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MEF2C is a critical transcription factor in neurodevelopment, whose loss-of-function mutation in humans results in MEF2C haploinsufficiency syndrome (MHS), a severe form of autism spectrum disorder (ASD)/intellectual disability (ID). Despite prior animal studies of MEF2C heterozygosity to mimic MHS, MHS-specific mutations have not been investigated previously, particularly in a human context as hiPSCs afford. Here, for the first time, we use patient hiPSC-derived cerebrocortical neurons and cerebral organoids to characterize MHS deficits. Unexpectedly, we found that decreased neurogenesis was accompanied by activation of a micro-(mi)RNA-mediated gliogenesis pathway. We also demonstrate network-level hyperexcitability in MHS neurons, as evidenced by excessive synaptic and extrasynaptic activity contributing to excitatory/inhibitory (E/I) imbalance. Notably, the predominantly extrasynaptic (e)NMDA receptor antagonist, NitroSynapsin, corrects this aberrant electrical activity associated with abnormal phenotypes. During neurodevelopment, MEF2C regulates many ASD-associated gene networks, suggesting that treatment of MHS deficits may possibly help other forms of ASD as well.
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INTRODUCTION: Thiazolidinediones (TZDs), represented by pioglitazone and rosiglitazone, are a class of cost-effective oral antidiabetic agents posing a marginal hypoglycaemia risk. Nevertheless, observations of heart failure have hindered the clinical use of both therapies. OBJECTIVE: Since the mechanism of TZD-induced heart failure remains largely uncharacterised, this study aimed to explore the as-yet-unidentified mechanisms underpinning TZD cardiotoxicity using a toxicometabolomics approach. METHODS: The present investigation included an untargeted liquid chromatography-mass spectrometry-based toxicometabolomics pipeline, followed by multivariate statistics and pathway analyses to elucidate the mechanism(s)of TZD-induced cardiotoxicity using AC16 human cardiomyocytes as a model, and to identify the prognostic features associated with such effects. RESULTS: Acute administration of either TZD agent resulted in a significant modulation in carnitine content, reflecting potential disruption of the mitochondrial carnitine shuttle. Furthermore, perturbations were noted in purine metabolism and amino acid fingerprints, strongly conveying aberrations in cardiac energetics associated with TZD usage. Analysis of our findings also highlighted alterations in polyamine (spermine and spermidine) and amino acid (L-tyrosine and valine) metabolism, known modulators of cardiac hypertrophy, suggesting a potential link to TZD cardiotoxicity that necessitates further research. In addition, this comprehensive study identified two groupings - (i) valine and creatine, and (ii) L-tryptophan and L-methionine - that were significantly enriched in the above-mentioned mechanisms, emerging as potential fingerprint biomarkers for pioglitazone and rosiglitazone cardiotoxicity, respectively. CONCLUSION: These findings demonstrate the utility of toxicometabolomics in elaborating on mechanisms of drug toxicity and identifying potential biomarkers, thus encouraging its application in the toxicological sciences. (245 words).
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Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Tiazolidinedionas , Humanos , Rosiglitazona/uso terapêutico , Pioglitazona , Miócitos Cardíacos , Cardiotoxicidade/complicações , Cardiotoxicidade/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Metabolômica , Tiazolidinedionas/toxicidade , Insuficiência Cardíaca/induzido quimicamente , Aminoácidos , Biomarcadores , Carnitina , ValinaRESUMO
Thiazolidinediones (TZDs) (e.g. pioglitazone and rosiglitazone), known insulin sensitiser agents for type II diabetes mellitus, exhibit controversial effects on cardiac tissue. Despite consensus on their association with increased heart failure risk, limiting TZD use in diabetes management, the underlying mechanisms remain uncharacterised. Herein, we report a comprehensive in vitro investigation utilising a novel toxicoproteomics pipeline coupled with cytotoxicity assays in human adult cardiomyocytes to elucidate mechanistic insights into TZD cardiotoxicity. The cytotoxicity assay findings showed a significant loss of mitochondrial adenosine triphosphate production upon exposure to either TZD agents, which may underpin TZD cardiotoxicity. Our toxicoproteomics analysis revealed that mitochondrial dysfunction primarily stems from oxidative phosphorylation impairment, with distinct signalling mechanisms observed for both agents. The type of cell death differed strikingly between the two agents, with rosiglitazone exhibiting features of caspase-dependent apoptosis and pioglitazone implicating mitochondrial-mediated necroptosis, as evidenced by the protein upregulation in the phosphoglycerate mutase family 5-dynamin-related protein 1 axis. Furthermore, our analysis revealed additional mechanistic aspects of cardiotoxicity, showcasing drug specificity. The downregulation of various proteins involved in protein machinery and protein processing in the endoplasmic reticulum was observed in rosiglitazone-treated cells, implicating proteostasis in the rosiglitazone cardiotoxicity. Regarding pioglitazone, the findings suggested the potential activation of the interplay between the complement and coagulation systems and the disruption of the cytoskeletal architecture, which was primarily mediated through the integrin-signalling pathways responsible for pioglitazone-induced myocardial contractile failure. Collectively, this study unlocks substantial mechanistic insight into TZD cardiotoxicity, providing the rationale for future optimisation of antidiabetic therapies.
