Helper Lipid-Enhanced mRNA Delivery for Treating Metabolic Dysfunction-Associated Fatty Liver Disease.

Lipid nanoparticles (LNPs) represent the forefront of mRNA delivery platforms, yet achieving precise delivery to specific cells remains a challenge. The current targeting strategies complicate the formulation and impede the regulatory approval process. Here, through a straightforward regulation of helper lipids within LNPs, we introduce an engineered LNP designed for targeted delivery of mRNA into hepatocytes for metabolic dysfunction-associated fatty liver disease (MAFLD) treatment. The optimized LNP, supplied with POPC as the helper lipid, exhibits a 2.49-fold increase in mRNA transfection efficiency in hepatocytes compared to that of FDA-approved LNPs. CTP:phosphocholine cytidylyltransferase α mRNA is selected for delivery to hepatocytes through the optimized LNP system for self-calibration of phosphatidylcholine levels to prevent lipid droplet expansion in MAFLD. This strategy effectively regulates lipid homeostasis, while demonstrating proven biosafety. Our results present a mRNA therapy for MAFLD and open a new avenue for discovering potent lipids enabling mRNA delivery to specific cells.

Multicomponent Synthesis of Imidazole-Based Ionizable Lipids for Highly Efficient and Spleen-Selective Messenger RNA Delivery.

The spleen emerges as a pivotal target for mRNA delivery, prompting a continual quest for specialized and efficient lipid nanoparticles (LNPs) designed to enhance spleen-selective transfection efficiency. Here we report imidazole-containing ionizable lipids (IMILs) that demonstrate a pronounced preference for mRNA delivery into the spleen with exceptional transfection efficiency. We optimized IMIL structures by constructing and screening a multidimensional IMIL library containing multiple heads, tails, and linkers to perform a structure-activity correlation analysis. Following high-throughput in vivo screening, we identified A3B7C2 as a top-performing IMIL in spleen-specific mRNA delivery via the formulated LNPs, achieving a remarkable 98% proportion of splenic transfection. Moreover, A3B7C2-based LNPs are particularly potent in splenic dendritic cell transfection. Comparative analyses revealed that A3B7C2-based LNPs achieved a notable 2.8-fold and 12.9-fold increase in splenic mRNA transfection compared to SM102 and DLin-MC3-DMA lipid formulations, respectively. Additionally, our approach yielded an 18.3-fold enhancement in splenic mRNA expression compared to the SORT method without introducing additional anionic lipids. Collectively, these IMILs highlight promising avenues for further research in spleen-selective mRNA delivery. This work offers valuable insights for the swift discovery and rational design of ionizable lipid candidates tailored for spleen-selective transfection, thereby facilitating the application of mRNA therapeutics in spleen-related interventions.

GCMSFormer: A Fully Automatic Method for the Resolution of Overlapping Peaks in Gas Chromatography-Mass Spectrometry.

Gas chromatography-mass spectrometry (GC-MS) is one of the most important instruments for analyzing volatile organic compounds. However, the complexity of real samples and the limitations of chromatographic separation capabilities lead to coeluting compounds without ideal separation. In this study, a Transformer-based automatic resolution method (GCMSFormer) is proposed to resolve mass spectra from GC-MS peaks in an end-to-end manner, predicting the mass spectra of components directly from the raw overlapping peaks data. Furthermore, orthogonal projection resolution (OPR) was integrated into GCMSFormer to resolve minor components. The GCMSFormer model was trained, validated, and tested using 100,000 augmented data. It achieves 99.88% of the bilingual evaluation understudy (BLEU) value on the test set, significantly higher than the 97.68% BLEU value of the baseline sequence-to-sequence model long short-term memory (LSTM). GCMSFormer was also compared with two nondeep learning resolution tools (MZmine and AMDIS) and two deep learning resolution tools (PARAFAC2 with DL and MSHub/GNPS) on a real plant essential oil GC-MS data set. Their resolution results were compared on evaluation metrics, including the number of compounds resolved, mass spectral match score, correlation coefficient, explained variance, and resolution speed. The results demonstrate that GCMSFormer has better resolution performance, higher automation, and faster resolution speed. In summary, GCMSFormer is an end-to-end, fast, fully automatic, and accurate method for analyzing GC-MS data of complex samples.

