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Objective: This study investigates the effects of caloric restriction (CR) on renal injury and fibrosis following ischemia-reperfusion injury (IRI), with a focus on the roles of the mechanistic/mammalian target of rapamycin complex 1 (mTORC1) signaling and autophagy., Methods: A mouse model of unilateral IRI with or without CR was used. Renal function was assessed through serum creatinine and blood urea nitrogen levels, while histological analysis and molecular assays evaluated tubular injury, fibrosis, mTORC1 signaling, and autophagy activation. Inducible renal tubule-specific Atg7 knockout mice and autophagy inhibitor 3-MA were used to elucidate autophagy's role in renal outcomes., Results: CR exacerbated renal dysfunction, tubular injury, and fibrosis in IRI mice, associated with suppressed mTORC1 signaling and enhanced autophagy. Rapamycin, an mTORC1 inhibitor, mimicked the effects of CR, further supporting the involvement of mTORC1-autophagy pathway. Tubule-specific Atg7 knockout and autophagy inhibitor 3-MA mitigated these effects, indicating a central role for autophagy in CR-induced renal damage. Glucose supplementation, but not branched-chain amino acids (BCAAs), alleviated CR-induced renal fibrosis and dysfunction by restoring mTORC1 activation. Finally, we identified leucyl-tRNA synthetase 1 (LARS1) as a key mediator of nutrient sensing and mTORC1 activation, demonstrating its glucose dependency under CR conditions., Conclusion: Our study provides novel insights into the interplay between nutrient metabolism, mTORC1 signaling, and autophagy in IRI-induced renal damages, offering potential therapeutic targets for mitigating CR-associated complications after renal IRI., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Renal ischemia-reperfusion injury (IRI) is a complex pathophysiological process and a major cause of delayed graft function (DGF) after transplantation. MicroRNA (miRNA) has important roles in the pathogenesis of IRI and may represent promising therapeutic targets for mitigating renal IRI. miRNA sequencing was performed to profile microRNA expression in mouse kidneys after cold storage and transplantation (CST). Lentivirus incorporating a miR-199a-5p modulator was injected into mouse kidney in situ before syngenetic transplantation and unilateral IRI to determine the effect of miR-199a-5p in vivo. miR-199a-5p mimic or inhibitor was transfected cultured tubular cells before ATP depletion recovery treatment to examine the role of miR-199a-5p in vitro. Sequencing data and microarray showed upregulation of miR-199a-5p in mice CST and human DGF samples. Lentivirus incorporating a miR-199a-5p mimic aggravated renal IRI, and protective effects were obtained with a miR-199a-5p inhibitor. Treatment with the miR-199a-5p inhibitor ameliorated graft function loss, tubular injury, and immune response after CST. In vitro experiments revealed exacerbation of mitochondria dysfunction upon ATP depletion and repletion model in the presence of the miR-199a-5p mimic, whereas dysfunction was attenuated when the miR-199a-5p inhibitor was applied. miR-199a-5p was shown to target A-kinase anchoring protein 1 (AKAP1) by double luciferase assay and miR-199a-5p activation reduced dynamin-related protein 1 (Drp1)-s637 phosphorylation and mitochondrial length. Overexpression of AKAP1 preserved Drp1-s637 phosphorylation and reduced mitochondrial fission. miR-199a-5p activation reduced AKAP1 expression, promoted Drp1-s637 dephosphorylation, aggravated the disruption of mitochondrial dynamics, and contributed to renal IRI. NEW & NOTEWORTHY This study identifies miR-199a-5p as a key regulator in renal ischemia-reperfusion injury through microRNA sequencing in mouse models and human delayed graft function. miR-199a-5p worsens renal IRI by aggravating graft dysfunction, tubular injury, and immune response, while its inhibition shows protective effects. miR-199a-5p downregulates A-kinase anchoring protein 1 (AKAP1), reducing dynamin-related protein 1 (Drp1)-s637 phosphorylation, increasing mitochondrial fission, and causing dysfunction. Targeting the miR-199a-5p/AKAP1/Drp1 axis offers therapeutic potential for renal IRI, as AKAP1 overexpression preserves mitochondrial integrity by maintaining Drp1-s637 phosphorylation.

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., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier B.V.)

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 log 10 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., Competing Interests: Competing interests The authors declare that they have no competing interests.

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., (© 2024. The Author(s).)

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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

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.

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., (© 2023. The Author(s).)

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., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Importance: Multiple SARS-CoV-2 variants have emerged over the COVID-19 pandemic. The implications for COVID-19 severity in children worldwide are unclear., Objective: To determine whether the dominant circulating SARS-CoV-2 variants of concern (VOCs) were associated with differences in COVID-19 severity among hospitalized children., Design, Setting, and Participants: Clinical data from hospitalized children and adolescents (younger than 18 years) who were SARS-CoV-2 positive were obtained from 9 countries (Australia, Brazil, Italy, Portugal, South Africa, Switzerland, Thailand, UK, and the US) during 3 different time frames. Time frames 1 (T1), 2 (T2), and 3 (T3) were defined to represent periods of dominance by the ancestral virus, pre-Omicron VOCs, and Omicron, respectively. Age groups for analysis were younger than 6 months, 6 months to younger than 5 years, and 5 to younger than 18 years. Children with an incidental positive test result for SARS-CoV-2 were excluded., Exposures: SARS-CoV-2 hospitalization during the stipulated time frame., Main Outcomes and Measures: The severity of disease was assessed by admission to intensive care unit (ICU), the need for ventilatory support, or oxygen therapy., Results: Among 31 785 hospitalized children and adolescents, the median age was 4 (IQR 1-12) years and 16 639 were male (52.3%). In children younger than 5 years, across successive SARS-CoV-2 waves, there was a reduction in ICU admission (T3 vs T1: risk ratio [RR], 0.56; 95% CI, 0.42-0.75 [younger than 6 months]; RR, 0.61, 95% CI; 0.47-0.79 [6 months to younger than 5 years]), but not ventilatory support or oxygen therapy. In contrast, ICU admission (T3 vs T1: RR, 0.39, 95% CI, 0.32-0.48), ventilatory support (T3 vs T1: RR, 0.37; 95% CI, 0.27-0.51), and oxygen therapy (T3 vs T1: RR, 0.47; 95% CI, 0.32-0.70) decreased across SARS-CoV-2 waves in children 5 years to younger than 18 years old. The results were consistent when data were restricted to unvaccinated children., Conclusions and Relevance: This study provides valuable insights into the impact of SARS-CoV-2 VOCs on the severity of COVID-19 in hospitalized children across different age groups and countries, suggesting that while ICU admissions decreased across the pandemic in all age groups, ventilatory and oxygen support generally did not decrease over time in children aged younger than 5 years. These findings highlight the importance of considering different pediatric age groups when assessing disease severity in COVID-19.