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Cardiotoxicidade , Miócitos Cardíacos , Pioglitazona , Proteômica , Rosiglitazona , Tiazolidinedionas , Humanos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Tiazolidinedionas/toxicidade , Proteômica/métodos , Rosiglitazona/farmacologia , Hipoglicemiantes/toxicidade , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismoRESUMO
Parkinson's disease is characterized by accumulation of α-synuclein (αSyn). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal death in part via microglial activation. Heretofore, it remained unknown if oligomeric/fibrillar αSyn could activate the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome in human microglia and whether anti-αSyn antibodies could prevent this effect. Here, we show that αSyn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) via dual stimulation involving Toll-like receptor 2 (TLR2) engagement and mitochondrial damage. In vitro, hiMG can be activated by mutant (A53T) αSyn secreted from hiPSC-derived A9-dopaminergic neurons. Surprisingly, αSyn-antibody complexes enhanced rather than suppressed inflammasome-mediated interleukin-1ß (IL-1ß) secretion, indicating these complexes are neuroinflammatory in a human context. A further increase in inflammation was observed with addition of oligomerized amyloid-ß peptide (Aß) and its cognate antibody. In vivo, engraftment of hiMG with αSyn in humanized mouse brain resulted in caspase-1 activation and neurotoxicity, which was exacerbated by αSyn antibody. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger inflammation in human microglia.
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Inflamassomos/metabolismo , Microglia/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doença de Parkinson/imunologia , alfa-Sinucleína/imunologia , Peptídeos beta-Amiloides/imunologia , Anticorpos/imunologia , Diferenciação Celular , Células Cultivadas , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Microglia/citologia , Receptor 2 Toll-Like/metabolismo , alfa-Sinucleína/genéticaRESUMO
INTRODUCTION: In healthcare settings, physical and verbal attacks are commonly encountered in the workplace among healthcare providers. Patients and patients' relatives and friends have been reported to be the perpetrators of workplace violence. Among all healthcare settings, emergency department (ED) have been designated as high-risk settings for violence, where more than one-quarter of emergency physicians reported that they were victims of physical assault. This study aimed to report the prevalence of workplace violence against emergency medicine physicians in military and non-military hospitals in Jeddah city. METHODOLOGY: A cross-sectional design has been used in this study. An electronic questionnaire was developed through the Google Form Platform and it included demographic data, the occurrence of verbal or physical violence in the workplace to participants, how many times they experienced this violence, the time of incidents, the location either inside or outside the hospital, whether the perpetrators were mostly patients, patient families, or friends, and whether they reported any violence or not. Categorical variables were used to describe frequencies and percentages, while descriptive statistics such as mean and 95% Confidence Interval (95% CI) were used to summarize the scale variables. P < 0.05 was considered for statistically significant differences. RESULTS: Among the 100 participants, 76 experienced either physical or verbal violence, or both. The remaining 24 did not experience any sort of violence. 83% of the physicians who have been physically violated were working in non-military hospitals. Of the 72 participants who had experienced verbal violence, 51 (70.8%) were working in a non-military hospital, while 21 (29.2%) were in a military hospital. The most common reason for not reporting was that the participants felt that reporting the violence incidence was useless. Moreover, 92% of participants chose "Train healthcare workers to deal with violent attacks" as a suggested helpful factor in decreasing the number of work-related violence. In addition, "Education of the public" and "Raising awareness of healthcare workers" were chosen as helpful factors as well by 91% and 90% of participants, respectively. CONCLUSION: This revealed that physicians in non-military hospitals experience higher levels of violence compared to their military counterparts. However, it is concerning that instances of violence are substantially under-reported across both military and non-military healthcare facilities.
