBC exposure reduced estrogen receptor alpha (ERα) expression and increased nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression, while E2 treatment rebalanced the expression levels of ERα and NF-κB to their normative states. Our findings indicate that TBC, as an antiestrogenic agent, may contribute to the pathogenesis of COPD through an ERα-mediated inflammatory pathway, but that E2 treatment could reverse the impairment, providing a potentially promising remedial treatment. Given the lung status as a primary target of air pollution, the presence of antiestrogenic compounds like TBC in atmospheric particulates presents a significant concern, with the potential to exacerbate respiratory conditions such as COPD and pneumonia.

Key genes and immune infiltration patterns and the clinical implications in psoriasis patients.

BACKGROUND: Psoriasis is an immune-mediated skin disease, closely related to immune regulation. The aim was to understand the pathogenesis of psoriasis further, reveal potential therapeutic targets, and provide new clues for its diagnosis, treatment, and prevention. MATERIALS AND METHODS: Expression profiling data were obtained from the Gene Expression Omnibus (GEO) database for skin tissues from healthy population and psoriasis patients. Differentially expressed genes (DEGs) were selected for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) analysis separately. Machine learning algorithms were used to obtain characteristic genes closely associated with psoriasis. Receiver operating characteristic (ROC) curve was used to assess the diagnostic value of the characteristic genes for psoriasis. The Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to calculate the proportion of immune cell infiltration. Correlation analysis was used to characterize the connection between gene expression and immune cell, Psoriasis Area and Severity Index (PASI). RESULTS: A total of 254 DEGs were identified in the psoriasis group, including 185 upregulated and 69 downregulated genes. GO was mainly enriched in cytokine-mediated signaling pathway, response to virus, and cytokine activity. KEGG was mainly focused on cytokine-cytokine receptor interaction and IL-17 signaling pathway. GSEA was mainly in chemokine signaling pathway and cytokine-cytokine receptor interaction. The machine learning algorithm screened nine characteristic genes C10orf99, GDA, FCHSD1, C12orf56, S100A7, INA, CHRNA9, IFI44, and CXCL9. In the validation set, the expressions of these nine genes increased in the psoriasis group, and the AUC values were all > 0.9, consistent with those of the training set. The immune infiltration results showed increased proportions of macrophages, T cells, and neutrophils in the psoriasis group. The characteristic genes were positively or negatively correlated to varying degrees with T cells and macrophages. Nine characteristic genes were highly expressed in the moderate to severe psoriasis group and positively correlated with PASI scores. CONCLUSION: High levels of nine characteristic genes C10orf99, GDA, FCHSD1, C12orf56, S100A7, INA, CHRNA9, IFI44, and CXCL9 were risk factors for psoriasis, the differential expression of which was related to the regulation of immune system activity and PASI scores, affecting the proportions of different immune cells and promoting the occurrence and development of psoriasis.

Evaluation of Postoperative Discomfort After Strabismus Surgery Under General Anesthesia in Children: A Prospective Observational Study.

Purpose: Strabismus surgery is most commonly performed on children under general anesthesia. However, few studies have focused on the postoperative discomfort in children after strabismus surgery. This study aimed to evaluate postoperative discomfort and the associated risk factors in children who underwent strabismus surgery under general anesthesia. Patients and Methods: A single-center prospective observational study including 300 children who underwent strabismus surgery after general anesthesia was conducted. Patients' characteristics, preoperative anxiety, surgical and anesthesia data, discomfort within 24 hours after postanesthesia care unit were recorded. The primary outcome was the incidence of postoperative discomfort. Results: Approximately 51.33% of the children complained of at least one of the following types of postoperative discomfort: postoperative nausea and vomiting (PONV) (23.00%), headache (4.33%), dizziness (20.33%) and emergence agitation (EA) (5.33%). Multivariate analysis indicated that history of motion sickness (P<0.001, odds ratio [OR]=3.72), and surgery in the dominant eye (P=0.010, OR=2.00) were independent predictors of postoperative discomfort; age was an independent predictor of EA (P<0.001, OR=0.36); prism diopter≥40 was an independent predictor of headache (P=0.005, OR=5.53); age (P=0.020, OR=1.12) and history of motion sickness (P=0.001, OR=2.80) were independent predictors of dizziness; history of motion sickness (P=0.001, OR=2.63) and surgery of inferior oblique anterior transposition (IOAT) (P=0.004, OR=3.10) were independent predictors of PONV. Conclusion: The most frequent postoperative symptoms in children after undergoing strabismus surgery under general anesthesia are PONV, dizziness, EA, and headache. Younger age, larger angle of strabismus, history of motion sickness, surgery on the dominant eye, and surgery of IOAT may be additional risk factors for postoperative discomfort.

