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4-Nitrophenol (4-NP), as a toxic and refractory pollutant, has generated significant concern due to its adverse effects. However, the potential toxic effects and mechanism remained unclear. In this study, the reproduction, development, locomotion and reactive oxygen species (ROS) production of Caenorhabditis elegans were investigated to evaluate the 4-NP toxicity. We used metabolomics to assess the potential damage mechanisms. The role of metabolites in mediating the relationship between 4-NP and phenotypes was examined by correlation and mediation analysis. 4-NP (8 ng/L and 8 µg/L) caused significant reduction of brood size, ovulation rate, total germ cells numbers, head thrashes and body bends, and an increase in ROS. However, the oosperm numbers in uterus, body length and body width were decreased in 8 µg/L. Moreover, 36 differential metabolites were enriched in the significant metabolic pathways, including lysine biosynthesis, ß-alanine metabolism, tryptophan metabolism, pentose phosphate pathway, pentose and glucuronate interconversions, amino sugar and nucleotide sugar metabolism, starch and sucrose metabolism, galactose metabolism, propanoate metabolism, glycerolipid metabolism, and estrogen signaling pathway. The mechanism of 4-NP toxicity was that oxidative stress caused by the perturbation of amino acid, which had effects on energy metabolism through disturbing carbohydrate and lipid metabolism, and finally affected the estrogen signaling pathway to exert toxic effects. Moreover, correlation and mediation analysis showed glycerol-3P, glucosamine-6P, glucosamine-1P, UDP-galactose, L-aspartic acid, and uracil were potential markers for the reproduction and glucose-1,6P2 for developmental toxicity. The results provided insight into the pathways involved in the toxic effects caused by 4-NP and developed potential biomarkers to evaluate 4-NP toxicity.
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Caenorhabditis elegans , Oestrogènes , Nitrophénols , Reproduction , Transduction du signal , Animaux , Caenorhabditis elegans/effets des médicaments et des substances chimiques , Caenorhabditis elegans/physiologie , Reproduction/effets des médicaments et des substances chimiques , Transduction du signal/effets des médicaments et des substances chimiques , Nitrophénols/toxicité , Oestrogènes/toxicité , Espèces réactives de l'oxygène/métabolisme , Stress oxydatif/effets des médicaments et des substances chimiquesRÉSUMÉ
The mucosal barrier is crucial for intestinal homeostasis, and goblet cells are essential for maintaining the mucosal barrier integrity. The proviral integration site for Moloney murine leukemia virus-1 (PIM1) kinase regulates multiple cellular functions, but its role in intestinal homeostasis during colitis is unknown. Here, we demonstrate that PIM1 is prominently elevated in the colonic epithelia of both ulcerative colitis patients and murine models, in the presence of intestinal microbiota. Epithelial PIM1 leads to decreased goblet cells, thus impairing resistance to colitis and colitis-associated colorectal cancer (CAC) in mice. Mechanistically, PIM1 modulates goblet cell differentiation through the Wnt and Notch signaling pathways. Interestingly, PIM1 interacts with histone deacetylase 2 (HDAC2) and downregulates its level via phosphorylation, thereby altering the epigenetic profiles of Wnt signaling pathway genes. Collectively, these findings investigate the unknown function of the PIM1-HDAC2 axis in goblet cell differentiation and ulcerative colitis/CAC pathogenesis, which points to the potential for PIM1-targeted therapies of ulcerative colitis and CAC.
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The interaction between extracellular polymeric substances (EPS) in municipal sludge and antibiotics in wastewater is critical in wastewater treatment, resource recovery, and sludge management. Therefore, it is increasingly urgent to investigate the distribution coefficient (Log K) of sulfonamide antibiotics (SAs) in EPS, particularly in sludge-derived dissolved organic carbon (DOC) and aqueous phase systems. Herein, through balance experiments, the concentrations of SAs were determined using alkaline extraction EPS (AEPS) and alginate-like extracellular polymer (ALE) systems, and the Log KDOC values were determined. The results showed that the Log KDOC of AEPS was higher than that of ALE, which exhibited a negative KDOC value, indicating an inhibitory effect on dissolution. For the three SAs studied, the Log KDOC values were in the following order: sulfamethoxazole > sulfapyridine > sulfadiazine. This order can be attributed to the differing physicochemical properties, such as polarity, of the SAs. Three-dimensional excitation-emission matrix fluorescence spectra and fitting results indicated a lack of aromatic proteins dominated by tryptophan and humus-like substances in ALE. Meanwhile, the hydrophobic interaction of aromatic proteins dominated by tryptophan was the main driving force in the binding process between AEPS and SAs.
