Natural Progression of Canine Glycogen Storage Disease Type IIIa

Glycogen storage disease type IIIa (GSD IIIa) is caused by a deficiency of glycogen debranching enzyme activity. Hepatomegaly, muscle degeneration, and hypoglycemia occur in human patients at an early age. Long-term complications include liver cirrhosis, hepatic adenomas, and generalized myopathy. A naturally occurring canine model of GSD IIIa that mimics the human disease has been described, with progressive liver disease and skeletal muscle damage likely due to excess glycogen deposition. In the current study, long-term follow-up of previously described GSD IIIa dogs until 32 mo of age (n = 4) and of family-owned GSD IIIa dogs until 11 to 12 y of age (n = 2) revealed that elevated concentrations of liver and muscle enzyme (AST, ALT, ALP, and creatine phosphokinase) decreased over time, consistent with hepatic cirrhosis and muscle fibrosis. Glycogen deposition in many skeletal muscles; the tongue, diaphragm, and heart; and the phrenic and sciatic nerves occurred also. Furthermore, the urinary biomarker Glc₄, which has been described in many types of GSD, was first elevated and then decreased later in life. This urinary biomarker demonstrated a similar trend as AST and ALT in GSD IIIa dogs, indicating that Glc₄ might be a less invasive biomarker of hepatocellular disease. Finally, the current study further demonstrates that the canine GSD IIIa model adheres to the clinical course in human patients with this disorder and is an appropriate model for developing novel therapies.Abbreviations: CCR, curly-coated retriever; CPK, creatine phosphokinase; GSD IIIa, glycogen storage disease type IIIa; Glc₄, Glcα1-6Glcα1-4Glcα1-4GlcGlycogen storage disease type IIIa (GSD IIIa; OMIM, 232400) is an autosomal recessive disorder caused by mutations in the glycogen debranching enzyme gene (AGL), leading to various clinical signs. The tissues mainly affected are liver, heart, and skeletal muscle. Clinical manifestations include hypoglycemia, elevated serum concentrations of liver and muscle enzymes, hepatomegaly, growth retardation, muscle weakness, cardiac hypertrophy with arrhythmia risk, polycystic ovaries and neuropathy.^15,17,29 Current treatments are mainly symptomatic and are not curative. The most frequently used therapies are dietary, such as providing uncooked corn starch to prevent hypoglycemia at young ages and high-protein diets, which have been shown to reverse the extent of cardiomyopathy associated with GSD IIIa.^7,8,30,37 In addition, the use of medium-chain triglycerides has shown positive therapeutic effects in patients with GSD Ia and GSD IIIa.^11,22 However, dietary therapies do not prevent the long-term complications of GSD IIIa, including hepatic cirrhosis, hepatocellular adenoma, hepatocellular carcinoma, cardiomyopathy, neuropathy, and myopathy.³¹An appropriate animal model is necessary to test novel therapies and address the long-term effects of GSD IIIa. Recently a mouse model for GSD III has been described that may prove beneficial in testing new therapies.¹⁹ However, the limitations of mouse models include a short lifespan that curtails the study of the long-term effects of novel treatments. In addition, a large animal model often mimics human disease more closely than do mouse models, as occurs in GSD type Ia dog models, which exhibit lactic acidosis similar to human patients, a characteristic that mouse models of GSD Ia lack.¹⁶ Therefore a naturally occurring large animal model for GSD IIIa may be more effective in terms of the development of new treatments than are available mouse models.GSD IIIa (OMIA, 001577) has been reported to occur in curly-coated retriever dogs (CCR) and is caused by a naturally occurring homozygous frameshift mutation in exon 32 that leads to the deletion of 126 amino acids at the C-terminus of glycogen debranching enzyme.^12,40 The dogs in these previous studies proved to have abnormalities similar to those seen in humans affected with the disorder, namely progressive glycogen accumulation in muscle and liver, elevated liver and muscle enzymes (ALP, AST, creatine phosphokinase [CPK], and ALT), and eventual liver fibrosis. However, these animals were not followed beyond 16 mo of age in the earlier studies.^12,40 The goal of the current study is to provide biochemical follow-up on these animals and analyze more extensively other tissues and organs involved in GSD IIIa in the dog model. A brief analysis of the naturally high protein diets of GSD IIIa dogs, as well as the effects of an increased protein diet in 2 dogs for the last few months of life, is included.We also include the analysis of a urinary biomarker, Glcα1–6Glcα1– 4Glcα1–4Glc (Glc₄), which is a breakdown product of glycogen by α-amylase and neutral α-1,4-glucosidase.³² Elevated levels of Glc₄ have been found in urine from patients with GSD types II, III, IV, VI, and IX and may correlate with disease advancement.^1,18,24,32 To our knowledge, Glc₄ has not been evaluated previously in dogs; we therefore here evaluated the utility of Glc₄ as a biomarker of canine GSD IIIa. A correlation of Glc₄ levels with liver enzyme concentrations in blood might indicate a role of Glc₄ as a less-invasive biomarker for determining the advancement of liver disease in human and canine patients.     

