In recent years, the intestinal mucosa has proven to be an intriguing organ to study tissue oxygenation. The highly vascularized lamina propria juxtaposed to an anaerobic lumen containing trillions ...of metabolically active microbes results in one of the most austere tissue microenvironments in the body. Studies to date have determined that a healthy mucosa contains a steep oxygen gradient along the length of the intestine and from the lumen to the serosa. Advances in technology have allowed multiple independent measures and indicate that, in the healthy mucosa of the small and large intestine, the lumen-apposed epithelia experience Po2 conditions of <10 mmHg, so-called physiologic hypoxia. This unique physiology results from a combination of factors, including countercurrent exchange blood flow, fluctuating oxygen demands, epithelial metabolism, and oxygen diffusion into the lumen. Such conditions result in the activation of a number of hypoxia-related signaling processes, including stabilization of the transcription factor hypoxia-inducible factor. Here, we review the principles of mucosal oxygen delivery, metabolism, and end-point functional responses that result from this unique oxygenation profile.
Commensal interactions between the enteric microbiota and distal intestine play important roles in regulating human health. Short-chain fatty acids (SCFAs), such as butyrate, produced through ...anaerobic microbial metabolism represent a major energy source for the host colonic epithelium and enhance epithelial barrier function through unclear mechanisms. Separate studies revealed that the epithelial anti-inflammatory IL-10 receptor α subunit (IL-10RA) is also important for barrier formation. Based on these findings, we examined if SCFAs promote epithelial barrier through IL-10RA-dependent mechanisms. Using human intestinal epithelial cells (IECs), we discovered that SCFAs, particularly butyrate, enhanced IEC barrier formation, induced IL-10RA mRNA, IL-10RA protein, and transactivation through activated Stat3 and HDAC inhibition. Loss and gain of IL-10RA expression directly correlates with IEC barrier formation and butyrate represses permeability-promoting claudin-2 tight-junction protein expression through an IL-10RA-dependent mechanism. Our findings provide a novel mechanism by which microbial-derived butyrate promotes barrier through IL-10RA-dependent repression of claudin-2.
Interactions between the microbiota and distal gut are fundamental determinants of human health. Such interactions are concentrated at the colonic mucosa and provide energy for the host epithelium ...through the production of the short-chain fatty acid butyrate. We sought to determine the role of epithelial butyrate metabolism in establishing the austere oxygenation profile of the distal gut. Bacteria-derived butyrate affects epithelial O2 consumption and results in stabilization of hypoxia-inducible factor (HIF), a transcription factor coordinating barrier protection. Antibiotic-mediated depletion of the microbiota reduces colonic butyrate and HIF expression, both of which are restored by butyrate supplementation. Additionally, germ-free mice exhibit diminished retention of O2-sensitive dyes and decreased stabilized HIF. Furthermore, the influences of butyrate are lost in cells lacking HIF, thus linking butyrate metabolism to stabilized HIF and barrier function. This work highlights a mechanism where host-microbe interactions augment barrier function in the distal gut.
Display omitted
•The mammalian colon exists in a state of relative hypoxia•Hypoxic regions of the normal colon provide a signaling axis through HIF-1•Microbial-derived butyrate depletes O2 and activates HIF-1•Microbiota-derived butyrate is barrier-protective in the mucosa
Decreased short-chain fatty acid (SCFA) production by the microbiota has been correlated with colonic inflammation and disease. Kelly et al. show that microbial-derived SCFAs, particularly butyrate, stimulate epithelial metabolism and deplete intracellular O2, resulting in stabilization of the transcription factor HIF-1 and increased epithelial barrier function.
