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1.
Nature ; 591(7849): 246-251, 2021 03.
Article in English | MEDLINE | ID: mdl-33692558

ABSTRACT

One challenge for the commercial development of solid oxide fuel cells as efficient energy-conversion devices is thermo-mechanical instability. Large internal-strain gradients caused by the mismatch in thermal expansion behaviour between different fuel cell components are the main cause of this instability, which can lead to cell degradation, delamination or fracture1-4. Here we demonstrate an approach to realizing full thermo-mechanical compatibility between the cathode and other cell components by introducing a thermal-expansion offset. We use reactive sintering to combine a cobalt-based perovskite with high electrochemical activity and large thermal-expansion coefficient with a negative-thermal-expansion material, thus forming a composite electrode with a thermal-expansion behaviour that is well matched to that of the electrolyte. A new interphase is formed because of the limited reaction between the two materials in the composite during the calcination process, which also creates A-site deficiencies in the perovskite. As a result, the composite shows both high activity and excellent stability. The introduction of reactive negative-thermal-expansion components may provide a general strategy for the development of fully compatible and highly active electrodes for solid oxide fuel cells.

2.
PLoS Genet ; 18(7): e1010262, 2022 07.
Article in English | MEDLINE | ID: mdl-35793278

ABSTRACT

Urinary cell-free DNA (ucfDNA) is a potential biomarker for bladder cancer detection. However, the biological characteristics of ucfDNA are not well understood. We explored the roles of deoxyribonuclease 1 (DNASE1) and deoxyribonuclease 1-like 3 (DNASE1L3) in the fragmentation of ucfDNA using mouse models. The deletion of Dnase1 in mice (Dnase1-/-) caused aberrations in ucfDNA fragmentation, including a 24-fold increase in DNA concentration, and a 3-fold enrichment of long DNA molecules, with a relative decrease of fragments with thymine ends and reduction of jaggedness (i.e., the presence of single-stranded protruding ends). In contrast, such changes were not observed in mice with Dnase1l3 deletion (Dnase1l3-/-). These results suggested that DNASE1 was an important nuclease contributing to the ucfDNA fragmentation. Western blot analysis revealed that the concentration of DNASE1 protein was higher in urine than DNASE1L3. The native-polyacrylamide gel electrophoresis zymogram showed that DNASE1 activity in urine was higher than that in plasma. Furthermore, the proportion of ucfDNA fragment ends within DNase I hypersensitive sites (DHSs) was significantly increased in Dnase1-deficient mice. In humans, patients with bladder cancer had lower proportions of ucfDNA fragment ends within the DHSs when compared with participants without bladder cancer. The area under the curve (AUC) for differentiating patients with and without bladder cancer was 0.83, suggesting the analysis of ucfDNA fragmentation in the DHSs may have potential for bladder cancer detection. This work revealed the intrinsic links between the nucleases in urine and ucfDNA fragmentomics.


Subject(s)
Cell-Free Nucleic Acids , Urinary Bladder Neoplasms , Animals , Cell-Free Nucleic Acids/genetics , DNA/genetics , Deoxyribonuclease I/genetics , Deoxyribonuclease I/metabolism , Endodeoxyribonucleases/genetics , Endonucleases , Humans , Mice , Mice, Knockout , Urinary Bladder Neoplasms/genetics
3.
Genome Res ; 31(11): 2008-2021, 2021 11.
Article in English | MEDLINE | ID: mdl-34470801

ABSTRACT

The effects of DNASE1L3 or DNASE1 deficiency on cell-free DNA (cfDNA) methylation were explored in plasma of mice deficient in these nucleases and in DNASE1L3-deficient humans. Compared to wild-type cfDNA, cfDNA in DNASE1L3-deficient mice was significantly hypomethylated, while cfDNA in DNASE1-deficient mice was hypermethylated. The cfDNA hypomethylation in DNASE1L3-deficient mice was due to increased fragmentation and representation from open chromatin regions (OCRs) and CpG islands (CGIs). These findings were absent in DNASE1-deficient mice, demonstrating the preference of DNASE1 to cleave in hypomethylated OCRs and CGIs. We also observed a substantial decrease of fragment ends at methylated CpGs in the absence of DNASE1L3, thereby demonstrating that DNASE1L3 prefers to cleave at methylated CpGs. Furthermore, we found that methylation levels of cfDNA varied by fragment size in a periodic pattern, with cfDNA of specific sizes being more hypomethylated and enriched for OCRs and CGIs. These findings were confirmed in DNASE1L3-deficient human cfDNA. Thus, we have found that nuclease-mediated cfDNA fragmentation markedly affects cfDNA methylation level on a genome-wide scale. This work provides a foundational understanding of the relationship between methylation, nuclease biology, and cfDNA fragmentation.


