The mechanism of linear ubiquitination in regulating cell death and correlative diseases.

Linear ubiquitination is a specific post-translational modification in which ubiquitin is linked through M1 residue to form multiple types of polyubiquitin chains on substrates in order to regulate cellular processes. LUBAC comprised by HOIP, HOIL-1L, and SHARPIN as a sole E3 ligase catalyzes the generation of linear ubiquitin chains, and it is simultaneously adjusted by deubiquitinases such as OTULIN and CYLD. Several studies have shown that gene mutation of linear ubiquitination in mice accompanied by different modalities of cell death would develop relative diseases. Cell death is a fundamental physiological process and responsible for embryonic development, organ maintenance, and immunity response. Therefore, it is worth speculating that linear ubiquitin mediated signaling pathway would participate in different diseases. The relative literature search was done from core collection of electronic databases such as Web of Science, PubMed, and Google Scholar using keywords about main regulators of linear ubiquitination pathway. Here, we summarize the regulatory mechanism of linear ubiquitination on cellular signaling pathway in cells with apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis. Intervening generation of linear ubiquitin chains in relative signaling pathway to regulate cell death might provide novel therapeutic insights for various human diseases.

The Effect of Family Fertility Support Policies on Fertility, Their Contribution, and Policy Pathways to Fertility Improvement in OECD Countries.

The cost of childbirth has been confirmed as a vital factor in families' fertility decision-making, and family welfare policies are capable of compensating for the increase in household living expenses regarding childbirth, such that the country's fertility situation can be optimized. In this study, the fertility promotion effects of family welfare policies in OECD(Organization for Economic Co-operation and Development) countries are investigated through regression analysis, grey correlation (GRA), and the fuzzy set qualitative comparative analysis fsQCA method. As indicated by the results: (1) Family welfare policies notably boost fertility, and the boosting effect is long-lasting. However, this boost will be weakened in countries where fertility rates remain below 1.5. (2) The contribution of welfare policy measures to the fertility-promotion effect varies by country. The contribution of cash benefits is highest in over half of the countries worldwide, the contribution of relevant services and in-kind expenditure is highest in 29% of the countries, and that of tax incentive expenditure is highest in 14% of the countries. (3) The policy mix to boost fertility also varies according to the social context, with three policy groups derived using the fsQCA method. To be specific, the core antecedent conditions comprise cash benefits, relevant services, and in-kind expenditure. On that basis, China should pay attention to the following three points when formulating family welfare policies to tackle their demographic challenges. First, a system of family welfare policies should be developed as early as possible in the context of increasingly severe demographic issues since the incentive effect of family welfare policies will be weakened in countries with chronically low fertility rates. Second, the effects of improvements vary by country, and China should comprehensively consider its national circumstances when formulating and dynamically adjusting the mix of government fertility support policies in accordance with its social development. Third, employment is the main means of securing family income and takes on critical significance to sustaining families. Unemployment exerts a significant disincentive effect, such that it is imperative to reduce youth unemployment and enhance the quality of youth employment. On that basis, the disincentive effect of unemployment on fertility can be reduced.

The oxygenated products of cryptotanshinone by biotransformation with Cunninghamella elegans exerting anti-neuroinflammatory effects by inhibiting TLR 4-mediated MAPK signaling pathway.

Cryptotanshinone (1), a major bioactive constituent in the traditional Chinese medicinal herb Dan-Shen Salvia miltiorrhiza Bunge, has been reported to possess remarkable pharmacological activities. To improve its bioactivities and physicochemical properties, in the present study, cryptotanshinone (1) was biotransformed with the fungus Cunninghamella elegans AS3.2028. Three oxygenated products (2-4) at C-3 of cryptotanshinone (1) were obtained, among them 2 was a new compound. Their structures were elucidated by comprehensive spectroscopic analysis including HRESIMS, NMR and ECD data. All of the biotransformation products (2-4) were found to inhibit significantly lipopolysaccharide-induced nitric oxide production in BV2 microglia cells with the IC50 values of 0.16-1.16 µM, approximately 2-20 folds stronger than the substrate (1). These biotransformation products also displayed remarkably improved inhibitory effects on the production of inflammatory cytokines (IL-1ß, IL-6, TNF-α, COX-2 and iNOS) in BV-2 cells via targeting TLR4 compared to substrate (1). The underlying mechanism of 2 was elucidated by comparative transcriptome analysis, which suggested that it reduced neuroinflammatory mainly through mitogen-activated protein kinase (MAPK) signaling pathway. Western blotting results revealed that 2 downregulated LPS-induced phosphorylation of JNK, ERK, and p38 in MAPK signaling pathway. These findings provide a basal material for the discovery of candidates in treating Alzheimer's disease.

