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Regulatory T (Treg) cells have an immunosuppressive function and highly express the immune checkpoint receptor PD-1 in the tumor microenvironment; however, the function of PD-1 in tumor-infiltrating (TI) Treg cells remains controversial. Here, we showed that conditional deletion of PD-1 in Treg cells delayed tumor progression. In Pdcd1fl/flFoxp3eGFP-Cre-ERT2(+/-) mice, in which both PD-1-expressing and PD-1-deficient Treg cells coexisted in the same tissue environment, conditional deletion of PD-1 in Treg cells resulted in impairment of the proliferative and suppressive capacity of TI Treg cells. PD-1 antibody therapy reduced the TI Treg cell numbers, but did not directly restore the cytokine production of TI CD8+ T cells in TC-1 lung cancer. Single-cell analysis indicated that PD-1 signaling promoted lipid metabolism, proliferation and suppressive pathways in TI Treg cells. These results suggest that PD-1 ablation or inhibition can enhance antitumor immunity by weakening Treg cell lineage stability and metabolic fitness in the tumor microenvironment.
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Neoplasias , Linfócitos T Reguladores , Animais , Camundongos , Linfócitos T CD8-Positivos , Expressão Gênica , Linfócitos do Interstício Tumoral , Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Microambiente TumoralRESUMO
With the scaling of lateral dimensions in advanced transistors, an increased gate capacitance is desirable both to retain the control of the gate electrode over the channel and to reduce the operating voltage1. This led to a fundamental change in the gate stack in 2008, the incorporation of high-dielectric-constant HfO2 (ref. 2), which remains the material of choice to date. Here we report HfO2-ZrO2 superlattice heterostructures as a gate stack, stabilized with mixed ferroelectric-antiferroelectric order, directly integrated onto Si transistors, and scaled down to approximately 20 ångströms, the same gate oxide thickness required for high-performance transistors. The overall equivalent oxide thickness in metal-oxide-semiconductor capacitors is equivalent to an effective SiO2 thickness of approximately 6.5 ångströms. Such a low effective oxide thickness and the resulting large capacitance cannot be achieved in conventional HfO2-based high-dielectric-constant gate stacks without scavenging the interfacial SiO2, which has adverse effects on the electron transport and gate leakage current3. Accordingly, our gate stacks, which do not require such scavenging, provide substantially lower leakage current and no mobility degradation. This work demonstrates that ultrathin ferroic HfO2-ZrO2 multilayers, stabilized with competing ferroelectric-antiferroelectric order in the two-nanometre-thickness regime, provide a path towards advanced gate oxide stacks in electronic devices beyond conventional HfO2-based high-dielectric-constant materials.
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4-Hydroxyphenylpyruvate dioxygenase (HPPD) plays a key role in tyrosine metabolism and has been identified as a promising target for herbicide and drug discovery. The structures of HPPD complexed with different types of inhibitors have been determined previously. We summarize the structures of HPPD complexed with structurally diverse molecules, including inhibitors, natural products, substrates, and catalytic intermediates; from these structures, the detailed inhibitory mechanisms of different inhibitors were analyzed and compared, and the key structural factors determining the slow-binding behavior of inhibitors were identified. Further, we propose four subpockets that accommodate different inhibitor substructures. We believe that these analyses will facilitate in-depth understanding of the enzymatic reaction mechanism and enable the design of new inhibitors with higher potency and selectivity.
