Altered sleep and neurovascular dysfunction in alpha-synucleinopathies: the perfect storm for glymphatic failure

Clinical and cognitive progression in alpha-synucleinopathies is highly heterogeneous. While some patients remain stable over long periods of time, other suffer early dementia or fast motor deterioration. Sleep disturbances and nocturnal blood pressure abnormalities have been identified as independent risk factors for clinical progression but a mechanistic explanation linking both aspects is lacking. We hypothesize that impaired glymphatic system might play a key role on clinical progression. Glymphatic system clears brain waste during specific sleep stages, being blood pressure the motive force that propels the interstitial fluid through brain tissue to remove protein waste. Thus, the combination of severe sleep alterations, such as REM sleep behavioral disorder, and lack of the physiological nocturnal decrease of blood pressure due to severe dysautonomia may constitute the perfect storm for glymphatic failure, causing increased abnormal protein aggregation and spreading. In Lewy body disorders (Parkinson’s disease and dementia with Lewy bodies) the increment of intraneuronal alpha-synuclein and extracellular amyloid-β would lead to cognitive deterioration, while in multisystemic atrophy, increased pathology in oligodendroglia would relate to the faster and malignant motor progression. We present a research model that may help in developing studies aiming to elucidate the role of glymphatic function and associated factors mainly in alpha-synucleinopathies, but that could be relevant also for other protein accumulation-related neurodegenerative diseases. If the model is proven to be useful could open new lines for treatments targeting glymphatic function (for example through control of nocturnal blood pressure) with the objective to ameliorate cognitive and motor progression in alpha-synucleinopathies

Effect of display resolution on time to diagnosis with virtual pathology slides in a systematic search task

Performing diagnoses using virtual slides can take pathologists significantly longer than with glass slides, presenting a significant barrier to the use of virtual slides in routine practice. Given the benefits in pathology workflow efficiency and safety that virtual slides promise, it is important to understand reasons for this difference and identify opportunities for improvement. The effect of display resolution on time to diagnosis with virtual slides has not previously been explored. The aim of this study was to assess the effect of display resolution on time to diagnosis with virtual slides. Nine pathologists participated in a counterbalanced crossover study, viewing axillary lymph node slides on a microscope, a 23-in 2.3-megapixel single-screen display and a three-screen 11-megapixel display consisting of three 27-in displays. Time to diagnosis and time to first target were faster on the microscope than on the single and three-screen displays. There was no significant difference between the microscope and the three-screen display in time to first target, while the time taken on the single-screen display was significantly higher than that on the microscope. The results suggest that a digital pathology workstation with an increased number of pixels may make it easier to identify where cancer is located in the initial slide overview, enabling quick location of diagnostically relevant regions of interest. However, when a comprehensive, detailed search of a slide has to be made, increased resolution may not offer any additional benefit

Simulating the Mammalian Blastocyst - Molecular and Mechanical Interactions Pattern the Embryo

Mammalian embryogenesis is a dynamic process involving gene expression and mechanical forces between proliferating cells. The exact nature of these interactions, which determine the lineage patterning of the trophectoderm and endoderm tissues occurring in a highly regulated manner at precise periods during the embryonic development, is an area of debate. We have developed a computational modeling framework for studying this process, by which the combined effects of mechanical and genetic interactions are analyzed within the context of proliferating cells. At a purely mechanical level, we demonstrate that the perpendicular alignment of the animal-vegetal (a-v) and embryonic-abembryonic (eb-ab) axes is a result of minimizing the total elastic conformational energy of the entire collection of cells, which are constrained by the zona pellucida. The coupling of gene expression with the mechanics of cell movement is important for formation of both the trophectoderm and the endoderm. In studying the formation of the trophectoderm, we contrast and compare quantitatively two hypotheses: (1) The position determines gene expression, and (2) the gene expression determines the position. Our model, which couples gene expression with mechanics, suggests that differential adhesion between different cell types is a critical determinant in the robust endoderm formation. In addition to differential adhesion, two different testable hypotheses emerge when considering endoderm formation: (1) A directional force acts on certain cells and moves them into forming the endoderm layer, which separates the blastocoel and the cells of the inner cell mass (ICM). In this case the blastocoel simply acts as a static boundary. (2) The blastocoel dynamically applies pressure upon the cells in contact with it, such that cell segregation in the presence of differential adhesion leads to the endoderm formation. To our knowledge, this is the first attempt to combine cell-based spatial mechanical simulations with genetic networks to explain mammalian embryogenesis. Such a framework provides the means to test hypotheses in a controlled in silico environment

