Transcriptome and Metabolome Analyses Provide Insight into the Glucose-Induced Adipogenesis in Porcine Adipocytes.

Glucose is a major energy substrate for porcine adipocytes and also serves as a regulatory signal for adipogenesis and lipid metabolism. In this study, we combined transcriptome and metabolome analyses to reveal the underlying regulatory mechanisms of high glucose (HG) on adipogenesis by comparing differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs) identified in porcine adipocytes. Results showed that HG (20 mmol/L) significantly increased fat accumulation in porcine adipocytes compared to low glucose (LG, 5 mmol/L). A total of 843 DEGs and 365 DAMs were identified. Functional enrichment analyses of DEGs found that multiple pathways were related to adipogenesis, lipid metabolism, and immune-inflammatory responses. PPARγ, C/EBPα, ChREBP, and FOS were identified as the key hub genes through module 3 analysis, and PPARγ acted as a central regulator by linking genes involved in lipid metabolism and immune-inflammatory responses. Gene-metabolite networks found that PPARγ-13-HODE was the most important interaction relationship. These results revealed that PPARγ could mediate the cross-talk between adipogenesis and the immune-inflammatory response during adipocyte maturation. This work provides a comprehensive view of the regulatory mechanisms of glucose on adipogenesis in porcine adipocytes.

Epigenetic competition reveals density-dependent regulation and target site plasticity of phosphorothioate epigenetics in bacteria.

Phosphorothioate (PT) DNA modifications-in which a nonbonding phosphate oxygen is replaced with sulfur-represent a widespread, horizontally transferred epigenetic system in prokaryotes and have a highly unusual property of occupying only a small fraction of available consensus sequences in a genome. Using Salmonella enterica as a model, we asked a question of fundamental importance: How do the PT-modifying DndA-E proteins select their GPSAAC/GPSTTC targets? Here, we applied innovative analytical, sequencing, and computational tools to discover a novel behavior for DNA-binding proteins: The Dnd proteins are "parked" at the G6mATC Dam methyltransferase consensus sequence instead of the expected GAAC/GTTC motif, with removal of the 6mA permitting extensive PT modification of GATC sites. This shift in modification sites further revealed a surprising constancy in the density of PT modifications across the genome. Computational analysis showed that GAAC, GTTC, and GATC share common features of DNA shape, which suggests that PT epigenetics are regulated in a density-dependent manner partly by DNA shape-driven target selection in the genome.

Correlation between menopausal symptoms and everyday cognition in Chinese (peri)menopausal women.

OBJECTIVE: The aim of this study was to evaluate the relationship between the severity of menopausal symptoms and everyday cognitive decline in Chinese peri and postmenopausal women. METHODS: The peri and postmenopausal Chinese Han female who first visited the menopausal clinic of Shanghai Jiao Tong University Affiliated Sixth People's Hospital was selected as the study participants. The general questionnaire was used to obtain the sociodemographic characteristics of the study participants. The menopausal rating scale (MRS) was used to assess the severity of menopausal symptoms. The short version of the Everyday Cognition (ECog-12) scales was used to assess everyday cognitive performance. RESULTS: A total of 295 women were included, with an average age of 51.12 ± 5.15 years. The average ECog scores were 1.51 ± 0.49 and the average MRS scores were 6.89 ± 4.77. In multiple linear regression analysis, after adjusting for confounding factors age, body mass index (BMI), monthly income, occupational status, education level, menopausal status, parity, regular exercise, and history of chronic diseases, complaints of anxiety and physical/mental fatigue were positively correlated with everyday cognitive decline. CONCLUSIONS: Menopausal anxiety and physical/mental fatigue were the independent predictors of everyday cognition.

Occurrence, evolution, and functions of DNA phosphorothioate epigenetics in bacteria.

