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Osteoarthritis (OA) is a joint disease featuring cartilage breakdown and chronic pain. Although age and joint trauma are prominently associated with OA occurrence, the trigger and signaling pathways propagating their pathogenic aspects are ill defined. Following long-term catabolic activity and traumatic cartilage breakdown, debris accumulates and can trigger Toll-like receptors (TLRs). Here we show that TLR2 stimulation suppressed the expression of matrix proteins and induced an inflammatory phenotype in human chondrocytes. Further, TLR2 stimulation impaired chondrocyte mitochondrial function, resulting in severely reduced adenosine triphosphate (ATP) production. RNA-sequencing analysis revealed that TLR2 stimulation upregulated nitric oxide synthase 2 (NOS2) expression and downregulated mitochondria function-associated genes. NOS inhibition partially restored the expression of these genes, and rescued mitochondrial function and ATP production. Correspondingly, Nos2-/- mice were protected from age-related OA development. Taken together, the TLR2-NOS axis promotes human chondrocyte dysfunction and murine OA development, and targeted interventions may provide therapeutic and preventive approaches in OA.
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Cartílago Articular , Osteoartritis , Humanos , Ratones , Animales , Condrocitos/metabolismo , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Osteoartritis/metabolismo , Receptores Toll-Like/metabolismo , Cartílago Articular/metabolismo , Células CultivadasRESUMEN
High-throughput computational materials discovery has promised significant acceleration of the design and discovery of new materials for many years. Despite a surge in interest and activity, the constraints imposed by large-scale computational resources present a significant bottleneck. Furthermore, examples of very large-scale computational discovery carried out through experimental validation remain scarce, especially for materials with product applicability. Here, we demonstrate how this vision became reality by combining state-of-the-art machine learning (ML) models and traditional physics-based models on cloud high-performance computing (HPC) resources to quickly navigate through more than 32 million candidates and predict around half a million potentially stable materials. By focusing on solid-state electrolytes for battery applications, our discovery pipeline further identified 18 promising candidates with new compositions and rediscovered a decade's worth of collective knowledge in the field as a byproduct. We then synthesized and experimentally characterized the structures and conductivities of our top candidates, the NaxLi3-xYCl6 (0≤ x≤ 3) series, demonstrating the potential of these compounds to serve as solid electrolytes. Additional candidate materials that are currently under experimental investigation could offer more examples of the computational discovery of new phases of Li- and Na-conducting solid electrolytes. The showcased screening of millions of materials candidates highlights the transformative potential of advanced ML and HPC methodologies, propelling materials discovery into a new era of efficiency and innovation.
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Multivalent battery chemistries have been explored in response to the increasing demand for high-energy rechargeable batteries utilizing sustainable resources. Solvation structures of working cations have been recognized as a key component in the design of electrolytes; however, most structure-property correlations of metal ions in organic electrolytes usually build upon favorable static solvation structures, often overlooking solvent exchange dynamics. We here report the ion solvation structures and solvent exchange rates of magnesium electrolytes in various solvents by using multimodal nuclear magnetic resonance (NMR) analysis and molecular dynamics/density functional theory (MD/DFT) calculations. These magnesium solvation structures and solvent exchange dynamics are correlated to the combined effects of several physicochemical properties of the solvents. Moreover, Mg2+ transport and interfacial charge transfer efficiency are found to be closely correlated to the solvent exchange rate in the binary electrolytes where the solvent exchange is tunable by the fraction of diluent solvents. Our primary findings are (1) most battery-related solvents undergo ultraslow solvent exchange coordinating to Mg2+ (with time scales ranging from 0.5 µs to 5 ms), (2) the cation transport mechanism is a mixture of vehicular and structural diffusion even at the ultraslow exchange limit (with faster solvent exchange leading to faster cation transport), and (3) an interfacial model wherein organic-rich regions facilitate desolvation and inorganic regions promote Mg2+ transport is consistent with our NMR, electrochemistry, and cryogenic X-ray photoelectron spectroscopy (cryo-XPS) results. This observed ultraslow solvent exchange and its importance for ion transport and interfacial properties necessitate the judicious selection of solvents and informed design of electrolyte blends for multivalent electrolytes.