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Hospitais Militares , Violência no Trabalho , Humanos , Estudos Transversais , Arábia Saudita/epidemiologia , Masculino , Feminino , Prevalência , Hospitais Militares/estatística & dados numéricos , Adulto , Violência no Trabalho/estatística & dados numéricos , Médicos/estatística & dados numéricos , Serviço Hospitalar de Emergência/estatística & dados numéricos , Inquéritos e Questionários , Pessoa de Meia-Idade , Abuso Físico/estatística & dados numéricos , Medicina de EmergênciaRESUMO
Background and Objectives: Screening for type 2 diabetes mellitus (DM2) aims to identify asymptomatic individuals who may be at a higher risk, allowing proactive interventions. The objective of this study was to predict the incidence of DM2 and prediabetes in the Saudi population over the next five years. Materials and Methods: The study was conducted in the Aseer region through August 2023 using a cross-sectional survey for data collection. A multistage stratified random sampling technique was adopted, and data were collected through face-to-face interviews using the validated Arabic version of the Australian Type 2 Diabetes Risk Assessment Tool (AUSDRISK). Results: In total, 652 individuals were included in the study. Their mean age was 32.0 ± 12.0 years; 53.8% were male, 89.6% were from urban areas, and 55.8% were single. There were statistically significant differences between males and females in AUSDRISK items, including age, history of high blood glucose, use of medications for high blood pressure, smoking, physical activity, and measurements of waist circumference (p < 0.05). Based on AUSDRISK scores, 46.2% of the included participants were predicted to develop impaired glucose tolerance within the coming five years (65.8% among females vs. 23.6%), and 21.9% were predicted to develop DM2 (35.6% among males vs. 6.0% among females); this difference was statistically significant (p = 0.0001). Conclusions: Urgent public health action is required to prevent the increasing epidemic of DM2 in Saudi Arabia.
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Diabetes Mellitus Tipo 2 , Estado Pré-Diabético , Humanos , Arábia Saudita/epidemiologia , Masculino , Feminino , Estado Pré-Diabético/epidemiologia , Estado Pré-Diabético/diagnóstico , Adulto , Estudos Transversais , Diabetes Mellitus Tipo 2/epidemiologia , Pessoa de Meia-Idade , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Incidência , Fatores de Risco , Programas de Rastreamento/métodos , Programas de Rastreamento/estatística & dados numéricosRESUMO
BACKGROUND: Self-confidence, is one of the critical variables influencing surgical resident's abilities, and lack of confidence maybe a reason for not entering medical practice immediately. Measuring the level of confidence of senior surgical residents (SSRs) is a crucial step in assessing preparedness to practice. In this study, we aim to measure their confidence level and the factors that might contribute to it. METHODS: Cross-sectional survey conducted at King Abdulaziz University Hospital on SSRs in Saudi Arabia (SA). We approached 142 SSRs, 127 responded. Statistical analysis was performed using RStudio v 3.6.2. Descriptive statistics were performed using counts and percentages for categorical variables and using mean ± standard deviation for continuous variables. Multivariate linear regression (t-statistics) was used to assess the factors associated with confidence in performing essential procedures, while the association between demographics and residency-related factor with the number of completed cases was tested using Chi-square. The level of significance was determined as 0.05. RESULTS: Response rate was 89.4%. Among surveyed residents, 66% had completed < 750 cases as a primary surgeon. More than 90% of SSRs were confident in performing appendectomy, open inguinal hernia repair, laparoscopic cholecystectomy, and trauma laparotomy, while 88% were confident in being on-call in level-I trauma center. No difference was noted in confidence level in relation to the number of performed cases. Residents from the Ministry of Health accounted for 56.3% of the study population and showed a higher confidence level compared to others. 94% of SSRs plan to pursue fellowship training program. CONCLUSION: The study showed that the confidence of SSRs in performing common general surgery procedures was as expected. However, it's important to recognize that confidence doesn't necessarily reflect competence. Considering the majority of SSRs planned to pursue fellowship training programs, it may be time to consider changing the structure of surgical training in SA to a modular format to allow earlier and more intensive exposure.
