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The use of strong acids and low atom efficiency in conventional hydrometallurgical recycling of spent lithium-ion batteries (LIBs) results in significant secondary wastes and CO2 emissions. Herein, we utilize the waste metal current collectors in spent LIBs to promote atom economy and reduce chemicals consumption in a conversion process of spent Li1-xCoO2 (LCO) â new LiNi0.80Co0.15Al0.05O2 (NCA) cathode. Mechanochemical activation is employed to achieve moderate valence reduction of transition metal oxides (Co3+âCo2+,3+) and efficient oxidation of current collector fragments (Al0âAl3+, Cu0âCu1+,2+), and then due to stored internal energy from ball-milling, the leaching rates of Li, Co, Al, and Cu in the ≤4 mm crushed products uniformly approach 100% with just weak acetic acid. Instead of corrosive precipitation reagents, larger Al fragments (≥4 mm) are used to control the oxidation/reduction potential (ORP) in the aqueous leachate and induce the targeted removal of impurity ions (Cu, Fe). After the upcycling of NCA precursor solution to NCA cathode powders, we demonstrate excellent electrochemical performance of the regenerated NCA cathode and improved environmental impact. Through life cycle assessments, the profit margin of this green upcycling path reaches about 18%, while reducing greenhouse gas emissions by 45%.
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BACKGROUND AND AIMS: The Hippo signaling has emerged as a crucial regulator of tissue homeostasis, regeneration, and tumorigenesis, representing a promising therapeutic target. Neurofibromin 2 (NF2), a component of Hippo signaling, is directly linked to human cancers but has been overlooked as a target for cancer therapy. APPROACH AND RESULTS: Through a high-content RNA interference genome-wide screen, the actin-binding protein Drebrin (DBN1) has been identified as a novel modulator of YAP localization. Further investigations have revealed that DBN1 directly interacts with NF2, disrupting the activation of large tumor suppressor kinases (LATS1/2) by competing with LATS kinases for NF2 binding. Consequently, DBN1 knockout considerably promotes YAP nuclear exclusion and repression of target gene expression, thereby preventing cell proliferation and liver tumorigenesis. We identified three lysine residues (K238, K248, and K252) essential for DBN1-NF2 interaction and developed a mutant DBN1 (DBN1-3Kmut) that is defective in NF2 binding and incompetent to trigger NF2-dependent YAP activation and tumorigenesis both in vitro and in vivo. Furthermore, BTP2, a DBN1 inhibitor, successfully restored NF2-LATS kinase binding and elicited potent antitumor activity. The combination of sorafenib and BTP2 exerted synergistic inhibitory effects against HCC. CONCLUSIONS: Our study identifies a novel DBN1-NF2-LATS axis, and pharmacological inhibition of DBN1 represents a promising alternative intervention targeting the Hippo pathway in cancer treatment.
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The hippocampus (HC) and the orbitofrontal cortex (OFC) jointly encode a map-like representation of a task space to guide behavior. It remains unclear how the OFC and HC interact in encoding this map-like representation, though previous studies indicated that both regions have different functions. We acquired the functional magnetic resonance imaging data under a social navigation task in which participants interacted with characters in a two-dimensional "social space." We calculate the social relationships between the participants and characters and used a drift-diffusion model to capture the inner process of social interaction. Then we used multivoxel pattern analysis to explore the brain-behavior relationship. We found that (i) both the HC and the OFC showed higher activations during the selective trial than the narrative trial; (ii) the neural pattern of the right HC was associated with evidence accumulation during social interaction, and the pattern of the right lateral OFC was associated with the social relationship; (iii) the neural pattern of the HC can decode the participants choices, while the neural pattern of the OFC can decode the task information about trials. The study provided evidence for distinct roles of the HC and the OFC in encoding different information when representing social space.