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Phase separation of components of ER exit sites (ERES) into membraneless compartments, the Sec bodies, occurs in Drosophila cells upon exposure to specific cellular stressors, namely, salt stress and amino acid starvation, and their formation is linked to the early secretory pathway inhibition. Here, we show Sec bodies also form in secretory mammalian cells upon the same stress. These reversible and membraneless structures are positive for ERES components, including both Sec16A and Sec16B isoforms and COPII subunits. We find that Sec16A, but not Sec16B, is a driver for Sec body formation, and that the coalescence of ERES components into Sec bodies occurs by fusion. Finally, we show that the stress-induced coalescence of ERES components into Sec bodies precedes ER exit inhibition, leading to their progressive depletion from ERES that become non-functional. Stress relief causes an immediate dissolution of Sec bodies and the concomitant restoration of ER exit. We propose that the dynamic conversion between ERES and Sec body assembly, driven by Sec16A, regulates protein exit from the ER during stress and upon stress relief in mammalian cells, thus providing a conserved pro-survival mechanism in response to stress.
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Vesículas Cubiertas por Proteínas de Revestimiento , Retículo Endoplásmico , Animales , Retículo Endoplásmico/metabolismo , Vesículas Cubiertas por Proteínas de Revestimiento/metabolismo , Aparato de Golgi/metabolismo , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo , Vías Secretoras , Transporte de Proteínas , Mamíferos/metabolismoRESUMEN
Membrane-based lateral flow immunoassays (LFAs) have been employed as early point-of-care (POC) testing tools in clinical settings. However, the varying membrane properties, uncontrollable sample transport in LFAs, visual readout, and required large sample volumes have been major limiting factors in realizing needed sensitivity and desirable precise quantification. Addressing these challenges, we designed a membrane-free system in which the desirable three-dimensional (3D) structure of the detection zone is imitated and used a small pump for fluid flow and fluorescence as readout, all the while maintaining a one-step assay protocol. A hydrogel-like protein-polyelectrolyte complex (PPC) within a polyelectrolyte multilayer (PEM) was developed as the test line by complexing polystreptavidin (pSA) with poly(diallyldimethylammonium chloride) (PDDA), which in turn was layered with poly(acrylic acid) (PAA) resulting in a superior 3D streptavidin-rich test line. Since the remainder of the microchannel remains material-free, good flow control is achieved, and with the total volume of 20 µL, 7.5-fold smaller sample volumes can be used in comparison to conventional LFAs. High sensitivity with desirable reproducibility and a 20 min total assay time were achieved for the detection of NT-proBNP in plasma with a dynamic range of 60-9000 pg·mL-1 and a limit of detection of 56 pg·mL-1 using probe antibody-modified fluorescence nanoparticles. While instrument-free visual detection is no longer possible, the developed lateral flow channel platform has the potential to dramatically expand the LFA applicability, as it overcomes the limitations of membrane-based immunoassays, ultimately improving the accuracy and reducing the sample volume so that finger-prick analyses can easily be done in a one-step assay for analytes present at very low concentrations.
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Biomarcadores , Compuestos de Amonio Cuaternario , Humanos , Inmunoensayo/métodos , Biomarcadores/análisis , Biomarcadores/sangre , Péptido Natriurético Encefálico/sangre , Péptido Natriurético Encefálico/análisis , Límite de Detección , Resinas Acrílicas/química , Fragmentos de Péptidos/análisis , Fragmentos de Péptidos/sangre , Polietilenos/química , Poliestirenos/químicaRESUMEN
We present a case of extensive spread of high-grade squamous intraepithelial lesion (HSIL)/cervical intraepithelial neoplasia grade 3 (CIN3) with foci of invasive squamous cell carcinoma (SCC) in a premenopausal woman. Superficial spread of CIN3 and cervical SCC to the endometrium and/or fallopian tubes is rare, especially in countries with cervical cancer screening programs. Our case occurred during the COVID-19 pandemic, which may have been a major contributing factor to delayed detection and, consequently extensive spread.
