Search

Silicosis is a pulmonary disease caused by the inhalation of silica. There is a lack of early and effective prevention, diagnosis, and treatment methods, and addressing silicotic fibrosis is crucial. Quercetin, a flavonoid with anti-carcinogenic, anti-inflammatory, and antiviral properties, is known to have a suppressive effect on fibrosis. The present study aimed to determine the therapeutic effect of quercetin on silicotic mice and macrophage polarity. We found that quercetin suppressed silicosis in mice. It was observed that SiO2 activated macrophage polarity and the macrophage-to-myofibroblast transition (MMT) by transforming the growth factor-β (TGF-β)-Smad2/3 signaling pathway in silicotic mice and MH-S cells. Quercetin also attenuated the MMT and the TGF-β-Smad2/3 signaling pathway in vivo and in vitro. The present study demonstrated that quercetin is a potential therapeutic agent for silicosis, which acts by regulating macrophage polarity and the MMT through the TGF-β-Smad2/3 signaling pathway.

Rosacea is a chronic inflammatory skin disease whose late manifestations have not yet been clearly reported in animal models. The objective of this study is to describe the skin lesions and major histopathological changes in a rosacea-like phenotype in mice induced by prolonged LL-37 administration and furthermore, to assess the potential of long-term LL-37 administration in inducing irreversible rosacea-like skin lesion models. Balb/c mice were continuously injected intradermally with LL-37 every 12 h to induce a rosacea-like phenotype. After LL-37 injections were administered for 20 consecutive days, the area of rosacea-like lesions gradually expanded in the first 13 days, then entered a stable phase. Haematoxylin and eosin (H&E) and Van Gieson’s staining showed a high degree of inflammatory cell aggregation, thickening of the epidermis and dermis, and collagen deposition in large quantities. The results of immunofluorescence staining and Western blotting showed that the expression of α-SMA, TNF-α, vimentin, and COL1 in the skin of mice was significantly upregulated. Short-term LL-37 administration induced rosacea-like lesions that only featured the aggregation of inflammatory factors and thickening of the epidermis, whereas no collagen hyperplasia was observed, and a full recovery was noticed. However, rosacea-like skin lesions induced by long-term LL-37 administration did not completely recover. Our study compares rosacea-like lesions induced by short-term versus long-term LL-37 administration, and the results suggest that irreversible rosacea-like lesions can be induced by long-term LL-37 administration.

Cos improved psoriasis-like lesions caused by imiquimod stimulation, and might have a therapeutic effect on skin inflammation through P2X7R/IL-36 related pathways.

A kind of functional BHV material has been exploited which exhibits superior anti-inflammation, improved anti-coagulation, minimal calcification and promoted proliferation of endothelial cells.

Mussel foot proteins (Mfps) display application potential with strong adhesion, enabling mussels to adhere firmly to various surfaces. Mytilus galloprovincialis foot protein 3B (Mgfp-3B) exhibits this characteristic remarkably. However, it remains a challenge for further research due to the low soluble expression of heterologous production. In this study, a small ubiquitin-related modifier (SUMO) and thioredoxin A (TrxA), which catalyzed the proper folding of disulfide bridges, were selected to increase the soluble expression of mfps. An additional ribosome binding site was introduced between the molecular chaperones and Mgfp-3B (fp-3) to form a bicistronic translation-coupled expression vector for co-expression. The results revealed that the combination of SUMO-TrxA increased the soluble expression of fp-3 by 18.07 %. Furthermore, the SUMO-TrxA also boosted the soluble expression of hybrid mfps Mgfp-3B-Mfp-1 (fp-3-1) by 11.29 %, Mgfp-3B-Mgfp-3B (fp-3-3) by 19.91 %, and Mgfp-3B-Mgfp-5 (fp-3-5) by 14.03 %. Ultimately, by high cell density cultivation in a 5 L bioreactor, the yields of fp-3, fp-3-3, and fp-3-5 co-expressed with SUMO-TrxA reached 217.75 mg/L, 127.2 mg/L, and 97.28 mg/L, respectively. Consequently, soluble production of mfps holds great potential for the sustainable supply of protein adhesive materials.

