RESUMEN
Huntington disease (HD) is caused by an expanded polyglutamine mutation in huntingtin (mHTT) that promotes prominent atrophy in the striatum and subsequent psychiatric, cognitive deficits, and choreiform movements. Multiple lines of evidence point to an association between HD and aberrant striatal mitochondrial functions; however, the present knowledge about whether (or how) mitochondrial mRNA translation is differentially regulated in HD remains unclear. We found that protein synthesis is diminished in HD mitochondria compared to healthy control striatal cell models. We utilized ribosome profiling (Ribo-Seq) to analyze detailed snapshots of ribosome occupancy of the mitochondrial mRNA transcripts in control and HD striatal cell models. The Ribo-Seq data revealed almost unaltered ribosome occupancy on the nuclear-encoded mitochondrial transcripts involved in oxidative phosphorylation (SDHA, Ndufv1, Timm23, Tomm5, Mrps22) in HD cells. By contrast, ribosome occupancy was dramatically increased for mitochondrially encoded oxidative phosphorylation mRNAs (mt-Nd1, mt-Nd2, mt-Nd4, mt-Nd4l, mt-Nd5, mt-Nd6, mt-Co1, mt-Cytb, and mt-ATP8). We also applied tandem mass tag-based mass spectrometry identification of mitochondrial proteins to derive correlations between ribosome occupancy and actual mature mitochondrial protein products. We found many mitochondrial transcripts with comparable or higher ribosome occupancy, but diminished mitochondrial protein products, in HD. Thus, our study provides the first evidence of a widespread dichotomous effect on ribosome occupancy and protein abundance of mitochondria-related genes in HD.
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Enfermedad de Huntington , Mitocondrias , Biosíntesis de Proteínas , Perfilado de Ribosomas , Humanos , Línea Celular , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/genética , Enfermedad de Huntington/patología , Espectrometría de Masas , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Fosforilación Oxidativa , ARN Mensajero/metabolismo , ARN Mensajero/genética , ARN Mitocondrial/metabolismo , ARN Mitocondrial/genéticaRESUMEN
The mechanistic target of rapamycin (mTOR) signaling is influenced by multiple regulatory proteins and post-translational modifications; however, underlying mechanisms remain unclear. Here, we report a novel role of small ubiquitin-like modifier (SUMO) in mTOR complex assembly and activity. By investigating the SUMOylation status of core mTOR components, we observed that the regulatory subunit, GßL (G protein ß-subunit-like protein, also known as mLST8), is modified by SUMO1, 2, and 3 isoforms. Using mutagenesis and mass spectrometry, we identified that GßL is SUMOylated at lysine sites K86, K215, K245, K261, and K305. We found that SUMO depletion reduces mTOR-Raptor (regulatory protein associated with mTOR) and mTOR-Rictor (rapamycin-insensitive companion of mTOR) complex formation and diminishes nutrient-induced mTOR signaling. Reconstitution with WT GßL but not SUMOylation-defective KR mutant GßL promotes mTOR signaling in GßL-depleted cells. Taken together, we report for the very first time that SUMO modifies GßL, influences the assembly of mTOR protein complexes, and regulates mTOR activity.
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Transducción de Señal , Sumoilación , Serina-Treonina Quinasas TOR , Humanos , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Células HEK293 , Proteína SUMO-1/metabolismo , Proteína SUMO-1/genética , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/metabolismo , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/genética , Homóloga LST8 de la Proteína Asociada al mTOR/metabolismo , Homóloga LST8 de la Proteína Asociada al mTOR/genética , Ubiquitinas/metabolismo , Ubiquitinas/genética , Lisina/metabolismoRESUMEN
Rhes (Ras homolog enriched in the striatum), a multifunctional protein that regulates striatal functions associated with motor behaviors and neurological diseases, can shuttle from cell to cell via the formation of tunneling-like nanotubes (TNTs). However, the mechanisms by which Rhes mediates diverse functions remain unclear. Rhes is a small GTPase family member which contains a unique C-terminal Small Ubiquitin-like Modifier (SUMO) E3-like domain that promotes SUMO post-translational modification of proteins (SUMOylation) by promoting "cross-SUMOylation" of the SUMO enzyme SUMO E1 (Aos1/Uba2) and SUMO E2 ligase (Ubc-9). Nevertheless, the identity of the SUMO substrates of Rhes remains largely unknown. Here, by combining high throughput interactome and SUMO proteomics, we report that Rhes regulates the SUMOylation of nuclear proteins that are involved in the regulation of gene expression. Rhes increased the SUMOylation of histone deacetylase 1 (HDAC1) and histone 2B, while decreasing SUMOylation of heterogeneous nuclear ribonucleoprotein M (HNRNPM), protein polybromo-1 (PBRM1) and E3 SUMO-protein ligase (PIASy). We also found that Rhes itself is SUMOylated at 6 different lysine residues (K32, K110, K114, K120, K124, and K245). Furthermore, Rhes regulated the expression of genes involved in cellular morphogenesis and differentiation in the striatum, in a SUMO-dependent manner. Our findings thus provide evidence for a previously undescribed role for Rhes in regulating the SUMOylation of nuclear targets and in orchestrating striatal gene expression via SUMOylation.