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STUDY OBJECTIVE: Button battery ingestion can cause alkaline esophageal injury. There is interest in first-aid household products to neutralize the injury. The objective was to investigate which household products are effective at reducing button battery injury. METHODS: Two cadaveric porcine experiments were performed. Experiment 1 utilized esophageal mucosal segments. A button battery (3VCR2032) was placed onto the mucosa, and substances (saline control, honey, jam, orange juice, yogurt, milk, and cola) were applied every 10 minutes for 6 applications. Tissue pH was measured every 10 minutes, and macroscopic ulceration size was assessed at 120 minutes. Experiment 2 used an intact esophageal model with a battery inserted into the lumen and jam, honey, and saline irrigation as per experiment 1. Tissue pH, macroscopic and histopathology changes were evaluated at 60, 90 and 120 minutes. RESULTS: In experiment 1, only honey and jam had a lower mean tissue pH at 120 minutes (8.0 [standard deviation [SD] 0.9, n=12] and 7.1 [SD 1.7, n=12], respectively) compared to saline solution 11.9 (SD 0.6, n=6, P<.0001). Both honey (0.24 cm2, SD 0.17) and jam (0.37 cm2, SD 0.40) had smaller mean areas of ulceration compared to saline solution (3.90 cm2, SD 1.03, P<.0001). In experiment 2, honey and jam had significantly lower mean tissue pH at all timepoints compared to saline solution. Histologic changes were evident at 60 minutes in the saline group, whereas honey and jam exhibited no or minimal changes until 120 minutes. CONCLUSIONS: Honey and jam were able to neutralize injury caused by a button battery resulting in a smaller area of ulceration. Jam should be further explored as a possible first-aid option as an alternative to honey in suspected button battery ingestion prior to definitive management.
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Cuerpos Extraños , Solución Salina , Humanos , Animales , Porcinos , Cuerpos Extraños/complicaciones , Cuerpos Extraños/terapia , Esófago/lesiones , Suministros de Energía Eléctrica , Primeros AuxiliosRESUMEN
BACKGROUND: Hepatitis B virus (HBV) vaccination in Vietnamese adults remains low and unequally distributed. We conducted a study on HBV-naïve adults living in Ho Chi Minh City, Viet Nam, to determine barriers associated with HBV vaccination uptake after removing the financial barrier by providing free coupons for HBV vaccination. METHODS: After being screened for HBsAg, anti-HBs, and anti-HBc, 284 HBV-naïve study participants aged 18 and over (i.e., negative for HBsAg, anti-HBs, and anti-HBc total) were provided free 3-dose HBV vaccine coupons. Next, study participants' receipt of 1st, 2nd, and 3rd doses of HBV vaccine was documented at a pre-specified study healthcare facility, where HBV vaccines were distributed at no cost to the participants. Upon study entry, participants answered questionnaires on sociodemographics, knowledge of HBV and HBV vaccination, and related social and behavioral factors. The proportions of three doses of HBV vaccine uptake and their confidence intervals were analyzed. Associations of HBV vaccine initiation with exposures at study entry were evaluated using modified Poisson regression. RESULTS: 98.9% (281 of 284) of study participants had complete data and were included in the analysis. The proportion of participants obtaining the 1st, 2nd, and 3rd doses of HBV vaccine was 11.7% (95% Confidence Interval [95% CI] 8.0-15.5%), 10.7% (95%CI 7.1-14.3%), and 8.9% (95%CI 5.6-12.2%), respectively. On the other hand, participants were more likely to initiate the 1st dose if they had adequate knowledge of transmission (adjusted relative risk [aRR] = 2.58, 95% CI 1.12-5.92), adequate knowledge of severity (aRR = 6.75, 95%CI 3.38-13.48), and annual health-checking seeking behavior (aRR = 2.04, 95%CI 1.07-3.87). CONCLUSION: We documented a low HBV vaccination uptake despite incentivization. However, increased vaccine initiation was associated with better HBV knowledge and annual health check-up adherence. When considering expanding HBV vaccination to the general adult population, we should appreciate that HBV knowledge is an independent predictor of vaccine uptake.
