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1.
iScience ; 24(11): 103327, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34805789

RESUMO

Light sensitivity of the vertebrate retina relies on the integrity of photoreceptors, including rods and cones. Research in patients with Alzheimer's disease (AD) and in AD transgenic mice reports that accumulated amyloid-ß (Aß) plaques in the retina are toxic to retinal neurons. Moreover, Aß plaques are deposited around the rods and cones, yet photoreceptor anomalies remain unclear in AD. Here, we identify the progressive degeneration of rods and cones characterized by impaired expression of phototransduction proteins, morphological alterations, functional deficits, and even cell loss. Furthermore, we demonstrate that cell senescence and necroptosis were involved in rod degeneration. Importantly, using in vivo scotopic electroretinogram, we detected rod degeneration in early-stage AD transgenic mice before Aß plaques were observed in the brain. Moreover, we demonstrate that rod degeneration was among the earliest AD retinal manifestations compared with other types of retinal neurons. Overall, our study is the first to identify and detect in vivo, early-onset photoreceptor degeneration in AD.

2.
Anal Chem ; 93(45): 14929-14933, 2021 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-34730331

RESUMO

Screening the metabolites of emerging organic contaminants (EOCs) from complicated biological matrices is an important but challenging task. Although stable isotope labeling (SIL) is frequently used to facilitate the identification of contaminant metabolites from redundant interfering components, the isotopically labeled reagents are expensive and difficult to synthesize, which greatly constrains the application of the SIL method. Herein, a new online noncovalent tagging method was developed for screening the metabolites of 1H-benzotriazol (BT) based on the characteristic structural moieties reserved in the metabolites. By selecting ß-cyclodextrin (ß-CD) as a macrocyclic tagging reagent, metabolites with the reserved moiety were expected to exhibit a characteristic shift of the mass-to-charge ratio (Δm/z = 1134.3698) after being noncovalently tagged by ß-CD. Based on the characteristic mass shift, the suspected features were reduced by 1 order of magnitude, as numerous interfering species that could not be effectively tagged by ß-CD were excluded. From these suspected features, two metabolites of BT that have not been reported before were successfully screened out. The significant characteristic mass shift caused by the noncovalent tagging method is easier to identify with more confidence than the previously reported SIL method. Besides, noncovalent tagging reagents can be much more accessible and less expensive than isotopically labeled reagents. Hence, this online noncovalent tagging method can be an intriguing alternative to the conventional SIL method.


Assuntos
Marcação por Isótopo , Indicadores e Reagentes , Íons
3.
Proc Natl Acad Sci U S A ; 118(46)2021 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-34750272

RESUMO

Artificial photosynthesis in ambient conditions is much less efficient than the solar-to-biomass conversion (SBC) processes in nature. Here, we successfully mimic the NADP-mediated photosynthetic processes in green plants by introducing redox moieties as the electron acceptors in the present conjugated polymeric photocatalyst. The current artificial process substantially promotes the charge carrier separation efficiency and the oxygen reduction efficiency, achieving a photosynthesis rate for converting Earth-abundant water and oxygen in air into hydrogen peroxide as high as 909 µmol⋅g-1⋅h-1 and a solar-to-chemical conversion (SCC) efficiency up to 0.26%. The SCC efficiency is more than two times higher than the average SBC efficiency in nature (0.1%) and the highest value under ambient conditions. This study presents a strategy for efficient SCC in the future.

4.
Aging Cell ; : e13511, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34725916

RESUMO

T cells, the critical immune cells of the adaptive immune system, are often dysfunctional in Alzheimer's disease (AD) and are involved in AD pathology. Reports highlight neuroinflammation as a crucial modulator of AD pathogenesis, and aberrant T cells indirectly contribute to neuroinflammation by secreting proinflammatory mediators via direct crosstalk with glial cells infiltrating the brain. However, the mechanisms underlying T-cell abnormalities in AD appear multifactorial. Risk factors for AD and pathological hallmarks of AD have been tightly linked with immune responses, implying the potential regulatory effects of these factors on T cells. In this review, we discuss how the risk factors for AD, particularly Apolipoprotein E (ApoE), Aß, α-secretase, ß-secretase, γ-secretase, Tau, and neuroinflammation, modulate T-cell activation and the association between T cells and pathological AD hallmarks. Understanding these associations is critical to provide a comprehensive view of appropriate therapeutic strategies for AD.

