Human adenovirus (HAdV) infection in children with acute respiratory tract infections in Guangzhou, China, 2010-2021: a molecular epidemiology study.

BACKGROUND: Human adenovirus (HAdV) infection can cause a variety of diseases. It is a major pathogen of pediatric acute respiratory tract infections (ARIs) and can be life-threatening in younger children. We described the epidemiology and subtypes shifting of HAdV among children with ARI in Guangzhou, China. METHODS: We conducted a retrospective study of 161,079 children diagnosed with acute respiratory illness at the Guangzhou Women and Children's Medical Center between 2010 and 2021. HAdV specimens were detected by real-time PCR and the hexon gene was used for phylogenetic analysis. RESULTS: Before the COVID-19 outbreak in Guangzhou, the annual frequency of adenovirus infection detected during this period ranged from 3.92% to 13.58%, with an epidemic peak every four to five years. HAdV demonstrated a clear seasonal distribution, with the lowest positivity in March and peaking during summer (July or August) every year. A significant increase in HAdV cases was recorded for 2018 and 2019, which coincided with a shift in the dominant HAdV subtype from HAdV-3 to HAdV-7. The latter was associated with a more severe disease compared to HAdV-3. The average mortality proportion for children infected with HAdV from 2016 to 2019 was 0.38% but increased to 20% in severe cases. After COVID-19 emerged, HAdV cases dropped to 2.68%, suggesting that non-pharmaceutical interventions probably reduced the transmission of HAdV in the community. CONCLUSION: Our study provides the foundation for the understanding of the epidemiology of HAdV and its associated risks in children in Southern China.

[Discovery and confirmation of protein action site AK1 of ginsenosides in brain based on DARTS technology].

This study aims to explore the targets of ginsenosides in brain based on drug affinity responsive target stability(DARTS) technology. Specifically, DARTS technology was combined with label-free liquid chromatography tandem mass spectrometry(LC-MS) to screen out the proteins in the brain that might interact with ginsenosides. Based on the screening results, adenylate kinase 1(AK1) was selected for further confirmation. First, the His-AK1 fusion protein was yielded successively through the construction of recombinant prokaryotic expression vector, expression of target protein, and purification of the fusion protein. Biolayer interferometry(BLI) was employed to detect the direct interaction of Rg_1, Re, Rb_1, Rd, Rh_2, F1, Rh_1, compound K(CK), 25-OH-PPD, protopanaxa-diol(PPD), and protopanaxatriol(PPT) with AK1, thereby screening the ginsenoside monomer or sapogenin that had strong direct interaction with the suspected target protein AK1. Then, the BLI was used to further determine the kinetic parameters for the binding of PPD(strongest interaction with AK1) to His-AK1 fusion protein. Finally, molecular docking technology was applied to analyze the binding properties between the two. With DARTS and LC-MS, multiple differential proteins were screened out, and AK1 was selected based on previous research for target verification. Fusion protein His-AK1 was obtained by prokaryotic expression, and the response(nm) of Re, Rg_1, Rd, Rb_1, Rh_1, Rh_2, F1, PPT, PPD, 25-OH-PPD, and CK with His-AK1 was respectively 0.003 1, 0.001 9, 0.042 8, 0.022 2, 0.013 4, 0.037 3, 0.013 9, 0.030 7, 0.140 2, 0.016 0, and 0.040 8. The K_(on), K_(off), and K_D values of PPD and His-AK1 were determined by the BLI as 1.22×10~2 mol~(-1)·L·s~(-1), 1.04×10~(-2) s~(-1), 8.52×10~(-5) mol·L~(-1). According to the molecular docking result, PPD bound to AK1 with the absolute value of the docking score of 3.438, and hydrogen bonds mainly formed between the two. Thus, AK1 is one of the protein action sites of ginsenosides in the brain. The direct interaction between ginsenoside metabolite PPD and AK1 is the strongest.

A novel P38α MAPK activator Bruceine A exhibits potent anti-pancreatic cancer activity.