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Conocimientos, Actitudes y Práctica en Salud , Vacunas contra Hepatitis B , Hepatitis B , Vacunación , Humanos , Masculino , Femenino , Adulto , Vacunas contra Hepatitis B/administración & dosificación , Hepatitis B/prevención & control , Vietnam , Vacunación/estadística & datos numéricos , Vacunación/psicología , Persona de Mediana Edad , Adulto Joven , Adolescente , Encuestas y Cuestionarios , Aceptación de la Atención de Salud/estadística & datos numéricos , Virus de la Hepatitis B/inmunologíaRESUMEN
Through enabling whole blood detection in point-of-care testing (POCT), sedimentation-based plasma separation promises to enhance the functionality and extend the application range of lateral flow assays (LFAs). To streamline the entire process from the introduction of the blood sample to the generation of quantitative immune-fluorescence results, we combined a simple plasma separation technique, an immunoreaction, and a micropump-driven external suction control system in a polymer channel-based LFA. Our primary objective was to eliminate the reliance on sample-absorbing separation membranes, the use of active separation forces commonly found in POCT, and ultimately allowing finger prick testing. Combining the principle of agglutination of red blood cells with an on-device sedimentation-based separation, our device allows for the efficient and fast separation of plasma from a 25-µL blood volume within a mere 10 min and overcomes limitations such as clogging, analyte adsorption, and blood pre-dilution. To simplify this process, we stored the agglutination agent in a dried state on the test and incorporated a filter trench to initiate sedimentation-based separation. The separated plasma was then moved to the integrated mixing area, initiating the immunoreaction by rehydration of probe-specific fluorophore-conjugated antibodies. The biotinylated immune complex was subsequently trapped in the streptavidin-rich detection zone and quantitatively analyzed using a fluorescence microscope. Normalized to the centrifugation-based separation, our device demonstrated high separation efficiency of 96% and a yield of 7.23 µL (= 72%). Furthermore, we elaborate on its user-friendly nature and demonstrate its proof-of-concept through an all-dried ready-to-go NT-proBNP lateral flow immunoassay with clinical blood samples.
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Péptido Natriurético Encefálico , Fragmentos de Péptidos , Humanos , Péptido Natriurético Encefálico/sangre , Péptido Natriurético Encefálico/aislamiento & purificación , Fragmentos de Péptidos/sangre , Pruebas en el Punto de Atención , Inmunoensayo/métodos , Inmunoensayo/instrumentación , Diseño de EquipoRESUMEN
Point-of-care sensors targeting blood marker analysis must be designed to function with very small volumes since acquiring a blood sample through a simple, mostly pain-free finger prick dramatically limits the sample size and comforts the patient. Therefore, we explored the potential of converting a conventional lateral flow assay (LFA) for a significant biomarker into a self-contained and compact polymer channel-based LFA to minimize the sample volume while maintaining the analytical merits. Our primary objective was to eliminate the use of sample-absorbing fleece and membrane materials commonly present in LFAs. Simultaneously, we concentrated on developing a ready-to-deploy one-step LFA format, characterized by dried reagents, facilitating automation and precise sample transport through a pump control system. We targeted the detection of the heart failure biomarker NT-proBNP in only 15 µL human whole blood and therefore implemented strategies that ensure highly sensitive detection. The biosensor combines streptavidin-functionalized magnetic beads (MNPs) as a 3D detection zone and fluorescence nanoparticles as signal labels in a sandwich-based immunoassay. Compared to the currently commercialized LFA, our biosensor demonstrates comparable analytical performance with only a tenth of the sample volume. With a detection limit of 43.1 pgâmL-1 and a mean error of 18% (n ≥ 3), the biosensor offers high sensitivity and accuracy. The integration of all-dried long-term stable reagents further enhances the convenience and stability of the biosensor. This lateral flow channel platform represents a promising advancement in point-of-care diagnostics for heart failure biomarkers, offering a user-friendly and sensitive platform for rapid and reliable testing with low finger-prick blood sample volumes.
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Insuficiencia Cardíaca , Péptido Natriurético Encefálico , Fragmentos de Péptidos , Humanos , Límite de Detección , Inmunoensayo , Insuficiencia Cardíaca/diagnóstico , Biomarcadores/análisis , Fenómenos MagnéticosRESUMEN
BACKGROUND: Colorectal cancer (CRC) has emerged as one of the most common cancers, with increasing survival rates globally. As patients with CRC experience diverse treatment effects corresponding to different survival stages, understanding their unmet needs based on the survival stage is critical to tailor supportive care with limited medical resources. AIM: This study aimed to understand the unmet needs of patients with CRC across survival stages. METHODS: This scoping review followed the 5-stage framework established by Arksey and O'Malley. Five online databases were searched with narrative synthesis performed after data extraction. RESULTS: Fifteen studies were identified for this review, with 12 focusing on the acute survival stage and three reporting on the extended survival stage. Ten studies used validated scales to assess unmet needs, with the Supportive Care Needs Survey being the most common scale. Unmet needs in patients with CRC demonstrate distinct patterns across survival stages. Most studies reported a higher prevalence of unmet needs during the extended survival stage compared to the acute survival stage. Unmet emotional needs predominate during the acute survival stage, whereas unmet physical needs become most prominent in the extended survival stage. LINKING EVIDENCE TO ACTION: Healthcare providers are encouraged to conduct assessments tailored to the specific survival stage, with particular emphasis on addressing unmet needs during the extended survival stage. The development of standardized scales is recommended to comprehensively assess the unmet needs of patients with CRC.