Subject(s)
Cell-Free Nucleic Acids , DNA Fragmentation , Endodeoxyribonucleases , Animals , Cell-Free Nucleic Acids/genetics , Cell-Free Nucleic Acids/metabolism , Chromatin , CpG Islands/genetics , DNA Methylation , Endodeoxyribonucleases/genetics , Humans , Mice
4.
Small ; 20(28): e2307900, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38334199

ABSTRACT

As a crucial component responsible for the oxygen reduction reaction (ORR), cobalt-rich perovskite-type cathode materials have been extensively investigated in protonic ceramic fuel cell (PCFC). However, their widespread application at a commercial scale is considerably hindered by the high cost and inadequate stability. In response to these weaknesses, the study presents a novel cobalt-free perovskite oxide, Ba0.95La0.05(Fe0.8Zn0.2)0.95O3-δ (BLFZ0.95), with the triple-conducting (H+|O2-|e-) property as an active and robust air electrode for PCFC. The B-site deficiency state contributes significantly to the optimization of crystal and electronic structure, as well as the increase in oxygen vacancy concentration, thus in turn favoring the catalytic capacity. As a result, the as-obtained BLFZ0.95 electrode demonstrates exceptional electrochemical performance at 700 °C, representing extremely low area-specific resistance of 0.04 Ω cm2 in humid air (3 vol.% H2O), extraordinarily high peak power density of 1114 mW cm-2, and improved resistance against CO2 poisoning. Furthermore, the outstanding long-term durability is achieved without visible deterioration in both symmetrical and single cell modes. This study presents a simple but crucial case for rational design of cobalt-free perovskite cathode materials with appreciable performance via B-site deficiency regulation.

5.
Eur Arch Otorhinolaryngol ; 281(3): 1425-1434, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37995006

ABSTRACT

OBJECTIVE: To analyze the interrelation between radiation dose and radiation-induced nasopharyngeal ulcer (RINU) in locoregional recurrent nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). METHODS: Clinical data were collected from 363 patients with locoregional recurrent NPC who received re-irradiated with definitive IMRT from 2009 to 2017. Twenty-nine patients were diagnosed with RINU. Univariate and multivariate analyses were used to re-evaluate the first and second radiotherapy plans and to identify predictive dosimetric factors. RESULTS: All dosimetric parameters were notably associated with the progression to RINU (p < 0.01) using paired samples Wilcoxon signed rank tests. Multivariate analysis showed that EQD2_ [Formula: see text]D80 (dose for 80 percent volume of the unilateral nasopharynx lesion) was an independent prognostic factor for RINU (p = 0.001). The area under the ROC curve for EQD2_ [Formula: see text]D80 was 0.846 (p < 0.001), and the cutoff point of 137.035 Gy could potentially be the dose tolerance of the nasopharyngeal mucosa. CONCLUSIONS: The sum of equivalent dose in 2 Gy fractions (EQD2) in the overlapping volumes between initial and re-irradiated nasopharyngeal mucosal tissue can be effective in predicting the hazard of developing RINU in NPC patients undergoing radical re­irradiation with IMRT and we propose a EQD2_ [Formula: see text]D80 threshold of 137.035 Gy for the nasopharynx.


Subject(s)
Nasopharyngeal Neoplasms , Radiation Injuries , Radiodermatitis , Radiotherapy, Intensity-Modulated , Re-Irradiation , Humans , Nasopharyngeal Carcinoma/radiotherapy , Radiotherapy, Intensity-Modulated/adverse effects , Nasopharyngeal Neoplasms/pathology , Ulcer/etiology , Radiotherapy Dosage , Radiation Injuries/etiology , Retrospective Studies , Nasopharynx/pathology , Radiodermatitis/etiology
6.
Angew Chem Int Ed Engl ; 63(16): e202314796, 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38391058

