Search

The activating molecule in Beclin1-regulated autophagy protein 1 (AMBRA1) is an intrinsically disordered protein that regulates the survival and death of cancer cells by modulating autophagy. Although the roles of autophagy in cancer are controversial and context-dependent, inhibition of autophagy under some circumstances can be a useful strategy for cancer therapy. As AMBRA1 is a pivotal autophagy-associated protein, targeting AMBRA1 similarly may be an underlying strategy for cancer therapy. Emerging evidence indicates that AMBRA1 can also inhibit cancer formation, maintenance, and progression by regulating c-MYC and cyclins, which are frequently deregulated in human cancer cells. Therefore, AMBRA1 is at the crossroad of autophagy, tumorigenesis, proliferation, and cell cycle. In this review, we focus on discussing the mechanisms of AMBRA1 in autophagy, mitophagy, and apoptosis, and particularly the roles of AMBRA1 in tumorigenesis and targeted therapy.

Abstract. Background:. Reduced application of percutaneous coronary intervention (PCI) is associated with higher mortality rates after ST-segment elevation myocardial infarction (STEMI). We aimed to evaluate potential factors contributing to the refusal of PCI in STEMI patients in China. Methods:. We studied 957 patients diagnosed with STEMI in the emergency departments (EDs) of six public hospitals in China. The differences in baseline characteristics and 30-day outcome were investigated between patients who refused PCI and those who underwent PCI. Multivariable logistic regression was used to evaluate the potential factors associated with refusing PCI. Results:. The potential factors contributing to refusing PCI were older than 65 years (odds ratio [OR] 2.66, 95% confidence interval [CI] 1.56–4.52, P 12 h) (OR 3.31, 95% CI 1.83–6.02, P

Background: For anaphylaxis, a life-threatening allergic reaction, the incidence rate was presented to have increased from the beginning of the 21st century. Underdiagnosis and undertreatment of anaphylaxis are public health concerns.Objective: This guideline aimed to provide high-quality and evidence-based recommendations for the emergency management of anaphylaxis.Method: The panel of health professionals from fifteen medical areas selected twenty-five clinical questions and formulated the recommendations with the supervision of four methodologists. We collected evidence by conducting systematic literature retrieval and using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.Results: This guideline made twenty-five recommendations that covered the diagnosis, preparation, emergency treatment, and post-emergency management of anaphylaxis. We recommended the use of a set of adapted diagnostic criteria from the American National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network (NIAID/FAAN), and developed a severity grading system that classified anaphylaxis into four grades. We recommended epinephrine as the first-line treatment, with specific doses and routes of administration for different severity of anaphylaxis or different conditions. Proper dosage is critical in the administration of epinephrine, and the monitor is important in the IV administration. Though there was only very low or low-quality evidence supported the use of glucocorticoids and H1 antagonists, we still weakly recommended them as second-line medications. We could not make a well-directed recommendation regarding premedication for preventing anaphylaxis since it is difficult to weigh the concerns and potential effects.Conclusion: For the emergency management of anaphylaxis we conclude that:• NIAID/FAAN diagnostic criteria and the four-tier grading system should be used for the diagnosis• Prompt and proper administration of epinephrine is critical.

This paper develops a hybrid data-driven physics-based model, which maps flight operational data to aircraft performance analysis, in order to estimate aircraft fuel consumption and flight condition information. The hybrid model is an adaptation of the enhanced high-fidelity flight performance analysis, with adjustments made for mission parameters. Through the proposed mission parameterization process, nominal parameters are substituted by the extracted mission and speed profiles. In other words, real flight operations are integrated into the physics-based analysis. The versatility of the hybrid model is demonstrated in three cases (short-, medium-, and long-haul flight sectors), which have very different characteristics. It is also validated against the corresponding fuel consumption data from an airline (with root mean square errors less than 3%) and shows great improvements relative to the pure physics-based model.

Multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) caused by phosphatidylinositol-glycan biosynthesis class N (PIGN) mutations is an autosomal recessive disease involving many systems of the body, such as the urogenital, cardiovascular, gastrointestinal, and central nervous systems. Here, compound heterozygous variants NM_012327.6:c.2427-2A > G and c.963G > A in PIGN were identified in a Chinese proband with MCAHS1. The features of the MCAHS1 family proband were evaluated to understand the mechanism of the PIGN mutation leading to the occurrence of MCAHS1. Ultrasound was conducted to examine the fetus, and his clinical manifestations were evaluated. Genetic testing was performed by whole-exome sequencing and the results were verified by Sanger sequencing of the proband and his parents. Reverse transcription-polymerase chain reaction was performed, and the products were subjected to Sanger sequencing. Quantitative PCR (Q-PCR) was conducted to compare gene expression between the patient and wild-type subjects. The compound heterozygous mutation NM_012327.6:c.2427-2A > G and c.963G > A was identified by whole-exome sequencing and was confirmed by Sanger sequencing. The NM_012327.6:c.2427-2A > G mutation led to skipping of exon 26, which resulted in a low expression level of the gene, as measured by Q-PCR. These findings provided a basis for genetic counseling and reproduction guidance in this family. Phenotype-genotype correlations may be defined by an expanded array of mutations.

Autosomal dominant non-syndromic hearing loss (ADNSHL) has a broad phenotypic spectrum which includes bilateral, symmetrical, and high-frequency sensorineural hearing loss, that eventually progresses into hearing loss at all frequencies. Several genetic variations have been identified as causal factors underlying deafness, autosomal dominant 5 (DFNA5) gene-related hearing loss. Here, we report a novel mutation (c.991-1G > C) in DFNA5, which co-segregated with late-onset ADNSHL in a Chinese family and was identified via exome sequencing and Sanger sequencing of DNA from peripheral blood of the family members. Further sequencing of cDNA derived from peripheral blood mRNA revealed that the c.991-1G >C mutation led to the skipping of exon 8, which is a known pathogenic mechanism for DFNA5-related hearing loss.

Alamethicin (ALM) inhibits the growth of bacteria by disrupting their cell membrane. ALM exhibits poor solubility in aqueous medium thus limiting its application. A method is proposed for encapsulation of ALM with γ-cyclodextrin (γ-CD) by forming a complex of higher solubility with thermal and pH stability as confirmed by FT-IR and DSC, thus greatly improving its application in food safety. Molecular dynamics simulation suggested a stable configuration of the complex when hydrophobic residues are inserted into the hydrophobic cavity of γ-CD. Aggregation of the complex was inhibited at higher γ-CD/ALM molar ratio. γ-CD/ALM complex exhibited significant antimicrobial activity against L. monocytogenes with the minimum inhibitory concentration being dependent on γ-CD/ALM molar ratio (>0.429 mg/mL for 1:1; >1.094 mg/mL for 5:1; >2.078 mg/mL for 10:1). Optimum γ-CD/ALM molar ratio for maximum antimicrobial activity is the result of competing effects of higher solubility and shielding of hydrophobic ALM groups by γ-CD.

Silver–Russell syndrome (SRS) is a rare, well-recognized disorder characterized by growth restriction, including intrauterine and postnatal growth. Most SRS cases are caused by hypomethylation of the paternal imprinting center 1 (IC1) in chromosome 11p15.5 and maternal uniparental disomy in chromosome 7 (UPD7). Here, we report on a Chinese family with a 4 year old male proband presenting with low birth weight, growth retardation, short stature, a narrow chin, delayed bone age, and speech delays, as a result of a rare molecular etiology. Whole-exome sequencing was conducted, and a novel de novo IGF2 splicing variant, NM_000612.4: c.157+5G > A, was identified on the paternal allele. In vitro functional analysis by RT-PCR and Sanger sequencing revealed that the variant leads to an aberrant RNA transcript lacking exon 2. Our results further confirm the IGF2 variant mediates SRS and expand the pathogenic variant and phenotypic spectrum of IGF2-mediated SRS. The results indicate that, beyond DNA methylation and UPD7 and CDKN1C variant tests, IGF2 gene screening should also be considered for SRS molecular diagnoses.

