Explore the vast range of titles available.

The deposition of mutant huntingtin (mHTT) protein aggregates in neurons of patients is a pathological hallmark of Huntington’s disease (HD). Previous investigations in cell-free and cell-based disease models showed mHTT exon-1 (mHTTex1) fragments with pathogenic polyglutamine (polyQ) tracts (>40 glutamines) to self-assemble into highly stable, β-sheet-rich protein aggregates with a fibrillar morphology. HD knock-in mouse models have not been extensively studied with regard to mHTT aggregation. They endogenously produce full-length mHTT with a pathogenic polyQ tract as well as mHTTex1 fragments. Here, we demonstrate that seeding-competent, fibrillar mHTT aggregates can be readily detected in brains of zQ175 knock-in HD mice. To do this, we applied a highly sensitive FRET-based protein amplification assay that is capable of detecting seeding-competent mHTT aggregate species down to the femtomolar range. Furthermore, we show that fibrillar structures with an average length of ∼200 nm can be enriched with aggregate-specific mouse and human antibodies from zQ175 mouse brain extracts through immunoprecipitations, confirming that such structures are formed in vivo . Together these studies indicate that small, fibrillar, seeding-competent mHTT structures are prominent aggregate species in brains of zQ175 mice.

We consider the Bardeen–Cooper–Schrieffer (BCS) free energy functional with weak and macroscopic external electric and magnetic fields and derive the Ginzburg–Landau functional. We also provide an asymptotic formula for the BCS critical temperature as a function of the external fields. This extends our previous results in Deuchert et al. (Microscopic derivation of Ginzburg-Landau theory and the BCS critical temperature shift in a weak homogeneous magnetic field, PMP 4 (1), 1–89 (2023)) for the constant magnetic field to general magnetic fields with a nonzero magnetic flux through the unit cell.

Alzheimer’s disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating—Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis. Aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ, reduces soluble and insoluble Aβ in the brain, an action accompanied by a dose-dependent slowing of clinical decline in treated patients. A prospect for amyloid-β-removal therapy Aducanumab is a recombinant human monoclonal antibody that selectively targets the amyloid-β (Aβ) peptide aggregates thought to play a part in the neurodegenerative process in Alzheimer's disease. Several Alzheimer's disease drugs have failed in development in recent years — including other anti-amyloid antibodies — so there is intense interest in any new developments. A new study reports interim results from a clinical trial of monthly infusions of aducanumab in subjects with prodromal or mild Alzheimer's disease. Treatment with aducanumab reduced brain Aβ plaques, an action accompanied by a dose-dependent slowing of clinical decline. The trial data support further development of aducanumab as an Aβ-removing therapy.

Non-natively folded variants of superoxide dismutase 1 (SOD1) are thought to contribute to the pathogenesis of familial amyotrophic lateral sclerosis (ALS), however the relative toxicities of these variants are controversial. Here, we aimed to decipher the relationships between the different SOD1 variants (aggregated, soluble misfolded, soluble total) and the clinical presentation of ALS in the SOD1 G93A mouse. Using a multi-approach strategy, we found that the CNS regions least affected by disease had the most aggregated SOD1. We also found that the levels of aggregated SOD1 in the spinal cord were inversely correlated with the disease progression. Conversely, in the most affected regions, we observed that there was a high soluble misfolded/soluble total SOD1 ratio. Taken together, these findings suggest that soluble misfolded SOD1 may be the disease driver in ALS, whereas aggregated SOD1 may serve to sequester the toxic species acting in a neuroprotective fashion.

Alzheimer's disease (AD) is characterized by deposition of amyloid-[beta] (A[beta]) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against A[beta] to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated A[beta]. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal A[beta], and reduce soluble and insoluble A[beta] in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain A[beta] in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating--Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

Long description: Das Personal in geriatrischen Pflegeinstitutionen ist häufig einem starken moralischen Stress ausgesetzt, welcher die psychische Gesundheit beeinträchtigen kann. Bisherige Ansätze der betrieblichen Gesundheitsförderung haben diesen Aspekt bislang noch nicht berücksichtigt. Ebenfalls weitestgehend unberücksichtigt, ist die Situation des nicht-pflegerischen Personals in einem geriatrischen Pflegeheim. Eine mögliche Interventionsform ist das so genannte Ethik-Café. Diese Form der ethischen Weiterbildung, mit niedriger Zugangsschwelle und praktischer Ausrichtung, ist speziell für eine interdisziplinäre Anspruchsgruppe in der Altenpflege entwickelt worden. Allerdings sind weder die Effekte der Ethik-Cafés auf das Belastungserleben und die psychische Gesundheit untersucht worden, noch wurde empirisch überprüft, ob deren in der Fachliteratur postulierten Eigenschaften auch tatsächlich von den Rezipienten wahrgenommen werden. Die vorliegende Studie hat deshalb Pioniercharakter, da erstmalig die gesundheitsfördernde Wirkung einer ethischen Intervention mit einer wissenschaftlich-empirischen Methodik untersucht wird.

This corrects the article DOI: 10.1038/nature21361.

In the main part of this PhD thesis, we consider a periodically realized microscopic superconductor described by BCS theory, which is subject to external electromagnetic fields. We show that the superconductor is properly described by Ginzburg--Landau theory in the macroscopic and weak magnetic field limit. The main novelty of our results is to allow for a non-vanishing magnetic flux through the unit cell of the lattice of periodicity. These main results are supplemented by various unpublished notes in the field of BCS theory. Furthermore, we preface the presentation of these results with a comprehensive introduction suitable for master's or PhD students. Thereby, we hope to contribute to filling the gap of missing introductory literature in the field. The thesis comprises a second topic, in which we provide ideas for setting up quantum lattice systems in order to prove exponential estimates for the adiabatic theorem. These notes are the result of studies in this field, which have been conducted during a research stay at the University of British Columbia (UBC) in Vancouver, Canada.