ABSTRACT

Zinc-air batteries (ZABs) have attracted considerable attention for their high energy density, safety, low noise, and eco-friendliness. However, the capacity of mechanically rechargeable ZABs was limited by the cumbersome procedure for replacing the zinc anode, while electrically rechargeable ZABs suffer from issues including low depth of discharge, zinc dendrite and dead zinc formation, and sluggish oxygen evolution reaction, etc. To address these issues, we report a hybrid redox-mediated zinc-air fuel cell (HRM-ZAFC) utilizing 7,8-dihydroxyphenazine-2-sulfonic acid (DHPS) as the anolyte redox mediator, which shifts the zinc oxidation reaction from the electrode surface to a separate fuel tank. This approach decouples fuel feeding and electricity generation, providing greater operation flexibility and scalability for large-scale power generation applications. The DHPS-mediated ZAFC exhibited a superior peak power density of 0.51 W/cm2 and a continuous discharge capacity of 48.82 Ah with ZnO as the discharge product in the tank, highlighting its potential for power generation.

7.
Am J Respir Cell Mol Biol ; 68(6): 610-624, 2023 06.
Article in English | MEDLINE | ID: mdl-36603194

ABSTRACT

Epidemiological surveys indicate that intrauterine inflammation increases the risk of asthma in offspring. However, the underlying mechanisms remain largely unknown. Previous studies in BALB/c and C57BL/6 mice showed that prenatal exposure to endotoxins prevented allergic airway inflammation in offspring, which is inconsistent with most clinical observations. In this study, we found that prenatal LPS exposure increased airway resistance and total exfoliated cell counts, eosinophils, and IL-4 concentrations in BAL fluid of ovalbumin-sensitized Institute of Cancer Research (ICR) mice. Importantly, long noncoding RNA (lncRNA) NONMMUT033452.2 was upregulated in the lungs of LPS-exposed ICR offspring. Fluorescence in situ hybridization and cytoplasmic and nuclear fraction analyses revealed that this lncRNA was distributed in both the nuclei and cytoplasm of lung and airway epithelial cells, smooth muscle cells, and fibroblasts. Intranasal administration of NONMMUT033452.2 siRNA markedly alleviated allergic airway inflammation in ovalbumin-sensitized ICR mice. In vitro functional experiments demonstrated that overexpression of NONMMUT033452.2 inhibited the proliferation of lung and bronchiolar epithelial cells and promoted oxidative stress. RNA pull-down assays proved that NONMMUT033452.2 could directly bind Eef1D (eukaryotic translation elongation factor 1 delta). Overexpression of NONMMUT033452.2 induced the redistribution of Eef1D and substantially inhibited the expression of its downstream heat shock genes. NONMMUT033452.2 was also involved in the modulation of IL-1, IL-12, and some key molecules related to asthma, including Npr3 (natriuretic peptide receptor 3), Rac1 (Rac family small GTPase 1), and Nr4a3 (nuclear receptor subfamily 4, group A, member 3). Furthermore, the human lncRNA NONHSAT078603.2 was identified as a functional homolog of NONMMUT033452.2. These findings provide new insight into the pathogenic mechanism underlying asthma development.


Subject(s)
Asthma , RNA, Long Noncoding , Pregnancy , Female , Animals , Humans , Mice , Lipopolysaccharides , Ovalbumin , Peptide Elongation Factor 1/metabolism , In Situ Hybridization, Fluorescence , Protein Binding , RNA, Long Noncoding/genetics , Mice, Inbred C57BL , Asthma/chemically induced , Asthma/genetics , Asthma/metabolism , Inflammation/pathology , Lung/pathology , Mice, Inbred BALB C , Disease Models, Animal , Bronchoalveolar Lavage Fluid , Cytokines/metabolism
8.
Am J Hum Genet ; 106(2): 202-214, 2020 02 06.
Article in English | MEDLINE | ID: mdl-32004449

ABSTRACT

Cell-free DNA (cf.DNA) is a powerful noninvasive biomarker for cancer and prenatal testing, and it circulates in plasma as short fragments. To elucidate the biology of cf.DNA fragmentation, we explored the roles of deoxyribonuclease 1 (DNASE1), deoxyribonuclease 1 like 3 (DNASE1L3), and DNA fragmentation factor subunit beta (DFFB) with mice deficient in each of these nucleases. By analyzing the ends of cf.DNA fragments in each type of nuclease-deficient mice with those in wild-type mice, we show that each nuclease has a specific cutting preference that reveals the stepwise process of cf.DNA fragmentation. Essentially, we demonstrate that cf.DNA is generated first intracellularly with DFFB, intracellular DNASE1L3, and other nucleases. Then, cf.DNA fragmentation continues extracellularly with circulating DNASE1L3 and DNASE1. With the use of heparin to disrupt the nucleosomal structure, we also show that the 10 bp periodicity originates from the cutting of DNA within an intact nucleosomal structure. Altogether, this work establishes a model of cf.DNA fragmentation.