The chemical diversity of physiological DNA modifications has expanded with the identification of phosphorothioate (PT) modification in which the nonbridging oxygen in the sugar-phosphate backbone of DNA is replaced by sulfur. Together with DndFGH as cognate restriction enzymes, DNA PT modification, which is catalyzed by the DndABCDE proteins, functions as a bacterial restriction-modification (R-M) system that protects cells against invading foreign DNA. However, the occurrence of dnd systems across a large number of bacterial genomes and their functions other than R-M are poorly understood. Here, a genomic survey revealed the prevalence of bacterial dnd systems: 1,349 bacterial dnd systems were observed to occur sporadically across diverse phylogenetic groups, and nearly half of these occur in the form of a solitary dndBCDE gene cluster that lacks the dndFGH restriction counterparts. A phylogenetic analysis of 734 complete PT R-M pairs revealed the coevolution of M and R components, despite the observation that several PT R-M pairs appeared to be assembled from M and R parts acquired from distantly related organisms. Concurrent epigenomic analysis, transcriptome analysis, and metabolome characterization showed that a solitary PT modification contributed to the overall cellular redox state, the loss of which perturbed the cellular redox balance and induced Pseudomonas fluorescens to reconfigure its metabolism to fend off oxidative stress. An in vitro transcriptional assay revealed altered transcriptional efficiency in the presence of PT DNA modification, implicating its function in epigenetic regulation. These data suggest the versatility of PT in addition to its involvement in R-M protection.

PX Domain-Containing Kinesin KIF16B and Microtubule-Dependent Intracellular Movements.

As a member of the kinesin-3 family, kinesin family member 16B (KIF16B) has a characteristic PhoX homology (PX) domain that binds to membranes containing phosphatidylinositol-3-phosphate (PI(3)P) and moves along microtubule filaments to the plus end via a process regulated by coiled coils in the stalk region in various cell types. The physiological function of KIF16B supports the transport of intracellular cargo and the formation of endosomal tubules. Ras-related protein (Rab) coordinates many steps of membrane transport and are involved in the regulation of KIF16B-mediated vesicle trafficking. Data obtained from clinical research suggest that KIF16B has a potential effect on the disease processes in intellectual disability, abnormal lipid metabolism, and tumor brain metastasis. In this review, we summarize recent advances in the structural and physiological characteristics of KIF16B as well as diseases associated with KIF16B disorders, and speculating its role as a potential adaptor for intracellular cholesterol trafficking.

Association of snoring and body composition in (peri-post) menopausal women.

BACKGROUND: Little attention has been paid to whether snoring frequency is associated with body composition in menopausal women, particularly in China. This study objected to investigate the association between self-reported snoring and body composition in (peri-post) menopausal Chinese women as well as metabolic indicators. METHODS: This cross-sectional study enrolled 715 participants aged 40-67 years from the Menopause Clinic in the Shanghai Sixth People's Hospital. Participants were categorized into four subgroups stratified by self-reported snoring frequency: never, rarely (< 1 night per week), occasionally (1-2 nights per week), regularly (≥3 nights per week), while body composition was measured using bioelectrical impedance analysis (BIA). Besides, blood sample were collected to test the glycolipid indicators. RESULTS: In our sample of investigation, regular snoring (≥3 nights per week) was found to be an independent risk factor for higher fat mass (total, upper limbs, trunk), with the highest risk of 2.4 times for fat mass of trunk after adjusting for metabolic confounders(p = 0.003). Meanwhile, regular snoring was independently associated with higher fat mass (total and each segment) only in menopausal transition (p = 0.023). CONCLUSIONS: We suggested that self-reported regular snoring may be taken as a simple alternative to predict higher fat mass (≥17.11 kg, upper quartile) in menopausal women. Similarly, body composition should be attached to the great importance to those who in menopausal transition in order to help to prevent obstructive sleep apnea (OSA).

Convergence of DNA methylation and phosphorothioation epigenetics in bacterial genomes.

