Alzheimer's disease pathology:pathways between central norepinephrine activity, memory, and neuropsychiatric symptoms

The locus coeruleus (LC) supplies norepinephrine to the brain, is one of the first sites of tau deposition in Alzheimer's disease (AD) and modulates a variety of behaviors and cognitive functions. Transgenic mouse models showed that norepinephrine dysregulation after LC lesions exacerbates inflammatory responses, blood-brain barrier leakage (BBB), and cognitive deficits. Here, we investigated relationships between central norepinephrine metabolism, tau and beta-amyloid (Aβ), inflammation, BBB-dysfunction, neuropsychiatric problems, and memory in-vivo in a memory clinic population (total n = 111, 60 subjective cognitive decline, 36 mild cognitively impaired, and 19 AD dementia). Cerebrospinal fluid (CSF) and blood samples were collected and analyzed for 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), CSF/plasma albumin ratio (Q-alb), Aβ, phosphorylated tau, and interleukins. The verbal word learning task and the neuropsychiatric inventory assessed memory functioning and neuropsychiatric symptoms. Structural equation models tested the relationships between all fluid markers, cognition and behavior, corrected for age, education, sex, and clinical dementia rating score. Our results showed that neuropsychiatric symptoms show strong links to both MHPG and p-tau, whereas memory deficits are linked to MHPG via a combination of p-tau and inflammation-driven amyloidosis (30-35% indirect effect contribution). These results suggest that the LC-norepinephrine may be pivotal to understand links between AD pathology and behavioral and cognitive deficits in AD

Investigation of metastable zones and induction times in glycine crystallisation across three different antisolvents

Experimental data on the effects that different antisolvents and antisolvent addition strategies have on nucleation behavior in antisolvent crystallization is very limited, and our understanding of these effects is sparse. In this work we measured the metastable zone width for the isothermal antisolvent crystallization of glycine from water utilizing methanol, ethanol, and dimethylformamide as antisolvents. We then investigated induction times for glycine crystallization across these metastable zones using the same three antisolvents. Supersaturated solutions were prepared by mixing of an antisolvent with undersaturated aqueous glycine solutions, either by batch rapid addition or using a continuous static mixer. Induction times were then recorded under agitated isothermal conditions in small vials with the use of webcam imaging and vary from apparently instant to thousands of seconds over a range of compositions and different mixing modes. Well-defined induction times were detected across most of the metastable zone, which shows that primary nucleation is significant at supersaturations much lower than those identified in conventional metastable zone width measurements. As supersaturation increases toward the metastable zone limit, crystal growth and secondary nucleation are likely to become rate-limiting factors in the observed induction times for antisolvent crystallization. Furthermore, the observed induction times were strongly dependent on the mode of mixing (batch rapid addition vs continuous static mixing), which demonstrates an interplay of antisolvent effects on nucleation with their effects on mixing, leading to crossover of mixing and nucleation time scales. This shows that appropriate mixing strategies are crucial for the rational development of robust scalable antisolvent crystallization processes

Trajectories and Determinants of Quality of Life in Dementia with Lewy Bodies and Alzheimer's Disease

Background: Quality of Life (QoL) is an important outcome measure in dementia, particularly in the context of interventions. Research investigating longitudinal QoL in dementia with Lewy bodies (DLB) is currently lacking. Objective: To investigate determinants and trajectories of QoL in DLB compared to Alzheimer’s disease (AD) and controls. Methods: QoL was assessed annually in 138 individuals, using the EQ5D-utility-score (0–100) and the health-related Visual Analogue Scale (VAS, 0–100). Twenty-nine DLB patients (age 69 ± 6), 68 AD patients (age 70 ± 6), and 41 controls (age 70 ± 5) were selected from the Dutch Parelsnoer Institute-Neurodegenerative diseases and Amsterdam Dementia Cohort. We examined clinical work-up over time as determinants of QoL, including cognitive tests, neuropsychiatric inventory, Geriatric Depression Scale (GDS), and disability assessment of dementia (DAD). Results: Mixed models showed lower baseline VAS-scores in DLB compared to AD and controls (AD: ±SE = -7.6 ± 2.8, controls: ±SE = -7.9 ± 3.0, p < 0.05). An interaction between diagnosis and time since diagnosis indicated steeper decline on VAS-scores for AD patients compared to DLB patients (±SE = 2.9 ± 1.5, p < 0.1). EQ5D-utility-scores over time did not differ between groups. Higher GDS and lower DAD-scores were independently associated with lower QoL in dementia patients (GDS: VAS ±SE = -1.8 ± 0.3, EQ5D-utility ±SE = -3.7 ± 0.4; DAD: VAS = 0.1 ± 0.0, EQ5D-utility ±SE = 0.1 ± 0.1, p < 0.05). No associations between cognitive tests and QoL remained in the multivariate model. Conclusion: QoL is lower in DLB, while in AD QoL shows steepe

Interplay between chromophore binding and domain assembly by the B₁₂-dependent photoreceptor protein, CarH.