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Cirurgia Geral , Internato e Residência , Humanos , Estudos Transversais , Competência Clínica , Processos Mentais , Inquéritos e Questionários , Cirurgia Geral/educaçãoRESUMO
Beginning at early stages, human Alzheimer's disease (AD) brains manifest hyperexcitability, contributing to subsequent extensive synapse loss, which has been linked to cognitive dysfunction. No current therapy for AD is disease-modifying. Part of the problem with AD drug discovery is that transgenic mouse models have been poor predictors of potential human treatment. While it is undoubtedly important to test drugs in these animal models, additional evidence for drug efficacy in a human context might improve our chances of success. Accordingly, in order to test drugs in a human context, we have developed a platform of physiological assays using patch-clamp electrophysiology, calcium imaging, and multielectrode array (MEA) experiments on human (h)iPSC-derived 2D cortical neuronal cultures and 3D cerebral organoids. We compare hiPSCs bearing familial AD mutations vs. their wild-type (WT) isogenic controls in order to characterize the aberrant electrical activity in such a human context. Here, we show that these AD neuronal cultures and organoids manifest increased spontaneous action potentials, slow oscillatory events (~1 Hz), and hypersynchronous network activity. Importantly, the dual-allosteric NMDAR antagonist NitroSynapsin, but not the FDA-approved drug memantine, abrogated this hyperactivity. We propose a novel model of synaptic plasticity in which aberrant neural networks are rebalanced by NitroSynapsin. We propose that hiPSC models may be useful for screening drugs to treat hyperexcitability and related synaptic damage in AD.
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Doença de Alzheimer , Células-Tronco Pluripotentes Induzidas , Potenciais de Ação , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Animais , Modelos Animais de Doenças , Camundongos , Redes Neurais de Computação , NeurôniosRESUMO
Interfacial tension (IFT) is a crucial parameter in many natural and industrial processes, such as enhanced oil recovery and subsurface energy storage. IFT determines how easy the fluids can pass through pore throats and hence will decide how much residual fluids will be left behind. Here, we use a porous glass micromodel to investigate the dynamic IFT between oil and Armovis viscoelastic surfactant (VES) solution based on the concept of drop deformation while passing through a pore throat. Three different concentrations of VES, that is, 0.5, 0.75, and 1.25% vol% prepared using 57 K ppm synthetic seawater, were used in this study. The rheology obtained using a rheometer at ambient temperature showed zero shear viscosity of 325, 1101, and 1953 cP for 0.5%, 0.75%, and 1.25% VES, respectively, with a power-law region between 2 and 50 1/s. The dynamic IFT increases with the shear rate and then reaches a plateau. The results of IFT were compared with those obtained from the spinning drop method, which shows 97% accuracy for 1.25% VES, whereas the accuracy decreased to 65% for 0.75 VES and 51% for 0.5% VES. The findings indicate that we can reliably estimate the IFT of VES at higher concentrations directly during multiphase flow in porous micromodels without the need to perform separate experiments and wait for a long time to reach equilibrium.
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In the brain, both HIV-1 and methamphetamine (meth) use result in increases in oxidative and nitrosative stress. This redox stress is thought to contribute to the pathogenesis of HIV-associated neurocognitive disorder (HAND) and further worsening cognitive activity in the setting of drug abuse. One consequence of such redox stress is aberrant protein S-nitrosylation, derived from nitric oxide, which may disrupt normal protein activity. Here, we report an improved, mass spectrometry-based technique to assess S-nitrosylated protein in human postmortem brains using selective enrichment of S-nitrosocysteine residues with an organomercury resin. The data show increasing S-nitrosylation of tricarboxylic acid (TCA) enzymes in the setting of HAND and HAND/meth use compared with HIV+ control brains without CNS pathology. The consequence is systematic inhibition of multiple TCA cycle enzymes, resulting in energy collapse that can contribute to the neuronal and synaptic damage observed in HAND and meth use.
