1,25-hydroxyvitamin D relieves colitis in rats via downregulation of toll-like receptor 9 expression

Aim To investigate the therapeutic and immunoregulatory effects of 1,25-dihydroxyvitamin D (1,25(OH)D3) on 2,4,6- trinitrobenzenesulfonic acid (TNBS) -induced colitis in rats. Methods Experimental colitis induced by enema administration of TNBS plus ethanol was treated with 5-aminosalicylic acid (5-ASA) and/or 1,25(OH)D3. Disease activity was measured using the disease activation index (DAI), colon macroscopic damage index (CMDI), histological colonic damage score, and myeloperoxidase (MPO) activity. The expression of toll-like receptor 9 (TLR9) in the colon was determined by reverse transcription-polymerase chain reaction and immunohistochemistry. Results Rats with TNBS-induced colitis had significantly elevated DAI, CMDI, histological colonic damage score, and MPO activity (all P < 0.001) compared to rats without colitis. Treatment with 5-ASA or 1,25(OH)D3 ameliorated colitis by lowering CMDI (P = 0.049, P = 0.040, respectively), histological colonic damage score (P = 0.010, P = 0.005, respectively), and MPO activity (P = 0.0003, P = 0.0013, respectively) compared with the TNBS group. Combined treatment with 5-ASA and 1,25(OH)D3 significantly decreased MPO activity (P = 0.003). 1,25(OH)D3 attenuated colitis without causing hypercalcemia or renal insufficiency. TNBS significantly increased the number of TLR9 positive cells compared to control (P < 0.010), while 5-ASA, 1,25(OH)D3, and combined treatment with 5-ASA and 1,25(OH)D3 significantly decreased it compared to TNBS group (all P < 0.010). In TNBS group a moderate correlation was observed between MPO activity and the number of TLR9-positive cells (r = 0.654, P < 0.001). Conclusion TLR9 expression correlates with the extent of inflammation in TNBS-induced colitis. 1,25(OH)D3 relieves this inflammation possibly by decreasing TLR9 expression

Epigenetic Enzyme Mutations: Role in Tumorigenesis and Molecular Inhibitors

Epigenetic modifications, such as DNA methylation and histone modification, result in heritable changes in gene expression without changing the DNA sequence. Epigenetic regulatory enzymes such as DNA methyltransferases, histone methyltransferases, and histone deacetylases are involved in epigenetic modification. Studies have shown that the dysregulation caused by changes in the amino acid sequence of these enzymes is closely correlated with tumor onset and progression. In addition, certain amino acid changes in the metabolic enzyme isocitrate dehydrogenase (IDH) are linked to altered epigenetic modifications in tumors. Some small molecule inhibitors targeting these aberrant enzymes have shown promising anti-cancer efficacy in preclinical and clinical trials. For example, the small molecule inhibitor ivosidenib, which targets IDH1 with a mutation at R132, has been approved by the FDA for the clinical treatment of acute myeloid leukemia. In this review, we summarize the recurrent “hotspot” mutations in these enzymes in various tumors and their role in tumorigenesis. We also describe candidate inhibitors of the mutant enzymes which show potential therapeutic value. In addition, we introduce some previously unreported mutation sites in these enzymes, which may be related to tumor development and provide opportunities for future study

A Non-stochastic Optimization Algorithm for Neural-network Quantum States

Neural-network quantum states (NQS) employ artificial neural networks to encode many-body wave functions in second quantization through variational Monte Carlo (VMC). They have recently been applied to accurately describe electronic wave functions of molecules and have shown the challenges in efficiency comparing with traditional quantum chemistry methods. Here we introduce a general non-stochastic optimization algorithm for NQS in chemical systems, which deterministically generates a selected set of important configurations simultaneously with energy evaluation of NQS. This method bypasses the need for Markov-chain Monte Carlo within the VMC framework, thereby accelerating the entire optimization process. Furthermore, this newly-developed non-stochastic optimization algorithm for NQS offers comparable or superior accuracy compared to its stochastic counterpart and ensures more stable convergence. The application of this model to test molecules exhibiting strong electron correlations provides further insight into the performance of NQS in chemical systems and opens avenues for future enhancements.Comment: 30 pages, 7 figures, and 1 tabl

CERKL regulates autophagy via the NAD-dependent deacetylase SIRT1

<p>Macroautophagy/autophagy is an important intracellular mechanism for the maintenance of cellular homeostasis. Here we show that the <i>CERKL</i> (ceramide kinase like) gene, a retinal degeneration (RD) pathogenic gene, plays a critical role in regulating autophagy by stabilizing SIRT1. <i>In vitro</i> and <i>in vivo</i>, suppressing CERKL results in impaired autophagy. SIRT1 is one of the main regulators of acetylation/deacetylation in autophagy. In CERKL-depleted retinas and cells, SIRT1 is downregulated. ATG5 and ATG7, 2 essential components of autophagy, show a higher degree of acetylation in CERKL-depleted cells. Overexpression of SIRT1 rescues autophagy in CERKL-depleted cells, whereas CERKL loses its function of regulating autophagy in SIRT1-depleted cells, and overexpression of CERKL upregulates SIRT1. Finally, we show that CERKL directly interacts with SIRT1, and may regulate its phosphorylation at Ser27 to stabilize SIRT1. These results show that CERKL is an important regulator of autophagy and it plays this role by stabilizing the deacetylase SIRT1.</p