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Understanding the diverse electrochemical reactions occurring at electrode-electrolyte interfaces (EEIs) is a critical challenge to developing more efficient energy conversion and storage technologies. Establishing a predictive molecular-level understanding of solid electrolyte interphases (SEIs) is challenging due to the presence of multiple intertwined chemical and electrochemical processes occurring at battery electrodes. Similarly, chemical conversions in reactive electrochemical systems are often influenced by the heterogeneous distribution of active sites, surface defects, and catalyst particle sizes. In this mini review, we highlight an emerging field of interfacial science that isolates the impact of specific chemical species by preparing precisely-defined EEIs and visualizing the reactivity of their individual components using single-entity characterization techniques. We highlight the broad applicability and versatility of these methods, along with current state-of-the-art instrumentation and future opportunities for these approaches to address key scientific challenges related to batteries, chemical separations, and fuel cells. We establish that controlled preparation of well-defined electrodes combined with single entity characterization will be crucial to filling key knowledge gaps and advancing the theories used to describe and predict chemical and physical processes occurring at EEIs and accelerating new materials discovery for energy applications.
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PURPOSE: Over the last decade, immune checkpoint inhibitors (ICI) have emerged as cornerstone in the treatment of many metastatic tumour types, including gastrointestinal cancers. In many solid tumours, the effective therapies in the metastatic field are progressively brought into the curative setting. Consequently, earlier tumoural settings have become a field of experiment for immunotherapies. In melanoma, lung, and bladder cancers, excellent results were recorded, possibly explained by differences in the tumour microenvironment between metastatic and non-metastatic settings. In gastrointestinal (GI) Oncology, nivolumab is the first immune checkpoint inhibitor to become a standard-of-care adjuvant treatment after curative surgery for oesophagal or gastroesophageal junction cancer. RECENT FINDINGS: We herein discuss the results of a selection of the most relevant studies presented/published over the last 18âmonths testing immunotherapies in non-metastatic GI cancers. Among immunotherapies, ICI have been investigated in pre-, peri- and postoperative setting across tumour types, alone or in combination with chemo- and/or radiotherapy. Vaccines are also a new field of investigation. SUMMARY: Promising results from two studies (NCT04165772 and NICHE-2 study) demonstrating never-seen-before responses to neoadjuvant immunotherapy in MMR deficient (dMMR) colorectal cancers raise hope for improving the patients' outcome and developing organ-sparing strategies in this situation.
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Neoplasias Gastrointestinales , Melanoma , Neoplasias Gástricas , Humanos , Nivolumab , Neoplasias Gastrointestinales/tratamiento farmacológico , Terapia Neoadyuvante/métodos , Inmunoterapia/métodos , Microambiente TumoralRESUMEN
BACKGROUND: Remote monitoring of pulmonary artery (PA) pressures and serial N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements guide heart failure (HF) treatment, but their association has yet to be described. METHODS AND RESULTS: In the Empagliflozin Evaluation by Measuring the Impact on Hemodynamics in Patients with Heart Failure (EMBRACE-HF) trial, patients with HF and a remote PA pressure monitoring device were randomized to empagliflozin vs placebo. PA diastolic pressures (PADP) and NT-proBNP levels were obtained at baseline and 6 and 12 weeks. We used linear mixed models to examine the association between change in PADP and change in NT-proBNP, adjusting for baseline covariates. Of 62 patients, the mean patient age was 66.2 years, and 63% were male. The mean baseline PADP was 21.8 ± 6.4 mm Hg, and the mean NT-proBNP was 1844.6 ± 2767.7 pg/mL. The mean change between baseline and averaged 6- and 12-week PADP was -0.4 ± 3.1 mm Hg, and the mean change between baseline and averaged 6- and 12-week NT-proBNP was -81.5 ± 878.6 pg/mL. In adjusted analyses, every 2-mm Hg decrease in PADP was associated with an NT-proBNP reduction of 108.9 pg/mL (95% confidence interval -4.3 to 222.0, Pâ¯=â¯.06). CONCLUSIONS: We observed that short-term decreases in ambulatory PADP seem to be associated with decreases in NT-proBNP. This finding may provide additional clinical context when tailoring treatment for patients with HF.
