RESUMEN
The study explores the intricate relationship between topological indices and the heat of formation in the benzyl sulfamoyl network. Topological indices of benzyl sulfamoyl networks are studied and also emphasize their properties statistically. The benzyl sulfamoyl has unique properties due to its crystalline structure and it is used in the form of artificial substance. We analyze the distributions and correlations of the benzyl sulfamoyl network with others by using statistical methods and also build a computational analysis for topological indices. The findings show a strong association between the variables, indicating that topological indices may be used to accurately predict thermodynamic characteristics and improve the effectiveness of molecular modelling and simulation procedures.
RESUMEN
Breast cancer covers a large area of research because of its prevalence and high frequency all over the world. This study is based on drug discovery against breast cancer from a series of imidazole derivatives. A 3D-QSAR and activity atlas model was developed by exploring the dataset computationally, using the machine learning process of Flare. The dataset of compounds was divided into active and inactive compounds according to their biological and structural similarity with the reference drug. The obtained PLS regression model provided an acceptable r 2 = 0.81 and q2 = 0.51. Protein-ligand interactions of active molecules were shown by molecular docking against six potential targets, namely, TTK, HER2, GR, NUDT5, MTHFS, and NQO2. Then, toxicity risk parameters were evaluated for hit compounds. Finally, after all these screening processes, compound C10 was recognized as the best-hit compound. This study identified a new inhibitor C10 against cancer and provided evidence-based knowledge to discover more analogs.
RESUMEN
Granulomatosis with polyangiitis (GPA) is a systemic vasculitis that is associated with antineutrophil cytoplasmic antibodies (c-ANCA). It classically presents with sinonasal, pulmonary and renal involvement. We are presenting a case of a 32-year-old male who presented with septal perforation, crusting and nasal obstruction. He had been operated on twice for sinonasal polyposis. Relevant investigations revealed that he was actually suffering from GPA. The patient was started on remission induction therapy. A combination of methotrexate and prednisolone was started with a 2-weekly follow-up. The patient had experienced his symptoms for 2 years before presentation. This case highlights the importance of correlating ENT and pulmonary symptoms to reach the correct diagnosis.
RESUMEN
The development of robotic applications necessitates the availability of useful, adaptable, and accessible programming frameworks. Robotic, IoT, and sensor-based systems open up new possibilities for the development of innovative applications, taking advantage of existing and new technologies. Despite much progress, the development of these applications remains a complex, time-consuming, and demanding activity. Development of these applications requires wide utilization of software components. In this paper, we propose a platform that efficiently searches and recommends code components for reuse. To locate and rank the source code snippets, our approach uses a machine learning approach to train the schema. Our platform uses trained schema to rank code snippets in the top k results. This platform facilitates the process of reuse by recommending suitable components for a given query. The platform provides a user-friendly interface where developers can enter queries (specifications) for code search. The evaluation shows that our platform effectively ranks the source code snippets and outperforms existing baselines. A survey is also conducted to affirm the viability of the proposed methodology.
Asunto(s)
Programas Informáticos , Interfaz Usuario-ComputadorRESUMEN
Parthenium hysterophorus has been used to cure cancer, fever, malaria, diarrhea, dysentery, and neurologic disorders. This study evaluates the anti-diabetic effects of methanolic extract of P. hysterophorus (MEPH) in alloxan-induced diabetic rabbits. Twenty-five rabbits were divided into 5groups (N=5). Group-I served as a negative control. Groups II to V were injected with freshly prepared alloxan solution 150 mg/kg intraperitoneally to induce diabetes. Group II till V received following treatments orally: Group II: Alloxan 150 mg/kg alone; group III: Alloxan + MEPH (50 mg/kg); group IV: Alloxan + MEPH (100 mg/kg); group V: Alloxan +Glucophage (62.5 mg/kg), respectively for 10 days. The body weight of all animals was recorded on the 1st, 4th, 7th and 10th days. Short-term (1st, 3rd, 5th and 7th hour) and long-term (4th, 7th and 10th day) hypoglycemic effects were also recorded. All animals were sacrificed on the 10th day to isolate the pancreas for histopathological examination. The results showed that MPEH reduced the blood glucose levels in all the groups of alloxan-induced diabetic rabbits. The histopathological studies depicted that 100 mg/kg of MEPH most effectively repaired alloxan-induced pancreatic damage. The study showed that the MPEH is useful for developing effective phytomedicine to treat diabetes mellitus.
