Gonorrhea remains one of the most common sexually transmitted diseases worldwide. Successful treatment has been hampered by emerging resistance to each of the antibiotics recommended as first-line ...therapies. We retrospectively analyzed the susceptibility of gonorrhea to azithromycin and ceftriaxone using data from the China Gonococcal Resistance Surveillance Programme (China-GRSP) in order to provide evidence for updating the treatment recommendations in China.
In this study, we included 3,849 isolates collected from patients with a confirmed positive Neisseria gonorrhoeae (N. gonorrhoeae) culture at clinic visits during the period of 1 January 2013 through 31 December 2016 in 7 provinces. Antimicrobial susceptibility testing of gonorrhea isolates using agar dilution was conducted to determine minimum inhibitory concentration (MIC). Resistance to azithromycin (RTA) was defined as MIC ≥ 1.0 mg/l, and decreased susceptibility to ceftriaxone (DSC) was defined as MIC ≥ 0.125 mg/l. The prevalence of isolates with RTA was 18.6% (710/3,827; 95% CI 17.4%-19.8%). The percentage of patients with DSC fluctuated between 9.7% and 12.2% over this period. The overall prevalence of isolates with both RTA and DSC was 2.3% (87/3,827; 95% CI 1.9%-2.8%) and it increased from 1.9% in 2013 to 3.3% in 2016 (chi-squared test for trend, P = 0.03). Study limitations include the retrospective study design and potential biases in the sample, which may overrepresent men with symptomatic infection, coastal residents, and people reporting as heterosexual.
To our knowledge, this is the first national study on susceptibility of N. gonorrhoeae to azithromycin and ceftriaxone in China. Our findings indicate high rates of RTA and DSC from 2013 to 2016. Although dual therapy with azithromycin and ceftriaxone has been recommended by WHO and many countries to treat gonorrhea, reevaluation of this therapy is needed prior to its introduction in China.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Virtual Screening (VS) based on molecular docking is an efficient method used for retrieving novel hit compounds in drug discovery. However, the accuracy of the current docking scoring function (SF) ...is usually insufficient. In this study, in order to improve the screening power of SF, a novel approach named EAT-Score was proposed by directly utilizing the energy auxiliary terms (EAT) provided by molecular docking scoring through eXtreme Gradient Boosting (XGBoost). Here, EAT specifically refers to the output of the Molecular Operating Environment (MOE) scoring, including the energy scores of five different classical SFs and the Protein–Ligand Interaction Fingerprint (PLIF) terms. The performance of EAT-Score to discriminate actives from decoys was strictly validated on the DUD-E diverse subset by using different performance metrics. The results showed that EAT-Score performed much better than classical SFs in VS, with its AUC values exhibiting an improvement of around 0.3. Meanwhile, EAT-Score could achieve comparable even better prediction performance compared with other state-of-the-art VS methods, such as some machine learning (ML)-based SFs and classical SFs implemented in docking programs, in terms of AUC, LogAUC, or BEDROC. Furthermore, the EAT-Score model can capture important binding pattern information from protein–ligand complexes by Shapley additive explanations (SHAP) analysis, which may be very helpful in interpreting the ligand binding mechanism for a certain target and thereby guiding drug design.
Abstract Scoring functions (SFs) based on complex machine learning (ML) algorithms have gradually emerged as a promising alternative to overcome the weaknesses of classical SFs. However, extensive ...efforts have been devoted to the development of SFs based on new protein–ligand interaction representations and advanced alternative ML algorithms instead of the energy components obtained by the decomposition of existing SFs. Here, we propose a new method named energy auxiliary terms learning (EATL), in which the scoring components are extracted and used as the input for the development of three levels of ML SFs including EATL SFs, docking-EATL SFs and comprehensive SFs with ascending VS performance. The EATL approach not only outperforms classical SFs for the absolute performance (ROC) and initial enrichment (BEDROC) but also yields comparable performance compared with other advanced ML-based methods on the diverse subset of Directory of Useful Decoys: Enhanced (DUD-E). The test on the relatively unbiased actives as decoys (AD) dataset also proved the effectiveness of EATL. Furthermore, the idea of learning from SF components to yield improved screening power can also be extended to other docking programs and SFs available.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Long non-coding RNAs (lncRNAs) are expressed in tissue-specific pattern, but it is not clear how these are regulated. We aimed to identify squamous cell carcinoma (SCC)-specific lncRNAs and ...investigate mechanisms that control their expression and function.
We studied expression patterns and functions of 4 SCC-specific lncRNAs. We obtained 113 esophageal SCC (ESCC) and matched non-tumor esophageal tissues from a hospital in Shantou City, China, and performed quantitative reverse transcription polymerase chain reaction assays to measure expression levels of LINC01503. We collected clinical data from patients and compared expression levels with survival times. LINC01503 was knocked down using small interfering RNAs and oligonucleotides in TE7, TE5, and KYSE510 cell lines and overexpressed in KYSE30 cells. Cells were analyzed by chromatin immunoprecipitation sequencing, luciferase reporter assays, colony formation, migration and invasion, and mass spectrometry analyses. Cells were injected into nude mice and growth of xenograft tumors was measured. LINC01503 interaction with proteins was studied using fluorescence in situ hybridization, RNA pulldown, and RNA immunoprecipitation analyses.