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Lóbulo Frontal , Corteza Prefrontal , Humanos , Corteza Prefrontal/diagnóstico por imagen , Conducta de Elección , Hipocampo/diagnóstico por imagen , Imagen por Resonancia Magnética , Medio SocialRESUMEN
OBJECTIVES: To explore the value of whole tumour- and subregion-based radiomics of contrast-enhanced mammography (CEM) in differentiating the HER2 expression status of breast cancers. METHODS: 352 patients underwent preoperative CEM from two centres were consecutively enroled and divided into the training, internal validation, and external validation cohorts. The lesions were divided into HER2-positive and HER2-negative groups. Besides the radiological features, radiomics features capturing the whole tumour-based (wITH) and subregion-based intratumoral heterogeneity (sITH) were extracted from the craniocaudal view of CEM recombined images. The XGBoost classifier was applied to develop the radiological, sITH, and wITH models. A combined model was constructed by fusing the prediction results of the three models. RESULTS: The mean age of the patients was 51.1 ± 10.7 years. Two radiological features, four wITH features, and three sITH features were selected to establish the models. The combined model significantly improved the AUC to 0.80 ± 0.03 (95% CI: 0.73-0.86), 0.79 ± 0.06 (95% CI: 0.67-0.90), and 0.79 ± 0.05 (95% CI: 0.69-0.89) in the training, internal validation, and external validation cohorts, respectively (All P < 0.05). The combined model showed good agreement between the predicted and observed probabilities and favourable net clinical benefit in the validation cohorts. CONCLUSIONS: Both whole tumour- and subregion-based ITH radiomics features of CEM exhibited potential for differentiating the HER2 expression status. Combining conventional radiological features and ITH features can improve the model's performance.
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Metagenomic next-generation sequencing (mNGS) is a valuable technique for identifying pathogens. However, conventional mNGS requires the separate processing of DNA and RNA genomes, which can be resource- and time-intensive. To mitigate these impediments, we propose a novel method called DNA/RNA cosequencing that aims to enhance the efficiency of pathogen detection. DNA/RNA cosequencing uses reverse transcription of total nucleic acids extracted from samples by using random primers, without removing DNA, and then employs mNGS. We applied this method to 85 cases of severe acute respiratory infections (SARI). Influenza virus was identified in 13 cases (H1N1: seven cases, H3N2: three cases, unclassified influenza type: three cases) and was not detected in the remaining 72 samples. Bacteria were present in all samples. Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii were detected in four influenza-positive samples, suggesting coinfections. The sensitivity and specificity for detecting influenza A virus were 73.33% and 95.92%, respectively. A κ value of 0.726 indicated a high level of concordance between the results of DNA/RNA cosequencing and SARI influenza virus monitoring. DNA/RNA cosequencing enhanced the efficiency of pathogen detection, providing a novel capability to strengthen surveillance and thereby prevent and control infectious disease outbreaks.
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Subtipo H1N1 del Virus de la Influenza A , Gripe Humana , Neumonía , Humanos , ARN , Subtipo H1N1 del Virus de la Influenza A/genética , Subtipo H3N2 del Virus de la Influenza A , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Sensibilidad y Especificidad , ADN , Metagenómica/métodosRESUMEN
Rotavirus group C is an important cause of sporadic cases and outbreaks of gastroenteritis worldwide. Whole-Genome sequences of human rotavirus C (RVC) in public databases are limited. We performed genome sequencing to analyze a RVC outbreak of acute gastroenteritis in China. Samples from 22 patients were screened for pathogens using RT-PCR, and six samples were positive for rotavirus. Whole-Genome sequencing analysis showed that the outbreak strain SJZ217 belongs to the G4-P[2]-I2-R2-C2-M3-A2-N2-T2-E2-H2 genotype and shares almost identical genomic sequences with Chungnam isolated in Korea. Phylogenetic analysis revealed strain SJZ217 also fell into a cluster with rotavirus C strains from Japan and Europe. Reassortment in the VP4 fragment was observed. These results helped to understand the genetic diversity and possible spread of RVC strains.