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4-Hidroxifenilpiruvato Dioxigenase , Herbicidas , 4-Hidroxifenilpiruvato Dioxigenase/química , 4-Hidroxifenilpiruvato Dioxigenase/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Herbicidas/farmacologia , Herbicidas/química , Catálise , BiologiaRESUMO
Understanding the structure and dynamic process of water at the solid-liquid interface is an extremely important topic in surface science, energy science and catalysis1-3. As model catalysts, atomically flat single-crystal electrodes exhibit well-defined surface and electric field properties, and therefore may be used to elucidate the relationship between structure and electrocatalytic activity at the atomic level4,5. Hence, studying interfacial water behaviour on single-crystal surfaces provides a framework for understanding electrocatalysis6,7. However, interfacial water is notoriously difficult to probe owing to interference from bulk water and the complexity of interfacial environments8. Here, we use electrochemical, in situ Raman spectroscopic and computational techniques to investigate the interfacial water on atomically flat Pd single-crystal surfaces. Direct spectral evidence reveals that interfacial water consists of hydrogen-bonded and hydrated Na+ ion water. At hydrogen evolution reaction (HER) potentials, dynamic changes in the structure of interfacial water were observed from a random distribution to an ordered structure due to bias potential and Na+ ion cooperation. Structurally ordered interfacial water facilitated high-efficiency electron transfer across the interface, resulting in higher HER rates. The electrolytes and electrode surface effects on interfacial water were also probed and found to affect water structure. Therefore, through local cation tuning strategies, we anticipate that these results may be generalized to enable ordered interfacial water to improve electrocatalytic reaction rates.
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Discovering and engineering herbicide-resistant genes is a crucial challenge in crop breeding. This study focuses on the 4-hydroxyphenylpyruvate dioxygenase Inhibitor Sensitive 1-Like (HSL) protein, prevalent in higher plants and exhibiting weak catalytic activity against many ß-triketone herbicides (ß-THs). The crystal structures of maize HSL1A complexed with ß-THs were elucidated, identifying four essential herbicide-binding residues and explaining the weak activity of HSL1A against the herbicides. Utilizing an artificial evolution approach, we developed a series of rice HSL1 mutants targeting the four residues. Then, these mutants were systematically evaluated, identifying the M10 variant as the most effective in modifying ß-THs. The initial active conformation of substrate binding in HSL1 was also revealed from these mutants. Furthermore, overexpression of M10 in rice significantly enhanced resistance to ß-THs, resulting in a notable 32-fold increase in resistance to methyl-benquitrione. In conclusion, the artificially evolved M10 gene shows great potential for the development of herbicide-resistant crops.
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Resistência a Herbicidas , Herbicidas , Oryza , Proteínas de Plantas , Oryza/genética , Oryza/metabolismo , Resistência a Herbicidas/genética , Herbicidas/farmacologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Melhoramento Vegetal/métodos , Plantas Geneticamente Modificadas/genética , MutaçãoRESUMO
Androgen receptor (AR) and its splice variants (AR-SVs) promote prostate cancer (PCa) growth by orchestrating transcriptional reprogramming. Mechanisms by which the low complexity and intrinsically disordered primary transactivation domain (AF-1) of AR and AR-SVs regulate transcriptional programming in PCa remains poorly defined. Using omics, live and fixed fluorescent microscopy of cells, and purified AF-1 and AR-V7 recombinant proteins we show here that AF-1 and the AR-V7 splice variant form molecular condensates by liquid-liquid phase separation (LLPS) that exhibit disorder characteristics such as rapid intracellular mobility, coactivator interaction, and euchromatin induction. The LLPS and other disorder characteristics were reversed by a class of small-molecule-selective AR-irreversible covalent antagonists (SARICA) represented herein by UT-143 that covalently and selectively bind to C406 and C327 in the AF-1 region. Interfering with LLPS formation with UT-143 or mutagenesis resulted in chromatin condensation and dissociation of AR-V7 interactome, all culminating in a transcriptionally incompetent complex. Biochemical studies suggest that C327 and C406 in the AF-1 region are critical for condensate formation, AR-V7 function, and UT-143's irreversible AR inhibition. Therapeutically, UT-143 possesses drug-like pharmacokinetics and metabolism properties and inhibits PCa cell proliferation and tumor growth. Our work provides critical information suggesting that clinically important AR-V7 forms transcriptionally competent molecular condensates and covalently engaging C327 and C406 in AF-1, dissolves the condensates, and inhibits its function. The work also identifies a library of AF-1-binding AR and AR-SV-selective covalent inhibitors for the treatment of PCa.