Downregulation of CENPF Remodels Prostate Cancer Cells and Alters Cellular Metabolism

Metabolic alterations in prostate cancer (PC) are associated with progression and aggressiveness. However, the underlying mechanisms behind PC metabolic functions are unknown. The authors’ group recently reported on the important role of centromere protein F (CENPF), a protein associated with the centromere–kinetochore complex and chromosomal segregation during mitosis, in PC MRI visibility. This study focuses on discerning the role of CENPF in metabolic perturbation in human PC3 cells. A series of bioinformatics analyses shows that CENPF is one gene that is strongly associated with aggressive PC and that its expression is positively correlated with metastasis. By identifying and reconstructing the CENPF network, additional associations with lipid regulation are found. Further untargeted metabolomics analysis using gas chromatography‐time‐of‐flight‐mass spectrometry reveals that silencing of CENPF alters the global metabolic profiles of PC cells and inhibits cell proliferation, which suggests that CENPF may be a critical regulator of PC metabolism. These findings provide useful scientific insights that can be applied in future studies investigating potential targets for PC treatment.     

Physiological model using diffuse reflectance spectroscopy for nonmelanoma skin cancer diagnosis

Diffuse reflectance spectroscopy (DRS) is a noninvasive, fast, and low‐cost technology with potential to assist cancer diagnosis. The goal of this study was to test the capability of our physiological model, a computational Monte Carlo lookup table inverse model, for nonmelanoma skin cancer diagnosis. We applied this model on a clinical DRS dataset to extract scattering parameters, blood volume fraction, oxygen saturation and vessel radius. We found that the model was able to capture physiological information relevant to skin cancer. We used the extracted parameters to classify (basal cell carcinoma [BCC], squamous cell carcinoma [SCC]) vs actinic keratosis (AK) and (BCC, SCC, AK) vs normal. The area under the receiver operating characteristic curve achieved by the classifiers trained on the parameters extracted using the physiological model is comparable to that of classifiers trained on features extracted via Principal Component Analysis. Our findings suggest that DRS can reveal physiologic characteristics of skin and this physiologic model offers greater flexibility for diagnosing skin cancer than a pure statistical analysis. Physiological parameters extracted from diffuse reflectance spectra data for nonmelanoma skin cancer diagnosis.     

Nest attendance by tropical and temperate passerine birds: Same constancy,different strategy

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Alterations in Phosphorylation of Hepatocyte Ribosomal Protein S6 Control Plasmodium Liver Stage Infection

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Conformational sampling with implicit solvent models: application to the PHF6 peptide in tau protein

Implicit solvent models approximate the effects of solvent through a potential of mean force and therefore make solvated simulations computationally efficient. Yet despite their computational efficiency, the inherent approximations made by implicit solvent models can sometimes lead to inaccurate results. To test the accuracy of a number of popular implicit solvent models, we determined whether implicit solvent simulations can reproduce the set of potential energy minima obtained from explicit solvent simulations. For these studies, we focus on a six-residue amino-acid sequence, referred to as the paired helical filament 6 (PHF6), which may play an important role in the formation of intracellular aggregates in patients with Alzheimer's disease. Several implicit solvent models form the basis of this work--two based on the generalized Born formalism, and one based on a Gaussian solvent-exclusion model. All three implicit solvent models generate minima that are in good agreement with minima obtained from simulations with explicit solvent. Moreover, free-energy profiles generated with each implicit solvent model agree with free-energy profiles obtained with explicit solvent. For the Gaussian solvent-exclusion model, we demonstrate that a straightforward ranking of the relative stability of each minimum suggests that the most stable structure is extended, a result in excellent agreement with the free-energy profiles. Overall, our data demonstrate that for some peptides like PHF6, implicit solvent can accurately reproduce the set of local energy minimum arising from quenched dynamics simulations with explicit solvent. More importantly, all solvent models predict that PHF6 forms extended beta-structures in solution, a finding consistent with the notion that PHF6 initiates neurofibrillary tangle formation in patients with Alzheimer's disease.     

Merremiadissecta (Convolvulaceae): Condiment, medicine, ornamental, and weed—a review

Merremia dissecta was first discovered in the Caribbean, then Florida, Mexico, and later in the Old World, where it had been introduced. Historically and currently, the species has been used as a condiment, medicine, and ornamental by an array of cultures. Although the plant has escaped in several areas to become a weed, it continues being sold as an ornament in even those regions. In Argentina, roots ofM. dissecta var. edentata are still used as food by a few indigenous groups. History, uses, and chemistry are discussed regarding these utilizations.