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BACKGROUND: Essential hypertension is a common clinical disease and a risk factor for cardiovascular and cerebrovascular diseases. Olmesartan medoxomil, amlodipine, and hydrochlorothiazide are commonly used antihypertensive drugs. The aim of this study was to establish a robust UPLC-MS/MS method for the simultaneous determination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide in dog plasma. At the same time, the release in vivo and in vitro studies were conducted, and a preliminary in vitro-in vivo correlation (IVIVC) evaluation was performed. METHODS: The bioequivalence experiment was conducted with a double-crossed design. Three major components were extracted and analyzed by UHPLC-MS/MS. With the MRM scan, olmesartan and amlodipine were quantified by fragment conversion (m/z 447.10â190.10) and (m/z 408.95â294.00) under positive ESI mode, while hydrochlorothiazide was quantified with fragment conversion (m/z 295.90â268.90) under negative ESI mode. The in vitro release studies were performed using a USP paddle, and the dissolution medium was chosen from pH 6.0 to pH 6.8 according to the BCS classification of compounds. The IVIVC was calculated using the Wagner-Nelson equation. RESULTS: The linear ranges of olmesartan, amlodipine, and hydrochlorothiazide in the plasma were 5.0-2500, 0.1-50, and 3.0-1500 ng/mL, respectively. All accuracies were within 3.8% of the target values, and the findings revealed that intra-day and inter-day accuracy was less than 12.1%. Moreover, the recoveries exceeded 88.3%, the matrix effect tests were positive, and the stability tests were positive. With the establishment of correlation, the distinguishable dissolution condition (pH 6.8) was selected as the predictable condition. CONCLUSION: The established method was suitable for the preclinical pharmacokinetic study of tripartite drugs with strong specificity and high sensitivity. Through the evaluation of IVIVC, the connection between in vivo and in vitro drug testing was initially established.
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Integrating genomics and histology for cancer prognosis demonstrates promise. Here, we develop a multi-classifier system integrating a lncRNA-based classifier, a deep learning whole-slide-image-based classifier, and a clinicopathological classifier to accurately predict post-surgery localized (stage I-III) papillary renal cell carcinoma (pRCC) recurrence. The multi-classifier system demonstrates significantly higher predictive accuracy for recurrence-free survival (RFS) compared to the three single classifiers alone in the training set and in both validation sets (C-index 0.831-0.858 vs. 0.642-0.777, p < 0.05). The RFS in our multi-classifier-defined high-risk stage I/II and grade 1/2 groups is significantly worse than in the low-risk stage III and grade 3/4 groups (p < 0.05). Our multi-classifier system is a practical and reliable predictor for recurrence of localized pRCC after surgery that can be used with the current staging system to more accurately predict disease course and inform strategies for individualized adjuvant therapy.
