Tau pathology is known to spread in a hierarchical pattern in Alzheimer's disease (AD) brain during disease progression, likely by trans-synaptic tau transfer between neurons. However, the tau ...species involved in inter-neuron propagation remains unclear. To identify tau species responsible for propagation, we examined uptake and propagation properties of different tau species derived from postmortem cortical extracts and brain interstitial fluid of tau-transgenic mice, as well as human AD cortices. Here we show that PBS-soluble phosphorylated high-molecular-weight (HMW) tau, though very low in abundance, is taken up, axonally transported, and passed on to synaptically connected neurons. Our findings suggest that a rare species of soluble phosphorylated HMW tau is the endogenous form of tau involved in propagation and could be a target for therapeutic intervention and biomarker development.
Summary
Ultrasound guidance is rapidly becoming the gold standard for regional anaesthesia. There is an ever growing weight of evidence, matched with improving technology, to show that the use of ...ultrasound has significant benefits over conventional techniques, such as nerve stimulation and loss of resistance. The improved safety and efficacy that ultrasound brings to regional anaesthesia will help promote its use and realise the benefits that regional anaesthesia has over general anaesthesia, such as decreased morbidity and mortality, superior postoperative analgesia, cost‐effectiveness, decreased postoperative complications and an improved postoperative course. In this review we consider the evidence behind the improved safety and efficacy of ultrasound‐guided regional anaesthesia, before discussing its use in pain medicine, paediatrics and in the facilitation of neuraxial blockade. The Achilles’ heel of ultrasound‐guided regional anaesthesia is that anaesthetists are far more familiar with providing general anaesthesia, which in most cases requires skills that are achieved faster and more reliably. To this ends we go on to provide practical advice on ultrasound‐guided techniques and the introduction of ultrasound into a department.
The spread of neurofibrillary tangle (NFT) pathology through the human brain is a hallmark of Alzheimer's disease (AD), which is thought to be caused by the propagation of "seeding" competent soluble ...misfolded tau. "TauC3", a C-terminally truncated form of tau that is generated by caspase-3 cleavage at D421, has previously been observed in NFTs and has been implicated in tau toxicity. Here we show that TauC3 is found in the seeding competent high molecular weight (HMW) protein fraction of human AD brain. Using a specific TauC3 antibody, we were able to substantially block the HMW tau seeding activity of human AD brain extracts in an in vitro tau seeding FRET assay. We propose that TauC3 could contribute to the templated tau misfolding that leads to NFT spread in AD brains.
Astronomy. ASASSN-15lh: A highly super-luminous supernova Dong, Subo; Shappee, B J; Prieto, J L ...
Science (American Association for the Advancement of Science),
2016-Jan-15, 20160115, Letnik:
351, Številka:
6270
Journal Article
Recenzirano
We report the discovery of ASASSN-15lh (SN 2015L), which we interpret as the most luminous supernova yet found. At redshift z = 0.2326, ASASSN-15lh reached an absolute magnitude of Mu ,AB = -23.5 ± ...0.1 and bolometric luminosity Lbol = (2.2 ± 0.2) × 10(45) ergs s(-1), which is more than twice as luminous as any previously known supernova. It has several major features characteristic of the hydrogen-poor super-luminous supernovae (SLSNe-I), whose energy sources and progenitors are currently poorly understood. In contrast to most previously known SLSNe-I that reside in star-forming dwarf galaxies, ASASSN-15lh appears to be hosted by a luminous galaxy (MK ≈ -25.5) with little star formation. In the 4 months since first detection, ASASSN-15lh radiated (1.1 ± 0.2) × 10(52) ergs, challenging the magnetar model for its engine.
Objective
Cerebrospinal fluid (CSF) tau is an excellent surrogate marker for assessing neuropathological changes that occur in Alzheimer's disease (AD) patients. However, whether the elevated tau in ...AD CSF is just a marker of neurodegeneration or, in fact, a part of the disease process is uncertain. Moreover, it is unknown how CSF tau relates to the recently described soluble high‐molecular‐weight (HMW) species that is found in the postmortem AD brain and can be taken up by neurons and seed aggregates.
Methods
We have examined seeding and uptake properties of brain extracellular tau from various sources, including interstitial fluid (ISF) and CSF from an AD transgenic mouse model and postmortem ventricular and antemortem lumbar CSF from AD patients.
Results
We found that brain ISF and CSF tau from the AD mouse model can be taken up by cells and induce intracellular aggregates. Ventricular CSF from AD patients contained a rare HMW tau species that exerted a higher seeding activity. Notably, the HMW tau species was also detected in lumbar CSF from AD patients, and its levels were significantly elevated compared to control subjects. HMW tau derived from CSF of AD patients was seed competent in vitro.