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Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Masculino , Humanos , Receptores Androgênicos/metabolismo , Cisteína , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Antagonistas de Receptores de Andrógenos/farmacologia , Neoplasias de Próstata Resistentes à Castração/patologia , Linhagem Celular Tumoral , Isoformas de Proteínas/metabolismoRESUMO
Regulation of microtubule dynamics is required to properly control various steps of neurodevelopment. In this study, we identified granule cell antiserum-positive 14 (Gcap14) as a microtubule plus-end-tracking protein and as a regulator of microtubule dynamics during neurodevelopment. Gcap14 knockout mice exhibited impaired cortical lamination. Gcap14 deficiency resulted in defective neuronal migration. Moreover, nuclear distribution element nudE-like 1 (Ndel1), an interacting partner of Gcap14, effectively corrected the downregulation of microtubule dynamics and the defects in neuronal migration caused by Gcap14 deficiency. Finally, we found that the Gcap14-Ndel1 complex participates in the functional link between microtubule and actin filament, thereby regulating their crosstalks in the growth cones of cortical neurons. Taken together, we propose that the Gcap14-Ndel1 complex is fundamental for cytoskeletal remodeling during neurodevelopmental processes such as neuronal processes elongation and neuronal migration.
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Actinas , Proteínas Associadas aos Microtúbulos , Neurônios , Animais , Camundongos , Actinas/metabolismo , Movimento Celular/fisiologia , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Neuritos/metabolismo , Neurônios/metabolismoRESUMO
BACKGROUND: ZFHX3 (zinc finger homeobox 3), a gene that encodes a large transcription factor, is at the second-most significantly associated locus with atrial fibrillation (AF), but its function in the heart is unknown. This study aims to identify causative genetic variation related to AF at the ZFHX3 locus and examine the impact of Zfhx3 loss on cardiac function in mice. METHODS: CRISPR-Cas9 genome editing, chromatin immunoprecipitation, and luciferase assays in pluripotent stem cell-derived cardiomyocytes were used to identify causative genetic variation related to AF at the ZFHX3 locus. Cardiac function was assessed by echocardiography, magnetic resonance imaging, electrophysiology studies, calcium imaging, and RNA sequencing in mice with heterozygous and homozygous cardiomyocyte-restricted Zfhx3 loss (Zfhx3 Het and knockout, respectively). Human cardiac single-nucleus ATAC (assay for transposase-accessible chromatin)-sequencing data was analyzed to determine which genes in atrial cardiomyocytes are directly regulated by ZFHX3. RESULTS: We found single-nucleotide polymorphism (SNP) rs12931021 modulates an enhancer regulating ZFHX3 expression, and the AF risk allele is associated with decreased ZFHX3 transcription. We observed a gene-dose response in AF susceptibility with Zfhx3 knockout mice having higher incidence, frequency, and burden of AF than Zfhx3 Het and wild-type mice, with alterations in conduction velocity, atrial action potential duration, calcium handling and the development of atrial enlargement and thrombus, and dilated cardiomyopathy. Zfhx3 loss results in atrial-specific differential effects on genes and signaling pathways involved in cardiac pathophysiology and AF. CONCLUSIONS: Our findings implicate ZFHX3 as the causative gene at the 16q22 locus for AF, and cardiac abnormalities caused by loss of cardiac Zfhx3 are due to atrial-specific dysregulation of pathways involved in AF susceptibility. Together, these data reveal a novel and important role for Zfhx3 in the control of cardiac genes and signaling pathways essential for normal atrial function.
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Fibrilação Atrial , Proteínas de Homeodomínio , Animais , Humanos , Camundongos , Fibrilação Atrial/genética , Cálcio/metabolismo , Dilatação , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Miócitos Cardíacos/metabolismo , Fatores de Transcrição/genéticaRESUMO
In myocardial infarction, ischemia-reperfusion injury (IRI) poses a significant challenge due to a lack of effective treatments. Bilirubin, a natural compound known for its anti-inflammatory and antioxidant properties, has been identified as a potential therapeutic agent for IRI. Currently, there are no reports about proteomic studies related to IRI and bilirubin treatment. In this study, we explored the effects of bilirubin nanoparticles in a rat model of myocardial IRI. A total of 3616 protein groups comprising 76,681 distinct peptides were identified using LC-MS/MS, where we distinguished two kinds of protein groups: those showing increased expression in IRI and decreased expression in IRI with bilirubin treatment, and vice versa, accounting for 202 and 35 proteins, respectively. Our proteomic analysis identified significant upregulation in the Wnt and insulin signaling pathways and increased Golgi markers, indicating their role in mediating bilirubin nanoparticle's protective effects. This research contributes to the proteomic understanding of myocardial IRI and suggests bilirubin nanoparticles as a promising strategy for cardiac protection, warranting further investigation in human models.