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Néphrocarcinome , Tumeurs du rein , Récidive tumorale locale , Humains , Néphrocarcinome/génétique , Néphrocarcinome/anatomopathologie , Tumeurs du rein/génétique , Tumeurs du rein/anatomopathologie , Tumeurs du rein/chirurgie , Mâle , Femelle , Récidive tumorale locale/génétique , Adulte d'âge moyen , Sujet âgé , Pronostic , Génomique/méthodes , Adulte , Stadification tumorale , Apprentissage profond , Survie sans rechuteRÉSUMÉ
BACKGROUND: Numerous studies have found that patients experiencing sudden sensorineural hearing loss (SSHL), with or without accompanying vertigo, often show impaired vestibular function. However, there is a dearth of studies analyzing vestibular-evoked myogenic potentials (VEMPs) in SSHL patients across various age groups. AIM: To investigate vestibular condition in SSHL patients across various age demographics. METHODS: Clinical data of 84 SSHL patients were investigated retrospectively. Audiometry, cervical vestibular evoked myogenic potentials (c-VEMPs), and ocular vestibular evoked myogenic potentials (o-VEMPs) were conducted on these patients. Parameters assessed included the latencies of P1 and N1 waves, as well as the amplitudes of P1-N1 waves. Moreover, the study evaluated the influence of factors such as sex, affected side, configuration of hearing loss, and presence of accompanying vertigo. RESULTS: Among the 84 SSHL patients, no significant differences were observed among the three groups in terms of gender, affected side, and the presence or absence of vertigo. Group II (aged 41-60 years) had the highest number of SSHL cases. The rates of absent o-VEMPs in the affected ears were 20.83%, 31.58%, and 22.72% for the three age groups, respectively, with no statistically significant difference among them. The rates of absent c-VEMPs in the affected ears were 8.3%, 34.21%, and 18.18% for the three age groups, respectively, with significant differences. In the unaffected ears, there were differences observed in the extraction rates of o-VEMPs in the unaffected ears among the age groups. In the three age groups, no significant differences were noted in the three age groups in the latencies of P1 and N1 waves or in the amplitude of N1-P1 waves for c-VEMPs and o-VEMPs, either on the affected side or on the unaffected side, across the three age groups. CONCLUSION: The extraction rate of VEMPs is more valuable than parameters. Regardless of the presence of vertigo, vestibular organs are involved in SSHL. Notably, SSHL patients aged 41-60 appear more susceptible to damage to the inferior vestibular nerve and saccule.
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Testosterone (T), an environmental androgen, significantly disrupts endocrine systems in wildlife and ecosystems. Despite growing concern over its high levels in aquatic environments, the reproductive toxicity of testosterone and its mechanisms are not well understood. In this study, we investigated the reproductive toxicity and mechanisms of testosterone using Caenorhabditis elegans (C. elegans) and assessed its ecological toxicity through the benchmark dose (BMD) method. Our results indicate that T concentrations exceeding 0.01 µg/L significantly reduce the brood size, decrease germ cell counts, and prolong the generation time in C. elegans as T concentrations increase. Furthermore, to elucidate the specific mechanisms, we analyzed the expression of nhr-69, mpk-1, and other genes involved in sex determination. These findings suggest that the nhr-69-mediated reproductive toxicity of T primarily affects sperm formation and the offspring number by influencing its downstream targets, mpk-1 and fog-1/3, which are critical in the germ cell sex-determining pathway. Additionally, this study determined that the 10% lower boundary of the baseline dose (BMDL10) is 1.160 ng/L, offering a more protective reference dose for the ecological risk assessment of T. The present study suggests that nhr-69 mediates the reproductive toxicity of T by influencing mpk-1 and fog-1/3, critical genes at the end of the germ cell sex-determining pathway, thereby providing a basis for establishing reproductive toxicity thresholds for T.
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Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant inherited disorder prevalent among adolescents. Typically, it manifests with hyperglycemia before the age of 25. MODY5 is attributed to a mutation in the Hepatocyte Nuclear Factor-1ß (HNF-1ß) gene. A complete absence of HNF-1ß is observed in 50% of those with MODY5. The 17q12 microdeletion syndrome closely linked with MODY5. Its incidence in the general population is around 1 in 14,500 and is linked with facial deformities, diabetes, polycystic kidneys, pancreatic hypertrophy, liver anomalies, and neuropsychological impairments. The most primary clinical signs are predominantly associated with the HNF-1ß gene deletion. We chronicle the case of a male of 19 years of age diagnosed with diabetes, who, alongside persistent liver damage and polycystic kidneys, was referred from a community hospital to the Xuzhou Central Hospital. His clinical presentation included diabetes, liver dysfunction, polycystic kidneys, lipid irregularities, insulin resistance, and fatty atrophy. Subsequent genetic screening unveiled a 17q12 chromosomal deletion and an absence of the Hepatocyte Nuclear Factor-1ß (HNF-1ß) gene. Hence, for adolescent patients lacking a familial diabetes history but exhibiting symptoms like polycystic kidneys, liver damage, lipid irregularities, and fatty atrophy, a thorough assessment for the 17q12 microdeletion syndrome becomes imperative.
