Elevated Membrane Potential as a Tetracycline Resistance Mechanism in Escherichia coli.

The metabolic environment is responsible for antibiotic resistance, which highlights the way in which the antibiotic resistance mechanism works. Here, GC-MS-based metabolomics with iTRAQ-based proteomics was used to characterize a metabolic state in tetracycline-resistant Escherichia coli K12 (E. coli-RTET) compared with tetracycline-sensitive E. coli K12. The repressed pyruvate cycle against the elevation of the proton motive force (PMF) and ATP constructed the most characteristic feature as a consequence of tetracycline resistance. To understand the role of the elevated PMF in tetracycline resistance, PMF inhibitor carbonyl cyanide 3-chlorophenylhydrazone (CCCP) and the pH gradient were used to investigate how the elevation influences bacterial viability and intracellular antibiotic concentration. A strong synergy was detected between CCCP and tetracycline to the viability, which was consistent with increasing intracellular drug and decreasing external pH. Furthermore, E. coli-RTET and E. coli-RGEN with high and low PMF concentrations were susceptible to gentamicin and tetracycline, respectively. The elevated PMF in E. coli-RTET was attributed to the activation of other metabolic pathways, except for the pyruvate cycle, including a malate-oxaloacetate-phosphoenolpyruvate-pyruvate-malate cycle. These results not only revealed a PMF-dependent mechanism for tetracycline resistance but also provided a solution to tetracycline-resistant pathogens by aminoglycosides and aminoglycoside-resistant bacteria by tetracyclines.

Personality traits predict treatment outcome of an antidepressant in untreated adolescents with depression: An 8-week, open-label, flexible-dose study.

BACKGROUND: Antidepressant response in adults with major depressive disorder (MDD) is probably influenced by personality dimensions. However, personality dimensions in depression and their association with antidepressant treatment in adolescents are relatively unknown. We sought to investigate whether personality traits (PTs) can influence antidepressant treatment response in adolescents with depression. METHODS: Eighty-two adolescents with MDD who had completed the 8 weeks of treatment with selective serotonin reuptake inhibitors (SSRI) were enrolled. The Revised NEO Five-Factor Inventory (NEO-FFI-R) was used to measure their personality at baseline, and the 17-item Hamilton Depression Rating Scale (HAMD-17) and Children's Depression Rating Scale-Revised (CDRS-R) were used to evaluate depressive symptoms at baseline and 8 weeks. Moreover, logistic regression was performed to investigate the relationship between personality dimensions and antidepressant response. Receiver operating characteristic analyses were employed to determine the accuracy of a PT-based model in predicting the antidepressant response rate. RESULTS: Adolescents with MDD had significantly different PTs at baseline. Multivariable logistic regression analysis showed that extroversion scores were associated with response to antidepressant treatment, the lower the extroversion score, the better the response to antidepressant treatment, after correcting for variables with significant differences and trends or all potential confounding variables. It was also found that the combination of disease duration, extraversion-gregariousness, and agreeableness-trust effectively predicted antidepressant response in adolescents with MDD, with a sensitivity of 79.4 % and specificity of 68.7 %. CONCLUSION: Personality dysfunction in adolescents is associated with MDD. The antidepressant treatment response is influenced by the degree of extroversion in adolescents with MDD.

Elevated proton motive force is a tetracycline resistance mechanism that leads to the sensitivity to gentamicin in Edwardsiella tarda.

Tetracycline is a commonly used human and veterinary antibiotic that is mostly discharged into environment and thereby tetracycline-resistant bacteria are widely isolated. To combat these resistant bacteria, further understanding for tetracycline resistance mechanisms is needed. Here, GC-MS based untargeted metabolomics with biochemistry and molecular biology techniques was used to explore tetracycline resistance mechanisms of Edwardsiella tarda. Tetracycline-resistant E. tarda (LTB4-RTET ) exhibited a globally repressed metabolism against elevated proton motive force (PMF) as the most characteristic feature. The elevated PMF contributed to the resistance, which was supported by the three results: (i) viability was decreased with increasing PMF inhibitor carbonylcyanide-3-chlorophenylhydrazone; (ii) survival is related to PMF regulated by pH; (iii) LTB4-RTET were sensitive to gentamicin, an antibiotic that is dependent upon PMF to kill bacteria. Meanwhile, gentamicin-resistant E. tarda with low PMF are sensitive to tetracycline is also demonstrated. These results together indicate that the combination of tetracycline with gentamycin will effectively kill both gentamycin and tetracycline resistant bacteria. Therefore, the present study reveals a PMF-enhanced tetracycline resistance mechanism in LTB4-RTET and provides an effective approach to combat resistant bacteria.

