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2.
Proc Natl Acad Sci U S A ; 121(29): e2323040121, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38985761

RESUMO

Stomata in leaves regulate gas (carbon dioxide and water vapor) exchange and water transpiration between plants and the atmosphere. SLow Anion Channel 1 (SLAC1) mediates anion efflux from guard cells and plays a crucial role in controlling stomatal aperture. It serves as a central hub for multiple signaling pathways in response to environmental stimuli, with its activity regulated through phosphorylation via various plant protein kinases. However, the molecular mechanism underlying SLAC1 phosphoactivation has remained elusive. Through a combination of protein sequence analyses, AlphaFold-based modeling and electrophysiological studies, we unveiled that the highly conserved motifs on the N- and C-terminal segments of SLAC1 form a cytosolic regulatory domain (CRD) that interacts with the transmembrane domain(TMD), thereby maintaining the channel in an autoinhibited state. Mutations in these conserved motifs destabilize the CRD, releasing autoinhibition in SLAC1 and enabling its transition into an activated state. Our further studies demonstrated that SLAC1 activation undergoes an autoinhibition-release process and subsequent structural changes in the pore helices. These findings provide mechanistic insights into the activation mechanism of SLAC1 and shed light on understanding how SLAC1 controls stomatal closure in response to environmental stimuli.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Estômatos de Plantas , Transdução de Sinais , Fosforilação , Estômatos de Plantas/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Arabidopsis/metabolismo , Arabidopsis/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Domínios Proteicos , Mutação
3.
Pediatr Res ; 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39025934

RESUMO

BACKGROUND: Extremely preterm infants (EPIs) are at high-risk of white matter injury (WMI), leading to long-term neurodevelopmental impairments. We aimed to develop nomograms for WMI. METHODS: The study included patients from 31 provinces, spanning ten years. 6074 patients before 2018 were randomly divided into a training and internal validation group (7:3). The external validation group comprised 1492 patients from 2019. Predictors were identified using the least absolute shrinkage and selection operator (LASSO) and multivariable logistic regression and nomograms were constructed. Models' performance was evaluated using receiver operating characteristic (ROC), decision curve analysis (DCA) and calibration curves. RESULTS: The prenatal nomogram included multiple gestation, premature rupture of membranes (PROM), chorioamnionitis, prenatal glucocorticoids, hypertensive disorder complicating pregnancy (HDCP) and Apgar 1 min, with area under the curve (AUC) of 0.805, 0.816 and 0.799 in the training, internal validation and external validation group, respectively. Days of mechanical ventilation (MV), shock, patent ductus arteriosus (PDA) ligation, intraventricular hemorrhage (IVH) grade III-IV, septicemia, hypothermia and necrotizing enterocolitis (NEC) stage II-III were identified as postpartum predictors. The AUCs were 0.791, 0.813 and 0.823 in the three groups, respectively. DCA and calibration curves showed good clinical utility and consistency. CONCLUSION: The two nomograms provide clinicians with precise and efficient tools for prediction of WMI. IMPACT: This study is a large-sample multicenter study, spanning 10 years. The two nomograms are convenient for identifying high-risk infants early, allowing for reducing poor prognosis.

4.
Org Lett ; 26(27): 5782-5787, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38940384

RESUMO

A palladium-catalyzed spirocyclopropanation of gem-difluoroalkenes with π-allylpalladium 1,4-dipoles has been successfully developed, which gives a powerful and straightforward synthetic strategy for the construction of novel gem-difluorinated spirocyclic compounds, 6,6-difluoro-5-oxa/azaspiro[2.4]heptanes. The scope of gem-difluoroalkenes can be extended to styrenes, acrylic esters, and acrylamides to realize the installment of various functional groups and different heteroatoms on the spirocyclic skeletons, which could be converted to valuable compounds with potential biological activity. The mechanistic investigations revealed the competition between spirocyclopropanation and ß-F elimination of π-allylpalladium zwitterionic intermediates.

