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Children typically experience more mild symptoms of Coronavirus Disease 2019 (COVID-19) when compared to adults. There is a strong body of evidence that children are also less susceptible to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection with the ancestral viral isolate. However, the emergence of SARS-CoV-2 variants of concern (VOCs) has been associated with an increased number of pediatric infections. Whether this is the result of widespread adult vaccination or fundamental changes in the biology of SARS-CoV-2 remain to be determined. Here, we use primary nasal epithelial cells (NECs) from children and adults, differentiated at an air-liquid interface to show that the ancestral SARS-CoV-2 replicates to significantly lower titers in the NECs of children compared to those of adults. This was associated with a heightened antiviral response to SARS-CoV-2 in the NECs of children. Importantly, the Delta variant also replicated to significantly lower titers in the NECs of children. This trend was markedly less pronounced in the case of Omicron. It is also striking to note that, at least in terms of viral RNA, Omicron replicated better in pediatric NECs compared to both Delta and the ancestral virus. Taken together, these data show that the nasal epithelium of children supports lower infection and replication of ancestral SARS-CoV-2, although this may be changing as the virus evolves.
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COVID-19 , SARS-CoV-2 , Adulto , Criança , Células Epiteliais , Humanos , SARS-CoV-2/genéticaRESUMO
BACKGROUND: Acute kidney injury (AKI) is a common clinical disorder with complex etiology and poor prognosis, and currently lacks specific and effective treatment options. Mitochondrial dynamics dysfunction is a prominent feature in AKI, and modulation of mitochondrial morphology may serve as a potential therapeutic approach for AKI. METHODS: We induced ischemia-reperfusion injury (IRI) in mice (bilateral) and Bama pigs (unilateral) by occluding the renal arteries. ATP depletion and recovery (ATP-DR) was performed on proximal renal tubular cells to simulate in vitro IRI. Renal function was evaluated using creatinine and urea nitrogen levels, while renal structural damage was assessed through histopathological staining. The role of Drp1 was investigated using immunoblotting, immunohistochemistry, immunofluorescence, and immunoprecipitation techniques. Mitochondrial morphology was evaluated using confocal microscopy. RESULTS: Renal IRI induced significant mitochondrial fragmentation, accompanied by Dynamin-related protein 1 (Drp1) translocation to the mitochondria and Drp1 phosphorylation at Ser616 in the early stages (30 min after reperfusion), when there was no apparent structural damage to the kidney. The use of the Drp1 inhibitor P110 significantly improved kidney function and structural damage. P110 reduced Drp1 mitochondrial translocation, disrupted the interaction between Drp1 and Fis1, without affecting the binding of Drp1 to other mitochondrial receptors such as MFF and Mid51. High-dose administration had no apparent toxic side effects. Furthermore, ATP-DR induced mitochondrial fission in renal tubular cells, accompanied by a decrease in mitochondrial membrane potential and an increase in the translocation of the pro-apoptotic protein Bax. This process facilitated the release of dsDNA, triggering the activation of the cGAS-STING pathway and promoting inflammation. P110 attenuated mitochondrial fission, suppressed Bax mitochondrial translocation, prevented dsDNA release, and reduced the activation of the cGAS-STING pathway. Furthermore, these protective effects of P110 were also observed renal IRI model in the Bama pig and folic acid-induced nephropathy in mice. CONCLUSIONS: Dysfunction of mitochondrial dynamics mediated by Drp1 contributes to renal IRI. The specific inhibitor of Drp1, P110, demonstrated protective effects in both in vivo and in vitro models of AKI.
