Probing Local Electrostatics of Glycine in Aqueous Solution by THz Spectroscopy.

Based upon precise terahertz (THz) measurements of the solvated amino acid glycine and accompanying ab-initio molecular-dynamics simulations, we show that the N-C-C-O open/close mode at 315 cm-1 serves as a sensitive, label-free probe for the local protonation of the amide group. Experimentally, we can show that this holds not only for glycine but also for diglycine and valine. The approach is more general, since the changes due to protonation result in intensity changes which can be probed by THz time domain (0-50 cm-1 ) as well as by precise THz-FT spectroscopy (50-400 cm-1 ). A detailed analysis allows us to directly correlate the titration spectra with pKa values. This demonstrates the potential of THz spectroscopy to probe the charge state of a natural amino acid in water in a label-free manner.

Lipoprotein receptor loss in forebrain radial glia results in neurological deficits and severe seizures.

The Alzheimer disease-associated multifunctional low-density lipoprotein receptor-related protein-1 is expressed in the brain. Recent studies uncovered a role of this receptor for the appropriate functioning of neural stem cells, oligodendrocytes, and neurons. The constitutive knock-out (KO) of the receptor is embryonically lethal. To unravel the receptors' role in the developing brain we generated a mouse mutant by specifically targeting radial glia stem cells of the dorsal telencephalon. The low-density lipoprotein receptor-related protein-1 lineage-restricted KO female and male mice, in contrast to available models, developed a severe neurological phenotype with generalized seizures during early postnatal development. The mechanism leading to a buildup of hyperexcitability and emergence of seizures was traced to a failure in adequate astrocyte development and deteriorated postsynaptic density integrity. The detected impairments in the astrocytic lineage: precocious maturation, reactive gliosis, abolished tissue plasminogen activator uptake, and loss of functionality emphasize the importance of this glial cell type for synaptic signaling in the developing brain. Together, the obtained results highlight the relevance of astrocytic low-density lipoprotein receptor-related protein-1 for glutamatergic signaling in the context of neuron-glia interactions and stage this receptor as a contributing factor for epilepsy.

Why do family dementia caregivers reject caregiver support services? Analyzing types of rejection and associated health-impairments in a cluster-randomized controlled intervention trial.

BACKGROUND: Although there are a number of support services accessible for most family dementia caregivers, many caregivers reject available and affordable support. Previous research suggests that rejections of support services may result from insufficient fit of available services with caregivers' unmet needs and a lack of acknowledgement of caregivers' unmet needs and associated support services. The present study investigates (a) the number, proportion and types of caregivers' rejection on recommended tailored support, (b) socio-demographic and clinical determinants of caregiver's rejection of both people with dementia (PwD) and caregivers, and (c) caregivers' health-related variables related to caregivers' rejection. METHODS: Caregivers' rejection of tailored support services was identified based on a standardized, computerized unmet needs assessment conducted by dementia-specific qualified nurses. The present analysis is based on data of n = 226 dyads of caregivers and their community-dwelling PwD who participated in a general practitioner (GP)-based, cluster-randomized intervention trial. The trial was approved by the Ethical Committee of the Chamber of Physicians of Mecklenburg-Western Pomerania, registry number BB 20/11. Data analyses were conducted using Stata/IC 13.1. We conducted Welch's t-test, Pearson's product-moment correlation, and conditional negative binomial regression models with random effects for GP to account for over-dispersed count data. RESULTS: In sum, n = 505 unmet needs were identified and the same number of tailored recommendations were identified for n = 171 family dementia caregivers from the intervention group at baseline. For n = 55 family dementia caregivers not a single unmet need and recommendation were identified. A total of 17.6% (n = 89) of the recommendations were rejected by caregivers. Rejection rates of caregivers differed by type of recommendation. Whereas caregivers' rejection rate on recommendations concerning mental health (3.6%), physical health (2.5%), and social, legal, and financial affairs (0%) were low, caregivers' rejection rates concerning social integration (especially caregiver supporting groups) was high (71.7%). Thus, the rejections of family dementia caregivers are mainly linked to the delegation to caregiver supporting groups. Caregivers' rejections were mainly related to personal factors of caregivers (n = 66), service-related factors (n = 6), relational factors (n = 1), and other factors (n = 17). Furthermore, our results showed that the number of caregivers' rejections was associated with a higher functional status of the PwD and are mainly associated with the rejection of caregiver supporting groups. Thus, caregivers visit supporting groups more often when the PwD shows low abilities in activities of daily living. Importantly, this is independent of the status of cognition and depression of the PwD as well as the physical and mental health of the family dementia caregivers. CONCLUSIONS: Our results underline the importance of understanding factors that determine caregivers' rejection of support services. These need to be specifically addressed in tailored solutions for caregivers' support services. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01401582 (date: July 25, 2011, prospective registered).