Targeted Modulation of Redox and Immune Homeostasis in Acute Lung Injury Using a Thioether-Functionalized Dendrimer.

Acute lung injury (ALI) is the pathophysiological precursor of acute respiratory distress syndrome. It is characterized by increased oxidative stress and exaggerated inflammatory response that disrupts redox reactions and immune homeostasis in the lungs, thereby posing significant clinical challenges. In this study, an internally functionalized thioether-enriched dendrimer Sr-G4-PEG is developed, to scavenge both proinflammatory cytokines and reactive oxygen species (ROS) and restore homeostasis during ALI treatment. The dendrimers are synthesized using an efficient and orthogonal thiol-ene "click" chemistry approach that involves incorporating thioether moieties within the dendritic architectures to neutralize the ROS. The ROS scavenging of Sr-G4-PEG manifests in its capacity to sequester proinflammatory cytokines. The synergistic effects of scavenging ROS and sequestering inflammatory cytokines by Sr-G4-PEG contribute to redox remodeling and immune homeostasis, along with the modulation of the NLRP3-pyroptosis pathway. Treatment with Sr-G4-PEG enhances the therapeutic efficacy of ALIs by alleviating alveolar bleeding, reducing inflammatory cell infiltration, and suppressing the release of inflammatory cytokines. These results suggest that Sr-G4-PEG is a potent nanotechnological candidate for remodeling redox and immune homeostasis in the treatment of ALIs, demonstrating the great potential of dendrimer-based nanomedicine for the treatment of respiratory pathologies.

Layered Hydride LiH4 with a Pressure-Insensitive Superconductivity.

For hydride superconductors, each significant advance is built upon the discovery of novel H-based structural units, which in turn push the understanding of the superconducting mechanism to new heights. Based on first-principles calculations, we propose a metastable LiH4 with a wavy H layer composed of the edge-sharing pea-like H18 rings at high pressures. Unexpectedly, it exhibits pressure-insensitive superconductivity manifested by an extremely small pressure coefficient (dTc/dP) of 0.04 K/GPa. This feature is attributed to the slightly weakened electron-phonon coupling with pressure, caused by the reduced charge transfer from Li atoms to wavy H layers, significantly suppressing the substantial increase in the contribution of phonons to Tc. Its superconductivity originates from the strong coupling between the H 1s electrons and the high-frequency phonons associated with the H layer. Our study extends the list of H-based structural units and enhances the in-depth understanding of pressure-related superconductivity.

Sleep Quality and Suicidal Ideation in Adolescent Depression: A Chain Mediation Effect of Perceived Social Support and Resilience.

BACKGROUND: The prevalence of suicide is high among major depressive adolescents. Poor sleep quality has been documented as a significant risk factor for suicide, influencing perceived social support. Enhanced social support acts as a buffer against suicidal ideation and positively impacts resilience, reducing the prevalence of suicidal ideation. This reciprocal relationship between sleep quality, social support and resilience forms the basis for understanding the mechanisms contributing to suicidal ideation in major depressive adolescents. METHODS: A total of 585 major depressive adolescents aged 11 to 24 years was conducted to explore these associations. Assessments included the Pittsburgh Sleep Quality Index, Multidimensional Scale of Perceived Social Support, Connor-Davidson Resilience Scale and Beck Scale for Suicide Ideation. Pearson correlation and Model 6 in the SPSS program were employed for chain mediating tests. RESULTS: Better sleep quality positively predicted decreased suicide ideation (ß = 0.207, p < 0.01) and predicted lower perceived social support (ß = -0.226, p < 0.01) and resilience (ß = -0.355, p < 0.01). Perceived social support positively predicted increased resilience (ß = 0.422, p < 0.01) and negatively predicted suicide ideation (ß = -0.288, p < 0.01). Resilience negatively predicted suicide ideation (ß = -0.187, p < 0.01). Sleep quality indirectly predicted suicide ideation through perceived social support and resilience, with a mediation value of 0.0678 (95% CI [0.0359, 0.1060]), constituting 10.65% of the total effect. CONCLUSIONS: This study establishes that sleep quality indirectly predicts suicide ideation in major depressive adolescents, mediated independently by perceived social support and resilience.

Meta-analysis of cortical thickness reduction in adult schizophrenia.