Subject(s)
Cell-Free Nucleic Acids/metabolism , Chromatin/metabolism , DNA Fragmentation , Deoxyribonuclease I/physiology , Deoxyribonucleases/physiology , Endodeoxyribonucleases/physiology , Nucleosomes/metabolism , Poly-ADP-Ribose Binding Proteins/physiology , Animals , Cell-Free Nucleic Acids/genetics , Chromatin/genetics , Female , Male , Mice , Mice, Knockout , Nucleosomes/genetics
9.
Am J Hum Genet ; 107(5): 882-894, 2020 11 05.
Article in English | MEDLINE | ID: mdl-33022220

ABSTRACT

Plasma DNA fragmentomics is an emerging area in cell-free DNA diagnostics and research. In murine models, it has been shown that the extracellular DNase, DNASE1L3, plays a role in the fragmentation of plasma DNA. In humans, DNASE1L3 deficiency causes familial monogenic systemic lupus erythematosus with childhood onset and anti-dsDNA reactivity. In this study, we found that human patients with DNASE1L3 disease-associated gene variations showed aberrations in size and a reduction of a "CC" end motif of plasma DNA. Furthermore, we demonstrated that DNA from DNASE1L3-digested cell nuclei showed a median length of 153 bp with CC motif frequencies resembling plasma DNA from healthy individuals. Adeno-associated virus-based transduction of Dnase1l3 into Dnase1l3-deficient mice restored the end motif profiles to those seen in the plasma DNA of wild-type mice. Our findings demonstrate that DNASE1L3 is an important player in the fragmentation of plasma DNA, which appears to act in a cell-extrinsic manner to regulate plasma DNA size and motif frequency.


Subject(s)
DNA/genetics , Endodeoxyribonucleases/genetics , Lupus Erythematosus, Systemic/genetics , Mutation , Animals , Case-Control Studies , DNA/blood , DNA Fragmentation , Dependovirus/genetics , Dependovirus/metabolism , Disease Models, Animal , Endodeoxyribonucleases/deficiency , Endodeoxyribonucleases/metabolism , Genetic Therapy , Genetic Vectors/chemistry , Genetic Vectors/metabolism , Humans , Lupus Erythematosus, Systemic/enzymology , Lupus Erythematosus, Systemic/pathology , Mice , Mice, Transgenic , Substrate Specificity , Transduction, Genetic
10.
Reprod Biomed Online ; 46(6): 983-994, 2023 06.
Article in English | MEDLINE | ID: mdl-37068978

ABSTRACT

RESEARCH QUESTION: Is ART associated with adverse neurodevelopmental outcome in 12-month-old offspring compared with those conceived through natural conception? DESIGN: In this prospective cohort study, 488 infertile women undergoing ART and 1397 women with natural conception were recruited and followed until their offspring were 12 months old. The primary outcome was the neurodevelopment in the offspring. The association between exposure to ART and Gesell developmental scale scores was investigated using multiple linear regression models after adjusting for confounders. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to verify the results. RESULTS: In total, 18 (3.7%) and 40 (2.9%) children in the ART and natural conception groups, respectively, had been diagnosed with neurodevelopmental delay at 12 months of age. It was found that gross motor, adaptive behaviour, language and total development quotient scores were comparable between the groups. Following multivariate linear regression and IPTW, social behaviour development quotient scores were found to be slightly higher in the ART group than the natural conception group. Higher social behaviour development quotient scores in the ART group were also observed in the male and the singleton subgroups. CONCLUSIONS: At 12 months, offspring born after ART appeared to have similar motor, language and adaptive behaviour skills, and total development quotient scores, to those born after natural conception. However, social behaviour development in 12-month-old infants was slightly higher in those conceived using ART than in naturally conceived offspring, especially in male or singleton infants. These findings may provide new information in evaluating the potential benefits and risks of ART.