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Brotes de Enfermedades , Gastroenteritis , Genoma Viral , Genotipo , Filogenia , Infecciones por Rotavirus , Rotavirus , Humanos , Gastroenteritis/virología , Gastroenteritis/epidemiología , Infecciones por Rotavirus/virología , Infecciones por Rotavirus/epidemiología , China/epidemiología , Rotavirus/genética , Rotavirus/clasificación , Rotavirus/aislamiento & purificación , Masculino , Preescolar , ARN Viral/genética , Secuenciación Completa del Genoma , Femenino , Análisis de Secuencia de ADN , Lactante , Variación Genética , Virus Reordenados/genética , Virus Reordenados/clasificación , Virus Reordenados/aislamiento & purificación , Análisis por ConglomeradosRESUMEN
d-Lactic acid holds significant industrial importance due to its versatility and serves as a crucial component in the synthesis of environmentally friendly and biodegradable thermal-resistant poly-lactic acid. This polymer exhibits promising potential as a substitute for nonbiodegradable, petroleum-based plastics. The production of d-lactic acid from lignocellulosic biomass, a type of biorenewable and nonfood resources, can lower costs and improve product competitiveness. Glucose and xylose are the most abundant sugar monomers in lignocellulosic biomass materials. Despite Escherichia coli possessing native xylose catabolic pathways and transport, their ability to effectively utilize xylose is often hindered in the presence of glucose. Here, the E. coli strain Rec1.0, previously engineered to overcome carbon catabolite repression, was selected as the initial strain for reengineering to produce d-lactic acid. An adaptive evolution approach was employed to achieve highly efficient fermentation of glucose-xylose mixtures. The resulting strain, QJL010, could produce d-lactic acid of 87.5 g/L with a carbon yield of 0.99 mol/mol. Notably, the consumption rates of glucose and xylose reached 0.75 and 0.82 g/gDCW/h, respectively. Further analysis revealed that increased Glk activity, resulting from glk mutations (A142V and R188H), along with their upregulated expression, contributed to an elevated glucose consumption rate. Additionally, a CRP G141D mutation, cAMP-independent, stimulated the expression of the xylR, xylE, and galABC* genes, resulting in an accelerated xylose consumption rate. These findings provide valuable support for the utilization of E. coli platform strains in the production of value-added chemicals from lignocellulosic biomass.
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Proteína Receptora de AMP Cíclico , Proteínas de Escherichia coli , Escherichia coli , Glucosa , Ácido Láctico , Xilosa , Escherichia coli/genética , Escherichia coli/metabolismo , Proteína Receptora de AMP Cíclico/metabolismo , Proteína Receptora de AMP Cíclico/genética , Xilosa/metabolismo , Ácido Láctico/metabolismo , Glucosa/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Glucoquinasa/genética , Glucoquinasa/metabolismo , Evolución Molecular Dirigida , Mutación , Ingeniería Metabólica/métodos , AMP Cíclico/metabolismo , Fermentación , DisacáridosRESUMEN
Different Zn/Al ratios of Cl- intercalated ZnAl-layered double hydroxide (ZnAl-LDH) were prepared using the coprecipitation method, and their adsorption performance for Cu2+ in aqueous solution was evaluated. The factors affecting adsorption properties, such as dosage, reaction time, and pH, were determined by adsorption experiments. Then, the adsorption kinetics and isotherm models were fitted to evaluate the adsorption mechanism. The results show that the Zn/Al ratio has a great influence on the adsorption effect, the best adsorption effect is obtained when the Zn/Al ratio is 4:1, and the maximum adsorption capacity of Cu2+ is 213 mg/g. The mechanism study shows that the adsorption of Cu2+ by ZnAl-LDH is mainly an isomorphic substitution. Additionally, during the adsorption of CuSO4, the presence of SO42- undergoes interlayer anion exchange with Cl-, and the process of SO42- entering the interlayer facilitates the isomorphic substitution of Cu2+ and Zn2+. X-ray diffraction (XRD) analysis shows that as the Zn/Al ratio increases, the interlayer spacing of ZnAl-LDH increases, and the crystallinity decreases. The adsorption process conforms to the pseudo-second-order kinetic process and the Langmuir isotherm adsorption model. Therefore, the adsorption type of ZnAl-LDH for Cu2+ is monolayer chemical adsorption. The adsorption thermodynamic results indicate that the adsorption of Cu2+ is a spontaneous endothermic process. The research results revealed the mechanism of ZnAl-LDH adsorbing Cu2+, providing ideas for removing and recovering copper-containing electroplating wastewater.
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The phospholipase A2 (PLA2) superfamily consists of lipolytic enzymes that hydrolyze specific cell membrane phospholipids and have long been considered a central hub of biosynthetic pathways, where their lipid metabolites exert a variety of physiological roles. A misregulated PLA2 activity is associated with mainly inflammatory-derived pathologies and thus has shown relevant therapeutic potential. Many natural and synthetic anti-inflammatory drugs (AIDs) have been proposed as direct modulators of PLA2 activity. However, despite the specific chemical properties that these drugs share in common, little is known about the indirect modulation able to finely tune membrane structural changes at the precise lipid-binding site. Here, we use a novel experimental strategy based on differential scanning calorimetry to systematically study the structural properties of lipid membrane systems during PLA2 cleavage and under the influence of several AIDs. For a better understanding of the AIDs-membrane interaction, we present a comprehensive and comparative set of molecular dynamics (MD) simulations. Our thermodynamic results clearly demonstrate that PLA2 cleavage is hindered by those AIDs that significantly reduce the lipid membrane cooperativity, while the rest of the AIDs oppositely tend to catalyze PLA2 activity to different extents. On the other hand, our MD simulations support experimental results by providing atomistic details on the binding, insertion, and dynamics of each AID on a pure lipid system; the drug efficacy to impact membrane cooperativity is related to the lipid order perturbation. This work suggests a membrane-based mechanism of action for diverse AIDs against PLA2 activity and provides relevant clues that must be considered in its modulation.