BACKGROUND: Numerous neuroimaging studies using surface-based morphometry analyses have reported altered cortical thickness among patients with schizophrenia, but the results have been inconsistent. We sought to provide a whole-brain meta-analysis, which may help enhance the spatial accuracy of identification. METHODS: We conducted a meta-analysis of whole-brain studies that explored cortical thickness alteration among adult patients with schizophrenia, including first-episode patients with schizophrenia, and patients with chronic schizophrenia, compared with healthy controls by using the seed-based d mapping with permutation of subject images (SDM-PSI) software. RESULTS: A systematic literature search identified 25 studies (33 data sets) of cortical thickness, including 2008 patients with schizophrenia and 2004 healthy controls. Overall, patients with schizophrenia showed decreased cortical thickness in the right inferior frontal gyrus (IFG) and bilateral insula extending to the superior temporal gyrus (STG). Subgroup meta-analysis reported that patients with chronic schizophrenia showed decreased cortical thickness in the right insula extending to the right IFG. There was no significant cortical thickness difference between first-episode patients with schizophrenia and healthy controls. LIMITATIONS: The results of meta-regression analyses should be viewed cautiously since they were driven by a small number of studies or did not overlap with the between-group differences found in the primary analyses. CONCLUSION: The meta-analysis suggested robust cortical thickness reduction in the IFG, insula and STG among adult patients with schizophrenia, particularly in those with chronic schizophrenia. The results provide useful insights to understanding the underlying pathophysiology of schizophrenia.

Population pharmacokinetics and pharmacogenetics of apatinib in adult cancer patients.

AIMS: Apatinib is widely used in Chinese cancer patients. As the in vivo drug disposition of apatinib has large individual differences, adverse events are prone to occur. Cytochrome P450 (CYP)3A5 and cancer types maybe the main factors affecting this individual differences. The objective of our study was to establish a population pharmacokinetics (PK) model of apatinib in adult cancer patients, and to explore optimal dosage regimens for individualized treatment. METHODS: Adult patients with various types of cancer treated with apatinib were enrolled. The concentration of apatinib in plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. CYP3A5 genotype was determined using TaqMan allelic discrimination technique. The population PK model was developed by NONMEM V7.4. The dosing regimen was optimized based on Monte Carlo simulations. RESULTS: A population PK model of apatinib in adult cancer patient was established. CYP3A5 genotype and systemic cancer type (digestive system cancers, nondigestive system cancers) were the most significant covariates for PK parameters. Patients with CYP3A5*1 expressers (CYP3A5*1/*1 and CYP3A5*1/*3) had lower apparent clearance and apparent volume of distribution than patients who do not express CYP3A5*1 (CYP3A5*3/*3). Patients with nondigestive system cancer had higher apparent volume of distribution and absorption rate constant than digestive system cancer. The results of dose simulation suggest that the apatinib dose in patients who do not express CYP3A5*1 should be 33.33-50.00% higher than that in CYP3A5*1 expressers. CONCLUSIONS: A population PK model of apatinib in adult cancer patients was established. CYP3A5 genotype and systemic cancer type had concurrent effects on PK parameters. CYP3A5 patients who do not express CYP3A5*1 required higher doses.

A Comparative Study of the Typing Performance of Two Mid-Air Text Input Methods in Virtual Environments.

Inputting text is a prevalent requirement among various virtual reality (VR) applications, including VR-based remote collaboration. In order to eliminate the need for complex rules and handheld devices for typing within virtual environments, researchers have proposed two mid-air input methods-the trace and tap methods. However, the specific impact of these input methods on performance in VR remains unknown. In this study, typing tasks were used to compare the performance, subjective report, and cognitive load of two mid-air input methods in VR. While the trace input method was more efficient and novel, it also entailed greater frustration and cognitive workload. Fortunately, the levels of frustration and cognitive load associated with the trace input method could be reduced to the same level as those of the tap input method via familiarity with VR. These findings could aid the design of virtual input methods, particularly for VR applications with varying text input demands.

Synthesis and Application of Liquid Metal Based-2D Nanomaterials: A Perspective View for Sustainable Energy.