Subject(s)
Infertility, Female , Child , Infant , Humans , Male , Female , Prospective Studies , Cohort Studies , Infertility, Female/etiology , Reproductive Techniques, Assisted/adverse effects , Fertilization
11.
J Neurooncol ; 161(1): 97-105, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36520380

ABSTRACT

PURPOSE: This study aims to investigate the spatial distribution difference of brain metastases (BM) between small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) and to identify the metastatic risk in brain regions. METHODS: T1-enhanced MR images of 2997 BM from 728 eligible patients with SCLC and NSCLC were retrospectively reviewed by three independent medical institutions in China. All images were spatially normalised according to the Montreal Neurological Institute space, following BM delineation confirmed by three senior radiologists. The brain regions in the normalised images were identified based on the merged Anatomical Automatic Labeling atlas, and all BM locations were mapped onto these brain regions. Two-tailed proportional hypothesis testing was used to compare the BM observed rate with the expected rate based on the region's volume, and metastatic risk regions were finally identified. RESULTS: In SCLC and NSCLC, BM was mainly present in the deep white matter (22.51% and 17.96%, respectively), cerebellar hemisphere (9.84% and 7.46%, respectively) and middle frontal gyrus (6.72% and 7.97%, respectively). The cerebellar hemisphere was a high-risk brain region in the SCLC. The precentral gyrus, middle frontal gyrus, paracentral lobule and cerebellar hemisphere were high-risk BM in the NSCLC. The inferior frontal gyrus and the temporal pole were a low-risk brain region in the SCLC and NSCLC, respectively. CONCLUSION: The spatial BM distribution between SCLC and NSCLC is similar. Several critical brain regions had relatively low BM frequency in both SCLC and NSCLC, where a low-dose radiation distribution can be delivered due to adequate preoperative evaluations.


Subject(s)
Brain Neoplasms , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Retrospective Studies , Small Cell Lung Carcinoma/diagnostic imaging , Brain Neoplasms/surgery
12.
BMC Pregnancy Childbirth ; 23(1): 369, 2023 May 20.
Article in English | MEDLINE | ID: mdl-37210503

ABSTRACT

BACKGROUND: Chorioamnionitis (CAM) is a common risk factor for preterm births, resulting in several adverse outcomes. The association between infertility treatment and CAM is unclear. Therefore, this study examined the association between infertility treatment and CAM and described subsequent neonatal outcomes. METHODS: This population-based cohort study used data from the National Vital Statistics System Database. We included women who had a singleton live birth from January 1, 2016 to December 31, 2018. Women-infant pairs were stratified by infertility treatment, and the main outcome was a reported diagnosis of CAM in a checkbox format: clinical CAM or maternal temperature of > 38 °C. Multivariate logistic regression was used to examine the association between infertility treatment and CAM and the effect of infertility treatment on neonatal outcomes in women diagnosed with CAM. RESULTS: The final sample comprised 10,900,495 woman-infant pairs, and 1.4% received infertility treatment. Compared with the natural conception group, women receiving infertility treatment had a significantly higher risk of CAM (adjusted odds ratio [aOR] 1.772 [95% confidence interval {CI}, 1.718-1.827]). Furthermore, newborns exposed to CAM had a higher risk of very low birth weight (VLBW) (aOR, 2.083 [95% CI, 1.664-2.606], P < .001), preterm birth (aOR, 1.497 [95% CI, 1.324-1.693]; P < .001), neonatal intensive care unit admission (aOR, 1.234 [95% CI, 1.156-1.317]; P < .001), and other adverse neonatal outcomes in the infertility treatment group compared with ones conceived naturally. CONCLUSIONS: This study found that women who received infertility treatment had a higher risk of CAM. And CAM deteriorated neonatal outcomes in the infertility treatment group.


Subject(s)
Chorioamnionitis , Infertility , Premature Birth , Pregnancy , Infant, Newborn , Humans , Female , Premature Birth/epidemiology , Premature Birth/etiology , Chorioamnionitis/epidemiology , Cohort Studies , Infertility/therapy , Live Birth/epidemiology
13.
Small ; 18(7): e2105887, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34889520

ABSTRACT

Zn-air batteries (ZABs) are very promising for flexible energy storage, but their application is limited to the primary battery. Developing an efficient and non-noble metal cathode toward oxygen reduction/evolution reactions (ORR/OER) is of great significance for the commercial application of rechargeable ZABs. Herein, a flexible self-supported integrated bifunctional cathode is presented in which the Co-N-C nanoparticles are in situ anchored on Co4 N nanosheets via a facile and scalable strategy. Benefiting from integrated 3D architecture with adequate active sites, porous structure, high conductivity originating from the metal substrate, and the synergistic effects of Co-N-C and Co4 N, the cathode exhibits excellent bifunctional activity (low overpotential of 275 mV at 10 mA cm-2 for OER, high half-wave potential of 0.833 V for ORR), and ultralong durability for ORR/OER in the alkaline medium. Impressively, this cathode enables the recyclable aqueous ZABs a record overall lifespan over 10 000 cycles at 20 mA cm-2 , and a superior fast-charging feature at an ultrahigh charging current density of 100 mA cm-2 . Furthermore, such a flexible integrated cathode can be directly used as a self-supported cathode for flexible solid-state ZABs, with excellent reversibility for 300 cycles, demonstrating its feasibility for practical application.