Background: Among the Omicron sublineages that have emerged, BA.1, BA.2, BA.5, and their related sublineages have resulted in the largest number of infections. While recent studies demonstrated that all Omicron sublineages robustly escape neutralizing antibody response, it remains unclear on whether these Omicron sublineages share any pattern of evolutionary trajectory on their replication efficiency and intrinsic pathogenicity along the respiratory tract., Methods: We compared the virological features, replication capacity of dominant Omicron sublineages BA.1, BA.2 and BA.5 in the human nasal epithelium, and characterized their pathogenicity in K18-hACE2, A129, young C57BL/6, and aged C57BL/6 mice., Findings: We found that BA.5 replicated most robustly, followed by BA.2 and BA.1, in the differentiated human nasal epithelium. Consistently, BA.5 infection resulted in higher viral gene copies, infectious viral titres and more abundant viral antigen expression in the nasal turbinates of the infected K18-hACE2 transgenic mice. In contrast, the Omicron sublineages are continuously attenuated in lungs of infected K18-hACE2 and C57BL/6 mice, leading to decreased pathogenicity. Nevertheless, lung manifestations remain severe in Omicron sublineages-infected A129 and aged C57BL/6 mice., Interpretation: Our results suggested that the Omicron sublineages might be gaining intrinsic replication fitness in the upper respiratory tract, therefore highlighting the importance of global surveillance of the emergence of hyper-transmissive Omicron sublineages. On the contrary, replication and intrinsic pathogenicity of Omicron is suggested to be further attenuated in the lower respiratory tract. Effective vaccination and other precautions should be in place to prevent severe infections in the immunocompromised populations at risk., Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xing, Xia, Lu, Lo, Lau and Woo.)

Background: Bacteria colonizing the nasopharynx play a key role as gatekeepers of respiratory health. Yet, dynamics of early life nasopharyngeal (NP) bacterial profiles remain understudied in low- and middle-income countries (LMICs), where children have a high prevalence of risk factors for lower respiratory tract infection. We investigated longitudinal changes in NP bacterial profiles, and associated exposures, among healthy infants from low-income households in South Africa., Methods: We used short fragment (V4 region) 16S rRNA gene amplicon sequencing to characterize NP bacterial profiles from 103 infants in a South African birth cohort, at monthly intervals from birth through the first 12 months of life and six monthly thereafter until 30 months., Results: Corynebacterium and Staphylococcus were dominant colonizers at 1 month of life; however, these were rapidly replaced by Moraxella- or Haemophilus-dominated profiles by 4 months. This succession was almost universal and largely independent of a broad range of exposures. Warm weather (summer), lower gestational age, maternal smoking, no day-care attendance, antibiotic exposure, or low height-for-age z score at 12 months were associated with higher alpha and beta diversity. Summer was also associated with higher relative abundances of Staphylococcus, Streptococcus, Neisseria, or anaerobic gram-negative bacteria, whilst spring and winter were associated with higher relative abundances of Haemophilus or Corynebacterium, respectively. Maternal smoking was associated with higher relative abundances of Porphyromonas. Antibiotic therapy (or isoniazid prophylaxis for tuberculosis) was associated with higher relative abundance of anerobic taxa (Porphyromonas, Fusobacterium, and Prevotella) and with lower relative abundances of health associated-taxa Corynebacterium and Dolosigranulum. HIV-exposure was associated with higher relative abundances of Klebsiella or Veillonella and lower relative abundances of an unclassified genus within the family Lachnospiraceae., Conclusions: In this intensively sampled cohort, there was rapid and predictable replacement of early profiles dominated by health-associated Corynebacterium and Dolosigranulum with those dominated by Moraxella and Haemophilus, independent of exposures. Season and antibiotic exposure were key determinants of NP bacterial profiles. Understudied but highly prevalent exposures prevalent in LMICs, including maternal smoking and HIV-exposure, were associated with NP bacterial profiles. Video Abstract., (© 2023. The Author(s).)

Esophageal cancer is a common malignant tumor with a high degree of malignancy. Understanding its pathogenesis and identifying early diagnostic biomarkers can significantly improve the prognosis of esophageal cancer patients. Exosomes are small double-membrane vesicles found in various body fluids containing various components (DNA, RNA, and proteins) that mediate intercellular signal communication. Non-coding RNAs are a class of gene transcription products that encode polypeptide functions and are widely detected in exosomes. There is growing evidence that exosomal non-coding RNAs are involved in cancer growth, metastasis and angiogenesis, and can also be used as diagnostic and prognostic markers. This article reviews the recent progress in exosomal non-coding RNAs in esophageal cancer, including research progress, diagnostic value, proliferation, migration, invasion, and drug resistance, provide new ideas for the precise treatment of esophageal cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Si, Rao, Xia, Sang, Mao, Liu, Zhang and Tang.)