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Targeted delivery of glutamine metabolism inhibitors holds promise for cholangiocarcinoma therapy, yet effective delivery vehicles remain a challenge. This study reports the development of a biomimetic nanosystem, termed R-CM@MSN@BC, integrating mesoporous organosilicon nanoparticles with reactive oxygen species-responsive diselenide bonds for controlled release of the glutamine metabolism inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) and the photosensitizer Ce6. Erythrocyte membrane coating, engineered with Arg-Gly-Asp (RGD) peptides, not only enhanced biocompatibility but also improved tumor targeting and tissue penetration. Upon laser irradiation, R-CM@MSN@BC executed both photodynamic and glutamine-metabolic therapies, inducing necroptosis in tumor cells and triggering significant immunogenic cell death. Time-of-flight mass cytometry analysis revealed that R-CM@MSN@BC can remodel the immunosuppressive tumor microenvironment by polarizing M1-type macrophages, reducing infiltration of M2-type and CX3CR1+ macrophages, and decreasing T cell exhaustion, thereby increasing the effectiveness of anti-programmed cell death ligand 1 immunotherapy. This strategy proposed in this study presents a viable and promising approach for the treatment of cholangiocarcinoma.
Sujet(s)
Cholangiocarcinome , Glutamine , Nécroptose , Photothérapie dynamique , Photosensibilisants , Cholangiocarcinome/traitement médicamenteux , Cholangiocarcinome/métabolisme , Nécroptose/effets des médicaments et des substances chimiques , Animaux , Photothérapie dynamique/méthodes , Souris , Glutamine/métabolisme , Photosensibilisants/pharmacologie , Humains , Nanoparticules/composition chimique , Modèles animaux de maladie humaine , Tumeurs des canaux biliaires/traitement médicamenteux , Tumeurs des canaux biliaires/métabolisme , Tumeurs des canaux biliaires/anatomopathologie , Lignée cellulaire tumorale , Biomimétique/méthodes , Matériaux biomimétiques/pharmacologie , Matériaux biomimétiques/composition chimique , Microenvironnement tumoral/effets des médicaments et des substances chimiquesRÉSUMÉ
INTRODUCTION: Physical activity (PA) is a promising way to improve mental health in children and adolescents with neurodevelopmental disorders (NDDs). However, the underlying mechanisms remain unclear. The current review aimed to explore the potential neurobiological, psychosocial, and behavioral mechanisms between PA interventions and mental health in children and adolescents with NDDs. METHODS: Web of Science, PsycINFO, SPORTDiscus, MEDLINE, CINAHL, and ERIC were searched from inception to June 2023. Randomized controlled trials/quasi-experimental designs applying PA interventions and reporting at least one mental health outcome and at least one potential mechanism in children and adolescents with NDDs were included. The best evidence synthesis rating system was adopted to determine the strength and consistency of potential mechanisms and was performed in 2024. RESULTS: In total, 45 studies were included, 29 of which were randomized controlled trials and 16 were quasi-experimental, with a total of 1,751 participants. According to the best evidence synthesis rating system, neurobiological (theta activity and P3 amplitude), psychosocial (social skills and social participation), and behavioral (motor skills and sleep) mechanisms were the frequently examined and consistent mechanisms through which PA affected mental health in children and adolescents with NDDs. However, evidence regarding P3 latency, beta activity, and physical self-concept was insufficient. DISCUSSION: Future PA interventions could consider neurobiological (theta activity and P3 amplitude), psychosocial (social skills and social participation), and behavioral (motor skills and sleep) mechanisms. Alternatively, PA can be developed as an adjunctive approach with interventions that specifically focus on these mechanisms to enhance mental health in children and adolescents with NDDs.