With the continuous exploration of low-dimensional nanomaterials, two dimensional metal oxides (2DMOs) has been received great interest. However, their further development is limited by the high cost in the preparation process and the unstable states caused by the polarization of surface chemical bonds. Recently, obtaining mental oxides via liquid metals have been considered a surprising method for obtaining 2DMOs. Therefore, how to scientifically choose different preparation methods to obtain 2DMOs applying in different application scenarios is an ongoing process worth discussing. This review will provide some new opportunities for the rational design of 2DMOs based on liquid metals. Firstly, the surface oxidation process and in situ electrical replacement reaction process of liquid metals are introduced in detail, which provides theoretical basis for realizing functional 2DMOs. Secondly, by simple sticking method, gas injection method and ultrasonic method, 2DMOs can be obtained from liquid metal, the characteristics of each method are introduced in detail. Then, this review provides some prospective new ideas for 2DMOs in other energy-related applications such as photodegradation, CO2 reduction and battery applications. Finally, the present challenges and future development prospects of 2DMOs applied in liquid metals are presented.

Early life Lactobacillus rhamnosus GG colonisation inhibits intestinal tumour formation.

BACKGROUND: Gut microbiota dysbiosis is closely related to the progression of colorectal cancer. Our previous study revealed that early life colonisation with Lactobacillus rhamnosus GG (LGG) had long-term positive effects on health. We sought to investigate whether early life LGG colonisation could inhibit intestinal tumour formation in offspring. METHODS: Adult C57BL/6 female mice were mated with Apcmin/+ male mice. Pregnant mice with the same conception date received 108 cfu live or fixed LGG from day 18 of pregnancy until natural delivery. After genotyping, offspring mice received 107 cfu of live or fixed LGG for 0-5 days after birth. RESULTS: Early life LGG colonisation significantly promoted intestinal development, inhibited low-grade intestinal inflammation and altered the gut microbiota composition of offspring in the weaning period (3 week old). Notably, early life LGG colonisation reduced the multiplicity of intestinal tumours in adulthood (12 week old), possibly due to inhibition of Wnt signalling and promotion of tumour cell apoptosis. Importantly, at the genus level, Bifidobacterium and Anaeroplasma with potential anti-tumour effects were increased in adulthood, while Peptostreptococcus, which potentially contributes to tumour formation, was decreased. CONCLUSIONS: Early life LGG colonisation inhibited the intestinal tumour formation of offspring in adulthood.

Amide Proton Transfer Could Provide More Accurate Lesion Characterization in the Transition Zone of the Prostate.

BACKGROUND: There is an overlap comparing transition zone prostate cancer (TZ PCa) and benign prostatic hyperplasia (BPH) on T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI), creating additional challenges for assessment of TZ tumors on MRI. PURPOSE: To evaluate whether amide proton transfer-weighted (APTw) imaging provides new diagnostic ideas for TZ PCa. STUDY TYPE: Prospective. POPULATION: A total of 51 TZ PCa patients (age, 49-89), 44 stromal BPH (age, 57-92), and 45 glandular BPH patients (age, 56-92). FIELD STRENGTH/SEQUENCE: A 3 T; T2WI turbo spin echo (TSE), quantitative T2*-weighted imaging, DWI echo planar imaging, 3D APTw TSE. ASSESSMENT: Differences in APTw, apparent diffusion coefficient (ADC), and T2* among three lesions were compared by one-way analysis of variance (ANOVA). Regions of interest were drawn by two radiologists (X.Q.Z. and X.Y.Q., with 21 and 15 years of experience, respectively). STATISTICAL TESTS: Multivariable logistic regression analyses; ANOVA with post hoc testing; receiver operator characteristic curve analysis; Delong test. Significance level: P < 0.05. RESULTS: APTw among TZ PCa, stromal BPH, and glandular BPH (3.48% ± 0.83% vs. 2.76% ± 0.49% vs. 2.72% ± 0.45%, respectively) were significantly different except between stromal BPH and glandular BPH (P > 0.99). Significant differences were found in ADC (TZ PCa 0.76 ± 0.16 × 10-3  mm2 /sec vs. stromal BPH 0.91 ± 0.14 × 10-3  mm2 /sec vs. glandular BPH 1.08 ± 0.18 × 10-3  mm2 /sec) among three lesions. APTw (OR = 12.18, 11.80, respectively) and 1/ADC (OR = 703.87, 181.11, respectively) were independent predictors of TZ PCa from BPH and stromal BPH. The combination of APTw and ADC had better diagnostic performance in the identification of TZ PCa from BPH and stromal BPH. DATA CONCLUSION: APTw imaging has the potential to be of added value to ADC in differentiating TZ PCa from BPH and stromal BPH. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Amide Proton Transfer MRI Could Be Used to Evaluate the Pathophysiological Status of White Matter Hyperintensities.

