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RNA can directly control protein activity in a process called riboregulation; only a few mechanisms of riboregulation have been described in detail, none of which have been characterized on structural grounds. Here, we present a comprehensive structural, functional, and phylogenetic analysis of riboregulation of cytosolic serine hydroxymethyltransferase (SHMT1), the enzyme interconverting serine and glycine in one-carbon metabolism. We have determined the cryoelectron microscopy (cryo-EM) structure of human SHMT1 in its free- and RNA-bound states, and we show that the RNA modulator competes with polyglutamylated folates and acts as an allosteric switch, selectively altering the enzyme's reactivity vs. serine. In addition, we identify the tetrameric assembly and a flap structural motif as key structural elements necessary for binding of RNA to eukaryotic SHMT1. The results presented here suggest that riboregulation may have played a role in evolution of eukaryotic SHMT1 and in compartmentalization of one-carbon metabolism. Our findings provide insights for RNA-based therapeutic strategies targeting this cancer-linked metabolic pathway.
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Microscopía por Crioelectrón , Glicina Hidroximetiltransferasa , Glicina Hidroximetiltransferasa/metabolismo , Glicina Hidroximetiltransferasa/genética , Glicina Hidroximetiltransferasa/química , Humanos , ARN/metabolismo , ARN/genética , Serina/metabolismo , Regulación Alostérica , Unión Proteica , Filogenia , Modelos Moleculares , Conformación Proteica , Relación Estructura-Actividad , Glicina/metabolismo , Glicina/química , Sitios de UniónRESUMEN
BACKGROUND: The investigation of plant-based therapeutic agents in medicinal plants has revealed their presence in the extracts and provides the vision to formulate novel techniques for drug therapy. Vitex negundo (V. negundo), a perennial herb belonging to the Varbanaceae family, is extensively used in conventional medication. AIM: To determine the existence of therapeutic components in leaf and callus extracts from wild V. negundo plants using gas chromatography-mass spectrometry (GC-MS). METHODS: In this study, we conducted GC-MS on wild plant leaf extracts and correlated the presence of constituents with those in callus extracts. Various growth regulators such as 6-benzylaminopurine (BAP), 2,4-dichlorophenoxyacetic acid (2,4-D), α-naphthylacetic acid (NAA), and di-phenylurea (DPU) were added to plant leaves and in-vitro callus and grown on MS medium. RESULTS: The results clearly indicated that the addition of BAP (2.0 mg/L), 2,4-D (0.2 mg/mL), DPU (2.0 mg/L) and 2,4-D (0.2 mg/mL) in MS medium resulted in rapid callus development. The plant profile of Vitex extracts by GC-MS analysis showed that 24, 10, and 14 bioactive constituents were detected in the methanolic extract of leaf, green callus and the methanolic extract of white loose callus, respectively. CONCLUSION: Octadecadienoic acid, hexadecanoic acid and methyl ester were the major constituents in the leaf and callus methanolic extract. Octadecadienoic acid was the most common constituent in all samples. The maximum concentration of octadecadienoic acid in leaves, green callus and white loose callus was 21.93%, 47.79% and 40.38%, respectively. These findings demonstrate that the concentration of octadecadienoic acid doubles in-vitro compared to in-vivo. In addition to octadecadienoic acid; butyric acid, benzene, 1-methoxy-4-(1-propenyl), dospan, tridecanedialdehyde, methylcyclohexenylbutanol, chlorpyrifos, n-secondary terpene diester, anflunine and other important active compounds were also detected. All these components were only available in callus formed in-vitro. This study showed that the callus contained additional botanical characteristics compared with wild plants. Due to the presence of numerous bioactive compounds, the medical use of Vitex for various diseases has been accepted and the plant is considered an important source of therapeutics for research and development.
