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Many growth factors and cytokines signal by binding to the extracellular domains of their receptors and driving association and transphosphorylation of the receptor intracellular tyrosine kinase domains, initiating downstream signaling cascades. To enable systematic exploration of how receptor valency and geometry affect signaling outcomes, we designed cyclic homo-oligomers with up to 8 subunits using repeat protein building blocks that can be modularly extended. By incorporating a de novo-designed fibroblast growth factor receptor (FGFR)-binding module into these scaffolds, we generated a series of synthetic signaling ligands that exhibit potent valency- and geometry-dependent Ca2+ release and mitogen-activated protein kinase (MAPK) pathway activation. The high specificity of the designed agonists reveals distinct roles for two FGFR splice variants in driving arterial endothelium and perivascular cell fates during early vascular development. Our designed modular assemblies should be broadly useful for unraveling the complexities of signaling in key developmental transitions and for developing future therapeutic applications.
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Diferenciação Celular , Fatores de Crescimento de Fibroblastos , Receptores de Fatores de Crescimento de Fibroblastos , Transdução de Sinais , Animais , Humanos , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Camundongos , Ligantes , Cálcio/metabolismo , Sistema de Sinalização das MAP QuinasesRESUMO
Protein crystallization plays a central role in structural biology. Despite this, the process of crystallization remains poorly understood and highly empirical, with crystal contacts, lattice packing arrangements and space group preferences being largely unpredictable. Programming protein crystallization through precisely engineered side-chain-side-chain interactions across protein-protein interfaces is an outstanding challenge. Here we develop a general computational approach for designing three-dimensional protein crystals with prespecified lattice architectures at atomic accuracy that hierarchically constrains the overall number of degrees of freedom of the system. We design three pairs of oligomers that can be individually purified, and upon mixing, spontaneously self-assemble into >100 µm three-dimensional crystals. The structures of these crystals are nearly identical to the computational design models, closely corresponding in both overall architecture and the specific protein-protein interactions. The dimensions of the crystal unit cell can be systematically redesigned while retaining the space group symmetry and overall architecture, and the crystals are extremely porous and highly stable. Our approach enables the computational design of protein crystals with high accuracy, and the designed protein crystals, which have both structural and assembly information encoded in their primary sequences, provide a powerful platform for biological materials engineering.
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Proteínas , Proteínas/química , CristalizaçãoRESUMO
The attachment of SARA-CoV-2 happens between ACE2 and the receptor binding domain (RBD) on the spike protein. Mutations in this domain can affect the binding affinity of the spike protein for ACE2. S477N, one of the most common mutations reported in the recent variants, is located in the RBD. Today's computational approaches in biology, especially during the SARS-CoV-2 pandemic, assist researchers in predicting a protein's behavior in contact with other proteins in more detail. In this study, we investigated the interactions of the S477N-hACE2 in silico to find the impact of this mutation on its binding affinity for ACE2 and immunity responses using dynamics simulation, protein-protein docking, and immunoinformatics methods. Our computational analysis revealed an increased binding affinity of N477 for ACE2. Four new hydrogen and hydrophobic bonds in the mutant RBD-ACE2 were formed (with S19 and Q24 of ACE2), which do not exist in the wild type. Also, the protein spike structure in this mutation was associated with an increase in stabilization and a decrease in its fluctuations at the atomic level. N477 mutation can be considered as the cause of increased escape from the immune system through MHC-II.
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COVID-19 , Glicoproteína da Espícula de Coronavírus , Humanos , Enzima de Conversão de Angiotensina 2 , SARS-CoV-2 , Mutação , Ligação Proteica , Simulação de Dinâmica MolecularRESUMO
BACKGROUND: Irritable bowel syndrome (IBS) is gastrointestinal functional disorder which is multifactorial with unknown etiology. There are several modalities for treatment of it. Acupuncture is increasingly used in numerous diseases, also in gastrointestinal disorders like IBS. The purpose of the study was to assess the effects of catgut embedding acupuncture in improving of IBS. MATERIALS AND METHODS: A randomized double blind sham control clinical trial was designed. A total of 60 IBS patients assigned to three separated groups. The first group received clofac as drug only group (DO). The second one received catgut embedding acupuncture in special point (AP) and the last group received sham acupuncture (SA). Symptoms, pain, depression and anxiety assessed before and after two weeks at the end of study. RESULTS: There was statistically significant difference between AP and SA and DO in constipation and bloating. Differences that were statistically significant favored acupuncture on pain (F = 6.409, P = 0.003), and depression (F = 6.735, P = 0.002) as the other outcomes. The average (standard deviation (SD)) of weight loss was 2 kg (0.88) in acupuncture group. CONCLUSION: Our finding showed a significant positive associated between acupuncture and IBS. Catgut embedding acupuncture is a new method which can eliminated IBS symptoms and can use as alternative therapeutic method for improvement of IBS.