5.
J Nanosci Nanotechnol ; 21(6): 3291-3298, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34739784

RESUMO

In this paper, a simple and effective method to prepare Ag-Ce/ZnO nanorods photocatalyst and grow them controllably on modified polyester fabrics was presented to fabricate multifunctional textiles. Analytical grade zinc acetate dihydrate and sodium hydroxide were used as the main raw materials to prepare Ag-Ce/ZnO nanorods. Morphological, structural and chemical characterization of the Ag-Ce/ZnO nanorods was performed by XRD, UV-vis and other spectroscopies. The results showed that the Ag-Ce/ZnO nanorods had a hexagonal wurtzite structure. After 60 minutes of irradiation under ultraviolet light, the Ag-Ce/ZnO nanorods showed a percentage photodegradation of 93.14% for a methylene blue (MB) solution. Modified polyester fabrics covered with the Ag-Ce/ZnO nanorods were then prepared in a water bath. By a series of tests, it was observed that the Ag-Ce/ZnO nanorods on the modified polyester surface were neatly arranged and had good photocatalytic properties. Moreover, the UPF of the modified polyester fabric after finishing increased from 30.4 to 877.2. The multifunctional properties of the finished fabric exhibited good durability.


Assuntos
Nanotubos , Óxido de Zinco , Catálise , Poliésteres , Água
6.
PLoS Genet ; 17(10): e1009835, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34634037

RESUMO

Increased production of fetal hemoglobin (HbF) can ameliorate the severity of sickle cell disease and ß-thalassemia. BCL11A has been identified as a key regulator of HbF silencing, although its precise mechanisms of action remain incompletely understood. Recent studies have identified pathogenic mutations that cause heterozygous loss-of-function of BCL11A and result in a distinct neurodevelopmental disorder that is characterized by persistent HbF expression. While the majority of cases have deletions or null mutations causing haploinsufficiency of BCL11A, several missense variants have also been identified. Here, we perform functional studies on these variants to uncover specific liabilities for BCL11A's function in HbF silencing. We find several mutations in an N-terminal C2HC zinc finger that increase proteasomal degradation of BCL11A. We also identify a distinct C-terminal missense variant in the fifth zinc finger domain that we demonstrate causes loss-of-function through disruption of DNA binding. Our analysis of missense variants causing loss-of-function in vivo illuminates mechanisms by which BCL11A silences HbF and also suggests potential therapeutic avenues for HbF induction to treat sickle cell disease and ß-thalassemia.


Assuntos
Hemoglobina Fetal/genética , Inativação Gênica/fisiologia , Mutação/genética , Proteínas Repressoras/genética , Anemia Falciforme/genética , Linhagem Celular Tumoral , Células Cultivadas , Humanos , Células K562 , Dedos de Zinco/genética , Talassemia beta/genética
7.
J Appl Toxicol ; 2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34601724

RESUMO

Vinyl chloride (VC) is a common industrial organic chlorine and environmental pollutant. In recent years, the dietary structure of residents especially Chinese has gradually shifted to western dietary patterns. VC aggravates dietary fatty acid-induced hepatic steatosis, but its mechanism is still unclear. And if the risk factors for steatosis persist, more severe diseases such as fibrosis and cirrhosis will occur. Therefore, we studied the effects and mechanisms of VC (160 and 800 mg/m3 ) and its metabolite (chloroacetaldehyde, 2.25, 4.5, and 9 µM) on hepatic steatosis of high-fat diet (HFD)-fed mice and palmitic acid (PA, 100 µM) treated HepG2 cells. Liver and serum biochemical indicators and pathological staining of the liver showed that the hepatic steatosis of VC combined with HFD groups was more severe than that of single-exposure groups (HFD group, low-dose VC group, and high-dose VC group). Moreover, VC enhanced HFD-induced oxidative stress (OS) and endoplasmic reticulum stress (ERS) and further upregulated the expression of sterol regulatory element-binding protein 1 (SREBP-1) and FAS. Besides, antioxidants and ERS inhibitors reduced the steatosis of HepG2 cells induced by VC metabolites and PA. These results suggest that VC exposure can enhance the degree of hepatic steatosis in HFD-fed mice. VC combined with HFD led to OS and ERS and upregulated the expression of de novo lipogenesis-related proteins, which may be related to the occurrence of hepatic steatosis. And the increased expression of CYP2E1 induced by VC combined with HFD may be the cause of OS.

