20 research outputs found

    The Golgin GMAP210/TRIP11 Anchors IFT20 to the Golgi Complex

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    Eukaryotic cells often use proteins localized to the ciliary membrane to monitor the extracellular environment. The mechanism by which proteins are sorted, specifically to this subdomain of the plasma membrane, is almost completely unknown. Previously, we showed that the IFT20 subunit of the intraflagellar transport particle is localized to the Golgi complex, in addition to the cilium and centrosome, and hypothesized that the Golgi pool of IFT20 plays a role in sorting proteins to the ciliary membrane. Here, we show that IFT20 is anchored to the Golgi complex by the golgin protein GMAP210/Trip11. Mice lacking GMAP210 die at birth with a pleiotropic phenotype that includes growth restriction, ventricular septal defects of the heart, omphalocele, and lung hypoplasia. Cells lacking GMAP210 have normal Golgi structure, but IFT20 is no longer localized to this organelle. GMAP210 is not absolutely required for ciliary assembly, but cilia on GMAP210 mutant cells are shorter than normal and have reduced amounts of the membrane protein polycystin-2 localized to them. This work suggests that GMAP210 and IFT20 function together at the Golgi in the sorting or transport of proteins destined for the ciliary membrane

    Effect of hyoscine butylbromide on prostate multiparametric MRI anatomical and functional image quality.

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    AIM: To evaluate the effect of the spasmolytic agent hyoscine butylbromide (HBB) on the quality of anatomical and functional imaging of the prostate. MATERIALS AND METHODS: One hundred and seventy-three patients were included in this retrospective study. Eighty-seven patients received intravenous HBB prior to scanning (HBB group) and 86 patients did not (non-HBB group). Multiparametric (mp) 3 T magnetic resonance imaging (MRI) was performed using a 32-channel body coil. Two radiologists independently evaluated the image quality of T2-weighted imaging (WI), diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps, using a five-point Likert scale. DWI was further assessed for distortion and artefact (four-point Likert scale), and T2WI for the presence of motion artefact or blurring. Dynamic contrast-enhanced (DCE) image quality was assessed by recording the number of corrupt contrast curve data points. RESULTS: T2W image quality in the HBB group was significantly higher than in the non-HBB group (3.63±1.11 versus 2.84±0.899); p<0.001. The HBB group also showed significantly less T2W motion and T2W blur than the non-HBB group (23% and 51.7% versus 53.5% and 83.7%, respectively; p<0.001); however, there was no significant improvement in DWI or ADC image quality, or DWI degree of distortion or artefact. There was a trend towards a lower number of corrupted data points from the contrast curve (2.47±2.44 versus 3.68±2.64), but this did not reach significance (p=0.052). CONCLUSION: Administration of HBB significantly improves the image quality of T2WI images. These results provide evidence for the use of HBB in routine patient preparation prior to prostate mpMRI.Cancer Research UK, National Institute of Health Research Cambridge Biomedical Research Centre, Cancer Research UK and the Engineering and Physical Sciences Research Council Imaging Centre in Cambridge and Manchester and the Cambridge Experimental Cancer Medicine Centre

    Evaluating the effect of rectal distension on prostate multiparametric MRI image quality