Alignment between PIN1 Polarity and Microtubule Orientation in the Shoot Apical Meristem Reveals a Tight Coupling between Morphogenesis and Auxin Transport

Morphogenesis during multicellular development is regulated by intercellular signaling molecules as well as by the mechanical properties of individual cells. In particular, normal patterns of organogenesis in plants require coordination between growth direction and growth magnitude. How this is achieved remains unclear. Here we show that in Arabidopsis thaliana, auxin patterning and cellular growth are linked through a correlated pattern of auxin efflux carrier localization and cortical microtubule orientation. Our experiments reveal that both PIN1 localization and microtubule array orientation are likely to respond to a shared upstream regulator that appears to be biomechanical in nature. Lastly, through mathematical modeling we show that such a biophysical coupling could mediate the feedback loop between auxin and its transport that underlies plant phyllotaxis

CLINICAL FEATURES AND REASONS FOR THE PROGRESSION OF ISCHEMIC STROKE IN THE ACUTE PERIOD

We examined 663 patients who were admitted to the clinic by ambulance, for determine the factors of clinical deterioration and progression of ischemic stroke in the acute period of the first 24-72 hours. Among the patients received in the acute period, a fatal out come occurred in 7.23% (48) patients, men- 45.8% and women - 54.2%.At the time of admission to the hospital, almost 96.7% of patients with acute ischemic stroke had a disorder of consciousness from stunning to coma. The most significant risk factors for the development of ischemic stroke among 663 patients were arterial hypertension - 80.1%, chronic heartfailure - 57.9%, coronary heart disease - 25.5%, atrial fibrillation - 19.5%, type 2 diabetesmellitus 12.5%. In accordance with the international criteria of TOAST (1993), pathogenetic mechanisms of the development of isch- emic stroke have been determined in patients. Atherothrombotic stroke developed in 303 (45.7%), cardioembolic stroke in 185 (27.9%) patients, lacunar stroke in 167 (25.2%) patients, undefined genesis stroke in 8 (1.2%) patients.The progression of neurological deficiency in ischemic stroke is a bad prognostic factor

CLINICAL FEATURES AND REASONS FOR THE PROGRESSION OF ISCHEMIC STROKE IN THE ACUTE PERIOD

We examined 663 patients who were admitted to the clinic by ambulance, for determine the factors of clinical deterioration and progression of ischemic stroke in the acute period of the first 24-72 hours. Among the patients received in the acute period, a fatal out come occurred in 7.23% (48) patients, men- 45.8% and women - 54.2%.At the time of admission to the hospital, almost 96.7% of patients with acute ischemic stroke had a disorder of consciousness from stunning to coma. The most significant risk factors for the development of ischemic stroke among 663 patients were arterial hypertension - 80.1%, chronic heartfailure - 57.9%, coronary heart disease - 25.5%, atrial fibrillation - 19.5%, type 2 diabetesmellitus 12.5%. In accordance with the international criteria of TOAST (1993), pathogenetic mechanisms of the development of isch- emic stroke have been determined in patients. Atherothrombotic stroke developed in 303 (45.7%), cardioembolic stroke in 185 (27.9%) patients, lacunar stroke in 167 (25.2%) patients, undefined genesis stroke in 8 (1.2%) patients.The progression of neurological deficiency in ischemic stroke is a bad prognostic factor