We identified a lncRNA, LINC01503, which is regulated by a super enhancer and is expressed at significantly higher levels in esophageal and head and neck SCCs than in non-tumor tissues. High levels in SCCs correlated with shorter survival times of patients. The transcription factor TP63 bound to the super enhancer at the LINC01503 locus and activated its transcription. Expression of LINC01503 in ESCC cell lines increased their proliferation, colony formation, migration, and invasion. Knockdown of LINC01503 in SCC cells reduced their proliferation, colony formation, migration, and invasion, and the growth of xenograft tumors in nude mice. Expression of LINC01503 in ESCC cell lines reduced ERK2 dephosphorylation by DUSP6, leading to activation of ERK signaling via MAPK. LINC01503 disrupted the interaction between EBP1 and the p85 subunit of PI3K, increasing AKT signaling.
We identified an lncRNA, LINC01503, which is increased in SCC cells compared with non-tumor cells. Increased expression of LINC01503 promotes ESCC cell proliferation, migration, invasion, and growth of xenograft tumors. It might be developed as a biomarker of aggressive SCCs in patients.
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A series of calcined hydrotalcite were prepared via natural hydrotalcite (Mg
6
Al
2
(OH)
16
CO
3
·4H
2
O) calcined at 200, 400, 600, and 800 °C. The potential use of calcined hydrotalcite as ...adsorbent for the recovery of Cd(II) species from aqueous solution was evaluated by an adsorption process in batch experiments at ambient temperature. The materials were characterized by XRD analysis, FT-IR spectroscopy, N
2
adsorption, SEM, and XPS technique. Results indicated that the structure and textural properties of hydrotalcite were obviously changed via thermal treatments of calcinations, and the surface area of the samples was increased with the raise of calcination temperature. The pH of solution after adsorption was increased in different degrees due to hydrolysis of MgO in hydrotalcite, leading to improving adsorption of Cd(II). The hydrotalcite calcined at 600 °C presented the maximum equilibrium adsorption capacity, and the adsorption process could be well described by Freundlich isotherm and pseudo-second-order kinetics model. Meanwhile, it could be found that the damaged interlayer structure of hydrotalcite calcined at high temperature could be restored during the adsorption process due to better memory effect of hydrotalcite, and Cd(II) was adsorbed on the hydrotalcite surface as the precipitations of Cd(OH)
2
and CdCO
3
.
To reproduce the nonlinear damage of sandstone under cyclic loading, a nonlinear parallel-bonded stress corrosion (N-PSC) model is developed based on the linear parallel bond (LPB) model in particle ...flow code (PFC). The damage caused by cyclic loading is simulated by nonlinearly changing the bond diameter according to the nonlinear changes in the axial plastic strain of sandstone. The results show that the N-PSC model can effectively reproduce the main mechanical characteristics observed in laboratory tests, including the stress-strain curve, peak strength, axial plastic deformation, elastic modulus, and energy evolution characteristics. The sandstone specimens are damaged slowly during the elastic cyclic loading stage and rapidly after the plastic stage. In the first stage of post-peak cycling, the number of cracks inside the specimen increases dramatically as microcracks expand, coalesce, and form macroscopic fracture zones, resulting in a sharp release of energy. The specimens exhibit shear fracture under triaxial cyclic loading. However, in addition to the main shear fracture, tensile cracks are visible at the top and bottom of the specimen, which are caused by stress concentration extrusion. The N-PSC model is a powerful tool for investigating the evolution of rock damage under cyclic loading.
Background: The Guangzhou Nutrition and Health Study (GNHS) aims to assess the determinants of metabolic disease in nutritional aspects, as well as other environmental and genetic factors, and ...explore possible biomarkers and mechanisms with multi-omics integration.Methods: The population-based sample of adults in Guangzhou, China (baseline: 40–83 years old; n = 5,118) was followed up about every 3 years. All are tracked via on-site follow-up and health information systems. We assessed detailed information on lifestyle factors, physical activities, dietary assessments, psychological health, cognitive function, body measurements, and muscle function. Instrument tests included dual-energy X-ray absorptiometry scanning, carotid artery and liver ultrasonography evaluations, vascular endothelial function evaluation, upper-abdomen and brain magnetic resonance imaging, and 14-day real-time continuous glucose monitoring tests. We also measured multi-omics, including host genome-wide genotyping, serum metabolome and proteome, gut microbiome (16S rRNA sequencing, metagenome, and internal transcribed spacer 2 sequencing), and fecal metabolome and proteome.Results: The baseline surveys were conducted from 2008 to 2015. Now, we have completed 3 waves. The 3rd and 4th follow-ups have started but have yet to end. A total of 5,118 participants aged 40–83 took part in the study. The median age at baseline was approximately 59.0 years and the proportion of female participants was about 69.4%. Among all the participants, 3,628 (71%) completed at least one on-site follow-up, with a median duration of 9.48 years.Conclusion: The cohort will provide data that will be influential in establishing the role of nutrition in metabolic diseases with multi-omics.