Exogenous pyruvate promotes gentamicin uptake to kill antibiotic-resistant Vibrio alginolyticus.

OBJECTIVES: Elucidating antibiotic resistance mechanisms is necessary for developing novel therapeutic strategies. The increasing incidence of antibiotic-resistant Vibrio alginolyticus infection threatens both human health and aquaculture, but the mechanism has not been fully elucidated. METHODS: Here, an isobaric tags for relative and absolute quantification (iTRAQ) functional proteomics analysis was performed on gentamicin-resistant V. alginolyticus (VA-RGEN) and a gentamicin-sensitive strain in order to characterize the global protein expression changes upon gentamicin resistance. Then, the bacterial killing assay and bacterial gentamicin pharmacokinetics were performed. RESULTS: Proteomics analysis demonstrated a global metabolic downshift in VA-RGEN, where the pyruvate cycle (the P cycle) was severely compromised. Exogenous pyruvate restored the P cycle activity, disrupting the redox state and increasing the membrane potential. It thereby potentiated gentamicin-mediated killing by approximately 3000- and 150-fold in vitro and in vivo, respectively. More importantly, bacterial gentamicin pharmacokinetics indicated that pyruvate enhanced gentamicin influx to a degree that exceeded the gentamicin expelled by the bacteria, increasing the intracellular gentamicin. CONCLUSION: Thus, our study suggests a metabolism-based approach to combating gentamicin-resistant V. algonolyticus, which paves the way for combating other types of antibiotic-resistant bacterial pathogens.

A glucose-mediated antibiotic resistance metabolic flux from glycolysis, the pyruvate cycle, and glutamate metabolism to purine metabolism.

Introduction: Bacterial metabolic environment influences antibiotic killing efficacy. Thus, a full understanding for the metabolic resistance mechanisms is especially important to combat antibiotic-resistant bacteria. Methods: Isobaric tags for relative and absolute quantification-based proteomics approach was employed to compare proteomes between ceftazidime-resistant and -sensitive Edwarsiella tarda LTB4 (LTB4-RCAZ and LTB4-S, respectively). Results: This analysis suggested the possibility that the ceftazidime resistance mediated by depressed glucose is implemented through an inefficient metabolic flux from glycolysis, the pyruvate cycle, glutamate metabolism to purine metabolism. The inefficient flux was demonstrated by the reduced expression of genes and the decreased activity of enzymes in the four metabolic pathways. However, supplement upstream glucose and downstream guanosine separately restored ceftazidime killing, which not only supports the conclusion that the inefficient metabolic flux is responsible for the resistance, but also provides an effective approach to reverse the resistance. In addition, the present study showed that ceftazidime is bound to pts promoter in E. tarda. Discussion: Our study highlights the way in fully understanding metabolic resistance mechanisms and establishing metabolites-based metabolic reprogramming to combat antibiotic resistance.

Aspartate metabolic flux promotes nitric oxide to eliminate both antibiotic-sensitive and -resistant Edwardsiella tarda in zebrafish.