Explosive growth in the study of microbial epigenetics has revealed a diversity of chemical structures and biological functions of DNA modifications in restriction-modification (R-M) and basic genetic processes. Here, we describe the discovery of shared consensus sequences for two seemingly unrelated DNA modification systems, 6mA methylation and phosphorothioation (PT), in which sulfur replaces a nonbridging oxygen in the DNA backbone. Mass spectrometric analysis of DNA from Escherichia coli B7A and Salmonella enterica serovar Cerro 87, strains possessing PT-based R-M genes, revealed d(GPS6mA) dinucleotides in the GPS6mAAC consensus representing ∼5% of the 1,100 to 1,300 PT-modified d(GPSA) motifs per genome, with 6mA arising from a yet-to-be-identified methyltransferase. To further explore PT and 6mA in another consensus sequence, GPS6mATC, we engineered a strain of E. coli HST04 to express Dnd genes from Hahella chejuensis KCTC2396 (PT in GPSATC) and Dam methyltransferase from E. coli DH10B (6mA in G6mATC). Based on this model, in vitro studies revealed reduced Dam activity in GPSATC-containing oligonucleotides whereas single-molecule real-time sequencing of HST04 DNA revealed 6mA in all 2,058 GPSATC sites (5% of 37,698 total GATC sites). This model system also revealed temperature-sensitive restriction by DndFGH in KCTC2396 and B7A, which was exploited to discover that 6mA can substitute for PT to confer resistance to restriction by the DndFGH system. These results point to complex but unappreciated interactions between DNA modification systems and raise the possibility of coevolution of interacting systems to facilitate the function of each.

Synthetic Genomics: From DNA Synthesis to Genome Design.

Rapid technological advances enabling the construction of designer gene networks, biosynthetic pathways, and even entire genomes are moving the fields of genetics and genomics from descriptive to synthetic applications. Following the synthesis of small viral genomes, advances in DNA assembly and rewriting have enabled the hierarchical synthesis of bacterial genomes, such as Mycoplasma genitalium, as well as recoding of the Escherichia coli genome by reducing the number of codons from 64 to 57. The field has advanced to the point of synthesizing an entire eukaryotic genome. The Synthetic Yeast Genome Project (Sc2.0) is underway and aims to rewrite all 16 Saccharomyces cerevisiae chromosomes by 2018; to date, 6.5 chromosomes have been designed and synthesized. Using bottom-up assembly and applying genome-wide alterations will improve our understanding of genome structure and function. This approach will not only provide a platform for systematic studies of eukaryotic chromosomes but will also generate diverse "streamlined" strains that are potentially suitable for medical and industrial applications. Herein, we review the current state of synthetic genome research and discuss potential applications of this emerging technology.

Effect of supplementation with Glycyrrhiza uralensis extract and Lactobacillus acidophilus on growth performance and intestinal health in broiler chickens.

Intestinal microbiota community is an important factor affecting the nutritional and health status of poultry, and its balance is crucial for improving the overall health of poultry. The study aimed to investigate the effect of dietary supplementation with Glycyrrhiza uralensis extract (GUE), Lactobacillus acidophilus (Lac) and their combination (GL) on growth performance and intestinal health in broilers in an 84-day feeding experiment. Supplementary 0.1% GUE and 4.5×107 CFU/g Lac significantly increased average daily gain (ADG), and GL (0.1% GUE and 4.5×107 CFU/g Lac) increased ADG and average daily feed intake (ADFI), and decreased feed conversion rate (FCR) in broilers aged 29 to 84 d and 1 to 84 d. Dietary GUE, Lac and GL increased the superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activity and decreased Malondialdehyde (MDA) content in the jejunum mucosa of broilers, and increased secretory IgA (sIgA) content in broilers at 84 d. Moreover, GUE, Lac and GL increased cecal microbial richness and diversity, and modulated microbial community composition. Both GUE and Lac reduced the harmful bacteria Epsilonbacteraeota, Helicobacter, and H. pullorum at 28 d and Proteobacteria, Escherichia, and E. coli at 84 d, while Lac and GL increased beneficial bacteria Lactobacillus and L. gallinarum at 28 d. Compared with individual supplementation, GL markedly increased the SOD activity and the sIgA content, and reduced Helicobacter and Helicobacter pullorum. In conclusion, GUE and Lactobacillus acidophilus as feed additives benefit growth performance and intestinal health, and their combined use shows an even more positive effect in broilers.