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Unveiling molecular mechanisms that dominate protein phase dynamics has been a pressing need for deciphering the intricate intracellular modulation machinery. While ions and biomacromolecules have been widely recognized for modulating protein phase separations, effects of small molecules that essentially constitute the cytosolic chemical atmosphere on the protein phase behaviors are rarely understood. Herein, we report that vitamin C (VC), a key small molecule for maintaining a reductive intracellular atmosphere, drives reentrant phase transitions of myosin II/F-actin (actomyosin) cytoskeletons. The actomyosin bundle condensates dissemble in the low-VC regime and assemble in the high-VC regime in vitro or inside neuronal cells, through a concurrent myosin II protein aggregation-dissociation process with monotonic VC concentration increase. Based on this finding, we employ in situ single-cell and single-vesicle electrochemistry to demonstrate the quantitative modulation of catecholamine transmitter vesicle exocytosis by intracellular VC atmosphere, i.e., exocytotic release amount increases in the low-VC regime and decreases in the high-VC regime. Furthermore, we show how VC regulates cytomembrane-vesicle fusion pore dynamics through counteractive or synergistic effects of actomyosin phase transitions and the intracellular free calcium level on membrane tensions. Our work uncovers the small molecule-based reversive protein phase regulatory mechanism, paving a new way to chemical neuromodulation and therapeutic repertoire expansion.
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Actines , Acide ascorbique , Exocytose , Acide ascorbique/composition chimique , Acide ascorbique/pharmacologie , Exocytose/effets des médicaments et des substances chimiques , Actines/métabolisme , Actines/composition chimique , Transition de phase , Animaux , Myosine de type II/métabolisme , Myosine de type II/antagonistes et inhibiteurs , Techniques électrochimiques , Actomyosine/métabolisme , Actomyosine/composition chimique , RatsRÉSUMÉ
Managing renal fibrosis is challenging owing to the complex cell signaling redundancy in diseased kidneys. Renal fibrosis involves an immune response dominated by macrophages, which activates myofibroblasts in fibrotic niches. However, macrophages exhibit high heterogeneity, hindering their potential as therapeutic cell targets. Herein, we aimed to eliminate specific macrophage subsets that drive the profibrotic immune response in the kidney both temporally and spatially. We identified the major profibrotic macrophage subset (Fn1+Spp1+Arg1+) in the kidney and then constructed a 12-mer glycopeptide that was designated as bioactivated in vivo assembly PK (BIVA-PK) to deplete these cells. BIVA-PK specifically binds to and is internalized by profibrotic macrophages. By inducing macrophage cell death, BIVA-PK reshaped the renal microenvironment and suppressed profibrotic immune responses. The robust efficacy of BIVA-PK in ameliorating renal fibrosis and preserving kidney function highlights the value of targeting macrophage subsets as a potential therapy for patients with CKD.
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Fibrose , Rein , Macrophages , Animaux , Macrophages/effets des médicaments et des substances chimiques , Macrophages/métabolisme , Macrophages/immunologie , Rein/anatomopathologie , Rein/effets des médicaments et des substances chimiques , Souris , Souris de lignée C57BL , Peptides/pharmacologie , Peptides/métabolisme , Mâle , Maladies du rein/anatomopathologie , Maladies du rein/traitement médicamenteux , HumainsRÉSUMÉ
As self-incompatibility is a major issue in pummelo breeding and production, its mechanism in citrus was analyzed to improve breeding efficiency and reduce production costs. Rutaceae belongs to S-RNase type of gametophytic self-incompatibility. While the function of S-RNase/SLF and the mechanism of self-incompatibility have been studied extensively, the transcriptional regulation of S-RNase has been less studied. We performed transcriptome sequencing with the styles of 'Shatian' pummelo on the day of anthesis and 1-5 days before anthesis, and found that the transcript level of S-RNase gradually decreased with flower development. By analyzing differentially expressed genes and correlation with the expression trend of S-RNase, we identified a candidate gene, CgHSFB1, and utilized biochemical experiments such as yeast one-hybrid assay, electrophoretic mobility shift assay and dual-luciferase assay, as well as transient transformation of citrus calli and Citrus microcarpa and demonstrated that CgHSFB1 could directly bind to the S1-RNase promoter and repress the expression of S1-RNase, which is involved in the pummelo self-incompatibility response. In contrast, CgHSFB1 did not bind to the promoter of S2-RNase, and there was specificity in the regulation of S-RNase.
