Gerstmann-Sträussler-Scheinker disease revisited: accumulation of covalently-linked multimers of internal prion protein fragments

Despite their phenotypic heterogeneity, most human prion diseases belong to two broadly defined groups: Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker disease (GSS). While the structural characteristics of the disease-related proteinase K-resistant prion protein (resPrPD) associated with the CJD group are fairly well established, many features of GSS-associated resPrPD are unclear. Electrophoretic profiles of resPrPD associated with GSS variants typically show 6-8 kDa bands corresponding to the internal PrP fragments as well as a variable number of higher molecular weight bands, the molecular nature of which has not been investigated. Here we have performed systematic studies of purified resPrPD species extracted from GSS cases with the A117V (GSSA117V) and F198S (GSSF198S) PrP gene mutations. The combined analysis based on epitope mapping, deglycosylation treatment and direct amino acid sequencing by mass spectrometry provided a conclusive evidence that high molecular weight resPrPD species seen in electrophoretic profiles represent covalently-linked multimers of the internal ~ 7 and ~ 8 kDa fragments. This finding reveals a mechanism of resPrPD aggregate formation that has not been previously established in prion diseases

Synaptic Protection in the Brain of WldS Mice Occurs Independently of Age but Is Sensitive to Gene-Dose

Disruption of synaptic connectivity is a significant early event in many neurodegenerative conditions affecting the aging CNS, including Alzheimer's disease and Parkinson's disease. Therapeutic approaches that protect synapses from degeneration in the aging brain offer the potential to slow or halt the progression of such conditions. A range of animal models expressing the slow Wallerian Degeneration (Wld(S)) gene show robust neuroprotection of synapses and axons from a wide variety of traumatic and genetic neurodegenerative stimuli in both the central and peripheral nervous systems, raising that possibility that Wld(S) may be useful as a neuroprotective agent in diseases with synaptic pathology. However, previous studies of neuromuscular junctions revealed significant negative effects of increasing age and positive effects of gene-dose on Wld(S)-mediated synaptic protection in the peripheral nervous system, raising doubts as to whether Wld(S) is capable of directly conferring synapse protection in the aging brain.We examined the influence of age and gene-dose on synaptic protection in the brain of mice expressing the Wld(S) gene using an established cortical lesion model to induce synaptic degeneration in the striatum. Synaptic protection was found to be sensitive to Wld(S) gene-dose, with heterozygous Wld(S) mice showing approximately half the level of protection observed in homozygous Wld(S) mice. Increasing age had no influence on levels of synaptic protection. In contrast to previous findings in the periphery, synapses in the brain of old Wld(S) mice were just as strongly protected as those in young mice.Our study demonstrates that Wld(S)-mediated synaptic protection in the CNS occurs independently of age, but is sensitive to gene dose. This suggests that the Wld(S) gene, and in particular its downstream endogenous effector pathways, may be potentially useful therapeutic agents for conferring synaptic protection in the aging brain

Enhanced Stability of Iridium Nanocatalysts via Exsolution for the CO₂ Reforming of Methane

\ua9 2023 The Authors. Published by American Chemical Society. The reforming reactions of greenhouse gases require catalysts with high reactivity, coking resistance, and structural stability for efficient and durable use. Among the possible strategies, exsolution has been shown to demonstrate the requirements needed to produce appropriate catalysts for the dry reforming of methane, the conversion of which strongly depends on the choice of active species, its interaction with the support, and the catalyst size and dispersion properties. Here, we exploit the exsolution approach, known to produce stable and highly active nanoparticle-supported catalysts, to develop iridium-nanoparticle-decorated perovskites and apply them as catalysts for the dry reforming of methane. By studying the effect of several parameters, we tune the degree of exsolution, and consequently the catalytic activity, thereby identifying the most efficient sample, 0.5 atomic % Ir-BaTiO3, which showed 82% and 86% conversion of CO2 and CH4, respectively. By comparison with standard impregnated catalysts (e.g., Ir/Al2O3), we benchmark the activity and stability of our exsolved systems. We find almost identical conversion and syngas rates of formation but observe no carbon deposition for the exsolved samples after catalytic testing; such deposition was significant for the traditionally prepared impregnated Ir/Al2O3, with almost 30 mgC/gsample measured, compared to 0 mgC/gsample detected for the exsolved system. These findings highlight the possibility of achieving in a single step the mutual interaction of the parameters enhancing the catalytic efficiency, leading to a promising pathway for the design of catalysts for reforming reactions

Are We Giving Them a Fair Chance? Racial Stereotypes and the Juvenile Justice System

Prior research indicates that there are racial disparities throughout the criminal justice system and that decision-makers may use stereotypes when determining guilt and deciding on sentences for juveniles. This study looked at sentence disparities between White and Latinx juveniles, as well as potential stereotypes that could be used in decision-making. There were no differences in sentence length and severity between the White and Latinx offender. Additionally, the likelihood of the offender receiving a lesser or greater sentence as an adult did not differ among conditions. Our results also showed that participants with prior juror experience used less stereotypical language in their sentence explanations. This research highlights the presence of sentence disparities in prior studies and generates avenues for future research

A Coding Variant in the Gene Bardet-Biedl Syndrome 4 (BBS4) Is Associated with a Novel Form of Canine Progressive Retinal Atrophy