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    Purpose To evaluate the effect of rectal distension on the quality of anatomical and functional prostate multiparametric (mp) MRI. Materials and methods Multiparametric (mp) 3T-MRI images of 173 patients were independently evaluated by two radiologists in this retrospective study. Planimetry rectal volumes were derived and a subjective assessment of rectal distension was made using a 5-point Likert scale (1 = no stool/gas, 5 = large amount of stool/gas). Image quality of diffusion-weighted imaging (DWI) was evaluated using a 5-point Likert scale. DWI was further scored for distortion and artefact. T2W images were evaluated for image sharpness and the presence of motion artefact. The stability of the dynamic contrast-enhancement acquisition was assessed by recording the number of corrupt data points during the wash-out phase. Results There was a strong correlation between subjective scoring of rectal loading and objectively measured rectal volume (r = 0.82), p < 0.001. A significant correlation was shown between increased rectal distension and both reduced DW image quality (r = −0.628, p < 0.001), and increased DW image distortion (r = 0.814, p < 0.001). There was also a significant trend for rectal distension to increase artefact at DWI (r = 0.154, p = 0.042). Increased rectal distension led to increased motion artefact on T2 (p = 0.0096), but did not have a significant effect on T2-sharpness (p = 0.0638). There was no relationship between rectal distension and DCE image quality (p = 0.693). 63 patients underwent lesion-targeted biopsy post MRI, there was a trend to higher positive predictive values in patients with minor rectal distension (34/38, 89.5%) compared to those with moderate/marked distension (18/25, 72%), p = 0.09. Conclusion Rectal distension has a significant negative effect on the quality of both T2W and DW images. Consideration should therefore be given to bowel preparation prior to prostate mpMRI to optimise image quality.The authors acknowledge research support from Cancer Research UK, National Institute of Health Research Cambridge Biomedical Research Centre, Cancer Research UK and the Engineering and Physical Sciences Research Council Imaging Centre in Cambridge and Manchester and the Cambridge Experimental Cancer Medicine Centre

    Community policing does not build citizen trust in police or reduce crime in the Global South.

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    Is it possible to reduce crime without exacerbating adversarial relationships between police and citizens? Community policing is a celebrated reform with that aim, which is now adopted on six continents. However, the evidence base is limited, studying reform components in isolation in a limited set of countries, and remaining largely silent on citizen-police trust. We designed six field experiments with Global South police agencies to study locally designed models of community policing using coordinated measures of crime and the attitudes and behaviors of citizens and police. In a preregistered meta-analysis, we found that these interventions led to mixed implementation, largely failed to improve citizen-police relations, and did not reduce crime. Societies may need to implement structural changes first for incremental police reforms such as community policing to succeed

    Primary Cilia: The Chemical Antenna Regulating Human Adipose-Derived Stem Cell Osteogenesis

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    Adipose-derived stem cells (ASC) are multipotent stem cells that show great potential as a cell source for osteogenic tissue replacements and it is critical to understand the underlying mechanisms of lineage specification. Here we explore the role of primary cilia in human ASC (hASC) differentiation. This study focuses on the chemosensitivity of the primary cilium and the action of its associated proteins: polycystin-1 (PC1), polycystin-2 (PC2) and intraflagellar transport protein-88 (IFT88), in hASC osteogenesis. To elucidate cilia-mediated mechanisms of hASC differentiation, siRNA knockdown of PC1, PC2 and IFT88 was performed to disrupt cilia-associated protein function. Immunostaining of the primary cilium structure indicated phenotypic-dependent changes in cilia morphology. hASC cultured in osteogenic differentiation media yielded cilia of a more elongated conformation than those cultured in expansion media, indicating cilia-sensitivity to the chemical environment and a relationship between the cilium structure and phenotypic determination. Abrogation of PC1, PC2 and IFT88 effected changes in both hASC proliferation and differentiation activity, as measured through proliferative activity, expression of osteogenic gene markers, calcium accretion and endogenous alkaline phosphatase activity. Results indicated that IFT88 may be an early mediator of the hASC differentiation process with its knockdown increasing hASC proliferation and decreasing Runx2, alkaline phosphatase and BMP-2 mRNA expression. PC1 and PC2 knockdown affected later osteogenic gene and end-product expression. PC1 knockdown resulted in downregulation of alkaline phosphatase and osteocalcin gene expression, diminished calcium accretion and reduced alkaline phosphatase enzymatic activity. Taken together our results indicate that the structure of the primary cilium is intimately associated with the process of hASC osteogenic differentiation and that its associated proteins are critical players in this process. Elucidating the dynamic role of the primary cilium and its associated proteins will help advance the application of hASC in generating autologous tissue engineered therapies in critical defect bone injuries
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