BACKGROUND: The pathophysiology of white matter hyperintensities (WMH) remains unclear, investigations of amide proton transfer (APT) signals in WMH disease may provide relevant pathophysiological information. PURPOSE: To evaluate the APT signals differences and heterogeneity of WMH and adjacent normal-appearing white matter (NAWM) at different Fazekas grades and different locations. STUDY TYPE: Prospective. POPULATION: In all, 180 WMH patients (age, 40-76; male/female, 77/103) and 59 healthy controls (age, 42-70; male/female, 23/36). FIELD STRENGTH/SEQUENCE: A 3 T; 3D fluid-attenuated inversion recovery (FLAIR), 3D APT-weighted (APTw). ASSESSMENT: The mean APTw values (APTwmean ) and the APTw signals heterogeneity (APTwmax-min ) among different grades WMH and NAWM and the APTwmean of the same grade deep WMH (DWMH) and paraventricular WMH (PWMH) were calculated and compared. Regions of interests were delineated on WMH lesions, NAWM and healthy white matter. STATISTICAL TESTS: One-way analysis of variance (ANOVA); independent sample t test; Chi-square test. Significance level: P < 0.05. RESULTS: APTwmean among different grade WMH (from grade 0 to 3, 0.58 ± 0.14% vs. 0.29 ± 0.23% vs. 0.37 ± 0.24% vs. 0.61 ± 0.22%, respectively) were significantly different except between grade 1 and 2 (P = 0.27) and between grade 0 and 3 (P = 0.97). The differences in APTwmean between WMH and NAWM were significant (WMH vs. NAWM from grade 1 to 3, 0.29% ± 0.23% vs. 0.55% ± 0.27%; 0.37% ± 0.24% vs. 0.59% ± 0.22%; 0.61% ± 0.22% vs. 0.42% ± 0.24%, respectively). Lower APTwmean values were found only in grade 3 NAWM than other grades NAWM and controls. The APTwmax-min values of grade 1-3 WMH (0.38% ± 0.27% vs. 0.51% ± 0.31% vs. 0.67% ± 0.34%, respectively) were significantly different. Higher APTmean values were found only in grade 2 PWMH (0.47% ± 0.22% vs. 0.32% ± 0.24%). DATA CONCLUSION: Significant differences of APT signals were found in WMH of different Fazekas grades and different locations. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

SF6 High-Voltage Circuit Breaker Contact Status Detection at Different Currents.

Currently, the online non-destructive testing (NDT) methods to measure the contact states of high-voltage circuit breakers (HVCBs) with SF6 gas as a quenching medium are lacking. This paper aims to put forward a novel method to detect the contact state of an HVCB based on the vibrational signal. First, for a 40.5-kV SF6 HVCB prototype, a mechanical vibration detection system along with a high-current generator to provide the test current is designed. Given this, vibration test experiments are carried out, and the vibration signal data under various currents and corresponding contact states are obtained. Afterward, a feature extraction method based on the frequency is designed. The state of the HVCB contacts is then determined using optimized deep neural networks (DNNs) along with the method of adaptive moment estimation (Adam) on the obtained experimental data. Finally, the hyperparameters for the DNNs are tuned using the Bayesian optimization (BO) technique, and a global HVCB contact state recognition model at various currents is proposed. The obtained results clearly depict that the proposed recognition model can accurately identify five various contact states of HVCBs for the currents between 1000 A and 3500 A, and the recognition accuracy rate is above 96%. The designed experimental and theoretical analysis in our study will provide the references for future monitoring and diagnosis of faults in HVCBs.

Long noncoding RNA SNHG4: a novel target in human diseases.