Absence of motor impairments or pathological changes in TMEM230 knockout rats.

Parkinson's disease (PD), which is the second most common neurodegenerative disorder, is characterized by progressive movement impairment and loss of midbrain dopaminergic neurons in the substantia nigra. Although mutations in TMEM230 are linked to familial PD, the pathogenic mechanism underlying TMEM230-associated PD remains to be elucidated. To explore the effect of TMEM230 depletion in vivo, we created TMEM230 knockout rats using CRISPR-Cas9 technology. TMEM230 knockout rats did not exhibit any core features of PD, including impaired motor function, loss of dopaminergic neurons in the substantia nigra, or altered expression of proteins related to autophagy, the Rab family, or vesicular trafficking. In addition, no glial reactions were observed in TMEM230 knockout rats. These results indicate that depletion of TMEM230 may not lead to dopaminergic neuron degeneration in rats, further supporting that PD-associated TMEM230 mutations lead to dopaminergic neuron death by gain-of-toxic function.

Controllable and selective fluoride precipitation from phosphate-rich wastewater.

Industrial wastewater containing high levels of fluoride and phosphate poses significant environmental challenges and results in the waste of non-renewable resources. This study investigates the use of La(OH)3 as a precipitating agent to selectively remove and separate fluoride from phosphate in such wastewater. The findings indicate that fluoride removal efficiency is highly dependent on the pH level and La(OH)3 dosage. Using Response Surface Methodology, the optimal conditions for fluoride precipitation were identified as a pH range of 1.0 to 2.5, a reaction time of 60-80 min, a La/3F molar ratio of 2.0, and reaction temperature of 25 °C. Under these parameters, the fluoride removal efficiency exceeded 96.9 %, while phosphate removal remained around 7.2 %. Further Density Functional Theory calculations and characterization confirmed La(OH)3 has a strong affinity for fluoride than phosphate under acidic conditions, leading to the formation of a LaF3 precipitate without forming LaPO4, effectively separating fluoride from phosphate. These results demonstrate an efficient strategy for treating wastewater with high fluoride and phosphate content, enabling the selective precipitation and recovery of these elements for sustainable management.

The Illness Experiences of Adolescents with Type 1 Diabetes Mellitus: A Qualitative Meta-synthesis.

This study aims to systematically review the illness experience of adolescent patients with type 1 diabetes mellitus (T1DM). The JBI qualitative systematic review method was used and meta-aggregate analysis of 14 qualitative studies was performed. Qualitative studies on the disease experience of adolescent patients with T1DM were obtained from Cochrane, PubMed, Web of Science, CINAHL, Embase, Wanfang, CNKI, and VIP, and the search period was from 1995 to 2024. The qualitative research quality evaluation tool of JBI the Evidence-based Health Care Center in Australia was used to evaluate the analysis results. Thirty-one results were distilled and categorized into 7 themes and then synthesized into 3 overarching findings: (1) experiencing psychological distress and developing coping mechanisms following adjustment; (2) acknowledging self-management shortcomings and actively seeking support; and (3) overcoming challenges and growing through experiences. The findings illuminate that adolescents with T1DM often experience negative physical and emotional challenges during their illness. Transitioning from dependency to independence poses numerous obstacles that can be overcome by improving both internal and external support, cultivating self-management skills, strengthening coping mechanisms, and achieving control over the disease while fostering personal growth.

Global, regional, and national burden of ischemic heart disease attributable to secondhand smoke from 1990 to 2019.