Human epidermal growth factor (hEGF) has multiple biological functions, such as promoting cell proliferation, differentiation, and migration. In addition, it is a very expensive polypeptide with attractive market prospects. However, the production of hEGF needs for high cost to manufacture polypeptide demands reinvestigations of process conditions so as to enhance economic benefits. Improving the expression of soluble hEGF is the fundamental method to reduce the cost. In this study, a non-extracellular engineered strain of expressed hEGF was constructed, using plasmid pET-22b(+) in Escherichia coli. Preliminary fermentation and high cell density cultivation were carried out in shake flasks and in a 5 L bioreactor, respectively. A high yield of 98 ± 10 mg/L of soluble hEGF and a dry cell weight (DCW) of 6.98 ± 0.3 g/L were achieved in shake flasks. Then, fermentation conditions were optimized for large-scale production, while taking into consideration the expensive equipment required for cooling and conforming to industrial standards. A yield of 285 ± 10 mg/L of soluble hEGF, a final cell density of 57.4 ± 2 g/L DCW (OD

Objective. Enteric-coated mycophenolate sodium (EC-MPS) is widely used in renal transplant recipients. There is a lack of study on the pharmacokinetics of this drug in children. This study is aimed at developing a population pharmacokinetic model of mycophenolic acid in children who were treated with EC-MPS after renal transplantation and to recommend initial dosage. Methods. Pediatric patients who had undergone renal transplantation and received EC-MPS were included. Data on demographic characteristics, biochemical tests, blood routine examinations, mycophenolic acid plasma concentrations, dosing amount and frequency of EC-MPS, and coadministered medications were retrospective collected from June 2018 to August 2019. Nonlinear mixed effect modeling methods were adopted to develop a population pharmacokinetic model with the data above. Additional data from September 2019 to July 2020 were used to validate the model. Simulations under different dosage regimen were conducted to evaluate the percentage of target attainment (PTA, AUC0-12h 30–60 mg·h/L). Results. A total of 96 pediatric patients aged at 13.3 (range 4.3–18.0) years were included in the modeling group. Data from 32 patients aged at 13.0 (range 3.6–18.3) years were used to validate the model. A one-compartment model with a double extravascular absorption was developed. Body surface area (BSA) was added as a covariate. Simulations showed that for different dosing regimens, the highest percentage of target attainment is around 50%. The best dosing regimen is 180 mg every 48 hours for patients with BSA of 0.22–0.46 m2, 180 mg every 24 hours with BSA of 0.47–0.67 m2, 180 mg every 24 hours with BSA of 0.68–0.96 m2, 360 mg every 24 hours with BSA of 0.97–1.18 m2, 540 mg every 24 hours with BSA of 1.19–1.58 m2, and 360 mg every 12 hours with BSA of 1.59–2.03 m2. Conclusion. BSA could affect the area under curve of mycophenolic acid with the administration of EC-MPS. Considering the inflexibility of the dosage form, future development of smaller amount per tablet suitable for younger children with BSA < 1.19 m 2 is warranted.

Pichia pastoris has been recognized as an important platform for the production of various heterologous proteins in recent years. The strong promoter AOX1, induced by methanol, with the help of the α-pre-pro signal sequence, can lead to a high expression level of extracellular protein. However, this combination was not always efficient, as protein secretion in P. pastoris involves numerous procedures mediated by several cellular proteins, including folding assisted by endoplasmic reticulum (ER) molecular chaperones, degradation through ubiquitination, and an efficient vesicular transport system. Efficient protein expression requires the cooperation of various intracellular pathways. This article summarizes the process of protein secretion, modification, and transportation in P. pastoris. In addition, the roles played by the key proteins in these processes and the corresponding co-expression effects are also listed. It is expected to lay the foundation for the industrial protein production of P. pastoris. KEY POINTS: • Mechanisms of chaperones in protein folding and their co-expression effects are summarized. • Protein glycosylation modifications are comprehensively reviewed. • Current dilemmas in the overall protein secretion pathway of Pichia pastoris and corresponding solutions are demonstrated.

Tiger pufferfish (Takifugu rubripes) is one of Asia's most economically valuable aquaculture species. However, winter production of this species in North China is limited by low water temperature and unavailability of high-quality feed, resulting in high mortality and low profitability. Therefore, the aim of this study was to evaluate the effect of feeding frequency (F1: one daily meal; F2: two daily meals; F3: four daily meals; F4: continuous diurnal feeding using a belt feeder) on the growth performance, plasma biochemistry, digestive and antioxidant enzyme activities, and expression of appetite-related genes in T. rubripes (initial weight: 266.80 ± 12.32 g) cultured during winter (18.0 ± 1.0 °C) for 60 days. The results showed that fish in the F3 group had the highest final weight, weight gain rate, specific growth rate, survival rate, and best feed conversion ratio. Additionally, daily feed intake increased significantly with increasing feeding frequency. The protein efficiency and lipid efficiency ratios of fish in the F3 group were significantly higher than those of fish in the other groups. Furthermore, total cholesterol, triglycerides, and glucose levels increased with increasing feeding frequency, peaking in the F2 group and decreasing under higher feeding frequencies. The antioxidant (superoxide dismutase, catalase, glutathione, and glutathione peroxidase) and digestive (trypsin, amylase, and lipase) enzyme activities of fish in the F1 group were significantly higher than those of fish in the F3 and F4 groups. Additionally, there was a decrease in orexin expression with increasing feeding frequency. In contrast, the expression levels of tachykinin, cholecystokinin, and leptin increased with increasing feeding frequency, peaking in the F4 group. Overall, the findings of this study indicated that a feeding frequency of four meals per day was optimal for improved growth performance of pufferfish juveniles cultured during winter.