From Europe PMC via Jisc Publications RouterHistory: ppub 2021-05-01, epub 2021-05-05Publication status: PublishedFunder: Biotechnology and Biological Sciences Research Council; Grant(s): BB/L002655/1, BB/L016486/1, BB/M011208/1Organisms across the natural world respond to their environment through the action of photoreceptor proteins. The vitamin B12-dependent photoreceptor, CarH, is a bacterial transcriptional regulator that controls the biosynthesis of carotenoids to protect against photo-oxidative stress. The binding of B12 to CarH monomers in the dark results in the formation of a homo-tetramer that complexes with DNA; B12 photochemistry results in tetramer dissociation, releasing DNA for transcription. Although the details of the response of CarH to light are beginning to emerge, the biophysical mechanism of B12-binding in the dark and how this drives domain assembly is poorly understood. Here - using a combination of molecular dynamics simulations, native ion mobility mass spectrometry and time-resolved spectroscopy - we reveal a complex picture that varies depending on the availability of B12. When B12 is in excess, its binding drives structural changes in CarH monomers that result in the formation of head-to-tail dimers. The structural changes that accompany these steps mean that they are rate-limiting. The dimers then rapidly combine to form tetramers. Strikingly, when B12 is scarcer, as is likely in nature, tetramers with native-like structures can form without a B12 complement to each monomer, with only one apparently required per head-to-tail dimer. We thus show how a bulky chromophore such as B12 shapes protein/protein interactions and in turn function, and how a protein can adapt to a sub-optimal availability of resources. This nuanced picture should help guide the engineering of B12-dependent photoreceptors as light-activated tools for biomedical applications

Dyrk1A Influences Neuronal Morphogenesis Through Regulation of Cytoskeletal Dynamics in Mammalian Cortical Neurons

Down syndrome (DS) is the most frequent genetic cause of mental retardation. Cognitive dysfunction in these patients is correlated with reduced dendritic branching and complexity, along with fewer spines of abnormal shape that characterize the cortical neuronal profile of DS. DS phenotypes are caused by the disruptive effect of specific trisomic genes. Here, we report that overexpression of dual-specificity tyrosine phosphorylation-regulated kinase 1A, DYRK1A, is sufficient to produce the dendritic alterations observed in DS patients. Engineered changes in Dyrk1A gene dosage in vivo strongly alter the postnatal dendritic arborization processes with a similar progression than in humans. In cultured mammalian cortical neurons, we determined a reduction of neurite outgrowth and synaptogenesis. The mechanism underlying neurite dysgenesia involves changes in the dynamic reorganization of the cytoskeleton

Experimental observation of nanophase segregation of aqueous salt solutions around the predicted liquid-liquid transition in water

The liquid-liquid transition in supercooled liquid water, predicted to occur around 220 K, is controversial due to the difficulty of studying it caused by competition from ice crystallization (the so-called “no man’s land”). In aqueous solutions, it has been predicted to give rise to phase separation on a nanometer scale between a solute-rich high-density phase and a water-rich low-density phase. Here we report direct experimental evidence for the formation of a nanosegregated phase in eutectic aqueous solutions of LiCl and LiSCN where the presence of crystalline water can be experimentally excluded. Femtosecond infrared and Raman spectroscopies are used to determine the temperature-dependent structuring of water, the solvation of the SCN- anion, and the size of the phase segregated domains

Interval post-colonoscopy colorectal cancer following a negative colonoscopy in a fecal immunochemical test-based screening program

Background In the Dutch colorectal (CRC) screening program, fecal immunochemical test (FIT)-positive individuals are referred for colonoscopy. If no relevant findings are detected at colonoscopy, individuals are reinvited for FIT screening after 10 years. We aimed to assess CRC risk after a negative colonoscopy in FIT-positive individuals. Methods In this cross-sectional cohort study, data were extracted from the Dutch national screening information system. Participants with a positive FIT followed by a negative colonoscopy between 2014 and 2018 were included. A negative colonoscopy was defined as a colonoscopy during which no more than one nonvillous, nonproximal adenoma &lt; 10mm or serrated polyp &lt; 10mm was found. The main outcome was interval post-colonoscopy CRC (iPCCRC) risk. iPCCRC risk was reviewed against the risk of interval CRC after a negative FIT (FIT IC) with a 2-year screening interval. Results 35 052 FIT-positive participants had a negative colonoscopy and 24 iPCCRCs were diagnosed, resulting in an iPCCRC risk of 6.85 (95%CI 4.60-10.19) per 10 000 individuals after a median follow-up of 1.4 years. After 2.5 years of follow-up, age-adjusted iPCCRC risk was approximately equal to FIT IC risk at 2 years. Conclusion Risk of iPCCRC within a FIT-based CRC screening program was low during the first years after colonoscopy but, after 2.5 years, was the same as the risk in FITnegative individuals at 2 years, when they are reinvited for screening. Colonoscopy quality may therefore require further improvement and FIT screening interval may need to be reduced after negative colonoscopy.</p

Analysis of Locally Coupled 3D Manipulation Mappings Based on Mobile Device Motion

We examine a class of techniques for 3D object manipulation on mobile devices, in which the device's physical motion is applied to 3D objects displayed on the device itself. This "local coupling" between input and display creates specific challenges compared to manipulation techniques designed for monitor-based or immersive virtual environments. Our work focuses specifically on the mapping between device motion and object motion. We review existing manipulation techniques and introduce a formal description of the main mappings under a common notation. Based on this notation, we analyze these mappings and their properties in order to answer crucial usability questions. We first investigate how the 3D objects should move on the screen, since the screen also moves with the mobile device during manipulation. We then investigate the effects of a limited range of manipulation and present a number of solutions to overcome this constraint. This work provides a theoretical framework to better understand the properties of locally-coupled 3D manipulation mappings based on mobile device motion