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Ciclo do Ácido Cítrico/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Infecções por HIV/metabolismo , Metanfetamina/efeitos adversos , Processamento de Proteína Pós-Traducional , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Autopsia , Bancos de Espécimes Biológicos , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Encéfalo/patologia , Ciclo do Ácido Cítrico/genética , Disfunção Cognitiva/complicações , Disfunção Cognitiva/patologia , Disfunção Cognitiva/virologia , Cisteína/análogos & derivados , Cisteína/metabolismo , Infecções por HIV/complicações , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/crescimento & desenvolvimento , HIV-1/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Mitocôndrias/patologia , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Neurônios/patologia , Óxido Nítrico/metabolismo , S-Nitrosotióis/metabolismo , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/patologia , Transtornos Relacionados ao Uso de Substâncias/virologia , Sinapses/efeitos dos fármacos , Sinapses/patologiaRESUMO
BACKGROUND: Fluctuations in pH of saliva during a prolonged treatment course influences the enamel demineralization progress, which is one of the complications of fixed orthodontic treatment. This randomized clinical trial aimed to evaluate and compare the short-term effects of stainless steel (SS) versus elastomeric (EM) ligatures on salivary pH in patients scheduled for fixed orthodontic treatment. METHODS: Seventy participants were enrolled in the study (54 female, 16 male) aged 19-36 years who met specific inclusion criteria. They were randomly selected and allocated into two equal groups through computer-generated randomization. All patients received fixed orthodontic treatment using conventional orthodontic brackets. Two commonly used archwire ligature methods were used: SS and EMs. An unstimulated (resting) salivary sample was collected before tying of the ligatures at T0 (baseline), 2 weeks, 6 (weeks), and 12 (weeks). Salivary pH was measured using a digital pH meter. The level of significance was set at p value < 0.05. RESULTS: The salivary pH level was stable between T0 and T1 (6.72 ± 0.14), then significantly and progressively increased from T1 to T2 (6.78 ± 0.13) and from T2 to T3 (6.81 ± 0.14) with (p < 0.05) in the SS group. In the EM group, the salivary pH level was significantly decreased in all follow-up periods; T0 (6.77 ± 0.16), T1 (6.72 ± 0.14), T2 (6.67 ± 0.13) and T3 (6.64 ± 0.13). CONCLUSION: The EM ligatures showed a significant decrease in salivary pH to an unfavorable level, which increased the risk of enamel demineralization. Therefore, EMs as ligature material is preferably should not be recommended in patients with high caries index or inadequate oral hygiene. Trial registration ANZCTR.org. (ACTRN12618001647224) http://www.anzctr.org.au/ACTRN12618001647224.aspx . Registration Date: 5/10/2018, "Retrospectively registered".
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Braquetes Ortodônticos , Aço Inoxidável , Elastômeros , Feminino , Humanos , Concentração de Íons de Hidrogênio , Masculino , Desenho de Aparelho Ortodôntico , Braquetes Ortodônticos/efeitos adversos , Fios OrtodônticosRESUMO
Recent studies have pointed to protein S-nitrosylation as a critical regulator of cellular redox homeostasis. For example, S-nitrosylation of peroxiredoxin-2 (Prx2), a peroxidase widely expressed in mammalian neurons, inhibits both enzymatic activity and protective function against oxidative stress. Here, using in vitro and in vivo approaches, we identify a role and reaction mechanism of the reductase sulfiredoxin (Srxn1) as an enzyme that denitrosylates (thus removing -SNO) from Prx2 in an ATP-dependent manner. Accordingly, by decreasing S-nitrosylated Prx2 (SNO-Prx2), overexpression of Srxn1 protects dopaminergic neural cells and human-induced pluripotent stem cell (hiPSC)-derived neurons from NO-induced hypersensitivity to oxidative stress. The pathophysiological relevance of this observation is suggested by our finding that SNO-Prx2 is dramatically increased in murine and human Parkinson's disease (PD) brains. Our findings therefore suggest that Srxn1 may represent a therapeutic target for neurodegenerative disorders such as PD that involve nitrosative/oxidative stress.
