1,004 research outputs found
Wnt/ -Catenin and MAPK Signaling: Allies and Enemies in Different Battlefields
No full textTwo papers published in Science Signaling reveal extensive crosstalk between Wnt/-catenin and mitogen-activated protein kinase (MAPK) signaling in cancer. Although both studies describe previously unknown links between these two signaling pathways, the relationship between Wnt/-catenin and MAPK signaling depends on the specific cellular context. Indeed, in melanoma, hyperactivated MAPK signaling down-regulates the Wnt/-catenin signal transduction cascade, thereby establishing a negative crosstalk between the two signaling pathways. In contrast, in colorectal cancer, stimulation of the Wnt/-catenin pathway leads to activation of the MAPK pathway through Ras stabilization, representing an example of positive crosstalk. Moreover, activation of Wnt/-catenin signaling has context-dependent functions that trigger opposing effects on tumor growth. In melanoma, aberrant activation of Wnt/-catenin signaling may have anti- oncogenic functions by promoting programmed cell death; by contrast, in the intestine, Wnt/-catenin signaling drives malignant transformation. Thus, there is no single correct way to target the Wnt/-catenin pathway for all cancers
Slide preparation for single-cell-resolution imaging of fluorescent proteins in their three-dimensional near-native environment
No full textIn recent years, many mouse models have been developed to mark and trace the fate of adult cell populations using fluorescent proteins. High-resolution visualization of such fluorescent markers in their physiological setting is thus an important aspect of adult stem cell research. Here we describe a protocol to produce sections (150-200 mum) of near-native tissue with optimal tissue and cellular morphology by avoiding artifacts inherent in standard freezing or embedding procedures. The activity of genetically expressed fluorescent proteins is maintained, thereby enabling high-resolution three-dimensional (3D) reconstructions of fluorescent structures in virtually all types of tissues. The procedure allows immunofluorescence labeling of proteins to depths up to 50 mum, as well as a chemical 'Click-iT' reaction to detect DNA-intercalating analogs such as ethynyl deoxyuridine (EdU). Generation of near-native sections ready for imaging analysis takes approximately 2-3 h. Postsectioning processes, such as antibody labeling or EdU detection, take up to 10 h. [KEYWORDS: Image Processing, Computer-Assisted, Imaging, Three-Dimensional, Luminescent Proteins/ analysis, Microscopy, Fluorescence/methods, Microtomy, Single-Cell Analysis/ methods
Symptom patterns in irritable bowel syndrome
No full textWho has never had them: symptoms in the abdominal region, such as pain, bloating, constipation, and diarrhoea? These are common symptoms of irritable bowel syndrome (IBS). IBS affects 5-10% of the population, especially females between the age of 16 and 40.
The good news is that IBS is a benign disorder: IBS does not increase the risk of cancer, and symptoms are not progressive. The bad news is that impact on quality of life is high due to symptoms in the abdomen as well as elsewhere (e.g. joint pain) and psychological symptoms (e.g. anxiety) or even psychiatric disorders (e.g. anxiety disorders). Specifically, symptom-related anxiety is a predictor of more severe symptoms and worsening quality of life.
Why exactly do people have symptoms? In part, symptoms can be explained by lifestyle factors, mainly food and stress. Common food triggers have been described for diarrhoea (confectionery, coffee, spices), flatulence (onions, fruits, bread), bloating (late eating), and pain (late eating, rice, bread). Before we start dieting, however, two important remarks must be made:
- Intolerances to food and stress are very person-specific. Person-specific food-symptom and stress-symptom relations may be identified when a patient keeps a diary of food intake, stress, and symptoms. The computer analyses the diary for possible symptom triggers. Exclusion of personal triggers may lead to symptom improvement for a group of patients.
- There are many non-lifestyle factors that drive symptoms in IBS. These include the gut bacteria and immune system. Therefore, it is possible that a patient does not benefit from any dietary or psychological therapy.
This thesis leads to two research suggestions, both aiming for personalised management of IBS:
- Personal symptom triggers. Although we know that the food/symptom diary concept can generate personalised lifestyle advice, we still lack evidence that it actually improves symptoms. Patients who keep a diary and receive personalised lifestyle advice should be followed up to monitor symptom evolution. A great opportunity would be to combine it with smart devices that measure physiologic variables, as these may explain how a trigger leads to symptoms.
