Aggregates and Disrupted Dynein-Dependent Trafficking in ALS

Amyotrophic Lateral Sclerosis (ALS) is an adult-onset neuro-degenerative disease. The death of motor neurons leads to progressive paralysis of voluntary muscles, making patients unable to control their movements, and ultimately leads to paralysis of respiratory muscles and death. So far there is no effective treatment available. It is not clear how motor neurons die in ALS-patients. 10% of the ALS-cases are familial, and so far mutations in 6 genes have been identified in ALS-families. Mutations in the gene for SOD1 were the first to be discovered and account for up to 20% of familial ALS-cases. Most likely, mutant SOD1-protein is misfolded and accumulates in insoluble aggregates, that are toxic to motor neurons. In the studies described in this thesis, we use transgenic mice that express human mutant SOD1, and that develop paralysis and other pathological changes resembling ALS. We have studied changes in motor neurons in the spinal cord of these SOD1-ALS mice in great detail, and show that the appearance of aggregates is a very early phenomenon in these cells. In addition, motor neurons develop accumulations resembling a traffic jam, and a fragmented Golgi apparatus, an indication for disrupted cellular transport. Supporting cell-types, as astrocytes and microglia, are also affected in the spinal cord of SOD1-ALS mice. To study which cell-types are primarily responsible for the death of motor neurons, we developed transgenic mice with a restricted expression of mutant SOD1 in neurons. These mice develop similar pathological changes as SOD1-ALS mice, indicating that mutant SOD1 acting solely in neurons is sufficient to induce an ALS-like disease. Several studies have indicated that disruptions of axonal transport could cause motor neuron death. We have generated transgenic mice with a disruption of the retrograde microtubule motor dynein/dynactin, by expressing the dominant-negative linker protein BICD2-N in neurons. These mice have impaired retrograde axonal transport and develop cellular changes that resemble those found in SOD1-ALS-mice, like a disrupted Golgi apparatus and neurofilament accumulations. However, up to two years the mice are healthy and do not show any forms of paralysis. Moreover, if we cross these BICD2-N mice with SOD1-ALS mice, animals develop paralysis at a later age and survive longer, indicating that a disruption of retrograde transport could be beneficial for SOD1-linked ALS. Mutations in the gene for VAPB were most recently discovered in ALS-patients. We show that this relatively unknown protein is expressed at high levels in motor neurons in humans and mice and localizes to the Endoplasmic Reticulum. The ALS-linked mutation mislocalize

Підтексти драм Лесі Українки

У драмах Лесі Українки має місце діалог з культурою декадансу, який увиразнює тематику меланхолії та похідних від неї мотивів усамітнення, небуття, долі, жертви.In Lesya Ukrainka’s dramas the dialogue with the culture of decadence is conducted that entails the prominent place of the theme of melancholy and the derivative motifs of solitude, non-existence, fate, martyr

Persistent cloud cover over mega-cities linked to surface heat release

Urban areas are a hotspot for the interactions between the built environment, its inhabitants, and weather. Unlike the impact of temperatures through the well-known urban heat island effect, urban effects on cloud formation remain unknown. In this study we show observational evidence of a systematic enhancement of cloud cover in the afternoon and evening over two large metropolitan areas in Europe (Paris and London). Long-term measurements in and around London show that during late-spring and summer, even though less moisture is available at the surface and the atmosphere is drier, low clouds can persist longer over the urban area as vertical mixing of the available moisture is maintained for a longer period of time, into the evening transition. Our findings show that urban impacts on weather extend beyond temperature effects. These prolonged clouds over the city might enhance the urban heat island via night-time radiative forcing

Long-Term Alendronate Use Not without Consequences?

A previously unknown side effect of biphosphonate use is emerging. In a specific patient group on long term biphosphonate therapy stress femur fractures seem to occur. The typical presentation consists of prodromal pain in the affected leg and/or a discrete cortical thickening on the lateral side of the femur in conventional radiological examination or the presentation with a spontaneous transverse subtrochanteric femur with typical features. We present three cases of this stress fracture in patients on bisphosphonate therapy. One of these patients suffered a bilateral femur fracture of the same type. In our opinion, in patients on bisphosphonate therapy who present with a spontaneous femur fracture, seizing therapy is advisable. In bilateral cases preventive nailing should be considered

Transthoracic Bioimpedance Monitoring Predicts Heart Failure Decompensation and Early Readmission after Heart Failure Hospitalization: Preliminary Data from SENTINEL-HF