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Proteínas Nucleares , Ubiquitina , Ubiquitina/metabolismo , Proteínas Nucleares/metabolismo , Procesamiento Proteico-Postraduccional , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinas/genética , Sumoilación , Expresión Génica , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/metabolismoRESUMEN
The CAG expansion of huntingtin (mHTT) associated with Huntington disease (HD) is a ubiquitously expressed gene, yet it prominently damages the striatum and cortex, followed by widespread peripheral defects as the disease progresses. However, the underlying mechanisms of neuronal vulnerability are unclear. Previous studies have shown that SUMO1 (small ubiquitin-like modifier-1) modification of mHtt promotes cellular toxicity, but the in vivo role and functions of SUMO1 in HD pathogenesis are unclear. Here, we report that SUMO1 deletion in Q175DN HD-het knockin mice (HD mice) prevented age-dependent HD-like motor and neurological impairments and suppressed the striatal atrophy and inflammatory response. SUMO1 deletion caused a drastic reduction in soluble mHtt levels and nuclear and extracellular mHtt inclusions while increasing cytoplasmic mHtt inclusions in the striatum of HD mice. SUMO1 deletion promoted autophagic activity, characterized by augmented interactions between mHtt inclusions and a lysosomal marker (LAMP1), increased LC3B- and LAMP1 interaction, and decreased interaction of sequestosome-1 (p62) and LAMP1 in DARPP-32-positive medium spiny neurons in HD mice. Depletion of SUMO1 in an HD cell model also diminished the mHtt levels and enhanced autophagy flux. In addition, the SUMOylation inhibitor ginkgolic acid strongly enhanced autophagy and diminished mHTT levels in human HD fibroblasts. These results indicate that SUMO is a critical therapeutic target in HD and that blocking SUMO may ameliorate HD pathogenesis by regulating autophagy activities.
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Autofagia/fisiología , Enfermedad de Huntington/metabolismo , Proteína SUMO-1/metabolismo , Animales , Muerte Celular Autofágica/fisiología , Encéfalo/patología , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/genética , Enfermedad de Huntington/fisiopatología , Proteínas de Membrana de los Lisosomas/metabolismo , Lisosomas/patología , Ratones , Ratones Transgénicos , Neostriado/patología , Neuronas/patología , Proteína SUMO-1/genética , Proteína SUMO-1/fisiologíaRESUMEN
MEK inhibitors have immunomodulatory activity and potential for synergistic activity when combined with PD-1 inhibitors. We evaluated selumetinib (inhibitor of MEK1/2) plus pembrolizumab (antiâPD-1 antibody) in patients with advanced/metastatic solid tumors. In this phase 1b study, adults with previously treated advanced/metastatic solid tumors received pembrolizumab 200 mg intravenously every 3 weeks plus selumetinib on days 1â14 per 3-week cycle (2 weeks on/1 week off); selumetinib dosing began at 50 mg orally twice daily with escalation in 25 mg increments for ≤ 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), adverse events (AEs), and treatment discontinuations due to AEs. Thirty-two patients were enrolled. Dose escalation was completed up to selumetinib 125 mg twice daily. The target DLT rate of 30% was not reached at any dose level. In the selumetinib 100 mg group, 2/11 patients (18.2%) experienced DLTs (n = 1 grade 3 diarrhea, n = 1 grade 3 fatigue). In the selumetinib 125 mg group, 3/14 (21.4%) experienced DLTs (n = 1 grade 2 retinal detachment, n = 1 grade 3 retinopathy, n = 1 grade 3 stomatitis). Dose-related changes in pharmacokinetic exposures were observed for selumetinib and N-desmethyl selumetinib up to 100 mg (saturation at 125 mg). Two patients achieved partial responses (1 each with selumetinib 75 mg and 125 mg) for an objective response rate of 6%. The study was stopped early because of insufficient efficacy. Although the target DLT rate was not reached at any dose level and no new safety signals were identified, selumetinib plus pembrolizumab had limited antitumor activity in this population. Trial registration: ClinicalTrials.gov , NCT03833427.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Bencimidazoles , Neoplasias , Humanos , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Bencimidazoles/uso terapéutico , Bencimidazoles/efectos adversos , Femenino , Masculino , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Persona de Mediana Edad , Anciano , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Adulto , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Dosis Máxima Tolerada , Relación Dosis-Respuesta a Droga , Anciano de 80 o más AñosRESUMEN
