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"Moffat, D"
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Aging and Spatial Navigation: What Do We Know and Where Do We Go?
Spatial navigation is a complex cognitive skill that is necessary for everyday functioning in the environment. However, navigational skills are not typically measured in most test batteries assessing cognitive aging. The present paper reviews what we know about behavioral differences between older and younger adults in navigational skill and reviews the putative neural mechanisms that may underlie these behavioral differences. Empirical studies to date clearly identify navigation as an aspect of cognitive function that is vulnerable to the aging process. The few functional and structural neuroimaging studies that speak to neurological correlates of these age-related differences point to the hippocampus, parahippocampal gyrus, posterior cingulate gyrus (retrosplenial cortex), parietal lobes and pre-frontal cortex as structures critically involved in age effects on navigation. Outstanding issues in the field are addressed and productive avenues of future research are suggested. Among these outstanding issues include the necessity of performing longitudinal studies and differentiating between hippocampal and extra-hippocampal contributions to aging in navigation. The field may also be advanced by empirical assessment of navigational strategies and investigations into the multisensory nature of navigation including assessing the relative contributions of visual, vestibular, and proprioceptive function to age differences in navigational skill.
Journal Article
Antitumor activity of a small-molecule inhibitor of the histone kinase Haspin
The approval of histone deacetylase inhibitors for treatment of lymphoma subtypes has positioned histone modifications as potential targets for the development of new classes of anticancer drugs. Histones also undergo phosphorylation events, and Haspin is a protein kinase the only known target of which is phosphorylation of histone H3 at Thr3 residue (H3T3ph), which is necessary for mitosis progression. Mitotic kinases can be blocked by small drugs and several clinical trials are underway with these agents. As occurs with Aurora kinase inhibitors, Haspin might be an optimal candidate for the pharmacological development of these compounds. A high-throughput screening for Haspin inhibitors identified the CHR-6494 compound as being one promising such agent. We demonstrate that CHR-6494 reduces H3T3ph levels in a dose-dependent manner and causes a mitotic catastrophe characterized by metaphase misalignment, spindle abnormalities and centrosome amplification. From the cellular standpoint, the identified small-molecule Haspin inhibitor causes arrest in G2/M and subsequently apoptosis. Importantly,
ex vivo
assays also demonstrate its anti-angiogenetic features;
in vivo
, it shows antitumor potential in xenografted nude mice without any observed toxicity. Thus, CHR-6494 is a first-in-class Haspin inhibitor with a wide spectrum of anticancer effects that merits further preclinical research as a new member of the family of mitotic kinase inhibitors.
Journal Article
Extrahippocampal Contributions to Age-Related Changes in Spatial Navigation Ability
Age-related decline in spatial navigation is well-known and the extant literature emphasizes the important contributions of a hippocampus-dependent spatial navigation system in mediating this decline. However, navigation is a multifaceted cognitive domain and some aspects of age-related navigational decline may be mediated by extrahippocampal brain regions and/or systems. The current review presents an overview of some key cognitive domains that contribute to the age-related changes in spatial navigation ability, and elucidates such domains in the context of an increased engagement of navigationally relevant extrahippocampal brain regions with advancing age. Specifically, this review focuses on age-related declines in three main areas: (i) allocentric strategy use and switching between egocentric and allocentric strategies, (ii) associative learning of landmarks/locations and heading directions, and (iii) executive functioning and attention. Thus far, there is accumulating neuroimaging evidence supporting the functional relevance of the striatum for egocentric/response strategy use in older adults, and of the prefrontal cortex for mediating executive functions that contribute to successful navigational performance. Notably, the functional role of the prefrontal cortex was particularly emphasized via the proposed relevance of the fronto-locus coeruleus noradrenergic system for strategy switching and of the fronto-hippocampal circuit for landmark-direction associative learning. In view of these putative prefrontal contributions to navigation-related functions, we recommend future spatial navigation studies to adopt a systems-oriented approach that investigates age-related alterations in the interaction between the prefrontal cortex, the hippocampus, and extrahippocampal regions, as well as an individual differences approach that clarifies the differential engagement of prefrontal executive processes among older adults.
Journal Article
Cardiorespiratory fitness is associated with fMRI signal in right cerebellum lobule VIIa Crus I and II during spatial navigation in older adult women
Spatial navigation is a cognitive skill critical for accomplishing daily goal-directed behavior in a complex environment; however, older adults exhibit marked decline in navigation performance with age. Neuroprotective interventions that enhance the functional integrity of navigation-linked brain regions, such as those in the medial temporal lobe memory system, may preserve spatial navigation performance in older adults. Importantly, a well-established body of literature suggests that cardiorespiratory fitness has measurable effects on neurobiological integrity in the medial temporal lobes, as well as in other brain areas implicated in spatial navigation, such as the precuneus and cerebellum. However, whether cardiorespiratory fitness modulates brain activity in these regions during navigation in older adults remains unknown. Thus, the primary objective of the current study was to examine cardiorespiratory fitness as a modulator of fMRI activity in navigation-linked brain regions in cognitively healthy older adults. To accomplish this objective, cognitively intact participants (N = 22, aged 60-80 years) underwent cardiorespiratory fitness testing to estimate maximal oxygen uptake (V̇O2max) and underwent whole-brain high-resolution fMRI while performing a virtual reality navigation task. Our older adult sample demonstrated significant fMRI signal in the right and left retrosplenial cortex, right precuneus, right and left inferior parietal cortex, right and left cerebellum lobule VIIa Crus I and II, right fusiform gyrus, right parahippocampal cortex, right lingual gyrus, and right hippocampus during encoding of a virtual environment. Most importantly, in women but not men (N = 16), cardiorespiratory fitness was positively associated with fMRI activity in the right cerebellum lobule VIIa Crus I and II, but not other navigation-linked brain areas. These findings suggest that the influence of cardiorespiratory fitness on brain function extends beyond the hippocampus, as observed in other work, to the cerebellum lobule VIIa Crus I and II, a component of the cerebellum that has recently been linked to cognition and more specifically, spatial processing.