Background: Patients, providers, and health systems are focused on reducing readmissions for patients with acute decompensated heart failure (ADHF). Readmission after hospitalization is common and often secondary to HF decompensation, but it remains challenging to identify patients at-risk. Bioimpedance is a validated marker of thoracic fluid accumulation. We examined whether transthoracic bioimpedance, measured using a Fluid Accumulation Vest (FAV), predicted HF decompensation in advance of a clinical event in patients discharged after ADHF. Methods: Participants included 42 patients hospitalized for ADHF. Participants were trained on the use of a FAV-smartphone dyad to obtain and transmit a 5-minute bioimpedance measurement once daily for 45-days after discharge. Readmission and diuretic dosing adjustments were identified using participant report and causes adjudicated using medical records. Receiver operating characteristic (ROC) curves and C-statistics were calculated to describe the characteristics of a bioimpedance based algorithm as a predictor of HF decompensation 3 or 7-days in advance of the clinical event. Results: Participants (mean age 69 ± 12 years, 43% female, 88% white, 11% cognitively impaired, 12% depressed) had a mean ejection fraction of 50 ± 18%. HF-related rehospitalization occurred in 10% (n=4) and 10% (n=4) reported diuretic up-titration during the 45-day follow-up. An algorithm analyzing bioimpedance up to 3 or 7 days prior to an event was related to HF readmission (C statistics for 3 and 7 days = 0.83, 0.94, respectively) and the combined outcome of HF hospitalization or diuretic up-titration (C statistics for 3 and 7 days = 0.76, 0.80, respectively). Conclusions: Early readmission after hospitalization for ADHF was common and predicted up to 7 days in advance by an algorithm analyzing transthoracic bioimpedance. Despite their advanced age and high burden of comorbid diseases, study participants with ADHF were able to make daily bioimpedance measurements using a FAV and transmit them using a smartphone. Transthoracic bioimpedance monitoring may offer possibilities for reducing HF readmissions by enabling identification and treatment of outpatients with early HF decompensation

Intrinsic plasticity complements long-term potentiation in parallel fiber input gain control in cerebellar Purkinje cells

Synaptic gain control and information storage in neural networks are mediated by alterations in synaptic transmission, such as in long-term potentiation (LTP). Here,weshowusingboth in vitroandin vivo recordingsfromthe rat cerebellum that tetanization protocols for the induction of LTP at parallel fiber (PF)-to-Purkinje cell synapsescanalsoevokeincreases in intrinsic excitability. Thisformof intrinsic plasticity shares with LTP a requirement for the activation of protein phosphatases 1, 2A, and 2B for induction. Purkinje cell intrinsic plasticity resembles CA1 hippocampal pyramidal cell intrinsic plasticity in that it requires activity of protein kinase A(PKA) and casein kinase 2 (CK2) and is mediated by a downregulation of SK-type calcium-sensitive K conductances. In addition, Purkinje cell intrinsic plasticity similarly results in enhanced spine calcium signaling. However, there are fundamental differences: first, while in the hippocampus increases in excitability result in a higher probability for LTP induction, intrinsic plasticity in Purkinj

Urban Water Storage Capacity Inferred From Observed Evapotranspiration Recession

Water storage plays an important role in mitigating heat and flooding in urban areas. Assessment of the water storage capacity of cities remains challenging due to the inherent heterogeneity of the urban surface. Traditionally, effective storage has been estimated from runoff. Here, we present a novel approach to estimate effective water storage capacity from recession rates of observed evaporation during precipitation-free periods. We test this approach for cities at neighborhood scale with eddy-covariance based latent heat flux observations from 14 contrasting sites with different local climate zones, vegetation cover and characteristics, and climates. Based on analysis of 583 drydowns, we find storage capacities to vary between 1.3 and 28.4 mm, corresponding to e-folding timescales of 1.8-20.1 days. This makes the urban storage capacity at least five times smaller than all the observed values for natural ecosystems, reflecting an evaporation regime characterized by extreme water limitation.Peer reviewe

Amyotrophic lateral sclerosis-associated mutant VAPBP56S perturbs calcium homeostasis to disrupt axonal transport of mitochondria

A proline-to-serine substitution at position 56 in the gene encoding vesicle-associated membrane protein-associated protein B (VAPB; VAPBP56S) causes some dominantly inherited familial forms of motor neuron disease, including amyotrophic lateral sclerosis (ALS) type-8. Here, we show that expression of ALS mutant VAPBP56S but not wild-type VAPB in neurons selectively disrupts anterograde axonal transport of mitochondria. VAPBP56S-induced disruption of mitochondrial transport involved reductions in the frequency, velocity and persistence of anterograde mitochondrial movement. Anterograde axonal transport of mitochondria is mediated by the microtubule-based molecular motor kinesin-1. Attachment of kinesin-1 to mitochondria involves the outer mitochondrial membrane protein mitochondrial Rho GTPase-1 (Miro1) which acts as a sensor for cytosolic calcium levels ([Ca2+]c); elevated [Ca2+]c disrupts mitochondrial transport via an effect on Miro1. To gain insight into the mechanisms underlying the VAPBP56S effect on mitochondrial transport, we monitored [Ca2+]c levels in VAPBP56S-expressing neurons. Expression of VAPBP56S but not VAPB increased resting [Ca2+]c and this was associated with a reduction in the amounts of tubulin but not kinesin-1 that were associated with Miro1. Moreover, expression of a Ca2+ insensitive mutant of Miro1 rescued defective mitochondrial axonal transport and restored the amounts of tubulin associated with the Miro1/kinesin-1 complex to normal in VAPBP56S-expressing cells. Our results suggest that ALS mutant VAPBP56S perturbs anterograde mitochondrial axonal transport by disrupting Ca2+ homeostasis and effecting the Miro1/kinesin-1 interaction with tubulin