Engineered synthetic scaffolds to organize metabolic pathway enzymes and system pathway engineering to fine-tune metabolic fluxes play essential roles in microbial production. Here, we first obtained the most favorable combination of key enzymes for 5-aminolevulinic acid (5-ALA) synthesis through the C5 pathway by screening enzymes from different sources and optimizing their combination in different pathways. Second, we successfully constructed a multienzyme complex assembly system with PduA*, which spatially recruits the above three key enzymes for 5-ALA synthesis in a designable manner. By further optimizing the ratio of these key enzymes in synthetic scaffolds, the efficiency of 5-ALA synthesis through the C5 pathway was significantly improved. Then, the competitive metabolism pathway was fine-tuned by rationally designing different antisense RNAs, further significantly increasing 5-ALA titers. Furthermore, for efficient 5-ALA synthesis, obstacles of NADH and NADPH imbalances and feedback inhibition of the synthesis pathway were also overcome through engineering the NADPH regeneration pathway and transport pathway, respectively. Finally, combining these strategies with further fermentation optimization, we achieved a final 5-ALA titer of 11.4 g/L. These results highlight the importance of synthetic scaffolds and system pathway engineering to improve the microbial cell factory production performance.

Rosin derivatives such as dehydroabietic acid and dehydroabietic amine belonging to diterpenoids have similar structure with androgen that inhibited the occurrence and development of prostate cancer. In this study, the effects and possible mechanism of the rosin derivative IDOAMP on prostate cancer were investigated. Our results showed that IDOAMP effectively inhibited cell viabilities of LNCaP, PC3, and DU145 prostate cells. After the treatment with IDOAMP, the levels of cleaved-PARP, LC3BII/I, and HMGB1 were increased, whereas the expression of GPX4 was decreased. Interestingly, cell viability was reversed by the supplements of necrostatin-1 and necrosulfonamide. Meanwhile, the IDOAMP downregulated the expression of human Aurora kinase A that was overexpressed in prostate cancer. In addition, co-IP results showed that IDOAMP inhibited the binding of Aurora kinase A to the receptor-interacting serine/threonine kinase 1 (RIPK1) and RIPK3. However, the binding of RIPK1 to FADD, RIPK3, or MLKL was significantly promoted. Further studies showed that the phosphorylation levels of RIPK1, RIPK, and MLKL were increased in a concentration-dependent manner. In in vivo model, IDOAMP reduced the tumor volumes and weights. In conclusion, IDOAMP directly inhibited Aurora kinase A and promoted the RIPK1/RIPK3/MLKL necrosome activation to inhibit the prostate cancer.

Aquilaria sinensis is an important non-timber tree species for producing high-value agarwood, which is widely used as a traditional medicine and incense. Agarwood is the product of Aquilaria trees in response to injury and fungal infection. The APETALA2/ethylene responsive factor ( AP2/ERF) transcription factors (TFs) play important roles in plant stress responses and metabolite biosynthesis. In this study, 119 AsAP2/ERF genes were identified from the A. sinensis genome and divided into ERF, AP2, RAV, and Soloist subfamilies. Their conserved motif, gene structure, chromosomal localization, and subcellular localization were characterized. A stress/defense-related ERF-associated amphiphilic repression (EAR) motif and an EDLL motif were identified. Moreover, 11 genes that were highly expressed in the agarwood layer in response to whole-tree agarwood induction technique (Agar-Wit) treatment were chosen, and their expression levels in response to methyl jasmonate (MeJA), salicylic acid (SA), or salt treatment were further analyzed using the quantitative real time PCR (qRT-PCR). Among the 11 genes, eight belonged to subgroup B-3. All 11 genes were significantly upregulated under salt treatment, while eight genes were significantly induced by both MeJA and SA. In addition, the gene clusters containing these upregulated genes on chromosomes were observed. The results obtained from this research not only provide useful information for understanding the functions of AP2/ERF genes in A. sinensis but also identify candidate genes and gene clusters to dissect their regulatory roles in agarwood formation for future research.