Journal Article
Understanding the biosynthesis, metabolic regulation, and anti-phytopathogen activity of 3,7-dihydroxytropolone in Pseudomonas spp
Pseudomonas bacteria produce various potent chemicals that influence interactions in nature, such as metal-binding molecules, antibiotics, or plant hormones. This ability to synthesize bioactive molecules means that Pseudomonas bacteria may be useful as biological control agents to protect plants from agricultural pathogens, as well as a source of antibiotic candidates. We have identified a plant-associated Pseudomonas strain that can produce 3,7-dihydroxytropolone, which has broad biological activity and can inhibit the growth of Streptomyces scabies , a bacterium that causes potato scab. Following the identification of this molecule, we used a combination of genetic, chemical, and biochemical experiments to identify key steps in the production of tropolones in Pseudomonas species. Understanding this biosynthetic process led to the discovery of an array of diverse pathways that we predict will produce new tropolone-like molecules. This work should also help us shed light on the natural function of antibiotics in nature.
Journal Article
Management of lateral skull base cancer: United Kingdom National Multidisciplinary Guidelines
This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. It provides recommendations on the work up and management of lateral skull base cancer based on the existing evidence base for this rare condition.
Journal Article
Aryl hydrocarbon receptor (AHR)-regulated transcriptomic changes in rats sensitive or resistant to major dioxin toxicities
Background
The major toxic effects of 2,3,7,8-tetrachlorodibenzo-
p
-dioxin (TCDD) appear to result from dysregulation of mRNA levels mediated by the aryl hydrocarbon receptor (AHR). Dioxin-like chemicals alter expression of numerous genes in liver, but it remains unknown which lie in pathways leading to major toxicities such as hepatotoxicity, wasting and lethality. To identify genes involved in these responses we exploited a rat genetic model. Rats expressing an AHR splice-variant lacking a portion of the transactivation domain are highly resistant to dioxin-induced toxicities. We examined changes in hepatic mRNA abundances 19 hours after TCDD treatment in two dioxin-resistant rat strains/lines and two dioxin-sensitive rat strains/lines.
Results
Resistant rat strains/lines exhibited fewer transcriptional changes in response to TCDD than did rats with wildtype AHR. However, well-known AHR-regulated and dioxin-inducible genes such as
CYP1A1
,
CYP1A2
, and
CYP1B1
remained fully responsive to TCDD in all strains/lines. Pathway analysis indicated that the genes which respond differently to TCDD between sensitive and resistant rats are mainly involved in lipid metabolism, cellular membrane function and energy metabolism. These pathways previously have been shown to respond differently to dioxin treatment in dioxin-sensitive versus dioxin-resistant rats at a biochemical level and in the differential phenotype of toxicologic responses.
Conclusion
The transactivation-domain deletion in dioxin-resistant rats does not abolish global AHR transactivational activity but selectively interferes with expression of subsets of genes that are candidates to mediate or protect from major dioxin toxicities such as hepatotoxicity, wasting and death.
Journal Article
Reproductive limitation mediates the response of white spruce (Picea glauca) to climate warming across the forest–tundra ecotone
Shifts in the extent of the boreal forest during past warm intervals and correlations between climate and the position of the forest–tundra ecotone suggest that recent temperature increases will facilitate forest expansion into tundra ecosystems. In this study, we used a unique set of high-resolution repeat photographs to characterize white spruce (Picea glauca (Moench) Voss) populations in 1980 and 2015 at 52 sites across the forest–tundra transition in the Northwest Territories, Canada. We also conducted field inventories at eight sites to examine mapping accuracy, construct age distributions, and assess cone production and seed viability. Our analysis shows that stand density in the forest–tundra has increased significantly since 1980 but that the density of spruce at sites in the tundra has not changed. Age distributions constructed from field sampling also indicate that recent recruitment has occurred in the forest–tundra but not at tundra sites. The nonlinear relationship between summer temperature and seed viability suggests that recent warming has facilitated recruitment in the northern Subarctic but that cold temperatures still limit recruitment at higher latitude tundra sites. Additional research to determine the extent of changes in forest density across the northern Subarctic should be conducted to determine if similar changes are occurring across this ecotone.
Journal Article