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Moringa oleifera (MO) phytochemicals and therapeutic properties improve hyperglycemia and treat type 2 diabetes. Thus, this study examined the effects of MO leaf capsules on blood glucose management in type 2 diabetic mellitus (T2DM) and hypertension and their safety. A prospective placebo-controlled experiment randomly assigned 24 patients to receive 3g and 6g of MO leaf capsules twice a day or a placebo for three months. Pre- and post-study lab and clinical outcomes were assessed. The placebo control group and 3g MO leaf showed a minor change, whereas 6g and control placebo showed a considerable drop in examined features. MO usage was safe. In T2DM patients, MO leaves lowered blood pressure, requiring further study. MO leaves may help T2DM patients manage blood pressure and blood sugar, according to the study. MO's therapeutic components need more research.
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Diabetes Mellitus Tipo 2 , Hipertensión , Moringa oleifera , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Cápsulas , Estudios Prospectivos , Hipertensión/tratamiento farmacológico , Hojas de la PlantaRESUMEN
In the present scenario, the SARS-CoV-2 virus has imposed enormous damage on human survival and the global financial system. It has been estimated that around 111 million people all around the world have been infected, and about 2.47 million people died due to this pandemic. The major symptoms were sneezing, coughing, cold, difficulty breathing, pneumonia, and multi-organ failure associated 1with SARS-CoV-2. Currently, two key problems, namely insufficient attempts to develop drugs against SARSCoV-2 and the lack of any biological regulating process, are mostly responsible for the havoc caused by this virus. Henceforth, developing a few novel drugs is urgently required to cure this pandemic. It has been noticed that the pathogenesis of COVID-19 is caused by two main events: infection and immune deficiency, that occur during the pathological process. Antiviral medication can treat both the virus and the host cells. Therefore, in the present review, the major approaches for the treatment have been divided into "target virus" and "target host" groups. These two mechanisms primarily rely on drug repositioning, novel approaches, and possible targets. Initially, we discussed the traditional drugs per the physicians' recommendations. Moreover, such therapeutics have no potential to fight against COVID-19. After that, detailed investigation and analysis were conducted to find some novel vaccines and monoclonal antibodies and conduct a few clinical trials to check their effectiveness against SARSCoV-2 and mutant strains. Additionally, this study presents the most successful methods for its treatment, including combinatorial therapy. Nanotechnology was studied to build efficient nanocarriers to overcome the traditional constraints of antiviral and biological therapies.
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In the present scenario, resistance to antibiotics is one of the crucial issues related to public health. Earlier, such resistance to antibiotics was limited to nosocomial infections, but it has now become a common phenomenon. Several factors, like extensive development, overexploitation of antibiotics, excessive application of broad-spectrum drugs, and a shortage of target-oriented antimicrobial drugs, could be attributed to this condition. Nowadays, there is a rise in the occurrence of these drug-resistant pathogens due to the availability of a small number of effective antimicrobial agents. It has been estimated that if new novel drugs are not discovered or formulated, there would be no effective antibiotic available to treat these deadly resistant pathogens by 2050. For this reason, we have to look for the formulation of some new novel drugs or other options or substitutes to treat such multidrug-resistant microorganisms (MDR). The current review focuses on the evolution of the most common multidrug-resistant bacteria and discusses how these bacteria escape the effects of targeted antibiotics and become multidrug resistant. In addition, we also discuss some alternative mechanisms to prevent their infection as well.
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Infección Hospitalaria , Farmacorresistencia Bacteriana Múltiple , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Bacterias , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/microbiología , Infección Hospitalaria/prevención & control , HumanosRESUMEN
The diagnosis and treatment of patients in the healthcare industry are greatly aided by data analytics. Massive amounts of data should be handled using machine learning approaches to provide tools for prediction and categorization to support practitioner decision-making. Based on the kind of tumor, disorders like breast cancer can be categorized. The difficulties associated with evaluating vast amounts of data should be overcome by discovering an efficient method for categorization. Based on the Bayesian method, we analyzed the influence of clinic pathological indicators on the prognosis and survival rate of breast cancer patients and compared the local resection value directly using the lymph node ratio (LNR) and the overall value using the LNR differences in effect between estimates. Logistic regression was used to estimate the overall LNR of patients. After that, a probabilistic Bayesian classifier-based dynamic regression model for prognosis analysis is built to capture the dynamic effect of multiple clinic pathological markers on patient prognosis. The dynamic regression model employing the total estimated value of LNR had the best fitting impact on the data, according to the simulation findings. In comparison to other models, this model has the greatest overall survival forecast accuracy. These prognostic techniques shed light on the nodal survival and status particular to the patient. Additionally, the framework is flexible and may be used with various cancer types and datasets.