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BACKGROUND: The prognostic and therapeutic implications of endothelial cells (ECs) heterogeneity in prostate cancer (PCa) are poorly understood. METHODS: We investigated associations of EC heterogeneity with PCa recurrence and castration resistance in 8 bulk transcriptomic and 4 single-cell RNA-seq cohorts. A recurrence-associated EC (RAEC) signature was constructed by comparing 11 machine learning algorithms through nested cross-validation. Functional relevances of RAEC-specific genes were also tested. RESULTS: A subset of ECs was significantly associated with recurrence in primary PCa and named RAECs. RAECs were characteristic of tip and immature cells and were enriched in migration, angiogenesis, and collagen-related pathways. We then developed an 18-gene RAEC signature (RAECsig) representative of RAECs. Higher RAECsig scores independently predicted tumor recurrence and performed better or comparably compared to clinicopathological factors and commercial gene signatures in multiple PCa cohorts. Of the 18 RAECsig genes, FSCN1 was upregulated in ECs from PCa with higher Gleason scores; and the silencing of FSCN1, TMEME255B, or GABRD in ECs either attenuated tube formation or inhibited PCa cell proliferation. Finally, higher RAECsig scores predicted castration resistance in both primary and castration-resistant PCa. CONCLUSION: This study establishes an endothelial signature that links a subset of ECs to prostate cancer recurrence and castration resistance.
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Electrocatalytic carbon-dioxide reduction reactions (ECO2 RR) are one of the most rational techniques to control one's carbon footprint. The desired product formation depends on deliberate reaction kinetics and a choice of electron-proton contribution. Herein the usage of novel CuS active centers decorated over stable 1T metallic N-WS2 /WO3 nanohybrids as an efficient selective formate conversion electrocatalyst with regard to ECO2 RR is reported. The preferred reaction pathway is identified as *OCHO, which is reduced (by gaining H+ + e- ) to HCOO- (HCOO- path) as the primary product. More significantly, at -1.3 V versus RHE yield of FEHCOO - is 55.6% ± 0.5 with a Jgeo of -125.05 mA cm-2 for CuS@1T-N-WS2 /WO3 nanohybrids. In addition, predominant catalytic activity, selectivity, and stability properties are observed; further post-mortem analysis demonstrates the choice of material importance. The present work describes an impressive approach to develop highly active electrocatalysts for selective ECO2 RR applications.
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Future energy loss can be minimized to a greater extent via developing highly active electrocatalysts for alkaline water electrolyzers. Incorporating an innovative design like high entropy oxides, dealloying, structural reconstruction, in situ activation can potentially reduce the energy barriers between practical and theoretical potentials. Here, a Fd-3m spinel group high entropy oxide is developed via a simple solvothermal and calcination approach. The developed (FeCoMnZnMg)3O4 electrocatalyst shows a near equimolar distribution of all the metal elements resulting in higher entropy (ΔS ≈1.61R) and higher surface area. The self-reconstructed spinel high entropy oxide (S-HEO) catalyst exhibited a lower overpotential of 240 mV to reach 10 mA cm-2 and enhanced reaction kinetics (59 mV dec-1). Noticeably, the S-HEO displayed an outstanding durability of 1000 h without any potential loss, significantly outperforming most of the reported OER electrocatalysts. Further, S-HEO is evaluated as the anode catalyst for an anion exchange membrane water electrolyzer (AEMWE) in 1 m, 0.1 m KOH, and DI water at 20 and 60 °C. These results demonstrate that S-HEO is a highly attractive, non-noble class of materials for high active oxygen evolution reaction (OER) electrocatalysts allowing fine-tuning beyond the limits of bi- or trimetallic oxides.