MIR938 rs2505901 T>C polymorphism is associated with increased neuroblastoma risk in Chinese children.

Neuroblastoma (NB) is a kind of childhood cancer that is a prevailing and deadly solid neoplasm among pediatric malignancies. The transcriptional output of MIR938 is capable of participating in the posttranscriptional modulation of gene expression, whereby it exerts its regulatory effect by modulating both the stability and translation of target mRNAs. Previous studies showed that MIR938 was associated with many cancers. Hence, functional genetic variants in the MIR938 can be attributed to NB risk. We recruited 402 neuroblastoma patients and 473 controls from the Children's Hospital of Nanjing Medical University and genotyped one MIR938 single-nucleotide polymorphism (SNP) (rs2505901 T>C). There were significant associations between the rs2505901 T>C and NB risk [CC vs. TT: adjusted odds ratio (OR) = 1.90, 95% confidence interval (CI) = 1.02-3.55, P=0.045; CC vs. TT/TC: adjusted OR = 2.02, 95% CI = 1.09-3.75, P=0.026]. This analysis of genotypes revealed that T>C increased the risk of NB. Some borderline significant different relationships were observed in the stratified analyses: age ≤ 18 months (adjusted OR = 2.95, 95% CI = 0.92-9.51, P=0.070), male sex (adjusted OR = 2.19, 95% CI = 0.95-5.08, P=0.067), and clinical stage III+IV (adjusted OR = 2.12, 95% CI = 0.98-4.56, P=0.055). The present study revealed that the MIR938 rs2505901 T>C polymorphism may be a potential risk factor for neuroblastoma in Chinese children. In the long term, conducting large and diverse sample studies from different ethnicities will indeed be crucial in determining the role of MIR938 polymorphisms in NB risk. By including individuals from various ethnic backgrounds, researchers can account for potential genetic variations that may exist between populations.

Monounsaturated and polyunsaturated fatty acids concerning prediabetes and type 2 diabetes mellitus risk among participants in the National Health and Nutrition Examination Surveys (NHANES) from 2005 to March 2020.

Objective: Unsaturated fatty acids (UFA) may be related to glycometabolism. While associations between UFA intake (especially their subtype) and prediabetes or type 2 diabetes mellitus (T2DM) need to be further studied. In this study, we aimed to evaluate the potential relation of UFA with prediabetes and T2DM. Methods: A total of 16,290 adults aged older than 18 years from the National Health and Nutrition Examination Survey (NHANES) from 2005 to March 2020 were included in the present analysis. Dietary intake was assessed by two day, 24-hour dietary recalls and daily intake of total monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA); four specific fatty acids of MUFA and seven specific fatty acids of PUFA were calculated. Prediabetes and T2DM were diagnosed by fasting glucose, glycohemoglobin, and self-reported medication or insulin. Rao-Scott modified chi-square tests, the Taylor series linearization method, and multivariable logistic regression analyses were applied to analyze the associations of dietary MUFA and PUFA intake with diabetes risk. Results: Of the participants, 44.34% had prediabetes and 13.16% had T2DM patients. From multivariate analysis, we found that intake of MUFA, PUFA, and some subtypes was negatively associated with the risk of prediabetes and T2DM in Americans. Compared with adults in the lowest tertile, those in the highest MUFA (PUFA) tertile had an approximately 50% (49%) and 69% (68%) lower risk of prediabetes and T2DM, respectively. Moreover, the effects of the subtypes of MUFA and PUFA on prediabetes and T2DM were different. Higher intakes of MFA 18:1, MFA 20:1, PFA 18:2, and PFA 18:3 and higher tertile intakes of MFA 16:1 and PFA 20:4 were related to a lower risk of prediabetes and T2DM. Similarly, the effects of MUFA, PUFA, and subtype on prediabetes and T2DM varied among different age groups, being weakened along with age. Conclusion: Our study suggested that total MUFA and PUFA intake might be essential in preventing prediabetes and T2DM, especially in Americans. However, this protective effect may decrease with age. Moreover, the effects of the specific UFA on prediabetes and T2DM need further consideration.