Sleep/wake cycle alterations as a cause of neurodegenerative diseases: a Mendelian randomization study

Sleep and/or wake cycle alterations are common in neurodegenerative diseases (ND). Our aim was to determine whether there is a causal relationship between sleep and/or wake cycle patterns and ND (Parkinson's disease (PD) age at onset (AAO), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS)) using two-sample Mendelian Randomization (MR). We selected 12 sleep traits with available Genome-Wide Association Study (GWAS) to evaluate their causal relationship with the ND risk through Inverse-Variance Weighted regression as main analysis. We used as outcome the latest ND GWAS with available summary-statistics: PD-AAO (N = 17,996), AD (N = 21,235) and ALS (N = 40,136). MR results pointed to a causal effect of subjective and objective-measured morning chronotype on later PD-AAO (95%CI:0.33-1.81, p = 8.47×10−09 and 95%CI:-7.28 to -4.44, p = 5.87×10−16, respectively). Sleep efficiency was causally associated with a decreased AD risk (95%CI:-20.408 to -0.66, p = 0.04) and daytime sleepiness with an increased ALS risk (95%CI:0.15 to 1.61, p = 0.01). Our study suggests that sleep and/or wake patterns have causal relationship with ND. Given that sleep and/or wake patterns are modifiable risk factors, sleep interventions should be investigated as a potential treatment in PD-AAO, AD and ALS

Assessing proxy signatures of temperature, salinity, and hypoxia in the Baltic Sea through foraminifera-based geochemistry and faunal assemblages

We acknowledge funding through the Swedish Research Council (VR) (project no. 621-2011-5090), the German Research Council (project GR 3528/3-1), the Lamm Foundation, the Centre for Environmental and Climate Research at Lund University for Jeroen Groeneveld’s guest research stay, NERC grants NE4/G018502/1 and NE/G020310/1 to William E. N. Austin, and the University of Bremen for covering the article processing costs for this open-access publication.Current climate and environmental changes strongly affect shallow marine and coastal areas like the Baltic Sea. This has created a need for a context to understand the severity and potential outcomes of such changes. The context can be derived from paleoenvironmental records during periods when comparable events happened in the past. In this study, we explore how varying bottom water conditions across a large hydrographic gradient in the Baltic Sea affect benthic foraminiferal faunal assemblages and the geochemical composition of their calcite tests. We have conducted both morphological and molecular analyses of the faunas and we evaluate how the chemical signatures of the bottom waters are recorded in the tests of several species of benthic foraminifera. We focus on two locations, one in the Kattegat (western Baltic Sea) and one in Hano Bay (southern Baltic Sea). We show that seawater Mn/Ca, Mg/Ca, and Ba/Ca (Mn/Casw, Mg/Casw, and Ba/Casw) variations are mainly controlled by dissolved oxygen concentration and salinity. Their respective imprints on the foraminiferal calcite demonstrate the potential of Mn/Ca as a proxy for hypoxic conditions, and Ba/Ca as a proxy for salinity in enclosed basins such as the Baltic Sea. The traditional use of Mg-Ca as a proxy to reconstruct past seawater temperatures is not recommended in the region, as it may be overprinted by the large variations in salinity (specifically on Bulimina marginata), Mg/Casw, and possibly also the carbonate system. Salinity is the main factor controlling the faunal assemblages: a much more diverse fauna occurs in the higher-salinity (similar to 32) Kattegat than in the low-salinity (similar to 15) Hano Bay. Molecular identification shows that only Elphidium clavatum occurs at both locations, but other genetic types of both genera Elphidium and Ammonia are restricted to either low-or high-salinity locations. The combination of foraminiferal geochemistry and environmental parameters demonstrates that in a highly variable setting like the Baltic Sea, it is possible to separate different environmental impacts on the foraminiferal assemblages and therefore use Mn/Ca, Mg/Ca, and Ba/Ca to reconstruct how specific conditions may have varied in the past.Publisher PDFPeer reviewe