Effluent from nuclear power plants, rocks, and minerals contains hazardous radionuclides that adversely affect human health and seriously threaten the environment. To address this issue, simple, economic, and sustainable magnetite nanoparticle loaded sodium alginate copper metal-organic framework composite beads (MNPs-SA@Cu MOF composite beads) have been designed, and their performance has been evaluated under varying conditions of pH, time, adsorbent dose, and initial concentration and have been studied by batch adsorption studies for optimizing the adsorption conditions. In this work, MNPs-SA@Cu MOF composite beads have been prepared in situ for the adsorptive removal of uranium [U(VI)] and thorium [Th(IV)] ions from an aqueous solution. The synthesized MNPs-SA@Cu MOF composite beads were characterized by model analytical techniques like Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, field emission scanning electron microscopy, Brunauer-Emmett-Teller, and thermal gravimetric analysis. Here, 6 mg of adsorbent with 10 mL of 50 mg/L uranium and thorium ion solution at pH 5 was capable of removing the U(VI) and Th(IV) ions with 99.9 and 97.7% removal efficiencies, respectively. The obtained results showed that the adsorption behavior of the adsorbent for U(VI) and Th(IV) follows pseudo-second-order kinetics, and Langmuir isotherm fitted well with a maximum adsorption capacity of 454.54 and 434.78 mg/g, respectively. The adsorption mechanism indicated that electrostatic interaction and hydrogen bonding are the main driving forces for removing the U(VI) and Th(IV) ions. It can be reused for up to 10 adsorption-desorption cycles with minimal loss of removal efficiency. The easy synthesis method of MNPs-SA@Cu MOF composite beads and the high removal efficiency of U(VI) and Th(IV) ions reveal that they can potentially treat radionuclide waste effectively.
RESUMEN
CRISPR-based (Clustered regularly interspaced short palindromic repeats-based) technologies have revolutionized molecular biology and diagnostics, offering unprecedented precision and versatility. However, challenges remain, such as high costs, demanding technical expertise, and limited quantification capabilities. To overcome these limitations, innovative microfluidic platforms are emerging as powerful tools for enhancing CRISPR diagnostics. This review explores the exciting intersection of CRISPR and microfluidics, highlighting their potential to revolutionize healthcare diagnostics. By integrating CRISPR's specificity with microfluidics' miniaturization and automation, researchers are developing more sensitive and portable diagnostic tools for a range of diseases. These microfluidic devices streamline sample processing, improve diagnostic performance, and enable point-of-care applications, allowing for rapid and accurate detection of pathogens, genetic disorders, and other health conditions. The review discusses various CRISPR/Cas systems, including Cas9, Cas12, and Cas13, and their integration with microfluidic platforms. It also examines the advantages and limitations of these systems, highlighting their potential for detecting DNA and RNA biomarkers. The review also explores the key challenges in developing and implementing CRISPR-driven microfluidic diagnostics, such as ensuring robustness, minimizing cross-contamination, and achieving robust quantification. Finally, it highlights potential future directions for this rapidly evolving field, emphasizing the transformative potential of these technologies for personalized medicine and global health.