Antifungal antibodies present in intravenous immunoglobulin derived from China.

Fungal infections usually occur in immunocompromised patients. Intravenous immunoglobulin (IVIG) has been used as therapeutic interventions for many infectious diseases, but seldom applied in mycosis due to unknown antifungal specificity. This study aims to determine the presence of antifungal antibodies in IVIG. Binding reactivity of IVIG with crude and recombinant antigens of Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans and Talaromyces marneffei were observed in a dose-dependent manner, similar with mixed normal human sera. The antifungal specificity was further confirmed by competitive enzyme-linked immunosorbent assays (ELISA) inhibited by rabbit specific antifungal polyclonal antibodies (PAbs) and homogenous crude antigens with inhibitions of 65.5-87.2% and 73.1-94.2%, respectively. Moreover, IVIG also reacted with fungal glycoproteins (Csa2, Cpl1 and Mp1p) in a dose-dependent way, which was inhibited by specific rabbit PAbs and homogenous antigens with different inhibitions and pulled down 72.8-83.8% of specific antibodies if preabsorption IVIG with Dynabeads® coupled with homogenous glycoproteins. These results furthermore verified the antifungal specificity of IVIG. Among four brands of IVIG, there was different antifungal IgG against C. albicans (P < 0.05) and C. neoformans (P < 0.05), while no difference for A. fumigatus (P = 0.086) and T. marneffei (P = 0.057). IVIG contained a significantly higher level of specific IgG for C. albicans than other three fungi (P <0.001). In conclusion, we proved antifungal IgG against C. albicans, A. fumigatus, C. neoformans and T. marneffei present in IVIG, which might be expected to provide a possible immunoregulation choice for mycosis and an evaluation to humoral immunity against fungi.

Promotion of the genipin crosslinked chitosan-fiber hydrogel loaded with sustained release of clemastine fumarate in diabetic wound repair.

Diabetic skin disorders are lingering and refractory clinical diseases. In this study, a genipin-crosslinked porous chitosan fiber (CSF) hydrogel was fabricated to achieve rapid wound healing. By embedding clemastine fumarate (CF) in the CSF hydrogel pores, we synthesised a CSF/CF hydrogel for the treatment of diabetic wounds. The microstructure, chemical elements, spectral variation, mechanical properties, swelling ratios, degradability, and toxicity of the CSF/CF hydrogels were studied. Compared with the typical CS power hydrogel, the porous CSF hydrogel crosslinked with genipin possesses a stable structure and improved physicochemical properties. Moreover, CF was slowly released from the CSF hydrogel. Molecular simulation also showed that CF was evenly embedded inside the cavity formed by the novel CSF hydrogel. The results suggested that CF can resist damage from high glucose levels and promote proliferation, tube formation, and migration of endothelial cells (ECs) and fibroblasts. The CSF/CF hydrogel promoted wound healing in a rat model. Mechanistically, the beneficial effect of CF on wound healing may be related to activation of the MEK/ERK and PI3K/Akt signalling pathways. In conclusion, genipin-crosslinked CSF/CF hydrogel can accelerate wound healing and may be an effective therapeutic method for treating diabetic skin lesions.

A DNA phosphorothioation-based Dnd defense system provides resistance against various phages and is compatible with the Ssp defense system.

