Description of a new laboratory evaluation method of interdental brush abrasion as a clinical hazard.

Objectives: To simulate the abrasive potential of an interdental brush when applied with toothpastes and prophylactic gels/solutions in a novel laboratory brushing simulation set-up.

Methods: A brushing device was customized to treat dentin samples mimicking a simplified interdental space with an interdental brush (ISO 2). The brushing, that is, 7200 strokes for 1 h, was performed with artificial saliva (control), a povidone-iodine solution, and slurries of chlorhexidine and fluoride gels as well as three toothpastes with different RDA values ranging from 29 to 100, respectively.

Effects of Diminished NADPH:cytochrome P450 Reductase in Human Hepatocytes on Lipid and Bile Acid Homeostasis.

NADPH:cytochrome P450 oxidoreductase (POR) is the obligate electron donor for microsomal cytochrome P450 (CYP) enzymes involved in the biosynthesis of endogenous substances like bile acids and other steroids as well as in the oxidative metabolism of xenobiotics. P450 oxidoreductase also supports other redox enzymes in fatty acid and cholesterol pathways. Recently, we have established CRISPR/Cas9-mediated POR knockdown in a human hepatic cell model, HepaRG, and demonstrated the differential effects of limited POR expression on CYP activity.

High-Throughput Assessment of Kinome-wide Activation States.

Aberrant kinase activity has been linked to a variety of disorders; however, methods to probe kinase activation states in cells have been lacking. Until now, kinase activity has mainly been deduced from either protein expression or substrate phosphorylation levels. Here, we describe a strategy to directly infer kinase activation through targeted quantification of T-loop phosphorylation, which serves as a critical activation switch in a majority of protein kinases.

Conserved crosstalk between histone deacetylation and H3K79 methylation generates DOT1L-dose dependency in HDAC1-deficient thymic lymphoma.

DOT1L methylates histone H3K79 and is aberrantly regulated in MLL-rearranged leukemia. Inhibitors have been developed to target DOT1L activity in leukemia, but cellular mechanisms that regulate DOT1L are still poorly understood. We have identified the histone deacetylase Rpd3 as a negative regulator of budding yeast Dot1.

Heartbeat-enhanced immersive virtual reality to treat complex regional pain syndrome.

Objectives: To develop and test a new immersive digital technology for complex regional pain syndrome (CRPS) that combines principles from mirror therapy and immersive virtual reality and the latest research from multisensory body processing.

Methods: In this crossover double-blind study, 24 patients with CRPS and 24 age- and sex-matched healthy controls were immersed in a virtual environment and shown a virtual depiction of their affected limb that was flashing in synchrony (or in asynchrony in the control condition) with their own online detected heartbeat (heartbeat-enhanced virtual reality [HEVR]). The primary outcome measures for pain reduction were subjective pain ratings, force strength, and heart rate variability (HRV).

Brain-actuated functional electrical stimulation elicits lasting arm motor recovery after stroke.

Brain-computer interfaces (BCI) are used in stroke rehabilitation to translate brain signals into intended movements of the paralyzed limb. However, the efficacy and mechanisms of BCI-based therapies remain unclear. Here we show that BCI coupled to functional electrical stimulation (FES) elicits significant, clinically relevant, and lasting motor recovery in chronic stroke survivors more effectively than sham FES.

Effect of an integrated intervention package of preventive chemotherapy, community-led total sanitation and health education on the prevalence of helminth and intestinal protozoa infections in Côte d'Ivoire.

Background: Preventive chemotherapy with donated anthelminthic drugs is the cornerstone for the control of helminthiases. However, reinfection can occur rapidly in the absence of clean water and sanitation coupled with unhygienic behaviour. The purpose of this study was to assess the effect of an integrated package of interventions, consisting of preventive chemotherapy, community-led total sanitation (CLTS) and health education, on the prevalence of helminth and intestinal protozoa infections and on participants' knowledge, attitude, practice and beliefs (KAPB) towards these diseases including water, sanitation and hygiene (WASH).

Non-invasive brain stimulation of motor cortex induces embodiment when integrated with virtual reality feedback.

Previous evidence highlighted the multisensory-motor origin of embodiment - that is, the experience of having a body and of being in control of it - and the possibility of experimentally manipulating it. For instance, an illusory feeling of embodiment towards a fake hand can be triggered by providing synchronous visuo-tactile stimulation to the hand of participants and to a fake hand or by asking participants to move their hand and observe a fake hand moving accordingly (rubber hand illusion). Here, we tested whether it is possible to manipulate embodiment not through stimulation of the participant's hand, but by directly tapping into the brain's hand representation via non-invasive brain stimulation.

Increasing upper limb training intensity in chronic stroke using embodied virtual reality: a pilot study.

Background: Technology-mediated neurorehabilitation is suggested to enhance training intensity and therefore functional gains. Here, we used a novel virtual reality (VR) system for task-specific upper extremity training after stroke. The system offers interactive exercises integrating motor priming techniques and embodied visuomotor feedback.

Assessment of SRM, MRM(3) , and DIA for the targeted analysis of phosphorylation dynamics in non-small cell lung cancer.

Hypothesis-driven MS-based targeted proteomics has gained great popularity in a relatively short timespan. Next to the widely established selected reaction monitoring (SRM) workflow, data-independent acquisition (DIA), also referred to as sequential window acquisition of all theoretical spectra (SWATH) was introduced as a high-throughput targeted proteomics method. DIA facilitates increased proteome coverage, however, does not yet reach the sensitivity obtained with SRM.

Diet-induced neuropeptide expression: feasibility of quantifying extended and highly charged endogenous peptide sequences by selected reaction monitoring.