Polyguluronate (PG) consists entirely of α-L-guluronic acid derived from alginate, which is an acidic polysaccharide extracted from brown algae. PG has a short half-life and is easily degraded by microorganisms, resulting in decreased activity and thus its application in the medical field. In this study, polyguluronate liposomes (PGLs) were prepared to improve the macrophage-stimulating activity of PG. The morphology, encapsulation efficiency, particle size distribution, zeta potential and stability of the PGLs were characterized. Results showed that PGLs were uniformly round with an encapsulation efficiency of 77.76 ± 0.89%, a particle size of 63.96 ± 3.98 nm and a zeta potential of -53.4 ± 1.75 mV. The stability studies showed that PGLs should be stored in a neutral environment at 4 °C. The macrophage-stimulating activity of PGLs was better than that of PG. This study provides a promising carrier for the further application of PG in food or medicine.

Background. In recent years, a growing body of research has revealed that long noncoding RNAs (lncRNAs) participate in regulating genomic instability. Materials and Methods. We obtained RNA expression profiles, somatic mutation profiles, clinical information, and pathological features of colorectal cancer (CRC) from The Cancer Genome Atlas project. We divided the cohort into two groups based on mutation frequency and identified genomic instability-related lncRNAs (GI-lncRNAs) using R software. We further analyzed the function of identified GI-lncRNAs and established a prognostic model through Cox regression. Using the established prognostic model, we divided the cohort into the high- and low-risk groups and further verified the prognostic differences between the two groups as well as the predictive power of prognosis-related lncRNAs in the genomic instability of CRC. Results. We identified a total of 143 GI-lncRNAs that were differentially expressed between the higher mutation frequency group and the lower mutation frequency group. According to Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology analyses, a series of cancer-associated terms were enriched. We further constructed a prognostic model that included five GI-lncRNAs (lncRNA PTPRD-AS1, lncRNA AC009237.14, lncRNA LINC00543, lncRNA AP003555.1, and lncRNA AL109615.3). We confirmed that the expression of the five GI-lncRNAs was associated with prognosis and the mutation of critical genes in the CRC patient cohort. Conclusions. The present research further confirmed the vital function of GI-lncRNAs in the genomic instability of CRC. The five GI-lncRNAs identified in our study are potential biomarkers and need to be studied in more depth.

Background: Flap endonuclease 1 (FEN1), well known for its structural-specific nuclease, possessing 5'-flap endonuclease and 5'-3' exonuclease ac-tivities, is mainly involved in DNA replication and repair. Protein lysine acetylation is an important posttranslational modification that could regulate numerous proteins’ activity, subcellular localization, protein-protein interac-tion etc., and influences many biological processes. Our previous studies on integrated succinylome profiles found that succinylation and acetylation lev-els of FEN1 would change under different conditions. Succinylation at FEN1 Lys200 site results in the accumulation of damaged DNA and in-creased susceptibility to fork-stalling agents. The interplay with other forms of modification could affects its protein interaction affinity and thus con-tribute to genome stability. Objective: This article studied the biological role of FEN1 by acyl modifica-tion in HeLa cells. Method: In order to explore the function of FEN1 acylation in cells, we mimicked the presence or absence of acetylation or succinylation by mutat-ing key amino acids to glutamic acid and glutamine. We carried out a series of experiments including cell cycle, MTS, enzyme kinetics measurements, immunofluorescence and so on. Results: The absence of acylation of FEN1 leads to the blocked cell cycle process and the reduced efficiency of FEN1 on its DNA substrates, affect-ing the interaction of FEN1 with both repair and replication related proteins and thus its role in the repair of DNA damage. Conclusion: We have verified acyl groups could modify Lys125, Lys252 and Lys254 of FEN1. Acylation level of these three is important for enzyme activity, cell proliferation and DNA damage response, thus contributing to genome stability.

