Hepatic Snai1 and Snai2 promote liver regeneration and suppress liver fibrosis in mice.

Liver injury stimulates hepatocyte replication and hepatic stellate cell (HSC) activation, thereby driving liver regeneration. Aberrant HSC activation induces liver fibrosis. However, mechanisms underlying liver regeneration and fibrosis remain poorly understood. Here, we identify hepatic Snai1 and Snai2 as important transcriptional regulators for liver regeneration and fibrosis. Partial hepatectomy or CCl4 treatment increases occupancies of Snai1 and Snai2 on cyclin A2 and D1 promoters in the liver. Snai1 and Snai2 in turn increase promoter H3K27 acetylation and cyclin A2/D1 expressions. Hepatocyte-specific deletion of both Snai1 and Snai2, but not one alone, suppresses liver cyclin A2/D1 expression and regenerative hepatocyte proliferation after hepatectomy or CCl4 treatments but augments CCl4-stimulated HSC activation and liver fibrosis. Conversely, Snai2 overexpression in the liver enhances hepatocyte replication and suppresses liver fibrosis after CCl4 treatment. These results suggest that hepatic Snai1 and Snai2 directly promote, via histone modifications, reparative hepatocyte replication and indirectly inhibit liver fibrosis.

Malnutrition Is Associated with Diabetic Retinopathy in Patients with Type 2 Diabetes.

Background: The relationship between malnutrition and diabetic retinopathy (DR) is still unclear. The purpose of this study is to investigate the relationship between malnutrition and DR in type 2 diabetic patients. Methods: A cross-sectional study was conducted on 612 patients with type 2 diabetes mellitus. Four malnutrition assessment tools: Global Leadership Initiative on Malnutrition (GLIM) criteria, controlling nutritional status (CONUT), nutritional risk index (NRI), and prognostic nutritional index (PNI), were applied to assess the nutritional status of the study population. The association between malnutrition and DR was examined using multivariable logistic regression and ordered logistic regression. Results: The proportion of malnutrition varied from 10.0% to 34.3% in total patients and from 16.3% to 45.1% in DR patients across the assessment tools. DR patients were more likely to be malnourished than patients without DR. The adjusted odds ratios (aOR) and 95% confidence interval (CI) for DR of malnutrition defined by different tools were 1.86 (1.01-3.14) for GLIM criteria, 1.67 (1.04-2.70) for NRI, and 2.24 (1.07-4.69) for PNI. The aOR and 95% CI for the severity of DR of malnutrition defined by different tools were 1.99 (1.12-3.51) for GLIM criteria, 1.65 (1.06-2.58) for NRI, and 2.51 (1.31-4.79) for PNI. Conclusions: Malnutrition was common in DR patients, and it was closely linked to the presence and severity of DR. Diabetic patients with DR should undergo nutritional assessment and early treatment of malnutrition to prevent the onset or progression of DR.

Ultrasound Assessment of the Gastrocnemius Muscle as a Potential Tool for Identifying Sarcopenia in Patients with Type 2 Diabetes.

Objective: This study aims to examine the clinical significance of ultrasound evaluation of the gastrocnemius muscle (GM) in identifying sarcopenia in patients with type 2 diabetes (T2D). Methods: One hundred and fifty-three patients with T2D were included in this study. We measured the appendicular skeletal muscle mass index (ASMI), handgrip strength, and 6-meter walking speed. The US-derived muscle thickness (MT), cross-sectional area (CSA), and shear wave ultrasound elastography (SWE) of GM were also measured. We assessed the correlations between clinical indicators and US features. The model for screening sarcopenia was established using stepwise logistic regression. Stepwise linear regression was used to identify a set of variables that jointly estimated ASMI. The model's ability to identify sarcopenia and low muscle mass was assessed by receiver operating characteristic (ROC) curve analysis. Results: The prevalence of sarcopenia in this study was 24.2%. The CSA, MT and SWE values of the patients with sarcopenia were lower than those of patients without sarcopenia (all p < 0.05). ASMI was positively correlated with CSA (r = 0.56, p < 0.001) and MT (r = 0.39, p < 0.001). Handgrip strength was positively correlated with CSA (r = 0.45, p < 0.001), MT (r = 0.25, p < 0.001), and SWE (r = 0.26, p = 0.002). A diagnostic model for sarcopenia was established with a sensitivity of 81.1%, specificity of 75.0%, and an area under the curve (AUC) of 0.800. The estimated ASMI equation was developed and found to have a positive correlation with actual ASMI (r = 0.70, p < 0.001). It was also effective in diagnosing low muscle mass, with an AUC of 0.787 for males and 0.783 for females. Conclusion: Ultrasonographic assessment of the gastrocnemius muscle was found to be a useful and convenient method for detecting sarcopenia in patients with T2D.