Understanding regulation and action of endogenous peptides, especially neuropeptides, which serve as inter- and intracellular signal transmitters, is key in understanding a variety of functional processes, such as energy balance, memory, circadian rhythm, drug addiction, etc. Therefore, accurate and reproducible quantification of these bioactive endogenous compounds is highly relevant. The biosynthesis of endogenous peptides, involving multiple possible trimming and modification events, hinders the de novo prediction of the active peptide sequences, making MS-based measurements very valuable in determining the actual active compounds.

Contribution of specific residues of the β-solenoid fold to HET-s prion function, amyloid structure and stability.

The [Het-s] prion of the fungus Podospora anserina represents a good model system for studying the structure-function relationship in amyloid proteins because a high resolution solid-state NMR structure of the amyloid prion form of the HET-s prion forming domain (PFD) is available. The HET-s PFD adopts a specific β-solenoid fold with two rungs of β-strands delimiting a triangular hydrophobic core. A C-terminal loop folds back onto the rigid core region and forms a more dynamic semi-hydrophobic pocket extending the hydrophobic core.

The epidemiology of polyparasitism and implications for morbidity in two rural communities of Côte d'Ivoire.

Background: Polyparasitism is still widespread in rural communities of the developing world. However, the epidemiology of polyparasitism and implications for morbidity are poorly understood. We studied patterns of multiple species parasite infection in two rural communities of Côte d'Ivoire, including associations and interactions between infection, clinical indicators and self-reported morbidity.

DIVE: a data intensive visualization engine.

Summary: Modern scientific investigation is generating increasingly larger datasets, yet analyzing these data with current tools is challenging. DIVE is a software framework intended to facilitate big data analysis and reduce the time to scientific insight. Here, we present features of the framework and demonstrate DIVE's application to the Dynameomics project, looking specifically at two proteins.

Effects of hygiene and defecation behavior on helminths and intestinal protozoa infections in Taabo, Côte d'Ivoire.

Background: More than 1 billion people are currently infected with soil-transmitted helminths and schistosomes. The global strategy to control helminthiases is the regular administration of anthelmintic drugs to at-risk populations. However, rapid re-infection occurs in areas where hygiene, access to clean water, and sanitation are inadequate.

Early steps in thermal unfolding of superoxide dismutase 1 are similar to the conformational changes associated with the ALS-associated A4V mutation.

There are over 100 mutations in Cu/Zn superoxide dismutase (SOD1) that result in a subset of familial amyotrophic lateral sclerosis (fALS) cases. The hypothesis that dissociation of the dimer, misfolding of the monomer and subsequent aggregation of mutant SOD1 leads to fALS has been gaining support as an explanation for how these disparate missense mutations cause the same disease. These forms are only responsible for a fraction of the ALS cases; however, the rest are sporadic.

Structural changes to monomeric CuZn superoxide dismutase caused by the familial amyotrophic lateral sclerosis-associated mutation A4V.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron degenerative disease, and the inherited form, familial ALS (fALS), has been linked to over 100 different point mutations scattered throughout the Cu-Zn superoxide dismutase protein (SOD1). The disease is likely due to a toxic gain of function caused by the misfolding, oligomerization, and eventual aggregation of mutant SOD1, but it is not yet understood how the structurally diverse mutations result in a common disease phenotype. The behavior of the apo-monomer fALS-associated mutant protein A4V was explored using molecular-dynamics simulations to elucidate characteristic structural changes to the protein that may allow the mutant form to improperly associate with other monomer subunits.

Single-gene deletions that restore mating competence to diploid yeast.

Using the Saccharomyces cerevisiae MATa/MATalpha ORF deletion collection, homozygous deletion strains were identified that undergo mating with MATa or MATalpha haploids. Seven homozygous deletions were identified that confer enhanced mating. Three of these, lacking CTF8, CTF18, and DCC1, mate at a low frequency with either MATa or MATalpha haploids.

Discovery and SAR of potent, orally available and brain-penetrable 5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen- and 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen derivatives as neuropeptide Y Y5 receptor antagonists.

Combination of structural elements from a potent Y5 antagonist (2) with thiazole fragments that exhibit weak Y5 affinities followed by lead optimisation led to the discovery of (5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino and (4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino derivatives. Both classes of compounds are capable of delivering potent and selective orally and centrally bioavailable NPY Y5 receptor antagonists.

Design, synthesis and SAR of a series of 2-substituted 4-amino-quinazoline neuropeptide Y Y5 receptor antagonists.

The design of a novel series of NPY-Y5 receptor antagonists is described. Key elements for the design were the identification of weak Y5 hits from a Y1 program, results from a combinatorial approach and database mining. This led to the discovery of the quinazoline 4 and the aryl-sulphonamide moiety as major components of the pharmacophore for Y5 affinity.

Modeling the G-protein-coupled neuropeptide Y Y1 receptor agonist and antagonist binding sites.

Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor (GPCR) superfamily and mediate several physiological responses, such as blood pressure, food intake, sedation and memory retention. To understand the interactions between the NPY Y1 receptor subtype and its ligands, computer modeling was applied to the natural peptide agonist, NPY and a small molecule antagonist, BIBP3226. An agonist and antagonist binding domain was elucidated using mutagenesis data for the Y1 receptor as well as for other GPCR families.

Risk factors for death in the 27 March 1994 Georgia and Alabama tornadoes.

Field surveys were made one week after tornadoes killed 40 persons and injured over 300 in rural regions of Alabama and Georgia, USA, on 27 March 1994. Surveys were completed for samples of 20 persons who were killed and 31 persons who were in the paths of the tornadoes but survived to determine whether there were differences in personal characteristics, behavior or location between the two groups. Persons who died were significantly older than persons who survived, more likely to be in mobile homes or in rooms above ground with windows, less likely to be watching television before the tornado, and were aware of the approaching tornado for less time than survivors.