DndABCDE-catalyzed DNA phosphorothioation (PT), in which the nonbridging oxygen is swapped with a sulfur atom, was first identified in the bacterial genome. Usually, this modification gene cluster is paired with a restriction module consisting of DndF, DndG, and DndH. Although the mechanisms for the antiphage activity conferred by this Dnd-related restriction and modification (R-M) system have been well characterized, several features remain unclear, including the antiphage spectrum and potential interference with DNA methylation. Recently, a novel PT-related R-M system, composed of the modification module SspABCD paired with a single restriction enzyme, SspE, was revealed to be widespread in the bacterial kingdom, which aroused our interest in the interaction between Dnd- and Ssp-based R-M systems. In this study, we discussed the action of Dnd-related R-M systems against phages and demonstrated that the host could benefit from the protection provided by Dnd-related R-M systems against infection by various lytic phages as well as temperate phages. However, this defense barrier would fail against lysogenic phages. Interestingly, DNA methylation, even in the consensus sequence recognized by the Dnd system, could not weaken the restriction efficiency. Finally, we explored the interaction between Dnd- and Ssp-based R-M systems and found that these two systems were compatible. This study not only expands our knowledge of Dnd-associated R-M systems but also reveals a complex interaction between different defense barriers that coexist in the cell. IMPORTANCE Recently, we decoded the mechanism of Dnd-related R-M systems against genetic parasites. In the presence of exogenous DNA that lacks PT, the macromolecular machine consisting of DndF, DndG, and DndH undergoes conformational changes to perform DNA binding, translocation, and DNA nicking activities and scavenge the foreign DNA. However, several questions remain unanswered, including questions regarding the antiphage spectrum, potential interference by DNA methylation, and interplay with other PT-dependent R-M systems. Here, we revealed that the host could benefit from Dnd-related R-M systems for a broad range of antiphage activities, regardless of the presence of DNA methylation. Furthermore, we demonstrated that the convergence of Dnd- and Ssp-related R-M systems could confer to the host a stronger antiphage ability through the additive suppression of phage replication. This study not only deepens our understanding of PT-related defense barriers but also expands our knowledge of the arms race between bacteria and their predators.

Structural and Functional Analysis of DndE Involved in DNA Phosphorothioation in the Haloalkaliphilic Archaea Natronorubrum bangense JCM10635.

Phosphorothioate (PT) modification, a sequence-specific modification that replaces the nonbridging oxygen atom with sulfur in a DNA phosphodiester through the gene products of dndABCDE or sspABCD, is widely distributed in prokaryotes. DNA PT modification functions together with gene products encoded by dndFGH, pbeABCD, or sspE to form defense systems that can protect against invasion by exogenous DNA particles. While the functions of the multiple enzymes in the PT system have been elucidated, the exact role of DndE in the PT process is still obscure. Here, we solved the crystal structure of DndE from the haloalkaliphilic archaeal strain Natronorubrum bangense JCM10635 at a resolution of 2.31 Å. Unlike the tetrameric conformation of DndE in Escherichia coli B7A, DndE from N. bangense JCM10635 exists in a monomeric conformation and can catalyze the conversion of supercoiled DNA to nicked or linearized products. Moreover, DndE exhibits preferential binding affinity to nicked DNA by virtue of the R19- and K23-containing positively charged surface. This work provides insight into how DndE functions in PT modification and the potential sulfur incorporation mechanism of DNA PT modification. IMPORTANCE DndABCDE proteins have been demonstrated to catalyze DNA PT modification with the nonbridging oxygen in the DNA sugar-phosphate backbone replaced by sulfur. In the PT modification pathway, DndA exerts cysteine desulfurase activity capable of catalyzing the mobilization of sulfur from l-cysteine, which involves the ion-sulfur cluster assembly of DndC. This is regarded as the initial step of the DNA PT modification. Moreover, DndD has ATPase activity in vitro, which is believed to provide energy for the oxygen-sulfur swap, while the function of DndE is unknown. However, the exact function of the key enzyme DndE remains to be elucidated. By determining the structure of DndE from the haloalkaliphilic strain Natronorubrum bangense JCM10635, we showed that the archaeal DndE adopts a monomer conformation. Notably, DndE can introduce nicks to supercoiled DNA and exhibits a binding preference for nicked DNA; the nicking is believed to be the initial step for DNA to facilitate the sulfur incorporation.

