Based on the RNAi technique, we have developed a new approach that generates transgenic animals capable of mimicking human genetic diseases. The new system is a combination of siRNA with Cre-loxP and ...tetracycline-on. It has the characteristics of being stable, inheritable, and inducible, with the siRNA able to be transcribed tissue specifically. To support the ability of this new method to generate a model for a disease, we created an ABCA1-deficient mouse line that mimics Tangier disease under controlled conditions. Thus, it should now be possible to rapidly establish human genetic diseases as a whole animal model without the use of embryonic stem cell and gene targeting. This system also provides a tool for pathological and pharmacological studies of aspects peculiar to particular human genetic diseases.
The Indus Basin Model Revised (IBMR) is a hydro-agro-economic optimization model for agricultural investment planning across Pakistan's Indus Basin provinces. This study describes IBMR-2012, an ...update and modification of the model that reflects the current agro-economic conditions in Pakistan for the purpose of evaluating the impact of climate change on water allocation and food security. Results of hydro-climatic parameter sensitivity and basin-wide and provincial-level climate change impacts on crop productions are presented. The study finds that compared to Punjab, Sindh faces both significantly larger climate change impacts on agriculture and higher uncertainty regarding climate change impacts in the future.
HPV16, a high-risk tumorigenic virus, has been identified as one of the causative agents for the development of cervical cancer. Subsequent to viral infection, the constitutive expression of the ...viral oncoproteins E6 and E7 plays a number of critical roles in maintaining the transformed phenotype. Here we demonstrate that a cellular kinase, dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), interacts with and phosphorylates HPV16E7
in vitro and
in vivo. Using substitution mutations, we identified that DYRK1A specifically phosphorylates HPV16E7 at Thr5 and Thr7, which are located within the N-terminal CRI domain. This interaction greatly increases the steady-state level of HPV-16E7 by interfering with the protein's 26S proteosome-dependent degradation. The half-life of E7 was extended significantly by replacing Thr5 and Thr7 with a phosphorylation mimetic residue, aspartic acid. In addition, DYRK1A-induced phosphorylation protected E7 from degradation and influenced E7's function when modulating pRb degradation. We propose a new mechanism whereby DYRK1A phosphorylates Thr5 and Thr7 within HPV16E7. This phosphorylation then interferes with the degradation of HPV16E7, extending the protein half-life of HPV16E7 and increasing the colony-formation efficacy of HPV16E7. Our findings suggest that DYRK1A increases the transforming potential of HPV16-infected cells because of the greater stability of HPV16E7.
Several reports in the literature have indicated that the E6 not only elevates the level of c-Myc level but that the protein also associates with the Myc complex and activates Myc-responsive genes. ...There would seem to be a mechanism by which this oncogene can modulate cell proliferation and differentiation. Furthermore, an increase in c-Myc levels has also observed during ectopic expression of HPV E7 alone. Using the yeast two-hybrid system, we further found that the c-Myc interacts and forms a specific complex with HPV-16E7. In this study, we have demonstrated that E7 does indeed interact with c-Myc and a sequential deletion analysis of E7 maps the c-Myc interaction site to the carboxyl-terminal region. We determined two HPV-18 E7 binding sites on c-Myc involving the amino acids regions 1–100 and 367–439. The interaction of the high-risk type HPV E7 with c-Myc can augment c-Myc transactivation activity but this does not occur with low-risk type HPV E7. Deletion within the Cys-X-X-Cys repeat motif at the C-terminus of HPV-18 E7 leads to a lost of association with c-Myc and also abolishes the enhancement of c-Myc's transactivation activity. Furthermore, the interaction of HPV-18 E7 with c-Myc functionally promotes c-Myc's DNA-binding ability. Using the hTERT promoter as a model, enhanced c-Myc binding ability to the hTERT promoter as measured by immunoprecipitation assay was observed and occurred in an E7 dose-dependent manner. Taken together, these results provide significant new insights into the association of c-Myc with E7 and the possible involvement of high-risk E7 in oncogenesis.
► Describes multi-factor model framework for vulnerability assessment. ► Projects sub-regional climate change impacts on Bangladeshi agriculture by factor. ► Identifies vulnerabilities and helps ...prioritize adaptation strategies by sub-region. ► Assesses key sources of uncertainty by sub-region and factor. ► Context for the Agricultural Model Intercomparison and Improvement Project (AgMIP).