Introduction: Metabolic reprogramming potentiates host protection against antibiotic-sensitive or -resistant bacteria. However, it remains unclear whether a single reprogramming metabolite is effective enough to combat both antibiotic-sensitive and -resistant bacteria. This knowledge is key for implementing an antibiotic-free approach. Methods: The reprogramming metabolome approach was adopted to characterize the metabolic state of zebrafish infected with tetracycline-sensitive and -resistant Edwardsiella tarda and to identify overlapping depressed metabolite in dying zebrafish as a reprogramming metabolite. Results: Aspartate was identify overlapping depressed metabolite in dying zebrafish as a reprogramming metabolite. Exogenous aspartate protects zebrafish against infection caused by tetracycline-sensitive and -resistant E. tarda. Mechanistically, exogenous aspartate promotes nitric oxide (NO) biosynthesis. NO is a well-documented factor of promoting innate immunity against bacteria, but whether it can play a role in eliminating both tetracycline-sensitive and -resistant E. tarda is unknown. Thus, in this study, aspartate was replaced with sodium nitroprusside to provide NO, which led to similar aspartate-induced protection against tetracycline-sensitive and -resistant E. tarda. Discussion: These findings support the conclusion that aspartate plays an important protective role through NO against both types of E. tarda. Importantly, we found that tetracycline-sensitive and -resistant E. tarda are sensitive to NO. Therefore, aspartate is an effective reprogramming metabolite that allows implementation of an antibiotic-free approach against bacterial pathogens.

Analysis of Lysine Acetylation and Acetylation-like Acylation In Vitro and In Vivo.

Protein lysine acetylation refers to the covalent transfer of an acetyl moiety from acetyl coenzyme A to the epsilon-amino group of a lysine residue and is critical for regulating protein functions in almost all living cells or organisms. Studies in the past decade have demonstrated the unexpected finding that acetylation-like acylation, such as succinylation, propionylation, butyrylation, crotonylation, and lactylation, is also present in histones and many non-histone proteins. Acetylation and acetylation-like acylation serve as reversible on/off switches for regulating protein function while interplaying with other post-translational modifications (such as phosphorylation and methylation) in a codified manner. Lysine acetylation and acetylation-like acylation are important for regulating different cellular and developmental processes in normal and pathological states. Thus, the detection of such modifications is important for related basic research and molecular diagnostics. Traditionally, lysine acetylation is detected by autoradiography, but recent decades have seen great improvement in the quality of site-specific antibodies against acetylation (or acetylation-like acylation), thereby providing competitive alternatives to the use of radioactive acetate and acetyl-coenzyme A for in vivo and in vitro labeling, respectively. This article describes protocols for the detection of lysine acetylation and acetylation-like acylation with site-specific antibodies to complement extant autoradiography-based methods (Pelletier et al., 2017). © 2023 Wiley Periodicals LLC. Basic Protocol 1: Acylation assays in vitro Basic Protocol 2: Determination of in vivo acylation.

[Effect of Sertraline on Serum Cytokine Levels in Adolescents With First-Episode Major Depressive Disorder].

Objective: To investigate the changes in serum inflammatory cytokines and the predictive factors for the efficacy of sertraline following medication therapy in adolescents with first-episode major depressive disorder (MDD). Methods: A total of 61 adolescent patients with first-episode drug-naïve MDD were enrolled for the MDD group and 55 healthy adolescents were enrolled for the healthy control (HC) group. Sertraline tablets were administered to the MDD group for 8 weeks after enrollment, while no medication was given to the HC group. In the MDD group, blood samples were collected to measure the cytokine levels and clinical data, including scores for the 17-item Hamilton Depression Scale (HAMD-17) and the Connor-Davidson Resilience Scale (CD-RISC), were assessed at baseline and at the end of the 8-week medication, whereas in the HC group, blood samples and clinical data were collected only at baseline. The correlation between the levels of serum inflammatory cytokines and depression severity in the MDD group was analyzed and stepwise linear regression of HAMD-17 in the MDD group was performed to find serologic indicators that could be used to predict the efficacy of sertraline. Results: At baseline, the levels of interleukin (IL)-1ß and IL-6 in the MDD group were significantly higher than those in the HC group (all P<0.0001), while the tumor necrosis factor (TNF)-α level in the MDD group was significantly lower than that in the HC group ( P=0.006). After 8 weeks of medication treatment, the MDD group showed decreased levels of IL-1ß and IL-6 and increased level of TNF-α compared to the pre-treatment levels. In addition, the HAMD-17 score, CD-RISC total score, and scores for perceived competence, trust and tolerance, and control, three factors of CD-RISC, all improved after treatment. There was no significant difference in serum cytokine levels at baseline between the subgroup showing response to the treatment and the non-responding subgroup. There was a weak correlation between IL-6 levels before and after treatment and CD-RISC scores and the scores for the trust and tolerance factor of CD-RISC before and after treatment. The baseline IL-1ß and TNF-α levels did not show significant effect on posttreatment HAMD-17 scores. Conclusions: Serum cytokine levels of adolescents with first-episode MDD differ significantly from those of healthy adolescents. Although IL-6 was found to be correlated with depression severity, there was not enough support for it to be used as a predictor of the antidepression efficacy of sertraline.