Adipose METTL14-Elicited N6 -Methyladenosine Promotes Obesity, Insulin Resistance, and NAFLD Through Suppressing ß Adrenergic Signaling and Lipolysis.

White adipose tissue (WAT) lipolysis releases free fatty acids as a key energy substance to support metabolism in fasting, cold exposure, and exercise. Atgl, in concert with Cgi-58, catalyzes the first lipolytic reaction. The sympathetic nervous system (SNS) stimulates lipolysis via neurotransmitter norepinephrine that activates adipocyte ß adrenergic receptors (Adrb1-3). In obesity, adipose Adrb signaling and lipolysis are impaired, contributing to pathogenic WAT expansion; however, the underling mechanism remains poorly understood. Recent studies highlight importance of N6 -methyladenosine (m6A)-based RNA modification in health and disease. METTL14 heterodimerizes with METTL3 to form an RNA methyltransferase complex that installs m6A in transcripts. Here, this work shows that adipose Mettl3 and Mettl14 are influenced by fasting, refeeding, and insulin, and are upregulated in high fat diet (HFD) induced obesity. Adipose Adrb2, Adrb3, Atgl, and Cgi-58 transcript m6A contents are elevated in obesity. Mettl14 ablation decreases these transcripts' m6A contents and increases their translations and protein levels in adipocytes, thereby increasing Adrb signaling and lipolysis. Mice with adipocyte-specific deletion of Mettl14 are resistant to HFD-induced obesity, insulin resistance, glucose intolerance, and nonalcoholic fatty liver disease (NAFLD). These results unravel a METTL14/m6A/translation pathway governing Adrb signaling and lipolysis. METTL14/m6A-based epitranscriptomic reprogramming impairs adipose Adrb signaling and lipolysis, promoting obesity, NAFLD, and metabolic disease.

Enzymatic synthesis of indigo derivatives by tuning P450 BM3 peroxygenases.

Indigoids, a class of bis-indoles, have long been applied in dyeing, food, and pharmaceutical industries. Recently, interest in these 'old' molecules has been renewed in the field of organic semiconductors as functional building blocks for organic electronics due to their excellent chemical and physical properties. However, these indigo derivatives are difficult to access through chemical synthesis. In this study, we engineer cytochrome P450 BM3 from an NADPH-dependent monooxygenase to peroxygenases through directed evolution. A select number of P450 BM3 variants are used for the selective oxidation of indole derivatives to form different indigoid pigments with a spectrum of colors. Among the prepared indigoid organic photocatalysts, a majority of indigoids demonstrate a reduced band gap than indigo due to the increased light capture and improved charge separation, making them promising candidates for the development of new organic electronic devices. Thus, we present a useful enzymatic approach with broad substrate scope and cost-effectiveness by using low-cost H2O2 as a cofactor for the preparation of diversified indigoids, offering versatility in designing and manufacturing new dyestuff and electronic/sensor components.

Magnetic resonance spectroscopy features of the thalamus and the cerebellum and their association with clinical features in children with autism spectrum disorder: a prospective study. / å­¤ç‹¬ç—‡è°±ç³»éšœç¢å„¿ç«¥ä¸˜è„‘å’Œå°è„‘ç£å ±æŒ¯æ³¢è°±ç‰¹å¾å’Œä¸´åºŠå ³ç³»çš„å‰çž»æ€§ç ”ç©¶.

OBJECTIVES: To study the changes in biochemical metabolites in the thalamus and the cerebellum and their association with clinical features in children with autism spectrum disorder (ASD). METHODS: In this prospective study, magnetic resonance spectroscopy (MRS) with point-resolved spatial selection was used to analyze the thalamus and the cerebellum at both sides in 50 children with ASD aged 2-6 years. Creatine (Cr) was as the internal standard to measure the relative values of N-acetylaspartate (NAA)/Cr, choline (Cho)/Cr, myoinositol (MI)/Cr, and glutamine and glutamate complex (Glx)/Cr, and the differences in metabolites and their association with clinical symptoms were compared. RESULTS: In the children with ASD, NAA/Cr in the left thalamus was positively correlated with the scores of hearing-language and hand-eye coordination in the Griffiths Development Scales-Chinese (P<0.05). Cho/Cr in the right cerebellum was positively correlated with the scores of personal-social competence, hearing-language, and hand-eye coordination (P<0.05). NAA/Cr and Glx/Cr in the left thalamus were positively correlated with those in the left cerebellum (P<0.05). There was no significant difference in metabolites between the left and right sides of the thalamus and the cerebellum in the children with ASD (P>0.05). CONCLUSIONS: There are metabolic disorders in the cerebellum and the thalamus in children with ASD, and there is a correlation between the changes of metabolites in the left cerebellum and the left thalamus. Some metabolic indexes are related to the clinical symptoms of ASD. MRS may reveal the pathological basis of ASD and provide a basis for diagnosis and prognosis assessment of ASD as a noninvasive and quantitative detection method.