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BACKGROUND: Machine learning (ML) models have the potential to accurately predict outcomes and offer novel insights into inter-variable correlations. In this study, we aimed to design ML models for the prediction of 1-year mortality after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome. METHODS: This study was performed on 13,682 patients at Tehran Heart Center from 2015 to 2021. Patients were split into 70:30 for testing and training. Four ML models were designed: a traditional Logistic Regression (LR) model, Random Forest (RF), Extreme Gradient Boosting (XGBoost), and Ada Boost models. The importance of features was calculated using the RF feature selector and SHAP based on the XGBoost model. The Area Under the Receiver Operating Characteristic Curve (AUC-ROC) for the prediction on the testing dataset was the main measure of the model's performance. RESULTS: From a total of 9,073 patients with >1-year follow-up, 340 participants died. Higher age and higher rates of comorbidities were observed in these patients. Body mass index and lipid profile demonstrated a U-shaped correlation with the outcome. Among the models, RF had the best discrimination (AUC 0.866), while the highest sensitivity (80.9%) and specificity (88.3%) were for LR and XGBoost models, respectively. All models had AUCs of >0.8. CONCLUSION: ML models can predict 1-year mortality after PCI with high performance. A classic LR statistical approach showed comparable results with other ML models. The individual-level assessment of inter-variable correlations provided new insights into the non-linear contribution of risk factors to post-PCI mortality.
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Síndrome Coronariana Aguda , Aprendizado de Máquina , Intervenção Coronária Percutânea , Humanos , Síndrome Coronariana Aguda/mortalidade , Síndrome Coronariana Aguda/cirurgia , Aprendizado de Máquina/tendências , Intervenção Coronária Percutânea/mortalidade , Intervenção Coronária Percutânea/tendências , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Irã (Geográfico)/epidemiologia , Valor Preditivo dos Testes , Seguimentos , Mortalidade/tendências , Fatores de TempoRESUMO
AIM: Sleep duration has been suggested to be associated with hypertension (HTN). However, evidence of the nature of the relationship and its direction has been inconsistent. Therefore, we performed a meta-analysis to assess the relationship between sleep duration and risk of HTN incidence, and to distinguish more susceptible populations. METHODS: PubMed, Embase, Scopus, Web of Science, and ProQuest were searched from January 2000 to May 2023 for cohort studies comparing short and long sleep durations with 7-8 hours of sleep for the risk of HTN incidence. Random-effect model (the DerSimonian-Laird method) was applied to pool risk ratios (RR) and 95% confidence interval (CI). RESULTS: We included sixteen studies ranging from 2.4 to 18 years of follow-up duration evaluating HTN incidence in 1,044,035 people. Short sleep duration was significantly associated with a higher risk of developing HTN (HR: 1.07, 95% CI: 1.06-1.09). The association was stronger when the sleep duration was less than 5 hours (HR: 1.11, 95% CI: 1.08-1.14). In contrast to males, females (HR: 1.07, 95% CI: 1.04-1.09) were more vulnerable to developing HTN due to short sleep duration. No significant difference between different follow-up durations and age subgroups was observed. Long sleep duration was not associated with an increased incidence of HTN. CONCLUSION: Short sleep duration was associated with higher risk of HTN incidence, however, there was no association between long sleep duration and incidence of HTN. These findings highlight the importance of implementing target-specific preventive and interventional strategies for vulnerable populations with short sleep duration to reduce the risk of HTN.