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Sistemas CRISPR-Cas , Microfluídica , Sistemas CRISPR-Cas/genética , Humanos , Microfluídica/métodos , Patología Molecular/métodos , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Técnicas de Diagnóstico Molecular/métodos , Edición Génica/métodos , Dispositivos Laboratorio en un ChipRESUMEN
The present study was conducted to understand transcriptional response of skin fibroblast of yak (Bos grunniens) and cows of Bos indicus origin to hypoxia stress. Six primary fibroblast cell lines derived from three individuals each of Ladakhi yak (Bos grunniens) and Sahiwal cows (Bos indicus) were exposed to low oxygen concentration for a period of 24 h, 48 h and 72 h. The expression of 10 important genes known to regulate hypoxia response such as HIF1A, VEGFA, EPAS1, ATP1A1, GLUT1, HMOX1, ECE1, TNF-A, GPx and SOD were evaluated in fibroblast cells of Ladakhi yak (LAY-Fb) and Sahiwal cows (SAC-Fb) during pre- and post-hypoxia stress. A panel of 10 reference genes (GAPDH, RPL4, EEF1A1, RPS9, HPRT1, UXT, RPS23, B2M, RPS15, ACTB) were also evaluated for their expression stability to perform accurate normalization. The expression of HIF1A was significantly (p < 0.05) induced in both LAY-Fb (2.29-fold) and SAC-Fb (2.07-fold) after 24 h of hypoxia stress. The angiogenic (VEGFA), metabolic (GLUT1) and antioxidant genes (SOD and GPx) were also induced after 24 h of hypoxia stress. However, EPAS1 and ATP1A1 induced significantly (p < 0.05) after 48 h whereas, ECE1 expression induced significantly (p < 0.05) at 72 h after exposure to hypoxia. The TNF-alpha which is a pro-inflammatory gene induced significantly (p < 0.05) at 24 h in SAC-Fb and at 72 h in LAY-Fb. The induction of hypoxia associated genes indicated the utility of skin derived fibroblast as cellular model to evaluate transcriptome signatures post hypoxia stress in populations adapted to diverse altitudes.
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Altitud , Fibroblastos , Hipoxia , Piel , Animales , Bovinos , Fibroblastos/metabolismo , Piel/metabolismo , Hipoxia/genética , Clima Tropical , Femenino , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Estrés Fisiológico/genéticaRESUMEN
Air pollution is growing at alarming rates on regional and global levels, with significant consequences for human health, ecosystems, and change in climatic conditions. The present 12 weeks (4 October 2021, to 26 December 2021) study revealed the different ambient air quality parameters, i.e., PM2.5, PM10, SO2, NO2, and O3 over four different sampling stations of Delhi-NCR region (Dwarka, Knowledge park III, Sector 125, and Vivek Vihar), India, by using satellite remote sensing data (MERRA-2, OMI, and Aura Satellite) and different ground-based instruments. The ground-based observation revealed the mean concentration of PM2.5 in Dwarka, Knowledge park III, Sector 125, and Vivek Vihar as 279 µg m-3, 274 µg m-3, 294 µg m-3, and 365 µg m-3, respectively. The ground-based instrumental concentration of PM2.5 was greater than that of satellite observations, while as for SO2 and NO2, the mean concentration of satellite-based monitoring was higher as compared to other contaminants. Negative and positive correlations were observed among particulate matter, trace gases, and various meteorological parameters. The wind direction proved to be one of the prominent parameter to alter the variation of these pollutants. The current study provides a perception into an observable behavior of particulate matter, trace gases, their variation with meteorological parameters, their health hazards, and the gap between the measurements of satellite remote sensing and ground-based measurements.
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Contaminantes Atmosféricos , Humanos , Dióxido de Nitrógeno , Ecosistema , Monitoreo del Ambiente , Material Particulado , GasesRESUMEN
This study delves into the intricate dynamics of air pollution in the rapidly expanding northern regions of India, examining the intertwined influences of agricultural burning, industrialization, and meteorological conditions. Through comprehensive analysis of key pollutants (PM2.5, PM10, NO2, SO2, CO, O3) across ten monitoring stations in Uttar Pradesh, Haryana, Delhi, and Punjab, a consistent pattern of high pollution levels emerges, particularly notable in Delhi. Varanasi leads in SO2 and O3 concentrations, while Moradabad stands out for CO levels, and Jalandhar for SO2 concentrations. The study further elucidates the regional distribution of pollutants, with Punjab receiving significant contributions from SW, SE, and NE directions, while Haryana and Delhi predominantly face air masses from SE and NE directions. Uttar Pradesh's pollution sources are primarily local, with additional inputs from various directions. Moreover, significant negative correlations (p < 0.05) between PM10, NO2, SO2, O3, and relative humidity (RH) underscore the pivotal role of meteorological factors in shaping pollutant levels. Strong positive correlations between PM2.5 and NO2 (0.71 to 0.93) suggest shared emission sources or similar atmospheric conditions in several cities. This comprehensive understanding highlights the urgent need for targeted mitigation strategies to address the multifaceted drivers of air pollution, ensuring the protection of public health and environmental sustainability across the region.
