Demyelination in Mild Cognitive Impairment Suggests Progression Path to Alzheimer’s Disease

The preclinical Alzheimer''s disease (AD) - amnestic mild cognitive impairment (MCI) - is manifested by phenotypes classified into exclusively memory (single-domain) MCI (sMCI) and multiple-domain MCI (mMCI). We suggest that typical MCI-to-AD progression occurs through the sMCI-to-mMCI sequence as a result of the extension of initial pathological processes. To support this hypothesis, we assess myelin content with a Magnetization Transfer Ratio (MTR) in 21 sMCI and 21 mMCI patients and in 42 age-, sex-, and education-matched controls. A conjunction analysis revealed MTR reduction shared by sMCI and mMCI groups in the medial temporal lobe and posterior structures including white matter (WM: splenium, posterior corona radiata) and gray matter (GM: hippocampus; parahippocampal and lingual gyri). A disjunction analysis showed the spread of demyelination to prefrontal WM and insula GM in executive mMCI. Our findings suggest that demyelination starts in the structures affected by neurofibrillary pathology; its presence correlates with the clinical picture and indicates the method of MCI-to-AD progression. In vivo staging of preclinical AD can be developed in terms of WM/GM demyelination.     

Catecholamine metabolism in children with Asperger’s and Kanner’s syndromes

In a stable state children with Asperger’s and Kanner’s syndromes demonstrate a similar decrease in plasma norepinephrine. In the aggravated state, these changes become more expressed and are characterized by a decrease in plasma tyrosine, norepinephrine, normetanephrine, and by an increase in dopamine and homovanillic acid and a decrease in excretion of norepinephrine and an increase in excretion of homovanillic acid, epinephrine and 3-methoxy-4-hydroxyphenylglycol (MHPG). In the aggravated state children with Kanner’s syndrome were characterized by increased plasma MHPG, decreased excretion of tyrosine and increased expression of normetanephrine. The observed imbalance in dopamine and epinephrine/norepinephrine systems suggests importance of combined analysis of changes in catecholamines and their metabolites as the most informative approach in the study of the effect of autistic disorders.     

Ubiquitin–proteasome system dysfunction in Parkinson’s disease: current evidence and controversies

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. Although a subject of intense research, the etiology of PD remains poorly understood. Over the last decade, the ubiquitin–proteasome system (UPS) has emerged as a compelling player in PD pathogenesis. Disruption of the UPS, which normally identifies and degrades intracellular proteins, is thought to promote the toxic accumulation of proteins detrimental to neuronal survival, thereby contributing to their demise. Support for this came from a broad range of studies, including genetics, gene profiling and post-mortem analysis, as well as in vitro and in vivo modeling. Notably, various cellular and animal models of PD based on direct disruption of UPS function reproduce the salient features of PD. However, several gaps remain in our current knowledge regarding the precise role of UPS dysfunction in the pathogenesis of the disease. Current thoughts regarding their relationship are reviewed here and some major unresolved questions, the clarification of which would considerably advance our understanding of the implicated role of the UPS in PD pathogenesis, are discussed.     

Lyme Disease Associated with Alzheimer’s Disease

This case report discusses a patient with co-occurring neuroborreliosis and Alzheimer’s disease (AD). Although no claim is made for causality nor is there objective evidence that spirochetes are involved in AD, co-infection may exacerbate the symptoms of either neuroborreliosis or AD. Much is to be learned about the role of spirochetes in degenerative central nervous system disease.     

Piloty’s acid derivative with improved nitroxyl-releasing characteristics

Recent studies have shown that nitroxyl (HNO) (¹HNO/³NO^?), which is the one-electron-reduced form of nitric oxide (NO), has unique biological activities, especially in the cardiovascular system, and HNO-releasing agents may have therapeutic potential. Since few HNO donors are available for use under physiological conditions, we synthesized and evaluated a series of Piloty’s acid (PA) derivatives and evaluated their HNO-releasing activity under physiological conditions. N-Hydroxy-2-nitrobenzenesulfonamide (17) was the most efficient HNO donor among our synthesized PA derivatives, including the lead compound, 2-bromo-N-hydroxybenzenesulfonamide (2). The high HNO-releasing activity is suggested to be due to electronic and steric effects. Compound 17 may be a useful tool for biological experiments.     