- Predictors of treatment response. For the patient, finding a good treatment is currently a process of trial and error. There is a need for an evidence-based treatment algorithm, as this makes IBS management more efficient and teaches us about the underlying mechanisms
Using hyperspectral remote sensing data for retrieving canopy water content
No full textCanopy water content (CWC) is important for understanding functioning of terrestrial ecosystems. Spectral derivatives at the slopes of the 970 nm and 1200 nm water absorption features offer good potential as estimators for CWC. An extensively grazed fen meadow is used as test site in this study. Results are compared with simulations with the PROSAIL radiative transfer model. The first derivative at the left slope of the feature at 970 nm is found to be highly correlated with CWC and the relationship corresponds to the one found with PROSAIL simulations. Use of the derivative over the 940 – 950 nm interval is suggested. In order to avoid interference with absorption by atmospheric water vapour, the potential of estimating CWC using the first derivative at the right slope of the 970 nm absorption feature is recommended. Correlations are a bit lower than those at the left slope, but better than those obtained with water band indices, as shown in previous studies. FieldSpec measurements show that one may use derivatives around the middle of the right slope within the interval between 1015 nm and 1050 nm
Reply
No full textReply. We thank Drs Siah and Gwee for their interest in our study, in which we reported an exploratory factor analysis of Rome IV symptoms (Clevers et al), which we refer to as the Rome IV exploratory model (R4EM) similar to Siah and Gwee
Structure of Stem Cell Growth Factor R-spondin 1 in Complex with the Ectodomain of Its Receptor LGR5
No full textLeucine-rich repeat-containing G protein-coupled receptors 4-6 (LGR4-LGR6) are receptors for R-spondins, potent Wnt agonists that exert profound trophic effects on Wnt-driven stem cells compartments. We present crystal structures of a signaling-competent fragment of R-spondin 1 (Rspo1) at a resolution of 2.0 Å and its complex with the LGR5 ectodomain at a resolution of 3.2 Å. Ecto-LGR5 binds Rspo1 at its concave leucine-rich-repeat (LRR) surface, forming a dimeric 2:2 complex. Fully conserved residues on LGR4-LGR6 explain promiscuous binding of R-spondins. A phenylalanine clamp formed by Rspo1 Phe106 and Phe110 pinches Ala190 of LGR5 and is critical for binding. Mutations related to congenital anonychia reduce signaling, but not binding of Rspo1 to LGR5. Furthermore, antibody binding to the extended loop of the C-terminal LRR cap of LGR5 activates signaling in a ligand-independent manner. Thus, our data reveal binding of R-spondins to conserved sites on LGR4-LGR6 and, in analogy to FSHR and related receptors, suggest a direct signaling role for LGR4-LGR6 in addition to its formation of Wnt receptor and coreceptor complexes
Wnt/beta-catenin/Tcf signaling: A critical pathway in gastrointestinal tumorigenesis
No full textCancers of the gastrointestinal tract, including the liver, bile ducts, and pancreas, constitute the largest group of malignant tumors. Colorectal cancer is one of the most common neoplastic diseases in Western countries and one of the leading causes of cancer-related deaths. Inactivation of the adenomatous polyposis coli (APC) tumor-suppressor gene during early adenoma formation is thought to be the first genetic event in the process of colorectal carcinogenesis followed by mutations in oncogenes like K-Ras and tumor-suppressor genes like p53. Identification of the interaction of APC with the proto-oncogene beta-catenin has linked colorectal carcinogenesis to the Wnt-signal transduction pathway. The main function of APC is thought to be the regulation of free beta-catenin in concert with the glycogen synthase kinase 3beta (GSK-3beta) and Axin proteins. Loss of APC function, inactivation of Axin or activating beta-catenin mutations result in the cellular accumulation of beta-catenin. Upon translocation to the nucleus beta-catenin serves as an activator of T-cell factor (Tcf)-dependent transcription leading to an increased expression of several specific target genes including c-Myc, cyclin D1, MMP-7, and ITF-2. While APC mutations are almost exclusively found in colorectal cancers, deregulation of Wnt/beta-catenin/Tcf signaling is also common in other gastrointestinal and extra-gastrointestinal human cancers. In a fraction of hepatocellular carcinomas the Writ pathway is deregulated by inactivation of Axin or stabilizing mutations of beta-catenin. The majority of hepatoblastomas and a group of gastric cancers also carry beta-catenin mutations. Clearly, this pathway harbors great potential for future applications in cancer diagnostics, staging, and therapy. Copyright (C) 2002 S. Karger AG, Basel
Using the right slope of the 970 nm absorption feature for estimating canopy water content
No full textCanopy water content (CWC) is important for understanding the functioning of terrestrial ecosystems. Biogeochemical processes like photosynthesis, transpiration and net primary production are related to foliar water. The first derivative of the reflectance spectrum at wavelengths corresponding to the left slope of the minor water absorption band at 970 nm was found to be highly correlated with CWC and PROSAIL model simulations showed that it was insensitive to differences in leaf and canopy structure, soil background and illumination and observation geometry. However, these wavelengths are also located close to the water vapour absorption band at about 940 nm. In order to avoid interference with absorption by atmospheric water vapour, the potential of estimating CWC using the first derivative at the right slope of the 970 nm absorption feature was studied. Measurements obtained with an ASD FieldSpec spectrometer for three test sites were related to CWC (calculated as the difference between fresh and dry weight). The first site was a homogeneous grassland parcel with a grass/clover mixture. The second site was a heterogeneous floodplain with natural vegetation like grasses and various shrubs. The third site was an extensively grazed fen meadow. Results for all three test sites showed that the first derivative of the reflectance spectrum at the right slope of the 970 nm absorption feature was linearly correlated with CWC. Correlations were a bit lower than those at the left slope (at 942.5 nm) as shown in previous studies, but better than those obtained with water band indices. FieldSpec measurements showed that one may use any derivative around the middle of the right slope within the interval between 1015 nm and 1050 nm. We calculated the average derivative at this interval. The first site with grassland yielded an R2 of 0.39 for the derivative at the previously mentioned interval with CWC (based on 20 samples). The second site at the heterogeneous floodplain yielded an R2 of 0.45 for this derivative with CWC (based on 14 samples). Finally, the third site with the fen meadow yielded an R2 of 0.68 for this derivative with CWC (based on 40 samples). Regression lines between the derivative at the right slope of the 970 nm absorption feature and CWC for all three test sites were similar although vegetation types were quite different. This indicates that results may be transferable to other vegetation types and other site
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