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Posttranslational modifications (PTMs) are common among proteins that aggregate in neurodegenerative disease, yet how PTMs impact the aggregate conformation and disease progression remains unclear. By engineering knockin mice expressing prion protein (PrP) lacking 2 N-linked glycans (Prnp180Q/196Q), we provide evidence that glycans reduce spongiform degeneration and hinder plaque formation in prion disease. Prnp180Q/196Q mice challenged with 2 subfibrillar, non-plaque-forming prion strains instead developed plaques highly enriched in ADAM10-cleaved PrP and heparan sulfate (HS). Intriguingly, a third strain composed of intact, glycophosphatidylinositol-anchored (GPI-anchored) PrP was relatively unchanged, forming diffuse, HS-deficient deposits in both the Prnp180Q/196Q and WT mice, underscoring the pivotal role of the GPI-anchor in driving the aggregate conformation and disease phenotype. Finally, knockin mice expressing triglycosylated PrP (Prnp187N) challenged with a plaque-forming prion strain showed a phenotype reversal, with a striking disease acceleration and switch from plaques to predominantly diffuse, subfibrillar deposits. Our findings suggest that the dominance of subfibrillar aggregates in prion disease is due to the replication of GPI-anchored prions, with fibrillar plaques forming from poorly glycosylated, GPI-anchorless prions that interact with extracellular HS. These studies provide insight into how PTMs impact PrP interactions with polyanionic cofactors, and highlight PTMs as a major force driving the prion disease phenotype.

Cofactors are essential for driving recombinant prion protein into pathogenic conformers. Polyanions promote prion aggregation in vitro, yet the cofactors that modulate prion assembly in vivo remain largely unknown. Here we report that the endogenous glycosaminoglycan, heparan sulfate (HS), impacts prion propagation kinetics and deposition sites in the brain. Exostosin-1 haploinsufficient (Ext1+/-) mice, which produce short HS chains, show a prolonged survival and a redistribution of plaques from the parenchyma to vessels when infected with fibrillar prions, and a modest delay when infected with subfibrillar prions. Notably, the fibrillar, plaque-forming prions are composed of ADAM10-cleaved prion protein lacking a glycosylphosphatidylinositol anchor, indicating that these prions are mobile and assemble extracellularly. By analyzing the prion-bound HS using liquid chromatography-mass spectrometry (LC-MS), we identified the disaccharide signature of HS differentially bound to fibrillar compared to subfibrillar prions, and found approximately 20-fold more HS bound to the fibrils. Finally, LC-MS of prion-bound HS from human patients with familial and sporadic prion disease also showed distinct HS signatures and higher HS levels associated with fibrillar prions. This study provides the first in vivo evidence of an endogenous cofactor that accelerates prion disease progression and enhances parenchymal deposition of ADAM10-cleaved, mobile prions.

Background: The creation of developing new generalized classes of distributions has attracted applied and theoretical statisticians owing to their properties of flexibility. The development of generalized distribution aims to find distribution flexibility and suitability for available data. In this decade, most authors have developed classes of distributions that are new, to become valuable for applied researchers. Methods: This study aims to develop the odd log-logistic generalized exponential distribution (OLLGED), one of the lifetime newly generated distributions in the field of statistics. The advantage of the newly generated distribution is the heavily tailed distributed lifetime data set. Most of the probabilistic properties are derived including generating functions, moments, and quantile and order statistics. Results: Estimation of the model parameter is done by the maximum likelihood method. The performance of parametric estimation is studied through simulation. Application of OLLGED and its flexibilities is done using two data sets and while its performance is done on the randomly simulated data set. Conclusions: The application and flexibility of the OLLGED are ensured through empirical observation using two sets of lifetime data, establishing that the proposed OLLGED can provide a better fit in comparison to existing rival models, such as odd generalized log-logistic, type-II generalized log-logistic, exponential distributions, odd exponential log-logistic, generalized exponential, and log-logistic.