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Contaminantes Atmosféricos , Contaminación del Aire , Ciudades , Monitoreo del Ambiente , Material Particulado , Dióxido de Azufre , Contaminantes Atmosféricos/análisis , India , Contaminación del Aire/estadística & datos numéricos , Material Particulado/análisis , Dióxido de Azufre/análisis , Dióxido de Nitrógeno/análisis , Ozono/análisis , Conceptos MeteorológicosRESUMEN
BACKGROUND: Immunotherapy-based combinations including pembrolizumab plus lenvatinib are the standard of care for patients with first-line clear-cell renal cell carcinoma, but these combinations are not well characterised in non-clear-cell renal cell carcinoma. We aimed to assess the activity and safety of pembrolizumab plus lenvatinib as a first-line treatment for patients with advanced non-clear-cell renal cell carcinoma. METHODS: KEYNOTE-B61 is a single-arm, phase 2 trial being conducted at 48 sites (hospitals and cancer centres) in 14 countries (Australia, Canada, France, Hungary, Ireland, Italy, Poland, South Korea, Russia, Spain, Türkiye, Ukraine, the UK, and the USA). Adult patients (aged ≥18 years) with previously untreated stage IV non-clear-cell renal cell carcinoma and a Karnofsky performance status of 70% or higher were eligible for enrolment. All enrolled patients received pembrolizumab 400 mg intravenously every 6 weeks for up to 18 cycles (2 years) plus lenvatinib 20 mg orally once daily or until disease progression, unacceptable toxicity, or withdrawal; lenvatinib could be continued beyond 2 years. The primary endpoint was the proportion of patients with a confirmed objective response as per adjusted Response Evaluation Criteria in Solid Tumours (version 1.1) assessed by independent central review. Activity and safety were analysed in all patients who received at least one dose of study treatment (the as-treated population). This trial is registered with ClinicalTrials.gov (NCT04704219) and is no longer recruiting participants but is ongoing. FINDINGS: Between Feb 23, 2021, and Jan 21, 2022, 215 patients were screened; 158 were enrolled and received treatment. Median age at baseline was 60 years (IQR 52-69), 112 (71%) of 158 patients were male, 46 (29%) were female, 128 (81%) were White, 12 (8%) were Asian, three (2%) were Black or African American, and 15 (9%) were missing data on race. As of data cutoff (Nov 7, 2022), median study follow-up was 14·9 months (IQR 11·1-17·4). 78 of 158 patients had a confirmed objective response (49%; 95% CI 41-57), including nine (6%) patients with a confirmed complete response and 69 (44%) with a confirmed partial response. Grade 3-4 treatment-related adverse events occurred in 81 (51%) of 158 patients, the most common of which were hypertension (37 [23%] of 158), proteinuria (seven [4%]), and stomatitis (six [4%]). Serious treatment-related adverse events occurred in 31 (20%) of 158 patients. Eight (5%) patients died due to adverse events, none of which was considered related to the treatment by the investigators (one each of cardiac failure, peritonitis, pneumonia, sepsis, cerebrovascular accident, suicide, pneumothorax, and pulmonary embolism). INTERPRETATION: Pembrolizumab plus lenvatinib has durable antitumour activity in patients with previously untreated advanced non-clear-cell renal cell carcinoma, with a safety profile consistent with that of previous studies. Results from KEYNOTE-B61 support the use of pembrolizumab plus lenvatinib as a first-line treatment option for these patients. FUNDING: Merck Sharp & Dohme (a subsidiary of Merck & Co, NJ, USA), and Eisai.