5.
Comput Biol Med ; 178: 108778, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38925086

RESUMO

Body-machine interfaces (BoMIs)-systems that control assistive devices (e.g., a robotic manipulator) with a person's movements-offer a robust and non-invasive alternative to brain-machine interfaces for individuals with neurological injuries. However, commercially-available assistive devices offer more degrees of freedom (DOFs) than can be efficiently controlled with a user's residual motor function. Therefore, BoMIs often rely on nonintuitive mappings between body and device movements. Learning these mappings requires considerable practice time in a lab/clinic, which can be challenging. Virtual environments can potentially address this challenge, but there are limited options for high-DOF assistive devices, and it is unclear if learning with a virtual device is similar to learning with its physical counterpart. We developed a novel virtual robotic platform that replicated a commercially-available 6-DOF robotic manipulator. Participants controlled the physical and virtual robots using four wireless inertial measurement units (IMUs) fixed to the upper torso. Forty-three neurologically unimpaired adults practiced a target-matching task using either the physical (sample size n = 25) or virtual device (sample size n = 18) involving pre-, mid-, and post-tests separated by four training blocks. We found that both groups made similar improvements from pre-test in movement time at mid-test (Δvirtual: 9.9 ± 9.5 s; Δphysical: 11.1 ± 9.9 s) and post-test (Δvirtual: 11.1 ± 9.1 s; Δphysical: 11.8 ± 10.5 s) and in path length at mid-test (Δvirtual: 6.1 ± 6.3 m/m; Δphysical: 3.3 ± 3.5 m/m) and post-test (Δvirtual: 6.6 ± 6.2 m/m; Δphysical: 3.5 ± 4.0 m/m). Our results indicate the feasibility of using virtual environments for learning to control assistive devices. Future work should determine how these findings generalize to clinical populations.


Assuntos
Robótica , Tecnologia Assistiva , Humanos , Adulto , Masculino , Feminino , Interface Usuário-Computador , Interfaces Cérebro-Computador
6.
Sci Rep ; 14(1): 12884, 2024 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-38839838

RESUMO

The aim of this study was to develop a real-time risk prediction model for extrauterine growth retardation (EUGR). A total of 2514 very preterm infants were allocated into a training set and an external validation set. The most appropriate independent variables were screened using univariate analysis and Lasso regression with tenfold cross-validation, while the prediction model was designed using binary multivariate logistic regression. A visualization of the risk variables was created using a nomogram, while the calibration plot and receiver operating characteristic (ROC) curves were used to calibrate the prediction model. Clinical efficacy was assessed using the decision curve analysis (DCA) curves. Eight optimal predictors that namely birth weight, small for gestation age (SGA), hypertensive disease complicating pregnancy (HDCP), gestational diabetes mellitus (GDM), multiple births, cumulative duration of fasting, growth velocity and postnatal corticosteroids were introduced into the logistic regression equation to construct the EUGR prediction model. The area under the ROC curve of the training set and the external verification set was 83.1% and 84.6%, respectively. The calibration curve indicate that the model fits well. The DCA curve shows that the risk threshold for clinical application is 0-95% in both set. Introducing Birth weight, SGA, HDCP, GDM, Multiple births, Cumulative duration of fasting, Growth velocity and Postnatal corticosteroids into the nomogram increased its usefulness for predicting EUGR risk in very preterm infants.


Assuntos
Idade Gestacional , Recém-Nascido Prematuro , Curva ROC , Humanos , Recém-Nascido , Feminino , Recém-Nascido Prematuro/crescimento & desenvolvimento , Gravidez , Masculino , Nomogramas , Peso ao Nascer , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Fatores de Risco , Diabetes Gestacional/diagnóstico , Retardo do Crescimento Fetal/diagnóstico , Modelos Logísticos
7.
Pharmacol Res ; 206: 107279, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38942340

RESUMO

Transfer RNA-derived small RNAs (tsRNAs) are a class of small non-coding RNA (sncRNA) molecules derived from tRNA, including tRNA derived fragments (tRFs) and tRNA halfs (tiRNAs). tsRNAs can affect cell functions by participating in gene expression regulation, translation regulation, intercellular signal transduction, and immune response. They have been shown to play an important role in various human diseases, including cardiovascular diseases (CVDs). Targeted regulation of tsRNAs expression can affect the progression of CVDs. The tsRNAs induced by pathological conditions can be detected when released into the extracellular, giving them enormous potential as disease biomarkers. Here, we review the biogenesis, degradation process and related functional mechanisms of tsRNAs, and discuss the research progress and application prospects of tsRNAs in different CVDs, to provide a new perspective on the treatment of CVDs.