Aggregated forms of different proteins are common hallmarks for several neurodegenerative diseases, including Alzheimer's disease, and ligands that selectively detect specific protein aggregates are vital. Herein, we investigate the molecular requirements of thiophene‐vinyl‐benzothiazole based ligands to detect a specific type of Aβ deposits found in individuals with dominantly inherited Alzheimer's disease caused by the Arctic APP E693G mutation. The staining of these Aβ deposits was alternated when switching the terminal heterocyclic moiety attached to the thiophene‐vinyl‐benzothiazole scaffold. The most prevalent staining was observed for ligands having a terminal 3‐methyl‐1H‐indazole moiety or a terminal 1,2‐dimethoxybenzene moiety, verifying that specific molecular interactions between these ligands and the aggregates were necessary. The synthesis of additional thiophene‐vinyl‐benzothiazole ligands aided in pinpointing additional crucial chemical determinants, such as positioning of nitrogen atoms and methyl substituents, for achieving optimal staining of Aβ aggregates. When combining the optimized thiophene‐vinyl‐benzothiazole based ligands with a conventional ligand, CN‐PiB, distinct staining patterns were observed for sporadic Alzheimer's disease versus dominantly inherited Alzheimer's disease caused by the Arctic APP E693G mutation. Our findings provide chemical insights for developing novel ligands that allow for a more precise assignment of Aβ deposits, and might also aid in creating novel agents for clinical imaging of distinct Aβ aggregates in AD. [ABSTRACT FROM AUTHOR]

Recently, it has been hypothesized that alpha-synuclein protein strain morphology may be associated with clinical subtypes of alpha-synucleinopathies, like Parkinson's disease and multiple system atrophy. However, direct evidence is lacking due to the caveat of conformation-specific characterization of protein strain morphology. Here we present a new cell model based in vitro method to explore various alpha-synuclein (αsyn) aggregate morphotypes. We performed a spectroscopic investigation of the HEK293 cell model, transfected with human wildtype-αsyn and A53T-αsyn variants, using the amyloid fibril-specific heptameric luminescent oligomeric thiophene h-FTAA. The spectral profile of h-FTAA binding to aggregates displayed a blue-shifted spectrum with a fluorescence decay time longer than in PBS, suggesting a hydrophobic binding site. In vitro spectroscopic binding characterization of h-FTAA with αsyn pre-formed fibrils suggested a binding dissociation constant Kd < 100 nM. The cells expressing the A53T-αsyn and human wildtype-αsyn were exposed to recombinant pre-formed fibrils of human αsyn. The ensuing intracellular aggregates were stained with h-FTAA followed by an evaluation of the spectral features and fluorescence lifetime of intracellular αsyn/h-FTAA, in order to characterize aggregate morphotypes. This study exemplifies the use of cell culture together with conformation-specific ligands to characterize strain morphology by investigating the spectral profiles and fluorescence lifetime of h-FTAA, based upon its binding to a certain αsyn aggregate. This study paves the way for toxicity studies of different αsyn strains in vitro and in vivo. Accurate differentiation of specific alpha-synucleinopathies is still limited to advanced disease stages. However, early subtype-specific diagnosis is of the utmost importance for prognosis and treatment response. The potential association of αsyn aggregates morphotypes detected in biopsies or fluids to disease phenotypes would allow for subtype-specific diagnosis in subclinical disease stage and potentially reveal new subtype-specific treatment targets. Notably, the method may be applied to the entire spectrum of neurodegenerative diseases by using a combination of conformation-specific ligands in a physicochemical environment together with other types of polymorphic amyloid variants and assess the conformation-specific features of various protein pathologies. [ABSTRACT FROM AUTHOR]

Human Resource Development (HRD) is first and foremost a field of practice, and efforts to transform the field must arise and prove themselves out in actual practice. Practice is always in motion and, thus, its transformation is not static or ever finished, but open-ended, searching, and evolving. This article in the special issue on transforming HRD is written in a personal and narrative style, offering wide-ranging accounts of specific transformation initiatives taken from our professional practice as two white, western HRD people, senior in experience and age. The goal is to tell the stories of particular transformation efforts in different contexts, cultures, and times and to draw out insights for the dynamics of transformation. We suggest that the value of the tales in this article, even in the limited space of a journal article, lies in offering the reader glimpses of the intricacies and dynamics of HRD transformation as it actually unfolds. We invite the readers to reflect on their own projects and draw their own conclusions on the fit between our portrayals of the matter at hand and their own experiences as calls for the need to transform HRD arise loud and clear in many different parts of the HRD ecosystem. [ABSTRACT FROM AUTHOR]