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Injúria Renal Aguda , Animais , Camundongos , Suínos , Proteína X Associada a bcl-2 , Dinaminas , Nucleotidiltransferases , Trifosfato de AdenosinaRESUMO
BACKGROUND: The Mitogen-activated protein kinase 1 (MAPK1) has both independent functions of phosphorylating histones as a kinase and directly binding the promoter regions of genes to regulate gene expression as a transcription factor. Previous studies have identified elevated expression of MAPK1 in human gastric cancer, which is associated with its role as a kinase, facilitating the migration and invasion of gastric cancer cells. However, how MAPK1 binds to its target genes as a transcription factor and whether it modulates related gene expressions in gastric cancer remains unclear. RESULTS: Here, we integrated biochemical assays (protein interactions and chromatin immunoprecipitation (ChIP)), cellular analysis assays (cell proliferation and migration), RNA sequencing, ChIP sequencing, and clinical analysis to investigate the potential genomic recognition patterns of MAPK1 in a human gastric adenocarcinoma cell-line (AGS) and to uncover its regulatory effect on gastric cancer progression. We confirmed that MAPK1 promotes AGS cells invasion and migration by regulating the target genes in different directions, up-regulating seven target genes (KRT13, KRT6A, KRT81, MYH15, STARD4, SYTL4, and TMEM267) and down-regulating one gene (FGG). Among them, five genes (FGG, MYH15, STARD4, SYTL4, and TMEM267) were first associated with cancer procession, while the other three (KRT81, KRT6A, and KRT13) have previously been confirmed to be related to cancer metastasis and migration. CONCLUSION: Our data showed that MAPK1 can bind to the promoter regions of these target genes to control their transcription as a bidirectional transcription factor, promoting AGS cell motility and invasion. Our research has expanded the understanding of the regulatory roles of MAPK1, enriched our knowledge of transcription factors, and provided novel candidates for cancer therapeutics.
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MicroRNAs , Neoplasias Gástricas , Humanos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , MicroRNAs/genética , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genéticaRESUMO
BackgroundMeta-analyses and single-site studies have established that children are less infectious than adults within a household when positive for ancestral SARS-CoV-2. In addition, children appear less susceptible to infection when exposed to ancestral SARS-CoV-2 within a household. The emergence of SARS-CoV-2 variants of concern (VOC) has been associated with an increased number of paediatric infections worldwide. However, the role of children in the household transmission of VOC, relative to the ancestral virus, remains unclear.AimWe aimed to evaluate children's role in household transmission of SARS-CoV-2 VOC.MethodsWe perform a meta-analysis of the role of children in household transmission of both ancestral SARS-CoV-2 and SARS-CoV-2 VOC.ResultsUnlike with the ancestral virus, children infected with VOC spread SARS-CoV-2 to an equivalent number of household contacts as infected adults and were equally as likely to acquire SARS-CoV-2 VOC from an infected family member. Interestingly, the same was observed when unvaccinated children exposed to VOC were compared with unvaccinated adults exposed to VOC.ConclusionsThese data suggest that the emergence of VOC was associated with a fundamental shift in the epidemiology of SARS-CoV-2. It is unlikely that this is solely the result of age-dependent differences in vaccination during the VOC period and may instead reflect virus evolution over the course of the pandemic.
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COVID-19 , SARS-CoV-2 , Adulto , Criança , Humanos , COVID-19/epidemiologia , COVID-19/transmissão , Pandemias , SARS-CoV-2/genética , Vacinação , Características da FamíliaRESUMO
OBJECTIVES: To investigate the clinical phenotypes, genetic characteristics, and pathological features of children with disorders of sex development (DSD). METHODS: A retrospective analysis was conducted on epidemiological, clinical phenotype, chromosomal karyotype, gonadal pathology, and genotype data of 165 hospitalized children with DSD at Children's Hospital of Hebei Province and Tangshan Maternal and Child Health Hospital from August 2008 to December 2022. RESULTS: Among the 165 children with DSD, common presenting symptoms were short stature (62/165, 37.6%), clitoromegaly (33/165, 20.0%), cryptorchidism (28/165, 17.0%), hypospadias (24/165, 14.5%), and skin pigmentation abnormalities/exteriorized pigmented labia majora (19/165, 11.5%). Chromosomal karyotype analysis was performed on 127 cases, revealing 36 cases (28.3%) of 46,XX DSD, 34 cases (26.8%) of 46,XY DSD, and 57 cases (44.9%) of sex chromosome abnormalities. Among the sex chromosome abnormal karyotypes, the 45,X karyotype (11/57, 19%) and 45,X/other karyotype mosaicism (36/57, 63%) were more common. Sixteen children underwent histopathological biopsy of gonadal tissues, resulting in retrieval of 25 gonadal tissues. The gonadal tissue biopsies revealed 3 cases of testes, 3 cases of dysplastic testes, 6 cases of ovaries, 11 cases of ovotestes, and 1 case each of streak gonad and agenesis of gonads. Genetic testing identified pathogenic/likely pathogenic variants in 23 cases (23/36, 64%), including 12 cases of 21-hydroxylase deficiency congenital adrenal hyperplasia caused by CYP21A2 pathogenic variants. CONCLUSIONS: Short stature, clitoromegaly, cryptorchidism, hypospadias, and skin pigmentation abnormalities are common phenotypes in children with DSD. 45,X/other karyotype mosaicism and CYP21A2 compound heterozygous variants are major etiological factors in children with DSD. The most commonly observed gonadal histopathology in children with DSD includes ovotestes, ovaries, and testes/dysgenetic testes.