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.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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., Competing Interests: Conflicts of Interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Long-term azithromycin (AZM) treatment reduces the frequency of acute respiratory exacerbation in children and adolescents with HIV-associated chronic lung disease (HCLD). However, the impact of this treatment on the respiratory bacteriome is unknown., Method: African children with HCLD (defined as forced expiratory volume in 1 s z-score (FEV1z) less than - 1.0 with no reversibility) were enrolled in a placebo-controlled trial of once-weekly AZM given for 48-weeks (BREATHE trial). Sputum samples were collected at baseline, 48 weeks (end of treatment) and 72 weeks (6 months post-intervention in participants who reached this timepoint before trial conclusion). Sputum bacterial load and bacteriome profiles were determined using 16S rRNA gene qPCR and V4 region amplicon sequencing, respectively. The primary outcomes were within-participant and within-arm (AZM vs placebo) changes in the sputum bacteriome measured across baseline, 48 weeks and 72 weeks. Associations between clinical or socio-demographic factors and bacteriome profiles were also assessed using linear regression., Results: In total, 347 participants (median age: 15.3 years, interquartile range [12.7-17.7]) were enrolled and randomised to AZM (173) or placebo (174). After 48 weeks, participants in the AZM arm had reduced sputum bacterial load vs placebo arm (16S rRNA copies/µl in log 10 , mean difference and 95% confidence interval [CI] of AZM vs placebo - 0.54 [- 0.71; - 0.36]). Shannon alpha diversity remained stable in the AZM arm but declined in the placebo arm between baseline and 48 weeks (3.03 vs. 2.80, p = 0.04, Wilcoxon paired test). Bacterial community structure changed in the AZM arm at 48 weeks compared with baseline (PERMANOVA test p = 0.003) but resolved at 72 weeks. The relative abundances of genera previously associated with HCLD decreased in the AZM arm at 48 weeks compared with baseline, including Haemophilus (17.9% vs. 25.8%, p < 0.05, ANCOM ω = 32) and Moraxella (1% vs. 1.9%, p < 0.05, ANCOM ω = 47). This reduction was sustained at 72 weeks relative to baseline. Lung function (FEV1z) was negatively associated with bacterial load (coefficient, [CI]: - 0.09 [- 0.16; - 0.02]) and positively associated with Shannon diversity (0.19 [0.12; 0.27]). The relative abundance of Neisseria (coefficient, [standard error]: (2.85, [0.7], q = 0.01), and Haemophilus (- 6.1, [1.2], q < 0.001) were positively and negatively associated with FEV1z, respectively. An increase in the relative abundance of Streptococcus from baseline to 48 weeks was associated with improvement in FEV1z (3.2 [1.11], q = 0.01) whilst an increase in Moraxella was associated with decline in FEV1z (-2.74 [0.74], q = 0.002)., Conclusions: AZM treatment preserved sputum bacterial diversity and reduced the relative abundances of the HCLD-associated genera Haemophilus and Moraxella. These bacteriological effects were associated with improvement in lung function and may account for reduced respiratory exacerbations associated with AZM treatment of children with HCLD. Video Abstract., (© 2023. The Author(s).)

Purpose: Robust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness., Methods: We conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 ( IFI27 ) in COVID-19 patients., Results: We show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression in the lower respiratory tract is associated with the presence of a high viral load. We further demonstrate that the systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 infection. For clinical outcome prediction (e.g., respiratory failure), IFI27 expression displays a high sensitivity (0.95) and specificity (0.83), outperforming other known predictors of COVID-19 outcomes. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For example, in the pandemic H1N1/09 influenza virus infection, IFI27- like genes were highly upregulated in the blood samples of severely infected patients., Conclusion: These data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet-to-be discovered respiratory virus., Competing Interests: FS-F-G is a consultant for Biotheus Inc. KS is a consultant for Sanofi, Roche and NovoNordisk. The opinions and data presented in this manuscript are of the authors and are independent of these relationships. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shojaei, Shamshirian, Monkman, Grice, Tran, Tan, Teo, Rodrigues Rossi, McCulloch, Nalos, Raei, Razavi, Ghasemian, Gheibi, Roozbeh, Sly, Spann, Chew, Zhu, Xia, Wells, Senegaglia, Kuniyoshi, Franck, dos Santos, Noronha, Motamen, Valadan, Amjadi, Gogna, Madan, Alizadeh-Navaei, Lamperti, Zuñiga, Nova-Lamperti, Labarca, Knippenberg, Herwanto, Wang, Phu, Chew, Kwan, Kim, Teoh, Pelaia, Kuan, Jee, Iredell, O’Byrne, Fraser, Davis, Belz, Warkiani, Gallo, Souza-Fonseca-Guimaraes, Nguyen, Mclean, Kulasinghe, Short and Tang.)

In order to explore the influence of different activators on the structure and properties of the prepared activated carbon, bamboo fiber-based activated carbons (BFACs) were prepared by four activators of phosphoric acid, pyrophosphoric acid, zinc chloride, and diammonium biphosphate (BFAC-H 3 PO 4 , BFAC-H 4 P 2 O 7 , BFAC-ZnCl 2 , and BFAC-(NH 4 ) 2 HPO 4 ) and BFACs adsorption performance and electrochemical properties were investigated. The main conclusions were: the specific surface area of the four BFACs varies greatly, among which BFAC-ZnCl 2 was the highest, at 1908.5074 m 2 /g, and BFAC-(NH 4 ) 2 HPO 4 was the lowest, at 641.5941 m 2 /g. In terms of the pore structure, BFAC-H 3 PO 4 and BFAC-H 4 P 2 O 7 are mainly mesopores and BFAC-ZnCl 2 and BFAC-(NH 4 ) 2 HPO 4 are mainly micropores. The BFAC-ZnCl 2 sample had the largest specific capacitance, with a specific capacitance of 121.2730 F/g at a current density of 0.2 A/g, with a small internal resistance and good electrochemical reversibility and capacitance performance. The adsorption properties were better for BFAC-ZnCl 2 and BFAC-H 3 PO 4 and the adsorption amounts were 648.75 and 548.75 mg/g, respectively.