INTRODUCTION: Assessing the burden of ischemic heart disease (IHD) attributable to secondhand smoke (SHS) exposure is crucial for informing evidence-based healthcare practices, prevention strategies, and resource allocation planning. METHODS: The burden of IHD attributable to SHS from 1990 to 2019 was assessed using the comparative risk assessment method as part of the Global Burden of Disease (GBD) study 2019. RESULTS: Globally, the absolute number of deaths and disability-adjusted life-years (DALYs) from IHD due to SHS increased substantially from 270.0 thousand and 6971.3 thousand in 1990 to 397.4 thousand and 9566.1 thousand in 2019. The corresponding age-standardized mortality rates (ASMR) and age-standardized DALYs rates (ASDR) were both in a decreasing trend with estimate of the annual percentage change (EAPC) of -1.38 (-1.42 - -1.34) and -1.43 (-1.47 - -1.38). Central Asia has the highest ASMR (16 per 100000, 95% uncertainty interval, UI: 12.8-19.4), and Oceania has the highest ASDR (323.2 per 100000, 95% UI: 228.9-443.1 per 100000) in 2019. All sociodemographic index (SDI) category regions showed a decreasing trend in ASMR and ASDR, with the decrease being more obvious in high and high-middle SDI regions. Our analysis identified an escalating trend concerning ASMR and ASDR in Oceania from 1990 to 2019. In 2019, the most significant number of deaths and DALYs occurred in the age group of 80-84 years (5.4 thousand, 95% UI: 3.7-7.3 in thousands) and the age group of 55-59 years (1140.8 thousand, 95% UI: 876.1-1435 in thousands). CONCLUSIONS: Our study reveals an absolute global increase in deaths and DALYs from IHD due to SHS from 1990 to 2019. Despite a declining trend in ASMR and ASDR, regional disparities persist. The elderly and middle-aged populations bore the most significant burden. These findings highlight the ongoing global health impact of SHS on IHD and emphasize the need for targeted interventions in regions with rising trends and vulnerable age groups.

The combination of modified acupuncture needle and melittin hydrogel as a novel therapeutic approach for rheumatoid arthritis treatment.

Rheumatoid arthritis (RA) involves chronic joint inflammation. Combining acupuncture and medication for RA treatment faces challenges like spatiotemporal variability, limited drug loading in acupuncture needles, and premature or untargeted drug release. Here, we designed a new type of tubular acupuncture needles, with an etched hollow honeycomb-like structure to enable the high loading of therapeutics, integrating the traditional acupuncture and drug repository into an all-in-one therapeutic platform. In these proof-of-concept experiments, we fabricated injectable hollow honeycomb electroacupuncture needles (HC-EA) loaded with melittin hydrogel (MLT-Gel), enabling the combination treatment of acupuncture stimulation and melittin therapy in a spatiotemporally synchronous manner. Since the RA microenvironment is mildly acidic, the acid-responsive chitosan (CS)/sodium beta-glycerophosphate (ß-GP)/ hyaluronic acid (HA) composited hydrogel (CS/GP/HA) was utilized to perform acupuncture stimulation and achieve the targeted release of injected therapeutics into the specific lesion site. Testing our therapeutic platform involved a mouse model of RA and bioinformatics analysis. MLT-Gel@HC-EA treatment restored Th17/Treg-mediated immunity balance, reduced inflammatory factor release (TNF-α, IL-6, IL-1ß), and alleviated inflammation at the lesion site. This novel combination of modified acupuncture needle and medication, specifically melittin hydrogel, holds promise as a therapeutic strategy for RA treatment.

PtbNet: Based on Local Few-Shot Classes and Small Objects to accurately detect PTB.

Pulmonary Tuberculosis (PTB) is one of the world's most infectious illnesses, and its early detection is critical for preventing PTB. Digital Radiography (DR) has been the most common and effective technique to examine PTB. However, due to the variety and weak specificity of phenotypes on DR chest X-ray (DCR), it is difficult to make reliable diagnoses for radiologists. Although artificial intelligence technology has made considerable gains in assisting the diagnosis of PTB, it lacks methods to identify the lesions of PTB with few-shot classes and small objects. To solve these problems, geometric data augmentation was used to increase the size of the DCRs. For this purpose, a diffusion probability model was implemented for six few-shot classes. Importantly, we propose a new multi-lesion detector PtbNet based on RetinaNet, which was constructed to detect small objects of PTB lesions. The results showed that by two data augmentations, the number of DCRs increased by 80% from 570 to 2,859. In the pre-evaluation experiments with the baseline, RetinaNet, the AP improved by 9.9 for six few-shot classes. Our extensive empirical evaluation showed that the AP of PtbNet achieved 28.2, outperforming the other 9 state-of-the-art methods. In the ablation study, combined with BiFPN+ and PSPD-Conv, the AP increased by 2.1, APs increased by 5.0, and grew by an average of 9.8 in APm and APl. In summary, PtbNet not only improves the detection of small-object lesions but also enhances the ability to detect different types of PTB uniformly, which helps physicians diagnose PTB lesions accurately. The code is available at https://github.com/Wenhui-person/PtbNet/tree/master.