14.
Small ; 18(40): e2203207, 2022 Oct.
Article in English | MEDLINE | ID: mdl-36057991

ABSTRACT

Triple ionic and electronic conductivity (TIEC) in cathode materials for protonic ceramic fuel cells (PCFCs) is a desirable feature that enhances the spatial expansion of active reaction sites for electrochemical oxygen reduction reaction. The realization of optimal TIEC in single-phase materials, however, is challenging. A facile route that facilitates the optimization of TIEC in PCFC cathodes is the strategic development of multiphase cathode materials. In this study, a cubic-rhombohedral TIEC nanocomposite material with the composition Ba(CeCo)0.4 (FeZr)0.1 O3- δ (BCCFZ) is designed via self-assembly engineering. The material consists of a mixed ionic and electronic conducting phase, BaCo1-( x + y + z ) Cex Fey Zrz O3- δ (M-BCCFZ), and a dominant proton-conducting phase, BaCe1-( x + y + z ) Cox Zry Fez O3- δ (H-BCCZF). The dominant cerium-rich H-BCCFZ phase enhances the material's oxygen vacancy concentration and the proton defects formation and transport with a low enthalpy of protonation of -30 ± 9 kJ mol-1 . The area-specific resistance of the BCCFZ symmetrical cell is 0.089 Ω cm2 at 650 °C in 2.5% H2 O-air. The peak power density of the anode-supported single cell based on BCCFZ cathode reaches 1054 mW cm-2 at 650 °C with good operation stability spanning over 500 h at 550 °C. These promote BCCFZ as a befitting cathode material geared toward PCFC commercialization.

15.
Brain ; 144(5): 1422-1434, 2021 06 22.
Article in English | MEDLINE | ID: mdl-33970200

ABSTRACT

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.


Subject(s)
Oxygenases/genetics , Spastic Paraplegia, Hereditary/genetics , Animals , Female , Humans , Male , Mice , Mutation , Pedigree , Rats , Zebrafish
16.
Eur J Nutr ; 61(2): 915-924, 2022 Mar.
Article in English | MEDLINE | ID: mdl-34657185

ABSTRACT

PURPOSE: To evaluate the effects of the association between first trimester vitamin D (VitD) concentrations and increased prepregnancy body mass index (BMI) on early fetal growth restriction (FGR). METHODS: This retrospective cohort study included 15,651 women with singleton pregnancy who delivered at the International Peace Maternity and Child Health Hospital between January 2015 and November 2016. Women were classified in two groups based on their serum 25(OH)D vitamin levels status: VitD sufficient (SUFF) group and VitD insufficient or deficient (INSUFF/DEF). The cut-off point for VitD concentration was 50.00 nmol/L. Comparisons were made between women with normal prepregnancy body weight (BMI 18.5-23.9 kg/m2) and overweight and obese (OWO) women (BMI > 24.0 kg/m2). Early FGR was defined as first-trimester gestational age-adjusted crown-rump length (CRL) in the lowest 20th centile of the population. Multivariate logistic regression was used to evaluate the association between maternal serum 25(OH)D levels and prepregnancy BMI with first trimester CRL and early FGR. RESULTS: In VitD INSUFF/DEF group, the first trimester CRL was decreased (P = 0.005), and the risk of early FGR was increased by 13% (95% CI 1.04-1.24, P = 0.004) compared to the VitD SUFF group. In OWO group, the first trimester CRL was also significantly decreased (P < 0.0001), and the risk of early FGR was significantly increased by 58% (95% CI 1.40-1.78, P < 0.001) compared with normal weight group. Furthermore, there was a significant combined effect of maternal VitD concentrations and OWO on CRL (P for interaction = 0.02) and the risk of early FGR (P for interaction = 0.07). CONCLUSION: Sufficient first trimester serum 25(OH)D concentration was a protective factor for early fetal growth, especially among OWO mothers. Chinese Clinical Trial Registry (Registration number: ChiCTR1900027447 with date of registration on November 13, 2019-retrospectively registered).