Background: The creation of developing new generalized classes of distributions has attracted applied and theoretical statisticians owing to their properties of flexibility. The development of generalized distribution aims to find distribution flexibility and suitability for available data. In this decade, most authors have developed classes of distributions that are new, to become valuable for applied researchers. Methods: This study aims to develop the odd log-logistic generalized exponential distribution (OLLGED), one of the lifetime newly generated distributions in the field of statistics. The advantage of the newly generated distribution is the heavily tailed distributed lifetime data set. Most of the probabilistic properties are derived including generating functions, moments, and quantile and order statistics. Results: Estimation of the model parameter is done by the maximum likelihood method. The performance of parametric estimation is studied through simulation. Application of OLLGED and its flexibilities is done using two data sets and while its performance is done on the randomly simulated data set. Conclusions: The application and flexibility of the OLLGED are ensured through empirical observation using two sets of lifetime data, establishing that the proposed OLLGED can provide a better fit in comparison to existing rival models, such as odd generalized log-logistic, type-II generalized log-logistic, exponential distributions, odd exponential log-logistic, generalized exponential, and log-logistic.

Für das Schweizer Mittelland liegt eine Bioindikationsmethode mit Flechten vor, die gesicherte und quantitative Aussagen über die Gesamtbelastung der Luft zuläßt (herzig, liebendörfer. urech 1987). Diese Methode stößt da an Grenzen, wo sich die für das Schweizer Mittelland typische, epiphytische (baumbewohnende) Flechtenvegetation aus klimatischen Gründen ändert. Die vorliegende Untersuchung prüft die Übertragbarkeit der «kalibrierten Flechtenmethode zur Luftgütebewertung» auf Gebiete mit unterschiedlicher Flechtenflora am Beispiel des Bündner Rheintales. Die Anpassung der Flechtenmethode an andere klimatische Verhältnisse bedingte verschiedene methodische Änderungen: Die Trägerbaum- sowie Flechtenarten wurden neu ausgewählt, die Neukalibrierung der Flechtenmethode und die Beschreibung der für das Bündner Rheintal gültigen Flechtenzonen drängten sich auf. Die «Bündner Rheintaler Flechtenmethode» liefert ebenfalls gesicherte, quantitative Aussagen über die Gesamt-Immissionsbelastung der Luft. Anhand dieser Methode wurde für das Bündner Rheintal eine fünfstufige, flächendeckende Luft-Gesamtbelastungskarte erstellt.

Oligothiophenes with specific photophysical properties and molecular organization are of great interest, since this class of materials are used in organic electronics and bioelectronics, as well as biosensing. Herein, 8 different pentameric oligothiophenes, denoted proteophenes, with different amino acid substitution patterns at distinct positions along the thiophene backbone were investigated. Spectroscopic and microscopic studies of the ligands revealed the formation of optically active self‐assembled materials under acidic or basic conditions. The distinct photophysical characteristics, including induced circular dichroism, as well as the supramolecular structures of the assemblies deduced from light scattering and transmission electron microscopy, were highly influenced by the positioning of distinct amino acid moieties along the thiophene backbone. Proteophenes functionalized with only glutamate residues or these functionalities in combination with hydrophobic valine moieties formed fibrillar structures with excellent chiroptical properties under acidic conditions. In addition, the amino acid functionality at the β‐position of distinct thiophene moieties influenced the induced circular dichroism pattern observed from the proteophenes. Overall, the obtained results demonstrate how changes in the position of various amino acid functionalities, as well as the chemical nature of the amino acid side chain functionality greatly affect the optical properties as well as the architecture of the self‐assembled materials. [ABSTRACT FROM AUTHOR]