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Hiperplasia Suprarrenal Congênita , Criptorquidismo , Transtornos do Desenvolvimento Sexual , Hipospadia , Masculino , Humanos , Criança , Transtornos do Desenvolvimento Sexual/genética , Transtornos do Desenvolvimento Sexual/diagnóstico , Transtornos do Desenvolvimento Sexual/patologia , Hipospadia/genética , Hipospadia/complicações , Criptorquidismo/complicações , Estudos Retrospectivos , Esteroide 21-HidroxilaseRESUMO
Hanging (aggregation stuck to the centrifugal tube) in the centrifugation process is always regarded as an unwanted condition. In this work, we develop a centrifugation-induced assembly of dense hotspots surface-enhanced Raman scattering (SERS) substrates from the hanging phenomenon. We discovered interesting sintering-resistant behavior (maintain the sharp nanotip features) of star-like Au nanoparticles after centrifugation-induced assembly, which is in stark contrast with the sintering phenomenon of sphere-like nanoparticles. We also found that one side of centrifugal-induced Au assemblies is two-dimensional (2D, root mean square (rms) roughness down to â¼10 nm), while the other is three-dimensional (3D, rms roughness more than 100 nm). The close-packed feature of the Au assemblies makes them candidates as dense hotspots based SERS substrates. Through systematic investigation of SERS performance of centrifugation-induced assemblies with different morphology (star-like and sphere-like, 2D and 3D), it was found that the 3D side of star-like Au nanoparticles assembly exhibits the highest SERS enhancement together with quenched fluorescence. The star-like SERS substrate also displays high detection uniformity (with 10-7M Rhodamine 6G) and a low detection limit (down to 10-12M Rhodamine 6G).
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OBJECTIVE: To investigate the effect of vitamin D/vitamin D receptor (VDR)/Atg16L1 signaling on podocyte autophagy and survival in diabetic nephropathy. METHODS: Diabetic rat models were induced by intraperitoneal injection of streptozotocin (STZ) (60 mg/kg) and treated with and without gavage of 0.1 µg/kg/d active vitamin D3 (aVitD3; 1,25- OH vitamin D3) and kidney tissues assessed by histopathology and immunohistochemistry. The murine podocyte cell line MPC-5 was cultured under hyperglycemic conditions in the absence or presence of 100 nmol/L calcitriol to investigate podocyte injury and autophagy. Cell survival rates were analyzed using Cell Counting Kit-8 (CCK-8) assays and the numbers of autophagosomes were determined after transduction with the mRFP-GFP-LC3 autophagy reporter construct. The expression of autophagy-related proteins (LC3-II, beclin-1, Atg16L1) and podocyte-related proteins (nephrin, podocin, synaptopodin, and desmin) was determined by Western blotting. RESULTS: VDR expression and autophagy were decreased in diabetic nephropathy. Calcitriol treatment repressed renal injury in rat diabetic kidneys and reduced high glucose-induced damage to cultured podocytes. Mechanistically, Atg16L1 was identified as a functional target of VDR, and siRNA-mediated knockdown of VDR and Atg16L1 blocked the protective effects of aVitD3 against podocyte damage. CONCLUSION: Autophagy protects podocytes from damage in DN and is modulated by VitD3/VDR signaling and downstream regulation of Atg16L1 expression.