8.
J Neurosurg Spine ; : 1-10, 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34678769

RESUMO

OBJECTIVE: The authors' objectives were: 1) to evaluate the incidence and risk factors of iatrogenic coronal malalignment (CM), and 2) to assess the outcomes of patients with all three types of postoperative CM (iatrogenic vs unchanged/worsened vs improved but persistent). METHODS: A single-institution, retrospective cohort study was performed on adult spinal deformity (ASD) patients who underwent > 6-level fusion from 2015 to 2019. Iatrogenic CM was defined as immediate postoperative C7 coronal vertical axis (CVA) ≥ 3 cm in patients with preoperative CVA < 3 cm. Additional subcategories of postoperative CM were unchanged/worsened CM, which was defined as immediate postoperative CVA within 0.5 cm of or worse than preoperative CVA, and improved but persistent CM, which was defined as immediate postoperative CVA that was at least 0.5 cm better than preoperative CVA but still ≥ 3 cm; both groups included only patients with preoperative CM. Immediate postoperative radiographs were obtained when the patient was discharged from the hospital after surgery. Demographic, radiographic, and operative variables were collected. Outcomes included major complications, readmissions, reoperations, and patient-reported outcomes (PROs). The t-test, Kruskal-Wallis test, and univariate logistic regression were performed for statistical analysis. RESULTS: In this study, 243 patients were included, and the mean ± SD age was 49.3 ± 18.3 years and the mean number of instrumented levels was 13.5 ± 3.9. The mean preoperative CVA was 2.9 ± 2.7 cm. Of 153/243 patients without preoperative CM (CVA < 3 cm), 13/153 (8.5%) had postoperative iatrogenic CM. In total, 43/243 patients (17.7%) had postoperative CM: iatrogenic CM (13/43 [30.2%]), unchanged/worsened CM (19/43 [44.2%]), and improved but persistent CM (11/43 [25.6%]). Significant risk factors associated with iatrogenic CM were anxiety/depression (OR 3.54, p = 0.04), greater preoperative sagittal vertical axis (SVA) (OR 1.13, p = 0.007), greater preoperative pelvic obliquity (OR 1.41, p = 0.019), lumbosacral fractional (LSF) curve concavity to the same side of the CVA (OR 11.67, p = 0.020), maximum Cobb concavity opposite the CVA (OR 3.85, p = 0.048), and three-column osteotomy (OR 4.34, p = 0.028). In total, 12/13 (92%) iatrogenic CM patients had an LSF curve concavity to the same side as the CVA. Among iatrogenic CM patients, mean pelvic obliquity was 3.1°, 4 (31%) patients had pelvic obliquity > 3°, mean preoperative absolute SVA was 8.0 cm, and 7 (54%) patients had preoperative sagittal malalignment. Patients with iatrogenic CM were more likely to sustain a major complication during the 2-year postoperative period than patients without iatrogenic CM (12% vs 33%, p = 0.046), yet readmission, reoperation, and PROs were similar. CONCLUSIONS: Postoperative iatrogenic CM occurred in 9% of ASD patients with preoperative normal coronal alignment (CVA < 3 cm). ASD patients who were most at risk for iatrogenic CM included those with preoperative sagittal malalignment, increased pelvic obliquity, LSF curve concavity to the same side as the CVA, and maximum Cobb angle concavity opposite the CVA, as well as those who underwent a three-column osteotomy. Despite sustaining more major complications, iatrogenic CM patients did not have increased risk of readmission, reoperation, or worse PROs.

