The Intestinal Gut Microbiome as a Biomarker and Driver of Obesity and Non-Alcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) affects almost 1 out of every 5 Americans. The development of NAFLD increases an individual’s risk for cardiovascular disease, cirrhosis, and cancer. Given that there are few treatments available for NALFD, it is imperative to understand the features that can prognosticate and alter the progression of NAFLD. One area of research that has gained significant traction is the role of the gut microbiome in the development and progression of NAFLD. By utilizing a multi’omics approach, we discovered that the gut microbiome can affect obesity through alterations of the brain-gut axis. In a study of over 100 patients, we saw that the gut microbiome was highly associated to food addiction. Patients with food addiction had significantly lower abundances of Bacteroides, Akkermansia, and Eubacterium, and a higher abundance of Megamonas. This was associated with a reduction in a neuroprotective tryptophan-related metabolite, indolepropionate, and altered connectivity in the brain’s reward regions. This data suggests that the gut microbiome plays a role in eating behavior and is likely a modifiable risk factor for obesity. Furthermore, research has shown that the microbiome and metabolite profile of patients with NAFLD differs at each stage of the disease. Using a machine learning algorithm, we created and validated a classifier based on the gut microbiome that highly predicts advanced fibrosis in patients with NAFLD. To explore the causal effects of the gut microbiome on the development of NAFLD, we utilized the microbiome of bariatric surgery patients and transplanted them into antibiotic treated mice. Through this model, we see that an obese phenotype microbiome is able to induce significant weight gain and hepatic steatosis. Associated with these changes we see a significant alteration of the expression levels of natural killer T-cells, cytotoxic T-cells, Kupffer cells, and monocyte-derived macrophages. The data shows that not only can the gut microbiome prognosticate NAFLD, it can also alter the progression of NAFLD through changes of the innate immune system of the liver. This work shows the feasibility of the gut microbiome both as a biomarker but also as a source for potential novel therapeutics against obesity and NAFLD

Overall viscoelastic properties of 2D and two-phase periodic composites constituted of elliptical and rectangular heterogeneities

International audienceThis paper presents analytical solutions for the effective rheological viscoelastic properties of 2D periodic structures. The solutions, based on Fourier series analysis, are derived first in the Laplace-Carson (LC) space for different inclusion shapes (rectangle or ellipse) and arrangements. The effective results are obtained in the form of rational functions of the LC transform variable. Two inversion methods are used to find the relaxation behavior. The first one is based on the exact inverse of the LC transform while the second approximates the overall behavior by using a Standard Linear Solid model, which yields very simple analytical formulas for the coefficients entering the constitutive equations. Results of the two methods are compared in the case of an application to real materials

Differential regulation of RNF8-mediated Lys48- and Lys63-based poly-ubiquitylation

Pairing of a given E3 ubiquitin ligase with different E2s allows synthesis of ubiquitin conjugates of different topologies. While this phenomenon contributes to functional diversity, it remains largely unknown how a single E3 ubiquitin ligase recognizes multiple E2s, and whether identical structural requirements determine their respective interactions. The E3 ubiquitin ligase RNF8 that plays a critically important role in transducing DNA damage signals, interacts with E2s UBCH8 and UBC13, and catalyzes both K48- and K63-linked ubiquitin chains. Interestingly, we report here that a single-point mutation (I405A) on the RNF8 polypeptide uncouples its ability in catalyzing K48- and K63-linked ubiquitin chain formation. Accordingly, while RNF8 interacted with E2s UBCH8 and UBC13, its I405A mutation selectively disrupted its functional interaction with UBCH8, and impaired K48-based poly-ubiquitylation reactions. In contrast, RNF8 I405A preserved its interaction with UBC13, synthesized K63-linked ubiquitin chains, and assembled BRCA1 and 53BP1 at sites of DNA breaks. Together, our data suggest that RNF8 regulates K48- and K63-linked poly-ubiquitylation via differential RING-dependent interactions with its E2s UBCH8 and UBC13, respectively.published_or_final_versio

Modeling Anti-HIV-1 HSPC-Based Gene Therapy in Humanized Mice Previously Infected with HIV-1.

Investigations of anti-HIV-1 human hematopoietic stem/progenitor cell (HSPC)-based gene therapy have been performed by HIV-1 challenge after the engraftment of gene-modified HSPCs in humanized mouse models. However, the clinical application of gene therapy is to treat HIV-1-infected patients. Here, we developed a new method to investigate an anti-HIV-1 HSPC-based gene therapy in humanized mice previously infected with HIV-1. First, humanized mice were infected with HIV-1. When plasma viremia reached >107 copies/mL 3 weeks after HIV-1 infection, the mice were myeloablated with busulfan and transplanted with anti-HIV-1 gene-modified CD34+ HSPCs transduced with a lentiviral vector expressing two short hairpin RNAs (shRNAs) against CCR5 and HIV-1 long terminal repeat (LTR), along with human thymus tissue under the kidney capsule. Anti-HIV-1 vector-modified human CD34+ HSPCs successfully repopulated peripheral blood and lymphoid tissues in HIV-1 previously infected humanized mice. Anti-HIV-1 shRNA vector-modified CD4+ T lymphocytes showed selective advantage in HIV-1 previously infected humanized mice. This new method will be useful for investigations of anti-HIV-1 gene therapy when testing in a more clinically relevant experimental setting

Stabilizing forces acting on ZnO polar surfaces: STM, LEED, and DFT

published_or_final_versio

The Microbe-Derived Short Chain Fatty Acid Butyrate Targets miRNA-Dependent p21 Gene Expression in Human Colon Cancer

