LCLS XTOD Attenuator System System Concept Report

The attenuator system for the Linac Coherent Light Source (LCLS) X-ray Transport, Optics and Diagnostics (XTOD) system has been configured and analyzed by the Lawrence Livermore National Laboratory's New Technologies Engineering Division (NTED) as requested by the SLAC/LCLS program. The system layout, performance analyses and selection of the vacuum components are presented in this System Conceptual Review (SCR) report. Also included are the plans for prototype, procurement, mechanical integration, and the cost estimates

CSF Protein Level of Neurotransmitter Secretion, Synaptic Plasticity, and Autophagy in PD and DLB

BACKGROUND: Molecular pathways associated with α-synuclein proteostasis have been detected in genetic studies and in cell models and include autophagy, ubiquitin-proteasome system, mitochondrial homeostasis, and synaptic plasticity. However, we lack biomarkers that are representative for these pathways in human biofluids. OBJECTIVE: The objective of this study was to evaluate CSF protein profiles of pathways related to α-synuclein proteostasis. METHODS: We assessed CSF protein profiles associated with neurotransmitter secretion, synapse plasticity, and autophagy in 2 monocentric cohorts with α-synucleinopathy (385 PD patients and 67 DLB patients). We included 80 PD patients and 17 DLB patients with variants in the glucocerebrosidase gene to serve as proxy for accelerated α-synuclein pathology with pronounced clinical trajectories. RESULTS: (1) Proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy were lower in PD and DLB patients compared with healthy controls. (2) These patterns were more pronounced in DLB than in PD patients, accentuated by GBA variant status in both entities. (3) CSF levels of these proteins were positively associated with CSF levels of total α-synuclein, with lower levels of proteostasis proteins related to lower levels of total α-synuclein. (4) These findings could be confirmed longitudinally. PD patients with low CSF profiles of proteostasis proteins showed lower CSF levels of α-synuclein longitudinally compared with PD patients with a normal proteostasis profile. CONCLUSION: CSF proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy might serve as biomarkers related to α-synuclein proteostasis in PD and DLB

Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson’s disease and dementia with Lewy bodies

The clinicopathological heterogeneity in Lewy-body diseases (LBD) highlights the need for pathology-driven biomarkers in-vivo. Misfolded alpha-synuclein (α-Syn) is a lead candidate based on its crucial role in disease pathophysiology. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has recently shown high sensitivity and specificity for the detection of misfolded α-Syn in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this study we performed the CSF RT-QuIC assay in 236 PD and 49 DLB patients enriched for different genetic forms with mutations in GBA, parkin, PINK1, DJ1, and LRRK2. A subgroup of 100 PD patients was also analysed longitudinally. We correlated kinetic seeding parameters of RT-QuIC with genetic status and CSF protein levels of molecular pathways linked to α-Syn proteostasis. Overall, 85% of PD and 86% of DLB patients showed positive RT-QuIC α-Syn seeding activity. Seeding profiles were significantly associated with mutation status across the spectrum of genetic LBD. In PD patients, we detected positive α-Syn seeding in 93% of patients carrying severe GBA mutations, in 78% with LRRK2 mutations, in 59% carrying heterozygous mutations in recessive genes, and in none of those with bi-allelic mutations in recessive genes. Among PD patients, those with severe GBA mutations showed the highest seeding activity based on RT-QuIC kinetic parameters and the highest proportion of samples with 4 out of 4 positive replicates. In DLB patients, 100% with GBA mutations showed positive α-Syn seeding compared to 79% of wildtype DLB. Moreover, we found an association between α-Syn seeding activity and reduced CSF levels of proteins linked to α-Syn proteostasis, specifically lysosome-associated membrane glycoprotein 2 and neurosecretory protein VGF. These findings highlight the value of α-Syn seeding activity as an in-vivo marker of Lewy-body pathology and support its use for patient stratification in clinical trials targeting α-Syn

[11C]MODAG 005 – a novel PET tracer targeting alpha-synuclein aggregates in the brain

Synucleinopathies are neurodegenerative diseases characterized by the presence of brain inclusions containing the pathologically aggregated protein α-synuclein (αSYN). The development of a positron emission tomography tracer to detect aggregates of misfolded αSYN would revolutionize disease monitoring and the evaluation of therapeutic efficacy. Here we present the development and preclinical in vitro and in vivo validation of [11C]MODAG-005. In vitro binding experiments demonstrate subnanomolar binding affinity to recombinant αSYN fibrils as well as to αSYN inclusions in human brain tissue. Specific binding in multiple system atrophy brain tissue was detected using autoradiography and microautoradiography, and was validated through immunostaining. In vivo, [11C]MODAG-005 shows good brain penetration, rapid clearance from brain tissue and low metabolite formation in rodents and non-human primates. In addition, a pronounced binding and a good signal-to-noise ratio were achieved in an αSYN fibril-injected rat model and in an αSYN(A30P) transgenic mouse model in correlation to the pathological load. To validate its value for therapy development, we show target engagement of the drug candidate anle138b in the brain tissues from αSYN(A30P) mouse and multiple system atrophy as well as in vivo in αSYN fibril-injected rats. Finally, our translational approach in a first-in-human patient with clinically established MSA, revealed a marked tracer binding in regions affected by αSYN pathology, particularly in the striatum, where the pattern corresponded with the neurodegeneration shown by dopamine transporter single-photon emission computed tomography

Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic

Biomarker discovery and development for clinical research, diagnostics and therapy monitoring in clinical trials have advanced rapidly in key areas of medicine - most notably, oncology and cardiovascular diseases - allowing rapid early detection and supporting the evolution of biomarker-guided, precision-medicine-based targeted therapies. In Alzheimer disease (AD), breakthroughs in biomarker identification and validation include cerebrospinal fluid and PET markers of amyloid-β and tau proteins, which are highly accurate in detecting the presence of AD-associated pathophysiological and neuropathological changes. However, the high cost, insufficient accessibility and/or invasiveness of these assays limit their use as viable first-line tools for detecting patterns of pathophysiology. Therefore, a multistage, tiered approach is needed, prioritizing development of an initial screen to exclude from these tests the high numbers of people with cognitive deficits who do not demonstrate evidence of underlying AD pathophysiology. This Review summarizes the efforts of an international working group that aimed to survey the current landscape of blood-based AD biomarkers and outlines operational steps for an effective academic-industry co-development pathway from identification and assay development to validation for clinical use

Mechanistic effect modeling of earthworms in the context of pesticide risk assessment: Synthesis of the FORESEE Workshop.

Earthworms are important ecosystem engineers, and assessment of the risk of plant protection products towards them is part of the European environmental risk assessment (ERA). In the current ERA scheme, exposure and effects are represented simplistically and are not well integrated, resulting in uncertainty when applying the results to ecosystems. Modeling offers a powerful tool to integrate the effects observed in lower tier laboratory studies with the environmental conditions under which exposure is expected in the field. This paper provides a summary of the FORESEE Workshop ((In)Field Organism Risk modEling by coupling Soil Exposure and Effect) held January 28‐30, 2020 in Düsseldorf, Germany. This workshop focussed on toxicokinetic‐toxicodynamic (TKTD) and population modeling of earthworms in the context of environmental risk assessment. The goal was to bring together scientists from different stakeholder groups to discuss the current state of soil invertebrate modeling, explore how earthworm modeling could be applied to risk assessments, and in particular how the different model outputs can be used in the tiered ERA approach. In support of these goals, the workshop aimed at addressing the requirements and concerns of the different stakeholder groups to support further model development. The modeling approach included four submodules to cover the most relevant processes for earthworm risk assessment: Environment, Behavior (feeding, vertical movement), TKTD, and Population. Four workgroups examined different aspects of the model with relevance for: Risk assessment, earthworm ecology, uptake routes, and cross‐species extrapolation and model testing. Here, we present the perspectives of each workgroup and highlight how the collaborative effort of participants from multidisciplinary backgrounds helped to establish common ground. In addition, we provide a list of recommendations for how earthworm TKTD modeling could address some of the uncertainties in current risk assessments for plant protection products

Local dynamics in supramolecular polymer networks probed by magnetic particle nanorheology

Transient supramolecular polymer networks are promising candidates as soft self-healing or stimuli-sensitive materials. In this paper, we employ a novel nanorheological approach, magnetic particle nanorheology (MPN), in order to better understand the local dynamic properties of model supramolecular networks from a molecular point of view. Hence, the bond strength between four-arm star-shaped polyethylene glycol (PEG) functionalized at the four extremities with terpyridine ligands is tuned by implementing different metal ions with variable complexation affinities for the ligand. We show that MNP allows for the evaluation of the strength and connectivity of the polymer networks by the estimation of relaxation times, mesh size, and also the viscoelastic properties of these materials. These results are compared and complemented to former outcomes on these systems that were obtained by macroscopic analytical methods. A clear dependence between the strength of the metal-ligand complex and the local dynamics of the polymeric network is observed by the nanorheological approach, which is in good agreement with previous predictions related to the complex formation constants

Dynamics of magnetic nanoparticles in viscoelastic media

We compare different models for the description of the complex susceptibility of magnetic nanoparticles in an aqueous gelatin solution representing a model system for a Voigt-Kelvin scheme. The analysis of susceptibility spectra with the numerical model by Raikher et al. [7] is compared with the analysis applying a phenomenological, modified Debye model. The fit of the models to the measured data allows one to extract the viscoelastic parameter dynamic viscosity. and shear modulus G. The experimental data were recorded on single-core thermally blocked CoFe2O4 nanoparticles in an aqueous solution with 2.5 wt% gelatin. Whereas the dynamic viscosities obtained by fitting the model - extended by distributions of hydrodynamic diameters and viscosities - agree very well, the derived values for the shear modulus show the same temporal behavior during the gelation process, but vary approximately by a factor of two. To verify the values for viscosity and shear modulus obtained from nanorheology, macrorheological measurements are in progress

Dynamics of CoFe2O4 Single-Core Nanoparticles in Viscoelastic Media

AbstractThe dynamics of single-core CoFe2O4 nanoparticles in viscoelastic media was studied utilizing ac susceptibility and fluxgate magnetorelaxometry measurements. As viscoelastic medium aqueous gelatin suspensions with gelatin contents between 2.5 wt% and 10 wt% were used. Specifically, the gelation kinetics after cooling the sample from the sol state (313K) to 296K was investigated. It is shown that the measurement results can be analyzed with the Voigt-Kelvin model thus providing information on local dynamic viscosity and shear modulus