9.
Neurospine ; 18(3): 570-579, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34610688

RESUMO

OBJECTIVE: To evaluate the effect of coronal alignment on: (1) surgical invasiveness and operative complexity and (2) postoperative complications. METHODS: A retrospective, cohort study of adult spinal deformity patients was conducted. Alignment groups were: (1) neutral alignment (NA): coronal vertical axis (CVA) ≤ 3 cm and sagittal vertical axis (SVA) ≤ 5 cm; (2) coronal malalignment (CM) only: CVA > 3 cm; (3) Sagittal malalignment (SM) only: SVA > 5 cm; and (4) coronal and sagittal malalignment (CCSM): CVA > 3 cm and SVA > 5 cm. RESULTS: Of 243 patients, alignment groups were: NA 115 (47.3%), CM 48 (19.8%), SM 38 (15.6%), and CCSM 42 (17.3%). Total instrumented levels (TILs) were highest in CM (14.5 ± 3.7) and CCSM groups (14 ± 4.0) (p < 0.001). More 3-column osteotomies (3COs) were performed in SM (21.1%) and CCSM (28.9%) groups than CM (10.4%) (p = 0.003). CM patients had more levels instrumented (p = 0.029), posterior column osteotomies (PCOs) (p < 0.001), and TLIFs (p = 0.002) than SM patients. CCSM patients had more TLIFs (p = 0.012) and higher estimated blood loss (EBL) (p = 0.003) than SM patients. CVA displayed a stronger relationship with TIL (p = 0.002), EBL (p < 0.001), and operative time (p < 0.001) than SVA, which had only one significant association with EBL (p = 0.010). Both SM/CCSM patients had higher readmissions (p = 0.003) and reoperations (p < 0.001) than CM patients. CONCLUSION: Amount of preoperative CM was a better predictor of surgical invasiveness than the amount of SM, despite 3COs more commonly performed in SM patients. CM patients had more instrumented levels, PCOs, and TLIFs than SM patients.

10.
Protein J ; 40(6): 940-954, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34480247

RESUMO

Tilia miqueliana produces woody seeds that exhibit deep dormancy. In this study, we used cell biology methods, including Paraffin section determination and Coomassie brilliant blue staining, as well as proteomics-based methods, including two-dimensional electrophoresis with matrix-assisted laser desorption/ionisation tandem time-of-flight mass spectrometry (2DE-MALDI-TOF/TOF), to examine the effects of H2SO4-GA3 and cold stratification (3 °C) treatment on proteins during dormancy release and germination in T. miqueliana seeds. The results revealed that during cold stratification, the area and density of proteins in the endosperm cells of H2SO4-GA3-treated seeds were significantly altered. Total protein content was continuously consumed and utilised. Storage proteins (albumin, globulin, prolamin, and glutelin) were degraded to varying degrees. Sixteen differential proteins were identified using mass spectrometry. Kyoto encyclopedia of genes (KEGG) pathway analysis revealed that the glycolysis/gluconeogenesis, secondary metabolite biosynthesis, glyoxylate and dicarboxylate metabolism, amino acid biosynthesis, and metabolic pathways were critical during dormancy release and germination. Gene ontology analysis and KEGG pathway annotation of differential proteins in the co-expression network indicated that the differential proteins are implicated in photosynthesis, glucose metabolism, biosynthesis of plant hormones, and glycolysis/gluconeogenesis. Synergistic interactions among these proteins accelerated dormancy release and germination. Therefore, H2SO4-GA3 cold stratification treatment is the best method for achieving rapid dormancy release and increasing the germination rate of T. miqueliana seeds.