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Simulación de Dinámica Molecular , Fosfolípidos , Fosfolipasas A2/química , Fosfolípidos/química , Membrana Celular/metabolismo , Fenómenos BiofísicosRESUMEN
Two efficient and convenient methods for the synthesis of 3-alkylideneoxindoles are described in this paper. The InCl3/TfOH-mediated tandem Knoevenagel condensation-deacylation sequence of various 2-oxindoles with 1,3-diones or acetoacetate furnished 3-alkylideneoxindoles in satisfactory to excellent yields (up to >99% yield). Employing the reaction system, the condensation of 2-oxindoles with ketones or aldehydes also proceeded smoothly to produce 3-alkylideneoxindoles. This protocol can be amenable to scale up. The effect of acids on this condensation reaction and intermolecular competition experiments were investigated to understand the aspect of the reaction.
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Photochemical ozone (O3) formation in the atmospheric boundary layer occurs at both the surface and elevated altitudes. Therefore, the O3 formation sensitivity is needed to be evaluated at different altitudes before formulating an effective O3 pollution prevention and control strategy. Herein, we explore the vertical evolution of O3 formation sensitivity via synchronous observations of the vertical profiles of O3 and proxies for its precursors, formaldehyde (HCHO) and nitrogen dioxide (NO2), using multi-axis differential optical absorption spectroscopy (MAX-DOAS) in urban areas of the Beijing-Tianjin-Hebei (BTH), Yangtze River Delta (YRD), and Pearl River Delta (PRD) regions in China. The sensitivity thresholds indicated by the HCHO/NO2 ratio (FNR) varied with altitude. The VOC-limited regime dominated at the ground level, whereas the contribution of the NOx-limited regime increased with altitude, particularly on heavily polluted days. The NOx-limited and transition regimes played more important roles throughout the entire boundary layer than at the surface. The feasibility of extreme NOx reduction to mitigate the extent of the O3 pollution was evaluated using the FNR-O3 curve. Based on the surface sensitivity, the critical NOx reduction percentage for the transition from a VOC-limited to a NOx-limited regime is 45-72%, which will decrease to 27-61% when vertical evolution is considered. With the combined effects of clean air action and carbon neutrality, O3 pollution in the YRD and PRD regions will transition to the NOx-limited regime before 2030 and be mitigated with further NOx reduction.
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Contaminantes Atmosféricos , Ozono , Compuestos Orgánicos Volátiles , Ozono/análisis , Contaminantes Atmosféricos/análisis , Dióxido de Nitrógeno/análisis , Compuestos Orgánicos Volátiles/análisis , Monitoreo del Ambiente/métodos , ChinaRESUMEN
Paternal exposure to environmental risk factors influences the offspring health. This study aimed to evaluate the association between paternal air pollution exposure mediated by sperm DNA methylation and adverse birth outcomes in offspring. We recruited 1607 fertile men and their partners from 2014 to 2016 and collected semen samples to detect sperm DNA methylation. Multivariate linear regression and weighted quantile sum regression models were used to assess the associations between paternal air pollution exposure and offspring birth outcomes. A critical exposure window was identified. Reduced representation bisulfite sequencing was used to detect sperm DNA methylation. The results demonstrated that high paternal exposure to PM2.5 (ß = -211.31, 95% CI: (-386.37, -36.24)), PM10 (ß = -178.20, 95% CI: (-277.13, -79.27)), and NO2 (ß = -84.22, 95% CI: (-165.86, -2.57)) was negatively associated with offspring's birthweight, especially in boys. Additionally, an early exposure window of 15-69 days before fertilization was recognized to be the key exposure window, which increased the risk of low birth weight and small for gestational age. Furthermore, paternal co-exposure to six air pollutants contributed to lower birthweight (ß = -51.91, 95% CI: (-92.72, -11.10)) and shorter gestational age (ß = -1.72, 95% CI: (-3.26, -0.17)) and PM2.5 was the most weighted pollutant. Paternal air pollution exposure resulted in 10,328 differentially methylated regions and the IGF2R gene was the key gene involved in the epigenetic process. These differentially methylated genes were predominantly associated with protein binding, transcriptional regulation, and DNA templating. These findings indicate that spermatogenesis is a susceptible window during which paternal exposure to air pollution affects sperm DNA methylation and the birth outcomes of offspring.
