Normalizing Microbiota-Induced Retinoic Acid Deficiency Stimulates Protective CD8(+) T Cell-Mediated Immunity in Colorectal Cancer.

Although all-trans-retinoic acid (atRA) is a key regulator of intestinal immunity, its role in colorectal cancer (CRC) is unknown. We found that mice with colitis-associated CRC had a marked deficiency in colonic atRA due to alterations in atRA metabolism mediated by microbiota-induced intestinal inflammation. Human ulcerative colitis (UC), UC-associated CRC, and sporadic CRC specimens have similar alterations in atRA metabolic enzymes, consistent with reduced colonic atRA. Inhibition of atRA signaling promoted tumorigenesis, whereas atRA supplementation reduced tumor burden. The benefit of atRA treatment was mediated by cytotoxic CD8(+) T cells, which were activated due to MHCI upregulation on tumor cells. Consistent with these findings, increased colonic expression of the atRA-catabolizing enzyme, CYP26A1, correlated with reduced frequencies of tumoral cytotoxic CD8(+) T cells and with worse disease prognosis in human CRC. These results reveal a mechanism by which microbiota drive colon carcinogenesis and highlight atRA metabolism as a therapeutic target for CRC.

A Perspective on 2D Fused-Ring Quad-Rotor-Shaped Nonfullerene Acceptors with an Anthracene Core.

Previous studies have demonstrated the remarkable properties of quad-rotor-shaped two-dimensional nonfullerene acceptors (2D NFAs), which encompass exceptional electron affinity, robust sunlight absorption, effective exciton separation, and accelerated electron transfer capabilities. Naphthalene has been demonstrated to be a significant 2D fused core to construct high-performance 2D NFAs. However, synthesizing such materials through existing synthetic pathways poses a significant challenge. In this work, we designed four 2D NFAs (TEA-SIC, TEA-SIC-8F, TEA-SIC-OH, and TEA-SIC-OH-8F) with an anthracene core. These NFAs can theoretically be synthesized into a quad-rotor configuration through a seven-step synthetic process. Theoretical calculations have demonstrated that these 2D NFAs exhibit superior electron-accepting abilities, enhanced sunlight absorption, and more efficient exciton dissociation compared to Y6. Furthermore, TEA-SIC and TEA-SIC-8F exhibited impressive electron mobilities of 1.76 × 10-3 cm2 V-1 s-1 and 1.18 × 10-3 cm2 V-1 s-1, respectively, indicating their suitability for the development of high-performance organic solar cells (OSCs). Although TEA-SIC-OH and TEA-SIC-OH-8F have lower electron mobility, their high sunlight absorption and efficient exciton separation suggest potential as third components in ternary OSCs. These 2D NFAs also exhibit a commendable solubility in most alcohol-based solvents, indicating their potential for specialized applications in the fabrication of stacked OSCs. These findings provide valuable insights for the future design of synthesizable high-performance 2D NFAs.

Replacing the cyano (-C[triple bond, length as m-dash]N) group to design environmentally friendly fused-ring electron acceptors.