Histone deacetylase (HDAC) 6 exists exclusively in cytoplasm and deacetylates cytoplasmic proteins such as α-tubulin. HDAC6 dysfunction is associated with several pathological conditions in renal disorders, including UUO-induced fibrotic kidneys and rhabdomyolysis-induced nephropathy. However, the role of HDAC6 in ischemic acute kidney injury (AKI) and the mechanism by which HDAC6 inhibition protects tubular cells after AKI remain unclear. In the present study, we observed that HDAC6 was markedly activated in kidneys subjected to ischemia- and cisplatin (cis)-induced AKI treatment. Pharmacological inhibition of HDAC6 alleviated renal impairment and renal tubular damage after ischemia and cisplatin treatment. HDAC6 dysfunction was associated with decreased acetylation of α-tubulin at the residue of lysine 40 and autophagy. HDAC6 inhibition preserved acetyl-α-tubulin-enhanced autophagy flux in AKI and cultured tubular cells. Genetic ablation of the renal tubular (RT) Atg7 gene or pharmacological inhibition of autophagy suppressed the protective effects of HDAC6. Taken together, our study indicates that HDAC6 contributes to ischemia- and cisplatin-induced AKI by inhibiting autophagy and the acetylation of α-tubulin. These results suggest that HDAC6 could be a potential target for ischemic and nephrotoxic AKI.

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.

Background: CircFBXW7 has been determined to be involved in various cancers; however, its role in nonsmall cell lung cancer (NSCLC) remains unclear. This study examined the function and potential mechanism of circFBXW7 in NSCLC., Methods: The structure of circFBXW7 was verified via RT-PCR and Sanger sequencing. The expression of circFBXW7 in NSCLC was determined by qRT-PCR. The effect of circFBXW7 overexpression on the proliferation, migration, and invasion of NSCLC cells was examined by CCK-8 and Transwell assays. Furthermore, a circFBXW7-miRNA network was established to explore their interaction. Predicted miRNA was determined by qRT-PCR. Moreover, the miRNA mimics were synthesized, wherein its effect on proliferation, migration, and invasion of NSCLC cells overexpressed circFBXW7 was assessed., Results: The circularity of circFBXW7 was verified. The expression of circFBXW7 was found to be downregulated in NSCLC cells compared with that in normal human lung epithelial BEAS-2B cells. Overexpression of circFBXW7 reduced cell proliferation, migration, and invasion. Furthermore, according to the circFBXW7-miRNA network prediction and qRT-PCR validation, miR-492 was identified to be the target of circFBXW7. The inhibitory effect of circFBXW7 overexpression on cell proliferation, migration, and invasion was reversed by miR-492 mimics., Conclusion: CircFBXW7 is downregulated in NSCLC. CircFBXW7 inhibits NSCLC cells proliferation, migration, and invasion by regulating miR-492., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Shen-Yu Zhu et al.)

Acute kidney injury (AKI) is a critical and severe clinical disease caused by a variety of factors. Toll-like receptors (TLRs) play a crucial role in pathogenesis of AKI. Radioprotective 105 kDa protein (RP105) is a member of the TLR family, but the role of RP105 in AKI is unknown. In this study, we overexpressed RP105 in renal tissue and cultured proximal tubular cells in which we then induced ischemic and septic AKI. Renal structure injuries were examined by hematoxylin eosin staining, while renal function was assessed by measuring serum blood urea nitrogen (BUN) and creatinine (SCr) levels. The TUNEL assay was used to detect apoptosis induced changes in the expression of RP105, and nuclear factor κB (NF-κB) in renal tissue detected by Western blot. Inflammatory cytokines including iNOS, IL-1β, IL-6, and TNF-α were detected by quantitative real-time PCR. The inflammatory indicators, F4/80 and MPO, were identified by IHC staining. The results showed that expression of the TLR4/NF-kB signaling pathway was enhanced in renal ischemia-reperfusion injury and septic renal injury, and that overexpression of RP105 in renal tissue alleviated ischemic and septic AKI. Moreover, RP105 gene delivery was associated with reduced renal inflammatory cells infiltration and inflammatory cytokines after AKI. RP105 overexpression also inhibited nuclear translocation of NF-κB after AKI in both in vitro and in vivo, and blunted the interaction between Myeloid Differentiation factor 2 (MD2) and TLR4. These results indicated that RP105 protected against renal ischemic and septic AKI injury by suppressing inflammatory responses mediated by TLR4 signaling pathways. This study suggests that the anti-inflammatory roles of RP105 have potential for preventing and treating renal ischemic and septic AKI., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: KRS is a consultant for Sanofi, Roche and NovoNordisk. The opinions and data presented in this manuscript are of the authors and are independent of these relationships.

Lung cancer is one of the most common malignant tumors in China and is the highest cause of mortality among male and female patients, both in urban and rural areas. A subset of patients with lung cancer only display chest tightness without any other obvious symptoms. This is because most symptoms do not manifest during the early stages of disease development. Consequently, most patients with lung cancer are diagnosed when the disease is in the advanced stages, when they are already unfit for surgical treatment. Furthermore, the prognosis of patients with lung cancer is poor. The 5-year survival rate of patients with stage IA lung cancer is 85%, compared with 6% in those with stage IV. This requires the development of strategies for early diagnosis, treatment and prognosis to improve the management of lung cancer. Circular RNAs (circRNAs) belong to a class of closed circular non-coding RNAs formed by reverse splicing of a precursor mRNA. These RNAs are highly stable, ubiquitously expressed, conserved, and show high specificity. CircRNAs regulate biological processes, such as the proliferation, differentiation and invasion of lung cancer cells. Therefore, they can be used as biomarkers for the early diagnosis and prognosis prediction of lung cancer, as well as novel targets for therapy design. In the present review, the biological characteristics and functions of circRNAs, as well as their application in the diagnosis, control of drug resistance and effect on the prognosis of patients with lung cancer, will be discussed., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Sang et al.)