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Contaminantes Atmosféricos , Contaminación del Aire , Humanos , Masculino , Metilación de ADN , Exposición Paterna/efectos adversos , Estudios de Cohortes , Peso al Nacer , Semen/química , Material Particulado/análisis , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Contaminantes Atmosféricos/análisis , EspermatozoidesRESUMEN
Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by loss of function mutations in maternally expressed UBE3A. No gene-specific treatment is available for patients so far. Although intact and transcriptionally active, paternally inherited UBE3A is silenced by elongation of antisense long noncoding RNA UBE3A-ATS in neurons. Here, we demonstrated that RNA targeting of paternal Ube3a-ATS with a high-fidelity CRISPR-Cas13 (hfCas13x.1) system could restore Ube3a expression to similar levels as that of maternal Ube3a in the cultured mouse neurons. Furthermore, injection into lateral ventricles with neuron-specific hSyn1 promoter-driven hfCas13x.1 packaged in adeno-associated virus (AAV-PHP.eb) could restore paternal Ube3a expression in cortex and hippocampus of neonatal AS mice for up to 4 months after treatment. Behavioral tests showed that expression of paternal Ube3a significantly alleviated AS-related symptoms, including obesity and motor function. Our results suggested that hfCas13x.1-mediated suppression of the Ube3a-ATS lncRNA potentially serves as a promising targeted intervention for AS.
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Síndrome de Angelman , Animales , Ratones , Síndrome de Angelman/genética , Síndrome de Angelman/terapia , ARN sin Sentido/genética , Obesidad , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Otoferlin (OTOF) gene mutations represent the primary cause of hearing impairment and deafness in auditory neuropathy. The c.2485C>T (p. Q829X) mutation variant is responsible for approximately 3% of recessive prelingual deafness cases within the Spanish population. Previous studies have used two recombinant AAV vectors to overexpress OTOF, albeit with limited efficacy. In this study, we introduce an enhanced mini-dCas13X RNA base editor (emxABE) delivered via an AAV9 variant, achieving nearly 100% transfection efficiency in inner hair cells. This approach is aimed at treating OTOFQ829X, resulting in an approximately 80% adenosine-to-inosine conversion efficiency in humanized OtofQ829X/Q829X mice. Following a single scala media injection of emxABE targeting OTOFQ829X (emxABE-T) administered during the postnatal day 0-3 period in OtofQ829X/Q829X mice, we observed OTOF expression restoration in nearly 100% of inner hair cells. Moreover, auditory function was significantly improved, reaching similar levels as in wild-type mice. This enhancement persisted for at least 7 months. We also investigated P5-P7 and P30 OtofQ829X/Q829X mice, achieving auditory function restoration through round window injection of emxABE-T. These findings not only highlight an effective therapeutic strategy for potentially addressing OTOFQ829X-induced hearing loss but also underscore emxABE as a versatile toolkit for treating other monogenic diseases characterized by premature termination codons.
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Sordera , Pérdida Auditiva Central , Pérdida Auditiva , Animales , Ratones , Edición Génica , Pérdida Auditiva/genética , Pérdida Auditiva/terapia , MutaciónRESUMEN
BACKGROUND: Obstructive sleep apnea (OSA) is a pervasive, chronic sleep-related respiratory condition that causes brain structural alterations and cognitive impairments. However, the causal association of OSA with brain morphology and cognitive performance has not been determined. METHODS: We conducted a two-sample bidirectional Mendelian randomization (MR) analysis to investigate the causal relationship between OSA and a range of neurocognitive characteristics, including brain cortical structure, brain subcortical structure, brain structural change across the lifespan, and cognitive performance. Summary-level GWAS data for OSA from the FinnGen consortium was used to identify genetically predicted OSA. Data regarding neurocognitive characteristics were obtained from published meta-analysis studies. Linkage disequilibrium score regression analysis was employed to reveal genetic correlations between OSA and related traits. RESULTS: Our MR study provided evidence that OSA was found to significantly increase the volume of the hippocampus (IVW ß (95% CI) = 158.997 (76.768 to 241.227), P = 1.51e-04), with no heterogeneity and pleiotropy detected. Nominally causal effects of OSA on brain structures, such as the thickness of the temporal pole with or without global weighted, amygdala structure change, and cerebellum white matter change covering lifespan, were observed. Bidirectional causal links were also detected between brain cortical structure, brain subcortical, cognitive performance, and OSA risk. LDSC regression analysis showed no significant correlation between OSA and hippocampus volume. CONCLUSIONS: Overall, we observed a positive association between genetically predicted OSA and hippocampus volume. These findings may provide new insights into the bidirectional links between OSA and neurocognitive features, including brain morphology and cognitive performance.