[Sequencing Analysis of miRNAs in Brain-Derived Exosomes of Adolescent Mice With Depression-Like Behaviors].

Objective: To explore the differential expression of microRNAs (miRNAs) in brain-derived exosomes (BDEs) of adolescent mice with depression-like behavior. Methods: The experimental group consisted of susceptible adolescent mice exposed to chronic social defeat stress (CSDS), and sucrose preference test (SPT) and open field test (OFT) were performed to evaluate their depression-like behaviors. BDEs were extracted by ultracentrifugation (UC). The morphology, particle size, and surface marker proteins of BDEs were examined by transmission electron microscopy, nano-flow cytometry and Western blot. The expression of miRNA in BDEs was evaluated by high-throughput RNA sequencing. GO enrichment analysis and KEGG pathway enrichment analysis were carried out based on bioinformatics. Results: The particle size of BDEs ranged between 50 to 100 nm and they displayed a typical disc-shaped vesicle structure. TSG101 and syntenin, the exosome-positive proteins, were detected. In the BDEs of mice with depression-like behaviors induced by CSDS, 13 miRNAs were significantly upregulated and 4 miRNAs were significantly downregulated. Go and KEGG analysis showed that differentially expressed miRNAs were significantly enriched in PI3K-Akt signaling pathway, axonal guidance, and hypoxic response. Conclusion: It was found in this study that exosomal miRNAs in brain tissue might be involved in such biological processes as insulin resistance, neuroplasticity, and hypoxic response, thereby regulating brain functions and causing depression-like behaviors.

Regulation of Gamma-Aminobutyric Acid Transaminase Expression and Its Clinical Significance in Hepatocellular Carcinoma.

Background: Gamma-aminobutyric acid transaminase (ABAT) catalyzes the conversion of gamma-aminobutyric acid (GABA) into succinic semialdehyde. Although some evidence supports a key role of ABAT in the progression of hepatocellular carcinoma (HCC), no systematic analysis is available. Thus, this study aimed to investigate the possible mechanisms related to low ABAT expression and the prognostic value and potential functions of ABAT in HCC. Methods: We obtained relevant datasets from the Encyclopedia of RNA Interactomes, MethSurv, cBioPortal, TISIDB and The Cancer Genome Atlas and used bioinformatic methods to analyze DNA methylation, copy number variation, gene mutation, and upstream microRNAs (miRNAs) of ABAT, exploring the potential relationship between ABAT expression and the prognosis, glycolysis, and immune infiltration in HCC. Results: The results indicated that ABAT expression was lower in HCC tumor tissues than in normal tissues or adjacent tissues. Low ABAT expression was related to patient age, T stage classification, pathologic stage, histological grade, and alpha-fetoprotein level of HCC. Kaplan-Meier survival analyses indicated that low ABAT expression was correlated with poor HCC prognosis. ABAT was also verified as an independent risk factor in HCC via Cox multivariate analysis. Gene set enrichment analysis showed enrichment in various signaling pathways. Furthermore, DNA methylation, copy number variation, and gene mutation potentially induced low ABAT expression; miR-135a-5p was a potential upstream miRNA of ABAT. Additionally, ABAT expression was associated with glycolysis-related genes, infiltrated immune cells, immunoinhibitors, and immunostimulators in HCC. Conclusions: Our study reveals that deficient ABAT expression is correlated with disease progression and poor prognosis in HCC because of its role in tumorigenesis and tumor immunity.

Serum extracellular vesicle microRNA dysregulation and childhood trauma in adolescents with major depressive disorder.