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 ∼10 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 -7 M Rhodamine 6G) and a low detection limit (down to 10 -12 M Rhodamine 6G)., (© 2022 IOP Publishing Ltd.)

The Yersinia outer protein J (YopJ) family effectors are widely deployed through the type III secretion system by both plant and animal pathogens. As non-canonical acetyltransferases, the enzymatic activities of YopJ family effectors are allosterically activated by the eukaryote-specific ligand inositol hexaphosphate (InsP6). However, the underpinning molecular mechanism remains undefined. Here we present the crystal structure of apo-PopP2, a YopJ family member secreted by the plant pathogen Ralstonia solanacearum. Structural comparison of apo-PopP2 with the InsP6-bound PopP2 reveals a substantial conformational readjustment centered in the substrate-binding site. Combining biochemical and computational analyses, we further identify a mechanism by which the association of InsP6 with PopP2 induces an α-helix-to-β-strand transition in the catalytic core, resulting in stabilization of the substrate recognition helix in the target protein binding site. Together, our study uncovers the molecular basis governing InsP6-mediated allosteric regulation of YopJ family acetyltransferases and further expands the paradigm of fold-switching proteins., (© 2021. The Author(s).)

Background: Septic acute kidney injury (AKI) is associated with increased morbidity and mortality in critically ill patients. MicroRNA is reportedly involved in sepsis-induced organ dysfunction, while the role of miR-150 in septic AKI remains ambiguous., Methods: Quantitative real-time PCR (qRT-PCR) was carried out to examine miR-150-5p expression in both septic AKI patients and volunteers without septic AKI. Lipopolysaccharide (LPS) was used to treat renal tubular epithelial cell line HK-2 and C57/BL6 mice to establish in vitro and in vivo sepsis-induced AKI models. Cell apoptosis was determined using TdT-mediated dUTP nick end labeling (TUNEL) staining and flow cytometry. Cell viability was tested using a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Renal pathological changes were examined via Hematoxylin-Eosin (H&E) staining, and renal function was measured via blood urea nitrogen (BUN) and creatinine (Cre) measurements. The MEKK3/JNK profile and oxidative stress markers (including COX2 and iNOS) were examined by immunoblot analysis, and the expression levels of inflammatory cytokines (TNF-α, IL-6, and IL-1β) and oxidative stress markers (MDA, SOD, and CAT) were evaluated by ELISA., Results: MiR-150-5p was down-regulated in the serum of patients with septic AKI (compared to healthy volunteers). Moreover, miR-150-5p levels were lower in LPS-treated HK-2 cell lines and in the septic AKI mouse model. Additionally, Stat-3 activation mediated the decrease of miR-150-5p. Functionally, miR-150-5p agomir attenuated LPS-induced apoptosis in HK-2 cells, in addition to renal inflammatory responses and oxidative stress. In contrast, inhibition of miR-150-5p aggravated LPS-induced apoptosis, inflammatory reactions and oxidative stress. Furthermore, miR-150-5p agomir decreased BUN and Scr levels in the septic AKI mice model repressed TNF-α, IL-6 and IL-1β, and up-regulated SOD and CAT down-regulated MDA in the kidney tissues. Moreover, miR-150-5p was identified as a target gene for Stat3, and the overexpression of Stat3 partially promoted the effect of down-regulating miR-150-5p on LPS-induced HK2 cell injury. Mechanistically, the MEKK3/JNK pathway was identified as a functional target of miR-150-5p, and the knockdown of MEKK3 showed protective effects against LPS mediated HK-2 cell apoptosis., Conclusion: Stat3-mediated miR-150-5p exerted protective effects in sepsis-induced acute kidney injury by regulating the MEKK3/JNK pathway., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Spinosyns are natural broad-spectrum biological insecticides with a double glycosylated polyketide structure that are produced by aerobic fermentation of the actinomycete, Saccharopolyspora spinosa. However, their large-scale overproduction is hindered by poorly understood bottlenecks in optimizing the original strain, and poor adaptability of the heterologous strain to the production of spinosyn. In this study, we genetically engineered heterologous spinosyn-producer Streptomyces albus J1074 and optimized the fermentation to improve the production of spinosad (spinosyn A and spinosyn D) based on our previous work. We systematically investigated the result of overexpressing polyketide synthase genes ( spnA , B , C , D , E ) using a constitutive promoter on the spinosad titer in S. albus J1074. The supply of polyketide synthase precursors was then increased to further improve spinosad production. Finally, increasing or replacing the carbon source of the culture medium resulted in a final spinosad titer of ∼70 mg/L, which is the highest titer of spinosad achieved in heterologous Streptomyces species . This research provides useful strategies for efficient heterologous production of natural products., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Wuhan University have applied patents based on this work., (© 2021 The Authors.)