Annular oxygenation and rearrangement products of cryptotanshinone by biotransformation with marine-derived fungi Cochliobolus lunatus and Aspergillus terreus.

Structural modification of natural products by biotransformation with fungi is an attractive tool to obtain novel bioactive derivatives. In the present study, cryptotanshinone (1), a quinoid abietane diterpene from traditional Chinese medicine Salvia miltiorrhiza (Danshen), was transformed by two marine-derived fungi. By using Cochliobolus lunatus TA26-46, one new oxygenated and rearranged product (2), containing a 5,6-dihydropyrano[4,3-b]chromene moiety, together with one known metabolite (10), were obtained from the converted broth of cryptotanshinone (1) with the isolated yields of 1.0% and 2.1%, respectively. While, under the action of Aspergillus terreus RA2905, seven new transformation products (3-9) as well as 10 with the fragments of 2-methylpropan-1-ol and oxygenated p-benzoquinone were produced and obtained with the isolated yields of 0.1%-1.3%. The structures of the new compounds were elucidated by comprehensive spectroscopic analysis including High Resolution Electrospray Ionization Mass Spectroscopy (HRESIMS), Nuclear Magnetic Resonance (NMR) and Electronic Circular Dichroism (ECD). The metabolic pathways of cryptotanshinone by these two fungi were presumed to be the opening and rearrangement of furan ring, and/or oxygenation of cyclohexane ring. Cryptotanshinone (1) and its metabolites displayed anti-inflammatory activities against NO production in LPS-stimulated BV-2 cells and antibacterial activities towards methicillin-resistant Staphylococcus aureus. These findings revealed the potential of marine fungi to transform the structures of natural products by biotransformation.

Benzyl Furanones and Pyrones from the Marine-Derived Fungus Aspergillus terreus Induced by Chemical Epigenetic Modification.

Chemical epigenetic modification on a marine-derived fungus Aspergillus terreus RA2905 using a histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), resulted in a significantly changed metabolic profile. A chemical investigation of its ethyl acetate (EtOAc) extract led to the isolation of a racemate of benzyl furanone racemate (±)-1, which further separated chirally as a pair of new enantiomers, (+)- and (-)-asperfuranone (1), together with two new benzyl pyrones, asperpyranones A (2) and B (3). Their structures were elucidated by analysis of the comprehensive spectroscopic data, including one-dimensional (1D) and two-dimensional (2D) NMR, and HRESIMS. The absolute configurations were determined by electronic circular dichroism (ECD) calculation and single-crystal X-ray crystallographic experiment. The structures with benzyl furanone or benzyl pyrone skeletons were discovered from natural products for the first time. Compounds (±)-1, (+)-1, (-)-1, and 2 displayed the antifungal activities against Candida albicans with MIC values of 32, 16, 64, and 64 µg/mL and PTP1B inhibitory activities with the IC50 values of 45.79, 17.32, 35.50, and 42.32 µM, respectively. Compound 2 exhibited antibacterial activity against Pseudomonas aeruginosa with the MIC value of 32 µg/mL.

New Thiodiketopiperazine and 3,4-Dihydroisocoumarin Derivatives from the Marine-Derived Fungus Aspergillus terreus.

Aspergillus terreus has been reported to produce many secondary metabolites that exhibit potential bioactivities, such as antibiotic, hypoglycemic, and lipid-lowering activities. In the present study, two new thiodiketopiperazines, emestrins L (1) and M (2), together with five known analogues (3-7), and five known dihydroisocoumarins (8-12), were obtained from the marine-derived fungus Aspergillus terreus RA2905. The structures of the new compounds were elucidated by analysis of the comprehensive spectroscopic data, including high-resolution electrospray ionization mass spectrometry (HRESIMS), one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR), and electronic circular dichroism (ECD) data. This is the first time that the spectroscopic data of compounds 3, 8, and 9 have been reported. Compound 3 displayed antibacterial activity against Pseudomonas aeruginosa (minimum inhibitory concentration (MIC) = 32 µg/mL) and antifungal activity against Candida albicans (MIC = 32 µg/mL). In addition, compound 3 exhibited an inhibitory effect on protein tyrosine phosphatase 1 B (PTP1B), an important hypoglycemic target, with an inhibitory concentration (IC)50 value of 12.25 µM.