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Hipertensão , Sono , Humanos , Hipertensão/epidemiologia , Sono/fisiologia , Incidência , Masculino , Estudos de Coortes , Feminino , Fatores de Risco , Fatores de Tempo , Duração do SonoRESUMO
OBJECTIVE: This study investigates the metabolic differences between normal, prediabetic and diabetic patients with good and poor glycaemic control (GGC and PGC). DESIGN: In this study, 1102 individuals were included, and 50 metabolites were analysed using tandem mass spectrometry. The diabetes diagnosis and treatment standards of the American Diabetes Association (ADA) were used to classify patients. METHODS: The nearest neighbour method was used to match controls and cases in each group on the basis of age, sex and BMI. Factor analysis was used to reduce the number of variables and find influential underlying factors. Finally, Pearson's correlation coefficient was used to check the correlation between both glucose and HbAc1 as independent factors with binary classes. RESULTS: Amino acids such as glycine, serine and proline, and acylcarnitines (AcylCs) such as C16 and C18 showed significant differences between the prediabetes and normal groups. Additionally, several metabolites, including C0, C5, C8 and C16, showed significant differences between the diabetes and normal groups. Moreover, the study found that several metabolites significantly differed between the GGC and PGC diabetes groups, such as C2, C6, C10, C16 and C18. The correlation analysis revealed that glucose and HbA1c levels significantly correlated with several metabolites, including glycine, serine and C16, in both the prediabetes and diabetes groups. Additionally, the correlation analysis showed that HbA1c significantly correlated with several metabolites, such as C2, C5 and C18, in the controlled and uncontrolled diabetes groups. CONCLUSIONS: These findings could help identify new biomarkers or underlying markers for the early detection and management of diabetes.
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Carnitina/análogos & derivados , Metabolômica , Estado Pré-Diabético , Espectrometria de Massas em Tandem , Humanos , Estado Pré-Diabético/diagnóstico , Estado Pré-Diabético/metabolismo , Metabolômica/métodos , Masculino , Espectrometria de Massas em Tandem/métodos , Feminino , Pessoa de Meia-Idade , Adulto , Hemoglobinas Glicadas/metabolismo , Hemoglobinas Glicadas/análise , Glicemia/metabolismo , Diabetes Mellitus/metabolismo , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico , Idoso , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico , Metaboloma , Controle GlicêmicoRESUMO
Purpose: The Discovery of underlying intermediates associated with the development of dyslipidemia results in a better understanding of pathophysiology of dyslipidemia and their modification will be a promising preventive and therapeutic strategy for the management of dyslipidemia. Methods: The entire dataset was selected from the Surveillance of Risk Factors of Noncommunicable Diseases (NCDs) in 30 provinces of Iran (STEPs 2016 Country report in Iran) that included 1200 subjects and was stratified into four binary classes with normal and abnormal cases based on their levels of triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and non-HDL-C.Plasma concentrations of 20 amino acids and 30 acylcarnitines in each class of dyslipidemia were evaluated using Tandem mass spectrometry. Then, these attributes, along with baseline characteristics data, were used to check whether machine learning (ML) algorithms could classify cases and controls. Results: Our ML framework accurately predicts TG binary classes. Among the models tested, the SVM model stood out, performing slightly better with an AUC of 0.81 and a standard deviation of test accuracy at 0.04. Consequently, it was chosen as the optimal model for TG classification. Moreover, the findings showed that alanine, phenylalanine, methionine, C3, C14:2, and C16 had great power in differentiating patients with high TG from normal TG controls. Conclusions: The comprehensive output of this work, along with sex-specific attributes, will improve our understanding of the underlying intermediates involved in dyslipidemia. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-024-01384-9.