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Diabetes Mellitus , Nefropatias Diabéticas , Podócitos , Animais , Autofagia , Proteínas Relacionadas à Autofagia/metabolismo , Calcitriol/metabolismo , Calcitriol/farmacologia , Colecalciferol/metabolismo , Colecalciferol/farmacologia , Nefropatias Diabéticas/patologia , Feminino , Humanos , Masculino , Camundongos , Podócitos/patologia , Ratos , Receptores de CalcitriolRESUMO
The role of children in the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains highly controversial. To address this issue, we performed a meta-analysis of the published literature on household SARS-CoV-2 transmission clusters (nâ =â 213 from 12 countries). Only 8 (3.8%) transmission clusters were identified as having a pediatric index case. Asymptomatic index cases were associated with a lower secondary attack in contacts than symptomatic index cases (estimate risk ratio [RR], 0.17; 95% confidence interval [CI], 0.09-0.29). To determine the susceptibility of children to household infections the secondary attack rate in pediatric household contacts was assessed. The secondary attack rate in pediatric household contacts was lower than in adult household contacts (RR, 0.62; 95% CI, 0.42-0.91). These data have important implications for the ongoing management of the COVID-19 pandemic, including potential vaccine prioritization strategies.
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COVID-19 , SARS-CoV-2 , Adulto , Criança , Características da Família , Humanos , Incidência , PandemiasRESUMO
The goal of this study was to compare the microbiota in different pig-present settings in China. Bioaerosol samples from pig farms and slaughterhouses and nasal samples from pig farmers and slaughterhouse workers were collected in Guangdong, southern China. The bacterial genomic DNA was isolated and subjected to 16S sequencing. The data were analyzed using QIIME2 with the DADA2 pipeline. A total of 14,923,551 clean reads and 2785 operational taxonomic units (OTUs) were obtained, which were mostly grouped into 4 phyla (Proteobacteria, Bacteroidetes, Firmicutes, and Actinobacteria) and 220 families. The microbiota richness of nasal samples in pig-present workers was higher than that of bioaerosols collected in the vicinity of the pig enclosures. There were 31.7% (620/1954) shared OTUs between pig farm bioaerosols and pig farmers which was higher than that between pig slaughterhouses and slaughterhouse workers (23.4%, 364/1553) (p < 0.001). Acinetobacter and Pseudomonas were the most abundant in pig-present bioaerosols, and Staphylococcus, Pseudomonas, and Corynebacterium were dominant bacterial genus in pig farmers. The bacterial patterns are also specific to the location of sample collected. The results suggest that bioaerosol microbiota interact with human nasal microbes in the vicinity of the pig farm enclosures, providing the basis for further analysis of microbial transmission across hosts in pig-present settings.
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Matadouros , Microbiota , Animais , China , Fazendas , RNA Ribossômico 16S/genética , SuínosRESUMO
BACKGROUND: To explore whether a polypropylene mesh is suitable for application as a new material for testicular prostheses. METHODS: The data of 65 patients with advanced prostate cancer who underwent surgical castration in hospital were collected and analyzed. Patients who preferred to undergo traditional orchidectomy (n = 16) were assigned to the control group, and patients who underwent subcapsular orchiectomy plus implantation of a polypropylene mesh testicular prosthesis (n = 49) were assigned to the experimental group. The presence of hematoma, infection, and other complications in patients in these two groups were investigated at 3 and 12 months following the surgery. The patients were also followed up using a self-designed testicular castration satisfaction questionnaire. RESULTS: A higher score indicated greater satisfaction. The mean score was 15.33 ± 2.85 in the experimental group and 4.63 ± 1.45 in the control group at 3 months after the surgery. The mean score was 14.92 ± 1.74 in the experimental group and 4.25 ± 1.61 in the control group at 12 months after the surgery. The difference between the two groups was statistically significant at the two time points (P < 0.01). CONCLUSIONS: Compared with orchidectomy alone, patients were more satisfied with subcapsular orchiectomy plus the implantation of a polypropylene mesh testicular prosthesis for the treatment of advanced prostate cancer. Furthermore, the polypropylene mesh testicular prosthesis maintained its original character over the duration of the study, with a good long-term effect. Thus, implantation of a polypropylene mesh testicular prosthesis is indicated to be safe and effective, and polypropylene mesh is potentially useful as a new material for testicular prostheses.