Perturbations in activity and dosage of the UBE3A ubiquitin-ligase have been linked to Angelman syndrome and autism spectrum disorders. UBE3A was initially identified as the cellular protein hijacked ...by the human papillomavirus E6 protein to mediate the ubiquitylation of p53, a function critical to the oncogenic potential of these viruses. Although a number of substrates have been identified, the normal cellular functions and pathways affected by UBE3A are largely unknown. Previously, we showed that UBE3A associates with HERC2, NEURL4, and MAPK6/ERK3 in a high-molecular-weight complex of unknown function that we refer to as the HUN complex (HERC2, UBE3A, and NEURL4). In this study, the combination of two complementary proteomic approaches with a rigorous network analysis revealed cellular functions and pathways in which UBE3A and the HUN complex are involved. In addition to finding new UBE3A-associated proteins, such as MCM6, SUGT1, EIF3C, and ASPP2, network analysis revealed that UBE3A-associated proteins are connected to several fundamental cellular processes including translation, DNA replication, intracellular trafficking, and centrosome regulation. Our analysis suggests that UBE3A could be involved in the control and/or integration of these cellular processes, in some cases as a component of the HUN complex, and also provides evidence for crosstalk between the HUN complex and CAMKII interaction networks. This study contributes to a deeper understanding of the cellular functions of UBE3A and its potential role in pathways that may be affected in Angelman syndrome, UBE3A-associated autism spectrum disorders, and human papillomavirus-associated cancers.
Display omitted
•UBE3A is associated with Angelman syndrome, autism, and HPV-associated cancers.•Several new UBE3A-associated proteins were identified (e.g., MCM6 and ASPP2).•UBE3A-associated proteins are connected to several fundamental cellular processes.•There is evidence for crosstalk between UBE3A and CAMKII interaction networks.•Network analyses provide new insights into the cellular functions of UBE3A.
The purpose of this study is to determine the effects of low-dose radiation on fibroblast cells irradiated by spectrally and dosimetrically well-characterized soft x-rays. To achieve this, a new cell ...culture x-ray irradiation system was designed. This system generates characteristic fluorescent x-rays to irradiate the cell culture with x-rays of well-defined energies and doses. 3T3 fibroblast cells were cultured in cups with Mylar® surfaces and were irradiated for one hour with characteristic iron (Fe) K x-ray radiation at a dose rate of approximately 550 μGy/hr. Cell proliferation, total protein analysis, flow cytometry, and cell staining were performed on fibroblast cells to determine the various effects caused by the radiation. Irradiated cells demonstrated increased proliferation and protein production compared to control samples. Flow cytometry revealed that a higher percentage of irradiated cells were in the G0/G1 phase of the cell cycle compared to control counterparts, which is consistent with other low-dose studies. Cell staining results suggest that irradiated cells maintained normal cell functions after radiation exposure, as there were no qualitative differences between the images of the control and irradiated samples. The result of this study suggest that low-dose soft x-ray radiation might cause an initial pause, followed by a significant increase, in proliferation. An initial "pause" in cell proliferation could be a protective mechanism of the cells to minimize DNA damage caused by radiation exposure. The new cell irradiation system developed here allows for unprecedented control over the properties of the x-rays given to the cell cultures. This will allow for further studies on various cell types with known spectral distribution and carefully measured doses of radiation, which may help to elucidate the mechanisms behind varied cell responses to low-dose x-rays reported in the literature.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Fast Learning of Fast Transforms, with Guarantees Le, Quoc-Tung; Zheng, Leon; Riccietti, Elisa ...
ICASSP 2022 - 2022 IEEE International Conference on Acoustics, Speech and Signal Processing (ICASSP),
2022-May-23
Conference Proceeding
Odprti dostop
Approximating a matrix by a product of few sparse factors whose supports possess the butterfly structure, which is common to many fast transforms, is key to learn fast transforms and speed up ...algorithms for inverse problems. We introduce a hierarchical approach that recursively factorizes the considered matrix into two factors. Using recent advances on the well-posedness and tractability of the two-factor fixed- support sparse matrix factorization problem, the proposed algorithm is endowed with exact recovery guarantees. Experiments show that speed and accuracy of the factorization can be jointly improved by several orders of magnitude, compared to gradient-based optimization methods.