Subject(s)
Obesity, Maternal , Vitamin D , Child , Female , Fetal Development , Fetal Growth Retardation/epidemiology , Humans , Pregnancy , Retrospective Studies , Vitamins
17.
BMC Psychiatry ; 22(1): 278, 2022 04 20.
Article in English | MEDLINE | ID: mdl-35443643

ABSTRACT

BACKGROUND: Depression and sarcopenia are common diseases in the elderly population. However, the association between them is controversial. Based on the Chinese Longitudinal Healthy Longevity Survey (CLHLS) database, a cross-sectional study was conducted to explore the relationship of calf circumference and physical performance with depression. METHODS: From the 8th wave of CLHLS conducted in 2018, data on calf circumference, physical performance, depressive symptoms, and demographic, socioeconomic, and health-related characteristics were collected. Multiple logistic regression was conducted to explore the impact of calf circumference, physical performance and their combination on depressive symptoms. RESULTS: We enrolled a total of 12,227 participants aged 83.4 ± 11.0 years, including 5689 (46.5%) men and 6538 (53.5%) women. Patients with depression were more likely to have low calf circumference (2274 [68.2%] vs. 5406 [60.8%], p<0.001) and poor physical performance (3[0, 6] vs. 1[0, 4], p<0.001). A significant multiplicative interaction was found between calf circumference and physical performance in their effect on depression. After adjusting for confounding factors, multiple logistic regression showed that a significant inverse correlation persisted between physical performance and depressive symptoms in normal (odds ratio [OR] = 1.20, 95% confidence interval [CI]: 1.15-1.26, p<0.001) and low (OR = 1.14, 95% CI: 1.11-1.18, p<0.001) calf circumference group, while the association between calf circumference and depression disappeared. Participants with low calf circumference and poor physical performance were 2.21 times more likely to have depression than those with normal calf circumference and physical performance. All results were found to be robust in sensitivity analyses. CONCLUSIONS: Physical performance was significantly associated with depression in the elderly Chinese population. Attention should be paid to assess depressive symptoms in patients with poor physical performance.


Subject(s)
Depression , Sarcopenia , Aged , China/epidemiology , Cross-Sectional Studies , Depression/epidemiology , Female , Humans , Male , Physical Functional Performance , Sarcopenia/diagnosis , Sarcopenia/epidemiology
18.
BMC Pediatr ; 22(1): 386, 2022 07 01.
Article in English | MEDLINE | ID: mdl-35778680

ABSTRACT

BACKGROUND: To investigate the association of crown-rump length (CRL) during the first trimester of pregnancy with neonatal outcomes. METHODS: A total of 15,524 women with a reliable first day of the last menstrual period and a regular menstrual cycle (28 ± 4 days) were included from January 2015 to November 2016. CRL was measured by ultrasound from 7+0 to 13+6 weeks during pregnancy and transformed to a standard deviation score (SDS) adjusted for gestational age. Linear regression was used to explore risk factors for CRL. A generalised linear model was used to evaluate the association between CRL and neonatal outcomes. RESULTS: In the multivariate analysis, maternal age (0.25 mm, 95% CI = [0.22-0.28], P < 0.001; 0.04 SDS, 95% CI = [0.03-0.04], P < 0.001), multipara (0.30 mm, 95% CI = [0.08-0.52], P = 0.007; 0.04 SDS, 95% CI = [0.00-0.07], P = 0.031) and folic acid supplement use (0.78 mm, 95% CI = [0.49-1.08], P < 0.001; 0.05 SDS, 95% CI = [0.01-0.10], P < 0.019) were positively associated with CRL, while pre-pregnancy BMI (-0.17 mm, 95% CI = [-0.21 to -0.13], P < 0.001; -0.02 SDS, 95% CI = [-0.03 to -0.02], P < 0.001) was negatively related to CRL. For neonatal outcomes, CRL was negatively associated with small for gestational age (SGA) ([risk ratio] (RR) = 0.733, 95% [CI] = 0.673-0.8004, Padjusted < 0.001) and neonatal intensive care unit (NICU) admission ([RR] = 0.928, 95% [CI] = 0.883-0.976, Padjusted = 0.003), and preterm birth ([RR] = 1.082, 95% [CI] = 1.008-1.162, Padjusted = 0.029), but positively related to large for gestational age (LGA) ([RR] = 1.241, 95% [CI] = 1.184-1.301, Padjusted = 0.012). When stratified by pre-pregnancy BMI, the risk of SGA and LGA remained significant in all groups, while the increased risk of preterm birth was only observed in the lean group (BMI < 18.5 kg/m2) and decreased risk of NICU admission rate in the normal group (BMI 18.5-24 kg/m2). CONCLUSIONS: Maternal characteristics were independently associated with CRL in the first trimester, which was negatively related to foetal size, SGA, preterm birth, and admission rate to the NICU, but positively related to LGA.


