Although Richard Gatschenberger can be regarded as one of the important sign theorists in the first third of the 20th century, nothing much about the man and his works is currently known. Long before ...there was a widespread philosophical interest in language, Gatschenberger had already laid the foundations of a semiotic turn although the linguistic turn had not even happened; but his role as a pioneer is one reason for the comparatively small response to his sematology. This volume contains a facsimile reprint of the Regensburger 1901 edition of Richard Gatschenberger's dissertation Grundzuge einer Psychologie des Zeichens, and is preceded by a preface 'Sematology as a Basic Science' by Achim Eschbach.
On the basis of previously described X-ray studies of an enzyme/aza-dipeptide complex, aza-dipeptide analogues carrying N-(bis-aryl-methyl) substituents on the (hydroxethyl)hydrazine moiety have been ...designed and synthesized as HIV-1 protease inhibitors. By using either equally (12) or orthogonally (13) protected dipeptide isosteres, symmetrically and asymmetrically acylated aza-dipeptides can be synthesized. This approach led to the discovery of very potent inhibitors with antiviral activities (ED50) in the subnanomolar range. Acylation of the (hydroxethyl)hydrazine dipeptide isostere with the l-tert-leucine derivative 29 increased the oral bioavailability significantly when compared to the corresponding l-valine or l-isoleucine derivatives. The bis(l-tert-leucine) derivatives CGP 75355, CGP 73547, CGP 75136, and CGP 75176 combine excellent antiviral activity with high blood concentration after oral administration. Furthermore, they show no cross-resistance with saquinavir-resistant strains and maintain activity against indinavir-resistant ones. Consequently they qualify for further profiling as potential clinical candidates.
Objectives: Stroke mortality rates are reported to be lower for Hispanics than non-Hispanic Whites. We investigate the degree to which this lower reported mortality is explained by inaccuracies ...introduced through omission of nativity, imprecise measurement of cause of death, and under-ascertainment of Hispanic ethnicity on death certificates. We used national vital registration data for the years 1989—1991 and 1999—2002, including foreign- and US-born Hispanics and non-Hispanic Whites. Hispanic deaths were adjusted for misclassification of ethnicity on the death certificate. Denominators for the rates were derived from census estimates. Results: Adjustment for nativity and death certificate misclassification removes the stroke mortality advantage for US-born Hispanic men, but not women. After adjustment, US-born Hispanic men and women have higher rates of mortality from subarachnoid hemorrhage than non-Hispanic Whites (RR: 1.23 and 1.23, respectively), but lower rates of mortality from Ischemic (RR: 0.76 and 0.73, respectively) and chronic effects of stroke (RR: 0.87 and 0.73, respectively). Conclusions: When adjusted for misclassification the lower stroke mortality remains for Hispanic men and women at older ages. Part of the previously reported advantage is a combination of imprecise measurement and data quality.
Increased mitochondrial mass, commonly termed mitochondrial proliferation, is frequently observed in many human diseases directly or indirectly involving mitochondrial dysfunction. Mitochondrial ...proliferation is thought to counterbalance a compromised energy metabolism, yet it might also be detrimental through alterations of mitochondrial regulatory functions such as apoptosis, calcium metabolism or oxidative stress. Here, we show that prominent mitochondrial proliferation occurs in Cramping mice, a model of hereditary neuropathy caused by a mutation in the dynein heavy chain gene Dync1h1. The mitochondrial proliferation correlates with post-prandial induction of full-length (FL) and N-terminal truncated (NT) isoforms of the transcriptional co-activator PGC-1 alpha . The selective knock-out of FL-PGC-1 alpha isoform, preserving expression and function of NT-PGC-1 alpha , led to a complete reversal of mitochondrial proliferation. Moreover, FL-PGC-1 alpha ablation potently exacerbated the mitochondrial dysfunction and led to severe weight loss. Finally, FL-PGC-1 alpha ablation triggered pronounced locomotor dysfunction, tremors and inability to rear in Cramping mice. In summary, endogenous FL-PGC-1 alpha activates mitochondrial proliferation and salvages neurological and metabolic health upon disease. NT-PGC-1 alpha cannot fulfil this protective action. Activation of this endogenous salvage pathway might thus be a valuable therapeutic target for diseases involving mitochondrial dysfunction.