Epigenetic Agents Trigger the Production of Bioactive Nucleoside Derivatives and Bisabolane Sesquiterpenes From the Marine-Derived Fungus Aspergillus versicolor.

Epigenetic agents, histone deacetylase inhibitor (SAHA) and DNA methyltransferase inhibitor (5-Aza), were added to Czapek-Dox medium to trigger the chemical diversity of marine-derived fungus Aspergillus versicolor XS-20090066. By HPLC and 1H NMR analysis, the diversity of fungal secondary metabolites was significantly increased compared with the control. With the aid of MS/MS-based molecular networking, two new nucleoside derivatives, kipukasins K (1) and L (2) were obtained. Meanwhile, the yields of four known nucleoside derivatives were significantly enhanced. In addition, one new bisabolane sesquiterpene, aspergillusene E (7), along with ten known derivatives were also isolated. The structures were elucidated by comprehensive spectroscopic methods of NMR and HRESIMS analysis. Compounds 1 and 7 displayed antibacterial activities against Staphylococcus epidermidis and Staphylococcus aureus with the MIC values of 8-16 µg/mL. Our study revealed that the fungus A. versicolor XS-20090066 has been effectively induced by chemical epigenetic manipulation with a combination of SAHA and 5-Aza to produce new metabolites.

Co-cultivation With 5-Azacytidine Induced New Metabolites From the Zoanthid-Derived Fungus Cochliobolus lunatus.

The zoanthid-derived fungus Cochliobolus lunatus (TA26-46) has been proven to be a source of bioactive 14-membered resorcylic acid lactones (RALs). In the present study, chemical epigenetic manipulation was applied to this fungal strain with a DNA methyltransferase inhibitor resulting in the significant changes of the secondary metabolites. Cultivation of C. lunatus (TA26-46) with 10 µM 5-azacytidine in Czapek-Dox liquid medium led to the isolation of new types of metabolites, including two α-pyrones, cochliobopyrones A (1) and B (2), along with three isocoumarins (3-5) and one chromone (6). The planar structures of the new compounds (1-2) were elucidated by comprehensive analyses of NMR and HRESIMS data. Their challenging relative configurations were established by a combination of acetonide reaction, coupling constants and NOESY correlations analysis, and DP4+ probability calculation. Their absolute configurations were determined by comparing with the ECD calculation data of the fragment molecules, 6-(1,2-dihydroxypropyl)-4-methoxy-2H-pyran-2-ones. It is the first time to obtain α-pyrone compounds with the epoxy ring or bromine atom on the seven-numbered side chain. It could be concluded that chemical epigenetic agents could induce C. lunatus to produce new types of secondary metabolites differing from its original products (RALs).

Simultaneously Improved Flame Retardance and Ceramifiable Properties of Polymer-Based Composites via the Formed Crystalline Phase at High Temperature.

Ceramifiable polyolefin materials have an excellent application prospect in high-temperature-resistant wires and cables because of their excellent fire safety performance via a ceramization process under fire conditions. During the ceramization process, the control of the crystalline phase plays a vital role in determining the final fire resistance and ceramifiable properties. In this work, ammonium polyphosphate/zinc borate (APP/ZB) was developed to achieve the highly efficient flame retardance and ceramization of the ethylene-vinyl acetate/mica powder/organo-modified montmorillonite (EVA/MP/OMMT) composite. In the combustion test, the EVA/MP/OMMT/APP/ZB system displayed obvious flame retardance feature, showing much lower total heat release and total smoke production than neat EVA. After treating at high temperatures, rigid ceramic products were formed for EVA/MP/OMMT/APP/ZB. The ceramic that was formed at 900 °C had a flexural strength of 10.3 MPa for EVA/MP/OMMT/APP/ZB containing 23 wt % of APP/ZB (9.9:13.1), increased by 2475.0, 635.7, and 586.7% compared to the corresponding values of EVA/MP/OMMT, EVA/MP/OMMT/ZB, and EVA/MP/OMMT/APP. For the latter two systems, the content of ZB or APP was 23 wt %. APP/ZB showed a remarkable fluxing effect on the ceramization of the MP-based EVA composite. The fluxing mechanism of APP/ZB was revealed by different measurements. Both APP and ZB led to the formation of a glass melt containing α-Zn3(PO4)2 and orthophosphate by increasing the temperature. Successively, the melt crystalline structure cohered the OMMT and MP together, accompanied by the gradual disappearance of the mica phase and the generation of eutectic phenomenon. Finally, a ceramic with high flexural strength was formed, leading to the improved flame retardance and ceramifiable properties of EVA-based composites.