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 (n = 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., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Wenzhou mammarenavirus (WENV) is a zoonotic pathogen newly discovered in east and southeast Asia. WENV has been found in wild rodent animals around the world while its standing is barely understood in Guangzhou city, where is known as a region of outbreak hotspot for zoonotic emerging infectious diseases. To investigate the prevalence and genomic characteristics of mammarenavirus in Guangzhou City, lung tissue samples from wild rodent species were collected from five districts of Guangzhou City in the year 2015 and 2016. The viral RNA was extracted and then subjected to mammarenavirus-specific PCR. The result revealed approximately 1.0% (3/306) nucleic acid positivity for lung tissue samples obtained from three rodent species: Mus musculus , Rattus flavipectus, and Rattus norvegicus . Viral metagenomic sequencing of three samples was then carried out and two full segment L and three full segment S sequences were obtained. Phylogenetics analysis indicated the sequences of the new mammarenavirus strain have 76.2% - 94.4% similarity to known WENV encoded genes, with the highest similarity to the WENV 9-24 strain. Population structure analysis grouped all known WENV into seven lineages, and this WENV Guangzhou strain was grouped with WENV 9-24 as well. Though the seroprevalence result was not available, our data provides the first nucleic acid evidence of circulating WENV in Guangzhou city, and it suggested WENV had a broader host tropism than previously known., Competing Interests: The authors declare no conflict of interest., (© 2021 Published by Elsevier B.V.)

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.

Lanthipeptides have extensive therapeutic and industrial applications. However, because many are bactericidal, traditional in vivo platforms are limited in their capacity to discover and mass produce novel lanthipeptides as bacterial organisms are often critical components in these systems. Herein, the development of a cell-free protein synthesis (CFPS) platform that enables rapid genome mining, screening, and guided overproduction of lanthipeptides in vivo is described. For proof-of-concept studies, a type I lanthipeptide, nisin, is selected. Four novel lanthipeptides with antibacterial activity are identified among all nisin analogs in the National Center for Biotechnology Information (NCBI) database in a single day. Further, the CFPS platform is coupled with a screening assay for anti-gram-negative bacteria growth, resulting in the identification of a potent nisin mutant, M5. The titers of nisin and the nisin analog are found to be improved with CFPS platform guidance. Owing to the similarities in biosynthesis, the CFPS platform is broadly applicable to other lanthipeptides, thereby providing a universal method for lanthipeptide discovery and overproduction., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.

That both stochastic neutral and deterministic niche forces are in effect in shaping the community assembly and diversity maintenance is becoming an increasingly important consensus. However, assessing the effects of disease on the balance between the two forces in the human microbiome has not been explored to the best of our knowledge. In this article, we applied a hybrid model to address this issue by analyzing the potential effect of HIV infection on the human gut microbiome and adopted a further step of multimodality testing to improve the interpretation of their model. Our study revealed that although niche process is the dominant force in shaping human gut microbial communities, niche process- and neutral process-driven taxa could coexist in the same microbiome, confirming the notion of their joint responsibility. However, we failed to detect the effect of HIV infection in changing the balance. This suggests that the rule governing community assembly and diversity maintenance may be changed by the disturbance from HIV infection-caused dysbiosis. Although we admit that the general question of disease effect on community assembly and diversity maintenance may still be an open question, our study presents the first piece of evidence to reject the significant influence of diseases.

The emergence and spread of antibiotic resistance have become emerging threats to human health. The human gut is a large reservoir for antibiotic resistance genes. The gut resistome may be influenced by many factors, but the consumption of antibiotics at both individual and country level should be one of the most significant factors. Previous studies have suggested that the gut resistome of different populations may vary, but lack quantitative characterization supported with relatively large datasets. In this study, we filled the gap by analyzing a large gut resistome dataset of 1,267 human gut samples of America, China, Denmark, and Spain. We built a stacking machine-learning model to determine whether the gut resistome can act as the sole feature to identify the nationality of an individual reliably. It turned out that the machine learning method could successfully identify American, Chinese, Danish, and Spanish populations with F1 score of 0.964, 0.987, 0.971, and 0.986, respectively. Our finding does highlight the significant differences in the composition of the gut resistome among different nationalities. Our study should be valuable for policy-makers to look into the influences of country-specific factors of the human gut resistome., Competing Interests: The authors declare that they have no competing interests.

Background: Identification of activated epidermal growth factor receptor (EGFR) mutations and application of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have greatly changed the therapeutic strategies of non-small-cell lung cancer (NSCLC). However, the long-term efficacy of EGFR-TKI therapy is limited due to the development of drug resistance. The aim of this study was to investigate the correlation between the aberrant alterations of 8 driver genes and the primary resistance to EGFR-TKIs in advanced NSCLC patients with activated EGFR mutations., Methods: We retrospectively reviewed the clinical data from 416 patients with stage III/IV or recurrent NSCLC who received an initial EGFR-TKI treatment, from April 2004 and March 2011, at the Sun Yat-sen University Cancer Center. Several genetic alterations associated with the efficacy of EGFR-TKIs, including the alterations in BIM, ALK, KRAS, PIK3CA, PTEN, MET, IGF1R, and ROS1, were detected by the routine clinical technologies. The progression-free survival (PFS) and overall survival (OS) were compared between different groups using Kaplan-Meier survival analysis with the log-rank test. A Cox regression model was used to estimate multivariable-adjusted hazard ratios (HRs) and their 95% confidence intervals (95% CIs) associated with the PFS and OS., Results: Among the investigated patients, 169 NSCLC patients harbored EGFR-sensitive mutations. EGFR-mutant patients having PTEN deletion had a shorter PFS and OS than those with intact PTEN (P = 0.003 for PFS, and P = 0.034 for OS). In the combined molecular analysis of EGFR signaling pathway and resistance genes, we found that EGFR-mutant patients coexisted with aberrant alterations in EGFR signaling pathway and those having resistant genes had a statistically poorer PFS than those without such alterations (P < 0.001). A Cox proportional regression model determined that PTEN deletion (HR = 4.29,95% CI = 1.72-10.70) and low PTEN expression (HR = 1.96, 95% CI = 1.22-3.13), MET FISH + (HR = 2.83,95% CI = 1.37-5.86) were independent predictors for PFS in patients with EGFR-TKI treatment after adjustment for multiple factor., Conclusions: We determined that the coexistence of genetic alterations in cancer genes may explain primary resistance to EGFR-TKIs.