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Neurônios Dopaminérgicos/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo , Doença de Parkinson/metabolismo , Peroxirredoxinas/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Encéfalo/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Neurônios Dopaminérgicos/citologia , Humanos , Hidrólise , Células-Tronco Pluripotentes Induzidas/citologia , Camundongos , Óxido Nítrico/química , Estresse Oxidativo , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/química , Peroxirredoxinas/química , FosforilaçãoRESUMO
Fibril formation of ß2-microglobulin and associated inflammation occur in patients on long term dialysis. We show that the plasma protein haptoglobin prevents the fatty acid-promoted de novo fibril formation of ß2-microglobulin even at substoichiometric concentration. The fibrils are cytotoxic, and haptoglobin abolishes the cytotoxicity by preventing fibril formation. Haptoglobin does not alleviate the cytotoxicity of preformed fibrils. Fibrillar ß2-microglobulin is resistant to lysosomal degradation. However, the species of ß2-microglobulin populated in the presence of haptoglobin is susceptible to degradation. We observed that haptoglobin interacts with oligomeric prefibrillar species of ß2-microglobulin but not with monomeric or fibrillar ß2-microglobulin that may underlie the molecular mechanism. 1,1'-Bis(4-anilino)naphthalene-5,5'-disulfonic acid cross-linking to haptoglobin significantly compromises its chaperone activity, suggesting the involvement of hydrophobic surfaces. Haptoglobin is an acute phase protein whose level increases severalfold during inflammation, where local acidosis can occur. Our data show that haptoglobin prevents fibril formation of ß2-microglobulin under conditions of physiological acidosis (between pH 5.5 and 6.5) but with relatively decreased efficiency. However, compromise in its chaperone activity under these conditions is more than compensated by its increased level of expression under inflammation. Erythrolysis is known to release hemoglobin into the plasma. Haptoglobin forms a 1:1 (mol/mol) complex with hemoglobin. This complex, like haptoglobin, interacts with the prefibrillar species of ß2-microglobulin, preventing its fibril formation and the associated cytotoxicity and resistance to intracellular degradation. Thus, our study demonstrates that haptoglobin is a potential extracellular chaperone for ß2-microglobulin even in moderately acidic conditions relevant during inflammation, with promising therapeutic implications in ß2-microglobulin amyloid-related diseases.
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Amiloide/metabolismo , Citotoxinas/metabolismo , Ácidos Graxos/metabolismo , Haptoglobinas/metabolismo , Lisossomos/metabolismo , Chaperonas Moleculares/metabolismo , Proteólise , Microglobulina beta-2/metabolismo , Amiloide/química , Amiloide/genética , Amiloidose/genética , Amiloidose/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/genética , Citotoxinas/química , Citotoxinas/genética , Ácidos Graxos/química , Ácidos Graxos/genética , Haptoglobinas/química , Haptoglobinas/genética , Humanos , Concentração de Íons de Hidrogênio , Inflamação/genética , Inflamação/metabolismo , Lisossomos/química , Lisossomos/genética , Camundongos , Chaperonas Moleculares/química , Chaperonas Moleculares/genética , Complexos Multiproteicos/química , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Microglobulina beta-2/química , Microglobulina beta-2/genéticaRESUMO
PURPOSE: The correlation between body weight and health is a significant public health concern. While the adverse effects of obesity on pulmonary function are well-known, the impact of being underweight remains debated due to limited research. This study aimed to investigate the correlation between Body Mass Index (BMI) categories and lung function parameters. RESULTS: A study of 3077 participants found significant differences in gender, age, height, and weight across various Body Mass Index (BMI) categories. The study found non-significant variations in forced expiratory flow (FVC) across BMI categories, with underweight individuals showing lower FVC compared to normal and overweight individuals. BMI significantly impacted mean forced expiratory flow during the middle half of FVC. A significant negative correlation was observed between age and FVC, FEV1, FEV1/FVC ratio, and FEF25-75. A significant positive correlation was observed between weight, height, and lung function parameters. Multiple regression analysis revealed a decrease in lung function with advancing age, while height showed significant positive associations. The study concluded that age, sex, smoking, height, and weight collectively explained 41.0% of the variance in FVC, FEV, and FEF25-75.
