We have investigated the expression of 52 of the 54 keratins in beard hair medulla. We found that not only 12 hair keratins but, unexpectedly, also 12 epithelial keratins are potentially expressed in medulla cells. The latter comprise keratins also present in outer- and inner-root sheaths and in the companion layer. Keratins K5, K14, K17, K25, K27, K28, and K75 define a "pre-medulla," composed of cells apposed to the upper dermal papilla. Besides K6, K16, K7, K19, and K80, all pre-medullary epithelial keratins continue to be expressed in the medulla proper, along with the 12 hair keratins. Besides this unique feature of cellular keratin co-expression, the keratin pattern itself is highly variable in individual medulla cells. Remarkably, both epithelial and hair keratins behave highly promiscuously with regard to heterodimer- and IF formation, which also includes keratin chain interactions in IF bundles. We also identified cortex cells within the medullary column. These exhibit all the properties of genuine cortex cells, including a particular type of keratin heterogeneity of their compact IF bundles. In both keratin expression profile and keratin number, medulla cells are distinct from all other cells of the hair follicle or from any other epithelium.
Background: There are no accurate indexes for determining the status of manganese in humans, and there is no clear recommended daily dose of this essential trace element to be administered in total parenteral nutrition solutions. Objective: The objectives were to evaluate accurate indexes of manganese status and elucidate the optimal manganese dose to be administered to adult patients undergoing home parenteral nutrition. Design: Patients were administered total parenteral nutrition solutions providing 0, 1, 2, or 20 mol Mn/d according to an onoff design, after which manganese concentrations in whole blood and plasma were determined. Magnetic resonance imaging (MRI) was performed to determine the intensity on T 1 -weighted images (MRI intensity) and T 1 values in the globus pallidus. Hematologic and biochemistry tests were also performed. Results: High degrees of correlation were found between whole-blood manganese concentrations and both MRI intensity (r = 0.7728) and T 1 values (r = Ϫ0.7519) in the globus pallidus. A strong negative correlation was found between MRI intensity and T 1 values (r = Ϫ0.8407). The dose of 1 mol Mn/d caused no change in MRI intensity or T 1 values, and the whole-blood manganese concentration remained within the normal range in all patients. Conclusions: Whole-blood manganese concentrations and MRI intensity and T 1 values in the globus pallidus are useful indexes of the status of manganese in humans. The optimal dose of manganese may be 1 mol/d for adult patients undergoing home parenteral nutrition.Am J Clin Nutr 2002;75:112-8. KEY WORDSHome parenteral nutrition, total parenteral nutrition, magnetic resonance imaging, manganese, trace elements, nutritional requirements, optimal dose INTRODUCTIONManganese is considered an essential trace element for humans (1) and is ordinarily administered in total parenteral nutrition (TPN) solutions, but the kinetics of manganese in the body have yet to be elucidated. Moreover, there are no generally accepted indexes for use in determining the status (excess or deficiency) of manganese in the body. There is also no clear, standard recommended daily dose of this element. The published literature indicates a broad, 200-fold range in the recommended daily manganese dose for adults, extending from a low dose of 0.18-0.91 mol (0.01Ϫ0.05 mg) (2) to a high dose of 40 mol (2.2 mg) (3).The past decade has brought reports that magnetic resonance imaging (MRI) can detect accumulation of manganese in the brain and that T 1 -weighted magnetic resonance images have shown high intensity in the basal ganglia, especially in the globus pallidus, of patients receiving TPN. These findings are thought to be due to excess administration of manganese (4Ϫ7). However, there have been no reports of clinical studies on relations or correlations among blood manganese concentrations, intensity on T 1 -weighted images (MRI intensity), and T 1 values.Accordingly, the present study was designed to elucidate MRI intensity and T 1 values in the globus pallidus of patients...