MiR-22 modulates brown adipocyte thermogenesis by synergistically activating the glycolytic and mTORC1 signaling pathways.

Background: Brown adipose tissue (BAT) dissipates chemical energy as heat and has the potential to be a protective strategy to prevent obesity. microRNAs (miRNAs) are emerging as important posttranscriptional factors affecting the thermogenic function of BAT. However, the regulatory mechanism underlying miRNA-mediated energy metabolism in BAT is not fully understood. Here, we explored the roles of miR-22 in BAT thermogenesis and energy metabolism. Methods: Using global and conditional knockout mice as in vivo models and primary brown adipocytes as an in vitro system, we investigated the function of miR-22 in BAT thermogenesis in vivo and in vitro. Results: miR-22 expression was upregulated in BAT in response to cold exposure and during brown preadipocyte differentiation. Both global and conditional knockout mice displayed BAT whitening, impaired cold tolerance, and decreased BAT thermogenesis. Moreover, we found that miR-22 deficiency impaired BAT glycolytic capacity, which is critical for thermogenesis. The mechanistic results revealed that miR-22 activated the mTORC1 signaling pathway by directly suppressing Tsc1 and concomitantly directly suppressing Hif1an, an inhibitor of Hif1α, which promotes glycolysis and maintains thermogenesis. Conclusions: Our findings identify miR-22 as a critical regulator in the control of thermogenesis in BAT and as a potential therapeutic target for human metabolic disorders.

Unveiling Chiral Phase Evolution in Rabi Oscillations from a Photonic Setting.

Rabi oscillation, originally proposed in nuclear magnetic resonance, is a well-known phenomenon associated with a driven two-level system. Although magnetic fields typically can bring about chirality into unusual phenomena such as chiral edge states in the quantum Hall effect, it is not clear if chirality exists in Rabi oscillations. Here we unveil the intrinsic chirality carried by the phase in a Rabi problem. For opposite detuning of the driving field, the phase evolution of the probability amplitude exhibits a mirror symmetry. Consequently, constructive or destructive interference of two off-resonant Rabi processes under different initial conditions is level dependent and symmetry protected. Experimentally, we demonstrate such features in a photonic setting with adjustable detuning, yet our results may prove pertinent to the study of similar phenomena in other driven two-level systems beyond photonics.

Cell-penetrating peptide-driven Cre recombination in porcine primary cells and generation of marker-free pigs.

Cell-penetrating peptides (CPPs) have been increasingly used to deliver various molecules, both in vitro and in vivo. However, there are no reports of CPPs being used in porcine fetal fibroblasts (PFFs). The increased use of transgenic pigs for basic research and biomedical applications depends on the availability of technologies for efficient genetic-modification of PFFs. Here, we report that three CPPs (CPP5, TAT, and R9) can efficiently deliver active Cre recombinase protein into PFFs via an energy-dependent endocytosis pathway. The three CPP-Cre proteins can enter PFFs and subsequently perform recombination with different efficiencies. The recombination efficacy of CPP5-Cre was found to be nearly 90%. The rate-limiting step for CPP-Cre-mediated recombination was the step of endosome escape. HA2 and chloroquine were found to improve the recombination efficiency of TAT-Cre. Furthermore, we successfully obtained marker-free transgenic pigs using TAT-Cre and CPP5-Cre. We provide a framework for the development of CPP-based farm animal transgenic technologies that would be beneficial to agriculture and biomedicine.

UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis.

Uncoupling protein 1 (UCP1) plays a central role in nonshivering thermogenesis in brown fat; however, its role in beige fat remains unclear. Here we report a robust UCP1-independent thermogenic mechanism in beige fat that involves enhanced ATP-dependent Ca2+ cycling by sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2). Inhibition of SERCA2b impairs UCP1-independent beige fat thermogenesis in humans and mice as well as in pigs, a species that lacks a functional UCP1 protein. Conversely, enhanced Ca2+ cycling by activation of α1- and/or ß3-adrenergic receptors or the SERCA2b-RyR2 pathway stimulates UCP1-independent thermogenesis in beige adipocytes. In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism and pyruvate dehydrogenase activity for ATP-dependent thermogenesis through the SERCA2b pathway; beige fat thereby functions as a 'glucose sink' and improves glucose tolerance independently of body weight loss. Our study uncovers a noncanonical thermogenic mechanism through which beige fat controls whole-body energy homeostasis via Ca2+ cycling.

Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance.