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Encéfalo , Análisis de la Aleatorización Mendeliana , Apnea Obstructiva del Sueño , Humanos , Apnea Obstructiva del Sueño/genética , Apnea Obstructiva del Sueño/complicaciones , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Cognición/fisiología , Estudio de Asociación del Genoma Completo , Imagen por Resonancia Magnética , Masculino , Disfunción Cognitiva/genética , Disfunción Cognitiva/fisiopatologíaRESUMEN
Chemotherapy, as a conventional strategy for tumor therapy, often leads to unsatisfied therapeutic effect due to the multi-drug resistance and the serious side effects. Herein, we genetically engineered a thermal-responsive murine Ferritin (mHFn) to specifically deliver mitoxantrone (MTO, a chemotherapeutic and photothermal agent) to tumor tissue for the chemotherapy and photothermal combined therapy of colorectal cancer, thanks to the high affinity of mHFn to transferrin receptor that highly expressed on tumor cells. The thermal-sensitive channels on mHFn allowed the effective encapsulation of MTO in vitro and the laser-controlled release of MTO in vivo. Upon irradiation with a 660 nm laser, the raised temperature triggered the opening of the thermal-sensitive channel in mHFn nanocage, resulting in the controlled and rapid release of MTO. Consequently, a significant amount of reactive oxygen species was generated, causing mitochondrial collapse and tumor cell death. The photothermal-sensitive controlled release, low systemic cytotoxicity, and excellent synergistic tumor eradication ability in vivo made mHFn@MTO a promising candidate for chemo-photothermal combination therapy against colorectal cancer.
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Neoplasias Colorrectales , Ferritinas , Rayos Láser , Mitoxantrona , Terapia Fototérmica , Animales , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/tratamiento farmacológico , Ratones , Ferritinas/química , Ferritinas/metabolismo , Terapia Fototérmica/métodos , Humanos , Mitoxantrona/farmacología , Mitoxantrona/química , Mitoxantrona/uso terapéutico , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Ratones Endogámicos BALB C , Antineoplásicos/farmacología , Antineoplásicos/química , Ratones Desnudos , FemeninoRESUMEN
BACKGROUND: The information of ZMYND15 in human reproduction is very limited, resulting in the unclear link between ZMYND15 variants and male infertility. METHODS: Whole exome sequencing and Sanger sequencing to identify the potential pathogenic variation of ZMYND15 in infertile men, Papanicolaou staining and electron microscopy to investigate the spermatozoa morphology, western blotting and immunofluorescence staining to confirm the pathogenicity of the identified variants, and proteomic analysis and coimmunoprecipitation to clarify the potential molecular mechanism. RESULTS: A total of 31 ZMYND15 variants were identified in 227 infertile patients. Three deleterious biallelic variants, including a novel compound heterozygous variant of c.1105delG (p.A369Qfs*15) and c.1853T>C (p.F618S), a new homozygous splicing mutation of c.1297+5G>A and a reported homozygous nonsense mutation of c.1209T>A (p.Y403*), were detected in three affected individuals with oligoasthenoteratozoospermia, showing a biallelic pathogenic mutation frequency of 1.3% (3/227). No biallelic pathogenic mutation was found in 692 fertile men. Morphology analysis showed abnormalities in sperm morphology in the patients harbouring ZMYND15 mutations. Western blotting and immunofluorescence staining confirmed the nearly absent ZMYND15 expression in the sperm of the patients. Mechanistically, ZMYND15 might regulate spermatogenesis by interacting with key molecules involved in sperm development, such as DPY19L2, AKAP4 and FSIP2, and might also mediate the expression of the autophagy-associated protein SPATA33 to maintain sperm individualisation and unnecessary cytoplasm removal. CONCLUSION: Our findings broaden the variant and phenotype spectrum of ZMYND15 in male infertility, and reveal the potential signalling pathway of ZMYND15 regulating spermatogenesis, finally confirming the essential role of ZMYND15 in human fertility.