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Índice de Massa Corporal , Pulmão , Testes de Função Respiratória , Humanos , Masculino , Feminino , Estudos Transversais , Pessoa de Meia-Idade , Adulto , Testes de Função Respiratória/métodos , Idoso , Pulmão/fisiologia , Pulmão/fisiopatologia , Adulto Jovem , Volume Expiratório Forçado/fisiologia , Peso Corporal/fisiologia , Capacidade Vital/fisiologia , Magreza/fisiopatologia , Adolescente , Sobrepeso/fisiopatologiaRESUMO
Obesity has reached epidemic proportions globally, accompanied by a parallel rise in the incidence of obstructive sleep apnea (OSA). The systematic study aims to assess the association between obesity and the onset and severity of OSA. A comprehensive computerized search of pertinent databases was done to find studies that fit the inclusion requirements. A comprehensive search was carried out on PubMed, SCOPUS, Science Direct, Systematic Library, and Web of Science to locate relevant material. Our data included 12 trials with 4095 participants, and 1456 (35.6%) were men. In individuals who were obese, the prevalence of OSA varied from 12.6% to 88.9%, with a total prevalence of 1291 (31.5%). One major factor that determined the level of OSA was obesity. It was consistently discovered by studies that there was a positive correlation between body mass index (BMI), and measures such as the Apnea-Hypopnea Index (AHI) are crucial in determining the extent of OSA. Besides, it was also observed that these comorbid conditions made OSA more severe and difficult to manage. Variability in findings suggests the influence of additional factors such as age, sex, and ethnicity on the obesity-OSA relationship. This comprehensive study offers strong evidence that OSA development and severity are significantly influenced by fat. The results emphasize the significance of weight control, especially for obese people, in treating and preventing OSA.
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Matrix acidizing is a technique that is widely used in the petroleum industry to remove scales and create channels in the rock. Removal of scales and creation of channels (wormhole) enhance productivity. Conventional acidizing fluids, such as hydrochloric acid (HCl) for carbonate and a mixture of hydrofluoric acid (HF) and HCl acid, are used for the matrix acidizing process. However, these fluids have some drawbacks, including strong acid strength, corrosion at high temperatures, and quick reactions with scale and particles. Emulsified acid systems (EASs) are used to address these drawbacks. EASs can create deeper and narrower wormholes by reducing the reaction rate of the acid due to the external oil phase. However, EASs have a much higher viscosity compared to conventional acidizing fluids. The high viscosity of EASs leads to a high drag that restricts pumping rates and consumes energy. This study aims to utilize environmentally friendly and widely available nanomaterials as drag-reducing agents (DRAs) of the EAS. The nanomaterials used in this study are carbon nanodots (CNDs). CNDs have unique properties and are used in diverse applications in different industries. The size of these CNDs is usually smaller than 10 nm. CNDs are characterized by their biocompatibility and chemical stability. This study investigates the use of CNDs as DRAs for EAS. Several experiments have been conducted to investigate the CNDs as a DRA for the EAS. The developed EAS was initially tested for conductivity and drop-test analysis to ensure the formation of an inverted emulsion. Thereafter, the thermal stability for the range of temperatures and the rheological properties of the EAS were evaluated to meet the criteria of field operation. Then flow experiments with EASs were conducted before and after adding the CNDs to investigate the efficacy of drag reduction of EASs. The results revealed that CNDs can be used as viscosity reducers for the EAS, where adding the CNDs to the EAS reduces the viscosity at two different HCl concentrations (15 and 20%). It reduces the viscosity of the EAS in the presence of corrosion inhibitors as well as other additives to the EAS, showing its compatibility with the field formulation. The drag reduction was observed at the range of temperatures investigated in the study. The conductivity, stability, and rheology experiments for the sample taken after the flow experiment are consistent, ensuring CNDs work as a DRA. The developed EAS with CNDs is robust in terms of field mixing procedures and thermally stable. The CNDs can be used as a DRA with EAS, which will reduce drag in pipes, increasing pumping rates and saving energy.