Involvement of the DNA Phosphorothioation System in TorR Binding and Anaerobic TMAO Respiration in Salmonella enterica.

Although the phosphorothioate (PT) modification, in which the nonbridging oxygen in the DNA sugar-phosphate backbone is replaced by sulfur, has been reported to play versatile roles in multiple cellular processes, very little data have been obtained to define the role of PT in epigenetic regulation. In this study, we report that the PT system in Salmonella enterica serovar Cerro 87 is involved in the transcriptional regulation of the torCAD operon encoding the trimethylamine N-oxide (TMAO) respiration machinery that enables the use of TMAO as a terminal electron acceptor for respiration when oxygen is not available. In vitro, PT enhanced the binding of the transcriptional activator of the torCAD operon, namely, TorR, to its DNA substrate (tor boxes). However, in vivo, the PT modification protein complex DndCDE downregulated torCAD transcription through competing with the binding of TorR to the tor boxes. The altered expression of torCAD caused by PT modification proteins affected cell growth that relied on TMAO respiration. To our knowledge, this is the first report supporting that PT proteins participate in transcriptional regulation, showing a new function of PT systems. IMPORTANCE Since the initial discovery of DNA phosphorothioate (PT) modification systems in Streptomyces lividans in the 1980s, explorations of the biological functions of DNA PT systems have advanced and yielded a number of important findings. However, the functions of PT systems, especially in genetic regulation, remain largely unknown. In this study, we report a case in which the PT system participates in the transcriptional regulation of the torCAD operon in Salmonella enterica serovar Cerro 87. While the PT modification enhanced the binding of TorR, the torCAD operon transcriptional activator, to its DNA substrate in vitro, we found that the PT modification protein complex DndCDE directly competed with TorR binding in vivo and subsequently repressed the expression of torCAD and attenuated cell growth that relied on TMAO respiration. These findings provide a deeper understanding of the characteristics of the PT chemical structure and broaden our understanding of the mechanisms by which PT regulates gene expression.

Simultaneous Photodynamic Eradication of Tooth Biofilm and Tooth Whitening with an Aggregation-Induced Emission Luminogen.

Dental caries is among the most prevalent dental diseases globally, which arises from the formation of microbial biofilm on teeth. Besides, tooth whitening represents one of the fastest-growing areas of cosmetic dentistry. It will thus be great if tooth biofilm eradication can be combined with tooth whitening. Herein, a highly efficient photodynamic dental therapy strategy is reported for tooth biofilm eradication and tooth discoloration by employing a photosensitizer (DTTPB) with aggregation-induced emission characteristics. DTTPB can efficiently inactivate S. mutans, and inhibit biofilm formation by suppressing the expression of genes associated with extracellular polymeric substance synthesis, bacterial adhesion, and superoxide reduction. Its inhibition performance can be further enhanced through combined treatment with chlorhexidine. Besides, DTTPB exhibits an excellent tooth-discoloration effect on both colored saliva-coated hydroxyapatite and clinical teeth, with short treatment time (less than 1 h), better tooth-whitening performance than 30% hydrogen peroxide, and almost no damage to the teeth. DTTPB also demonstrates excellent biocompatibility with neglectable hemolysis effect on mouse red blood cells and almost no killing effect on mammalian cells, which enables its potential applications for simultaneous tooth biofilm eradication and tooth whitening in clinical dentistry.

Insulin sensitivity, ß cell function, and adverse pregnancy outcomes in women with gestational diabetes.