Major depressive disorder (MDD) seriously endangers adolescent mental and physical health. Extracellular vesicles (EVs) are mediators of cellular communication and are involved in many physiological brain processes. Although EV miRNAshave been implicated in adults with major psychiatric disorders, investigation into their effects in adolescent MDDremains scarce. In discovery set, we conducted a genome-wide miRNA sequencing of serum EVs from 9 untreated adolescents with MDD and 8 matched healthy controls (HCs), identifying 32 differentially expressed miRNAs (18 upregulated and 14 downregulated). In the validation set, 8 differentially expressed and highly enriched miRNAs were verified in independent samples using RT-PCR, with 4 (miR-450a-2-3p, miR-3691-5p, miR-556-3p, and miR-2115-3p) of the 8 miRNAs found to be significantly elevated in 34 untreated adolescents with MDD compared with 38 HCs and consistent with the sequencing results. After the Bonferroni correction, we found that three miRNAs (miR-450a-2-3p, miR-556-3p, and miR-2115-3p) were still significantly different. Among them, miR-450a-2-3p showed the most markeddifferential expression and was able to diagnose disease with 67.6% sensitivity and 84.2% specificity. Furthermore, miR-450a-2-3p partially mediated the associations between total childhood trauma, emotional abuse, and physical neglect and adolescent MDD. We also found that the combination of miR-450a-2-3p and emotional abuse could effectively diagnose MDD in adolescents with 82.4% sensitivity and 81.6% specificity. Our data demonstrate the association of serum EV miRNA dysregulation with MDD pathophysiology and, furthermore, show that miRNAs may mediate the relationship between early stress and MDD susceptibility. We also provide a valid integrated model for the diagnosis of adolescent MDD.

ISOC1 is a novel potential tumor suppressor in hepatocellular carcinoma.

Isochorismatase domain-containing 1 (ISOC1) plays a carcinogenic role in various tumors. However, its expression and role in hepatocellular carcinoma (HCC) have not been elucidated. This is the first study to investigate the involvement of ISOC1 in HCC growth and migration. ISOC1 expression was analyzed using public databases and clinical samples, and clinical specimens were analyzed by real-time quantitative polymerase chain reaction, western blotting, and immunohistochemistry. ISOC1 was also overexpressed in two HCC cell lines (Huh7 and HepG2) to explore how ISOC1 affects HCC cells. Finally, a nude mouse xenograft tumor model was used to investigate the role of ISOC1 in HCC cell tumorigenicity. ISOC1 was downregulated in HCC tissues compared to that in matched paracancerous tissues, and low ISOC1 expression was associated with a poor prognosis. The proliferation and single-cell colony-forming ability of the ISOC1-overexpressing cell lines Huh7 and HepG2 were significantly inhibited. Moreover, ISOC1 overexpression suppressed the migration and invasion abilities of HCC cells in vitro, and ISOC1 upregulation hindered tumor growth in the xenograft tumor model in vivo. Therefore, ISOC1 is a potential HCC suppressor protein.

Simultaneously Enhanced Thermal Conductivity and Breakdown Performance of Micro/Nano-BN Co-Doped Epoxy Composites.

Micro/nano- BN co-doped epoxy composites were prepared and their thermal conductivity, breakdown strength at power frequency and voltage endurance time under high frequency bipolar square wave voltage were investigated. The thermal conductivity and breakdown performance were enhanced simultaneously in the composite with a loading concentration of 20 wt% BN at a micro/nano proportion of 95/5. The breakdown strength of 132 kV/mm at power frequency, the thermal conductivity of 0.81 W·m-1·K-1 and voltage endurance time of 166 s were obtained in the composites, which were approximately 28%, 286% and 349% higher than that of pristine epoxy resin. It is proposed that thermal conductive pathways are mainly constructed by micro-BN, leading to improved thermal conductivity and voltage endurance time. A model was introduced to illustrate the enhancement of the breakdown strength. The epoxy composites with high thermal conductivity and excellent breakdown performance could be feasible for insulating materials in high-frequency devices.

Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder.

Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex, SIN3A variants cause syndromic intellectual disability, but the clinical consequences of SIN3B haploinsufficiency in humans are uncharacterized. Here, we describe a syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spectrum disorder, congenital malformations, corpus callosum defects, and impaired growth caused by disruptive SIN3B variants. Using chromosomal microarray or exome sequencing, and through international data sharing efforts, we identified nine individuals with heterozygous SIN3B deletion or single-nucleotide variants. Five individuals harbor heterozygous deletions encompassing SIN3B that reside within a ∼230 kb minimal region of overlap on 19p13.11, two individuals have a rare nonsynonymous substitution, and two individuals have a single-nucleotide deletion that results in a frameshift and predicted premature termination codon. To test the relevance of SIN3B impairment to measurable aspects of the human phenotype, we disrupted the orthologous zebrafish locus by genome editing and transient suppression. The mutant and morphant larvae display altered craniofacial patterning, commissural axon defects, and reduced body length supportive of an essential role for Sin3 function in growth and patterning of anterior structures. To investigate further the molecular consequences of SIN3B variants, we quantified genome-wide enhancer and promoter activity states by using H3K27ac ChIP-seq. We show that, similar to SIN3A mutations, SIN3B disruption causes hyperacetylation of a subset of enhancers and promoters in peripheral blood mononuclear cells. Together, these data demonstrate that SIN3B haploinsufficiency leads to a hitherto unknown intellectual disability/autism syndrome, uncover a crucial role of SIN3B in the central nervous system, and define the epigenetic landscape associated with Sin3 complex impairment.

Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.

Histone deacetylases play crucial roles in the regulation of chromatin structure and gene expression in the eukaryotic cell, and disruption of their activity causes a wide range of developmental disorders in humans. Loss-of-function alleles of HDAC4, a founding member of the class IIa deacetylases, have been reported in brachydactyly-mental retardation syndrome (BDMR). However, while disruption of HDAC4 activity and deregulation of its downstream targets may contribute to the BDMR phenotype, loss of HDAC4 function usually occurs as part of larger deletions of chromosome 2q37; BDMR is also known as chromosome 2q37 deletion syndrome, and the precise role of HDAC4 within the phenotype remains uncertain. Thus, identification of missense variants should shed new light on the role of HDAC4 in normal development. Here, we report seven unrelated individuals with a phenotype distinct from that of BDMR, all of whom have heterozygous de novo missense variants that affect a major regulatory site of HDAC4, required for signal-dependent 14-3-3 binding and nucleocytoplasmic shuttling. Two individuals possess variants altering Thr244 or Glu247, whereas the remaining five all carry variants altering Pro248, a key residue for 14-3-3 binding. We propose that the variants in all seven individuals impair 14-3-3 binding (as confirmed for the first two variants by immunoprecipitation assays), thereby identifying deregulation of HDAC4 as a pathological mechanism in a previously uncharacterized developmental disorder.

Effect of Air Gap on Electrical Tree in Epoxy Resin Under High Frequency Bipolar Square-Wave Voltage.

Insulation fails quickly under high-frequency AC high voltage, especially bipolar square-wave voltage with a high dV/dt. It is of great significance to study the failure mechanism of epoxy casting insulation under such kind of voltage. In this paper, pin-plane epoxy casting insulation samples with air gaps were prepared, and the relation between the electrical trees under the high frequency bipolar square-wave voltage and the air gap conditions and voltage frequencies (1~20 kHz) were studied. Results indicated that, with the presence of air gaps, the electrical trees were bush-type and had a relatively slow growth rate, which was different from the fast-growing branch-type trees in the samples without air gap. The electrical tree characteristics related with the size of air gap and voltage frequency were also studied. The electrical tree grew faster under higher voltage frequency or with a smaller air gap. Results proved that discharge introduced a lot of defects for the surface layer of the epoxy resin samples and hence induced the possibility of multi-directional expansion of electrical trees. In addition, the resulting heat accumulation and unique charge transport synergistically affected the electrical tree characteristics under the high frequency bipolar square-wave voltage.

Prophylaxis of ibuprofen in acute mountain sickness: A protocol for systematic review and meta-analysis.