Asunto(s)
Diabetes Mellitus Experimental , Extractos Vegetales , Poaceae , Animales , Conejos , Aloxano/efectos adversos , Glucemia , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Metanol , Páncreas/patología , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéuticoRESUMEN
Parthenium hysterophorus is conventionally used to treat urinary tract infections, joint pain, and hyperglycaemia. This study evaluates the reno-curative effects of methanolic extract of P. hysterophorus (MEPH) in paracetamol-induced nephrotoxic rabbits. Thirty male rabbits were divided into V groups: Group I served as the negative control. Group-II to V were treated with 2 g/kg of paracetamol to induce nephrotoxicity. Group II served as paracetamol (PCM) intoxicated control. Group III till V were fed orally with the following treatments: III paracetamol (PCM) 40 mg/kg MEPH; IV PCM+80 mg/kg MEPH; V PCM+Cystone (5 ml/kg), respectively, for 14 days. The body weight of all animals was recorded on days 1, 7 and 14. All the animals were dissected on the 14th day and blood, urine and kidneys were collected. The results showed that P. hysterophorus had no effect on body weight but lowered urea and creatinine levels and brought urine parameters back to the normal range in experimental groups of PCM-induced nephrotoxic rabbits. The 80 mg/kg dose of MEPH reduced urea and creatinine levels and normalized urine parameters more effectively compared to low doses of MEPH and the standard drug, i.e., Cystone. Kidney histopathological studies exhibited that 80 mg/kg of MEPH repaired paracetamol-induced renal damage, whereas Cystone only provided reno protection as no repair in damaged tissue was investigated in histopathology of Cystone treated animals. The results suggested that P. hysterophorus exhibited significant reno-curative activity on paracetamol-induced nephrotoxic rabbits.
Asunto(s)
Acetaminofén , Extractos Vegetales , Poaceae , Animales , Masculino , Conejos , Acetaminofén/toxicidad , Peso Corporal , Metanol , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , UreaRESUMEN
Public health and its related facilities are crucial for thriving cities and societies. The optimum utilization of health resources saves money and time, but above all, it saves precious lives. It has become even more evident in the present as the pandemic has overstretched the existing medical resources. Specific to patient appointment scheduling, the casual attitude of missing medical appointments (no-show-ups) may cause severe damage to a patient's health. In this paper, with the help of machine learning, we analyze six million plus patient appointment records to predict a patient's behaviors/characteristics by using ten different machine learning algorithms. For this purpose, we first extracted meaningful features from raw data using data cleaning. We applied Synthetic Minority Oversampling Technique (SMOTE), Adaptive Synthetic Sampling Method (Adasyn), and random undersampling (RUS) to balance our data. After balancing, we applied ten different machine learning algorithms, namely, random forest classifier, decision tree, logistic regression, XG Boost, gradient boosting, Adaboost Classifier, Naive Bayes, stochastic gradient descent, multilayer perceptron, and Support Vector Machine. We analyzed these results with the help of six different metrics, i.e., recall, accuracy, precision, F1-score, area under the curve, and mean square error. Our study has achieved 94% recall, 86% accuracy, 83% precision, 87% F1-score, 92% area under the curve, and 0.106 minimum mean square error. Effectiveness of presented data cleaning and feature selection is confirmed by better results in all training algorithms. Notably, recall is greater than 75%, accuracy is greater than 73%, F1-score is more significant than 75%, MSE is lesser than 0.26, and AUC is greater than 74%. The research shows that instead of individual features, combining different features helps make better predictions of a patient's appointment status.
Asunto(s)
Algoritmos , Citas y Horarios , Aprendizaje Automático , Pacientes no Presentados/estadística & datos numéricos , Área Bajo la Curva , Teorema de Bayes , Biología Computacional , Interpretación Estadística de Datos , Bases de Datos Factuales , Árboles de Decisión , Humanos , Modelos Logísticos , Redes Neurales de la Computación , Procesos Estocásticos , Máquina de Vectores de SoporteRESUMEN
OBJECTIVE: To evaluate the phenotypic detection of extended-spectrum betalactamase in multidrug-resistant acinetobacter baumannii. METHODS: The cross-sectional study was conducted at the Department of Microbiology, Fauji Foundation Hospital, Rawalpindi, Pakistan, from August 2018 to April 2019, after the ethical approval from the Institutional Review Committee. Consecutive Non- probability sampling technique was used, and comprised clinical specimens, including pus, blood, sputum, urine, tracheal tubes and canula double lumen, which were processed using standard protocols. Colonies of acinetobacter baumannii were identified by gram staining and Analytical Profile Index-20E kit. Combination disc method was used for the identification of extended-spectrum beta-lactamse. Clinical and Laboratory Standards Institute guidelines were used for antimicrobial susceptibility. Data was analysed using SPSS 22 and Sample size was calculated by using earlier study with 5 % margin of error and 95 % confidence level. RESULTS: Of the 78 isolates, 58(74.4%) related to females and 20(25.6%) to males. There was no extended-spectrum beta-lactamse producer. Imipenem, meropenem, cefotaxime, ampicillin and ceftazidime showed 100% resistance, while colistin and polymyxin B were sensitive to all strains. The incidence rate was high in samples isolated from tracheal tubes 47(60.3%), followed by pus 21(26.9%). Age was not found to be a significant factor (p>0.05). CONCLUSIONS: Acinetobacter baumannii showed a high resistance to multiple drugs and was not confined to any specific age group. Colistin and polymyxin B were found to be better choices.