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Neoplasias Ósseas/cirurgia , Orquiectomia/métodos , Polipropilenos/química , Neoplasias da Próstata/cirurgia , Próteses e Implantes , Telas Cirúrgicas , Neoplasias Testiculares/cirurgia , Idoso , Neoplasias Ósseas/secundário , Estudos de Casos e Controles , Seguimentos , Humanos , Masculino , Prognóstico , Neoplasias da Próstata/patologia , Neoplasias Testiculares/patologiaRESUMO
BACKGROUND: Modern agricultural practices create environmental conditions conducive to the emergence of novel pathogens. Current surveillance efforts to assess the burden of emerging pathogens in animal production facilities in China are sparse. In Guangdong Province pig farms, we compared bioaerosol surveillance for influenza A virus to surveillance in oral pig secretions and environmental swab specimens. METHODS: During the 2014 summer and fall/winter seasons, we used 3 sampling techniques to study 5 swine farms weekly for influenza A virus. Samples were molecularly tested for influenza A virus, and positive specimens were further characterized with culture. Risk factors for influenza A virus positivity for each sample type were assessed. RESULTS: Seventy-one of 354 samples (20.1%) were positive for influenza A virus RNA by real-time reverse-transcription polymerase chain reaction analysis. Influenza A virus positivity in bioaerosol samples was a statistically significant predictor for influenza A virus positivity in pig oral secretion and environmental swab samples. Temperature of <20°C was a significant predictor of influenza A virus positivity in bioaerosol samples. DISCUSSIONS: Climatic factors and routine animal husbandry practices may increase the risk of human exposure to aerosolized influenza A viruses in swine farms. Data suggest that bioaerosol sampling in pig barns may be a noninvasive and efficient means to conduct surveillance for novel influenza viruses.
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Aerossóis , Criação de Animais Domésticos , Microbiologia Ambiental , Monitoramento Ambiental , Vírus da Influenza A/isolamento & purificação , Animais , China , Exposição Ambiental , Feminino , Humanos , Masculino , Doenças Profissionais/epidemiologia , Doenças Profissionais/prevenção & controle , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medição de Risco , SuínosRESUMO
BACKGROUND: Patients with diabetes are prone to acute kidney injury (AKI) with a high mortality rate, poor prognosis, and a higher risk of progression to chronic kidney disease than non-diabetic patients. METHODS: Streptozotocin (STZ)-treated type 1 and db/db type 2 diabetes model were established, AKI model was induced in mice by ischemia-reperfusion injury(IRI). Mouse proximal tubular cell cells were subjected to high glucose and hypoxia-reoxygenation in vitro. Transcriptional RNA sequencing was performed for clustering analysis and target gene screening. Renal structural damage was determined by histological staining, whereas creatinine and urea nitrogen levels were used to measure renal function. RESULTS: Deteriorated renal function and renal tissue damage were observed in AKI mice with diabetic background. RNA sequencing showed a decrease in fatty acid oxidation (FAO) pathway and an increase in abnormal glycolysis. Treatment with Dapa, Sitagliptin(a DPP-4 inhibitor)and insulin reduced blood glucose levels in mice, and improved renal function. However, Dapa had a superior therapeutic effect and alleviated aberrant FAO and glycosis. Dapa reduced cellular death in cultured cells under high glucose hypoxia-reoxygenation conditions, alleviated FAO dysfunction, and reduced abnormal glycolysis. RNA sequencing showed that SIRT3 expression was reduced in diabetic IRI, which was largely restored by Dapa intervention. 3-TYP, a SIRT3 inhibitor, reversed the renal protective effects of Dapa and mediated abnormal FAO and glycolysis in mice and tubular cells. CONCLUSION: Our study provides experimental evidence for the use of Dapa as a means to reduce diabetic AKI by ameliorating metabolic reprogramming in renal tubular cells.