Pancreatic cancer remains one of the cancers with the poorest prognosis bearing an overall 5-year survival rate of about 5%. Efficient new chemotherapic drugs are still highly desired. Here, bruceine A, a quassinoid identified from the dried fruits of Brucea javanica (L.) Merr., displayed the most potent anti-proliferation activity against pancreatic cancer in vitro and in vivo. Phosphoproteomic analysis revealed p38α MAPK phosphorylation was involved in bruceine A's action in MIA PaCa-2 cells. Utilizing fortebio octet system and microscale thermophoresis, we found p38α MAPK had high affinity for bruceine A. Molecular docking and molecular dynamic simulations showed that bruceine A widely bound to residues (Leu171, Ala172, Met179, Thr180, Val183) in P-loop of p38α MAPK. Key determinants of bruceine A binding with P-loop of p38α MAPK were 19-C[bond, double bond]O, 22-CH3, 32-CH3, and 34-CH3. Taken together, our findings demonstrate that bruceine A binds directly to p38α MAPK, which can be used to probe the role of p38α MAPK phosphorylation in pancreatic cancer progression, and as a novel lead compound for pancreatic cancer therapy.

Global discovery the PstP interactions using Mtb proteome microarray and revealing novel connections with EthR.

Mycobacterium tuberculosis (Mtb) serine/threonine protein phosphatase PstP plays an important role in regulating Mtb cell division and growth by reversible phosphorylation signaling. However, the substrates of Mtb with which the PstP interacts, and the underlying molecular mechanisms are still largely unknown. In this study, we performed an Mtb proteome microarray to globally identify the PstP bindings. In this way, we discovered 78 interactors between PstP and Mtb proteins, and found a novel connections with EthR. The interaction between PstP and EthR has been validated by Bio-Layer interferometry and Yeast-two-hybrid. And functional studies showed that PstP significantly enhances the binding between EthR and related DNA domain through its interaction with EthR. Phenotypically, overexpression of PstP promoted the resistance of Mycobacterium smegmatis with the antibiotic of ethionamide. Overall, we hopefully wish that the PstP interactors identified in this study will serve as a useful resource for further systematic studies of the roles that PstP plays in the regulation of Mtb dephosphorylation. SIGNIFICANCE: Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, which is responsible of ~1.5 million death per year. Understanding the knowledge about the basic biological regulation pathways in Mtb is an effective approach to discover the novel drug targets for cure TB. PstP is a serine/threonine protein phosphatase in Mtb, and plays important roles in regulating Mtb cell division and growth by reversible phosphorylation signaling. In this study, we identified 78 PstP interacting Mtb proteins using Mtb proteome microarray, which could preliminarily explain the roles of PstP played in Mtb. Moreover, functional analysis showed that a novel transcription factor EthR had been found regulated by PstP through binding, which could enhance the resistance to the antibiotic ETH. Overall, this network constructed with PstP-Mtb proteins could serve as a valuable resource for studying Mtb growth.

Pentoxifylline plus ACEIs/ARBs for proteinuria and kidney function in chronic kidney disease: a meta-analysis.

Objective This meta-analysis aimed to investigate the efficacy and safety of pentoxifylline (PTF) plus angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) for proteinuria and kidney function in chronic kidney disease (CKD). Methods CENTRAL, EMBASE, Ovid-MEDLINE, PubMed, and CNKI were searched for relevant, randomized, controlled trials (RCTs). A meta-analysis was performed to review the effect of PTF plus ACEIs/ARBs vs. ACEIs/ARBs alone on proteinuria and kidney function in CKD. Results Eleven RCTs including 705 patients were retrieved. PTF plus ACEI/ARB treatment significantly decreased proteinuria in patients with CKD within 6 months (standard mean difference [SMD] -0.52; 95% CI -0.90 to 0.15; I2 = 68%) and significantly attenuated a decrease in estimated glomerular filtration rate (eGFR) in patients with stages 3-5 CKD after 6 months of treatment (standard mean difference [SMD] 0.30; confidence limit [Cl] 95% CI 0.06 to 0.54; I2 = 0%). PTF plus ACEIs/ARBs for 9 to 12 months significantly reduced albuminuria in patients with CKD (SMD-0.30, 95% CI -0.57 to 0.03; I2 = 0%) and alleviated the decline in eGFR in patients with stages 3-5 CKD (SMD 0.51; 95% CI 0.06 to 0.96; I2 = 61%). Conclusion The combination of an ACEI or ARB and PTF has a protective effect in reducing proteinuria by ameliorating the decline in eGFR in patients with stages 3-5 CKD.