[Self-determination despite dementia! Participant protection instead of incapacitation in research : Report on the 5th Ethics Conference of the German Center for Neurodegenerative Diseases]. / Selbstbestimmung trotz Demenz! Probandenschutz statt Entmündigung in der Forschung : Tagungsbericht zur 5. Ethiktagung des Deutschen Zentrums für Neurodegenerative Erkrankungen (DZNE) Rostock/Greifswald.

In March 2019 the Ethics Conference of the German Center for Neurodegenerative Diseases (DZNE) was held for the fifth time. It was organized by the DZNE Rostock/Greifswald site and chaired by Prof. Wolfgang Hoffmann. The conference provided scientists, physicians, representatives of the German Alzheimer Society, (informal) caregivers of people with dementia (PwD), and other interested people with the opportunity to talk about the opportunities and limitations of research on and for PwD.Nationally and internationally recognized experts on healthcare services research, clinical research, nursing research, (geriatric) psychiatry, interdisciplinary ageing research, economic law, and psychotherapy discussed the pros and cons of a multitude of topics like self-determination, research participant decree, informed consent, and participation of PwD in research. The aim of the event was to reconcile the view of practice pleading for an ethically correct, human treatment of PwD and respecting their autonomy with participation in (clinical) studies. Experts controversially discussed and consolidated different points of view of practice and research.

Toward theoretical terahertz spectroscopy of glassy aqueous solutions: partially frozen solute-solvent couplings of glycine in water.

The molecular-level understanding of THz spectra of aqueous solutions under ambient conditions has been greatly advanced in recent years. Here, we go beyond previous analyses by performing ab initio molecular dynamics simulations of glycine in water with artificially frozen solute or solvent molecules, respectively, while computing the total THz response as well as its decomposition into mode-specific resonances based on the "supermolecular solvation complex" technique. Clamping the water molecules and keeping glycine moving breaks the coupling of glycine to the structural dynamics of the solvent, however, the polarization and dielectric solvation effects in the static solvation cage are still at work since the full electronic structure of the quenched solvent is taken into account. The complementary approach of fixing glycine reveals both the dynamical and electronic response of the solvation cage at the level of its THz response. Moreover, to quantitatively account for the electronic contribution solely due to solvent embedding, the solute species is "vertically desolvated", thus preserving the fully coupled solute-solvent motion in terms of the solute's structural dynamics in solution, while its electronic structure is no longer subject to solute-solvent polarization and charge transfer effects. When referenced to the free simulation of Gly(aq), this three-fold approach allows us to decompose the THz spectral contributions due to the correlated solute-solvent dynamics into entirely structural and purely electronic effects. Beyond providing hitherto unknown insights, the observed systematic changes of THz spectra in terms of peak shifts and lineshape modulations due to conformational freezing and frozen solvation cages might be useful to investigate the solvation of molecules in highly viscous H-bonding solvents such as ionic liquids and even in cryogenic ices as relevant to polar stratospheric and dark interstellar clouds.

Mode specific THz spectra of solvated amino acids using the AMOEBA polarizable force field.

We have used the AMOEBA model to simulate the THz spectra of two zwitterionic amino acids in aqueous solution, which is compared to the results on these same systems using ab initio molecular dynamics (AIMD) simulations. Overall we find that the polarizable force field shows promising agreement with AIMD data for both glycine and valine in water. This includes the THz spectral assignments and the mode-specific spectral decomposition into intramolecular solute motions as well as distinct solute-water cross-correlation modes some of which cannot be captured by non-polarizable force fields that rely on fixed partial charges. This bodes well for future studies for simulating and decomposing the THz spectra for larger solutes such as proteins or polymers for which AIMD studies are presently intractable. Furthermore, we believe that the current study on rather simple aqueous solutions offers a way to systematically investigate the importance of charge transfer, nuclear quantum effects, and the validity of computationally practical density functionals, all of which are needed to fully quantitatively capture complex dynamical motions in the condensed phase.

A hybrid approach unveils drug repurposing candidates targeting an Alzheimer pathophysiology mechanism.

The high number of failed pre-clinical and clinical studies for compounds targeting Alzheimer disease (AD) has demonstrated that there is a need to reassess existing strategies. Here, we pursue a holistic, mechanism-centric drug repurposing approach combining computational analytics and experimental screening data. Based on this integrative workflow, we identified 77 druggable modifiers of tau phosphorylation (pTau). One of the upstream modulators of pTau, HDAC6, was screened with 5,632 drugs in a tau-specific assay, resulting in the identification of 20 repurposing candidates. Four compounds and their known targets were found to have a link to AD-specific genes. Our approach can be applied to a variety of AD-associated pathophysiological mechanisms to identify more repurposing candidates.

Identifying Unmet Needs of Family Dementia Caregivers: Results of the Baseline Assessment of a Cluster-Randomized Controlled Intervention Trial.