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Citrus , Fleurs , Régulation de l'expression des gènes végétaux , Protéines végétales , Ribonucléases , Auto-incompatibilité chez les plantes à fleurs , Citrus/génétique , Citrus/physiologie , Citrus/métabolisme , Protéines végétales/génétique , Protéines végétales/métabolisme , Fleurs/génétique , Fleurs/physiologie , Fleurs/croissance et développement , Auto-incompatibilité chez les plantes à fleurs/génétique , Ribonucléases/génétique , Ribonucléases/métabolisme , Régions promotrices (génétique)/génétique , Transcriptome , Analyse de profil d'expression de gènesRÉSUMÉ
The recovery of biopolymers, particularly alginate-like extracellular polymers, from municipal sludge represents a promising step toward sustainable sludge treatment practices. Originating from wastewater plants in complexly polluted environments, alginate-like extracellular polymers carry potential environmental risks concerning their reuse. This study employs ultrahigh-performance liquid chromatography-tandem mass spectrometry to investigate the distribution coefficients and occurrence of alginate-like extracellular polymers and sulfamethoxazole. Results demonstrate a negative distribution coefficient, suggesting an inhibitory effect on sulfamethoxazole dissolution. The ethanol-extracted alginate-like extracellular polymers exhibits higher sulfamethoxazole levels (approximately 52%) than those obtained via dialysis extraction. Three-dimensional excitation-emission matrix analysis and adsorption studies indicate the absence of tyrosine-like substances in the alginate-like extracellular polymers, unlike in other extracellular polymeric substances. This absence diminishes hydrophobic interactions, highlighting that electrostatic interactions play a more important role. These insights are crucial for understanding the adsorption behavior of alginate-like extracellular polymers and optimizing their large-scale extraction processes.
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Alginates , Eaux d'égout , Sulfaméthoxazole , Alginates/composition chimique , Eaux d'égout/composition chimique , Adsorption , Acide glucuronique/composition chimique , Chromatographie en phase liquide à haute performance , Matrice de substances polymériques extracellulaires/composition chimique , Matrice de substances polymériques extracellulaires/métabolisme , Polymères/composition chimique , Spectrométrie de masse en tandemRÉSUMÉ
Temperature-dependent electroluminescence (TDEL) measurements have been employed to investigate the carrier transport and recombination processes of InGaN red micro-LED based on dual-wavelength InGaN/GaN MQWs structure. EL peak energy and carrier transport of the red micro-LED both show temperature dependence, due to temperature-induced changes in defect activation. In addition, the current density at which the blue peak of the low-In-content appears in the EL spectrum varies with temperature. As the temperature increases, the blue peak of the low In component tends to appear at higher current densities, which may be attributed to the increase in thermally activated defects hindering the injection of holes into the low-In-content MQWs further away from p-GaN. Furthermore, the IQEs of the high-In-content MQWs are estimated from the TDEL method and then reveal the temperature-dependent efficiency droop. The IQE decreases as temperature increases, particularly above 50 K, where it drops sharply due to temperature-dependent nonradiative recombination. And the two different variation trends in IQE of MQWs with high and low In content reveal a competitive mechanism in carrier distribution, implying that more escaping holes from high-In-content MQWs will further reduce red emission efficiency but enhance carrier injection and blue emission in low-In-content MQWs.
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BACKGROUND: The global prevalence of iron deficiency has posed significant public health risks. Animal-derived collagen peptides have been recognized for their potent metal ion-chelating capabilities, which can greatly enhance the bioavailability of iron. Yak skins, typically discarded during production and processing, serve as a valuable resource. Based on yak skin collagen peptide (YSP), we have developed a novel iron-chelating peptide: yak skin collagen iron-chelating peptide (YSP-Fe). RESULTS: The maximum level of iron chelation of YSP-Fe achieved was 42.72 ± 0.65 mg g-1. Structural analysis indicated that YSP-Fe was primarily formed from amino, carboxyl and carbonyl groups combined with ferrous ions. Through examination of the amino acid composition, molecular docking and peptide sequence identification, it was determined that Gly, Asp and Arg played crucial roles in the chelation of ferrous ions by YSP. Furthermore, YSP-Fe was more stable in simulated gastrointestinal digestion compared to FeSO4. CONCLUSION: YSP-Fe demonstrated dual benefits of iron supplementation and antioxidant effects. These significant findings provide a foundation for the development of novel iron supplements and the effective utilization of yak skin as a valuable resource. © 2024 Society of Chemical Industry.