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Electrochemical carbon dioxide reduction reaction (ECO2RR) is a promising approach to synthesize fuels and value-added chemical feedstocks while reducing atmospheric CO2 levels. Here, high surface area cerium and sulfur-doped hierarchical bismuth oxide nanosheets (Ce@S-Bi2O3) are develpoed by a solvothermal method. The resulting Ce@S-Bi2O3 electrocatalyst shows a maximum formate Faradaic efficiency (FE) of 92.5% and a current density of 42.09 mA cm-2 at -1.16 V versus RHE using a traditional H-cell system. Furthermore, using a three-chamber gas diffusion electrode (GDE) reactor, a maximum formate FE of 85% is achieved in a wide range of applied potentials (-0.86 to -1.36 V vs RHE) using Ce@S-Bi2O3. The density functional theory (DFT) results show that doping of Ce and S in Bi2O3 enhances formate production by weakening the OH* and H* species. Moreover, DFT calculations reveal that *OCHO is a dominant pathway on Ce@S-Bi2O3 that leads to efficient formate production. This study opens up new avenues for designing metal and element-doped electrocatalysts to improve the catalytic activity and selectivity for ECO2RR.
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A novel green-absorbing organic molecule featuring dual intramolecular chalcogen bonds is synthesized and characterized. This molecule incorporates two such bonds: one between a tellurium atom and the oxygen atom of a carbonyl moiety, and the other between the tellurium atom and the adjacent nitrogen atom within a pyridine moiety. The molecule, featuring dual intramolecular chalcogen bonds exhibits a narrow absorption spectrum and elevated absorption coefficients, closely aligned with a resonance parameter of approximately 0.5. This behavior is due to its cyanine-like characteristics and favorable electrical properties, which are a direct result of its rigid, planar molecular structure. Therefore, this organic molecule forming dual intramolecular chalcogen bonds achieves superior optoelectronic performance in green-selective photodetectors, boasting an external quantum efficiency of over 65% and a full-width at half maximum of less than 95 nm while maintaining the performance after 1000 h of heating aging at 85 °C. Such organic photodetectors are poised to enhance stacked organic photodetector-on-silicon hybrid image sensors, paving the way for the next-generation of high-resolution and high-sensitivity image sensors.
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OBJECTIVE: To investigate the effects of the serum HCQ concentration on clinical manifestations, disease activity and organ damage in a longitudinal cohort of SLE patients. METHODS: The 338 SLE patients were assessed with respect to their demographic data, clinical and laboratory findings, Physician's Global Assessment (PGA), adjusted mean SLEDAI-2000 (AMS) and SLICC Damage Index (SDI) annually for 5 consecutive years. Patients were divided into two groups according to their serum HCQ concentration at baseline: subtherapeutic (<500 ng/ml) and therapeutic (≥500 ng/ml) groups. The impact of the HCQ concentration on the clinical outcomes was evaluated in a longitudinal analysis using a generalized estimating equation (GEE). RESULTS: Of the 338 patients, 287 (84.9%) were in the subtherapeutic group at baseline. This group had a higher incidence of newly developed LN (P = 0.036) and had been prescribed higher mean and cumulative doses of prednisolone (P = 0.003 and P = 0.013, respectively) than the therapeutic group. In multivariable analyses based on GEE, the subtherapeutic group had a higher AMS score (ß = 1.398, 95% CI 0.607, 2.189; P < 0.001), higher PGA score (ß = 0.328, 95% CI 0.215, 0.441; P < 0.001) and higher SDI score (ß = 0.366, 95% CI 0.061, 0.671; P = 0.019) across all 5 years. CONCLUSION: The subtherapeutic HCQ concentration was associated with the development of new-onset LN, and had significant associations with disease activity and cumulative organ damage in SLE patients over time.
