Neuroinflammation by cytotoxic T-lymphocytes impairs retrograde axonal transport in an oligodendrocyte mutant mouse

Mice overexpressing proteolipid protein (PLP) develop a leukodystrophy-like disease involving cytotoxic, CD8+ T-lymphocytes. Here we show that these cytotoxic T-lymphocytes perturb retrograde axonal transport. Using fluorogold stereotactically injected into the colliculus superior, we found that PLP overexpression in oligodendrocytes led to significantly reduced retrograde axonal transport in retina ganglion cell axons. We also observed an accumulation of mitochondria in the juxtaparanodal axonal swellings, indicative for a disturbed axonal transport. PLP overexpression in the absence of T-lymphocytes rescued retrograde axonal transport defects and abolished axonal swellings. Bone marrow transfer from wildtype mice, but not from perforin- or granzyme B-deficient mutants, into lymphocyte-deficient PLP mutant mice led again to impaired axonal transport and the formation of axonal swellings, which are predominantly located at the juxtaparanodal region. This demonstrates that the adaptive immune system, including cytotoxic T-lymphocytes which release perforin and granzyme B, are necessary to perturb axonal integrity in the PLP-transgenic disease model. Based on our observations, so far not attended molecular and cellular players belonging to the immune system should be considered to understand pathogenesis in inherited myelin disorders with progressive axonal damage

Towards a methodical framework for comprehensively assessing forest multifunctionality

Funded by Deutsche Forschungsgemeinschaft. Grant Number: DFG FOR 891/1-3 National Natural Science Foundation of China. Grant Numbers: 30710103907, 30930005, 31170457, 31210103910 Swiss National Science Foundation (SNSF) Sino-German Centre for Research Promotion in Beijing. Grant Number: GZ 986Peer reviewedPublisher PD

The MeDoc Distributed Electronic Library Accounting and Security Aspects (Extended Abstract)

Michael Breu Anne Bruggemann-Klein y Cornelia Haber z Ricarda Weber x November 1, 1996 Abstract The MeDoc service provides access to a distributed full-text library for computer scientists over the internet. Since the library provides commercial information products, accounting and security aspects are of considerable importance in this electronic-publishing project. MeDoc has developed business, cost, and payment models suitable for an electronic library service. Communication channels are secured by transparent encryption mechanisms based on SSL. These mechanisms are implemented in a prototype that will be evaluated in a first field test starting at the end of 1996. 1 Introduction The MeDoc 1 service provides a distributed electronic full-text library of high quality computer-science literature. This library can only be furnished with commercial products, if usage is billable and protected. Therefore flexible business, cost and payment models and user-transparent ways to s..

The MeDoc Distributed Electronic Library Accounting and Security Aspects

The MeDoc service provides access to a distributed full-text library for computer scientists over the Internet. Since the library provides commercial information products, accounting and security aspects are of considerable importance in this electronic-publishing project. MeDoc has developed business, cost, and payment models suitable for electronic library services. The partners cooperating in the MeDoc service are users, providers and producers of information products. Their business interaction is based on trade as opposed to systems financed by advertising. The cost models offered to the users are various forms of subscription and "pay per view"-purchase. As payment models both credit and debit models are considered suitable for the MeDoc service. Initially only registered users are admitted to the MeDoc library, so the users can be charged via accounts. Currently a clearing agency handles the actual invoice process for the MeDoc service. To secure the communication over the Inter..