Synucleinopathies are neurodegenerative diseases that are associated with the misfolding and aggregation of [alpha]-synuclein, including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy.sup.1. Clinically, it is challenging to differentiate Parkinson's disease and multiple system atrophy, especially at the early stages of disease.sup.2. Aggregates of [alpha]-synuclein in distinct synucleinopathies have been proposed to represent different conformational strains of [alpha]-synuclein that can self-propagate and spread from cell to cell.sup.3-6. Protein misfolding cyclic amplification (PMCA) is a technique that has previously been used to detect [alpha]-synuclein aggregates in samples of cerebrospinal fluid with high sensitivity and specificity.sup.7,8. Here we show that the [alpha]-synuclein-PMCA assay can discriminate between samples of cerebrospinal fluid from patients diagnosed with Parkinson's disease and samples from patients with multiple system atrophy, with an overall sensitivity of 95.4%. We used a combination of biochemical, biophysical and biological methods to analyse the product of [alpha]-synuclein-PMCA, and found that the characteristics of the [alpha]-synuclein aggregates in the cerebrospinal fluid could be used to readily distinguish between Parkinson's disease and multiple system atrophy. We also found that the properties of aggregates that were amplified from the cerebrospinal fluid were similar to those of aggregates that were amplified from the brain. These findings suggest that [alpha]-synuclein aggregates that are associated with Parkinson's disease and multiple system atrophy correspond to different conformational strains of [alpha]-synuclein, which can be amplified and detected by [alpha]-synuclein-PMCA. Our results may help to improve our understanding of the mechanism of [alpha]-synuclein misfolding and the structures of the aggregates that are implicated in different synucleinopathies, and may also enable the development of a biochemical assay to discriminate between Parkinson's disease and multiple system atrophy. Protein misfolding cyclic amplification (PMCA) technology can discriminate between patients with Parkinson's disease and patients with multiple system atrophy on the basis of the characteristics of the [alpha]-synuclein aggregates in the cerebrospinal fluid., Author(s): Mohammad Shahnawaz [sup.1] , Abhisek Mukherjee [sup.1] , Sandra Pritzkow [sup.1] , Nicolas Mendez [sup.1] , Prakruti Rabadia [sup.1] , Xiangan Liu [sup.2] , Bo Hu [sup.2] , Ann [...]

We present a short, inquiry-based learning course on concepts and methods underlying ordinary least squares (OLS), least absolute deviation (LAD), and quantile regression (QR). Students investigate squared, absolute, and weighted absolute distance functions (metrics) as location measures. Using differential calculus and properties of convex functions, students discover the sample mean, median, and "p"th quantile by minimizing sums of distances. Students use these metrics to define loss functions for OLS, LAD, and QR, and explore methods to minimize them. We discuss classroom experiences over two semesters. Classroom activities, Maple worksheets, and R demonstration code are available at a companion website.

The study contributes to the work values literature as well as to the knowledge base of meaning of working in Asian economies. It represents the results of an empirical study of Korean mid-level employees in diverse industries, investigating the effects of different understandings of work and non-work dimensions on job satisfaction, career satisfaction, and organizational commitment. With a sample size of some 420 responses from 16 different companies, age differences were found for overall meaning of work and also for the effects of importance of working for global organizational commitment. Non-work related dimensions appeared unrelated to work-related outcome variables. We conclude that to a limited degree, age related differentiation exist in relation to work meanings and separation of work and non-work domains for work-related effects. The implications for theory and practice of this research are also discussed. (Contains 7 tables.)

On February 11, 2023, Emeritus Professor Isztar Zawadzki--internationally known for his groundbreaking work in radar meteorology and precipitation physics--succumbed to a stroke. With great effort, determination, and much help from [...]

The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders, and heterozygous, proteintruncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5bΔARID allele that lacks demethylase activity. Kdm5bΔARID/ΔARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon a learning stimulus compared with wild-type (WT) mice. A number of other learning-associated genes were also significantly dysregulated in the Kdm5bΔARID/ΔARID hippocampus. Next, we knocked down Kdm5b specifically in the adult, WT mouse hippocampus with shRNA. Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms. [ABSTRACT FROM AUTHOR]