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INTRODUCTION: A variety of key human physiological processes rely on angiogenesis, ranging from reproduction and fetal growth to wound healing and tissue repair. Furthermore, this process significantly contributes to tumor progression, invasion, and metastasis. As the strongest inducer of angiogenesis, Vascular Endothelial Growth Factor (VEGF) and its receptor (VEGFR) are targets of therapeutic research for blocking pathological angiogenesis. OBJECTIVE: Preventing the interaction between VEGF and VEGFR2 by a peptide is a promising strategy for developing antiangiogenic drug candidates. This study was aimed at designing and evaluating VEGF-targeting peptides using in silico and in vitro techniques. METHODS: The VEGF binding site of VEGFR2 was considered a basis for peptide design. The interaction of VEGF and all three peptides derived from VEGFR2 were analyzed using ClusPro tools. In a complex with VEGF, the peptide with a higher docking score was evaluated to confirm its stability using molecular dynamics (MD) simulation. The gene coding for the selected peptide was cloned and expressed in E. coli BL21. The bacterial cells were cultured on a large scale, and the expressed recombinant peptide was purified using Ni-NTA chromatography. Refolding of the denatured peptide was carried out by the stepwise removal of the denaturant. The reactivity of peptides was confirmed using western blotting and enzyme-linked immunosorbent assay (ELISA) assays. Finally, the inhibition potency of the peptide on human umbilical vein endothelial cells was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl- 2H-tetrazolium bromide (MTT) assay. RESULTS: Among three peptides, the peptide with the best docking pose and the highest affinity for VEGF was selected for further studies. Then the stability of the peptide was confirmed over the 100 ns MD simulation. After in silico analyses, the selected peptide was presented for in vitro analysis. Expression of the selected peptide in E. coli BL21 resulted in a pure peptide with a yield of approximately 200 µg/ml. Analysis by ELISA revealed the high reactivity of the peptide with VEGF. Western blot analysis confirmed the specific reactivity of selected peptides with VEGF. The MTT assay revealed the growth inhibitory effect of the peptide on human umbilical vein endothelial cells with an IC50 value of 247.8 µM. CONCLUSION: In summary, the selected peptide demonstrated a promising inhibitory effect on human umbilical vein endothelial cells that could be a valuable anti-angiogenic candidate for further assessment. Additionally, these in silico and in vitro data provide new insights into peptide design and engineering.
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Escherichia coli , Fator A de Crescimento do Endotélio Vascular , Humanos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana , Escherichia coli/metabolismo , Proliferação de Células , Fatores de Crescimento do Endotélio Vascular/metabolismo , Peptídeos/farmacologia , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Movimento CelularRESUMO
Anti-VEGF therapies are common for the treatment of cancer. Carboxypeptidase G (CPG-2) enzyme is a zinc-dependent metalloenzyme that metabolizes non-toxic synthetic 'benzoic mustard prodrugs' to cytotoxic moieties in tumor cells. In this study, we designed a dual-activity agent by combining a designed anti-VEGF- and CPG-2 enzyme to convert methotrexate (MTX). VEGF-A was docked against a set of scaffolds, and suitable inverse rotamers were made. Rosetta design was used for the interface design. The top 1200 binders were chosen by flow cytometry and displayed in yeast. The activity of CPG-2 enzyme was analyzed at different temperature conditions and in the presence of the substrate, MTX. Optimal binders were selected and protein was eluted using immobilized metal affinity chromatography and size-exclusion chromatography. Both, native PAGE and on-yeast flow cytometry confirmed the binding of the binder to VEGF-A. The activity of truncated enzymes was slightly lower than that of full-length enzymes linked to VEGF-A. The method should be generally useful as a dual-activity agent for targeting VEGF-A and combination therapy with the enzyme CPG-2 for metabolizing non-toxic prodrugs to cytotoxic moieties.Communicated by Ramaswamy H. Sarma.
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Antineoplásicos , Pró-Fármacos , gama-Glutamil Hidrolase , Pró-Fármacos/farmacologia , Pró-Fármacos/metabolismo , Fator A de Crescimento do Endotélio Vascular , Saccharomyces cerevisiae , Metotrexato/química , Antineoplásicos/farmacologia , AnticorposRESUMO
Growth factors and cytokines signal by binding to the extracellular domains of their receptors and drive association and transphosphorylation of the receptor intracellular tyrosine kinase domains, initiating downstream signaling cascades. To enable systematic exploration of how receptor valency and geometry affects signaling outcomes, we designed cyclic homo-oligomers with up to 8 subunits using repeat protein building blocks that can be modularly extended. By incorporating a de novo designed fibroblast growth-factor receptor (FGFR) binding module into these scaffolds, we generated a series of synthetic signaling ligands that exhibit potent valency- and geometry-dependent Ca2+ release and MAPK pathway activation. The high specificity of the designed agonists reveal distinct roles for two FGFR splice variants in driving endothelial and mesenchymal cell fates during early vascular development. The ability to incorporate receptor binding domains and repeat extensions in a modular fashion makes our designed scaffolds broadly useful for probing and manipulating cellular signaling pathways.