Progressive retinal atrophy is a common cause of blindness in the dog and affects >100 breeds. It is characterized by gradual vision loss that occurs due to the degeneration of photoreceptor cells in the retina. Similar to the human counterpart retinitis pigmentosa, the canine disorder is clinically and genetically heterogeneous and the underlying cause remains unknown for many cases. We use a positional candidate gene approach to identify putative variants in the Hungarian Puli breed using genotyping data of 14 family-based samples (CanineHD BeadChip array, Illumina) and whole-genome sequencing data of two proband and two parental samples (Illumina HiSeq 2000). A single nonsense SNP in exon 2 of BBS4 (c.58A > T, p.Lys20*) was identified following filtering of high quality variants. This allele is highly associated (P-CHISQ = 3.425e(-14), n = 103) and segregates perfectly with progressive retinal atrophy in the Hungarian Puli. In humans, BBS4 is known to cause Bardet-Biedl syndrome which includes a retinitis pigmentosa phenotype. From the observed coding change we expect that no functional BBS4 can be produced in the affected dogs. We identified canine phenotypes comparable with Bbs4-null mice including obesity and spermatozoa flagella defects. Knockout mice fail to form spermatozoa flagella. In the affected Hungarian Puli spermatozoa flagella are present, however a large proportion of sperm are morphologically abnormal andPeer reviewe

Mutant p53R270H drives altered metabolism and increased invasion in pancreatic ductal adenocarcinoma

Pancreatic cancer is characterized by nearly universal activating mutations in KRAS. Among other somatic mutations, TP53 is mutated in more than 75% of human pancreatic tumors. Genetically engineered mice have proven instrumental in studies of the contribution of individual genes to carcinogenesis. Oncogenic Kras mutations occur early during pancreatic carcinogenesis and are considered an initiating event. In contrast, mutations in p53 occur later during tumor progression. In our model, we recapitulated the order of mutations of the human disease, with p53 mutation following expression of oncogenic Kras. Further, using an inducible and reversible expression allele for mutant p53, we inactivated its expression at different stages of carcinogenesis. Notably, the function of mutant p53 changes at different stages of carcinogenesis. Our work establishes a requirement for mutant p53 for the formation and maintenance of pancreatic cancer precursor lesions. In tumors, mutant p53 becomes dispensable for growth. However, it maintains the altered metabolism that characterizes pancreatic cancer and mediates its malignant potential. Further, mutant p53 promotes epithelial-mesenchymal transition (EMT) and cancer cell invasion. This work generates new mouse models that mimic human pancreatic cancer and expands our understanding of the role of p53 mutation, common in the majority of human malignancies

Real-time insight into the multistage mechanism of nanoparticle exsolution from a perovskite host surface

In exsolution, nanoparticles form by emerging from oxide hosts by application of redox driving forces, leading to transformative advances in stability, activity, and efficiency over deposition techniques, and resulting in a wide range of new opportunities for catalytic, energy and net-zero-related technologies. However, the mechanism of exsolved nanoparticle nucleation and perovskite structural evolution, has, to date, remained unclear. Herein, we shed light on this elusive process by following in real time Ir nanoparticle emergence from a SrTiO3 host oxide lattice, using in situ high-resolution electron microscopy in combination with computational simulations and machine learning analytics. We show that nucleation occurs via atom clustering, in tandem with host evolution, revealing the participation of surface defects and host lattice restructuring in trapping Ir atoms to initiate nanoparticle formation and growth. These insights provide a theoretical platform and practical recommendations to further the development of highly functional and broadly applicable exsolvable materials

A novel mechanism of phenotypic heterogeneity in Creutzfeldt-Jakob disease

One of remarkable features of sporadic Creutzfeldt-Jakob disease (sCJD) is the great phenotypic variability. Understanding the molecular basis of this variability has important implications for the development of therapeutic approaches. It is well established that, in many cases, phenotypic heterogeneity of sCJD is under control of two determinants: the genotype at the methionine (M)/valine (V) polymorphic codon 129 of the human prion protein gene and the type, 1 or 2, of the pathogenic and disease-related form of the prion protein, PrPD. However, this scenario fails to explain the existence of distinct heterozygous sCJDMV2 subtypes, where heterogeneity occurs without any variation of the 129 allotype and PrPD type. One of these subtypes, denoted sCJDMV2C, associated with PrPD type 2, is characterized by widespread spongiform degeneration of the cerebral cortex (C). The second variant, denoted sCJDMV2K, features prominent deposition of PrPD amyloid forming kuru type (K) plaques. Here we used a mass spectrometry based approach to test the hypothesis that phenotypic variability within the sCJDMV2 subtype is at least partly determined by the abundance of 129 M and 129 V polymorphic forms of proteinase K-resistant PrPD (resPrPD). Consistent with this hypothesis, our data demonstrated a strong correlation of the MV2C and MV2K phenotypes with the relative populations of protease-resistant forms of the pathogenic prion proteins, resPrPD-129 M and resPrPD-129 V, where resPrPD-129 M dominated in the sCJDMV2C variant and resPrPD-129 V in the sCJDMV2K variant. This finding suggests an important, previously unrecognized mechanism for phenotypic determination in human prion diseases