Introduction of d-Glutamate at a Critical Residue of Aβ42 Stabilizes a Prefibrillary Aggregate with Enhanced Toxicity.

The amyloid beta peptide 42 (Aβ42) is an aggregation-prone peptide that plays a pivotal role in Alzheimer's disease. We report that a subtle perturbation to the peptide through a single chirality change at glutamate 22 leads to a pronounced delay in the β-sheet adoption of the peptide. This was accompanied by an attenuated propensity of the peptide to form fibrils, which was correlated with changes at the level of the fibrillary architecture. Strikingly, the incorporation of d-glutamate was found to stabilize a soluble, ordered macromolecular assembly with enhanced cytotoxicity to PC12 cells, highlighting the importance of advanced prefibrillary Aβ aggregates in neurotoxicity

Factors contributing to the distress, concerns, and needs of UK Neuroscience health care workers during the COVID-19 pandemic

COVID‐19 research from China suggests health care workers are at risk of distress, have specific concerns, and need support. It remains unknown whether findings are applicable to UK health care staff and whether psychological support based on generic approaches is effective. We administered an online survey at a leading neuroscience hospital in the UK to examine how individual staff characteristics contribute to distress, concerns, and interventions most valued during the COVID‐19 pandemic. We found a high incidence of distress, particularly in females and staff with previous mental health history. Concerns fell into three factors: ‘risk of infection’, ‘work challenges’, and ‘social change’, and were affected by professional role and contact with COVID‐19 patients. These three factors predicted distress. Psychological support and clear updates were deemed most useful, with specific needs affected by age, professional role, and contact with COVID‐19 patients. This is the first documentation of a high incidence of psychological distress predicted by three types of concerns in health care workers of a neuroscience hospital. Distress, concerns, and interventions most valued were all affected by individual staff characteristics. These findings highlight the importance of providing stratified, one to one support interventions, tailored to professional group, and background, rather than more generic approaches

In vitro efficacy of tavaborole topical solution, 5% after penetration through nail polish on ex vivo human fingernails

This document is the Accepted Manuscript of the following article: Aditya K. Gupta, et al, 'In vitro efficacy of tavaborole topical solution, 5% after penetration through nail polish on ex vivo human fingernails', Journal of Dermatological Treatment, Jan 2018. Under embargo until 10 January 2019. The final, published version is available online at doi: https://doi.org/10.1080/09546634.2017.1422078.Background: Topical antifungal treatments for onychomycosis are applied to clean, unpolished nails for 48 weeks or longer. Patients often wish to mask their infection with nail polish yet there is no evidence to suggest antifungal efficacy in the presence of nail polish. Objective: To determine if tavaborole retains the ability to penetrate the nail plate and inhibit fungal growth in the presence of nail polish. Method: Tavaborole was applied to human fingernails painted with 2 or 4 coats of nail polish, and unpainted nails in an ex vivo model. Nails were mounted on TurChub ® chambers seeded with Trichophyton rubrum and allowed to incubate for 7 days. Antifungal activity was assessed by measuring zones of inhibition. Results and conclusion: Tavaborole exhibited antifungal activity in all experimental groups. The zones of inhibition of T. rubrum for all experimental groups (2 or 4 coats of polish, unpolished) were greater than infected controls (polished and unpolished), p s <.001. Tavaborole penetrates polished nails and kills T. rubrum in this ex vivo model.Peer reviewe

Dual task performance in Parkinson's disease

Several studies have found dual tasking to be impaired in Alzheimer’s disease (AD), but unaffected by healthy ageing. It is not known if this deficit is specific to AD, or also present in other neurodegenerative disorders that can occur in later life, such as Parkinson’s disease (PD). Therefore, this study investigated dual tasking in 13 people with PD, 26 AD and 42 healthy age-matched controls. The people with AD demonstrated a specific impairment in dual tasking, which worsened with increasing disease severity. The people with PD did not demonstrate any deficits in dual tasking ability, when compared to healthy controls, suggesting that the dual task impairment is specific to AD

Novel clinicopathological characteristics differentiate dementia with Lewy bodies from Parkinson's disease dementia

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) known as Lewy body dementias have overlapping clinical and neuropathological features. Neuropathology in both includes combination of Lewy body and Alzheimer's disease (AD) pathology. Cerebral amyloid angiopathy (CAA), often seen in AD, is increasingly recognised for its association with dementia. AIMS: This study investigated clinical and neuropathological differences between DLB and PDD. METHODS: 52 PDD and 16 DLB cases from the Queen Square Brain Bank (QSBB) for Neurological disorders were included. Comprehensive clinical data of motor and cognitive features were obtained from medical records. Neuropathological assessment included examination of CAA, Lewy body and AD pathology. RESULTS: CAA was more common in DLB than in PDD (p = 0.003). The severity of CAA was greater in DLB than in PDD (p = 0.009), with significantly higher CAA scores in the parietal lobe (p = 0.043), and the occipital lobe (p = 0.008), in DLB than in PDD. The highest CAA scores were observed in cases with APOE ε4/4 and ε2/4. Survival analysis showed worse prognosis in DLB, as DLB reached each clinical milestone sooner than PDD. Absence of dyskinesia in DLB is linked to the significantly lower lifetime cumulative dose of levodopa in comparison with PDD. CONCLUSIONS: This is the first study which identified prominent concurrent CAA pathology as a pathological substrate of DLB. More prominent CAA and rapid disease progression as measured by clinical milestones distinguish DLB from PDD