Beige adipocytes gained much attention as an alternative cellular target in anti-obesity therapy. While recent studies have identified a number of regulatory circuits that promote beige adipocyte differentiation, the molecular basis of beige adipocyte maintenance remains unknown. Here, we demonstrate that beige adipocytes progressively lose their morphological and molecular characteristics after withdrawing external stimuli and directly acquire white-like characteristics bypassing an intermediate precursor stage. The beige-to-white adipocyte transition is tightly coupled to a decrease in mitochondria, increase in autophagy, and activation of MiT/TFE transcription factor-mediated lysosome biogenesis. The autophagy pathway is crucial for mitochondrial clearance during the transition; inhibiting autophagy by uncoupled protein 1 (UCP1(+))-adipocyte-specific deletion of Atg5 or Atg12 prevents beige adipocyte loss after withdrawing external stimuli, maintaining high thermogenic capacity and protecting against diet-induced obesity and insulin resistance. The present study uncovers a fundamental mechanism by which autophagy-mediated mitochondrial clearance controls beige adipocyte maintenance, thereby providing new opportunities to counteract obesity.

Lats2 modulates adipocyte proliferation and differentiation via hippo signaling.

First identified in Drosophila and highly conserved in mammals, the Hippo pathway controls organ size. Lats2 is one of the core kinases of the Hippo pathway and plays major roles in cell proliferation by interacting with the downstream transcriptional cofactors YAP and TAZ. Although the function of the Hippo pathway and Lats2 is relatively well understood in several tissues and organs, less is known about the function of Lats2 and Hippo signaling in adipose development. Here, we show that Lats2 is an important modulator of adipocyte proliferation and differentiation via Hippo signaling. Upon activation, Lats2 phosphorylates YAP and TAZ, leading to their retention in the cytoplasm, preventing them from activating the transcription factor TEAD in the nucleus. Because TAZ remains in the cytoplasm, PPARγ regains its transcriptional activity. Furthermore, cytoplasmic TAZ acts as an inhibitor of Wnt signaling by suppressing DVL2, thereby preventing ß-catenin from entering the nucleus to stimulate TCF/LEF transcriptional activity. The above effects contribute to the phenotype of repressed proliferation and accelerated differentiation in adipocytes. Thus, Lats2 regulates the balance between proliferation and differentiation during adipose development. Interestingly, our study provides evidence that Lats2 not only negatively modulates cell proliferation but also positively regulates cell differentiation.

[Study of aspirin and its interaction with DNA by Raman and UV spectroscopies].

Normal Raman spectroscopy and surface-enhanced Raman spectroscopy of aspirin and aspirin tablet were reported, and the vibrational and enhanced peaks were assigned; the interaction of aspirin with DNA was investigated by SERS and UV. The results showed that NRS and SERS of aspirin and aspirin tablet were consistent basically, which indicated that excipient hardly affected the detection of aspirin; in SERS, aspirin was absorbed perpendicularly on silver colloid through the carboxyl group and the benzene ring; The interaction was mainly caused by the inserting-action mode between aspirin and DNA, and the benzene ring and C=O of aspirin were inserted between the base pair of the double helix structure of DNA, which provided important information and useful reference for understanding deeply the mechanism of action of this kind of drug.

[Study of the epimers of dexamethasone sodium phosphate and betamethasone sodium phosphate by FTIR, FT-Raman and SERS].

Abstract Infrared spectroscopy (FTIR), normal Raman spectroscopy (NRS) of the solids and saturated solutions and surface-enhanced Raman spectroscopy (SERS) on the silver colloidal substrate were reported. The vibrational modes of each group were analyzed, and the enhanced peaks were assigned and compared. The results showed that the major differences between the epimers were the frequency of the CH3 asymmetric stretching vibration and symmetric in-plane deformation vibration of them. According to the mechanism and laws of SERS, the epimers were absorbed on the silver colloid through the P-O bond, carboxyl group and the five-membered ring perpendicularly. The establishment of this adsorption model which realized the rapid identification and the discrimination between the epimers provided important information and useful reference of the adrenal cortical hormone drugs.

[IR, Raman and DFT studies of Sudan red III and IV].

Infrared spectroscopy (IR) and normal Raman spectroscopy (NRS) of Sudan red(III) and Sudan red(IV), and surface -enhanced Raman spectroscopy(SERS) of them on Cu-Ag nanocomposite material were reported in the present paper. The density functional theory (DFT) calculation was applied to calculate IR and NRS on a B3LYP/6-311+G (d, p) level, and the theoretically calculated spectra were carefully compared with the obtained experimental spectra. The vibrational peaks were assigned by the software of Gauss view 5.0. Rapid identification of Sudan red was realized, which provided profitable basis for characteristics and quick test of Sudan dyes, and reliable detection method of food security.