Objective Aggregation of alpha-synuclein (alpha-syn) and alpha-syn cytotoxicity are hallmarks of sporadic and familial Parkinson disease (PD), with accumulating evidence that prefibrillar oligomers ...and protofibrils are the pathogenic species in PD and related synucleinopathies. Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), a key regulator of mitochondrial biogenesis and cellular energy metabolism, has recently been associated with the pathophysiology of PD. Despite extensive effort on studying the function of PGC-1alpha in mitochondria, no studies have addressed whether PGC-1alpha directly influences oligomerization of alpha-syn or whether alpha-syn oligomers impact PGC-1alpha expression. Materials and Methods We tested whether pharmacological or genetic activation of PGC-1alpha or PGC-11alpha knockdown could modulate the oligomerization of alpha-syn in vitro by using an alpha-syn -fragment complementation assay. Results In this study, we found that both PGC-1alpha reference gene (RG-PGC-1alpha) and the central nervous system (CNS)-specific PGC-1alpha (CNS-PGC-1alpha) are downregulated in human PD brain, in A30P alpha-syn transgenic animals, and in a cell culture model for alpha-syn oligomerization. Importantly, downregulation of both RG-PGC-1alpha and CNS-PGC-1alpha in cell culture or neurons from RG-PGC-1alpha-deficient mice leads to a strong induction of alpha-syn oligomerization and toxicity. In contrast, pharmacological activation or genetic overexpression of RG-PGC-1alpha reduced alpha-syn oligomerization and rescued alpha-syn-mediated toxicity. Interpretation Based on our results, we propose that PGC-1alpha downregulation and alpha-syn oligomerization form a vicious circle, thereby influencing and/or potentiating each other. Our data indicate that restoration of PGC-1alpha is a promising approach for development of effective drugs for the treatment of PD and related synucleinopathies. ANN NEUROL 2015;77:15-32
This study evaluated the ability of beta-tricalcium phosphate particles (beta-TCP) and autograft (AUTO) to maintain joint surface morphology when used to supplement massive subchondral bone defects ...in a caprine model.
This was a prospective, parallel arm study with 2 experimental arms and a control group.
Unilateral, 11 mm diameter, 25 mm deep cylindrical defects were created in tibial subchondral bone of anesthetized goats (n = 16) and filled with autograft or beta-tricalcium phosphate particles. The contralateral limbs served as internal controls. Goats were killed at 3 months and both tibiae harvested. Molds made of the tibial plateau surface were used to create positive casts from which medial and lateral tibial plateau surfaces of both experimental (beta-tricalcium phosphate particles, autograft) and control limbs were digitized in 3 dimensions. Mirror images of the medial condyle surface contours from the controls were superimposed onto the experimental surfaces and deviations were compared using a Student t test (alpha = 0.05). Tibiae were then cut sagittally into medial (biomechanics) and lateral (histology) halves. Compressive modulus within the defect area was assessed by indentation to 2.0 mm at 0.2 mm per second using a 6-mm diameter pin. Specimens from the lateral tibial plateau were processed for undecalcified histology and the area of bone within the defect region measured. The articular surface of 86% of the autograft and 0% of the beta-tricalcium phosphate particles group had degenerative changes, with 29% of autograft goats exhibiting large-scale plateau collapse. Mean surface deviation for autograft was significantly greater than for beta-tricalcium phosphate particles (2.19 +/- 1.49 mm versus 0.78 +/- 0.19 mm), as was maximum surface deviation (11.19 +/- 8.02 mm versus 4.39 +/- 1.33 mm) (P < 0.05). The compressive modulus within the defect area for control animals was significantly higher than the experimental groups (P < 0.05). Significantly more bone was regenerated within beta-tricalcium phosphate particle-grafted defects compared to autograft (P < 0.05). These results indicated that beta-tricalcium phosphate particles might be a useful graft material for local repair of load bearing skeletal sites such as depressed tibial plateau fractures.
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