Background: Acinetobacter baumannii has emerged as an important pathogen causing a variety of infections. Using data from the China Surveillance of Antimicrobial Resistance Program conducted biennially, we investigated the secular changes in the resistance of 2917 isolates of A. baumannii from 2004 to 2014 to differ antimicrobial agents. Methods: Pathogen samples were collected from 17 to 20 hospitals located in the eastern, central, and western regions of China. Minimum inhibitory concentrations (MICs) were determined by a 2-fold agar dilution method, and antimicrobial susceptibility was established using the 2014 Clinical Laboratory Standards Institute-approved breakpoints. Isolates not susceptible to all the tested aminoglycosides, fluoroquinolones, β-lactams, β-lactam/β-lactam inhibitors and carbapenems were defined as extensively drug resistant. Results: The rates of nonsusceptibility to common antimicrobial agents remained high (>65%) over the years with some fluctuations to certain agents. The prevalence of imipenem-resistant A. baumannii (IRAB) increased from 13.3% in 2004 to 70.5% in 2014 and that of extensively drug-resistant A. baumannii (XDRAB) increased from 11.1% in 2004 to 60.4% in 2014. The activity of tigecycline was stable with MIC90 ≤4 mg/L against A. baumannii from 2009 to 2014. Susceptibility to colistin remained high (97.0%) from 2009 to 2014. The prevalence of XDRAB increased in all the three surveillance regions over the years and was significantly higher in Intensive Care Unit (ICU) wards than non-ICU wards. Conclusions: This longitudinal multicenter surveillance program revealed the nationwide emergence of A. baumannii in China and showed a significant increase in prevalence from 2004 to 2014. High levels of bacterial resistance were detected among samples collected from clinical settings in China, with IRAB and XDRAB being especially prevalent. This study will help to guide empirical therapy and identify at-risk groups requiring more intense interventional infection control measures, while also helping to focus surveillance efforts.

Background: Antimicrobial resistance is a serious problem that compromises the empirical treatment of infections, resulting in a lack of effective antibiotics and high medical expenses. Here, we aimed to monitor the trends in antimicrobial resistance among Enterobacteriaceae isolated from blood samples in mainland China. Methods: A total of 2240 Enterobacteriaceae isolates from blood were collected from hospitalized patients at 19 tertiary hospitals between October 2004 and June 2014. The minimum inhibitory concentrations of all isolates were determined using the agar dilution method according to the Clinical and Laboratory Standards Institute 2016 guidelines. Results: The most commonly isolated bacteria were Escherichia coli, compromising 47.0% (1053/2240) of the total isolates, followed by Klebsiella spp. (26.3%), Salmonella spp. (10.4%), and Enterobacter spp. (9.2%). The detection rates of extended-spectrum β-lactamases (ESBLs) among E. coli were 68.9% (2004–2005), 73.2% (2007–2008), 67.9% (2009–2010), 72.6% (2011–2012), and 58.4% (2013–2014), whereas those in ESBL-producing Klebsiella pneumoniae were slightly decreased (75.9%, 50.0%, 41.4%, 40.2%, and 43.0%, respectively). Carbapenems were the most potent agents against the Enterobacteriaceae isolates, followed by moxalactam, tigecycline, and amikacin. However, there was a decrease in the susceptibility rates for carbapenems in all species, particularly K. pneumoniae(decreased by 10.6% for imipenem) and Enterobacter aerogenes (decreased by 21.1% for imipenem). Reviving antibiotics (tigecycline and polymyxins) showed good in vitro activity against Enterobacteriaceae. Conclusions: The activity of antibiotics against Enterobacteriaceae isolated from blood was decreased overall. Large proportions of ESBL-producing isolates were identified among E. coli and Klebsiella spp. Carbapenem-resistant isolates have become a major challenge in the treatment of infections.

Eschrichia coli urinary isolates were collected from 20 Chinese hospitals during five 1-year periods from 2004 to 2014. The susceptibility of E. coli to levofloxacin has remained stable during the past 11 years, and 90% of strains had minimum inhibitory concentrations of ≤32 mg/L. The urine-specific susceptibility breakpoints for levofloxacin should be reset based on more relevant clinical studies and the current pharmacokinetic/pharmacodynamic considerations in this field.