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Injúria Renal Aguda , Compostos Benzidrílicos , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Glucosídeos , Reprogramação Metabólica , Insuficiência Renal Crônica , Animais , Masculino , Camundongos , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/patologia , Injúria Renal Aguda/etiologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/patologia , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Reprogramação Metabólica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/patologia , Transdução de Sinais/efeitos dos fármacos , Sirtuína 3/metabolismo , Sirtuína 3/genética , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêuticoRESUMO
Background: Lower respiratory tract infection (LRTI) is a leading cause of infant morbidity and mortality globally. LRTI may be caused by viral or bacterial infections, individually or in combination. We investigated associations between LRTI and infant nasopharyngeal (NP) viruses and bacteria in a South African birth cohort. Methods: In a case-control study of infants enrolled in the Drakenstein Child Health Study (DCHS), LRTI cases were identified prospectively and age-matched with controls from the cohort. NP swabs were tested using quantitative real-time polymerase chain reaction (qPCR) and 16S rRNA gene amplicon sequencing. We calculated adjusted Conditional Odds Ratios (aORs) for qPCR targets and used mixed effects models to identify differentially abundant taxa between LRTI cases and controls and explore viral-bacterial interactions. Results: Respiratory Syncytial Virus (RSV) [aOR: 5.69, 95% CI: 3.03-10.69], human rhinovirus (HRV) [1.47, 1.03-2.09], parainfluenza virus [3.46, 1.64-7.26], adenovirus [1.99, 1.08-3.68], enterovirus [2.32, 1.20-4.46], Haemophilus influenzae [1.72, 1.25-2.37], Klebsiella pneumoniae [2.66, 1.59-4.46], or high-density (> 6.9 log10 copies/mL) Streptococcus pneumoniae [1.53, 1.01-2.32] were associated with LRTI. Using 16S sequencing, LRTI was associated with increased relative abundance of Haemophilus (q = 0.0003) and decreased relative abundance of Dolosigranulum (q = 0.001), Corynebacterium (q = 0.091) and Neisseria (q = 0.004). In samples positive for RSV, Staphylococcus and Alloprevotella were present at lower relative abundance in cases than controls. In samples positive for parainfluenza virus or HRV, Haemophilus was present at higher relative abundance in cases. Conclusions: The associations between bacterial taxa and LRTI are strikingly similar to those identified in high-income countries, suggesting a conserved phenotype. RSV was the major virus associated with LRTI. H. influenzae appears to be the major bacterial driver of LRTI, acting synergistically with viruses. The Gram-positive bacteria Dolosigranulum and Corynebacteria may protect against LRTI, while Staphylococcus was associated with reduced risk of RSV-related LRTI. Funding: National Institutes of Health of the USA, Bill and Melinda Gates Foundation, National Research Foundation South Africa, South African Medical Research Council, L'Oréal-UNESCO For Women in Science South Africa, Australian National Health and Medical Research Council.
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BACKGROUND: Earlier Omicron subvariants including BA.1, BA.2, and BA.5 emerged in waves, with a subvariant replacing the previous one every few months. More recently, the post-BA.2/5 subvariants have acquired convergent substitutions in spike that facilitated their escape from humoral immunity and gained ACE2 binding capacity. However, the intrinsic pathogenicity and replication fitness of the evaluated post-BA.2/5 subvariants are not fully understood. METHODS: We systemically investigated the replication fitness and intrinsic pathogenicity of representative post-BA.2/5 subvariants (BL.1, BQ.1, BQ.1.1, XBB.1, CH.1.1, and XBB.1.5) in weanling (3-4 weeks), adult (8-10 weeks), and aged (10-12 months) mice. In addition, to better model Omicron replication in the human nasal epithelium, we further investigated the replication capacity of the post-BA.2/5 subvariants in human primary nasal epithelial cells. FINDINGS: We found that the evaluated post-BA.2/5 subvariants are consistently attenuated in mouse lungs but not in nasal turbinates when compared with their ancestral subvariants BA.2/5. Further investigations in primary human nasal epithelial cells revealed a gained replication fitness of XBB.1 and XBB.1.5 when compared to BA.2 and BA.5.2. INTERPRETATION: Our study revealed that the post-BA.2/5 subvariants are attenuated in lungs while increased in replication fitness in the nasal epithelium, indicating rapid adaptation of the circulating Omicron subvariants in the human populations. FUNDING: The full list of funding can be found at the Acknowledgements section.