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Neoplasias de la Mama , Teorema de Bayes , Neoplasias de la Mama/patología , Femenino , Humanos , Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Estadificación de Neoplasias , Pronóstico , Estudios RetrospectivosRESUMEN
Resolution-dependent loss of contrast in cryo-EM maps may obscure features at high resolution that are critical for map interpretation. Post-processing of cryo-EM maps can improve the interpretability by adjusting the resolution-dependence of structure factor amplitudes through map sharpening. Traditionally this has been done by rescaling the relative contribution of low and high-resolution frequencies globally. More recently, the realisation that molecular motion and heterogeneity cause non-uniformity of resolution throughout the map has inspired the development of techniques that optimise sharpening locally. We previously developed LocScale, a method that utilises the radial structure factor from a refined atomic model as a restraint for local map sharpening. While this method has proved beneficial for the interpretation of cryo-EM maps, the dependence on the availability of (partial) model information limits its general applicability. Here, we review the basic assumptions of resolution-dependent contrast loss in cryo-EM maps and propose a route towards a robust alternative for local map sharpening that utilises information on expected scattering properties of biological macromolecules, but requires no detailed knowledge of the underlying molecular structure. We examine remaining challenges for implementation and discuss possible applications.
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Electrones , Microscopía por Crioelectrón/métodos , Modelos Moleculares , Conformación ProteicaRESUMEN
Inborn errors of metabolism (IEM) are a heterogeneous group of rare genetic disorders that are generally transmitted as autosomal or X-linked recessive disorders. These defects arise due to mutations associated with specific gene(s), especially the ones associated with key metabolic enzymes. These enzymes or their product(s) are involved in various metabolic pathways, leading to the accumulation of intermediary metabolite(s), reflecting their toxic effects upon mutations. The diagnosis of these metabolic disorders is based on the biochemical analysis of the clinical manifestations produced and their molecular mechanism. Therefore, it is imperative to devise diagnostic tests with high sensitivity and specificity for early detection of IEM. Recent advances in biochemical and polymerase chain reaction-based genetic analysis along with pedigree and prenatal diagnosis can be life-saving in nature. The latest development in exome sequencing for rapid diagnosis and enzyme replacement therapy would facilitate the successful treatment of these metabolic disorders in the future. However, the longterm clinical implications of these genetic manipulations is still a matter of debate among intellectuals and requires further research.
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Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/terapia , Tamizaje Neonatal/métodos , Profilaxis Posexposición/métodos , Terapia Genética/métodos , Humanos , Recién Nacido , Errores Innatos del Metabolismo/genética , Mutación/genéticaRESUMEN
In the present study, an effort has been made to utilize different types of organic wastes, i.e. kitchen waste, agro residue, institutional waste and cow dung through the process of vermicomposting. These organic wastes were collected separately, air dried, grinded and mixed in 4:1 ratio with cow dung (w/w). During the period of vermicomposting (75 days), different physico-chemical parameters were analyzed separately. During this process, pH, organic carbon, organic matter and C:N ratio of different organic waste mixtures showed a declining trend, however, total nitrogen, available phosphorus and exchangeable potassium contents showed increasing trend with the advancement of vermicomposting period. Besides, physico-chemical investigations of these wastes, estimation of earthworm population, biomass and number of cocoon produced during vermicomposting were also analyzed separately. It was found that earthworm population, biomass and cocoon production increased significantly as the duration of vermicomposting process increased upto 75 days.