The Underestimation Of Egocentric Distance: Evidence From Frontal Matching Tasks

There is controversy over the existence, nature, and cause of error in egocentric distance judgments. One proposal is that the systematic biases often found in explicit judgments of egocentric distance along the ground may be related to recently observed biases in the perceived declination of gaze (Durgin & Li, Attention, Perception, & Psychophysics, in press), To measure perceived egocentric distance nonverbally, observers in a field were asked to position themselves so that their distance from one of two experimenters was equal to the frontal distance between the experimenters. Observers placed themselves too far away, consistent with egocentric distance underestimation. A similar experiment was conducted with vertical frontal extents. Both experiments were replicated in panoramic virtual reality. Perceived egocentric distance was quantitatively consistent with angular bias in perceived gaze declination (1.5 gain). Finally, an exocentric distance-matching task was contrasted with a variant of the egocentric matching task. The egocentric matching data approximate a constant compression of perceived egocentric distance with a power function exponent of nearly 1; exocentric matches had an exponent of about 0.67. The divergent pattern between egocentric and exocentric matches suggests that they depend on different visual cues

Size constancy in bat biosonar?

Perception and encoding of object size is an important feature of sensory systems. In the visual system object size is encoded by the visual angle (visual aperture) on the retina, but the aperture depends on the distance of the object. As object distance is not unambiguously encoded in the visual system, higher computational mechanisms are needed. This phenomenon is termed "size constancy". It is assumed to reflect an automatic re-scaling of visual aperture with perceived object distance. Recently, it was found that in echolocating bats, the 'sonar aperture', i.e., the range of angles from which sound is reflected from an object back to the bat, is unambiguously perceived and neurally encoded. Moreover, it is well known that object distance is accurately perceived and explicitly encoded in bat sonar. Here, we addressed size constancy in bat biosonar, recruiting virtual-object techniques. Bats of the species Phyllostomus discolor learned to discriminate two simple virtual objects that only differed in sonar aperture. Upon successful discrimination, test trials were randomly interspersed using virtual objects that differed in both aperture and distance. It was tested whether the bats spontaneously assigned absolute width information to these objects by combining distance and aperture. The results showed that while the isolated perceptual cues encoding object width, aperture, and distance were all perceptually well resolved by the bats, the animals did not assign absolute width information to the test objects. This lack of sonar size constancy may result from the bats relying on different modalities to extract size information at different distances. Alternatively, it is conceivable that familiarity with a behaviorally relevant, conspicuous object is required for sonar size constancy, as it has been argued for visual size constancy. Based on the current data, it appears that size constancy is not necessarily an essential feature of sonar perception in bats

Biophysical suitability, economic pressure and land-cover change: a global probabilistic approach and insights for REDD+

There has been a concerted effort by the international scientific community to understand the multiple causes and patterns of land-cover change to support sustainable land management. Here, we examined biophysical suitability, and a novel integrated index of “Economic Pressure on Land” (EPL) to explain land cover in the year 2000, and estimated the likelihood of future land-cover change through 2050, including protected area effectiveness. Biophysical suitability and EPL explained almost half of the global pattern of land cover (R 2 = 0.45), increasing to almost two-thirds in areas where a long-term equilibrium is likely to have been reached (e.g. R 2 = 0.64 in Europe). We identify a high likelihood of future land-cover change in vast areas with relatively lower current and past deforestation (e.g. the Congo Basin). Further, we simulated emissions arising from a “business as usual” and two reducing emissions from deforestation and forest degradation (REDD) scenarios by incorporating data on biomass carbon. As our model incorporates all biome types, it highlights a crucial aspect of the ongoing REDD + debate: if restricted to forests, “cross-biome leakage” would severely reduce REDD + effectiveness for climate change mitigation. If forests were protected from deforestation yet without measures to tackle the drivers of land-cover change, REDD + would only reduce 30 % of total emissions from land-cover change. Fifty-five percent of emissions reductions from forests would be compensated by increased emissions in other biomes. These results suggest that, although REDD + remains a very promising mitigation tool, implementation of complementary measures to reduce land demand is necessary to prevent this leakage

Sosa on Knowledge, Judgment and Guessing

In Chapter 3 of Judgment and Agency, Sosa (Judgment and Agency, 2015) explicates the concept of a fully apt performance. In the course of doing so, he draws from illustrative examples of practical performances and applies lessons drawn to the case of cognitive performances, and in particular, to the cognitive performance of judging. Sosa’s examples in the practical sphere are rich and instructive. But there is, I will argue, an interesting disanalogy between the practical and cognitive examples he relies on. Ultimately, I think the source of the disanalogy is a problematic picture of the cognitive performance of guessing and its connection to knowledge and defeat. Once this critical line of argument is advanced, an alternative picture of guessing, qua cognitive performance, is articulated, one which avoids the problems discussed, and yet remains compatible with Sosa’s broader framework