Enzymes catalyze biochemical reactions and play critical roles in human health and disease. Enzyme variants and deficiencies can lead to variable expression of glycans, which can affect physiology, ...influence predilection for disease, and/or directly contribute to disease pathogenesis. Although certain well-characterized enzyme deficiencies result in overt disease, some of the most common enzyme deficiencies in humans form the basis of blood groups. These carbohydrate blood groups impact fundamental areas of clinical medicine, including the risk of infection and severity of infectious disease, bleeding risk, transfusion medicine, and tissue/organ transplantation. In this review, we examine the enzymes responsible for carbohydrate-based blood group antigen biosynthesis and their expression within the human population. We also consider the evolutionary selective pressures, e.g. malaria, that may account for the variation in carbohydrate structures and the implications of this biology for human disease.
Display omitted
Biological sciences; Biochemistry; Evolutionary biology
Vitamin B
12
is a critical nutrient for humans as well as microbes. Due to saturable uptake, high dose oral B
12
supplements are largely unabsorbed and reach the distal gut where they are available ...to interact with the microbiota. The aim of this study was to determine if oral B
12
supplementation in mice alters 1) the concentration of B
12
and related corrinoids in the distal gut, 2) the fecal microbiome, 3) short chain fatty acids (SCFA), and 4) susceptibility to experimental colitis. C57BL/6 mice (up to 24 animals/group) were supplemented with oral 3.94 µg/ml cyanocobalamin (B
12
), a dose selected to approximate a single 5 mg supplement for a human. Active vitamin B
12
(cobalamin), and four B
12
-analogues (ADECN-Cba, 2Me-ADECN-Cba, 2MeS-ADECN-Cba, CN-Cbi) were analyzed in cecal and fecal contents using liquid chromatography/mass spectrometry (LC/MS), in parallel with evaluation of fecal microbiota, cecal SCFA, and susceptibility to dextran sodium sulfate (DSS) colitis. At baseline, active B
12
was a minor constituent of overall cecal (0.86%) and fecal (0.44%) corrinoid. Oral B
12
supplementation increased active B
12
at distal sites by >130-fold (cecal B
12
increased from 0.08 to 10.60 ng/mg, fecal B
12
increased from 0.06 to 7.81 ng/ml) and reduced microbe-derived fecal corrinoid analogues (ADECN-Cba, 2Me-ADECN-Cba, 2MeS-ADECN-Cba). Oral B
12
had no effect on cecal SCFA. Microbial diversity was unaffected by this intervention, however a selective decrease in
Bacteroides
was observed with B
12
treatment. Lastly, no difference in markers of DSS-induced colitis were detected with B
12
treatment.
Abnormal centrosome and centriole numbers are frequently detected in tumor cells where they can contribute to mitotic aberrations that cause chromosome missegregation and aneuploidy. The molecular ...mechanisms of centriole overduplication in malignant cells, however, are poorly characterized. Here, we show that the core SKP1-cullin-F-box component cullin 1 (CUL1) localizes to maternal centrioles and that CUL1 is critical for suppressing centriole overduplication through multiplication, a recently discovered mechanism whereby multiple daughter centrioles form concurrently at single maternal centrioles. We found that this activity of CUL1 involves the degradation of Polo-like kinase 4 (PLK4) at maternal centrioles. PLK4 is required for centriole duplication and strongly stimulates centriole multiplication when aberrantly expressed. We found that CUL1 is critical for the degradation of active PLK4 following deregulation of cyclin E/cyclin-dependent kinase 2 activity, as is frequently observed in human cancer cells, as well as for baseline PLK4 protein stability. Collectively, our results suggest that CUL1 may function as a tumor suppressor by regulating PLK4 protein levels and thereby restraining excessive daughter centriole formation at maternal centrioles.
PDF