Where was the Toaster? A systematic investigation of semantic construction in a new virtual episodic memory paradigm

Experiences that are retrieved from memory are often not accurate, but prone to biases. The interplay of already existing semantic knowledge and recently generated episodic memory traces might explain some of the underlying mechanisms. The scenario construction model postulates that during encoding, only the gist of an episode is stored in the episodic memory trace and during retrieval, any needed information that is missing from that trace is constructed from semantic knowledge. The current study aimed to investigate semantic construction in a realistic, yet controlled setting. Using a desktop virtual reality (VR) participants navigated through a flat in which some household items appeared in unexpected rooms, creating conflicts between the experienced episode and semantic expectations. During recall after two separate retrieval delays (one day vs one week) we were able to identify influences from semantic knowledge. To manipulate salience, some objects were task-relevant, and some were irrelevant to the sequence of actions. We used spatial and temporal recall measures. Both congruency and task-relevance, but not time, predicted correct episodic memory retrieval. In the spatial memory retrieval, semantic construction was more likely than guessing in cases of episodic memory failure and occurred more frequently for task-irrelevant objects. In the temporal recall at the second retrieval delay we could show that object-pairs belonging to the same semantic room-category were temporally clustered together compared to object-pairs from different semantic room-categories. Taken together, our findings support the predictions of the scenario construction model, as we found influences of semantic knowledge on both spatial and temporal memory recall. The new VR-paradigm appears to be a promising tool for investigating semantic construction

CD34T+ Humanized Mouse Model to Study Mucosal HIV-1 Transmission and Prevention

Humanized mice are critical for HIV-1 research, but humanized mice generated from cord blood are inefficient at mucosal HIV-1 transmission. Most mucosal HIV-1 transmission studies in mice require fetal tissue-engraftment, the use of which is highly restricted or prohibited. We present a fetal tissue-independent model called CD34T+ with enhanced human leukocyte levels in the blood and improved T cell homing to the gut-associated lymphoid tissue. CD34T+ mice are highly permissive to intra-rectal HIV-1 infection and also show normal env diversification in vivo despite high viral replication. Moreover, mucosal infection in CD34T+ mice can be prevented by infusion of broadly neutralizing antibodies. CD34T+ mice can be rapidly and easily generated using only cord blood cells and do not require any complicated surgical procedures for the humanization process. Therefore, CD34T+ mice provide a novel platform for mucosal HIV-1 transmission studies as well as rapid in vivo testing of novel prevention molecules against HIV-1

Cohort profile:the Oxford Parkinson's Disease Centre Discovery Cohort MRI substudy (OPDC-MRI)

Purpose: The Oxford Parkinson’s Disease Centre (OPDC) Discovery Cohort MRI substudy (OPDC-MRI) collects high-quality multimodal brain MRI together with deep longitudinal clinical phenotyping in patients with Parkinson’s, at-risk individuals and healthy elderly participants. The primary aim is to detect pathological changes in brain structure and function, and develop, together with the clinical data, biomarkers to stratify, predict and chart progression in early-stage Parkinson’s and at-risk individuals. Participants: Participants are recruited from the OPDC Discovery Cohort, a prospective, longitudinal study. Baseline MRI data are currently available for 290 participants: 119 patients with early idiopathic Parkinson’s, 15 Parkinson’s patients with pathogenic mutations of the leucine-rich repeat kinase 2 or glucocerebrosidase (GBA) genes, 68 healthy controls and 87 individuals at risk of Parkinson’s (asymptomatic carriers of GBA mutation and patients with idiopathic rapid eye movement sleep behaviour disorder-RBD). Findings to date: Differences in brain structure in early Parkinson’s were found to be subtle, with small changes in the shape of the globus pallidus and evidence of alterations in microstructural integrity in the prefrontal cortex that correlated with performance on executive function tests. Brain function, as assayed with resting fMRI yielded more substantial differences, with basal ganglia connectivity reduced in early Parkinson’sand RBD. Imaging of the substantia nigra with the more recent adoption of sequences sensitive to iron and neuromelanin content shows promising results in identifying early signs of Parkinsonian disease. Future plans: Ongoing studies include the integration of multimodal MRI measures to improve discrimination power. Follow-up clinical data are now accumulating and will allow us to correlate baseline imaging measures to clinical disease progression. Follow-up MRI scanning started in 2015 and is currently ongoing, providing the opportunity for future longitudinal imaging analyses with parallel clinical phenotyping.</p