The Physical Relationship between Infectivity and Prion Protein Aggregates Is Strain-Dependent

Prions are unconventional infectious agents thought to be primarily composed of PrPSc, a multimeric misfolded conformer of the ubiquitously expressed host-encoded prion protein (PrPC). They cause fatal neurodegenerative diseases in both animals and humans. The disease phenotype is not uniform within species, and stable, self-propagating variations in PrPSc conformation could encode this ‘strain’ diversity. However, much remains to be learned about the physical relationship between the infectious agent and PrPSc aggregation state, and how this varies according to the strain. We applied a sedimentation velocity technique to a panel of natural, biologically cloned strains obtained by propagation of classical and atypical sheep scrapie and BSE infectious sources in transgenic mice expressing ovine PrP. Detergent-solubilized, infected brain homogenates were used as starting material. Solubilization conditions were optimized to separate PrPSc aggregates from PrPC. The distribution of PrPSc and infectivity in the gradient was determined by immunoblotting and mouse bioassay, respectively. As a general feature, a major proteinase K-resistant PrPSc peak was observed in the middle part of the gradient. This population approximately corresponds to multimers of 12–30 PrP molecules, if constituted of PrP only. For two strains, infectivity peaked in a markedly different region of the gradient. This most infectious component sedimented very slowly, suggesting small size oligomers and/or low density PrPSc aggregates. Extending this study to hamster prions passaged in hamster PrP transgenic mice revealed that the highly infectious, slowly sedimenting particles could be a feature of strains able to induce a rapidly lethal disease. Our findings suggest that prion infectious particles are subjected to marked strain-dependent variations, which in turn could influence the strain biological phenotype, in particular the replication dynamics

Familial and Sporadic Breast Cancer: Differences in Clinical, Histopathological and Immunoistochemical Features

In the present study, the authors investigated the clinical, histopathological, and immunohistochemical features in familial breast cancer (FBC) patients and compared them with findings in sporadic breast cancers (SBCs); hormone receptor status was stratified by age. A total of 849 patients treated for breast cancer were included in the study. The patients were stratified into 2 groups: FBC, 160 patients (19%), and SBC, 689 patients (81%). FBC tumors differed from SBC tumors by earlier age of diagnosis and low content of progesterone receptor (PR). These characteristics should be of value in evaluating the possibility of mutation and in targeting mutation screening in such families. PR gene polymorphism leads to an increased risk of breast cancer because it determines inadequate control of estrogen receptor (ER)-driven proliferative function. ER+/PR- tumors more frequently showed HER2 (human epidermal growth factor receptor) overexpression and represent a distinct subset in FBC patients. The authors suggest that late-onset FBCs need more intensive therapy and a more careful follow-up

Synthesis, radiolabeling and in vivo evaluation of [11C](R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol, a potential PET radioligand for the 5-HT7 receptor

In the search for a novel serotonin 7 (5-HT7) receptor PET radioligand we synthesized and evaluated a new series of biphenylpiperazine derivatives in vitro. Among the studied compounds, (R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol ((R)-16), showed the best combination of affinity, selectivity, and lipophilicity, and was thus chosen for carbon-11 labelling and evaluation in pigs. After intravenous injection, [(11)C](R)-16 entered the pig brain and displayed reversible tracer kinetics. Pretreatment with the 5-HT7 receptor selective antagonist SB-269970 (1) resulted in limited decrease in the binding of [(11)C](R)-16, suggesting that this radioligand is not optimal for imaging the brain 5-HT7 receptor in vivo but it may serve as a lead compound for the design of novel 5-HT7 receptor PET radioligands

Evaluation of neural network performance and generalisation using thresholding functions

The application of a simple thresholding technique to help assess the satisfactory performance of classification networks formed from Multi-Layer Perceptron (MLP) artificial neural networks (ANNs) is discussed. Both conventional Maximum Likelihood and Bayesian Evidence based training paradigms were implemented. Firstly a simulated data set drawn from a two-dimensional Gaussian distribution was investigated to illustrate the physical significance of the threshold plots compared to the classifier output probability contours. Secondly a real world application data set comprising of low-frequency vibration measurements on an aircraft wing (a GNAT trainer) is considered. It is demonstrated that simple threshold based plots applied to classifier network outputs may provide a simple yet powerful technique to aid in the rejection of poorly regularised network structures