Diverse vulnerabilities of Bangladesh's agricultural sector in 16 sub-regions are assessed using experiments designed to investigate climate impact factors in isolation and in combination. Climate information from a suite of global climate models (GCMs) is used to drive models assessing the agricultural impact of changes in temperature, precipitation, carbon dioxide concentrations, river floods, and sea level rise for the 2040–2069 period in comparison to a historical baseline. Using the multi-factor impacts analysis framework developed in Yu et al. (2010), this study provides new sub-regional vulnerability analyses and quantifies key uncertainties in climate and production. Rice (aman, boro, and aus seasons) and wheat production are simulated in each sub-region using the biophysical Crop Environment REsource Synthesis (CERES) models. These simulations are then combined with the MIKE BASIN hydrologic model for river floods in the Ganges-Brahmaputra-Meghna (GBM) Basins, and the MIKE21 Two-Dimensional Estuary Model to determine coastal inundation under conditions of higher mean sea level. The impacts of each factor depend on GCM configurations, emissions pathways, sub-regions, and particular seasons and crops. Temperature increases generally reduce production across all scenarios. Precipitation changes can have either a positive or a negative impact, with a high degree of uncertainty across GCMs. Carbon dioxide impacts on crop production are positive and depend on the emissions pathway. Increasing river flood areas reduce production in affected sub-regions. Precipitation uncertainties from different GCMs and emissions scenarios are reduced when integrated across the large GBM Basins’ hydrology. Agriculture in Southern Bangladesh is severely affected by sea level rise even when cyclonic surges are not fully considered, with impacts increasing under the higher emissions scenario.
TGF-β plays a significant role in regulating pancreas islet function and maintaining their mass. KLF10, a TGF-β downstream gene, belongs to a group of Krüppel-like transcription factors that bind to ...the promoters of target genes and produce effects that mimic TGF-β as a tumor suppressor. Using ChIP-chip screening, SEI-1 was identified as a target gene that may be regulated by KLF10. We conducted a series of assays to verify the presence of unknown regulation events between SEI-1 and KLF10. These showed that KLF10 transcriptionally activates the SEI-1 promoter and, furthermore, induces SEI-1 protein expression in pancreatic carcinoma cells. SEI-1 is one of the key factors involved in cell cycle control through the regulation of other transcription factors such as the p21Cip1 gene. Interestingly, it has been shown previously that p21Cip1 is indirectly activated by KLF10. Our results first demonstrated that KLF10 acts as a transcriptional activator on SEI-1, which can then result in increased p21Cip1 expression. Furthermore, KLF10-deficiency in mice is associated with a decrease in the pancreatic islet mass, which is similar to the effects found in SEI-1 deficient mice. The KLF10-defect was also associated with the nuclear accumulation of the p21Cip1 in islet cells. Based on our molecular and histological findings, we conclude that KLF10 plays an important role in pancreatic β-cells and this supports a functional link between KLF10 and various cell cycle regulators, most notably in the context of the pancreas.
This paper examines the health crisis in Bangladesh due to dissolved arsenic in groundwater. First, we use geostatistical methods to construct a map of arsenic concentrations that divides Bangladesh ...into regions and estimate vertical concentration trends in these regions. Then, we use census data to estimate exposure distributions in the regions; we use epidemiological data from West Bengal and Taiwan to estimate dose response functions for arsenicosis and arsenic‐induced cancers; and we combine the regional exposure distributions and the dose response models to estimate the health effects of groundwater arsenic in Bangladesh. We predict that long‐term exposure to present arsenic concentrations will result in approximately 1,200,000 cases of hyperpigmentation, 600,000 cases of keratosis, 125,000 cases of skin cancer, and 3000 fatalities per year from internal cancers. Although these estimates are very uncertain, the method provides a framework for incorporating better data as it becomes available. Moreover, we examine the remedy of drilling deeper wells in selected regions of Bangladesh. By replacing 31% of the wells in the country with deeper wells the health effects of drinking groundwater arsenic could be reduced by approximately 70% provided that arsenic concentrations in deep wells remain relatively low.
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