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Antirreumáticos , Lúpus Eritematoso Sistêmico , Humanos , Hidroxicloroquina/efeitos adversos , Antirreumáticos/efeitos adversos , Prednisolona/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológicoRESUMO
OBJECTIVE: This study aimed to assess the efficacy and safety of intravenous ramosetron for pain relief in patients with fibromyalgia (FM) unresponsive to conventional treatments. METHODS: . In this prospective, double-blind, placebo-controlled trial, 80 FM patients were randomly allocated to receive either placebo (n = 40) or ramosetron (n = 40) at a dosage of 0.3 mg/day intravenously for five consecutive days. The primary outcome was the reduction in pain intensity at the end of the treatment period, evaluated using a visual analogue scale (VAS). Secondary outcome measures included the FM Impact Questionnaire, Beck Depression Inventory (BDI), Multi-Dimensional Health Assessment Questionnaire (MDHAQ), EQ-5D, and State-Trait Anxiety Inventory on days 5 (end of treatment), 7, 10, and 28. Safety was continuously monitored throughout the study. RESULTS: . At the end of the treatment phase, the ramosetron group demonstrated a significantly greater reduction in VAS pain scores compared with the placebo group (1.18 ± 1.60 vs 0.54 ± 1.59, p< 0.05). Additionally, the ramosetron group exhibited significant improvements in BDI (4.42 ± 5.18 vs 1.33 ± 4.87, p< 0.05) and MDHAQ pain scale (0.37 ± 0.74 vs 0.04 ± 0.52, p< 0.05) scores. However, these improvements in pain VAS and BDI scores were not sustained through day 28. The safety profile of ramosetron was favorable, with gastrointestinal symptoms, particularly constipation, being the most commonly reported adverse events. CONCLUSIONS: . Intravenous administration of ramosetron provided safe and effective short-term relief of pain intensity in FM patients with inadequate response to standard treatments.
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An open-label, single-center, phase I study was conducted to determine the absolute bioavailability and absorption, distribution, metabolism, and excretion of capivasertib-a potent, selective AKT serine/threonine kinase inhibitor-in healthy males. In part 1, six participants received a single oral dose of capivasertib (400 mg; tablets) followed by a [14C]-radiolabeled intravenous microdose of capivasertib (100 µg). After a 14-day washout, five of the participants proceeded to part 2 and received a single oral dose of [14C]capivasertib (400 mg; solution). In part 1, median time of maximum observed concentration for capivasertib was 1.7 hours, geometric mean terminal elimination half-life was 12.9 hours, and absolute bioavailability was estimated at 28.6% (90% confidence interval, 23.9 to 34.2). In part 2, a high proportion of the administered radioactivity was recovered over the 168-hour sampling period [mean recovery: 95.1% (feces, 50.4%; urine, 44.7%)]. Unchanged capivasertib in urine accounted for 7.4% of the total dose and 21.1% of the systemically available drug. Geometric mean renal clearance was 8.3 L/h, suggesting active tubular secretion. Twelve metabolites were identified in plasma. M11 (AZ14102143)-the glucuronide conjugate of capivasertib, inactive as an AKT serine/threonine kinase inhibitor-was the most abundant, accounting for a mean 78.4% of the plasma drug-related area under the curve. Of 22 metabolites identified in excreta, M11 was the most abundant (mean 28.2% of administered dose), indicating direct glucuronidation as one of the major routes of metabolism. No new safety concerns were identified. SIGNIFICANCE STATEMENT: This study provides characterization of the pharmacokinetics of capivasertib-a potent, selective AKT serine/threonine kinase (AKT) inhibitor-including absolute bioavailability, mass balance, and metabolic fate in humans; the findings are being used to inform further clinical development. Absolute bioavailability was estimated at 28.6%, and mean recovery of the administered dose in excreta over 168 hours was 95.1%. M11 (AZ14102143)-the glucuronide conjugate, inactive as an AKT inhibitor-was the most abundant identified metabolite in plasma and excreta.