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Infertilidad Masculina , Proteínas Represoras , Teratozoospermia , Humanos , Masculino , Pueblos del Este de Asia , Infertilidad Masculina/patología , Mutación/genética , Proteómica , Semen/metabolismo , Espermatozoides/patología , Teratozoospermia/genética , Teratozoospermia/metabolismo , Teratozoospermia/patología , Proteínas Represoras/genéticaRESUMEN
This study aims to audit the potential algorithmic bias in TikTok's health-related video recommendation toward geographically diverse groups in China. We employed 120 cloud phones and conducted two agent-based testing experiments simulating users' geographical locations and online behaviors. The results indicated significant regional inequality in video sources recommended by the TikTok algorithm, t(118) = 3.02, p = .003, with users from developed cities encountering a higher proportion of professional videos than those from underdeveloped cities. However, when users from both regions expressed a similar preference for the same type of information, an equal proportion of professional videos was recommended. Our findings suggest that widely used algorithms may covertly perpetuate social inequities and reinforce preexisting class-based inequalities, particularly affecting vulnerable population from low-income regions. This study also highlights the importance of enhancing eHealth literacy among disadvantaged users to mitigate problematic outcomes in the AI-based communication landscape.
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Airway invasion is common in patients with Parkinson's disease (PD) and can cause serious complications. However, a PD-related dysphagic pattern has not been clearly elucidated. In this study, 53 patients with early to moderate PD were enrolled to undergo a videofluoroscopic study of swallowing evaluation (VFSS) and a battery of neuropsychological assessments. A set of VFSS variables (three visuoperceptual, nine temporal, and six spatial) were measured. The main effects of bolus viscosity and volume on airway invasion were calculated. Statistical analyses were performed to determine key kinematic factors of airway invasion for swallowing each bolus type. Airway invasion frequency was significantly higher for liquid boluses (liquid vs. pudding P < 0.001; liquid vs. honey P = 0.006). Laryngeal vestibule closure reaction time (LVCrt) was the key kinematic factor of airway invasion for 3 ml liquid swallow (P = 0.040), anterior displacement of hyoid bone was the key kinematic factor for both 5 ml and 10 ml liquid swallows (P = 0.010, 0.034, respectively). Male sex and advanced Hoehn and Yahr stage were significantly related to reduced anterior displacement of hyoid bone. These results reveal the dysphagic pattern related to PD, demonstrating that prolonged LVCrt and reduced anterior displacement of hyoid bone are two crucial kinematic factors contributing to airway invasion during the liquid swallow. In addition, hyoid bone dysfunction was correlated with disease severity and male sex. Our findings warrant further investigation of the pathophysiological mechanism of dysphagia in PD and would guide clinical intervention.
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Trastornos de Deglución , Deglución , Enfermedad de Parkinson , Faringe , Humanos , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/complicaciones , Masculino , Trastornos de Deglución/fisiopatología , Trastornos de Deglución/etiología , Femenino , Anciano , Fenómenos Biomecánicos , Persona de Mediana Edad , Faringe/fisiopatología , Deglución/fisiología , Fluoroscopía/métodos , Hueso Hioides/fisiopatologíaRESUMEN
Due to the similar physical and chemical properties of ilmenite and olivine, separating them is challenging. The flotation process, with the use of collectors, is an effective method. In this study, a ternary collector consisting of aluminum ion (III), benzohydroxamic acid (BHA), and sodium oleate (NaOL) was prepared for the flotation separation of ilmenite and olivine. Through micro-flotation experiments, molecular dynamics simulation (MD), density functional theory (DFT), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and time-of-flight secondary ion mass spectrometry (TOF-SIMS) analysis, the synergistic effect between the components of the ternary collector and the adsorption configuration on the surface of ilmenite was investigated. The results revealed that at pH = 8, Al (III), BHA, and NaOL could coordinate and adsorb effectively on the surface of ilmenite, enhancing its floatability for separation from olivine. The adsorption configuration differed from previous reports, showing a co-adsorption of multiple forms on the surface of ilmenite.