Colonic microbiota ferment non-absorbed dietary fiber to produce prodigious amounts of short chain fatty acids (SCFAs) that benefit the host through a myriad of metabolic, trophic, and chemopreventative effects. The chemopreventative effects of the SCFA butyrate are, in part, mediated through induction of p21 gene expression. In this study, we assessed the role of microRNA(miRNA) in butyrate's induction of p21 expression. The expression profiles of miRNAs in HCT-116 cells and in human sporadic colon cancers were assessed by microarray and quantitative PCR. Regulation of p21 gene expression by miR-106b was assessed by 3′ UTR luciferase reporter assays and transfection of specific miRNA mimics. Butyrate changed the expression of 44 miRNAs in HCT-116 cells, many of which were aberrantly expressed in colon cancer tissues. Members of the miR-106b family were decreased in the former and increased in the latter. Butyrate-induced p21 protein expression was dampened by treatment with a miR-106b mimic. Mutated p21 3′UTR-reporter constructs expressed in HCT-116 cells confirmed direct miR-106b targeting. Butyrate decreased HCT-116 proliferation, an effect reversed with the addition of the miR-106b mimic. We conclude that microbe-derived SCFAs regulate host gene expression involved in intestinal homeostasis as well as carcinogenesis through modulation of miRNAs.</p

The Microbe-Derived Short Chain Fatty Acid Butyrate Targets miRNA-Dependent p21 Gene Expression in Human Colon Cancer

Colonic microbiota ferment non-absorbed dietary fiber to produce prodigious amounts of short chain fatty acids (SCFAs) that benefit the host through a myriad of metabolic, trophic, and chemopreventative effects. The chemopreventative effects of the SCFA butyrate are, in part, mediated through induction of p21 gene expression. In this study, we assessed the role of microRNA(miRNA) in butyrate's induction of p21 expression. The expression profiles of miRNAs in HCT-116 cells and in human sporadic colon cancers were assessed by microarray and quantitative PCR. Regulation of p21 gene expression by miR-106b was assessed by 3′ UTR luciferase reporter assays and transfection of specific miRNA mimics. Butyrate changed the expression of 44 miRNAs in HCT-116 cells, many of which were aberrantly expressed in colon cancer tissues. Members of the miR-106b family were decreased in the former and increased in the latter. Butyrate-induced p21 protein expression was dampened by treatment with a miR-106b mimic. Mutated p21 3′UTR-reporter constructs expressed in HCT-116 cells confirmed direct miR-106b targeting. Butyrate decreased HCT-116 proliferation, an effect reversed with the addition of the miR-106b mimic. We conclude that microbe-derived SCFAs regulate host gene expression involved in intestinal homeostasis as well as carcinogenesis through modulation of miRNAs

Overexpression of eIF-5A2 in mice causes accelerated organismal aging by increasing chromosome instability

<p>Abstract</p> <p>Background</p> <p>Amplification of 3q26 is one of the most frequent genetic alterations in many human malignancies. Recently, we isolated a novel oncogene <it>eIF-5A2 </it>within the 3q26 region. Functional study has demonstrated the oncogenic role of <it>eIF-5A2 </it>in the initiation and progression of human cancers. In the present study, we aim to investigate the physiological and pathological effect of <it>eIF-5A2 </it>in an <it>eIF-5A2 </it>transgenic mouse model.</p> <p>Methods</p> <p>An <it>eIF-5A2 </it>transgenic mouse model was generated using human <it>eIF-5A2 </it>cDNA. The <it>eIF-5A2 </it>transgenic mice were characterized by histological and immunohistochemistry analyses. The aging phenotypes were further characterized by wound healing, bone X-ray imaging and calcification analysis. Mouse embryo fibroblasts (MEF) were isolated to further investigate molecular mechanism of <it>eIF-5A2 </it>in aging.</p> <p>Results</p> <p>Instead of resulting in spontaneous tumor formation, overexpression of eIF-5A2 accelerated the aging process in adult transgenic mice. This included decreased growth rate and body weight, shortened life span, kyphosis, osteoporosis, delay of wound healing and ossification. Investigation of the correlation between cellular senescence and aging showed that cellular senescence is not required for the aging phenotypes in <it>eIF-5A2 </it>mice. Interestingly, we found that activation of <it>eIF-5A2 </it>repressed p19 level and therefore destabilized p53 in transgenic mouse embryo fibroblast (MEF) cells. This subsequently allowed for the accumulation of chromosomal instability, such as errors in cell dividing during metaphase and anaphase. Additionally, a significantly increase in number of aneuploidy cells (<it>p </it>< 0.05) resulted from an increase in the incidences of misaligned and lagging chromosomal materials, anaphase bridges, and micronuclei in the transgenic mice.</p> <p>Conclusion</p> <p>These observations suggest that <it>eIF-5A2 </it>mouse models could accelerate organismal aging by increasing chromosome instability.</p

Observation of inhibited electron-ion coupling in strongly heated graphite

Creating non-equilibrium states of matter with highly unequal electron and lattice temperatures (Tele≠Tion) allows unsurpassed insight into the dynamic coupling between electrons and ions through time-resolved energy relaxation measurements. Recent studies on low-temperature laser-heated graphite suggest a complex energy exchange when compared to other materials. To avoid problems related to surface preparation, crystal quality and poor understanding of the energy deposition and transport mechanisms, we apply a different energy deposition mechanism, via laser-accelerated protons, to isochorically and non-radiatively heat macroscopic graphite samples up to temperatures close to the melting threshold. Using time-resolved x ray diffraction, we show clear evidence of a very small electron-ion energy transfer, yielding approximately three times longer relaxation times than previously reported. This is indicative of the existence of an energy transfer bottleneck in non-equilibrium warm dense matter