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COVID-19 , SARS-CoV-2 , Adulto , Humanos , Animais , Camundongos , Virulência , Células Epiteliais , Mucosa NasalRESUMO
OBJECTIVE: To investigate the risk factors for hearing impairment in premature infants. METHODS: A total of 895 premature infants who were admitted to the neonatal intensive care unit from January to December 2010 were evaluated using distortion product otoacoustic emission to detect hearing impairment. The failure rates in initial screening and secondary screening were recorded. The risk factors for failure to pass hearing screenings were elucidate using multivariate logistic regression analysis. RESULTS: The failure rate in initial screening was 38.4%, and the failure rate in secondary screening was 18.3%. In the auditory brainstem response test conducted at three months after birth, the failure rate was 22.2%. In premature infants with a gestational age of 28-29(+6) weeks, 60.5% did not pass the initial screening; 48.1% of the premature infants with a birth weight of 1 001-1 499 g failed the initial screening; 70.0% of the premature infants with a birth weight of ≤1 000 g failed the initial screening; 53.8% of the premature infants who had severe asphyxia failed the initial screening; 45.0% of the premature infants who used invasive ventilation failed the initial screening; 47.9% of the premature infants with a total bilirubin of ≥340 µmol/L failed the initial screening; 54.6% of the premature infants with septicemia failed the initial screenings. The multivariate logistic regression analysis revealed the following independent risk factors for failing the initial and secondary hearing screenings: gestational age, birth weight, hyperbilirubinemia and septicemia. CONCLUSIONS: Premature infants are susceptible to hearing impairment because they have immature organs and tissues and incomplete blood-brain barrier function and are sensitive to such factors as hyperbilirubinemia and infection. Early hearing screening and follow-up are necessary for premature infants to ensure timely interventions.
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Perda Auditiva/etiologia , Doenças do Prematuro/etiologia , Potenciais Evocados Auditivos do Tronco Encefálico , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Modelos Logísticos , Masculino , Triagem Neonatal , Fatores de RiscoRESUMO
Renal ischemia/reperfusion injury (IRI) is a significant clinical problem without effective therapy. Unbiased omics approaches may reveal key renal mediators to initiate IRI. S100-A8/A9 was identified as the most significantly upregulated gene and protein base on proteomic analysis and RNA sequencing during the early reperfusion stage. S100-A8/A9 levels were significantly increased 1 day after transplantation in patients with donation after brain death (DBD). S100-A8/A9 production was associated with CD11b+Ly6G+ CXCR2+ immunocytes infiltration. Administration of S100-A8/A9 blocker ABR238901 significantly alleviates renal tubular injury, inflammatory cell infiltration, and renal fibrosis after renal IRI. Mechanistically, S100-A8/A9 could promote renal tubular cell injury and profibrotic cytokine production via TLR4. In conclusion, our findings found that early activation of S100-A8/A9 in renal IRI and targeting S100-A8/A9 signaling alleviates tubular injury and inhibits inflammatory response and renal fibrosis, which may provide a novel target for the prevention and treatment of acute kidney injury.