Subject(s)
Premature Birth , Crown-Rump Length , Female , Fetal Growth Retardation , Humans , Infant, Newborn , Infant, Small for Gestational Age , Pregnancy , Pregnancy Trimester, First , Premature Birth/etiology , Risk Factors
19.
Proc Natl Acad Sci U S A ; 116(2): 641-649, 2019 01 08.
Article in English | MEDLINE | ID: mdl-30593563

ABSTRACT

Circulating DNA in plasma consists of short DNA fragments. The biological processes generating such fragments are not well understood. DNASE1L3 is a secreted DNASE1-like nuclease capable of digesting DNA in chromatin, and its absence causes anti-DNA responses and autoimmunity in humans and mice. We found that the deletion of Dnase1l3 in mice resulted in aberrations in the fragmentation of plasma DNA. Such aberrations included an increase in short DNA molecules below 120 bp, which was positively correlated with anti-DNA antibody levels. We also observed an increase in long, multinucleosomal DNA molecules and decreased frequencies of the most common end motifs found in plasma DNA. These aberrations were independent of anti-DNA response, suggesting that they represented a primary effect of DNASE1L3 loss. Pregnant Dnase1l3-/- mice carrying Dnase1l3+/- fetuses showed a partial restoration of normal frequencies of plasma DNA end motifs, suggesting that DNASE1L3 from Dnase1l3-proficient fetuses could enter maternal systemic circulation and affect both fetal and maternal DNA fragmentation in a systemic as well as local manner. However, the observed shortening of circulating fetal DNA relative to maternal DNA was not affected by the deletion of Dnase1l3 Collectively, our findings demonstrate that DNASE1L3 plays a role in circulating plasma DNA homeostasis by enhancing fragmentation and influencing end-motif frequencies. These results support a distinct role of DNASE1L3 as a regulator of the physical form and availability of cell-free DNA and may have important implications for the mechanism whereby this enzyme prevents autoimmunity.


Subject(s)
Cell-Free Nucleic Acids/blood , DNA Fragmentation , DNA/blood , Endodeoxyribonucleases/metabolism , Nucleotide Motifs , Animals , Cell-Free Nucleic Acids/genetics , DNA/genetics , Endodeoxyribonucleases/genetics , Female , Fetus/metabolism , Gene Deletion , Mice , Mice, Knockout , Pregnancy
20.
Small ; 17(2): e2006638, 2021 Jan.
Article in English | MEDLINE | ID: mdl-33325635

ABSTRACT

Developing robust and highly efficient electrocatalysts for oxygen evolution reaction (OER) is critical for renewable, secure, and emission-free energy technologies. Perovskite Ba0.5 Sr0.5 Co0.8 Fe0.2 O3-δ (BSCF) has emerged as a promising OER electrocatalyst with desirable intrinsic activity. Inspired by the factor that substituting in transition-metal sublattice of the perovskite can further optimize the OER activity, herein, nickel-substituted BSCF is adopted, that is, Ba0.5 Sr0.5 Co0.8- x Fe0.2 Nix O3-δ (x = 0.05, 0.1, 0.2, denoted as BSCFNx, x = 5, 10, 20, respectively), as efficient and stable OER catalysts in alkaline solution. The phase structure, microchemistry, oxygen vacancy, and electrochemical activity of such samples are well-investigated. Endowed with an overpotential of only 278 mV at 10 mA cm-2 and a Tafel slope of merely 47.98 mV dec-1 , BSCFN20 exhibits the optimum OER activity. When constructing a two-electrode cell with BSCFN20 as anode and Pt/C as cathode (BSCFN20||Pt/C) for water splitting, it only requires a voltage of 1.63 V to achieve 50 mA cm-2 , and the BSCFN20||Pt/C remains stable within 80 h at 10 mA cm-2 , superior to the state-of-the-art RuO2 ||Pt/C counterpart. This work provides a feasible strategy for designing stable and highly active perovskite electrocatalysts for future energy storage and conversion.

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