The cyano-group (-C[triple bond, length as m-dash]N) is an electron-withdrawing group, which has been widely used to construct high-performance fused-ring electron acceptors (FREAs). Benefiting from these FREAs, the power conversion efficiency of organic solar cells has recently exceeded 18%. However, malononitrile is a highly toxic substance used to introduce -C[triple bond, length as m-dash]N during the synthesis of these FREAs. Therefore, the synthesis processes of most high-performance FREAs are typically harmful to the environment. Our previous work demonstrated that the electron-withdrawing ability of -C[triple bond, length as m-dash]N is necessary for FREAs. Thus, the use of other electron-withdrawing groups instead of -C[triple bond, length as m-dash]N to design environmentally friendly FREAs is feasible. We utilized seven electron-withdrawing groups, namely, -C[double bond, length as m-dash]NH, -N[double bond, length as m-dash]O, -CH[double bond, length as m-dash]O, -CO-CH3, -CO-OH, -CO-Cl, and -CO-Br, to replace -C[triple bond, length as m-dash]N in the commonly used acceptor Y6 to design new FREAs (Y6-CNH, Y6-NO, Y6-CHO, Y6-COCH3, Y6-COOH, Y6-COCl, and Y6-COBr). Multi-scale theoretical calculation methods were used to investigate the photoelectronic properties of these new FREAs, including energy level, absorption spectrum, exciton binding energy, and electron mobility. The results showed that Y6-CNH, Y6-COCH3 and Y6-COOH are unsuitable for use as acceptor materials because of their high frontier molecular orbital energy level and weak electron affinity. The strong absorption intensity and weak exciton binding energy of Y6-CHO, Y6-COCl, and Y6-COBr indicated that they can absorb more solar energy than Y6 and excitons are easier to separate into free charges. The electron mobility of Y6-CHO (3.53 × 10-4 cm2 V-1 s-1) was found to be approximately 28 times that of Y6-COCl (1.24 × 10-5 cm2 V-1 s-1) and Y6-COBr (1.28 × 10-5 cm2 V-1 s-1). The possible synthetic routes to Y6-CHO are environmentally friendly. Therefore, -CH[double bond, length as m-dash]O is the most suitable electron-withdrawing group for constructing high-performance environmentally friendly FREAs. This work can provide a new molecular design perspective in experimental science for developing high-performance environmentally friendly FREAs.

Pubertal exposure to bisphenol-A affects social recognition and arginine vasopressin in the brain of male mice.

Social recognition is an ability of animals to identify and distinguish conspecifics, which is essential for nearly all social species to establish social relationships. Social recognition provides the basis for a variety of social behaviors. Because of modulated by gonadal hormones, it is possible that social cognition is affected by environmental endocrine disruptors (EEDs). In the present study, after being pubertal exposed to bisphenol A (BPA, 0.04, 0.4, and 4 mg/kg) for 18 days, adult male mice did not show significant dishabituation to a novel female stimulus in habituation-dishabituation task. The capacity for discriminating the odors between familiar and novel female urine or between male and female urine was suppressed in BPA-exposed male. In addition, BPA (0.4, 4 mg/kg) decreased the number of immunoreaction of AVP (AVP-ir) neurons in both the bed nucleus of the stria terminalis (BNST) and the medial amygdala (MeA), and BPA (0.04, 0.4, 4 mg/kg) reduced the level of V1αR in the lateral septum (LS) of adult male. Further, BPA decreased the levels of testosterone (T) in the brain and androgens receptor (AR) in the LS, the amygdala, and BNST, as well the levels of estrogen receptor α and ß (ERα/ß) in the amygdala and BNST. These results indicate that pubertal exposure to BPA affected the actions of both androgens and estrogens in the brain and inhibited AVP system of social circuits, and these alterations may be associated with impaired social recognition of adult male mice.

The Effects of RKI-1447 in a Mouse Model of Nonalcoholic Fatty Liver Disease Induced by a High-Fat Diet and in HepG2 Human Hepatocellular Carcinoma Cells Treated with Oleic Acid.

BACKGROUND This study aimed to investigate the effects of RKI-1447, a selective inhibitor of Rho-associated ROCK kinases, in a mouse model of nonalcoholic fatty liver disease (NAFLD) induced by a high-fat diet, and in oleic acid-treated HepG2 human hepatocellular carcinoma cells in vitro. MATERIAL AND METHODS Four study groups of mice included: the control group; the high-fat diet (HFD) group; the HFD+RKI-1447 (2 mg/kg) group; and the HFD+RKI-1447 (8 mg/kg) group. Mice were fed a high-fat diet for 12 weeks. Mice in the HFD+RKI-1447 groups were fed a high-fat diet for 12 weeks and treated with RKI-1447 twice weekly for three weeks. The HepG2 human hepatocellular carcinoma cells were treated with or without RKI-1447 for 2 h and treated with oleic acid for 24 h. RESULTS In the mouse model of NAFLD, RKI-1447 reduced insulin resistance and the levels of alanine aminotransferase (ALT), aspartate transaminase (AST), total cholesterol, triglyceride, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), malondialdehyde (MDA), and superoxide dismutase (SOD). RKI-1447 reduced the histological changes in the mouse model of NAFLD in mice fed a high-fat diet and significantly inhibited the generations of triglyceride, IL-6, and TNF-alpha. RKI-1447 reduced the levels of oxidative stress in HepG2 cells treated with oleic acid and significantly down-regulated the expression of RhoA, ROCK1, ROCK2, toll-like receptor 4 (TLR4), p-TBK1, and p-IRF3. RKI-1447 treatment also inhibited RhoA expression. CONCLUSIONS In a mouse model of NAFLD, RKI-1447 inhibited ROCK and modulated insulin resistance, oxidative stress, and inflammation through the ROCK/TLR4/TBK1/IRF3 pathway.