Urinary tract infection control in intensive care patients.

This retrospective study tried to find the potential approach for reducing the urinary tract infection (UTI) in intensive care patients (ICPs) among adult population.In total, 96 eligible ICP cases were included. Of these, 48 cases received 10% povidone-iodine and were assigned to the intervention group, while the other 48 cases underwent sterile water, and were assigned to the control group for the prevention of catheter-associated UTI before indwelling urinary catheter insertion in ICP. The primary outcome was the occurrence of an UTI after the indwelling catheter. The secondary outcome was the identification of pathogenic species. The outcomes were assessed after catheter removed.After catheter removal, the occurrence of an UTI did not differ significantly between the 2 groups (P = .34). In addition, no significant differences regarding the pathogenic species were detected between the 2 groups (Escherichia coli, P = .73; Candida albicans, P = .57; Enterococcus, P = .65; Proteus mirabilis, P = .50; Citrobacter, P = .50; Klebsiella pneumoniae, P = .57).The use of 10% povidone-iodine may not help reducing UTI in ICP.

Laparoscopic-assisted ileal pouch-rectal muscle sheath anastomosis for the treatment of familial adenomatous polyposis.

PURPOSE: Familial adenomatous polyposis (FAP) is a colorectal disease treated by proctocolectomy. While ileal pouch-anal anastomosis preserves the anus, defecation dysfunction and incontinence can occur. We herein report the results of an improved laparoscopic-assisted ileal pouch-rectal muscle sheath anastomosis after total proctocolectomy which preserves anal function, and compare the results with ileal pouch-anal anastomosis. METHODS: A total of 22 patients with FAP were randomized to receive either ileal pouch-anal anastomosis (n = 11) or ileal pouch-rectal muscle sheath anastomosis (n = 11) after total proctocolectomy. Operation time, intraoperative blood loss, postoperative complications, length of hospitalization and postoperative anal pressure, defecation frequency, and quality of life were recorded and compared between the two groups. RESULTS: All patients completed a minimum follow-up of 1 year. At the 1 year after the surgery, the daytime defecation frequency was 4.64 ± 0.92 times/day in the ileal pouch-rectal muscle sheath anastomosis group and 6.55 ± 1.13 times/day in the ileal pouch-anal anastomosis group (P = 0.004). Resting anal pressure, maximum squeeze pressure, and average number of daytime defecations in the ileal pouch-rectal muscle sheath group were all better than in the ileal pouch-anal anastomosis group (all, P < 0.05) CONCLUSIONS: Ileal pouch-rectal muscle sheath anastomosis is associated with better anal function than ileal pouch-anal anastomosis.

[Investigation of aerobic granular sludge cultivation by feed loading as a control strategy].

The key cultivation strategy for aerobic granular sludge cultivation was investigated using feed loading control as a main operational parameter in an aerobic/anaerobic SBR system. The results showed that the feed loading by influent COD 0-900 mg x L(-1) could effectively control the growth of sludge. The settling characteristic of inoculated sludge was important for aerobic granules formation, and its SVI 20-50 mg x L(-1) was favourable to granulation development process. Pure aeration without substrate feeding can greatly improve the settleability of sludge, and stimulate the granulation process. The activated sludge with good settleability could be converted to completely aerobic granular sludge through reducing operational loading in a certain condition. The granulation process occurred in COD feeding 400-500 mg x L(-1), and sludge concentration 8-10 g x L(-1). The developed granules were approximately 1.0 mm in diameter, SVI 25-35 mg x L(-1), settling velocity 60 m x h(-1). The authors proposed that granulation formation process was attributed to a unique operational mode in SBR system, i.e. the famine-feast alternation of substrate in reactor. The control strategy of organic loading by reducing substrate could enhance the variation of famine-feast in substrate, and made the driving force for granulation development.