Assuntos
Doenças Cardiovasculares , Pequeno RNA não Traduzido , RNA de Transferência , Humanos , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/terapia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Animais , RNA de Transferência/genética , RNA de Transferência/metabolismo , Pequeno RNA não Traduzido/genética , Pequeno RNA não Traduzido/uso terapêutico , Pequeno RNA não Traduzido/metabolismo
8.
J Med Virol ; 96(6): e29757, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38899432

RESUMO

No effective treatments can ameliorate symptoms of long COVID patients. Our study assessed the safety and efficacy of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) in the treatment of long COVID patients. Ten long COVID patients were enrolled and received intravenous infusions of UC-MSCs on Days 0, 7, and 14. Adverse events and clinical symptoms were recorded, and chest-high-resolution CT (HRCT) images and laboratory parameters were analyzed. During UC-MSCs treatment and follow-up, we did not observe serious adverse events, the symptoms of long COVID patients were significantly relieved in a short time, especially sleep difficulty, depression or anxiety, memory issues, and so forth, and the lung lesions were also repaired. The routine laboratory parameters did not exhibit any significant abnormalities following UC-MSCs transplantation (UMSCT). The proportion of regulatory T cells gradually increased, but it was not statistically significant until 12 months. The proportion of naive B cells was elevated, while memory B cells, class-switched B-cells, and nonswitched B-cells decreased at 1 month after infusion. Additionally, we observed a transient elevation in circulating interleukin (IL)-6 after UMSCT, while tumor necrosis factor (TNF)-α, IL-17A, and IL-10 showed no significant changes. The levels of circulating immunoglobulin (Ig) M increased significantly at month 2, while IgA increased significantly at month 6. Furthermore, the SARS-CoV-2 IgG levels remained consistently high in all patients at Month 6, and there was no significant decrease during the subsequent 12-month follow-up. UMSCT was safe and tolerable in long COVID patients. It showed potential in alleviating long COVID symptoms and improving interstitial lung lesions.


Assuntos
COVID-19 , Transplante de Células-Tronco Mesenquimais , Cordão Umbilical , Humanos , COVID-19/terapia , COVID-19/imunologia , Transplante de Células-Tronco Mesenquimais/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Cordão Umbilical/citologia , Células-Tronco Mesenquimais , Idoso , Resultado do Tratamento , Adulto , SARS-CoV-2 , Linfócitos T Reguladores/imunologia , Linfócitos B/imunologia , Interleucina-6/sangue
9.
Artigo em Inglês | MEDLINE | ID: mdl-38829385

RESUMO

Garlic exhibits hypolipidemic, hypoglycemic, and cardiovascular benefits. The inconsistent results of garlic preparations on adipogenesis have caused more confusion in the public and academia. The compounds responsible for the anti-adipogenesis effect of garlic remain unknown. The present study aimed to verify the real anti-adipogenesis and anti-obesity component in garlic and explored its possible effects in metabolic syndrome. We verified the real anti-adipogenesis and anti-obesity components of garlic in 3T3-L1 preadipocytes and a 10-week-high fat diet (HFD)-induced obese mice. In vitro, two water-soluble and four typical lipid-soluble compounds of garlic were tested for their anti-adipogenesis. Then, the water-soluble compound, alliin, and two processing methods produced garlic oils, were evaluated in vivo study. Mice received oral administration of alliin (25 mg/kg) and garlic oils (15 mg/kg) daily for 8 weeks. Serum lipids, parameters of obesity, and indicators involved in regulating glycolipid metabolism were examined. Our findings confirmed that both water-soluble and lipid-soluble organosulfur compounds of garlic contributed to garlic's anti-adipogenesis effect, in which water-soluble sulfides, especially alliin, exhibited greater potency. Alliin possessed potent effects of anti-obesity and improvement in glucose and lipid metabolism in HFD-induced obese mice. Alliin mediated these effects partly attributed to its modulation of enzymatic activities within glycolipid metabolism and activating PPARγ signaling pathway. In contrast to odorous lipid-soluble sulfides, alliin is odorless, stable, and safe, and is an ideal nutraceutical or even medicinal candidates for the treatment of metabolic diseases. Alliin could be used to standardize the quality of garlic products.