Cryptotanshinone ameliorates hemorrhagic shock-induced liver injury via activating the Nrf2 signaling pathway

Introduction. Hemorrhagic shock (HS) is an important cause of high mortality in traumatized patients. Cryptotanshinone(CTS) is a bioactive compound extracted from Salvia miltiorrhiza Bunge (Danshen). The current study aimed to explore the effect and underlying mechanism of CTS on the liver injury induced by HS.Material and methods. Male Sprague-Dawley rats were used to establish the HS model by hemorrhaging and monitoring mean arterial pressure (MAP). CTS was intravenously administered at concentration of 3.5 mg/kg, 7 mg/kg, or 14 mg/kg 30 minutes before resuscitation. Twenty-four hours after resuscitation, the liver tissue and serum samples were collected for the following examinations. Hematoxylin and eosin (H&amp;E) staining was used to evaluate hepatic morphology changes. The myeloperoxidase (MPO) activity in liver tissue and the serum activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were examined to reveal the extent of liver injury. The protein expression of Bax and Bcl-2 in liver tissue was detected by western blot. The TUNEL assay determined the apoptosis of hepatocytes. Oxidative stress of liver tissue was assessed by the examination of reactive oxygen species (ROS) generation. The content of malondialdehyde (MDA), glutathione (GSH), and adenosine triphosphate (ATP), the activity of superoxide dismutase (SOD) and oxidative chain complexes (complex I, II, III, IV), as well as cytochrome c expression in cytoplasm and mitochondria, were also used to determine the extent of oxidative injury in the liver. Immunofluorescence (IF) was employed to estimate nuclear factor E2-related factor 2 (Nrf2) expression. The mRNA and protein levels of heme oxygenase 1 (HO-1), NAD(P)H: quinone oxidoreductases 1 (NQO1), cyclooxygenase-2 (COX-2), and nitric oxide synthase (iNOS) were assessed by real-time qPCR, western blot to investigate the mechanism of CTS regulating HS-induced liver injury.Results. H&amp;E staining and a histological score of rat liver suggested that HS induced liver injury. The activity of ALT, AST, and MPO was significantly increased by HS treatment. After CTS administration the ALT, AST, and MPO activities were suppressed, which indicates the liver injury was alleviated by CTS. The HS-induced upregulation of the TUNEL-positive cell rate was suppressed by various doses of CTS. HS-induced ROS production was decreased and the protein expression of Bax and Bcl-2 in the HS-induced rat liver was reversed by CTS administration. In the liver of HS-induced rats, the upregulation of MDA content and the downregulation of GSH content and SOD activity were suppressed by CTS. Additionally, CTS increases ATP content and mitochondrial oxidative complexes activities and suppressed the release of cytochrome c from mitochondria to the cytoplasm. Moreover, IF and western blot demonstrated that the activation of Nrf2 blocked by HS was recovered by different doses of CTS in liver tissue. The expression of downstream enzymes of the Nrf2 pathway, including HO-1, NQO1, COX-2, and iNOS, was reversed by CTS in the HS rat model.Conclusions. The current study for the first time revealed the protective effect of CTS in HS-induced liver injury. CTSeffectively recovered hepatocyte apoptosis, oxidative stress, and mitochondria damage induced by HS in the rat liverpartly via regulating the Nrf2 signaling pathway

Exploring the potential of blended learning to promote retention and achievement in higher education professional study programs

In this paper, we present a blended learning model designed for a university professional study program attended by full-time professional workers, i.e. in-service teachers studying in the field of School Administration. The model integrates four main instructional strategies at the program level: mentoring; participation in an online community of professional learning and practice; collaborative concept-mapping with an object-typed knowledge modeling software, and face-to-face seminars in a work setting. Based on interview and observation data collected during two successive small-scale experimentations of the model, we explored potential factors that could have had an impact on students’ academic retention and achievement. Four types of factors were identified: personal, professional, institutional and pedagogical. We found that pedagogical and professional factors, which are insufficiently considered in theoretical models of student retention, are of primary concern for students who work full-time as professionals. A blended learning model designed at the program level and strongly “situated” in the professional practice of the students is a promising avenue to adjust to their career constraints and aspirations and, thus, promoting their academic retention and achievement

Tulp1 deficiency causes early-onset retinal degeneration through affecting ciliogenesis and activating ferroptosis in zebrafish