BackgroundPlasma cell mastitis (PCM) is a complex breast disease in the clinic. Currently, there are no unified diagnostic criteria for the disease and no standard treatment methods. The effects of hormone, Conventional Chinese medicine and other treatments are uncertain, with long treatment duration and notable side effects. Surgery is the preferred treatment, but the recurrence rate after conventional surgery is very high, which may be related to depression of the nipple. This study aimed to evaluate the efficacy of a novel corrective procedure in patients with cellular mastitis and depressed nipples.MethodsPatients with PCM who received surgical treatment in the Third Medical Center of PLA General Hospital from January 1996 to January 2018 were retrospectively analyzed. According to the presence or absence of nipple depression before surgery, the patients were divided into the nipple depression group and the non-nipple depression group. In the nipple depression group, patients were subdivided into a novel corrective surgery group (“one” suture or half pocket suture) and a conventional corrective surgery group (oil yarn traction valgus correction of nipple depression). Demographic, clinical, therapeutic, and postoperative relapse data were collected and analyzed.ResultsCompared with the patients in the non-nipple depression group, patients in the nipple depression group had a significantly higher recurrence risk after surgery (HR = 2.129 95% CI: 1.110–4.083, p = 0.023). Patients who underwent novel corrective surgery had a significantly lower recurrence risk than those who underwent conventional corrective surgery (HR = 0.363 95% CI: 0.150–0.880, p = 0.025). In addition, the novel corrective surgery significantly reduced the postoperative recurrence risk (HR = 0.088 95% CI: 0.009–0.886, p = 0.037).ConclusionHow to correct nipple depression is a critical factor for postoperative recurrence of PCM, and this novel corrective surgery for nipple depression can effectively reduce the postoperative recurrence rate in patients with nipple depression.

Minimal change disease (MCD) is the most common cause of idiopathic nephrotic syndrome in children. The current major therapy is hormones for most steroid-sensitive patients. However, many patients have recurrent relapses of the disease and require long-term immunosuppression, leading to significant morbidity due to the side effects of the drugs. Therefore, better drugs need to be urgently explored to treat nephrotic syndrome while avoiding the side effects of drugs. Minnelide, a water-soluble prodrug of triptolide, has been proved to be effective in treating cancers in many clinical trials. This study aimed to investigate the therapeutic effect of minnelide in mice with adriamycin (ADR) nephropathy, its underlying protection mechanisms, and its reproductive toxicity. Minnelide was administered intraperitoneally to 6–8-week female mice with adriamycin nephropathy for 2 weeks, and the urine, blood, and kidney tissues were taken to analyze the therapeutic effect. In addition, we evaluated reproductive toxicity by measuring the levels of gonadal hormones and observing the histological changes in ovaries and testes. Primary mouse podocytes were exposed to puromycin (PAN) to damage the cytoskeleton and induce apoptosis, and then, triptolide was used to evaluate the therapeutic effect and underlying protection mechanisms in vitro. It was observed that minnelide dramatically alleviated proteinuria and apoptosis in mice with adriamycin nephropathy. In vitro, triptolide ameliorated puromycin-induced cytoskeletal rearrangement and apoptosis via reactive oxygen species-mediated mitochondrial pathway. In addition, minnelide caused no reproductive toxicity to male and female mice. The results suggested that minnelide might be a promising drug for nephrotic syndrome.

Background: The majority of individuals with dementia will suffer from behavioral and psychological symptoms of dementia (BPSD). These symptoms contribute to functional impairment and caregiver burden. Objective: To characterize BPSD in Alzheimer’s disease (AD), vascular dementia (VaD), mixed (Mixed) dementia, Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and unspecified dementia in individuals residing in long-term care facilities. Methods: We included 10,405 individuals with dementia living in long-term care facilities from the Swedish registry for cognitive/dementia disorders (SveDem) and the Swedish BPSD registry. BPSD was assessed with the Neuropsychiatric Inventory - Nursing Home Version (NPI-NH). Multivariate logistic regression models were used to evaluate the associations between dementia diagnoses and different BPSDs. Results: The most common symptoms were aberrant motor behavior, agitation, and irritability. Compared to AD, we found a lower risk of delusions (in FTD, unspecified dementia), hallucinations (FTD), agitation (VaD, PDD, unspecified dementia), elation/euphoria (DLB), anxiety (Mixed, VaD, unspecified dementia), disinhibition (in PDD), irritability (in DLB, FTD, unspecified dementia), aberrant motor behavior (Mixed, VaD, unspecified dementia), and sleep and night-time behavior changes (unspecified dementia). Higher risk of delusions (DLB), hallucinations (DLB, PDD), apathy (VaD, FTD), disinhibition (FTD), and appetite and eating abnormalities (FTD) were also found in comparison to AD. Conclusion: Although individuals in our sample were diagnosed with different dementia disorders, they all exhibited aberrant motor behavior, agitation, and irritability. This suggests common underlying psychosocial or biological mechanisms. We recommend prioritizing these symptoms while planning interventions in long-term care facilities.