BACKGROUND: Acute mountain sickness (AMS) is the effect when people accessing high altitude in a short period of time. As a cyclooxygenase (COX) inhibitor, ibuprofen could alleviate the symptoms of AMS. However, whether it can prevent AMS or not is still controversial. It is necessary to perform a meta-analysis to evaluate the role of ibuprofen in AMS prophylaxis. METHODS: PubMed, EMBASE, Medline, ISI Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI) will be searched for the relevant published studies that explored the value of ibuprofen in AMS prophylaxis from inception to October 2020. The data will be independently extracted by 2 researchers. Risk of bias will be evaluated based on Cochrane risk of bias assessment tool. Heterogeneity among the included studies will be evaluated by χ and I values. The meta-analysis was conducted by RevMan software version 5.3. RESULTS: This study will evaluate the role of ibuprofen in AMS prophylaxis. CONCLUSION: This study will summarize the current evidence of ibuprofen in AMS prophylaxis, which could further guide the recommendation in prevention of AMS.Open Science Framework (OSF) registration number: October 8, 2020. osf.io/n3mjt.

De Novo KAT5 Variants Cause a Syndrome with Recognizable Facial Dysmorphisms, Cerebellar Atrophy, Sleep Disturbance, and Epilepsy.

KAT5 encodes an essential lysine acetyltransferase, previously called TIP60, which is involved in regulating gene expression, DNA repair, chromatin remodeling, apoptosis, and cell proliferation; but it remains unclear whether variants in this gene cause a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with one at the chromodomain (p.Arg53His) and two at or near the acetyl-CoA binding site (p.Cys369Ser and p.Ser413Ala). All three individuals have cerebral malformations, seizures, global developmental delay or intellectual disability, and severe sleep disturbance. Progressive cerebellar atrophy was also noted. Histone acetylation assays with purified variant KAT5 demonstrated that the variants decrease or abolish the ability of the resulting NuA4/TIP60 multi-subunit complexes to acetylate the histone H4 tail in chromatin. Transcriptomic analysis in affected individual fibroblasts showed deregulation of multiple genes that control development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control) in agreement with sleep anomalies in all of the individuals. In conclusion, dominant missense KAT5 variants cause histone acetylation deficiency with transcriptional dysregulation of multiples genes, thereby leading to a neurodevelopmental syndrome with sleep disturbance, cerebellar atrophy, and facial dysmorphisms, and suggesting a recognizable syndrome.

Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.

Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the cases. H3K23 acylation is also impaired by cancer-derived somatic BRPF1 mutations. Valproate, vorinostat, propionate and butyrate promote H3K23 acylation. These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation.

Characterization of Gut Microbiota, Bile Acid Metabolism, and Cytokines in Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC), a type of bile duct cancer, has a high mortality rate. Gut microbiota, bile acid (BA) metabolism, and cytokines have not been characterized in patients with ICC, and better noninvasive diagnostic approaches for ICC are essential to be established. Therefore, in this study we aimed to improve our understanding of changes in gut microbiota, BA metabolism, and cytokines in patients with ICC. We found that the α-diversities and ß-diversities of ICC were highest and that the abundances of four genera (Lactobacillus, Actinomyces, Peptostreptococcaceae, and Alloscardovia) were increased in patients with ICC compared with those in patients with hepatocellular carcinoma or liver cirrhosis and in healthy individuals. The glycoursodeoxycholic acid and tauroursodeoxycholic acid (TUDCA) plasma-stool ratios were obviously increased in patients with ICC. Furthermore, the genera Lactobacillus and Alloscardovia that were positively correlated with TUDCA plasma-stool ratios were combined to discriminate ICC from the other three diseases. Vascular invasion (VI) frequently led to a poor prognosis in patients with ICC. Compared with patients with ICC without VI, patients with VI had a greater abundance of the family Ruminococcaceae, increased levels of plasma interleukin (IL)-4 and six conjugated BAs, and decreased levels of plasma IL-6 and chenodeoxycholic acid. A positive correlation between plasma taurocholic acid and IL-4 was observed in patients with ICC. Plasma TUDCA was negatively correlated with the abundance of the genus Pseudoramibacter and the survival time of patients with ICC, but had no effect on tumor size, as determined in two murine tumor models. Conclusion: In this study, we identified some biomarkers, including gut microbiota, BAs and inflammatory cytokines, for the diagnosis of ICC and prediction of VI in patients with ICC.