10.
J Ovarian Res ; 17(1): 105, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760835

RESUMO

BACKGROUND: In the realm of assisted reproduction, a subset of infertile patients demonstrates high ovarian response following controlled ovarian stimulation (COS), with approximately 29.7% facing the risk of Ovarian Hyperstimulation Syndrome (OHSS). Management of OHSS risk often necessitates embryo transfer cancellation, leading to delayed prospects of successful pregnancy and significant psychological distress. Regrettably, these patients have received limited research attention, particularly regarding their metabolic profile. In this study, we aim to utilize gas chromatography-mass spectrometry (GC-MS) to reveal these patients' unique serum metabolic profiles and provide insights into the disease's pathogenesis. METHODS: We categorized 145 infertile women into two main groups: the CON infertility group from tubal infertility patients and the Polycystic Ovary Syndrome (PCOS) infertility group. Within these groups, we further subdivided them into four categories: patients with normal ovarian response (CON-NOR group), patients with high ovarian response and at risk for OHSS (CON-HOR group) within the CON group, as well as patients with normal ovarian response (PCOS-NOR group) and patients with high ovarian response and at risk for OHSS (PCOS-HOR group) within the PCOS group. Serum metabolic profiles were analyzed using GC-MS. The risk criteria for OHSS were: the number of developing follicles > 20, peak Estradiol (E2) > 4000pg/mL, and Anti-Müllerian Hormone (AMH) levels > 4.5ng/mL. RESULTS: The serum metabolomics analysis revealed four different metabolites within the CON group and 14 within the PCOS group. Remarkably, 10-pentadecenoic acid emerged as a discernible risk metabolite for the CON-HOR, also found to be a differential metabolite between CON-NOR and PCOS groups. cysteine and 5-methoxytryptamine were also identified as risk metabolites for the PCOS-HOR. Furthermore, KEGG analysis unveiled significant enrichment of the aminoacyl-tRNA biosynthesis pathway among the metabolites differing between PCOS-NOR and PCOS-HOR. CONCLUSION: Our study highlights significant metabolite differences between patients with normal ovarian response and those with high ovarian response and at risk for OHSS within both the tubal infertility control group and PCOS infertility group. Importantly, we observe metabolic similarities between patients with PCOS and those with a high ovarian response but without PCOS, suggesting potential parallels in their underlying causes.


Assuntos
Fertilização in vitro , Infertilidade Feminina , Indução da Ovulação , Humanos , Feminino , Infertilidade Feminina/metabolismo , Infertilidade Feminina/sangue , Adulto , Síndrome de Hiperestimulação Ovariana/sangue , Síndrome de Hiperestimulação Ovariana/metabolismo , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/complicações , Cromatografia Gasosa-Espectrometria de Massas , Metaboloma , Metabolômica/métodos , Gravidez , Ovário/metabolismo
11.
ACS Infect Dis ; 10(6): 2161-2171, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38770797

RESUMO

Serotypes 6C and 6D of Streptococcus pneumoniae are two major variants that cause invasive pneumococcal disease (IPD) in serogroup 6 alongside serotypes 6A and 6B. Since the introduction of the pneumococcal conjugate vaccines PCV7 and PCV13, the number of cases of IPD caused by pneumococcus in children and the elderly population has greatly decreased. However, with the widespread use of vaccines, a replacement effect has recently been observed among different serotypes and lowered the effectiveness of the vaccines. To investigate protection against the original serotypes and to explore protection against variants and replacement serotypes, we created a library of oligosaccharide fragments derived from the repeating units of the capsular polysaccharides of serotypes 6A, 6B, 6C, and 6D through chemical synthesis. The library includes nine pseudosaccharides with or without exposed terminal phosphate groups and four pseudotetrasaccharides bridged by phosphate groups. Six carbohydrate antigens related to 6C and 6D were prepared as glycoprotein vaccines for immunogenicity studies. Two 6A and two 6B glycoconjugate vaccines from previous studies were included in immunogenicity studies. We found that the conjugates containing four phosphate-bridged pseudotetrasaccharides were able to induce good immune antibodies and cross-immunogenicity by showing superior activity and broad cross-protective activity in OPKA bactericidal experiments.