Asunto(s)
Infecciones por Acinetobacter , Acinetobacter baumannii , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/epidemiología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Estudios Transversales , Farmacorresistencia Bacteriana Múltiple , Femenino , Hospitales , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Pakistán , beta-LactamasasRESUMEN
BACKGROUND: Plasmodium vivax contributes to over 70% malaria burden in Pakistan, but limited data exists on various aspects including genetic diversity of the parasite as compared to other parts of the world. Since the information about the genetic diversity of P. vivax assists to understand the population dynamics of the parasite, the current study was designed to understand population divergence of P. vivax in Pakistan using circumsporozoite protein (pvcsp) and merozoite surface protein-1 (pvmsp-1) genes as molecular markers. METHODS: The PCR for pvcsp and pvmsp-1 genes was carried out for 150 P. vivax isolates, followed by DNA sequencing of 35 and 30, respectively. Genetic diversity and polymorphism were analysed using ChromasPro, ClustalW, MEGA7, DnaSP v.5 and WebLogo programs. RESULTS: The PCR for pvcsp and pvmsp-1 genes was carried out for 150 P. vivax isolates and resulting the PCR products of 1100 bp for pvcsp and ~ 400 bp for pvmsp-1 genes, respectively. In the central-repeat region (CRR) of pvcsp gene, sequences comprised of four variable repeats of PRMs, out of which GDRADGQPA (PRM1), GDRAAGQPA (PRM2) were more extensively dispersed among the P. vivax isolates. Partial sequences (~ 400 bp) of block 2 of pvmsp-1 gene depicted high level of diversity. CONCLUSION: The results revealed the polymorphism and genetic diversity especially at the CRR of pvcsp and block 2 of pvmsp-1 genes, respectively. The base-line data presented here warrants future studies to investigate more into the genetic diversity of P. vivax with large sample size from across the country for better understanding of population dynamics of P. vivax that will help to control malaria at individual and community level.
Asunto(s)
Proteína 1 de Superficie de Merozoito/genética , Plasmodium vivax/genética , Proteínas Protozoarias/genética , Marcadores Genéticos , Malaria Vivax , PakistánRESUMEN
The purpose of this work is to provide an effective social distance monitoring solution in low light environments in a pandemic situation. The raging coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus has brought a global crisis with its deadly spread all over the world. In the absence of an effective treatment and vaccine the efforts to control this pandemic strictly rely on personal preventive actions, e.g., handwashing, face mask usage, environmental cleaning, and most importantly on social distancing which is the only expedient approach to cope with this situation. Low light environments can become a problem in the spread of disease because of people's night gatherings. Especially, in summers when the global temperature is at its peak, the situation can become more critical. Mostly, in cities where people have congested homes and no proper air cross-system is available. So, they find ways to get out of their homes with their families during the night to take fresh air. In such a situation, it is necessary to take effective measures to monitor the safety distance criteria to avoid more positive cases and to control the death toll. In this paper, a deep learning-based solution is proposed for the above-stated problem. The proposed framework utilizes the you only look once v4 (YOLO v4) model for real-time object detection and the social distance measuring approach is introduced with a single motionless time of flight (ToF) camera. The risk factor is indicated based on the calculated distance and safety distance violations are highlighted. Experimental results show that the proposed model exhibits good performance with 97.84% mean average precision (mAP) score and the observed mean absolute error (MAE) between actual and measured social distance values is 1.01 cm.