Recently, long noncoding RNAs (lncRNAs) have attracted great attention from researchers. LncRNAs are non-protein-coding RNAs of more than 200 nucleotides in length. Multiple studies have been published on the relationship between lncRNA expression and the progression of human diseases. LncRNA small nucleolar RNA host gene 4 (SNHG4), a member of the lncRNA SNHG family, is abnormally expressed in a variety of human diseases, including gastric cancer, renal cell carcinoma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, osteosarcoma, cervical cancer, liver cancer, lung cancer, non-small-cell lung cancer, neonatal pneumonia, diabetic retinopathy, neuropathic pain, acute cerebral infarction, acute myeloid leukaemia, and endometriosis. In this paper, the structure of SNHG4 is first introduced, and then studies in humans, animal models and cells are summarized to highlight the expression and function of SNHG4 in the above diseases. In addition, the specific mechanism of SNHG4 as a competing endogenous RNA (ceRNA) is discussed. The findings indicate that SNHG4 can be used as a biomarker for disease prognosis evaluation and as a potential target for disease diagnosis and treatment.

High-fat diet-induced dysbiosis mediates MCP-1/CCR2 axis-dependent M2 macrophage polarization and promotes intestinal adenoma-adenocarcinoma sequence.

High-fat diet (HFD) is a well-known risk factor for gut microbiota dysbiosis and colorectal cancer (CRC). However, evidence relating HFD, gut microbiota and carcinogenesis is limited. Our study aimed to demonstrate that HFD-induced gut dysbiosis promoted intestinal adenoma-adenocarcinoma sequence. In clinical study, we found that HFD increased the incidence of advanced colorectal neoplasia (AN). The expression of monocyte chemoattractant protein 1 (MCP-1), CC chemokine receptor 2 (CCR2) and CD163 in CRC patients with HFD was significantly higher than that in CRC patients with normal diet. When it comes to the Apcmin/+ mice, HFD consumption could induce gut dysbiosis and promote intestinal carcinogenesis, accompanying with activation of MCP-1/CCR2 axis that recruited and polarized M2 tumour-associated macrophages. Interestingly, transfer of faecal microbiota from HFD-fed mice to another batch of Apcmin/+ mice in the absence of HFD could also enhance carcinogenesis without significant body weight gain and induced MCP-1/CCR2 axis activation. HFD-induced dysbiosis could also be transmitted. Meanwhile, antibiotics cocktail treatment was sufficient to inhibit HFD-induced carcinogenesis, indicating the vital role of dysbiosis in cancer development. Conclusively, these data indicated that HFD-induced dysbiosis accelerated intestinal adenoma-adenocarcinoma sequence through activation of MCP-1/CCR2 axis, which would provide new insight into better understanding of the mechanisms and prevention for HFD-related CRC.

The gut microbiota at the intersection of bile acids and intestinal carcinogenesis: An old story, yet mesmerizing.

The prevalence of colorectal cancer (CRC) has markedly increased worldwide in the last decade. Alterations of bile acid metabolism and gut microbiota have been reported to play vital roles in intestinal carcinogenesis. About trillions of bacteria have inhabited in the human gut and maintained the balance of host metabolism. Bile acids are one of numerous metabolites that are synthesized in the liver and further metabolized by the gut microbiota, and are essential in maintaining the normal gut microbiota and lipid digestion. Multiple receptors such as FXR, GPBAR1, PXR, CAR and VDR act as sensors of bile acids have been reported. In this review, we mainly discussed interplay between bile acid metabolism and gut microbiota in intestinal carcinogenesis. We then summarized the critical role of bile acids receptors involving in CRC, and also addressed the rationale of multiple interventions for CRC management by regulating bile acids-microbiota axis such as probiotics, metformin, ursodeoxycholic acid and fecal microbiota transplantation. Thus, by targeting the bile acids-microbiota axis may provide novel therapeutic modalities in CRC prevention and treatment.

Prediction of Unbound Ceftriaxone Concentration in Children: Simple Bioanalysis Method and Basic Mathematical Equation.