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Breast cancer will be easier and more effective to treat if detected early. Breast cancer is assessed and detected using imaging as a primary approach. The capacity to diagnose breast cancers is continually improving thanks to developments in imaging technologies. However, some of these enhancements have been linked to delays in the initiation of treatment procedures of breast cancer. Overall, cancer management relies heavily on imaging procedures such as screening and symptomatic disease management. Mammography, which is considered the gold standard, and breast ultrasonography are employed as routine imaging modalities. Previous research has shown that, despite recent developments, no single imaging modality can detect and characterizing majority of breast lesions. Various imaging methods and their uses in diagnosing and caring the breast cancer are discussed in this study.
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INTRODUCTION: Susceptibility weighted imaging can be used to study intracranial venous blood arteries based on the paramagnetic sensitivity of blood discharged by oxygen (SWI). Significant hypotensive drainage channels have been discovered in the ischemic tissue of the brain, which have been recognized by SWI. The compliance or non-compliance between the variation in venous drainage of ischemic brain tissue by SWI and diffusion limitation. MATERIAL AND METHODS: This cross-sectional study was conducted in 2019 on 20 patients (15 men and 5 females) who were assigned to the Ghaem Hospital MRI Institute in Rasht, Iran. RESULTS: Infarction has been detected in a total of 20 vascular regions. The caliber of the sulcal and intramedullary veins, on the other hand, was increased in 80 percent and 65 percent of the infarcted regions, respectively. In 45 percent of the vascular regions, a match between SWI and diffusion-weighted magnetic resonance imaging (DWI) was detected, mismatch was detected in two; follow-up revealed infarct progression. CONCLUSIONS: Significant data on critically perfused cerebral cortex with possibility of infarction growth was focused on in elevated SWI investigations, contributing to SWI as a worthy MR implies that could be attached as complementary protocols to neuroimaging techniques for acute ischemia, according to the findings of this study.
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INTRODUCTION: The COVID-19 pandemic is now affecting all people around the world and getting worse. New antiviral medications are desperately needed other than the few approved medications that have shown no promising efficacy so far. METHODS: Here we report three blocking binders for targeting SARS-CoV-2 spike protein to block the interaction between the spike protein on the SARS-CoV-2 and the angiotensin-converting enzyme 2 (ACE2) receptors, responsible for viral homing into the alveolar epithelium type II cells (AECII). RESULTS: The design process is based on the collected natural scaffolds and using Rosetta interface for designing the binders. CONCLUSION: Based on the structural analysis, three binders were selected, and the results showed that they might be promising as new therapeutic targets for blocking COVID-19.
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BACKGROUND: Literature has suggested that major depressive disorder (MDD) is accompanied by higher concentrations of inflammatory biomarkers, which could sabotage response to conventional treatments. AIMS: This study aimed to evaluate the efficacy and safety of adalimumab adjunct to sertraline in adults with MDD and increased levels of systemic inflammation. METHODS: In a 6-week, randomized, double-blind, placebo-controlled trial, 36 patients with MDD and high-sensitivity C-reactive protein ≥3 mg/L were equally assigned to receive sertraline plus either adalimumab or placebo. Participants were assessed using the Hamilton Depression Rating Scale (HAM-D) at baseline, week 3, and week 6. Moreover, serum concentrations of inflammatory biomarkers were measured at baseline and trial end point. Finally, patients were assessed for any adverse event during the trial. RESULTS: Fifteen patients in each group completed the trial course. All baseline characteristics of participants were similar between the groups. Adalimumab adjunct to sertraline resulted in a greater improvement in HAM-D score compared with placebo over the trial period ( P < 0.001). Participants receiving adalimumab significantly experienced greater response to treatment (≥50% reduction in the HAM-D score) than those receiving placebo ( P = 0.042). Furthermore, after 6 weeks of adalimumab combination therapy with sertraline, inflammatory biomarkers significantly decreased ( P ≤ 0.001), whereas no significant alteration was found in the placebo group. No serious adverse event was documented in the treatment arms. CONCLUSIONS: Adalimumab adjunctive therapy remarkably improves depressive symptoms of patients with MDD. Further investigations with larger sample sizes and longer follow-up periods are required to confirm the findings.
