Dysregulation of microtubule stability impairs morphofunctional connectivity in primary neuronal networks

Functionally related neurons assemble into connected networks that process and transmit electrochemical information. To do this in a coordinated manner, the number and strength of synaptic connections is tightly regulated. Synapse function relies on the microtubule (MT) cytoskeleton, the dynamics of which are in turn controlled by a plethora of MT-associated proteins, including the MT-stabilizing protein Tau. Although mutations in the Tau-encodingMAPT gene underlie a set of neurodegenerative disorders, termed tauopathies, the exact contribution of MT dynamics and the perturbation thereof to neuronal network connectivity has not yet been scrutinized. Therefore, we investigated the impact of targeted perturbations of MT stability on morphological (e.g., neurite- and synapse density) and functional (e.g., synchronous calcium bursting) correlates of connectivity in networks of primary hippocampal neurons. We found that treatment with MT-stabilizing or -destabilizing compounds impaired morphofunctional connectivity in a reversible manner. We also discovered that overexpression of MAPT induced significant connectivity defects, which were accompanied by alterations in MT dynamics and increased resistance to pharmacological MT depolymerization. Overexpression of a MAPT variant harboring the P301L point mutation in the MT-binding domain did far less, directly linking neuronal connectivity with Tau's MT binding affinity. Our results show that MT stability is a vulnerable node in tauopathies and that its precise pharmacological tuning may positively affect neuronal network connectivity. However, a critical balance in MT turnover causes it to be a difficult therapeutic target with a narrow operating window

Determinants of soil organic matter chemistry in maritime temperate forest ecosystems

While the influence of climate, vegetation, management and abiotic site factors on total carbon budgets and turn-over is intensively assessed, the influences of these ecosystem properties on the chemical complexity of soil organic matter (SOM) remains poorly understood. This study addresses the chemical composition of NaOH-extracted SOM from maritime temperate forest sites in Flanders (Belgium) by pyrolysis-GC/MS. The studied forests were chosen based on dominant tree species (Pinus sylvestris, Fagus sylvatica, Quercus robur and Populus spp.), soil texture and soil-moisture conditions. Differences in extractable-SOM pyrolysis products were correlated to site variables including dominant tree species, management of the woody biomass, site history, soil properties, total carbon stocks and indicators for microbial activity. Despite of a typical high intercorrelation between these site variables, the influence of the dominant tree species is prominent. The extractable-SOM composition is strongly correlated to litter quality and available nutrients. In nutrient-poor forests with low litter quality, the decomposition of relatively recalcitrant compounds (i.e. short and mid-chain alkanes/alkenes and aromatic compounds) appears hampered, causing a relative accumulation of these compounds in the soil. However, if substrate quality is favorable, no accumulations of recalcitrant compounds were observed, not even under high soil-moisture conditions. Former heathland vegetation still had a profound influence on extractable-SOM chemistry of young pine forests after a minimum of 60 year

Targeting the Beta-2-Adrenergic Receptor and the Risk of Developing Alzheimer's Disease:A Retrospective Inception Cohort Study

BACKGROUND: Animal studies suggested that β2-Adrenergic receptors (β2AR) may be a potential target for the treatment of Alzheimer's disease (AD). OBJECTIVE: This retrospective inception cohort study aimed to assess the association between antagonists and agonists of the β2AR and the risk of starting treatment for AD in older adults. METHODS: A retrospective inception cohort study was conducted among older adults who initiated either non-selective βAR antagonists or selective β2AR agonists using the University Groningen IADB.nl prescription database (study period 1994-2019). For each exposed cohort, two reference cohorts (A and B) were matched on age at index date. The main outcome was defined as at least two prescriptions for cholinesterase inhibitors (rivastigmine, galantamine, and donepezil) and/or memantine. Cox proportional hazard regression models were used to estimate hazard ratios (HR). RESULTS: The risk of developing AD was elevated among patients exposed to non-selective βAR antagonists (A: aHR 3.303, 95% CI 1.230-8.869, B: aHR 1.569, 95% CI 0.560-4.394) and reduced among patients exposed to selective β2AR agonists (A: aHR 0.049, 95% CI 0.003-0.795, B: aHR 0.834, 95% CI 0.075-9.273) compared to reference patients. CONCLUSION: These findings suggest that exposure to non-selective βAR antagonists is associated with an increased risk for developing AD whereas there may be a decreased risk for developing AD after exposure to selective β2AR agonists

Optical extinction due to intrinsic structural variations of photonic crystals

Unavoidable variations in size and position of the building blocks of photonic crystals cause light scattering and extinction of coherent beams. We present a new model for both 2 and 3-dimensional photonic crystals that relates the extinction length to the magnitude of the variations. The predicted lengths agree well with our new experiments on high-quality opals and inverse opals, and with literature data analyzed by us. As a result, control over photons is limited to distances up to 50 lattice parameters ($\sim 15 \mu$m) in state-of-the-art structures, thereby impeding large-scale applications such as integrated circuits. Conversely, scattering in photonic crystals may lead to novel physics such as Anderson localization and non-classical diffusion.Comment: 10 pages, 3 figures. Changes include: added Lagendijk as author; simplified and generalized the tex