Small interfering RNA (siRNA) is currently being evaluated not only as a powerful tool for functional genomics, but also as a potentially promising therapeutic agent for cancer and infectious diseases. Inhibitory effect of siRNA on viral replication has been demonstrated in multiple pathogenic viruses. However, because of the high sequence specificity of siRNA-mediated RNA degradation, antiviral efficacy of siRNA directed to viral genome will be largely limited by emergence of escape variants resistant to siRNA due to high mutation rates of virus, especially RNA viruses such as poliovirus and hepatitis C virus (HCV). To investigate the therapeutic feasibility of siRNAs specific for the putative cellular cofactors for HCV, we constructed adenovirus vectors expressing siRNAs against La, polypyrimidine tract-binding protein (PTB), subunit gamma of human eukaryotic initiation factors 2B (eIF2Bgamma), and human VAMP-associated protein of 33 kDa (hVAP-33). Adenoviral-mediated expression of siRNAs markedly diminished expression of the endogenous genes, and silencing of La, PTB, and hVAP-33 by siRNAs substantially blocked HCV replication in Huh-7 cells. Thus, our studies demonstrate the feasibility and potential of adenoviral-delivered siRNAs specific for cellular cofactors in combating HCV infection, which can be used either alone or in combination with siRNA against viral genome to prevent the escape of mutant variants and provide additive or synergistic anti-HCV effects.
RNA-binding proteins (RBPs) have important roles in tumorigenesis. Although IGF2BP3, an evolutionally conserved RBP, has been reported as a useful diagnostic marker for various cancers and has been considered a regulator of tumorigenesis, little is known of the function of IGF2BP3 because of lack of information regarding IGF2BP3 target mRNAs. Here, we report the identification of IGF2BP3 target mRNAs and IGF2BP3 function in cancer proliferation. We identified mRNAs with altered expression in IGF2BP3-depleted cells by massive sequencing analysis and IGF2BP3-binding RNAs by immunoprecipitation of IGF2BP3 followed by massive sequencing analysis, resulting in the identification of 110 candidates that are negatively regulated by IGF2BP3. We found that IGF2BP3 destabilized EIF4E-BP2 and MEIS3 mRNAs. Co-immunoprecipitation analysis revealed the interaction between IGF2BP3 and ribonucleases such as XRN2 and exosome component. The retarded proliferation of IGF2BP3-depleted cells was partially rescued by the depletion of EIF4E-BP2, which negatively regulates eukaryotic translation initiation factor 4E (eIF4E), an activator of translation and a well-known proto-oncogene. Consistent with this observation, IGF2BP3 depletion reduced phosphorylated eIF4E, the active form, and translational efficiency of eIF4E target transcripts. Reduction of phosphorylated eIF4E by IGF2BP3 depletion was rescued by EIF4E-BP2 depletion. At last, we found an inverse correlation between the expression level of IGF2BP3 and EIF4E-BP2 in human lung adenocarcinoma tissues. Together, these results suggest that IGF2BP3 promotes eIF4E-mediated translational activation through the reduction of EIF4E-BP2 via mRNA degradation, leading to enhanced cell proliferation. This is the first report demonstrating that IGF2BP3 is an RNA-destabilizing factor. Notably, here we provide the first evidence for the functional linkage between two previously well-known cancer biomarkers, IGF2BP3 and eIF4E.
Rodents have brownish-yellow incisors whose colour represents their iron content. Iron is deposited into the mature enamel by ameloblasts that outline enamel surface of the teeth. Nrf 2 is a basic regionleucine zipper type transcription factor that regulates expression of a range of cytoprotective genes in response to oxidative and xenobiotic stresses. We found that genetically engineered Nrf 2-deficient mice show decolourization of the incisors. While incisors of wild-type mice were brownish yellow, incisors of Nrf 2-deficient mice were greyish white in colour. Micro X-ray imaging analysis revealed that the iron content in Nrf 2-deficient mouse incisors were significantly decreased compared to that of wild-type mice. We found that iron was aberrantly deposited in the papillary layer cells of enamel organ in Nrf 2-deficient mouse, suggesting that the iron transport from blood vessels to ameloblasts was disturbed. We also found that ameloblasts of Nrf 2-null mouse show degenerative atrophy at the late maturation stage, which gives rise to the loss of iron deposition to the surface of mature enamel. Our results thus demonstrate that the enamel organ of Nrf 2-deficient mouse has a reduced iron transport capacity, which results in both the enamel cell degeneration and disturbance of iron deposition on to the enamel surface.
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