11.
Mol Ther Oncolytics ; 22: 565-573, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34553041

RESUMO

Endostatin (ES, ENDO) has been reported to suppress the growth of tumors while inducing the proliferation of lung cancer stem cells (LCSCs), causing a poor prognosis for lung cancer. In this study, we aimed to clarify whether BRM270 can inhibit the proliferation of cancer stem cells (CSCs). Endostatin + BRM270 showed anti-tumor effects by reducing tumor volume and increasing survival. Administration of BRM270 reduced the number of aldehyde dehydrogenase-positive (ALDH+) cells and the level of ALDH1A1 expression in tumors by increasing the level of miR-128 while decreasing the levels of BMI-1, ABCC-5, E2F3, and c-MET. The luciferase activity of miR-128 promoter was increased by an increasing concentration of BRM270. In addition, BMI-1, ABCC-5, E2F3, and c-MET were identified as candidate targets of miR-128, and the overexpression of miR-128 significantly reduced mRNA/protein levels of BMI-1, ABCC-5, E2F3, and c-MET in A549 and H460 cells. Administration of BRM270 inhibited the expression of BMI-1, ABCC-5, E2F3, and c-MET in a dose-dependent manner. In this study, we showed for the first time that the combined administration of endostatin and BRM270 achieved anti-tumor effects while suppressing the proliferation of stem cells.

12.
Entropy (Basel) ; 23(9)2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34573825

RESUMO

Particle swarm optimization (PSO) has the disadvantages of easily getting trapped in local optima and a low search accuracy. Scores of approaches have been used to improve the diversity, search accuracy, and results of PSO, but the balance between exploration and exploitation remains sub-optimal. Many scholars have divided the population into multiple sub-populations with the aim of managing it in space. In this paper, a multi-stage search strategy that is dominated by mutual repulsion among particles and supplemented by attraction was proposed to control the traits of the population. From the angle of iteration time, the algorithm was able to adequately enhance the entropy of the population under the premise of satisfying the convergence, creating a more balanced search process. The study acquired satisfactory results from the CEC2017 test function by improving the standard PSO and improved PSO.

13.
J Mater Chem B ; 9(38): 8074-8080, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34490430

RESUMO

Dermal substitutes are indispensable for repairing large full-thickness skin defects. Only a few biomaterials for dermal substitution have been put into clinical practice. Therefore, novel artificial dermal substitutes that can meet clinical requirements are in urgent need. Biodegradable poly(4-hydroxybutyrate) (P4HB), which has been approved by the U.S. FDA, can be considered as a possible alternative biomaterial to construct dermal substitutes. In this work, three-dimensional P4HB fibrous membranes were constructed by an electrospinning technique. These P4HB fibrous membranes showed excellent air-permeability, and better water uptake capacity compared to P4HB strip and polycaprolactone (PCL) fibrous membrane controls. The in vitro hemocompatibility and cytotoxicity of P4HB fibrous membranes were investigated. In vivo Sprague-Dawley (SD) rat model studies revealed that P4HB fibrous membranes can be used as artificial dermis to improve wound healing for full-thickness skin defects.

14.
Crit Rev Food Sci Nutr ; : 1-15, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34491124

RESUMO

As a notorious food-borne pathogen, Staphylococcus aureus can readily cause diseases in humans via contaminated food. Biofilm formation on various surfaces can increase the capacity of viable S. aureus cells for self-protection due to the stubborn structure of the biofilm matrix. Increased disease risk and economic losses caused by biofilm contamination in the food industry necessitate the urgent development of effective strategies for the inhibition and removal of S. aureus biofilms. Natural products have been extensively used as important sources of "eco-friendly" antibiofilm agents to avoid the side effects of conventional strategies on human health and the environment. This review discusses biofilm formation of S. aureus in food industries and focuses on providing an overview of potential promising target-oriented natural products and their mechanisms of S. aureus biofilm inhibition or removal. Hoping to provide valuable information of attractive research targets or potential undeveloped targets to screen potent natural anti-biofilm agents in food industries.

15.
Brain Behav Immun ; 98: 337-348, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34500034

RESUMO

Circulating CD4+ T cells are dysfunctional in Alzheimer's disease (AD), however, the underlying molecular mechanisms are not clear. In this study, we demonstrate that CD4+ T cells from AD patients and 5xFAD transgenic mice exhibit elevated levels of ß-secretase 1 (BACE1). Overexpression of BACE1 in CD4+ T cells potentiated CD4+ T-cell activation and T-cell-dependent immune responses. Mechanistically, BACE1 modulates prostaglandin E2 (PGE2) synthetase-microsomal prostaglandin E synthase 2 (mPGES2)-to promote mPGES2 maturation and PGE2 production, which increases T-cell receptor (TCR) signalling. Moreover, administration of peripheral PGE2 signalling antagonists partially ameliorates CD4+ T cell overactivation and AD pathology in 5xFAD mice. Overall, our results reveal a potential role for BACE1 in mediating CD4+ T-cell dysfunction in AD.