Numerical simulation of heat induced flow-mediated dilation of blood vessels.

Local heat can accelerate the blood circulation and induce the vasodilatation. Investigators reported that local heat causes an increase in skin blood flow consisting of two phases. The first is solely sensory neural, and the second is nitric oxide mediated. However, the mechanism underlying the skin blood flow response to local heating are complex and poorly understood. The mechanisms behind these two phases are deduced to be linked by flow-mediated dilation. In this study, the variation of the blood flow and the blood vessel diameter are monitored during local heating. According to the dynamic blood flow, the theoretical model of flow mediated dilation involving the key agents production and transportation was first used to study vasodilatation process during heating, and the variations of blood vessel was obtained. Finally, accurate distributions of the nitric oxide, calcium and myosin concentrations in the arterial wall were found during autoregulation. We evaluated the time course of the blood vessel changing and verified the fact that the second increase in blood flow is the result of flow dilation mediation. The effects of dilation of blood vessel were also analyzed.

MiR-27a-5p regulates apoptosis of liver ischemia-reperfusion injury in mice by targeting Bach1.

Ischemia-reperfusion (I/R) injury causes cellular dysfunction and a series of immune or apoptotic reactions. Bach1 is a mammalian transcription factor that represses Hmox1, which encodes heme oxygenase-1 (HO-1) that can degrade heme into free iron, carbon monoxide, and biliverdin, to play an important role in antioxidant, anti-inflammatory, and antiapoptotic activities. MicroRNAs (miRNAs) can be found in a variety of eukaryotic cells and viruses, a class of noncoding small RNAs that are encoded by endogenous genes. The aims of this study were to determine whether miR-27a-5p targets Bach1 and regulates cellular death; the dual-luciferase reporter assay was used to detect this and the results showed that miR-27a-5p significantly decreased the luciferase activity of the Bach1 3'-untranslated region. MiR-27a-5p was increased in mice during hepatic I/R and Bach1 was decreased. By transfecting the AML12 cells with the mimic, inhibitor miR-27a-5p in hypoxia/reoxygenation (H/R) models showed that overexpression of miR-27a-5p decreased Bach1 messenger RNA, upregulated HO-1 expression, and promoted antiapoptotic Bcl-2 and downregulated proapoptotic caspase-3 gene expression. In contrast, the miR-27a-5p inhibitor yielded the opposite results. Meanwhile, transfection with Bach1 small interference RNA obviously upregulated the protein levels of HO-1 and resulted in an increase in Bcl-2 and a decrease in caspase-3 protein levels. Thus, we can conclude that miR-27a-5p is relevant to liver I/R injury and overexpression of miR-27a-5p may alleviate apoptosis in H/R injury by targeting Bach1 in vitro.

Immunotherapy Added to Antibiotic Treatment Reduces Relapse of Disease in a Mouse Model of Tuberculosis.

Immune-modulating drugs that target myeloid-derived suppressor cells or stimulate natural killer T cells have been shown to reduce mycobacterial loads in tuberculosis (TB). We aimed to determine if a combination of these drugs as adjunct immunotherapy to conventional antibiotic treatment could also increase therapeutic efficacy against TB. In our model of pulmonary TB in mice, we applied treatment with isoniazid, rifampicin, and pyrazinamide for 13 weeks alone or combined with immunotherapy consisting of all-trans retinoic acid, 1,25(OH)2-vitamin D3, and α-galactosylceramide. Outcome parameters were mycobacterial load during treatment (therapeutic activity) and 13 weeks after termination of treatment (therapeutic efficacy). Moreover, cellular changes were analyzed using flow cytometry and cytokine expression was assessed at the mRNA and protein levels. Addition of immunotherapy was associated with lower mycobacterial loads after 5 weeks of treatment and significantly reduced relapse of disease after a shortened 13-week treatment course compared with antibiotic treatment alone. This was accompanied by reduced accumulation of immature myeloid cells in the lungs at the end of treatment and increased TNF-α protein levels throughout the treatment period. We demonstrate, in a mouse model of pulmonary TB, that immunotherapy consisting of three clinically approved drugs can improve the therapeutic efficacy of standard antibiotic treatment.