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Merremia dissecta (Convolvulaceas): Un condimento, medicina, ornamental, y maleza— Una revista

Resumen  Merremia dissecta fue primeramente descubierta en el Caribe, luego en la Florida, México y más tarde fue introducida en el Viejo Mundo. Históricamente y aún actualmente se ha usado como condimento, medicina, y ornamentatión por varias culturas. A pesar de que en varias áreas se ha transformado en una mala hierba, se continua vendiendo como un ornamento aún en esas areas. En Argentina, as raices deM. dissecta var. edentata aún son usadas como alimento por unos cuantos grupos indígenas. La historia, los usos y la química de estas utilizaciónes son aquí discutidas.

     

The selenium-rich C-terminal domain of mouse selenoprotein P is necessary for the supply of selenium to brain and testis but not for the maintenance of whole body selenium

Selenoprotein P (Sepp1) has two domains with respect to selenium content: the N-terminal, selenium-poor domain and the C-terminal, selenium-rich domain. To assess domain function, mice with deletion of the C-terminal domain have been produced and compared with Sepp1-/- and Sepp1+/+ mice. All mice studied were males fed a semipurified diet with defined selenium content. The Sepp1 protein in the plasma of mice with the C-terminal domain deleted was determined by mass spectrometry to terminate after serine 239 and thus was designated Sepp1Delta240-361. Plasma Sepp1 and selenium concentrations as well as glutathione peroxidase activity were determined in the three types of mice. Glutathione peroxidase and Sepp1Delta240-361 accounted for over 90% of the selenium in the plasma of Sepp1Delta240-361 mice. Calculations using results from Sepp1+/+ mice revealed that Sepp1, with a potential for containing 10 selenocysteine residues, contained an average of 5 selenium atoms per molecule, indicating that shortened and/or selenium-depleted forms of the protein were present in these wild-type mice. Sepp1Delta240-361 mice had low brain and testis selenium concentrations that were similar to those in Sepp1-/- mice but they better maintained their whole body selenium. Sepp1Delta240-361 mice had depressed fertility, even when they were fed a high selenium diet, and their spermatozoa were defective and morphologically indistinguishable from those of selenium-deficient mice. Neurological dysfunction and death occurred when Sepp1Delta240-361 mice were fed selenium-deficient diet. These phenotypes were similar to those of Sepp1-/- mice but had later onset or were less severe. The results of this study demonstrate that the C terminus of Sepp1 is critical for the maintenance of selenium in brain and testis but not for the maintenance of whole body selenium.     

Breeding populations of Little Ringed Plover Charadrius dubius and Ringed Plover Charadrius hiaticula in the United Kingdom in 2007

Capsule: The 2007 national survey of the UK breeding population of Little Ringed Plovers shows a further spread into Scotland and Wales since the previous survey in 1984. In contrast, there has been a significant decrease in the Ringed Plover breeding population.

Aims: To provide new breeding population estimates in the UK and Great Britain for Little Ringed Plover Charadrius dubius and Ringed Plover Charadrius hiaticula in 2007 and investigate changes in breeding distribution and habitat use since 1984.

Methods: Breeding population estimates were made by combining counts of pairs from ‘key sites’ (2?×?2?km tetrads known to be occupied in/since 1984) and estimates of the numbers of pairs away from these sites based on stratified sampling. Survey periods for Little Ringed Plover: 15 April to 15 July, three visits; Ringed Plover: 15 April to 30 June, two visits.

Results: Population estimates, for 2007, of 1239 (95% confidence intervals: 1175–1311) pairs of Little Ringed Plover and 5291 (5106–5478) pairs of Ringed Plovers were calculated for Great Britain, with 5438 (5257–5622) pairs of Ringed Plover estimated in the UK. Counts of Ringed Plover at inland and coastal sites, covered in both 1984 and 2007, decreased by 83% and 53%, respectively. The Little Ringed Plover population has expanded in range northward and westward since 1984. Main habitats used in 2007 by Little Ringed Plover were inland gravel and sand (25.9%) and river shingle (17.8%); and, for Ringed Plover, coastal shingle and sand (38.5% and 13.7%, respectively) and machair plus associated habitats (23.8%) in the Outer Hebrides.

Conclusions: Between 1984 and 2007, the Little Ringed Plover breeding population in the UK increased considerably, expanding northward and westward, with increased use of river shingle habitats. During the same period Ringed Plover breeding numbers in the UK declined considerably in both coast and inland habitats, likely to be due to human disturbance and habitat change, respectively.