Asunto(s)
COVID-19/prevención & control , Aprendizaje Profundo , Distanciamiento Físico , Humanos , Luz , Pandemias , Fotograbar/instrumentaciónRESUMEN
This descriptive cross-sectional study was performed in the Department of Microbiology, Fauji Foundation Hospital, Rawalpindi, from March 2019 to September 2019 to determine the in vitro efficacy of Daptomycin against clinical isolates of Methicillin-Resistant Staphylococcus aureus (MRSA). Consecutive non-probability sampling technique was used and a total number of 270 patients' Pan Cultures having MRSA growth on Cefoxatin Disc with size less than 22 mm zone size were included in the study. Cultures were inoculated on MacConkey, Chocolate and Blood agar and then incubated for 24 hours at 37 degree Celsius. After incubation, Coagulase test, Catalase test and Gram staining technique were used for further identification. Minimum Inhibitory Concentration (MIC) of the isolates for Daptomycin was obtained by using E strips (Oxoid UK) according to Clinical & Laboratory Standards Institute (CLSI) guidelines. The mean age of the patients was 46.73±12.22 years, and the study included 147 (54.44%) males and 123 (45.56%) females. Regarding the type of specimen, there were 154 (57.04%) pus specimens, 54 (20.00%) blood specimens, 27 (10.00%) fluid specimens, 18 (6.67%) urine specimens, 10 (3.70%) high vaginal swabs (HVS) specimens and 7 (2.59%) sputum specimens. Daptomycin was effective in 264 (97.78%) patients with MIC range from .015 to 1 µg/ml on E strip.
Asunto(s)
Daptomicina , Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Adulto , Antibacterianos/farmacología , Estudios Transversales , Daptomicina/farmacología , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Infecciones Estafilocócicas/tratamiento farmacológicoRESUMEN
The current study was conducted in the Department of Microbiology, Fauji Foundation Hospital, Rawalpindi, from July 2018 to January 2019. The main purpose of the study was to evaluate Methicillin-resistant Staphylococcus aureus antimicrobial susceptibility pattern. Clinical samples were collected and cultured according to Clinical and Laboratory Standards Institute (CLSI) guidelines. A total of 90(30%) samples were found to be methicillin-resistant out of 300 samples of Staphylococcus aureus. Major isolates were 42 (46.67%) from pus and 22 (24.44%) from tracheal tubes. The incidence ratio of Methicillin-resistant Staphylococcus aureus was high in the samples isolated from 69 (76.67%) females compared to those of 21 (23.33%) males. Patients were more in the age group of 41 to 60 years. Vancomycin 90 (100%) was sensitive to all strains followed by Chloramphenicol 66 (73.33%) and Doxycycline 52 (57.78%). Imipenem, Meropenem andAugmentin showed resistance to all strains.
Asunto(s)
Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Adulto , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Femenino , Hospitales , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/epidemiologíaRESUMEN
Non-healing wounds are a major health problem worldwide and a significant cause of morbidity and mortality. Effective treatments for acute and chronic skin wounds are the focus of intensive research. Eggshell membrane (ESM) is a natural proteinaceous by-product of the food industry and is suitable for biomedical applications. The objective of this study was to evaluate processed eggshell membrane powder (PEP) for the promotion of skin wound healing. PEP was characterized using proteomics and bioinformatics. Proteomic analysis of PEP identified 110 proteins, including structural proteins such as collagen and cysteine-rich eggshell membrane proteins (CREMPs) that together constitute about 40% of PEP. Functional annotation clustering showed various predicted functionalities related to wound healing including response to external stimulus, defense response, inflammatory response, and cell-substrate adhesion. The impact of PEP on wound healing was determined using the mouse excisional wound splinting model with a subsequent assessment by histopathology. PEP was found to significantly accelerate wound closure at days 3, 7, and 10. Histological assessment showed significantly thicker granulation tissue in wounds treated with PEP than non-treated controls at days 10 and 17. In addition, histological scoring showed higher levels of collagen deposition at day 10 in wounds treated with PEP, with limited inflammatory reaction. Therefore, PEP is a biocompatible and non-cytotoxic biomaterial that has great potential for development into a cost-effective wound healing product.