Interobserver Variation of Colour Duplex Scanning of the Popliteal,Tibial and Pedal Arteries

AbstractObjectives: to determine interobserver variation in the measurement of Peak Systolic Velocity (PSV) and grading of disease by means of Duplex scanning (DS) in the popliteal, tibial and pedal arteries. Design: prospective validation study. Materials twenty-four consecutive patients with severe claudication (n=6), ischaemic rest pain (n=11) and tissue loss (n=7). Methods two vascular technologists independently examined the popliteal, tibial and pedal arteries. The PSV was recorded in 15 arterial segments that were graded with B-mode and Doppler parameters as fully patent, severely diseased or occluded. Concordance in PSV recordings was expressed as intraclass correlation coefficients (ICC). Agreement in artery assessment was expressed as weighted κ-values. Results the ICC for PSV measurements was 0.90 (95% CI, 0.86 to 0.93) within the popliteal and tibial arteries and 0.64 (95% CI, 0.37 to 0.81) within the pedal arteries. Agreement for grading disease was good within the popliteal and tibial arteries (κ 0.66, 95% CI, 0.58 to 0.74), and moderate within the pedal arteries (κ 0.54, 95% CI 0.33 to 0.74). The presence of diabetes or stage of disease did not influence interobserver agreement. Conclusion interobserver agreement of DS is good within the popliteal and tibial arteries and moderate within the pedal arteries

Single-cell and neuronal network alterations in an in vitro model of Fragile X syndrome

The Fragile X mental retardation protein (FMRP) is involved in many cellular processes and it regulates synaptic and network development in neurons. Its absence is known to lead to intellectual disability, with a wide range of comorbidities including autism. Over the past decades, FMRP research focused on abnormalities both in glutamatergic and GABAergic signaling, and an altered balance between excitation and inhibition has been hypothesized to underlie the clinical consequences of absence of the protein. Using Fmrp knockout mice, we studied an in vitro model of cortical microcircuitry and observed that the loss of FMRP largely affected the electrophysiological correlates of network development and maturation but caused less alterations in single-cell phenotypes. The loss of FMRP also caused a structural increase in the number of excitatory synaptic terminals. Using a mathematical model, we demonstrated that the combination of an increased excitation and reduced inhibition describes best our experimental observations during the ex vivo formation of the network connections

Toxicity Profiles In Vivo in Mice and Antitumour Activity in Tumour-Bearing Mice of Di- and Triorganotin Compounds

The in vivo toxicity profiles in mice and the antitumour activity in tumour bearing mice were screened for four di-n-butyltin and five triorganotin carboxylates, di-n-butyltin diterebate (5), bis(phenylacetate) (6), bis(deoxycholate) (7), bis(lithocholate) (8), tri-n-butyltin terebate (9), cinnamate (10), and triphenyltin terebate (11)

The orbits of subdwarf B + main-sequence binaries. I: The sdB+G0 system PG 1104+243

The predicted orbital period histogram of an sdB population is bimodal with a peak at short ( 250 days) periods. Observationally, there are many short-period sdB systems known, but only very few long-period sdB binaries are identified. As these predictions are based on poorly understood binary interaction processes, it is of prime importance to confront the predictions to observational data. In this contribution we aim to determine the absolute dimensions of the long-period sdB+MS binary system PG1104+243. High-resolution spectroscopy time-series were obtained with HERMES at the Mercator telescope at La Palma, and analyzed to obtain radial velocities of both components. Photometry from the literature was used to construct the spectral energy distribution (SED) of the binary. Atmosphere models were used to fit this SED and determine the surface gravity and temperature of both components. The gravitational redshift provided an independent confirmation of the surface gravity of the sdB component. An orbital period of 753 +- 3 d and a mass ratio of q = 0.637 +- 0.015 were found from the RV-curves. The sdB component has an effective temperature of Teff = 33500 +- 1200 K and a surface gravity of logg = 5.84 +- 0.08 dex, while the cool companion is found to be a G-type star with Teff = 5930 +- 160 K and logg = 4.29 +- 0.05 dex. Assuming a canonical mass of Msdb = 0.47 Msun, the MS component has a mass of 0.74 +- 0.07 Msun, and its Teff corresponds to what is expected for a terminal age main-sequence star with sub-solar metalicity. PG1104+243 is the first long-period sdB binary in which accurate physical parameters of both components could be determined, and the first sdB binary in which the gravitational redshift is measured. Furthermore, PG1104+243 is the first sdB+MS system that shows consistent evidence for being formed through stable Roche-lobe overflow.Comment: Accepted by A&A on 05-10-201

Combinations of idelalisib with rituximab and/or bendamustine in patients with recurrent indolent non-Hodgkin lymphoma

Key Points Combining phosphatidylinositol-3-kinase δ inhibition with rituximab, bendamustine, or both is feasible and active in relapsed iNHL. The safety of novel combinations should be proven in phase 3 trials before adoption in clinical practice.</jats:p