Interpretation
These findings suggest that CSF from an AD brain contains potentially bioactive HMW tau species, giving new insights into the role of CSF tau and biomarker development for AD. Ann Neurol 2016;80:355–367
We report the discovery of ASASSN-15lh (SN 2015L), which we interpret as the most luminous supernova yet found. At redshift z = 0.2326, ASASSN-15lh reached an absolute magnitude of Mu,AB = −23.5 ± ...0.1 and bolometric luminosity Lbol = (2.2 ± 0.2) × 10⁴⁵ ergs s⁻¹, which is more than twice as luminous as any previously known supernova. It has several major features characteristic of the hydrogen-poor super-luminous supernovae (SLSNe-l), whose energy sources and progenitors are currently poorly understood. In contrast to most previously known SLSNe-l that reside in star-forming dwarf galaxies, ASASSN-15lh appears to be hosted by a luminous galaxy (MK ≈ −25.5) with little star formation. In the 4 months since first detection, ASASSN-15lh radiated (1.1 ± 0.2) × 10⁵² ergs, challenging the magnetar model for its engine.
In early stages of Alzheimer's disease (AD), neurofibrillary tangles (NFT) are largely restricted to the entorhinal cortex and medial temporal lobe. At later stages, when clinical symptoms generally ...occur, NFT involve widespread limbic and association cortices. At this point in the disease, amyloid plaques are also abundantly distributed in the cortex. This observation from human neuropathological studies led us to pose two alternative hypotheses: that amyloid in the cortex is permissive for the spread of tangles from the medial temporal lobe, or that these are co-occurring but not causally related events simply reflecting progression of AD pathology.
We now directly test the hypothesis that cortical amyloid acts as an accelerant for spreading of tangles beyond the medial temporal lobe. We crossed rTgTauEC transgenic mice that demonstrate spread of tau from entorhinal cortex to other brain structures at advanced age with APP/PS1 mice, and examined mice with either NFTs, amyloid pathology, or both. We show that concurrent amyloid deposition in the cortex 1) leads to a dramatic increase in the speed of tau propagation and an extraordinary increase in the spread of tau to distal brain regions, and 2) significantly increases tau-induced neuronal loss.
These data strongly support the hypothesis that cortical amyloid accelerates the spread of tangles throughout the cortex and amplifies tangle-associated neural system failure in AD.
Since the first approval of the anti-CD3 recombinant monoclonal antibody (mAb), muromonab-CD3, a mouse antibody for the prevention of transplant rejection, by the US Food and Drug Administration ...(FDA) in 1986, mAb therapeutics have become increasingly important to medical care. A wealth of information about mAbs regarding their structure, stability, post-translation modifications, and the relationship between modification and function has been reported. Yet, substantial resources are still required throughout development and commercialization to have appropriate control strategies to maintain consistent product quality, safety, and efficacy. A typical feature of mAbs is charge heterogeneity, which stems from a variety of modifications, including modifications that are common to many mAbs or unique to a specific molecule or process. Charge heterogeneity is highly sensitive to process changes and thus a good indicator of a robust process. It is a high-risk quality attribute that could potentially fail the specification and comparability required for batch disposition. Failure to meet product specifications or comparability can substantially affect clinical development timelines. To mitigate these risks, the general rule is to maintain a comparable charge profile when process changes are inevitably introduced during development and even after commercialization. Otherwise, new peaks or varied levels of acidic and basic species must be justified based on scientific knowledge and clinical experience for a specific molecule. Here, we summarize the current understanding of mAb charge variants and outline risk-based control strategies to support process development and ultimately commercialization.
We present basic statistics for all supernovae discovered by the All-Sky Automated Survey for SuperNovae (ASAS-SN) during its first year-and-a-half of operations, spanning 2013 and 2014. We also ...present the same information for all other bright (mV less than or equal to 17), spectroscopically confirmed supernovae discovered from 2014 May 1 through the end of 2014, providing a comparison to the ASAS-SN sample starting from the point where ASAS-SN became operational in both hemispheres. In addition, we present collected redshifts and near-UV through IR magnitudes, where available, for all host galaxies of the bright supernovae in both samples. This work represents a comprehensive catalogue of bright supernovae and their hosts from multiple professional and amateur sources, allowing for population studies that were not previously possible because the all-sky emphasis of ASAS-SN redresses many previously existing biases. In particular, ASAS-SN systematically finds bright supernovae closer to the centres of host galaxies than either other professional surveys or amateurs, a remarkable result given ASAS-SN's poorer angular resolution. This is the first of a series of yearly papers on bright supernovae and their hosts that will be released by the ASAS-SN team.
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