Blood extracellular vesicles (BEVs) carry bioactive cargo (proteins, genetic materials, lipids, licit, and illicit drugs) that regulate diverse functions in target cells. The cannabinoid drug delta-9-tetrahydrocannabinol (THC) is FDA approved for the treatment of anorexia and weight loss in people living with HIV. However, the effect of THC on BEV characteristics in the setting of HIV/SIV infection needs to be determined. Here, we used the SIV-infected rhesus macaque model of AIDS to evaluate the longitudinal effects of THC (THC/SIV) or vehicle (VEH/SIV) treatment in HIV/SIV infection on the properties of BEVs. While BEV concentrations increased longitudinally (pre-SIV (0), 30, and 150 days post-SIV infection (DPI)) in VEH/SIV macaques, the opposite trend was observed with THC/SIV macaques. SIV infection altered BEV membrane properties and cargo composition late in infection, since i) the electrostatic surface properties (zeta potential, ζ potential) showed that RM BEVs carried negative surface charge, but at 150 DPI, SIV infection significantly changed BEV ζ potential; ii) BEVs from the VEH/SIV group altered tetraspanin CD9 and CD81 levels compared to the THC/SIV group. Furthermore, VEH/SIV and THC/SIV BEVs mediated divergent changes in monocyte gene expression, morphometrics, signaling, and function. These include altered tetraspanin and integrin β1 expression; altered levels and distribution of polymerized actin, FAK/pY397 FAK, pERK1/2, cleaved caspase 3, proapoptotic Bid and truncated tBid; and altered adhesion of monocytes to collagen I. These data indicate that HIV/SIV infection and THC treatment result in the release of bioactive BEVs with potential to induce distinct structural adaptations and signaling cues to instruct divergent cellular responses to infection.

Inhibition of cancer cell adhesion is an effective approach to killing adherent cancer cells. B49 and its analog B49Mod1 peptides, derived from the extracellular domain (ECD) of bone marrow stromal antigen 2 (BST-2), display anti-adhesion activity on breast cancer cells. However, the minimal sequence required for this anti-adhesion activity is unknown. Here, we further characterized the anti-adhesion activity of B49Mod1. We show that the anti-adhesion activity of B49Mod1 may require cysteine-linked disulfide bond and that the peptide is susceptible to proteolytic deactivation. Using structure-activity relationship studies, we identified an 18-Mer sequence (B18) as the minimal peptide sequence mediating the anti-adhesion activity of B49Mod1. Atomistic molecular dynamic (MD) simulations reveal that B18 forms a stable complex with the ECD of BST-2 in aqueous solution. MD simulations further reveal that B18 may cause membrane defects that facilitates peptide translocation across the bilayer. Placement of four B18 chains as a transmembrane bundle results in water channel formation, indicating that B18 may impair membrane integrity and form pores. We hereby identify B18 as the minimal peptide sequence required for the anti-adhesion activity of B49Mod1 and provide atomistic insight into the interaction of B18 with BST-2 and the cell membrane.

Background: As a time-dependent antibiotic, the time of cefazedone concentration exceeds the minimum inhibitory concentration (MIC) is the key pharmacokinetic-pharmacodynamic (PK-PD) variable associated with the killing of pathogens. The purpose of the study was to evaluate the clinical regimen rationality of intravenous cefazedone sodium in the treatment of community-acquired pneumonia (CAP) by PK/PD study. Methods: Ten patients with mild to moderate CAP were enrolled to receive intravenous cefazedone sodium (2 g q12 h) for 7-14 days. Blood samples were collected in any day during day 5-7. Sputum specimens were collected before treatment for bacteria isolated, and susceptibility to cefazedone determined. PK-PD analysis was performed using the noncompartmental analysis of Phoenix WinNolin software (version 6.1, Pharsight Corporation, CA, USA). The maximal time above MIC (ƒT > MIC) was calculated, and its correlation with clinical efficacy was analyzed. Results: All 10 patients completed the study and 8 of them were cured. Six strains were isolated from patients before treatment (one for each patient) and all susceptible to cefazedone. Five patients of six in culture positive group were cured. All pathogens were cleared at the end of therapy. The MICs were between 0.25 and 1 mg/L. The main PK parameters were C max 175.22 ± 36.28 mg/L; T½ 1.52 ± 0.23 h; AUC (0-∞) 280.51 ± 68.17 mg·L -1·h -1 ; CL 7.37 ± 1.84 L/h; Vd 16.06 ± 4.42 L. The average ƒT > MIC was 55.45 ± 8.12%. Conclusions: Intravenous injection of cefazodone sodium with 2 g q12 h dosage regimen is used in the treatment of CAP caused by sensitive bacteria, either ƒT > MIC or clinical efficacy shows that such dosing regimen is reasonable.