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Correlations of fluctuations are essential to understanding many-body systems and key information for advancing quantum technologies. To fully describe the dynamics of a physical system, all time-ordered correlations (TOCs), i.e., the dynamics-complete set of correlations are needed. The current measurement techniques can only access a limited set of TOCs, and there has been no systematic and feasible solution for extracting the dynamic-complete set of correlations hitherto. Here we propose a platform-universal protocol to selectively detect arbitrary types of TOCs via quantum channels. In our method, the quantum channels are synthesized with various controls, and engineer the evolution of a sensor-target system along a specific path that corresponds to a desired correlation. Using nuclear magnetic resonance, we experimentally demonstrate this protocol by detecting a specific type of fourth-order TOC that has never been accessed previously. We also show that the knowledge of the TOCs can be used to significantly improve the precision of quantum optimal control. Our method provides a new toolbox for characterizing the quantum many-body states and quantum noise, and hence for advancing the fields of quantum sensing and quantum computing.
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Nontuberculous mycobacteria (NTM) are exceedingly rare etiological agents of intracranial infections. Among them, Mycobacterium rhodesiae stands out as an even less common pathogen. In this paper, we report the first documented case of a central nervous system (CNS) infection in humans caused by Mycobacterium rhodesiae, which has specific imaging findings and good response to the therapy by using Linezolid, Clarithromycin, and Minocycline. The diagnosis was facilitated by a comprehensive multimodal approach, incorporating multisite imaging, cerebrospinal fluid analysis via next-generation sequencing (NGS), and targeted genetic testing. Furthermore, this paper provides a derivation of the clinical characteristics observed in other documented instances of CNS infections attributable to NTM and based on a review of the current literature. Our experience contributes to the evidence that is needed to understand the full spectrum of NTM-related CNS pathologies and underscores the importance of a multidisciplinary diagnostic process in atypical presentations of intracranial infections.
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Polyethers play a crucial role in the development of anticancer drugs. To enhance the anticancer efficacy and reduce the toxicity of these compounds, thereby advancing their application in cancer treatment, herein, guided by the structure-activity relationships of aglycone polyethers, novel aglycone polyethers are rationally redesigned with potentially improved efficacy and reduced toxicity against tumors. To realize the biosynthesis of the novel aglycone polyethers, the gene clusters and the post-polyketide synthase tailoring pathways for aglycone polyethers endusamycin and lenoremycin are identified and subjected to combinatorial biosynthesis studies, resulting in the creation of a novel aglycone polyether termed End-16, which demonstrates significant potential for treating bladder cancer (BLCA). End-16 demonstrates the ability to suppress the proliferation, migration, invasion, and cellular protrusions formation of BLCA cells, as well as induce cell cycle arrest in the G1 phase in vitro. Notably, End-16 exhibits superior inhibitory activity and fewer side effects against BLCA compared to the frontline anti-BLCA drug cisplatin in vivo, thereby warranting further preclinical studies. This study highlights the significant potential of integrating combinatorial biosynthesis strategies with rational design to create unnatural products with enhanced pharmacological properties.
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Previous studies have indicated a link between neutrophil to lymphocyte ratio (NLR) and impaired fasting glucose (IFG), but the findings have been disputed. By conducting a real-world follow-up study, we can monitor the development of diseases and confirm the connection between NLR and IFG. A total of 1168 patients without IFG or T2DM were followed up for six years. At baseline, participants' NLR levels, fasting plasma glucose and other clinical characteristics were recorded. During the follow-up period, NLR levels and the prevalence of IFG were recorded. Ultimately, 45 individuals were lost to follow-up, leaving 1,123 participants for analysis. Using Group-Based Trajectory Modeling (GBTM), the sample was divided into three groups. The prevalence of IFG in the three groups was 12.1%, 19.4%, and 20.85%, respectively. Compared with the low-level NLR group, the hazard ratio of IFG in the moderate-level NLR group and high-level NLR group were 1.628 (1.109-2.390) and 1.575 (1.001-2.497), respectively. There was a significant interaction effect of BMI and NLR on the risk of IFG (P < 0.001). In this real-world follow-up study, we observed a positive association between NLR and the risk of IFG, with this relationship being exacerbated by obesity status.