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Carcinoma de Células Renales , Adulto , Humanos , Masculino , Femenino , Adolescente , Persona de Mediana Edad , Anciano , Carcinoma de Células Renales/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
The past several decades have witnessed the emergence and re-emergence of many infectious viral agents, flaviviruses, influenza, filoviruses, alphaviruses, and coronaviruses since the advent of human deficiency virus (HIV). Some of them even become serious threats to public health and have raised major global health concerns. Several different medicinal compounds such as anti-viral, anti-malarial, and anti-inflammatory agents, are under investigation for the treatment of these viral diseases. These therapies are effective improving recovery rates and overall survival of patients but are unable to heal lung damage caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, there is a critical need to identify effective treatments to combat this unmet clinical need. Due to its antioxidant and immunomodulatory properties, stem cell therapy is considered a novel approach to regenerate damaged lungs and reduce inflammation. Stem cell therapy uses a heterogeneous subset of regenerative cells that can be harvested from various adult tissue types and is gaining popularity due to its prodigious regenerative potential as well as immunomodulatory and anti-inflammatory properties. These cells retain expression of cluster of differentiation markers (CD markers), interferon-stimulated gene (ISG), reduce expression of pro-inflammatory cytokines and, show a rapid proliferation rate, which makes them an attractive tool for cellular therapies and to treat various inflammatory and viral-induced injuries. By examining various clinical studies, this review demonstrates positive considerations for the implications of stem cell therapy and presents a necessary approach for treating virally induced infections in patients.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/terapia , Interferones , Pulmón , Trasplante de Células MadreRESUMEN
Rampant use of antibiotics has resulted in their seepage into groundwater and ultimately ending up in the food chain, causing antimicrobial resistance. To address this issue, it is imperative to not only quantitatively detect but eliminate them from water. An eco-friendly, one-step microwave-induced pyrolysis of waste papaya seeds (PS) with ethylenediamine (EDA) for just 5min gave green fluorescent nitrogen-doped carbon dots (PS-CDs), which are capable of detecting and photocatalytically degrading TC. The fluorescence properties of PS-CDs displayed that it has high sensitivity and selectivity towards sensing of TC with a detection limit as low as 120 nM. Also, the method gave satisfactory recovery results when extrapolated to determine TC in spiked milk, orange juice, tap water, and honey samples. On the other hand, PS-CDs alone potentially function as an efficient photocatalyst for the degradation of TC. PS-CDs' dual functionality provides an effectual method for the simultaneous detection and degradation of TC by a single nanoprobe.
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Carica , Puntos Cuánticos , Tetraciclina , Agua , Carbono , Colorantes Fluorescentes , Nitrógeno , Espectrometría de Fluorescencia/métodosRESUMEN
An easy synthesis of two 1,3,4-oxadiazole derivatives, namely, 2-phenyl-5-(pyridin-3-yl)-1,3,4-oxadiazole (POX) and 2-(4-methoxyphenyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole (4-PMOX), and their corrosion-inhibition efficacy against mild steel corrosion in 1 N HCl, is evaluated using weight loss from 303 to 323 K, Electrochemical Impedance Spectroscopy (EIS), Potentiodynamic Polarization (PDP), Scanning Electron Microscopy (SEM), Energy Dispersive X-ray (EDX), UV-Vis spectroscopy, along with theoretical evaluation. Both POX and 4-PMOX exhibit excellent inhibition efficiency, with values reaching 97.83% and 98% at 500 ppm, respectively. The PDP analysis reveals that both derivatives act as mixed-type inhibitors. The Langmuir adsorption isotherm provides insights into the adsorption phenomena, demonstrating that 4-PMOX exhibits superior adsorption behavior on the mild steel surface compared to POX. This finding is further supported by SEM, DFT, RDF, and MSD analyses. Quantum mechanical parameters, including EHOMO, ELUMO, dipole moment (µ), energy gap (ΔE), etc., are in good agreement with the effectiveness of inhibition performance revealing ΔE values of 3.10 and 2.75 for POX and 4-PMOX, respectively. The results obtained from this study hold significant implications for researchers aiming to design more efficient organic inhibitors to combat metal corrosion.
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Oxadiazoles , Acero , Acero/química , Corrosión , PiridinasRESUMEN
The role of pesticides in enhancing global agricultural production is magnificent. However, their unmanaged use threatens water resources and individual health. A significant pesticide concentration leaches to groundwater or reaches surface waters through runoff. Water contaminated with pesticides may cause acute or chronic toxicity to impacted populations and exert adverse environmental effects. It necessitates the monitoring and removing pesticides from water resources as prime global concerns. This work reviewed the global occurrences of pesticides in potable water and discussed the conventional and advanced technologies for the removal of pesticides. The concentration of pesticides highly varies in freshwater resources across the globe. The highest concentration of α-HCH (6.538 µg/L, at Yucatan, Mexico), lindane (6.08 µg/L at Chilka lake, Odisha, India), 2,4, DDT (0.90 µg/L, at Akkar, Lebanon), chlorpyrifos (9.1 µg/L, at Kota, Rajasthan, India), malathion (5.3 µg/L, at Kota, Rajasthan, India), atrazine (28.0 µg/L, at Venado Tuerto City, Argentina), endosulfan (0.78 µg/L, at Yavtmal, Maharashtra, India), parathion (4.17 µg/L, at Akkar, Lebanon), endrin (3.48 µg/L, at KwaZuln-Natl Province, South Africa) and imidacloprid (1.53 µg/L, at Son-La province, Vietnam) are reported. Pesticides can be significantly removed through physical, chemical, and biological treatment. Mycoremediation technology has the potential for up to 90% pesticide removal from water resources. Complete removal of the pesticides through a single biological treatment approach such as mycoremediation, phytoremediation, bioremediation, and microbial fuel cells is still a challenging task, however, the integration of two or more biological treatment approaches can attain complete removal of pesticides from water resources. Physical methods along with oxidation methods can be employed for complete removal of pesticides from drinking water.