Assuntos
Anticorpos Antibacterianos , Oligossacarídeos , Infecções Pneumocócicas , Vacinas Pneumocócicas , Sorogrupo , Streptococcus pneumoniae , Streptococcus pneumoniae/imunologia , Streptococcus pneumoniae/química , Oligossacarídeos/química , Oligossacarídeos/síntese química , Vacinas Pneumocócicas/imunologia , Vacinas Pneumocócicas/química , Infecções Pneumocócicas/prevenção & controle , Infecções Pneumocócicas/microbiologia , Infecções Pneumocócicas/imunologia , Anticorpos Antibacterianos/imunologia , Animais , Camundongos , Cápsulas Bacterianas/imunologia , Cápsulas Bacterianas/química , Humanos , Feminino
12.
Neurochem Res ; 49(8): 1993-2004, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38782837

RESUMO

Phosphodiesterase 8 (PDE8), as a member of PDE superfamily, specifically promotes the hydrolysis and degradation of intracellular cyclic adenosine monophosphate (cAMP), which may be associated with pathogenesis of Alzheimer's disease (AD). However, little is currently known about potential role in the central nervous system (CNS). Here we investigated the distribution and expression of PDE8 in brain of mouse, which we believe can provide evidence for studying the role of PDE8 in CNS and the relationship between PDE8 and AD. Here, C57BL/6J mice were used to observe the distribution patterns of two subtypes of PDE8, PDE8A and PDE8B, in different sexes in vivo by western blot (WB). Meanwhile, C57BL/6J mice were also used to demonstrate the distribution pattern of PDE8 in selected brain regions and localization in neural cells by WB and multiplex immunofluorescence staining. Furthermore, the triple transgenic (3×Tg-AD) mice and wild type (WT) mice of different ages were used to investigate the changes of PDE8 expression in the hippocampus and cerebral cortex during the progression of AD. PDE8 was found to be widely expressed in multiple tissues and organs including heart, kidney, stomach, brain, and liver, spleen, intestines, and uterus, with differences in expression levels between the two subtypes of PDE8A and PDE8B, as well as two sexes. Meanwhile, PDE8 was widely distributed in the brain, especially in areas closely related to cognitive function such as cerebellum, striatum, amygdala, cerebral cortex, and hippocampus, without differences between sexes. Furthermore, PDE8A was found to be expressed in neuronal cells, microglia and astrocytes, while PDE8B is only expressed in neuronal cells and microglia. PDE8A expression in the hippocampus of both female and male 3×Tg-AD mice was gradually increased with ages and PDE8B expression was upregulated only in cerebral cortex of female 3×Tg-AD mice with ages. However, the expression of PDE8A and PDE8B was apparently increased in both cerebral cortex and hippocampus in both female and male 10-month-old 3×Tg-AD mice compared WT mice. These results suggest that PDE8 may be associated with the progression of AD and is a potential target for its prevention and treatment in the future.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases , Doença de Alzheimer , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Animais , Doença de Alzheimer/metabolismo , Feminino , Masculino , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , 3',5'-AMP Cíclico Fosfodiesterases/genética , Camundongos , Encéfalo/metabolismo , Hipocampo/metabolismo
13.
Cell Death Discov ; 10(1): 267, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38821929