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Transtorno Depressivo Maior , Adalimumab/uso terapêutico , Adulto , Anti-Inflamatórios/uso terapêutico , Antidepressivos/efeitos adversos , Biomarcadores , Proteína C-Reativa/uso terapêutico , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/tratamento farmacológico , Método Duplo-Cego , Humanos , Projetos Piloto , Sertralina/uso terapêutico , Resultado do TratamentoRESUMO
Multivalent display of receptor-engaging antibodies or ligands can enhance their activity. Instead of achieving multivalency by attachment to preexisting scaffolds, here we unite form and function by the computational design of nanocages in which one structural component is an antibody or Fc-ligand fusion and the second is a designed antibody-binding homo-oligomer that drives nanocage assembly. Structures of eight nanocages determined by electron microscopy spanning dihedral, tetrahedral, octahedral, and icosahedral architectures with 2, 6, 12, and 30 antibodies per nanocage, respectively, closely match the corresponding computational models. Antibody nanocages targeting cell surface receptors enhance signaling compared with free antibodies or Fc-fusions in death receptor 5 (DR5)-mediated apoptosis, angiopoietin-1 receptor (Tie2)-mediated angiogenesis, CD40 activation, and T cell proliferation. Nanocage assembly also increases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus neutralization by α-SARS-CoV-2 monoclonal antibodies and Fc-angiotensin-converting enzyme 2 (ACE2) fusion proteins.
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Anticorpos/química , Anticorpos/imunologia , Nanoestruturas , Engenharia de Proteínas , Transdução de Sinais , Angiopoietinas/química , Angiopoietinas/imunologia , Angiopoietinas/metabolismo , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Antígenos CD40/química , Antígenos CD40/imunologia , Antígenos CD40/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Simulação por Computador , Genes Sintéticos , Humanos , Fragmentos Fc das Imunoglobulinas/química , Ativação Linfocitária , Modelos Moleculares , Ligação Proteica , Receptor TIE-2/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/imunologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Linfócitos T/fisiologiaRESUMO
Background: Thyroid disorders such as subclinical hypothyroidism and isolated maternal hypothyroxinemia are understudied in pregnant women, despite their possible adverse effects on the health of mother and child. Also, the role of iodine deficiency in developing such disorders has not yet been fully understood. Methods: The present national population-based cross-sectional study was conducted on 1080 randomly recruited pregnant women, aged 20-40 from 12 provinces of Iran from 2013 to 2014. Serum concentrations of thyrotropin, T4, thyroid peroxidase antibody (TPOAb), and triiodothyronine (T3) resin uptake values were measured in fasting blood samples, and urinary iodine concentration (UIC) was measured in three separate urine samples. Multinomial logistic regression was run to analyze the possible risk factors regarding thyroid disorders. To clarify the role of iodine in thyroid status specifically, the determinants of UIC and its correlations with thyroid function tests were investigated independently and through subgroup analysis. Results: Isolated hypothyroxinemia was the most common thyroid disorder (9.9%), followed by subclinical hypothyroidism (8%). In comparison to euthyroid pregnant women, isolated hypothyroxinemia was more likely in pregnant women older than 30 years (odds ratio [OR] = 1.6), in the second and the third trimesters (OR = 2.62 and 2.12 respectively), with history of multiparity (OR = 1.72), residing in rural areas (OR = 1.57) and in the capital province of the country (OR = 3.3). Subclinical hypothyroidism was more likely in TPOAb positive pregnant women (OR = 2.56). All the mentioned ORs were statistically significant (p < 0.05). The UIC did not correlate significantly with any of the thyroid function tests in the study population. Subgroup analysis showed a significant correlation between UIC and T4 in pregnant women with subclinical hypothyroidism (p < 0.05). Conclusion: Isolated maternal hypothyroxinemia was the most prevalent thyroid disorder in Iranian pregnant women and its associated risk factors were identified. Although the calculated prevalence of thyroid disorders was expected in a moderately iodine deficient setting, no correlations between UICs and thyroid function tests were found at the individual level. The contribution of iodine deficiency to thyroid condition for each pregnant woman may be more evident in pregnant women with certain thyroid disorders or those with long-term iodine deficiency.