16.
Mol Nutr Food Res ; 65(19): e2100626, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34342385

RESUMO

SCOPE: The consumption of green tea is considered to be associated with a lower incidence of neurodegenerative diseases. In the present study, it is investigated the role of amyloid precursor protein cleavage, glial cell activation, neuroinflammation, and synaptic alterations in the protective effects of green tea against the amyloid ß (Aß) accumulation and cognitive impairment. METHODS AND RESULTS: 5XFAD mice are treated with green tea extract (GTE) for 8 or 16 weeks. Barnes maze and Y maze testing demonstrated that spatial learning and memory ability are markedly improved by GTE treatment. Immunofluorescence staining, ELISA, and western blot showed GTE significantly alleviate the formation of Aß and reduce the levels of sAPPß and C99, as well as sAPPα and C83. Meanwhile, GTE suppressed GFAP and Iba1 levels in the glial cells, increased PSD95 and synaptophysin levels in synaptic cells. Further, the IL-1ß level is decreased, RNA sequencing reveals the genes annotated in response to stimulus and immune response are regulated. CONCLUSION: Our findings indicate GTE suppresses Aß levels and alleviate cognitive impairment in 5XFAD mice. These beneficial effects are accompanied by inhibition of APP cleavage pathways, suppression of glial cell activation and pro-inflammatory responses, and a reduction of synapse loss.

17.
Acta Trop ; 223: 106072, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34358513

RESUMO

OBJECTIVE: On May 2, 2017, an outbreak of unexplained fever with rashes was reported in Lu'an, China. In this study, we aimed to identify the possible pathogens, epidemiological characteristics, and risk factors of this outbreak. METHODS: We conducted descriptive field epidemiological studies. Blood samples were tested using an indirect immunofluorescence assay for Rickettsia rickettsii antibody, and nested polymerase chain reaction and gene sequencing assays were performed. RESULTS: We recruited 39 cases who had symptomatic onset from April 20 to June 8, 2017. Among these, 9 were suspected cases, 18 were probable cases, and 12 were confirmed cases. No one died. The main clinical manifestations were fever (100%), rash (100%), fatigue (97.3%), myalgia (83.8%), and anorexia (83.8%). None of the patients died. Thirty-seven patients who were treated with antibiotics during hospitalization showed significant improvement. The cases were distributed across 14 townships in 2 counties. The median age was 59 (43.0-81.0) years, of which 93.3% had a history of tea picking (28/30), and 77.3% (17/22) had a history of tick bites. The mean incubation period was 5.0 days (2.0-13.0 days). Serum IgG titers were higher in convalescent patients than in the general population (p = 0.016). Phylogenetic analysis revealed that the ompA sequences of Rickettsia sp. Lu'an-2018 had an 86.8%-99.0% sequence identity with the 23 strains of Rickettsia found worldwide. CONCLUSIONS: This was the first reported outbreak of an undetermined species of a human infection with the spotted fever group of Rickettsia in China, which might be caused by ticks biting local residents when picking tea.


Assuntos
Rickettsia , Febre Maculosa das Montanhas Rochosas , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Mordeduras e Picadas , China/epidemiologia , Surtos de Doenças , Humanos , Pessoa de Meia-Idade , Filogenia , Rickettsia/genética , Febre Maculosa das Montanhas Rochosas/epidemiologia , Carrapatos
18.
Nat Commun ; 12(1): 4991, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404810

RESUMO

Key mechanisms of fetal hemoglobin (HbF) regulation and switching have been elucidated through studies of human genetic variation, including mutations in the HBG1/2 promoters, deletions in the ß-globin locus, and variation impacting BCL11A. While this has led to substantial insights, there has not been a unified understanding of how these distinct genetically-nominated elements, as well as other key transcription factors such as ZBTB7A, collectively interact to regulate HbF. A key limitation has been the inability to model specific genetic changes in primary isogenic human hematopoietic cells to uncover how each of these act individually and in aggregate. Here, we describe a single-cell genome editing functional assay that enables specific mutations to be recapitulated individually and in combination, providing insights into how multiple mutation-harboring functional elements collectively contribute to HbF expression. In conjunction with quantitative modeling and chromatin capture analyses, we illustrate how these genetic findings enable a comprehensive understanding of how distinct regulatory mechanisms can synergistically modulate HbF expression.