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Disponibilidade Biológica , Voluntários Saudáveis , Humanos , Masculino , Adulto , Adulto Jovem , Administração Oral , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Distribuição Tecidual , Pirróis/farmacocinética , Pirróis/administração & dosagem , Pirróis/metabolismo , Pirróis/urina , Pirróis/sangue , Pessoa de Meia-Idade , Meia-Vida , Fezes/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirimidinas/farmacocinética , Pirimidinas/sangue , Pirimidinas/administração & dosagemRESUMO
Although large-scale genome-wide association studies (GWAS) have identified an association between MAD1L1 (Mitotic Arrest Deficient-1 Like 1) and the pathology of schizophrenia, the molecular mechanisms underlying this association remain unclear. In the present study, we aimed to address these mechanisms by examining the role of MAD1 (the gene product of MAD1L1) in key neurodevelopmental processes in mice and human organoids. Our findings indicated that MAD1 is highly expressed during active cortical development and that MAD1 deficiency leads to impairments in neuronal migration and neurite outgrowth. We also observed that MAD1 is localized to the Golgi apparatus and regulates vesicular trafficking from the Golgi apparatus to the plasma membrane, which is required for the growth and polarity of migrating neurons. In this process, MAD1 physically interacts and collaborates with the kinesin-like protein KIFC3 (kinesin family member C3) to regulate the morphology of the Golgi apparatus and neuronal polarity, thereby ensuring proper neuronal migration and differentiation. Consequently, our findings indicate that MAD1 is an essential regulator of neuronal development and that alterations in MAD1 may underlie schizophrenia pathobiology.
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Neocórtex , Esquizofrenia , Animais , Humanos , Camundongos , Proteínas de Ciclo Celular/genética , Estudo de Associação Genômica Ampla , Cinesinas/genética , Cinesinas/metabolismo , Neocórtex/metabolismo , Neurônios/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismoRESUMO
Understanding the microscopic electronic structure determines the macroscopic properties of the materials. Sufficient sampling has the same foundational importance in understanding the interactions. The NO2/MoS2 interaction is well known, but there are still many inconsistencies in the basic data, and the source of the NO2 direct dissociation activity has not been revealed. Based on a large-scale sampling density functional theory (DFT) study, the optimal adsorption of the NO2/MoS2 monolayer system is determined. The impurity state on the top of the valence band of the S-vacancy monolayer (MoS2-VS) was determined by cross-analysis of the band structure and density of states, which has been neglected for a long time. This provides a reasonable explanation for the direct dissociation of NO2 on the MoX2 monolayers. Further atomic structure analysis reveals that the impurity state originates from the not-fully occupied valence orbitals. This also corroborates the fact that the Mo material has dissociation activity, while the W material does not. There is no impurity state on the top of the valence band of the X-vacancy WS2 and WSe2 monolayers. Interestingly, NO2 dissociation did not occur in the MoTe2-VTe monolayer. This may be related to the 6s inert electron pair effect of the Te atom. The double-oriented adsorption behavior of NO2is also revealed. In contrast to the MoSe2 and MoTe2 monolayers, NO2-oriented adsorption on the MoS2 perfect monolayer deviates obviously, which is speculated to be related to space limitation and larger electronegativity of the S atom. The oriented adsorption ability of the MoX2 monolayers followed the order MoTe2 (64.4%) > MoSe2 (44.8%) > MoS2 (42.7%), according to the directed proportion. Renewed insights into the adsorption basic data and the understanding of the electronic structure of NO2/MoX2 (X = S, Se, Te) monolayer systems provide a basic understanding of the gas-surface interactions and various future surface-related advanced applications.
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This study aimed to visualize the microstructures of starch hydrogels using synchrotron-based X-ray micro-computed tomography (µCT). Waxy maize starch (WMS, 3.3% amylose, db), pea starch (PS, 40.3% amylose), and high-amylose maize starch (HMS, 63.6% amylose) were cooked at 95 and 140 °C to prepare starch hydrogels. WMS and HMS failed to form a gel after 95 °C cooking and storage, while PS developed a firm gel. At 140 °C cooking, HMS of a high amylose nature was fully gelatinized and generated a rigid gel with the highest strength. Both scanning electron microscopy (SEM) and µCT revealed the unique structural features of various starch hydrogels/pastes prepared at different temperatures, which were greatly affected by the degree of swelling and dispersity of the starches. As a nondestructive method, µCT showed certain advantages over SEM, including minimal shrinkage of the hydrogels, relatively simple sample preparation, and allowing for three-dimensional reconstruction of the hydrogel microstructure. This study indicated that synchrotron-based µCT could be a useful technique in visualizing biopolymer-based hydrogels.