The B3 Subunit of the Cone Cyclic Nucleotide-gated Channel Regulates the Light Responses of Cones and Contributes to the Channel Structural Flexibility.

Cone photoreceptor cyclic nucleotide-gated (CNG) channels play a pivotal role in cone phototransduction, which is a process essential for daylight vision, color vision, and visual acuity. Mutations in the cone channel subunits CNGA3 and CNGB3 are associated with human cone diseases, including achromatopsia, cone dystrophies, and early onset macular degeneration. Mutations in CNGB3 alone account for 50% of reported cases of achromatopsia. This work investigated the role of CNGB3 in cone light response and cone channel structural stability. As cones comprise only 2-3% of the total photoreceptor population in the wild-type mouse retina, we used Cngb3(-/-)/Nrl(-/-) mice with CNGB3 deficiency on a cone-dominant background in our study. We found that, in the absence of CNGB3, CNGA3 was able to travel to the outer segments, co-localize with cone opsin, and form tetrameric complexes. Electroretinogram analyses revealed reduced cone light response amplitude/sensitivity and slower response recovery in Cngb3(-/-)/Nrl(-/-) mice compared with Nrl(-/-) mice. Absence of CNGB3 expression altered the adaptation capacity of cones and severely compromised function in bright light. Biochemical analysis demonstrated that CNGA3 channels lacking CNGB3 were more resilient to proteolysis than CNGA3/CNGB3 channels, suggesting a hindered structural flexibility. Thus, CNGB3 regulates cone light response kinetics and the channel structural flexibility. This work advances our understanding of the biochemical and functional role of CNGB3 in cone photoreceptors.

The luminescence properties of Sr2-1.5x-1.5y P2 O7 :xDy3+ ,yCe3+ phosphor for near-UV-based white LEDs synthesized by a chemical co-precipitation method.

A series of Sr2 P2 O7 :Dy3+ , Sr2 P2 O7 :Ce3+ and Sr2 P2 O7 :Dy3+ ,Ce3+ phosphors was synthesized via the one-step calcination process for the precursors prepared by co-precipitation methods. The phases, morphology, quantum efficiency and photoluminescence properties of the obtained phosphors were characterized systematically. These results show that the near-spherical particles prepared through calcining the precursors by means of ammonium dibasic phosphate co-precipitation (method 3) have the smallest particle size and strongest emission intensity among the three methods in the paper. With Dy3+ concentration increasing in Sr2 P2 O7 :Dy3+ phosphors, the luminescence intensity first increases, reaches maximum, and then decreases. A similar trend was followed by Sr2 P2 O7 :Ce3+ with Ce3+ concentration increasing. A successful attempt was made to initiate the energy transfer mechanism from Ce3+ to Dy3+ in the host lattice and an overlap between the emission band of Ce3+ and the excitation band of Dy3+ indicated that the Ce3+  â†’ Dy3+ energy transfer may indeed exist. It is clear that the photoluminescence intensity of Dy3+ as well as the quantum efficiency of the phosphor can be enhanced markedly by co-doping Ce3+ . Sr2 P2 O7 :Dy3+ ,Ce3+ has its (CIE) chromaticity coordinates in the bluish-white-light region, near the standard illuminant D65 . The CIE 1913 chromaticity coordinates of Sr2 P2 O7 :Dy3+ phosphors fall in the white-light region, and are adjacent to the ideal white-light coordinates. In addition, the colour temperature and colour tone of Sr2 P2 O7 :Dy3+ could be adjusted by changing the relative concentration of Dy3+ . In short, Sr2 P2 O7 :Dy3+ can be a promising single-phased white-light emitting phosphor for near-UV (NUV) w-LEDs.