The pharmacological activity of ceftriaxone depends on the unbound concentration. However, direct measurement of unbound concentrations is obstructive, and high individual variability of the unbound fraction of ceftriaxone was shown in children. We aim to evaluate and validate a method to predict unbound ceftriaxone concentrations in pediatric patients. Ninety-five pairs of concentrations (total and unbound) from 92 patients were measured by the bioanalysis method that we developed. The predictive performance of the three equations (empirical in vivo equation, disease-adapted equation, and multiple linear regression equation) was assessed by the mean absolute prediction error (MAPE), the mean prediction error (MPE), the proportions of the prediction error within ±30% (P30) and ±50% (P50), and linear regression of predicted versus actual unbound levels (R2). The average total and unbound ceftriaxone concentrations were 126.18 ± 81.46 µg/ml and 18.82 ± 21.75 µg/ml, and the unbound fraction varied greatly from 4.75% to 39.97%. The MPE, MAPE, P30, P50, and R2 of the empirical in vivo equation, disease equation, and multiple linear equation were 0.17 versus 0.00 versus 0.06, 0.24 versus 0.15 versus 0.27, 63.2% versus 89.5% versus 74.7%, 96.8% versus 97.9% versus 86.3%, and 0.8730 versus 0.9342 versus 0.9315, respectively. The disease-adapted equation showed the best predictive performance. We have developed and validated a bioanalysis method with one-step extraction pretreatment for the determination of total ceftriaxone concentrations, and a prediction equation of the unbound concentration is recommended. The proposed method can facilitate clinical practice and research on unbound ceftriaxone in children. (This study has been registered at ClinicalTrials.gov under identifier NCT03113344.).

Comparison of the effects of salinity on microbial community structures and functions in sequencing batch reactors with and without carriers.

This study investigated and compared the microbial communities between a sequencing batch reactor (SBR) without carriers and a hybrid SBR with addition of carriers for the treatment of saline wastewater. The two systems were operated over 292 days with alternating aerobic/anoxic mode (temperature: 28℃, salinity: 0.0-3.0%). High removal efficiency of chemical oxygen demand (COD) and total inorganic nitrogen (TIN) was achieved in both the SBR (above 86.7 and 95.4% respectively) and hybrid SBR (above 84.4 and 94.0%) at 0.0-2.5% salinity. Further increasing salinity to 3.0% decreased TIN removal efficiency to 78.4% in the hybrid SBR. Steep decline of biodiversity and relative abundance of ammonia-oxidizing bacteria (AOB) contributed to the worse performance. More genera related to sulfide-oxidizing and sulfate-reducing bacteria were detected in the hybrid SBR than the SBR at 3.0% salinity. The abundance of halotolerant bacteria increased with the salinity increase for both reactors, summing up to 25.5% in the suspended sludge (S-sludge) from the SBR, 28.9 and 22.9% in the S-sludge and biofilm taken from the hybrid SBR, respectively. Nitrification and denitrification via nitrate was the main nitrogen removal pathway in the SBR and hybrid SBR at 0.0 and 0.5% salinity, while partial nitrification and denitrification via nitrite became the key process for nitrogen removal in the two reactors when the salinity was increased to 1.0-3.0%. Higher abundance of anaerobic ammonium-oxidizing (ANAMMOX) and sulfide-oxidizing autotrophic denitrification (SOAD) bacteria were found in the hybrid SBR at 3.0% salinity.

Diammonium Glycyrrhizinate Protects against Nonalcoholic Fatty Liver Disease in Mice through Modulation of Gut Microbiota and Restoration of Intestinal Barrier.

Nonalcoholic fatty liver disease (NAFLD), as a common chronic liver disorder, is prevalent in the world. Recent evidence demonstrates that the "gut-liver axis" is related well to the progression of NAFLD, which regards gut microbiota and the intestinal barrier as two critical factors correlated with NAFLD. Diammonium glycyrrhizinate (DG), a compound of the natural bioactive pentacyclic triterpenoid glycoside, is the main component of licorice root extracts. The anti-inflammatory and liver protection effects of DG have already been reported, but to date, the mechanism has not been fully elucidated. In this research, we observed that DG reduced body weight, liver steatosis, as well as hepatic inflammation in NAFLD model mice induced by a high-fat diet. Illumina sequencing of the 16S rRNA revealed that DG intervention notably altered the composition of the gut microbiota in NAFLD mice. The richness of gut microbiota was significantly increased by DG. Specifically, DG reduced the Firmicutes-to- Bacteroidetes ratio and the endotoxin-producing bacteria such as Desulfovibrio and elevated the abundance of probiotics such as Proteobacteria and Lactobacillus. DG could augment the levels of short-chain fatty acid (SCFA)-producing bacteria such as Ruminococcaceae and Lachnospiraceae and promote SCFA production. In addition, DG supplementation dramatically alleviated the intestinal low-grade inflammation. Meanwhile, DG improved the expression of tight junction proteins, the goblet cell number, and mucin secretion and sequentially enhanced the function of intestinal barrier. Collectively, the prevention of NAFLD by DG might be mediated by modulating gut microbiota and restoring the intestinal barrier.