Exploring and validating heating dynamics in a radio-frequency electromagnetic field-based resonant chamber for mouse hyperthermia research.

Mild whole-body hyperthermia has been shown to have anti-tumor effects through an immune-modulating mechanism. Before it is widely applied in the clinic, tremendous mechanistic research in animals is necessary to adhere to evidence-based principles. The radio frequency electromagnetic field (RF-EMF) based heating facility could be a good choice for hyperthermia treatment, but the heating characteristics of a facility, including structure design, electromagnetic and thermal dosimetry, and the biologic effects of hyperthermia, need to be well elucidated. Here, we reported the heating characteristic study on a resonant chamber (RC) excited by a 1800 MHz solid source. The EMF in the RC was stirred by 24 static reflectors, which resulted in the standard deviation of electric field intensity being below 3 dB in the EM homogeneity evaluation. For the exposure scenario, six free-moving mice were loaded into separate cases and exposed simultaneously in the RC. The EMF energy absorption and distribution in exposed mice were calculated with the 12-plane-waves method of numerical simulation. Different levels of core body temperature increment in exposed mice were achieved through regulation of the source output power. Overexpression of heat shock proteins (HSPs) was detected in the liver, lung and muscle, but not in the brain of the exposed mice. The levels of representative inflammatory cytokines in the serum, TNF-α and IL-10 increased post RC exposure. Based on the heating characteristic study and validation, the applied RC would be a qualified heating system for mild whole-body hyperthermia effect research in mice.

Mild whole-body hyperthermia has potential anti-tumor effects by modulating the immune system. A radio frequency electromagnetic field (RF-EMF)-based heating facility emerges as a suitable option for hyperthermia treatment. However, a qualified heating facility for scientific research must elucidate its heating characteristics and validate the biological effects associated with hyperthermia. In this study, we report the characteristics of a rodent heating chamber using EMF energy. The special structure of the chamber not only achieved efficient EMF usage but also ensured the homogeneity in EMF spatial distribution, animal EM absorption, and EMF-caused biological effects. Our work may offer insights for designing a low-cost yet reliable heating facility for scientific research.

Preclinical Systemic Pharmacokinetics, Dose Proportionality, and Central Nervous System Distribution of the ATM Inhibitor WSD0628, a Novel Radiosensitizer for the Treatment of Brain Tumors.

Radiation therapy, a standard treatment option for many cancer patients, induces DNA double-strand breaks (DSBs), leading to cell death. Ataxia telangiectasia mutated (ATM) kinase is a key regulator of DSB repair, and ATM inhibitors are being explored as radiosensitizers for various tumors, including primary and metastatic brain tumors. Efficacy of radiosensitizers for brain tumors may be influenced by a lack of effective drug delivery across the blood-brain barrier. The objective of this study was to evaluate the systemic pharmacokinetics and mechanisms that influence the central nervous system (CNS) distribution of WSD0628, a novel and potent ATM inhibitor, in the mouse. Further, we have used these observations to form the basis of predicting effective exposures for clinical application. We observed a greater than dose proportional increase in exposure, likely due to saturation of clearance processes. Our results show that WSD0628 is orally bioavailable and CNS penetrant, with unbound partitioning in CNS (i.e., unbound tissue partition coefficient) between 0.15 and 0.3. CNS distribution is not limited by the efflux transporters P-glycoprotein and breast cancer resistant protein. WSD0628 is distributed uniformly among different brain regions. Thus, WSD0628 has favorable pharmacokinetic properties and potential for further exploration to determine the pharmacodynamics-pharmacokinetics efficacy relationship in CNS tumors. This approach will provide critical insights for the clinical translation of WSD0628 for the treatment of primary and secondary brain tumors. SIGNIFICANCE STATEMENT: This study evaluates the preclinical systemic pharmacokinetics, dose proportionality, and mechanisms influencing CNS distribution of WSD0628, a novel ATM inhibitor for the treatment of brain tumors. Results indicate that WSD0628 is orally bioavailable and CNS penetrant without efflux transporter liability. We also observed a greater than dose proportional increase in exposure in both the plasma and brain. These favorable pharmacokinetic properties indicate WSD0628 has potential for further exploration for use as a radiosensitizer in the treatment of brain tumors.