Influence of biological scaffold regulation on the proliferation of chondrocytes and the repair of articular cartilage.

PURPOSE: To investigate the effects of hard tissue engineering scaffold (the material is ß-TCP) with different micro-structures on the proliferation of chondrocytes, and the influence of its composite erythrocytes on the repair of articular cartilage defects. METHODS: Rabbit cartilage cells were on ß-TCP bioceramic scaffold with different micro-structures in vitro, the proliferation growth trend of chondrocytes within the scaffold was calculated, and a optimal micro-structure suitable for cartilage cell growth was determined. Composite chondrocytes were implanted into rabbit models of articular cartilage defects, and the repair situation was observed. RESULTS: the bioceramic scaffold with an inner diameter of 120 µm and an aperture of 500-630 µm was suitable for the growth of cartilage cells. Scaffold loaded with second generation of cartilage cell suspension got a top histological score of 20.76±2.13, which was closely similar to that of normal cartilage. CONCLUSION: When loaded with the second generation of cartilage cells, the ß-TCP biological ceramic scaffold with a pore size of 500-630 µm, and an inner diameter of 120 µm, shows a best repairing effect on animal articular cartilage defects.

Inorganic phosphate-triggered release of anti-cancer arsenic trioxide from a self-delivery system: an in vitro and in vivo study.

On-demand drug delivery is becoming feasible via the design of either exogenous or endogenous stimulus-responsive drug delivery systems. Herein we report the development of gadolinium arsenite nanoparticles as a self-delivery platform to store, deliver and release arsenic trioxide (ATO, Trisenox), a clinical anti-cancer drug. Specifically, unloading of the small molecule drug is triggered by an endogenous stimulus: inorganic phosphate (Pi) in the blood, fluid, and soft or hard tissue. Kinetics in vitro demonstrated that ATO is released with high ON/OFF specificity and no leakage was observed in the silent state. The nanoparticles induced tumor cell apoptosis, and reduced cancer cell migration and invasion. Plasma pharmacokinetics verified extended retention time, but no obvious disturbance of phosphate balance. Therapeutic efficacy on a liver cancer xenograft mouse model was dramatically potentiated with reduced toxicity compared to the free drug. These results suggest a new drug delivery strategy which might be applied for ATO therapy on solid tumors.

[Identification of multidrug resistance gene MDR1 associated microRNA of salvianolic acid A reversal in lung cancer].

This paper was aimed to investigate the microRNA associated with multidrug resistance gene MDR1 of salvianolic acid A reversal in lung cance. Human lung cancer A549 cells were divided into normal control group and drug group, and the MDR1 expression levels were determined by real-time quantitative PCR. MicroRNA expression profiling of normal control group and drug group were detected by using the latest microRNA microarray. Quantitative RT-PCR was used to validate the differentially expressed miRNA. Forecast of miRNA associated with MDR1 multi-resistant genes of up-regulated miRNA. Experimental results showed that the dosage of MDR1 expression level significantly lowered compared with control group. The miRNA expression spectrum analyses of human lung cancer A549 cells to drug group and the control group were detected by microRNA microarray, 426 differentially expressed miRNA were screened out. Then target prediction were performed for difference up-expression of miRNA and found that there were four obvious increase of miRNA associated with MDR1 multi-resistant genes. Real-time quantitative PCR for 4 microRNA verification, the results were consistent with the chip. So the author considered that salvianolic acid A down lung cancer multidrug resistance gene MDR1 is likely to be affected by the miRNA expression and regulation of target genes, to further clarify the traditional Chinese medicine to reverse multi-drug resistant mechanism provides the experimental basis.