RESUMO

Cervical cancer, significantly affecting women worldwide, often involves treatment with bleomycin, an anticancer agent targeting breast, ovarian, and cervical cancers by generating reactive oxygen species (ROS) to induce cancer cell death. The Peroxiredoxin (PRDX) family, particularly PRDX1 and 2, plays a vital role in maintaining cellular balance by scavenging ROS, thus mitigating the damaging effects of bleomycin-induced mitochondrial and cellular oxidative stress. This process reduces endoplasmic reticulum (ER) stress and prevents cell apoptosis. However, reducing PRDX1 and 2 levels reverses their protective effect, increasing apoptosis. This research highlights the importance of PRDX1 and 2 in cervical cancer treatments with bleomycin, showing their potential to enhance treatment efficacy by managing ROS and ER stress and suggesting a therapeutic strategy for improving outcomes in cervical cancer treatment.

14.
Front Pediatr ; 12: 1399615, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38808102

RESUMO

Objective: To systematically evaluate the effect of vitamin D deficiency during pregnancy on neonatal adverse outcomes, such as preterm infants, low birth weight infants (LBWI), and small for gestational age (SGA) infants. Methods: A comprehensive literature search was conducted across multiple databases including PubMed, Embase, Cochrane Library, SinoMed, Wanfang Data Knowledge Service Platform, China National Knowledge Internet (CNKI), and VIP Chinese Science and Technology Journal Database (VIP). Following predefined inclusion and exclusion criteria, two researchers independently screened, extracted data, and assessed the quality of the included studies. Meta-analysis was performed using RevMan 5.4 and Stata 14 software to synthesize the findings. Results: This study incorporated 13 cohort studies from 8 different countries and regions, encompassing a total of 55,162 pregnant women, among whom 28,155 were identified as having vitamin D deficiency. The Newcastle-Ottawa Scale (NOS) score ranged from 7-9 points. Meta-analysis results indicated a higher incidence of LBWI (OR = 5.52, 95% CI = 1.31-23.22. P = 0.02) in the group of pregnant women with vitamin D deficiency compared to those with adequate levels. However, there was no statistically significant difference in the likelihood of premature birth (OR = 1.25, 95% CI = 0.78-1.99. P = 0.36) or SGA (OR = 1.47, 95% CI = 0.81-2.68. P = 0.21) among newborns born to mothers with vitamin D deficiency vs. those with sufficient levels of vitamin D. Subgroup analysis based on the timing of maternal blood collection revealed that there was no statistically significant association between vitamin D levels during pregnancy and the incidence of preterm birth across all stages of pregnancy. Furthermore, vitamin D deficiency throughout the entire pregnancy was associated with an increased incidence of neonatal LBWI, whereas vitamin D levels during the first, second, and third trimesters did not demonstrate statistically differences on LBWI. Neonates born to mothers with vitamin D deficiency throughout pregnancy were found to have a higher likelihood of developing SGA. However, there was no statistically significant association between vitamin D levels and the development of SGA during the first and second trimesters. Conclusions: Adequate levels of vitamin D during pregnancy may decrease the incidence of LBWI, although further research is needed to determine its impact on the occurrence of preterm birth and SGA. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024535950, Identifier: (CRD42024535950).

15.
NPJ Genom Med ; 9(1): 32, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38811629

RESUMO

Incontinentia pigmenti (IP) is a rare X-linked dominant neuroectodermal dysplasia that primarily affects females. The only known causative gene is IKBKG, and the most common genetic cause is the recurrent IKBKG△4-10 deletion resulting from recombination between two MER67B repeats. Detection of variants in IKBKG is challenging due to the presence of a highly homologous non-pathogenic pseudogene IKBKGP1. In this study, we successfully identified four pathogenic variants in four IP patients using a strategy based on single-tube long fragment read (stLFR) sequencing with a specialized analysis pipeline. Three frameshift variants (c.519-3_519dupCAGG, c.1167dupC, and c.700dupT) were identified and subsequently validated by Sanger sequencing. Notably, c.519-3_519dupCAGG was found in both IKBKG and IKBKGP1, whereas the other two variants were only detected in the functional gene. The IKBKG△4-10 deletion was identified and confirmed in one patient. These results demonstrate that the proposed strategy can identify potential pathogenic variants and distinguish whether they are derived from IKBKG or its pseudogene. Thus, this strategy can be an efficient genetic testing method for IKBKG. By providing a comprehensive understanding of the whole genome, it may also enable the exploration of other genes potentially associated with IP. Furthermore, the strategy may also provide insights into other diseases with detection challenges due to pseudogenes.