Semen exosomes (SE) from HIV-uninfected (HIV−) individuals potently inhibit HIV infection in vitro. However, morphological changes in target cells in response to SE have not been characterized or have the effect of HIV infection or the use of illicit substances, specifically psychostimulants, on the function of SE been elucidated. The objective of this study was to evaluate the effect of HIV infection, psychostimulant use, and both together on SE-mediated regulation of monocyte function. SE were isolated from semen of HIV− and HIV-infected (HIV+) antiretroviral therapy (ART)-naive participants who reported either using or not using psychostimulants. The SE samples were thus designated as HIV−Drug−, HIV−Drug+, HIV+Drug−, and HIV+Drug+. U937 monocytes were treated with different SEs and analyzed for changes in transcriptome, morphometrics, actin reorganization, adhesion, and chemotaxis. HIV infection and/or use of psychostimulants had minimal effects on the physical characteristics of SE. However, different SEs had diverse effects on the messenger RNA signature of monocytes and rapidly induced monocyte adhesion and spreading. SE from HIV infected or psychostimulants users but not HIV−Drug− SE, stimulated actin reorganization, leading to the formation of filopodia-like structures and membrane ruffles containing F-actin and vinculin that in some cases were colocalized. All SE stimulated monocyte chemotaxis to HIV secretome and activated the secretion of matrix metalloproteinases, a phenotype exacerbated by HIV infection and psychostimulant use. SE-directed regulation of cellular morphometrics and chemotaxis depended on the donor clinical status because HIV infection and psychostimulant use altered SE function. Although our inclusion criteria specified the use of cocaine, humans are poly-drug and alcohol users and our study participants used psychostimulants, marijuana, opiates, and alcohol. Thus, it is possible that the effects observed in this study may be due to one of these other substances or due to an interaction between different substances.

Background: The aim of this study is to investigate how Guilu Erxian gum treats osteoporosis by using network pharmacology and related experiments. Methods: The TCMSP database, ETCM database, Chemical Specialties database, and DrugBank database were used to retrieve the potential active ingblueients and corresponding targets of Guilu Erxian gum. Therapeutic targets associated with osteoporosis were obtained from the OMIM and Genecards databases. The network was analyzed using Cytoscape 3.8.0 software to determine topological parameters and identify key active ingblueients and targets. Additionally, the effects of Guilu Erxian gum on osteogenic differentiation of bone marrow mesenchymal stem cells were evaluated through alkaline phosphatase assay and alizarin blue calcium nodule staining. The expression of osteogenesis-related genes (Runx2, Osterix, OPN) was assessed using RT-PCR and Western blot. Results: The analysis revealed that Guilu Erxian gum contained 41 active ingblueients and 236 targets, while there were 5,262 known therapeutic targets for osteoporosis. A protein-protein interaction network diagram was constructed using the String database. Enrichment analysis suggested that Guilu Erxian gum may regulate osteoporosis through various signaling pathways and cellular metabolism. The experiments demonstrated that Guilu Erxian gum could promote osteogenic differentiation of bone marrow mesenchymal stem cells, potentially contributing to the treatment of osteoporosis. Moreover, the results showed that Guilu Erxian gum could increase the expression of osteogenesis-related genes (Runx2, Osterix, OPN). Conclusion: Guilu Erxian gum may have anti-osteoporosis effects by stimulating the osteogenic differentiation of stem cells. This study provides a theoretical basis for further understanding the pharmacological mechanism of Guilu Erxian gum in treating osteoporosis. [ABSTRACT FROM AUTHOR]