Angiogenesis inhibitors targeting the VEGF signaling pathway are developed into drugs for the treatment of vaious diseases, such as cancer, rheumatoid arthritis, and age-related macular degeneration. Recent studies have revealed that oleanolic acid (OA), a natural pentacyclic triterpenoid, inhibited the VEGF/VEGFR2 signaling pathway and angiogenesis in HUVECs, which may represent an attractive VEGF inhibitor. In this paper, rational structural modification towards OA was performed in order to improve its inhibitory effects aganist VEGF and anti-angiogenesis potential. As a result, a series of novel OA derivatives, possessing α,β-unsaturated ketone system in ring A and amide functional group at C-28, were prepared and evaluated for cytotoxicity and their ability to inhibit VEGF-induced abnormal proliferation of HUVECs. The results showed that two promising derivatives, OA-1 and OA-16, exhibited no in vitro cytotoxicity against HUVECs but showed more potent inhibitory activity against VEGF-induced proliferation and angiogenesis in HUVECs, compared with OA. The results of Western blot indicated that OA-1 and OA-16 inhibited VEGF-induced VEGFR2 activation. Furthermore, small interfering RNA experiments were performed to confirm that both compounds inhibited VEGF-induced angiogenesis via VEGFR2. Thus, the present study resulted in the discovery of new promising OA-inspired VEGF inhibitors, which can serve as potential lead compounds for the treatment of angiogenesis-related diseases.

Background:More than half of Chinese patients with hormone receptor positive (HR+) ductal carcinoma in situ (DCIS) are treated with mastectomy, and usually subjected to postoperative endocrine therapy (ET). Given that long-term ET can cause severe adverse effects it is important to determine the beneficial effect and safety of post-mastectomy ET on the disease-free survival (DFS) and adverse events in patients with HR+ DCIS.Methods:To explore beneficial effect and safety of post-mastectomy ET in patients with HR+ DCIS, we performed a multicenter, population-based study. This retrospective study analyzed the DFS and adverse events in 1037 HR+ DCIS Chinese patients with or without post-mastectomy ET from eight breast centers between 2006 and 2016. The median follow-up time period was 86 months.Results:There were 791 DCIS patients receiving ET (ET group). Those patients were followed up for a median of 86 months (range, 60–177 months). There were 23 cases with tumor recurrence or distant metastasis. There were similar 5-year DFS rates and DFS between the ET and non-ET groups, even for those with high-risk factors. Conversely, 37.04% of patients suffered from adverse events after ET, which were significantly higher than those in the non-ET group.Conclusions:ET after mastectomy did not benefit patients with HR+ DCIS for their DFS, rather increased adverse events in those patients. Therefore, ET after mastectomy may not be recommended for patients with HR+ DCIS, even for those with high-risk factors, such as multifocal, microinvasive, and higher T stage.Funding:This study was supported by grants from Outstanding Scientific Fund of Shengjing Hospital (201803) and Outstanding Young Scholars of Liaoning Province (2019-YQ-10).

BackgroundThe long-term overall survival of children with T-cell acute lymphoblastic leukemia (T-ALL) is limited to approximately 80–85% because of a high incidence of relapse after achieving remission with intensive chemotherapy and hematopoietic stem cell transplantation (HSCT). Novel treatment strategies inducing long-term remission are needed to improve the outcome. Histone deacetylase inhibitors (HDACis) have been reported to be effective in a series of T-ALL cases. Preclinical studies suggested that T-ALL cells are sensitive to Chidamide, which is a selective HDACi.MethodsThis preliminary clinical study evaluated the efficacy and safety of Chidamide in combination with chemotherapy or post-HSCT for children with T-ALL at a dose of 0.5 mg/kg weight of patient twice per week for at least 6 months.ResultsIn total, 27 children with a mean age of 7.88 years were included. The high-risk proportion was 66.7%. After a median follow-up period of 37.8 months (9.5–67.9 months), the overall survival and event-free survival in the patients treated with Chidamide were 94.1 and 95.2%, respectively. All patients except two maintained persistent remission with ConclusionThe combination therapy with Chidamide in a case series of T-ALL shows the promising clinical efficacy and good safety in children.Clinical trial registrationhttps://www.chictr.org.cn/, identifier ChiCTR2000030357.