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Agua Potable , Plaguicidas , Contaminantes Químicos del Agua , Plaguicidas/análisis , Contaminantes Químicos del Agua/análisis , Monitoreo del Ambiente , India , Agua Dulce , Agua Potable/análisisRESUMEN
Huntington disease (HD) is caused by an expansion mutation of the N-terminal polyglutamine of huntingtin (mHTT). mHTT is ubiquitously present, but it induces noticeable damage to the brain's striatum, thereby affecting motor, psychiatric, and cognitive functions. The striatal damage and progression of HD are associated with the inflammatory response; however, the underlying molecular mechanisms remain unclear. Here, we report that cGMP-AMP synthase (cGAS), a DNA sensor, is a critical regulator of inflammatory and autophagy responses in HD. Ribosome profiling revealed that the cGAS mRNA has high ribosome occupancy at exon 1 and codon-specific pauses at positions 171 (CCG) and 172 (CGT) in HD striatal cells. Moreover, the protein levels and activity of cGAS (based on the phosphorylated STING and phosphorylated TBK1 levels), and the expression and ribosome occupancy of cGAS-dependent inflammatory genes (Ccl5 and Cxcl10) are increased in HD striatum. Depletion of cGAS diminishes cGAS activity and decreases the expression of inflammatory genes while suppressing the up-regulation of autophagy in HD cells. In contrast, reinstating cGAS in cGAS-depleted HD cells activates cGAS activity and promotes inflammatory and autophagy responses. Ribosome profiling also revealed that LC3A and LC3B, the two major autophagy initiators, show altered ribosome occupancy in HD cells. We also detected the presence of numerous micronuclei, which are known to induce cGAS, in the cytoplasm of neurons derived from human HD embryonic stem cells. Collectively, our results indicate that cGAS is up-regulated in HD and mediates inflammatory and autophagy responses. Thus, targeting the cGAS pathway may offer therapeutic benefits in HD.
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Autofagia/fisiología , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Animales , Quimiocina CCL5/metabolismo , Quimiocina CXCL10/metabolismo , Cuerpo Estriado/metabolismo , Células Madre Embrionarias , Humanos , Proteína Huntingtina/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/metabolismo , Neostriado/metabolismo , Neuronas/metabolismo , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Transcriptoma , Regulación hacia ArribaRESUMEN
INTRODUCTION: Extracorporeal Membrane Oxygenation (ECMO) is used as a bridge to recovery of cardiac function following completion of congenital cardiac surgeries where there is failure to wean from cardiopulmonary bypass (CPB) or severe low cardiac output states in the post operative periods. Although ECMO is a well-established form of mechanical circulatory support, the associated cost can be a huge financial burden on families. We are an ECMO center and use the same in post operative congenital cardiac surgeries for mechanical cardiovascular support if needed. However, a significant proportion of the children, whom we operate, are funded by government aides. The resources are limited in such circumstances. If needed, we use the same CPB circuit and cannulae used in the Operating Room (OR) and support them at a significantly lower cost compared to ECMO. METHODS: We report our experience of using conventional CPB machine as a short-term bridge to recovery of cardiac function in Intensive Care Unit where there was limitation of funds. Essentially same CPB circuit with roller pump is retained, by omitting cardiotomy suckers. We use D901 Lilliput 1 Oxygenator (Sorin, Italy) for children <5 kg and D902 Lilliput 2 (Sorin, Italy) Oxygenator for children >5 Kg. RESULTS: We supported nine patients on CPB between March 2019 and December 2021. During this time, 1392 congenital cardiac surgeries were performed. We could wean off three patients (33.3%) and discharge two patients (22.2%). Our support time ranged from 21 h to 60 h with a median of 48 h. Beyond 48 h of support, we experienced several CPB induced complications in our cohort. CONCLUSION: In resource-limited settings, conventional CPB machines can be used for short-term cardiac support. Although results may not be comparable to using ECMO, some patients can be definitely salvaged, who would otherwise die in the absence of institution of mechanical circulatory support.