Inflammatory bowel disease (IBD) is an immunologically mediated disease and may be caused by abnormal immunological response to gut microbes. Although several studies on the ecological changes associated with IBD, such as community diversities, were reported, no previous studies have investigated the changes in the spatial heterogeneity and the mechanism of community assembly of the gut microbiota associated with IBD. In the present study, we first applied the Taylor's power law extensions to compare the community spatial heterogeneity between the gut microbial communities of the IBD patients and those of the healthy individuals. We found that the community spatial heterogeneity of gut microbiota in IBD patients is slightly lower than in the healthy individuals. This finding suggests that IBD may lower the spatial heterogeneity of gut microbiota, possibly via lowering the abundance of dominant species. We further applied the neutral theory of biodiversity to comparatively investigate the community assembly and diversity maintenance of the gut microbiota with and without IBD, and our application suggested that deterministic factors such as host immunity should be dominant forces shaping gut microbiota assembly, and diseases such as IBD may not be strong enough to change the trend set by the deterministic host factors.

Abnormal levels of guanine closely associated with plenty of diseases are usually used as a biomarker for clinical diagnosis. In order to detect guanine and its derivatives accurately, in this paper, a defective G-quadruplex (DGQ) containing a G-vacancy at one of its G-quartet layers, and two kinds of G-quadruplex specific indicators including thioflavine T (ThT) and hemin were used for constructing a fluorescent and an electrochemical biosensor, respectively. In brief, a G-rich DNA probe is designed to form either hairpin or DGQ structure. In the absence of guanine, G-rich probes prefer to maintain hairpin structure and nearly have no interaction with ThT or hemin, leading to almost negligible signals. Upon addition of guanine, the G-rich probe fold into DGQ structure and then the G-vacancy in it is filled up immediately by guanine via Hoogsteen hydrogen bonds, resulting canonical G-quadruplex formation. Accordingly, ThT or hemin can selectively combine with G-quadruplex, giving rise to distinct fluorescent or current signal changes for label-free detection of guanine. Benefiting from the perfect discriminative ability of guanine towards DGQ and ThT/hemin against standard G-quadruplex, the fluorescent and electrochemical biosensors present better sensitivity and selectivity for guanine detection with the limit of detection (LOD) as low as 18.26 and 0.36 nM, respectively. Successful attempts were also made in applying the proposed electrochemical biosensor to detect guanine in drugs and urine, obtaining satisfactory recovery rates of 99~104% and 96~106%, respectively., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The implications of gut microbiome to obesity have been extensively investigated in recent years although the exact mechanism is still unclear. The question whether or not obesity influences gut microbiome assembly has not been addressed. The question is significant because it is fundamental for investigating the diversity maintenance and stability of gut microbiome, and the latter should hold a key for understanding the etiological implications of gut microbiome to obesity. Methods: In this study, we adopt a dual neutral theory modeling strategy to address this question from both species and community perspectives, with both discrete and continuous neutral theory models. The first neutral theory model we apply is Hubbell's neutral theory of biodiversity that has been extensively tested in macro-ecology of plants and animals, and the second we apply is Sloan's neutral theory model that was developed particularly for microbial communities based on metagenomic sequencing data. Both the neutral models are complementary to each other and integrated together offering a comprehensive approach to more accurately revealing the possible influence of obesity on gut microbiome assembly. This is not only because the focus of both neutral theory models is different (community vs. species), but also because they adopted two different modeling strategies (discrete vs. continuous). Results: We test both the neutral theory models with datasets from Turnbaugh et al. (2009). Our tests showed that the species abundance distributions of more than ½ species (59-69%) in gut microbiome satisfied the prediction of Sloan's neutral theory, although at the community level, the number of communities satisfied the Hubbell's neutral theory was negligible (2 out of 278). Conclusion: The apparently contradictory findings above suggest that both stochastic neutral effects and deterministic environmental (host) factors play important roles in shaping the assembly and diversity of gut microbiome. Furthermore, obesity may just be one of the host factors, but its influence may not be strong enough to tip the balance between stochastic and deterministic forces that shape the community assembly. Finally, the apparent contradiction from both the neutral theories should not be surprising given that there are still near 30-40% species that do not obey the neutral law.

Cystic fibrosis (CF) is a hereditary disease that is characterized by defective mucociliary clearance, airway obstruction, chronic infection, and persistent inflammation. Cystic fibrosis pulmonary exacerbation (CFPE) majorly causes the morbidity of CF patients. Although CF has been demonstrated to change the composition of lung microbial community, previous studies have not made efforts to study the differences in the mechanism of assembly and diversity maintenance of lung microbial community in CF patients. In this study, we applied the neutral theory of biodiversity to comparatively investigate the assembly and diversity maintenance of the lung microbial community before and after the antibiotic treatment by reanalyzing the dataset from Fodor et al's study. We found that no one sample in the lung microbial communities of the sputum samples of Exacerbation group, nor those of End-of-treatment group satisfied the predictions of neutral model, suggesting that the neutral-process does not dominate in CF patients before and after antibiotic treatments. By comparing the biodiversity parameter between Exacerbation and End-of-treatment group, we found that the former had the significantly higher biodiversity, but the change in diversity parameter is slight and the P value is close to.05 (P value = .41). Therefore, our second finding is that although CFPE may increase the biodiversity of lung microbial community, the change is not essential.