BACKGROUND: The potential impact of ß cell function and insulin sensitivity on adverse pregnancy outcomes in women with gestational diabetes mellitus (GDM) remains uncertain. We aimed to investigate the association between ß cell dysfunction, insulin resistance, and the composite adverse pregnancy outcomes. METHODS: This observational study included 482 women diagnosed with GDM during pregnancy. Quantitative metrics on ß cell function and insulin sensitivity during pregnancy were calculated using traditional equations. The association of ß cell dysfunction and insulin resistance with the risk of the composite adverse pregnancy outcomes was investigated using multivariable-adjusted logistic regression models. RESULTS: Multivariable-adjusted odds ratios (ORs) of adverse pregnancy outcomes across quartiles of homeostatic model assessment for insulin resistance (HOMA-IR) were 1.00, 0.95, 1.34, and 2.25, respectively (P for trend = 0.011). When HOMA-IR was considered as a continuous variable, the multivariable-adjusted OR of adverse pregnancy outcomes was 1.34 (95% confidence interval 1.16-1.56) for each 1-unit increase in HOMA-IR. Multivariable-adjusted ORs of adverse pregnancy outcomes across quartiles of homeostatic model assessment for ß cell function (HOMA-ß) were 1.00, 0.51, 0.60, and 0.53, respectively (P for trend = 0.068). When HOMA-ß was considered as a continuous variable, the multivariable-adjusted OR of adverse pregnancy outcomes was 0.57 (95% CI 0.24-0.90) for each 1-unit increase in HOMA-ß. However, other quantitative metrics were not associated with the composite adverse pregnancy outcomes. CONCLUSIONS: We demonstrated a significant association of ß cell function and insulin sensitivity with the risk of adverse pregnancy outcomes. We have provided additional evidence on the early identification of adverse pregnancy outcomes besides the glycemic values.

Curcumin nicotinate decreases serum LDL cholesterol through LDL receptor-mediated mechanism.

Curcumin nicotinate (Curtn) is a synthesized ester derivative of curcumin and niacin. Our previous study has shown that Curtn lowers serum low-density lipoprotein cholesterol (LDL-C) levels in apoE-/- mice and promotes LDL-C uptake into HepG2 cells in vitro. The present study was to test the hypothesis that Curtn decreases serum LDL-C levels through decreased expression of pro-protein convertase subtilisin/kexin type 9 (PCSK9) and subsequent increase in LDL receptor expression. Male Wistar rats on high-fat diet (HFD) were treated with Curtn or rosuvastatin. Curtn or rosuvastatin treatment significantly decreased serum levels of total cholesterol (TC) and LDL-C in rats on HFD with increased liver LDL receptor expression. LDL-C-lowering effect of Curtn was not observed in LDL receptor deficient (LDLR-/-) mice on HFD, while rosuvastatin still decreased serum lipid levels in LDLR-/- mice, indicating that the reduction of serum LDL-C levels by Curtn treatment was LDL receptor-dependent. Curtn treatment also significantly decreased the protein expression of PCSK9 in Wistar rats and LDLR-/- mice. In HepG2 cells with overexpression of human PCSK9, Curtn treatment significantly increased LDL-C uptakes into hepatocytes, and increased LDL receptor distribution on cell surface in association with decreased PCSK9 protein expression. RNAi-LDLR significantly attenuated the effect of Curtn on LDLR distribution on cell surface. These data indicates that Curtn would decrease serum LDL-C level at least partially through inhibition of PCSK9 expression, and subsequent increase in LDL receptor expression and distribution in hepatocytes, serving as a potential novel compound to treat hyperlipidemia.

MMP-12 as a potential biomarker to forecast ischemic stroke in obese patients.

Human health is threatened by obesity which causes the increasing incidence of various diseases, especially stroke. Ischemic stroke (IS) is mostly caused by the rupture of arterial plaque, whose instability is positively associated with matrix metalloproteinases (MMPs) that degrades extracellular matrix components. Studies have shown that matrix metalloproteinase-12 (MMP-12) may be involved in the pathogenesis of IS. Because of the higher incidence of stroke in obese patients than that in normal weight people, it is urgent for obesity to forecast stroke early. Considering high levels MMP-12 in obesity, we put forward that MMP-12 may be a potential biomarker for IS in obese patients.