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Hyperphosphatemia and anemia were both associated with several complications in chronic kidney disease (CKD) patients. This study aimed to determine the risk factors of hyperphosphatemia and its relation with anemia among hemodialysis (HD) patients. Secondly, it aimed to determine the prevalence of hyperphosphatemia and anemia. Material and methods: A prospective cross-sectional study was conducted among 146 HD patients from two HD centers in Syria, between June 2021 and March 2022. All patients at least 18 years old on maintenance HD were enrolled. The threshold of phosphorus (phos) level was divided by the upper normal range among HD patients (5.5 mg/dl). We used parametric and nonparametric statistics, the Pearson and Spearman correlations with simple and multiple linear regressions between study variables. Results: 36.9% of patients had a serum phos level of 5.5 or less (norm phos group), and 63.1% of patients had a serum phos level higher than 5.5 (high phos group). Also, 60.9% of patients had hemoglobin (Hb) less than 10 g/dl, and 40.4% of patients had Hb at least 10 g/dl. Age, type of HD access, phos binders (P-binders), parathyroid hormone (PTH), and calcium (Ca) showed significant effects on phos levels. Most patients were using arteriovenous fistula (AVF) (89.7%) as a HD access, and the meantime on HD was higher in the norm phos group compared to the high phos group. In a multivariate and univariate logistic regression analysis, hyperphosphatemia increased with increasing urea (Ur) and creatinine (Cr) levels, while the odds declined with increasing time on HD. Hb did not show a significant relation with phos by using several statistical methods. Discussion/Conclusion: A high prevalence of hyperphosphatemia and anemia was encountered among this sample of HD patients from Syria. There was no correlation between phos and Hb levels in contrast to previous conflicting studies, which mandates future studies to evaluate this correlation and further efforts to determine the range of phos that could have a benefit on anemia with respect to other comorbidities.
RESUMO
A viscoelastic surfactant (VES) has the combined properties of a surfactant and a polymer. Injection of VES fluids into naturally fractured reservoirs (NFRs) can control the mobility of the injected fluid and enhance the total oil recovery. This paper presents a field-scale simulation to evaluate the performance of a noble VES fluid in enhancing the oil recovery from a naturally fractured reservoir. In this work, the results of coreflooding, computerized tomography (CT)-scan, rheology, interfacial tension (IFT), and adsorption measurements were used to build and calibrate a lab-scale model. Thereafter, a chemical enhanced oil recovery (EOR) modeling simulator developed by a computer modeling group (CMG-STARS) was used to build a field-scale simulation. Real seismic data, permeability and porosity distributions, and operating conditions were utilized to develop and evaluate the simulation model. The results show that VES can outperform the surfactant-polymer (SP) flooding and waterflooding in NFRs; VES improved the oil recovery by 10% and reduced the water cut by 47%, at the same conditions. VES reduced the IFT by two orders of magnitude (100 times) compared to waterflooding. Also, VES altered the rock wettability to a more water-wet status, leading to reduce the relative permeability to water (K rw) by a factor of 10, on average. Finally, the simulation study indicated that applying waterflooding after VES flooding leads to a minor increase in the oil recovery. Overall, this study provides a detailed comparison between VES flooding, SP flooding, and conventional waterflooding in NFRs. Sensitivity analysis was performed to study the impact of treatment parameters on the oil recovery from naturally fractured reservoirs. Using actual NFR data, the optimum VES flooding was determined, which will help in conducting VES flooding for real EOR operations.
RESUMO
In this study, chitosan (CT) and naturally occurring acacia gum (AG) blends were employed as emulsifiers to form a series of emulsions developed from diesel and water. Effects of pH level (3, 5, 10, and 12) and various NaCl salt concentrations (0.25-1%) on the stability, viscosity, and interfacial properties of CT-(1%)/AG-(4%) stabilized Pickering emulsions were evaluated. Bottle test experiment results showed that the stability indexes of the CT/AG emulsions were similar under acidic (3 and 5) and alkaline (10 and 12) pH media. On the other hand, the effects of various NaCl concentrations on the stability of CT-(1%)/AG-(4%) emulsion demonstrated analogous behavior throughout. From all the NaCl concentrations and pH levels examined, viscosities of this emulsion decreased drastically with the increasing shear rate, indicating pseudoplastic fluid with shear thinning characteristics of these emulsions. The viscosity of CT-(1%)/AG-(4%) emulsion increased at a low shear rate and decreased with an increasing shear rate. The presence of NaCl salt and pH change in CT/AG solutions induced a transformation in the interfacial tension (IFT) at the diesel/water interface. Accordingly, the IFT values of diesel/water in the absence of NaCl/CT/AG (without emulsifier and salt) remained fairly constant for a period of 500 s, and its average IFT value was 26.16 mN/m. In the absence of salt, the addition of an emulsifier (CT-(1%)/AG-(4%)) reduced the IFT to 16.69 mN/m. When the salt was added, the IFT values were further reduced to 12.04 mN/m. At low pH, the IFT was higher (17.1 mN/M) compared to the value of the IFT (10.8 mN/M) at high pH. The results obtained will help understand the preparation and performance of such emulsions under different conditions especially relevant to oil field applications.