Objective: To evaluate the clinical therapeutic effects of excision of invaded sacrospinous ligament on pelvic cavity pain caused by endometriosis., Methods: Eighty endometriotic patients treated in our hospital from January 2013 to December 2014 were chosen, and divided into a control group and an observation group. Regular operation (i.e. excision of endometriotic nidus and separation of pelvic cavity adhesion) was performed for the control group, while regular operation and sacrospinous ligament excision were conducted for the observation group. Intraoperative and postoperative conditions as well as postoperative pain remission of both groups were compared., Results: For the amount of bleeding during operation, the control group was (120±5.2) ml, while the observation group was (160±4.0) ml. For the duration of operation, the control group was (65±3.4) minutes, while the observation group was (92±2.6) min (p<0.05), with a significant difference. For the independent urination time after operation, the control group was (32±8.8) hour, while the observation group was (33±6.4) hour. For the evacuation time after operation, the control group was (38±2.6) hour, while the observation group was (39±3.0) hour (p>0.05), with a significant difference. The postoperative VAS scores of the two groups were significantly lower than those before operation, and the VAS score of the observation group was significantly lower than that of the control group, p<0.05., Conclusions: Sacrospinous ligament excision relieved pain caused by endometriosis, so it may be applicable to the endometriosis patients with sacrospinous ligament infiltration or severe pain., Competing Interests: Conflicts of Interest: None.

Sensitive and selective detection of microRNAs (miRNAs) in cancer cells derived exosomes have attracted rapidly growing interest owing to their potential in diagnostic and prognostic applications. Here, we design a ratiometric electrochemical biosensor based on bipedal DNA walkers for the attomolar detection of exosomal miR-21. In the presence of miR-21, DNA walkers are activated to walk continuously along DNA tracks, resulting in conformational changes as well as considerable increases of the signal ratio produced by target-respond and target-independent reporters. With the signal cascade amplification of DNA walkers, the biosensor exhibits ultrahigh sensitivity with the limit of detection (LOD) down to 67 aM. Furthermore, owing to the background-correcting function of target-independent reporters termed as reference reporters, the biosensor is robust and stable enough to be applied in the detection of exosomal miR-21 extracted from breast cancer cell lines and serums. In addition, because locked nucleic acid (LNA) modified toehold mediate strand displacement reaction (TMSDR) has extraordinary discriminative ability, the biosensor displays excellent selectivity even against the single-base-mismatched target. It is worth mentioning that our sensor is regenerative and stable for at least 5 cycles without diminution in sensitivity. In brief, the high sensitivity, selectivity and reproducibility, together with cheap, make the proposed biosensor a promising approach for exosomal miRNAs detection, in conjunction with early point-of-care testing (POCT) of cancer., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: This study aimed to investigate the spatiotemporal clustering and socio-environmental factors associated with dengue fever (DF) incidence rates at street level in Guangzhou city, China., Methods: Spatiotemporal scan technique was applied to identify the high risk region of DF. Multiple regression model was used to identify the socio-environmental factors associated with DF infection. A Poisson regression model was employed to examine the spatiotemporal patterns in the spread of DF., Results: Spatial clusters of DF were primarily concentrated at the southwest part of Guangzhou city. Age group (65+ years) (Odd Ratio (OR) = 1.49, 95% Confidence Interval (CI) = 1.13 to 2.03), floating population (OR = 1.09, 95% CI = 1.05 to 1.15), low-education (OR = 1.08, 95% CI = 1.01 to 1.16) and non-agriculture (OR = 1.07, 95% CI = 1.03 to 1.11) were associated with DF transmission. Poisson regression results indicated that changes in DF incidence rates were significantly associated with longitude (β = -5.08, P<0.01) and latitude (β = -1.99, P<0.01)., Conclusions: The study demonstrated that social-environmental factors may play an important role in DF transmission in Guangzhou. As geographic range of notified DF has significantly expanded over recent years, an early warning systems based on spatiotemporal model with socio-environmental is urgently needed to improve the effectiveness and efficiency of dengue control and prevention.

Colorectal cancer (CRC) is the third commonest malignant tumor. Previous studies have revealed that the composition change of the human gut microbiome, measured by community diversity, is associated with the progression of CRC. However, a further question, whether or not the mechanism of community assembly and diversity maintenance of the gut microbiome is influenced by CRC has not been addressed. To address this question, we applied Hubbell's neutral theory for biodiversity to reanalyze the dataset from Wang et al.'s (2012) study of the gut microbiome sampled from 46 CRC patients and 56 healthy individuals. Our reanalysis presents two important findings. Firstly, our analysis demonstrated that only around 4% ( 4/102 ) samples (in total of both the CRC and control groups) have their species abundance distribution (SAD) satisfied the prediction of the neutral theory null model. No significant difference in the number of the samples satisfying the neutral null model was detected between the healthy individuals and CRC patients, suggesting that the nature or mechanism of community assembly and diversity maintenance of the gut microbiome is not significantly influenced by CRC. That is, the stochasticity of survival, reproduction and migration of gut microbes, as implied by the neutral theory model, does not play a significant role in shaping the community assembly and diversity maintenance. We further infer that the alternative hypothesis to the neutral null model, i.e., the deterministic niche differentiations should be the driving forces that shape the assembly and diversity maintenance of the gut microbiome in both the healthy individuals and CRC patients. Secondly, although CRC does not seem to influence the nature of community assembly, we postulate that it may indirectly influence the outcome (i.e., the community composition as measured by community diversity) of the community assembly, possibly by influencing niche differentiations. This postulation is supported by our second finding: the diversity of the gut microbiome in CRC patients is significantly lower than that in the healthy individuals as demonstrated by the fundamental diversity parameter ( θ ) of the neutral theory model. This second finding offers an independent confirmation of the relationship between the CRC disease and diversity of the gut microbiome, about which existing studies have presented conflicting evidences. Finally, we suggest that hybrid modeling which integrates both the neutral and niche theories should be explored in future studies to further understanding of the CRC influence on the human gut microbiome., Competing Interests: The authors declare there are no competing interests.