Asunto(s)
Materiales Biocompatibles/farmacología , Proteínas del Huevo/farmacología , Cáscara de Huevo/química , Proteómica/métodos , Cicatrización de Heridas/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Proteínas del Huevo/química , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
One of the major challenges of nano-biotechnology is to engineer potent antimicrobial nanostructures (NS) with high biocompatibility. Keeping this in view, we have performed aqueous olive leaf extract mediated one pot facile synthesis of CuO-NS and CeO2-NS. Prepared NS were homogenous, less than 26 nm in size, and small crystallite units as revealed by scanning electron microscopy (SEM) and X-ray diffraction (XRD) analyses. Fourier transform infrared spectroscopy (FTIR) of CuO-NS and CeO2-NS showed typical Cu-O prints around 592-660 cm-1 and Ce-O bond vibrations at 453 cm-1. The successful capping of CuO-NS and CeO2-NS by compounds present in the plant extract was further validated by high performance liquid chromatography (HPLC) and thermal gravimetric analysis (TGA). Active phyto-chemicals from the leaf extract simultaneously acted as strong reducing as well as capping agent in the NS synthesis. NS engineered in the present study showed antibacterial potential at extremely low concentration against highly virulent multidrug-resistant (MDR) gram-negative strains (Escherichia coli, Enterobacter cloacae, Acinetobacter baumannii and Pseudomonas aeruginosa), alarmed by World Health Organization (WHO). Furthermore, CuO-NS and CeO2-NS did not show any cytotoxicity on HEK-293 cell lines and Brine shrimp larvae indicating that the NS green synthesized in the present study are biocompatible.
RESUMEN
The use of an automated biopsy device, and real-time ultrasound for percutaneous kidney biopsies (PKBs) has improved the likelihood of obtaining adequate tissue for diagnosis and also has reduced the complications associated with the procedure. We aimed to determine the frequency and type of complications associated with PKB and to determine the diagnostic yield. It was a retrospective file-based review of cases who underwent PKB of native kidney between January 2003 and December 2013 at the Aga Khan University Hospital in Karachi, Pakistan. PKBs were performed by trained nephrologists or radiologists using an automated device with a 16/18-gauge needle under real-time ultrasound. The data obtained included age, gender, clinical and histopathological diagnosis, and complications associated with the procedure (minor: hematuria, local infections, and hematoma; major: transfusions, severe infections, surgery, nephrectomy, arteriography, embolism, and death. Yield of the procedure was based on the number of glomeruli obtained. Patients having major complications were compared with the patients who had minor or no complications. A total of 433 native kidney biopsies were performed. The mean age of the patients was 41 ± 15.9 years, and 58% of the patients were male. The main histological findings were membranoproliferative glomerulonephritis (17.6%) followed by focal and segmental glomerulosclerosis (16.4%) and interstitial nephritis (13.9%). Majority of the procedures were performed by nephrologists (67.4%). The overall complication rate was 14.2%. Among those, 21 patients (4.8%) had a major complication while the others had minor complications. Of those who had a major complication, 17 patients required blood transfusion(s) and had hematuria or a major hematoma, three had prolonged hospitalization >24 hours, and one patient required surgical intervention. Only 10 procedures (2.3%) had inadequate tissue to establish the histopathologic diagnosis. PKB under real-time ultrasound guidance is a safe and efficacious procedure to establish the histological diagnosis of the renal disease.
Asunto(s)
Biopsia Guiada por Imagen/métodos , Enfermedades Renales/patología , Riñón/patología , Centros de Atención Terciaria , Ultrasonografía Intervencional , Adulto , Automatización , Diseño de Equipo , Femenino , Humanos , Biopsia Guiada por Imagen/efectos adversos , Biopsia Guiada por Imagen/instrumentación , Masculino , Persona de Mediana Edad , Pakistán , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Ultrasonografía Intervencional/efectos adversos , Adulto JovenRESUMEN
Malaria and HIV are amongst the two main diseases worldwide and creating troubles of our time. Together, they grounds extra than four million deaths a year. Malaria causes around about for more than a million deaths each year, of which over 80-90 % come about in tropical Africa, somewhere malaria is the primary source of mortality in children below six years of age. Sideways as of adolescent, children, pregnant women are surrounded by the largest part exaggerated by the disease. In the wide geographical extend beyond in event and the follow-on co-infection, the interface flanked as a result of the two diseases visibly has foremost communal strength results. Thus both are dangerous for health at the same time.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Coinfección/epidemiología , Malaria/complicaciones , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Femenino , Humanos , Malaria/tratamiento farmacológico , Embarazo , Complicaciones del Embarazo/tratamiento farmacológico , Combinación Trimetoprim y Sulfametoxazol/uso terapéuticoRESUMEN