Molybdenum ions are covalently bound to molybdenum pterin (MPT) to produce molybdenum cofactor (Moco), a compound essential for the catalytic activity of molybdenum enzymes, which is involved in a variety of biological functions. MoaE is the large subunit of MPT synthase and plays a key role in Moco synthesis. Here, we investigated the function of MoaE in Deinococcus radiodurans (DrMoaE) in vitro and in vivo, demonstrating that the protein contributed to the extreme resistance of D. radiodurans. The crystal structure of DrMoaE was determined by 1.9 Å resolution. DrMoaE was shown to be a dimer and the dimerization disappeared after Arg110 had been mutated. The deletion of drmoaE resulted in sensitivity to DNA damage stress and a slower growth rate in D. radiodurans. The increase in drmoaE transcript levels the and accumulation of intracellular reactive oxygen species levels under oxidative stress suggested that it was involved in the antioxidant process in D. radiodurans. In addition, treatment with the base analog 6-hydroxyaminopurine decreased survival and increased intracellular mutation rates in drmoaE deletion mutant strains. Our results reveal that MoaE plays a role in response to external stress mainly through oxidative stress resistance mechanisms in D. radiodurans.

Surgical resection remains the preferred approach for some patients with glioblastoma (GBM), and eradication of the residual tumour niche after surgical resection is very helpful for prolonging patient survival. However, complete surgical resection of invasive GBM is difficult because of its ambiguous boundary. Herein, a novel targeting material, c(RGDyk)-poloxamer-188, was synthesized by modifying carboxyl-terminated poloxamer-188 with a glioma-targeting cyclopeptide, c(RGDyk). Quantum dots (QDs) as fluorescent probe were encapsulated into the self-assembled c(RGDyk)-poloxamer-188 polymer nanoparticles (NPs) to construct glioma-targeted QDs-c(RGDyk)NP for imaging-guided surgical resection of GBM. QDs-c(RGDyk)NP exhibited a moderate hydrodynamic diameter of 212.4 nm, a negative zeta potential of –10.1 mV and good stability. QDs-c(RGDyk)NP exhibited significantly lower toxicity against PC12 and C6 cells and HUVECs than free QDs. Moreover, in vitro cellular uptake experiments demonstrated that QDs-c(RGDyk)NP specifically targeted C6 cells, making them display strong fluorescence. Combined with ultrasound-targeted microbubble destruction (UTMD), QDs-c(RGDyk)NP specifically accumulated in glioma tissue in orthotropic tumour rats after intravenous administration, evidenced by ex vivo NIR fluorescence imaging of bulk brain and glioma tissue sections. Furthermore, fluorescence imaging with QDs-c(RGDyk)NP guided accurate surgical resection of glioma. Finally, the safety of QDs-c(RGDyk)NP was verified using pathological HE staining. In conclusion, QDs-c(RGDyk)NP may be a potential imaging probe for imaging-guided surgery.

Sulfate-reducing bacteria Desulfovibrio fairfieldensis is an opportunistic pathogen that widely exists in the human intestine and can cause severe infectious diseases. However, the mechanisms contributing to its pathogenesis remain of great interest. In this study, we aim to investigate the outer membrane vesicles (OMVs) secreted by D. fairfieldensis and their pathogenic effect. The OMVs separated by ultracentrifugation were spherical and displayed a characteristic bilayer lipid structure observed by transmission electron microscopy, with an average hydrodynamic diameter of 75 nm measurement using the particle size analyzer. We identified 1496 and 916 proteins from D. fairfieldensis and its OMVs using label-free non-target quantitative proteomics, respectively. The 560 co-expressed proteins could participate in bacterial life activities by function prediction. The translocation protein TolB, which participates in OMVs biogenesis and transporting toxins was highly expressed in OMVs. The OMVs inhibited the expression of tight junction proteins OCCLUDIN and ZO-1 in human colonic epithelial cells (Caco-2). The OMVs decreased the cell viability of monocyte macrophages (THP-1-Mφ) and activated various inflammatory factors secretion, including interferon-γ (IFN-γ), tumor necrosis factor (TNF-α), and many interleukins. Further, we found the OMVs induced the expression of cleaved-gasdermin D, caspase-1, and c-IL-1β and caused pyroptosis in THP-1-Mφ cells. Taken together, these data reveal that the D. fairfieldensis OMVs can damage the intestinal epithelial barrier and activate intrinsic inflammation.

Mussel foot proteins (Mfps), which help mussels attach to various surfaces, are considered to be promising biomaterials due to their outstanding adhesive properties. However, limited production and lack of post-translational modifications of tyrosine residues into 3,4-dihydroxyphenylalanine (Dopa) in bacterial expression systems have hampered their applications. In the present study, for the first time we established the expression of recombinant Mytilus galloprovincialis foot protein type 3 variant B (fp-3B) in Escherichia coli; and achieved its viable production (~51 mg/L). Additionally, the Dopa content and adhesive properties of fp-3B co-expressed using various types of tyrosinases were compared. Consequently, the co-expression of fp-3B construct together with tyrosinase from Verrucomicrobium spinosum (TyrVs) yielded up to 87 mg/L of modified fp-3B; hydroxylation of tyrosine residues accounted for 57.18% by acid-borate difference spectroscopy. The modified fp-3B also showed significant coating and adhesive ability, and its bulk-scale adhesive strength was 2.9-fold higher than that of unmodified fp-3B. Compared with other type 3 mussel foot proteins, the high-yield expression and extensive hydroxylation level of the recombinant protein indicate that fp-3B co-expressed with TyrVs (3B-Vs) has the potential to be widely used as bioglues.