16.
Mol Biol Rep ; 51(1): 607, 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38704801

RESUMO

BACKGROUND: Intracerebral hemorrhage (ICH) is a critical neurological condition with few treatment options, where secondary immune responses and specific cell death forms, like pyroptosis, worsen brain damage. Pyroptosis involves gasdermin-mediated membrane pores, increasing inflammation and neural harm, with the NLRP3/Caspase-1/GSDMD pathway being central to this process. Peroxiredoxin II (Prx II), recognized for its mitochondrial protection and reactive oxygen species (ROS) scavenging abilities, appears as a promising neuronal pyroptosis modulator. However, its exact role and action mechanisms need clearer definition. This research aims to explore Prx II impact on neuronal pyroptosis and elucidate its mechanisms, especially regarding endoplasmic reticulum (ER) stress and oxidative stress-induced neuronal damage modulation. METHODS AND RESULTS: Utilizing MTT assays, Microscopy, Hoechst/PI staining, Western blotting, and immunofluorescence, we found Prx II effectively reduces LPS/ATP-induced pyroptosis and neuroinflammation in HT22 hippocampal neuronal cells. Our results indicate Prx II's neuroprotective actions are mediated through PI3K/AKT activation and ER stress pathway inhibition, diminishing mitochondrial dysfunction and decreasing neuronal pyroptosis through the ROS/MAPK/NF-κB pathway. These findings highlight Prx II potential therapeutic value in improving intracerebral hemorrhage outcomes by lessening secondary brain injury via critical signaling pathway modulation involved in neuronal pyroptosis. CONCLUSIONS: Our study not only underlines Prx II importance in neuroprotection but also opens new therapeutic intervention avenues in intracerebral hemorrhage, stressing the complex interplay between redox regulation, ER stress, and mitochondrial dynamics in neuroinflammation and cell death management.


Assuntos
Estresse do Retículo Endoplasmático , Estresse Oxidativo , Peroxirredoxinas , Piroptose , Animais , Camundongos , Linhagem Celular , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/complicações , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Peroxirredoxinas/metabolismo , Piroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Saudi Med J ; 45(4): 369-378, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38657990

RESUMO

OBJECTIVES: To examine the risk factors for severe bronchopulmonary dysplasia (BPD) in a cohort of very preterm infants (VPIs) in China, as BPD is common among VPIs and associated with a high mortality rate. METHODS: In this multicenter retrospective study, medical records from infants with BPD born at gestation age (GA) of <32 weeks with birth weight (BW) of <1,500 grams (g) in 7 regions of China were included. The cohort was stratified into different BPD severity groups based on their fraction of inspired oxygen requirement at a modified GA of 36 weeks or post discharge. Risk factors were identified using logistic regression analysis. RESULTS: A significant inverse correlation was revealed between BPD severity and both GA and BW (p<0.001). Independent risk factors for severe BPD (sBPD) were identified as invasive mechanical ventilation (≥7d), multiple blood transfusion (≥3), nosocomial infection (NI), hemodynamically significant patent ductus arteriosus (hsPDA), delayed initiation of enteral nutrition, and longer time to achieve total caloric intake of 110 kcal/kg. Conversely, administration of antenatal steroids was associated with reduced risk of sBPD. CONCLUSION: Our study not only reaffirmed the established risk factors of low GA and BW for sBPD in VPIs, but also identified additional, potentially modifiable risk factors. Further research is warranted to explore whether intervention in these modifiable factors might reduce the risk of sBPD.Clinical Trial Reg. No.: ChiCTR1900023418.