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Injúria Renal Aguda , Traumatismo por Reperfusão , Humanos , Animais , Camundongos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Proteômica , Rim/patologia , Traumatismo por Reperfusão/metabolismo , Injúria Renal Aguda/patologia , Fibrose , Camundongos Endogâmicos C57BLRESUMO
Radiation Pneumonitis (RP) is one of the most common and severe complication in patients receiving thoracic radiotherapy. The release of cytokines contribute to activating the RP process. Macrophages also play an important role in the pathogenesis of RP. The differential activation of macrophages is regulated by microRNA (miRNA). Exosomes containing miRNAs are one of the important ways to mediate cellular communication. However, the exosomes mediate communication between tumor cells and macrophages during the pathogenesis of RP remains understudied. In this study, we isolated and characterized the exosomes secreted by lung cancer cells after irradiation. Co-culture of exosomes with macrophages revealed that exosomes could induce macrophage proliferation activation and M2 polarization. miRNA array was used to analyze the differential expression of miRNAs in exosomes, and it was found that miR-4655-5p was stably and highly expressed in exosomes. The function of miR-4655-5p in macrophages was confirmed by overexpression/inhibition of miR-4655-5p expression in macrophages. The targeting association between miR-4655-5p and MID1 was determined by bioinformatics prediction followed by a confirmatory dual luciferase reporter assay. We showed that miR-4655-5p regulate the macrophage proliferation and inflammatory response by forming a negative regulatory loop that alters MID1 activity and its downstream PP2Ac. Overall, our results indicated that exosomal miR-4655-5p secreted by lung cancer cells after irradiation promoted the proliferation and M2 polarization of macrophages. It can be speculated that exosomes play an immunomodulatory role in the pathogenesis of RP and provided a new target for the prevention and treatment of RP.
Assuntos
Exossomos , Neoplasias Pulmonares , MicroRNAs , Humanos , Exossomos/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Macrófagos/metabolismo , Comunicação Celular , Neoplasias Pulmonares/patologia , Ubiquitina-Proteína Ligases/metabolismoRESUMO
The mechanism underlying acute kidney injury (AKI) and AKI-to-Chronic kidney disease (CKD) transition remains unclear, but mitochondrial dysfunction may be a key driving factor. Literature reports suggest that dual-specificity phosphatase 1 (DUSP1) plays a critical role in maintaining mitochondrial function and structural integrity. In this study, ischemic Acute Kidney Injury (AKI) and post-ischemic fibrosis models were established by clamping the renal pedicle with different reperfusion times. To investigate the role of DUSP1, constitutional Dusp1 knockout mice and tubular-specific Sting knockout mice were used. Mitochondrial damage was assessed through electron microscopy observation, measurements of mitochondrial membrane potential, mtDNA release, and BAX translocation. We found that Dusp1 expression was significantly upregulated in human transplant kidney tissue and mouse AKI tissue. Dusp1 gene deletion exacerbated acute ischemic injury, post-ischemic renal fibrosis, and tubular mitochondrial dysfunction in mice. Mechanistically, DUSP1 could directly bind to JNK, and DUSP1 deficiency could lead to aberrant phosphorylation of JNK and BAX mitochondria translocation. BAX translocation promoted mitochondrial DNA (mtDNA) leakage and activated the cGAS-STING pathway. Inhibition of JNK or BAX could inhibit mtDNA leakage. Furthermore, STING knockout or JNK inhibition could significantly mitigate the adverse effects of DUSP1 deficiency in ischemic AKI model. Collectively, our findings suggest that DUSP1 is a regulator for the protective response during AKI. DUSP1 protects against AKI by preventing BAX-induced mtDNA leakage and blocking excessive activation of the cGAS-STING signaling axis through JNK dephosphorylation.
Assuntos
Injúria Renal Aguda , Traumatismo por Reperfusão , Animais , Humanos , Camundongos , Injúria Renal Aguda/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Fosfatase 1 de Especificidade Dupla/genética , Fosfatase 1 de Especificidade Dupla/metabolismo , Rim/metabolismo , Camundongos Knockout , Mitocôndrias/metabolismo , Nucleotidiltransferases/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismoRESUMO
Nocardia species do not replicate as rapidly as other pyogenic bacteria and nocardial infections can be highly fatal, particularly in immunocompromised patients. Here, we present the first report of fatal Nocardia kroppenstedtii bacteremic pneumonia and empyema thoracis diagnosed by next-generation sequencing (NGS) using the Oxford Nanopore Technologies' MinION device. The bacterium was not identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Due to its low equipment cost, short turn-around-time, and portable size, the Oxford Nanopore Technologies' MinION device is a useful platform for NGS in routine clinical microbiology laboratories.