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Procedimientos Quirúrgicos Cardíacos , Oxigenación por Membrana Extracorpórea , Niño , Humanos , Puente Cardiopulmonar/métodos , Corazón , Oxigenación por Membrana Extracorpórea/métodos , Unidades de Cuidados Intensivos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Landfills are commonly used to manage solid waste, but they can contribute to microplastic (MPs) pollution. As plastic waste degrades in landfills, MPs are released into the surrounding environment, contaminating soil, groundwater, and surface water. This poses a threat to human health and the environment, as MPs can adsorb toxic substances. This paper provides a comprehensive review of the degradation process of macroplastics into microplastics, the types of MPs found in landfill leachate (LL), and the potential toxicity of microplastic pollution. The study also evaluates various physical-chemical and biological treatment methods for removing MPs from wastewater. The concentration of MPs in young landfills is higher than in old landfills, and specific polymers such as polypropylene, polystyrene, nylon, and polycarbonate contribute significantly to microplastic contamination. Primary treatments such as chemical precipitation and electrocoagulation can remove up to 60-99% of total MPs from wastewater, while tertiary treatments such as sand filtration, ultrafiltration, and reverse osmosis can remove up to 90-99%. Advanced techniques, such as a combination of membrane bioreactor, ultrafiltration, and nanofiltration (MBR + UF + NF), can achieve even higher removal rates. Overall, this paper highlights the importance of continuous monitoring of microplastic pollution and the need for effective microplastic removal from LL to protect human and environmental health. However, more research is needed to determine the actual cost and feasibility of these treatment processes at a larger scale.
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Microplásticos , Contaminantes Químicos del Agua , Humanos , Plásticos , Aguas Residuales , Contaminantes Químicos del Agua/química , Residuos SólidosRESUMEN
Nowadays, the hectic work life of people has led to sleep deprivation. This may further result in sleep-related disorders and adverse physiological conditions. Therefore, sleep study has become an active research area. Sleep scoring is crucial for detecting sleep-related disorders like sleep apnea, insomnia, narcolepsy, periodic leg movement (PLM), and restless leg syndrome (RLS). Sleep is conventionally monitored in a sleep laboratory using polysomnography (PSG) which is the recording of various physiological signals. The traditional sleep stage scoring (SSG) done by professional sleep scorers is a tedious, strenuous, and time-consuming process as it is manual. Hence, developing a machine-learning model for automatic SSG is essential. In this study, we propose an automated SSG approach based on the biorthogonal wavelet filter bank's (BWFB) novel least squares (LS) design. We have utilized a huge Wisconsin sleep cohort (WSC) database in this study. The proposed study is a pioneering work on automatic sleep stage classification using the WSC database, which includes good sleepers and patients suffering from various sleep-related disorders, including apnea, insomnia, hypertension, diabetes, and asthma. To investigate the generalization of the proposed system, we evaluated the proposed model with the following publicly available databases: cyclic alternating pattern (CAP), sleep EDF, ISRUC, MIT-BIH, and the sleep apnea database from St. Vincent's University. This study uses only two unipolar EEG channels, namely O1-M2 and C3-M2, for the scoring. The Hjorth parameters (HP) are extracted from the wavelet subbands (SBS) that are obtained from the optimal BWFB. To classify sleep stages, the HP features are fed to several supervised machine learning classifiers. 12 different datasets have been created to develop a robust model. A total of 12 classification tasks (CT) have been conducted employing various classification algorithms. Our developed model achieved the best accuracy of 83.2% and Cohen's Kappa of 0.7345 to reliably distinguish five sleep stages, using an ensemble bagged tree classifier with 10-fold cross-validation using WSC data. We also observed that our system is either better or competitive with existing state-of-art systems when we tested with the above-mentioned five databases other than WSC. This method yielded promising results using only two EEG channels using a huge WSC database. Our approach is simple and hence, the developed model can be installed in home-based clinical systems and wearable devices for sleep scoring.
RESUMEN
Retained foreign bodies following penetrating brain injuries continue to pose therapeutic dilemmas. Previously used aggressive approach involving extensive wound debridement and removal of foreign bodies caused additional neurological deficit with higher mortality. Less aggressive approach used more recently involving decompressive craniectomy has lead to higher incidence of retained foreign bodies with potential of infective sequelae. We describe one such case where, in presence of a retained foreign body, an intracranial abscess formed after a gap of 17 yrs. The case has peculiar radiological and morphological findings.