BACKGROUND: Increasing evidence indicates that neuroinflammation is a critical factor contributing to the progression of various neurodegenerative diseases. The IKK/NF-κB signalling system is a central regulator of inflammation, but it also affects neuronal survival and differentiation. A complex interplay between different CNS resident cells and infiltrating immune cells, which produce and respond to various inflammatory mediators, determines whether neuroinflammation is beneficial or detrimental. The IKK/NF-κB system is involved in both production of and responses to these mediators, although the precise contribution depends on the cell type as well as the cellular context, and is only partially understood. Here we investigated the specific contribution of neuronal IKK/NF-κB signalling on the regulation of neuroinflammatory processes and its consequences. To address this issue, we established and analysed a conditional gain-of-function mouse model that expresses a constitutively active allele of IKK2 in principal forebrain neurons (IKK2nCA). Proinflammatory gene and growth factor expression, histopathology, microgliosis, astrogliosis, immune cell infiltration and spatial learning were assessed at different timepoints after persistent canonical IKK2/NF-κB activation. RESULTS: In contrast to other cell types and organ systems, chronic IKK2/NF-κB signalling in forebrain neurons of adult IKK2nCA animals did not cause a full-blown inflammatory response including infiltration of immune cells. Instead, we found a selective inflammatory response in the dentate gyrus characterized by astrogliosis, microgliosis and Tnf-α upregulation. Furthermore, downregulation of the neurotrophic factor Bdnf correlated with a selective and progressive atrophy of the dentate gyrus and a decline in hippocampus-dependent spatial learning. Neuronal degeneration was associated with increased Fluoro-jade staining, but lacked activation of apoptosis. Remarkably, neuronal loss could be partially reversed when chronic IKK2/NF-κB signalling was turned off and Bdnf expression was restored. CONCLUSION: Our results demonstrate that persistent IKK2/NF-κB signalling in forebrain neurons does not induce overall neuroinflammation, but elicits a selective inflammatory response in the dentate gyrus accompanied by decreased neuronal survival and impaired learning and memory. Our findings further suggest that chronic activation of neuronal IKK2/NF-κB signalling, possibly as a consequence of neuroinflammatory conditions, is able to induce apoptosis-independent neurodegeneration via paracrine suppression of Bdnf synthesis.
Asunto(s)
Envejecimiento/metabolismo , Quinasa I-kappa B/metabolismo , FN-kappa B/metabolismo , Degeneración Nerviosa/metabolismo , Neuronas/metabolismo , Transducción de Señal/fisiología , Envejecimiento/patología , Animales , Modelos Animales de Enfermedad , Activación Enzimática/fisiología , Ensayo de Inmunoadsorción Enzimática , Técnica del Anticuerpo Fluorescente , Immunoblotting , Etiquetado Corte-Fin in Situ , Inflamación/metabolismo , Inflamación/patología , Aprendizaje/fisiología , Memoria/fisiología , Ratones , Ratones Transgénicos , Degeneración Nerviosa/patología , Neuronas/patología , Prosencéfalo/metabolismo , Prosencéfalo/patología , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Alterations of learning and memory in mice with deregulated neuron-specific nuclear factor κB (NF-κB) activity support the idea that plastic changes of synaptic contacts may depend at least in part on IκB kinase (IKK)/NF-κB-related synapse-to-nucleus signaling. There is, however, little information on the molecular requirements and mechanisms regulating this IKK/NF-κB-dependent synapse development and remodeling. Here, we report that the NF-κB inducing IKK kinase complex is localized at the postsynaptic density (PSD) and activated under basal conditions in the adult mouse brain. Using different models of conditional genetic inactivation of IKK2 function in mouse principal neurons, we show that IKK/NF-κB signaling is critically involved in synapse formation and spine maturation in the adult brain. IKK/NF-κB blockade in the forebrain of mutant animals is associated with reduced levels of mature spines and postsynaptic proteins PSD95, SAP97, GluA1, AMPAR-mediated basal synaptic transmission and a spatial learning impairment. Synaptic deficits can be restored in adult animals within 1 week by IKK/NF-κB reactivation, indicating a highly dynamic IKK/NF-κB-dependent regulation process. We further identified the insulin-like growth factor 2 gene (Igf2) as a novel IKK/NF-κB target. Exogenous Igf2 was able to restore synapse density and promoted spine maturation in IKK/NF-κB signaling-deficient neurons within 24 h. This process depends on Igf2/Igf2R-mediated MEK/ERK activation. Our findings illustrate a fundamental role of IKK/NF-κB-Igf2-Igf2R signaling in synapse formation and maturation in adult mice, thus providing an intriguing link between the molecular actions of IKK/NF-κB in neurons and the memory enhancement factor Igf2.