Mutations in TUB-like protein 1 (TULP1) are associated with severe early-onset retinal degeneration in humans. However, the pathogenesis remains largely unknown. There are two homologous genes of TULP1 in zebrafish, namely tulp1a and tulp1b. Here, we generated the single knockout (tulp1a(−/−) and tulp1b(−/−)) and double knockout (tulp1-dKO) models in zebrafish. Knockout of tulp1a resulted in the mislocalization of UV cone opsins and the degeneration of UV cones specifically, while knockout of tulp1b resulted in mislocalization of rod opsins and rod-cone degeneration. In the tulp1-dKO zebrafish, mislocalization of opsins was present in all types of photoreceptors, and severe degeneration was observed at a very early age, mimicking the clinical manifestations of TULP1 patients. Photoreceptor cilium length was significantly reduced in the tulp1-dKO retinas. RNA-seq analysis showed that the expression of tektin2 (tekt2), a ciliary and flagellar microtubule structural component, was downregulated in the tulp1-dKO zebrafish. Dual-luciferase reporter assay suggested that Tulp1a and Tulp1b transcriptionally activate the promoter of tekt2. In addition, ferroptosis might be activated in the tulp1-dKO zebrafish, as suggested by the up-regulation of genes related to the ferroptosis pathway, the shrinkage of mitochondria, reduction or disappearance of mitochondria cristae, and the iron and lipid droplet deposition in the retina of tulp1-dKO zebrafish. In conclusion, our study establishes an appropriate zebrafish model for TULP1-associated retinal degeneration and proposes that loss of TULP1 causes defects in cilia structure and opsin trafficking through the downregulation of tekt2, which further increases the death of photoreceptors via ferroptosis. These findings offer insight into the pathogenesis and clinical treatment of early-onset retinal degeneration

Phototunable biomemory based on light-mediated charge trap

Phototunable biomaterial‐based resistive memory devices and understanding of their underlying switching mechanisms may pave a way toward new paradigm of smart and green electronics. Here, resistive switching behavior of photonic biomemory based on a novel structure of metal anode/carbon dots (CDs)‐silk protein/indium tin oxide is systematically investigated, with Al, Au, and Ag anodes as case studies. The charge trapping/detrapping and metal filaments formation/rupture are observed by in situ Kelvin probe force microscopy investigations and scanning electron microscopy and energy‐dispersive spectroscopy microanalysis, which demonstrates that the resistive switching behavior of Al, Au anode‐based device are related to the space‐charge‐limited‐conduction, while electrochemical metallization is the main mechanism for resistive transitions of Ag anode‐based devices. Incorporation of CDs with light‐adjustable charge trapping capacity is found to be responsible for phototunable resistive switching properties of CDs‐based resistive random access memory by performing the ultraviolet light illumination studies on as‐fabricated devices. The synergistic effect of photovoltaics and photogating can effectively enhance the internal electrical field to reduce the switching voltage. This demonstration provides a practical route for next‐generation biocompatible electronics

Rod genesis driven by mafba in an nrl knockout zebrafish model with altered photoreceptor composition and progressive retinal degeneration

Neural retina leucine zipper (NRL) is an essential gene for the fate determination and differentiation of the precursor cells into rod photoreceptors in mammals. Mutations in NRL are associated with the autosomal recessive enhanced S-cone syndrome and autosomal dominant retinitis pigmentosa. However, the exact role of Nrl in regulating the development and maintenance of photoreceptors in the zebrafish (Danio rerio), a popular animal model used for retinal degeneration and regeneration studies, has not been fully determined. In this study, we generated an nrl knockout zebrafish model via the CRISPR-Cas9 technology and observed a surprising phenotype characterized by a reduced number, but not the total loss, of rods and over-growth of green cones. We discovered two waves of rod genesis, nrl-dependent and -independent at the embryonic and post-embryonic stages, respectively, in zebrafish by monitoring the rod development. Through bulk and single-cell RNA sequencing, we characterized the gene expression profiles of the whole retina and each retinal cell type from the wild type and nrl knockout zebrafish. The over-growth of green cones and mis-expression of green-cone-specific genes in rods in nrl mutants suggested that there are rod/green-cone bipotent precursors, whose fate choice between rod versus green-cone is controlled by nrl. Besides, we identified the mafba gene as a novel regulator of the nrl-independent rod development, based on the cell-type-specific expression patterns and the retinal phenotype of nrl/mafba double-knockout zebrafish. Gene collinearity analysis revealed the evolutionary origin of mafba and suggested that the function of mafba in rod development is specific to modern fishes. Furthermore, the altered photoreceptor composition and abnormal gene expression in nrl mutants caused progressive retinal degeneration and subsequent regeneration. Accordingly, this study revealed a novel function of the mafba gene in rod development and established a working model for the developmental and regulatory mechanisms regarding the rod and green-cone photoreceptors in zebrafish