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Insuficiencia Cardíaca , Humanos , Masculino , Anciano , Femenino , Insuficiencia Cardíaca/tratamiento farmacológico , Arteria Pulmonar , Biomarcadores , Péptido Natriurético Encefálico/uso terapéutico , Fragmentos de PéptidosRESUMEN
Our goal was to determine if "Nomenclature 2.0," the classification of lumbar disk pathology consensus, should be updated. We conducted a social media and e-mail-based survey on preferences regarding the use of classification on magnetic resonance spine reporting. Members of the European Society of Neuroradiology, European Society of Musculoskeletal Radiology, American Society of Neuroradiology, and American Society of Spine Radiology received a 15-question online survey between February and March 2022. A total of 600 responses were received from 63 countries. The largest number of responses came from Italy and the United States. We found that 71.28% of respondents used Nomenclature 2.0, Classification of Lumbar Disk Pathology. But classification on stenosis is used less often: 53.94% and 60% of respondents do not use any classification of spinal canal stenosis and foraminal stenosis, respectively. When queried about which part of Nomenclature needs improving, most respondents asked for a Structured Reporting Template (SRT), even though 58.85% of respondents do not currently use any template and 54% routinely use a clinical information questionnaire. These results highlight the importance of an updated Nomenclature 3.0 version that integrates the classifications of lumbar disk disease and spinal canal and foraminal stenosis. Further attention should also be directed toward developing a robust endorsed SRT.
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Degeneración del Disco Intervertebral , Estenosis Espinal , Humanos , Estados Unidos , Constricción Patológica/patología , Vértebras Lumbares/diagnóstico por imagen , Imagen por Resonancia Magnética , Estenosis Espinal/diagnóstico por imagen , Encuestas y CuestionariosRESUMEN
Background: The Active Healthy Kids 2022 Viet Nam Report Card provides an evidence-based assessment of 10 indicators of community and government-led initiatives that impact the physical activity levels of children and youth in Vietnam. Methods: A systematic framework developed by the Active Healthy Kids Global Alliance was used. Each indicator: Overall Physical Activity, Organized Sport Participation, Active Play, Active Transportation, Sedentary Behaviors, Physical Fitness, Family and Peers, School, Community and Environment, and Government, and a new indicator: Obesity was assessed against predefined benchmarks. EBSCOhost databases and Google Scholar were searched for relevant academic and grey literature (e.g., government reports) respectively to inform indicator grading. Results: The School indicator received the highest grade 'A', followed by the Government indicator which was graded as 'B-'. Three indicators (Sedentary Behaviors, Family and Peers, Community and Environment) received 'C' grades. Active Transportation was graded 'D+'. Overall Physical Activity received the lowest grade of 'F'. Organized Sport and Physical Activity, Active Play, and Physical Fitness were not graded due to lack of data. Obesity was graded B-. Conclusions: This is the first physical activity report card for children and adolescents in Viet Nam. Evidence suggests that Vietnamese children and adolescents have low physical activity levels and high levels of sedentary behaviors. Initiatives to promote physical activity in children predominantly focus on promoting physical education in schools. Increased community-based programs promoting physical activity outside of school settings are required. Future research should address the surveillance gap in Organized Sport and Physical Activity, Active Play, and Physical Fitness.
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The asymmetric cell division of stem or progenitor cells generates daughter cells with distinct fates that balance proliferation and differentiation. Asymmetric segregation of Notch signaling regulatory protein Numb plays a crucial role in cell diversification. However, the molecular mechanism remains unclear. Here, we examined the unequal distribution of Numb in the daughter cells of murine erythroleukemia cells (MELCs) that undergo DMSO-induced erythroid differentiation. In contrast to the cytoplasmic localization of Numb during uninduced cell division, Numb is concentrated at the cell boundary in interphase, near the one-spindle pole in metaphase, and is unequally distributed to one daughter cell in anaphase in induced cells. The inheritance of Numb guides this daughter cell toward erythroid differentiation while the other cell remains a progenitor cell. Mitotic spindle orientation, critical for distribution of cell fate determinants, requires complex communication between the spindle microtubules and the cell cortex mediated by the NuMA-LGN-dynein/dynactin complex. Depletion of each individual member of the complex randomizes the position of Numb relative to the mitotic spindle. Gene replacement confirms that multifunctional erythrocyte protein 4.1R (4.1R) functions as a member of the NuMA-LGN-dynein/dynactin complex and is necessary for regulating spindle orientation, in which interaction between 4.1R and NuMA plays an important role. These results suggest that mispositioning of Numb is the result of spindle misorientation. Finally, disruption of the 4.1R-NuMA-LGN complex increases Notch signaling and decreases the erythroblast population. Together, our results identify a critical role for 4.1R in regulating the asymmetric segregation of Numb to mediate erythropoiesis.