Assuntos
Displasia Broncopulmonar , Humanos , Displasia Broncopulmonar/epidemiologia , Fatores de Risco , Recém-Nascido , China/epidemiologia , Masculino , Feminino , Estudos Retrospectivos , Recém-Nascido Prematuro , Índice de Gravidade de Doença , Idade Gestacional , Lactente Extremamente Prematuro , Estudos de Coortes , Respiração Artificial , Permeabilidade do Canal Arterial/epidemiologia , Recém-Nascido de muito Baixo Peso , População do Leste Asiático
18.
World J Clin Cases ; 12(12): 2040-2049, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38680260

RESUMO

BACKGROUND: This study was designed to investigate the clinical outcomes of enhanced recovery after surgery (ERAS) in the perioperative period in elderly patients with non-small cell lung cancer (NSCLC). AIM: To investigate the potential enhancement of video-assisted thoracic surgery (VATS) in postoperative recovery in elderly patients with NSCLC. METHODS: We retrospectively analysed the clinical data of 85 elderly NSCLC patients who underwent ERAS (the ERAS group) and 327 elderly NSCLC patients who received routine care (the control group) after VATS at the Department of Thoracic Surgery of Peking University Shenzhen Hospital between May 2015 and April 2017. After propensity score matching of baseline data, we analysed the postoperative stay, total hospital expenses, postoperative 48-h pain score, and postoperative complication rate for the 2 groups of patients who underwent lobectomy or sublobar resection. RESULTS: After propensity score matching, ERAS significantly reduced the postoperative hospital stay (6.96 ± 4.16 vs 8.48 ± 4.18 d, P = 0.001) and total hospital expenses (48875.27 ± 18437.5 vs 55497.64 ± 21168.63 CNY, P = 0.014) and improved the satisfaction score (79.8 ± 7.55 vs 77.35 ± 7.72, P = 0.029) relative to those for routine care. No significant between-group difference was observed in postoperative 48-h pain score (4.68 ± 1.69 vs 5.28 ± 2.1, P = 0.090) or postoperative complication rate (21.2% vs 27.1%, P = 0.371). Subgroup analysis showed that ERAS significantly reduced the postoperative hospital stay and total hospital expenses and increased the satisfaction score of patients who underwent lobectomy but not of patients who underwent sublobar resection. CONCLUSION: ERAS effectively reduced the postoperative hospital stay and total hospital expenses and improved the satisfaction score in the perioperative period for elderly NSCLC patients who underwent lobectomy but not for patients who underwent sublobar resection.

19.
Dalton Trans ; 53(17): 7257-7262, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38629404

RESUMO

A reduced polyoxometalate-based organo-metallophosphate (MOPO) framework formulated as [Co4(PO4)(C7H8N4)6](PWVI10WV2O40) (Co-PO4-PW12) with an ultra-high CO production rate of 13 676 µmol g-1 h-1 has been presented through photocatalytic CO2 reduction investigations.

20.
Biol Direct ; 19(1): 29, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38654312

RESUMO

BACKGROUND: Oocyte quality is critical for the mammalian reproduction due to its necessity on fertilization and early development. During aging, the declined oocytes showing with organelle dysfunction and oxidative stress lead to infertility. AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase which is important for energy homeostasis for metabolism. Little is known about the potential relationship between AMPK with oocyte aging. RESULTS: In present study we reported that AMPK was related with low quality of oocytes under post ovulatory aging and the potential mechanism. We showed the altered AMPK level during aging and inhibition of AMPK activity induced mouse oocyte maturation defect. Further analysis indicated that similar with its upstream regulator PKD1, AMPK could reduce ROS level to avoid oxidative stress in oocytes, and this might be due to its regulation on mitochondria function, since loss of AMPK activity induced abnormal distribution, reduced ATP production and mtDNA copy number of mitochondria. Besides, we also found that the ER and Golgi apparatus distribution was aberrant after AMPK inhibition, and enhanced lysosome function was also observed. CONCLUSIONS: Taken together, these data indicated that AMPK is important for the organelle function to reduce oxidative stress during oocyte meiotic maturation.


Assuntos
Proteínas Quinases Ativadas por AMP , Oócitos , Estresse Oxidativo , Animais , Feminino , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Senescência Celular , Mitocôndrias/metabolismo , Oócitos/metabolismo , Organelas/metabolismo , Espécies Reativas de Oxigênio/metabolismo
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