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Hipotireoidismo/epidemiologia , Hipotireoidismo/etiologia , Iodo/deficiência , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/etiologia , Tiroxina/sangue , Adulto , Estudos Transversais , Feminino , Humanos , Hipotireoidismo/sangue , Iodo/urina , Irã (Geográfico) , Gravidez , Complicações na Gravidez/sangue , Prevalência , Testes de Função Tireóidea , Adulto JovemRESUMO
Despite the great search for an effective approach to minimize secondary injury in spinal cord injury (SCI) setting, there have been limited advances. Roflumilast is a selective inhibitor of phosphodiesterase 4 with potent anti-inflammatory properties. Here, we sought to explore Roflumilast efficacy in the improvement of locomotor and sensory deficits of SCI. In an animal setting, 50 male rats were randomly assigned to five groups: an SCI group receiving Placebo, three SCI groups receiving Roflumilast at the doses of 0.25, 0.5, and 1 mg/kg prior to T9 vertebra laminectomy, and a sham-operated group. Locomotor, mechanical, and thermal activities were evaluated for 28 days. At the end of the study, spinal cord samples were taken to assess the relative ratio of microglial subtypes, including M1 and M2, histopathological changes, levels of pro-inflammatory (TNF-α and IL-1ß) and anti-inflammatory (IL-10) biomarkers, and cAMP level. Repeated measure analysis revealed significant effect for time-treatment interaction on locomotion [F (24, 270) = 280.7, p < 0.001], thermal sensitivity [F (16, 180) = 4.35, p < 0.001], and mechanical sensitivity [F (16, 180) = 7.96, p < 0.001]. As expected, Roflumilast significantly increased the expression of spinal cAMP. H&E staining exhibited lesser histopathological disruptions in Roflumilast-treated rodents. We also observed a significant reduction in the M1/M2 ratio (p values < 0.001) as well as in pro-inflammatory biomarkers following the administration of Roflumilast to the injured rats. Furthermore, IL-10 level was increased in rodents receiving 1 mg/kg of the reagent. In conclusion, the increased spinal cAMP following Roflumilast therapy might attenuate neuroinflammation via altering microglial activity; therefore, it could be considered as an alternative therapeutic agent for SCI complications.
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Agnosia/metabolismo , Aminopiridinas/uso terapêutico , Benzamidas/uso terapêutico , Microglia/metabolismo , Inibidores da Fosfodiesterase 4/uso terapêutico , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Tabes Dorsal/metabolismo , Agnosia/etiologia , Agnosia/prevenção & controle , Animais , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Ciclopropanos/uso terapêutico , Modelos Animais de Doenças , Humanos , Masculino , Microglia/patologia , Inflamação Neurogênica , Ratos , Medula Espinal/patologia , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/tratamento farmacológico , Tabes Dorsal/etiologia , Tabes Dorsal/prevenção & controleRESUMO
Antibodies are widely used in biology and medicine, and there has been considerable interest in multivalent antibody formats to increase binding avidity and enhance signaling pathway agonism. However, there are currently no general approaches for forming precisely oriented antibody assemblies with controlled valency. We describe the computational design of two-component nanocages that overcome this limitation by uniting form and function. One structural component is any antibody or Fc fusion and the second is a designed Fc-binding homo-oligomer that drives nanocage assembly. Structures of 8 antibody nanocages determined by electron microscopy spanning dihedral, tetrahedral, octahedral, and icosahedral architectures with 2, 6, 12, and 30 antibodies per nanocage match the corresponding computational models. Antibody nanocages targeting cell-surface receptors enhance signaling compared to free antibodies or Fc-fusions in DR5-mediated apoptosis, Tie2-mediated angiogenesis, CD40 activation, and T cell proliferation; nanocage assembly also increases SARS-CoV-2 pseudovirus neutralization by α-SARS-CoV-2 monoclonal antibodies and Fc-ACE2 fusion proteins. We anticipate that the ability to assemble arbitrary antibodies without need for covalent modification into highly ordered assemblies with different geometries and valencies will have broad impact in biology and medicine.