Travelling with tea: a Tuckerella’s tale

Tuckerella japonica Ehara appears strongly associated with tea (Camellia sinensis (L.) Kuntze, Theaceae) and, due to certain cultural practices in tea production, has in fact become a world traveller, accompanying the greatly coveted tea plant as it spread across the planet. The history of tea production and culture, and its arrival in the USA, provides the backdrop for this traveller’s tale. Tuckerella japonica is morphologically similar to T. flabellifera Miller, described from Tasmania in Australia from Bedfordia salicina (Labill.) D.G. (Asteraceae). These two species have historically been misidentified as each other, creating inaccuracies in the collection records. The implications of this in terms of host plant lists and world distribution are discussed further, along with their morphological separation. The male and immature stages of T. japonica are described for the first time. Tuckerella xinglongensis Lin and Fu, from tea in China, is considered a junior synonym of T. japonica. The loss of the ancestral prostigmatan condition of three nymphal stages during ontogeny is confirmed for males of T. flabellifera, which do not retain a tritonymphal stage.     

Do People Use the Shortest Path? An Empirical Test of Wardrop’s First Principle

Most recent route choice models, following either the random utility maximization or rule-based paradigm, require explicit enumeration of feasible routes. The quality of model estimation and prediction is sensitive to the appropriateness of the consideration set. However, few empirical studies of revealed route characteristics have been reported in the literature. This study evaluates the widely applied shortest path assumption by evaluating routes followed by residents of the Minneapolis—St. Paul metropolitan area. Accurate Global Positioning System (GPS) and Geographic Information System (GIS) data were employed to reveal routes people used over an eight to thirteen week period. Most people did not choose the shortest path. Using three weeks of that data, we find that current route choice set generation algorithms do not reveal the majority of paths that individuals took. Findings from this study may guide future efforts in building better route choice models.     

Structures of REV1 UBM2 Domain Complex with Ubiquitin and with a Small-Molecule that Inhibits the REV1 UBM2–Ubiquitin Interaction

REV1 is a DNA damage tolerance protein and encodes two ubiquitin-binding motifs (UBM1 and UBM2) that are essential for REV1 functions in cell survival under DNA-damaging stress. Here we report the first solution and X-ray crystal structures of REV1 UBM2 and its complex with ubiquitin, respectively. Furthermore, we have identified the first small-molecule compound, MLAF50, that directly binds to REV1 UBM2. In the heteronuclear single quantum coherence NMR experiments, peaks of UBM2 but not of UBM1 are significantly shifted by the addition of ubiquitin, which agrees to the observation that REV1 UBM2 but not UBM1 is required for DNA damage tolerance. REV1 UBM2 interacts with hydrophobic residues of ubiquitin such as L8 and L73. NMR data suggest that MLAF50 binds to the same residues of REV1 UBM2 that interact with ubiquitin, indicating that MLAF50 can compete with the REV1 UBM2–ubiquitin interaction orthosterically. Indeed, MLAF50 inhibited the interaction of REV1 UBM2 with ubiquitin and prevented chromatin localization of REV1 induced by cisplatin in U2OS cells. Our results structurally validate REV1 UBM2 as a target of a small-molecule inhibitor and demonstrate a new avenue to targeting ubiquitination-mediated protein interactions with a chemical tool.     

Associational resistance for mule’s ears with sagebrush neighbors

Many examples of associational resistance have been reported, in which a plant’s neighbors reduce the rate of damage by herbivores that it experiences. Despite 30 years of interest and hundreds of examples of associational resistance, we still know very little about how plants avoid their herbivores. This lack of mechanistic understanding prevents us from predicting when or where associational resistance will be important or might affect species’ distributions. I demonstrate here that the plant neighborhoods that surrounded focal mule’s ears (Wyethia mollis) individuals affected the damage they received. In particular, distance between a focal mule’s ears individual and its nearest sagebrush neighbor (Artemisia tridentata) was a good predictor of how much leaf area the mule’s ears would lose to herbivores over 2 years. Mule’s ears close to sagebrush suffered less loss than those with more distant nearest sagebrush neighbors. Mule’s ears with near sagebrush neighbors suffered half the leaf loss as mule’s ears with sagebrush experimentally removed. This associational resistance was probably not caused by sagebrush attracting or increasing populations of predators of generalist herbivores. Sagebrush is known to emit chemicals that are feeding deterrents to generalist grasshoppers and these deterrents were probably involved here. Volatile chemicals emitted by damaged sagebrush have been found to induce resistance in neighboring plants of several species. However, I found no evidence for such eavesdropping here as mule’s ears gained associational resistance from sagebrush neighbors whether or not those sagebrush neighbors had been experimentally damaged. Understanding the mechanisms responsible for associational resistance is critical to predicting where and when it will be important.