As a special type of biomass, herbal medicine often contains a variety of biologically active substances, and taking it as a carbon source, it is expected to produce various types of biologically functional carbon dots (CDs). However, there are few reports in this field, especially in achieving enhanced performance of CDs by improving the utilization efficiency of active substances in medicinal materials. In this work, by adding glycine as an auxiliary agent in the preparation of CDs from herbal medicine (Exocarpium Citri Grandis), the carboxyl and amino groups of the adjuvant provided more reactive sites, which greatly improved the yield of CDs (about 6 times). More importantly, the antioxidant and biological activities of herbal CDs were also improved. By controlling the functional groups of adjuvants, the effects of carboxyl and amino groups in adjuvants on the synthesis of herbal CDs were compared. The results reveal that both carboxyl and amino groups can react with the substances in the carbon source, and the influence of amino groups was greater. After adding glycine, the size of the CDs became larger, resulting from the more abundant functional groups on the carbon skeleton, which was the main reason for the improved performance of the CDs. Finally, the biological activity experiment demonstrated that CDs derived from Exocarpium Citri Grandis and glycine could greatly enhance the vitality of cells and activate immune cells, which are expected to be applied in the field of cell reproduction and biological immunity. The method proposed in this work provides a potential strategy for high-yield preparation of CDs from biomass.

Background Fabry disease (FD) remains poorly recognized, especially in children in China. Considering the diversity and nonspecific clinical manifestations accompanying with life-threatening aspect of this disease, methods to improve effective screening and management of the suspects are needed. This study aims to explore how it can be done effectively from a multidisciplinary perspective for children with FD at a tertiary children’s hospital in China. Methods A multidisciplinary team (MDT) of pediatric FD experts was launched at Children’s Hospital of Fudan University. Children with high-risk characteristics were referred by the MDT screening team using the dried blood spot (DBS) triple-test (α-galactosidase A, globotriaosylsphingosine, GLA gene). For newborns who were undergoing genetic testing in the hospital, the GLA gene was listed as a routine analysis gene. Evaluation, family screening, and genetic counselling were implemented after screening by the MDT management team. Results Before the establishment of the MDT, no case was diagnosed with FD in the hospital. However, twelve months following the MDT program's implementation, thirty-five children with high-risk profiles were referred for screening by DBS triple-test, with a yield of diagnosis of 14.3% (5/35). These 5 diagnosed children were referred due to a high-risk profile of pain accompanied by dermatological angiokeratoma and hypohidrosis (n = 2), pain accompanied by abnormal liver function (n = 1), pain only (n = 1), and unexplained renal tubular dysfunction (n = 1). Two neonates were detected early with GLA mutations in the hospital, with a yield of detection of 0.14% (2/1420). Furthermore, another 3 children diagnosed with FD were referred from other hospitals. Family screening of these 10 diagnosed children indicated that 9 boys inherited it from their mothers and 1 girl inherited it from her father. Four of them started to receive enzyme replacement therapy. Conclusion Screening and management of children with FD is effective based on a defined screening protocol and a multidisciplinary approach. We should pay more attention to the high-risk profiles of pain, angiokeratoma, decreased sweating, and unexplained chronic kidney disease in children.

Conjugated organic radical polymers with stable radical features are difficult to design because the π conjugation in the polymer backbones makes the radicals readily delocalize and tend to undergo covalent bonding processes. In this work, we report an electronic isolation strategy to design stable porous radical polymers by homocoupling reaction from a meta-position active monomer. The meta linkage ensures less conjugation in the polymer skeletons, localizes the resonant radicals, and prevents them from recombination. The resulting porous radical polymer exhibits exceptional radical characters with ultralow band gap of 0.68 eV, strong yet extended UV/Vis-NIR absorption up to 1800 nm, and high spin density. The above features make the polymer very promising in the photothermal conversion with record-high photothermal temperature increment of ≈∼240 °C and striking solar-driven water evaporation efficiency of 96.8 %. Our results demonstrate the feasibility of electronic isolation of radicals for producing outstanding photothermal materials.