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División Celular Asimétrica , Células Eritroides/citología , Células Eritroides/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Microfilamentos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Animales , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Complejo Dinactina/genética , Complejo Dinactina/metabolismo , Dineínas/genética , Dineínas/metabolismo , Proteínas de la Membrana/genética , Ratones , Proteínas de Microfilamentos/genética , Mitosis , Proteínas del Tejido Nervioso/genética , Unión Proteica , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Huso Acromático/genética , Huso Acromático/metabolismoRESUMEN
Atrial fibrillation (AF) is a common cardiac arrhythmia and affects one to two percent of the population. In this work, we leverage the three-dimensional atrial endocardial unipolar/bipolar voltage map to predict the AF type and recurrence of AF in 1 year. This problem is challenging for two reasons: (1) the unipolar/bipolar voltages are collected at different locations on the endocardium and the shapes of the endocardium vary widely in different patients, and thus the unipolar/bipolar voltage maps need aligning to the same coordinate; (2) the collected dataset size is very limited. To address these issues, we exploit a pretrained 3D point cloud registration approach and finetune it on left atrial voltage maps to learn the geometric feature and align all voltage maps into the same coordinate. After alignment, we feed the unipolar/bipolar voltages from the registered points into a multilayer perceptron (MLP) classifier to predict whether patients have paroxysmal or persistent AF, and the risk of recurrence of AF in 1 year for patients in sinus rhythm. The experiment shows our method classifies the type and recurrence of AF effectively.
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Fibrilación Atrial , Ablación por Catéter , Fibrilación Atrial/cirugía , Ablación por Catéter/métodos , Atrios Cardíacos/cirugía , Humanos , Redes Neurales de la Computación , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Magnesium bis(hexamethyldisilazide) (Mg(HMDS)2)-based electrolytes are compelling candidates for rechargeable magnesium batteries due to their high compatibility with magnesium metal anode. However, the usual combination of Mg(HMDS)2 with chloride salts limits their practical application due to severe corrosion of cell components and low anodic stability. Herein, we report for the first time, a chloride-free Mg(HMDS)2-based electrolyte in 1,2-dimethoxyethane. By chemically controlling the moisture content using tetrabutylammonium borohydride as a moisture scavenger, the electrolyte demonstrates outstanding electrochemical performance in magnesium plating/stripping, with an average Coulombic efficiency of 98.3% over 150 cycles, and is noncorrosive to cell components. Surface analysis and depth profiling of the magnesium metal anode reveals the formation of a robust solid electrolyte interphase at the anode-electrolyte nanointerface, which allows magnesium plating/stripping to occur reversibly. The electrolyte also demonstrates good compatibility with a copper sulfide nanomaterial cathode, which exhibits a high initial discharge capacity of 261.5 mAh g-1.
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Room-temperature sodium-sulfur batteries have potential in stationary applications, but challenges such as loss of active sulfur and low electrical conductivity must be solved. Nitrogen-doped nanocarbon host cathodes have been employed in metal-sulfur batteries: polar interactions mitigate the loss of sulfur, while the conductive nanostructure addresses the low conductivity. Nevertheless, these two properties run contrary to each other as greater nitrogen-doping of nanocarbon hosts is associated with lower conductivity. Herein, we investigate the polarity-conductivity dilemma to determine which of these properties have the stronger influence on cycling performance. Lower carbonization temperatures produce more pyridinic nitrogen and pyrrolic nitrogen, which from density functional theory calculations preferentially bind discharge products (Na2S and short-chain polysulfides). Despite its lower conductivity, the highly doped composite showed better Coulombic efficiency and stability, retaining a high capacity of 980 mAh g(S)-1 after 800 cycles. Our findings represent a paradigm shift where nitrogen-doping should be prioritized in designing shuttle-free, long-life sodium-sulfur batteries.