Assuntos
Edição de Genes , Hemoglobinas/genética , Hemoglobinas/metabolismo , Sistemas CRISPR-Cas , Cromatina , Cromossomos , Proteínas de Ligação a DNA/metabolismo , Hemoglobina Fetal/genética , Hemoglobina Fetal/metabolismo , Expressão Gênica , Globinas , Humanos , Mutação , Proteínas Repressoras , Fatores de Transcrição/metabolismo , Globinas beta/genética
19.
Horm Metab Res ; 53(8): 504-511, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34384107

RESUMO

Insulin resistance (IR) is one of the most common features of polycystic ovary syndrome (PCOS), which is related to obesity. Whether increased anti-Müllerian hormone (AMH) levels in PCOS are involved in the pathogenesis of insulin resistance remains unclear. We investigated serum levels of leptin and AMH along with basic clinical and metabolic parameters in 114 PCOS patients and 181 non-PCOS women. PCOS patients presented higher fasting blood glucose, insulin concentrations and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) in addition to body mass index (BMI), lipids profiles and hormone levels. HOMA-IR showed a positive correlation with BMI, AMH, leptin, and low-density lipoprotein-cholesterol (LDL-c) levels. Interestingly, AMH is strongly positively correlated with HOMA-IR and insulin concentrations for 1st and 2nd hours of glucose treatment after fasting. Among PCOS women with BMI≥25 kg/m2, high AMH level group showed an increased HOMA-IR when compared to normal AMH level. However, among PCOS women with normal BMI, women with high AMH presented an elevated fasting insulin levels but not HOMA-IR when compared to normal AMH group. In vitro treatment of isolated islet cells with high concentration of leptin (200 ng/ml) or high leptin plus high concentration of AMH (1 ng/ml) significantly enhanced insulin secretion. Importantly, co-treatment of AMH plus leptin upregulates the expression of pro-apoptotic proteins, such as Bax, caspase-3, and caspase-8 after incubating with a high level of glucose. These results suggest that AMH may involve in the pathological process of pancreatic ß-cells in obese PCOS women.

20.
BMC Anesthesiol ; 21(1): 209, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34461833

RESUMO

BACKGROUND: Caudal block is one of the most preferred regional anesthesia for sub-umbilical region surgeries in the pediatric population. However, few studies are available on caudal block performed in laparoscopic-assisted Soave pull-through of Hirschsprung disease (HD). We aimed to compare general anesthesia (GA) and general anesthesia combined with caudal block (GA + CA) in laparoscopic-assisted Soave pull-through of HD. METHODS: A retrospective review was performed in children with HD operated in our hospital between 2017 and 2020. Patients were divided into the GA and GA + CA group. The primary outcome was the duration of operation, and secondary outcomes included intraoperative hemodynamic changes, the Face, Legs, Activity, Cry, Consolability (FLACC) scale, dose of anesthetics, and incidence of side effects. RESULTS: A total of 47 children with HD were included in the study, including 20 in the GA group and 27 in the GA + CA Group. The two groups were similar in age, gender, weight and type of HD (P > 0.05). The GA + CA group had significantly shorter duration of operation (especially the transanal operation time) (median 1.20 h vs. 0.83 h, P < 0.01) and recovery time (mean 18.05 min vs. 11.89 min, P < 0.01). The mean doses of sufentanil and rocuronium bromide during the procedure and FLACC scores at 1 h and 6 h after surgery were also lower in the GA + CA group (p < 0.01). The hemodynamic changes in the GA + CA group were more stable at time of t2 (during transanal operation) and t3 (10 min after transanal operation), but there was no significant difference in the incidence of postoperative side effects between the two groups (P = 1.000). CONCLUSION: General anesthesia combined with caudal block can shorten the duration of operation, and provide more stable intraoperative hemodynamics and better postoperative analgesia.

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