Eukaryotic elongation factor-2 kinase (eEF2K), a calcium/calmodulin-dependent protein kinase, is a potential target for treating cancer. eEF2K can reduce the binding ability of eEF2 to ribosomes by ...phosphorylating eEF2, thereby inhibiting peptide chain extension and negatively regulating protein synthesis, which provides a cytoprotective mechanism for the development of cancer. eEF2K has been reported to be overexpressed in various types of cancers. Therefore, it is of high importance to discover new eEF2K inhibitors for cancer therapy. Here, we proposed a three-step screening strategy to seek eEF2K inhibitors from the FDA approved drug library: homology modeling of eEF2K protein, SAR-based virtual screening, and docking-based virtual screening. Based on the screening strategy, 13 drugs with high evaluation scores were purchased to measure their binding affinity (
K
D
) to eEF2K by using the SPR assay. The assay results suggested that 4 drugs may be potential eEF2K inhibitors, which are Pemetrexed (
K
D
= 0.104 μM), Entecavir (
K
D
= 2.16 μM), calcium levofolinate (
K
D
= 11.7 μM), and Fosbretabulin (
K
D
= 34.5 μM). To further validate whether these drugs act on eEF2K, Western blot (WB) analysis was performed, which showed that Pemetrexed and Entecavir could inhibit the eEF2K activity. Furthermore, molecular dynamics (MD) simulation was carried out to further demonstrate the interaction of eEF2K with Pemetrexed, the most bioactive drug. The specific
in vitro
/
in vivo
interaction mechanisms between these drugs and eEF2K are under investigation.
Eukaryotic elongation factor-2 kinase (eEF2K), a calcium/calmodulin-dependent protein kinase, is a potential target for treating cancer.
Uric acid (UA) has been proposed as an important risk factor for cardiovascular and renal morbidity. We conducted an interventional trial to assess effects of altered salt intake on plasma and urine ...UA levels and the relationship between UA levels and salt sensitivity in humans. Ninety subjects (18-65 years old) were sequentially maintained on a normal diet for 3 days at baseline, a low-salt diet for 7 days (3.0 g/day, NaCl), and a high-salt diet for an additional 7 days (18.0 g/day of NaCl). Plasma UA levels significantly increased from baseline to low-salt diet and decreased from low-salt to high-salt diet. By contrast, daily urinary levels of UA significantly decreased from baseline to low-salt diet and increased from low-salt to high-salt diet. The 24 h urinary sodium excretions showed inverse correlation with plasma UA and positive correlation with urinary UA excretions. Additionally, salt-sensitive subjects presented significantly higher plasma UA changes in comparison to salt-resistant subjects, and a negative correlation was observed between degree of salt sensitivity and plasma UA difference. The present study indicates that variations in dietary salt intake affect plasma and urine UA levels, and plasma UA may be involved in pathophysiological process of salt sensitivity.
Purpose
Previous studies have suggested that serum carotenoids might be inversely associated with non-alcoholic fatty liver disease (NAFLD), but little data came from longitudinal studies. We ...prospectively examined the associations between serum-carotenoid levels and NAFLD severity and the intermediary effects of retinol-binding protein 4 (RBP4), HOMA insulin-resistance index (HOMA-IR), body mass index (BMI), and serum triglycerides in middle-aged and elderly Chinese adults.
Methods
This prospective study included 3336 Chinese adults (40–75 years). We assessed serum concentrations of carotenoids at baseline and determined serum RBP4, triglycerides, and HOMA-IR levels at year 3. Abdominal ultrasonography was conducted to assess the presence and degree of NAFLD at years 3 and 6.
Results
The 2687 subjects who completed both NAFLD tests were classified into stable, improved and progressed groups according to changes in the degree of NAFLD between two visits. Analyses of covariance showed that ln-transformed serum concentrations of α-carotene, β-cryptoxanthin, β-carotene, lycopene, lutein/zeaxanthin, and total carotenoids were positively associated with NAFLD improvement (all
p
-trend < 0.05). After multivariable adjustment, mean differences in serum carotenoids were higher by 29.6% (β-carotene), 18.2% (α-carotene), 15.6% (β-cryptoxanthin), 11.5% (lycopene), 8.9% (lutein/zeaxanthin), and 16.6% (total carotenoids) in the improved vs. progressed subjects. Path analyses indicated the carotenoid–NAFLD association was mediated by lowering serum RBP4, triglycerides, HOMA-IR, and BMI, which were positively associated with the prevalence and progression of NAFLD.
Conclusions
In middle-aged and elderly adults, higher serum-carotenoid concentrations were favorably associated with NAFLD improvement, mediated by reducing serum RBP4, triglycerides, HOMA-IR, and BMI.
Trial registrations
This study has been registered at
http://www.clinicaltrials.gov
as NCT03179657.
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