BACKGROUND: Caregivers providing informal care for people with dementia (PwD) often report unmet needs, burden, and health impairments. Optimal support for family dementia caregivers will likely benefit from better understanding and assessment of the prevalence and types of caregivers' unmet needs and associated socio-demographic and clinical characteristics. OBJECTIVE: The present study investigates 1) the number and types of caregivers' unmet needs, 2) socio-demographic and clinical characteristics of both PwD and caregivers, and 3) caregivers' burden and health-related outcomes that are related to caregivers' unmet needs. METHODS: The present analyses are based on cross-sectional data of n = 226 dyads of caregivers and their community-dwelling PwD participating in a comprehensive standardized, computer-based caregivers' needs assessment within a general practitioner (GP)-based, cluster-randomized intervention trial. RESULTS: A total of n = 505 unmet needs were identified for n = 171 caregivers from the intervention group at baseline. Only 24.3% caregivers reported no unmet need (n = 55), whereas 75.7% caregivers had at least one unmet need (n = 171). Caregivers had on average 2.19 unmet needs (mean = 2.19, SD = 2.15). Specifically, 53.1% of caregivers had one up to three unmet needs (n = 120), 18.6% (n = 42) had three up to six unmet needs, and 4.0% (n = 9) had more than six unmet needs. DISCUSSION: Our results underline the importance of a comprehensive needs assessment for family dementia caregivers to develop and implement concepts that can provide family dementia caregivers with optimal support.

Tagging effects on the mid-infrared spectrum of microsolvated protonated methane.

Although bare protonated methane is by now essentially understood at the level of intramolecular large-amplitude motion, scrambling dynamics and broadband vibrational spectra, the microsolvated species still offer plenty of challenges. One aspect is the effect of the attached solvent molecules on the infrared absorption spectra of microsolvated CH5+ complexes compared to the bare parent molecule. In this study we analyze, based on ab initio molecular dynamics simulations, protonated methane molecules that have been microsolvated with up to three hydrogen molecules, i.e. CH5+·(H2) n . In particular, upon introducing a novel multi-channel maximum entropy methodology described herein, we are able to decompose the infrared spectra of these weakly-bound complexes in the frequency window from 1000 to 4500 cm-1 into additive single mode contributions. Detailed comparisons to the bare CH5+ parent reveal that these perturbed modes encode distinct features that depend on the exact microsolvation pattern. Beyond the specific case, such understanding is relevant to assess tagging artifacts in vibrational spectra of parent molecules based on messenger predissociation action spectroscopy.

Hydrophilic Solvation Dominates the Terahertz Fingerprint of Amino Acids in Water.

Spectroscopy in the terahertz frequency regime is a sensitive tool to probe solvation-induced effects in aqueous solutions. Yet, a systematic understanding of spectral lineshapes as a result of distinct solvation contributions remains terra incognita. We demonstrate that modularization of amino acids in terms of functional groups allows us to compute their distinct contributions to the total terahertz response. Introducing the molecular cross-correlation analysis method provides unique access to these site-specific contributions. Equivalent groups in different amino acids lead to look-alike spectral contributions, whereas side chains cause characteristic but additive complexities. Specifically, hydrophilic solvation of the zwitterionic groups in valine and glycine leads to similar terahertz responses which are fully decoupled from the side chain. The terahertz response due to H-bonding within the large hydrophobic solvation shell of valine turns out to be nearly indistinguishable from that in bulk water in direct comparison to the changes imposed by the charged functional groups that form strong H-bonds with their hydration shells. Thus, the hydrophilic groups and their solvation shells dominate the terahertz absorption difference, while on the same intensity scale, the influence of hydrophobic water can be neglected.

The Impact of Hospitalization on Readmission, Institutionalization, and Mortality of People with Dementia: A Systematic Review and Meta-Analysis.

BACKGROUND: People with dementia (PwD) are at a high risk of hospitalization. Hospitals are often not adequately equipped for PwD and discharges often come unexpected. Therefore, PwD are at a risk of adverse outcomes. However, information about those outcomes is rare but crucial for the development of preventive strategies. OBJECTIVES: To conduct a quantitative systematic review and meta-analyses on the impact of a hospitalization on readmission, institutionalization, and mortality in PwD. To identify factors associated with these outcomes. METHODS: PubMed, CENTRAL, and ScienceDirect were searched for studies including terms for dementia, hospital, readmission, institutionalization, and mortality. Relevant were assessed by a quality criteria sheet. Results were summarized in a table. Meta-analysis was conducted with Review Manager 5.3. RESULTS: The search yielded 1,108 studies; 20 fulfilled the inclusion criteria and 10 studies were eligible for meta-analyses. The incidence and relative risk (RR) of mortality (RR 1.74 CI95 % 1.50, 2.05) and institutionalization (RR: 2.16 CI95 % 1.31, 3.56) of PwD was significantly higher when compared to people without dementia. Results according to readmission rate were inconsistent. Factors significantly associated with the examined adverse outcomes were severity of dementia, number of medications, and deficits in daily living activities. CONCLUSION: Hospitalization of PwD lead to adverse outcomes. An improvement in the identification of and care for PwD in the acute setting as well as in after care in the community setting, especially in the interface between both settings, is required to prevent adverse outcomes in hospitalized PwD.