Bone morphogenetic protein 4 derived from the cerebrospinal fluid in patients with postherpetic neuralgia induces allodynia via the crosstalk between microglia and astrocyte.

INTRODUCTION: During postherpetic neuralgia (PHN), the cerebral spinal fluid (CSF) possesses the capability to trigger glial activation and inflammation, yet the specific changes in its composition remain unclear. Recent findings from our research indicate elevations of central bone morphogenetic protein 4 (BMP4) during neuropathic pain (NP), serving as an independent modulator of glial cells. Herein, the aim of the present study is to test the CSF-BMP4 expressions and its role in the glial modulation in the process of PHN. METHODS: CSF samples were collected from both PHN patients and non-painful individuals (Control) to assess BMP4 and its antagonist Noggin levels. Besides, intrathecal administration of both CSF types was conducted in normal rats to evaluate the impact on pain behavior, glial activity, and inflammation.; Additionally, both Noggin and STAT3 antagonist-Stattic were employed to treat the PHN-CSF or exogenous BMP4 challenged cultured astrocytes to explore downstream signals. Finally, microglial depletion was performed prior to the PHN-CSF intervention so as to elucidate the microglia-astrocyte crosstalk. RESULTS: BMP4 levels were significantly higher in PHN-CSF compared to Control-CSF (P < 0.001), with a positive correlation with pain duration (P < 0.05, r = 0.502). Comparing with the Control-CSF producing moderate paw withdrawal threshold (PWT) decline and microglial activation, PHN-CSF further exacerbated allodynia and triggered both microglial and astrocytic activation (P < 0.05). Moreover, PHN-CSF rather than Control-CSF evoked microglial proliferation and pro-inflammatory transformation, reinforced iron storage, and activated astrocytes possibly through both SMAD159 and STAT3 signaling, which were all mitigated by the Noggin application (P < 0.05). Next, both Noggin and Stattic effectively attenuated BMP4-induced GFAP and IL-6 upregulation, as well as SMAD159 and STAT3 phosphorylation in the cultured astrocytes (P < 0.05). Finally, microglial depletion diminished PHN-CSF induced astrogliosis, inflammation and endogenous BMP4 expression (P < 0.05). CONCLUSION: Our study highlights the role of CSF-BMP4 elevation in glial activation and allodynia during PHN, suggesting a potential therapeutic avenue for future exploration.

Construction of a Novel Mitochondria-Associated Gene Model for Assessing ESCC Immune Microenvironment and Predicting Survival.

Esophageal squamous cell carcinoma (ESCC) is among the most common malignant tumors of the digestive tract, with the sixth highest fatality rate worldwide. The ESCC-related dataset, GSE20347, was downloaded from the Gene Expression Omnibus (GEO) database, and weighted gene co-expression network analysis was performed to identify genes that are highly correlated with ESCC. A total of 91 transcriptome expression profiles and their corresponding clinical information were obtained from The Cancer Genome Atlas database. A mitochondria-associated risk (MAR) model was constructed using the least absolute shrinkage and selection operator Cox regression analysis and validated using GSE161533. The tumor microenvironment and drug sensitivity were explored using the MAR model. Finally, in vitro experiments were performed to analyze the effects of hub genes on the proliferation and invasion abilities of ESCC cells. To confirm the predictive ability of the MAR model, we constructed a prognostic model and assessed its predictive accuracy. The MAR model revealed substantial differences in immune infiltration and tumor microenvironment characteristics between high- and low-risk populations and a substantial correlation between the risk scores and some common immunological checkpoints. AZD1332 and AZD7762 were more effective for patients in the low-risk group, whereas Entinostat, Nilotinib, Ruxolutinib, and Wnt.c59 were more effective for patients in the high-risk group. Knockdown of TYMS significantly inhibited the proliferation and invasive ability of ESCC cells in vitro. Overall, our MAR model provides stable and reliable results and may be used as a prognostic biomarker for personalized treatment of patients with ESCC.