Numerical magnitude processing in abacus-trained children with superior mathematical ability: an EEG study.

Distance effect has been regarded as the best established marker of basic numerical magnitude processes and is related to individual mathematical abilities. A larger behavioral distance effect is suggested to be concomitant with lower mathematical achievement in children. However, the relationship between distance effect and superior mathematical abilities is unclear. One could get superior mathematical abilities by acquiring the skill of abacus-based mental calculation (AMC), which can be used to solve calculation problems with exceptional speed and high accuracy. In the current study, we explore the relationship between distance effect and superior mathematical abilities by examining whether and how the AMC training modifies numerical magnitude processing. Thus, mathematical competencies were tested in 18 abacus-trained children (who accepted the AMC training) and 18 non-trained children. Electroencephalography (EEG) waveforms were recorded when these children executed numerical comparison tasks in both Arabic digit and dot array forms. We found that: (a) the abacus-trained group had superior mathematical abilities than their peers; (b) distance effects were found both in behavioral results and on EEG waveforms; (c) the distance effect size of the average amplitude on the late negative-going component was different between groups in the digit task, with a larger effect size for abacus-trained children; (d) both the behavioral and EEG distance effects were modulated by the notation. These results revealed that the neural substrates of magnitude processing were modified by AMC training, and suggested that the mechanism of the representation of numerical magnitude for children with superior mathematical abilities was different from their peers. In addition, the results provide evidence for a view of non-abstract numerical representation.

HDAC5 promotes osteosarcoma progression by upregulation of Twist 1 expression.

Histone deacetylases (HDACs) form a family of enzymes, which have fundamental roles in the epigenetic regulation of gene expression and contribute to the growth, differentiation, and apoptosis of cancer cells. In this study, we firstly investigated the biological function of HDAC5 in osteosarcoma cells. We found that mRNA and protein levels of HDAC5 were upregulated in osteosarcoma tissues and cell lines. Furthermore, overexpression of HDAC5 could promote cell proliferation in osteosarcoma cell lines. In contrast, HDAC5 knockdown using small interfering RNA inhibited cell proliferation. At the molecular level, we demonstrated that HDAC5 promoted mRNA expression of twist 1, which has been reported as an oncogene. Together, these results highlighted for the first time an unrecognized link between HDAC5 and osteosarcoma progression and demonstrated that its specific inhibition might contribute to the treatment of tumorigenesis.

[Adrenal mitochondrial injury in early stage of sepsis in rats].

OBJECTIVE: To study the pathogenesis of adrenal mitochondrial dysfunction in septic rats. METHODS: Thirty SPF rats were randomized into 3 groups, including a normal control group and 2 sepsis groups receiving intraperitoneal injection of 10 mg/kg lipopolysaccharide (LPS) and observed at 6 and 24 h after the injection. The adrenal mitochondria were extracted from the rats at the corresponding time points for observation by electronic microscopy. The membrane potential of the mitochondria was detected by flow cytometry. The oxidative stress levels in the mitochondria (activities of NOS and levels of MDA and NO) were assessed. RESULTS: With the progression of sepsis, the serum levels of corticosterone in LPS groups increased significantly as compared with that in the control group. Ultrastructural observation of the adrenal mitochondria showed mild mitochondrial injury in LPS groups in comparison with the control group. The mitochondrial membrane potential was lowered in the LPS groups, but all these changes appeared to be reversible. The activities of NOS and the levels of MDA and NO showed no significant difference between the sepsis groups and the control group. CONCLUSIONS: No obvious adrenal dysfunction occurs in the early stage of sepsis in rats. Mitochondrial injury, which is reversible, occurs in early sepsis without obvious evidence of oxidative stress injury in the adrenal mitochondria, suggesting a strong resistance and capacity of self-repair of the adrenal gland and the mitochondria against sepsis-induced injury.