P 30. Evoking language errors using online paired-pulse TMS – A proof-of-principle study

ZusammenfassungDer Ersatz dopaminerger Neurone bei Patienten mit Morbus Parkinson bleibt eine attraktive Behandlungsstrategie. Die Implantation von embryonalem Mittelhirngewebe war die erste Therapie, die nicht nur den »Proof-of-Principle« in Tierversuchen lieferte, sondern auch Eingang in klinische Applikationen fand. 1987 wurde zunächst eine Reihe von kleinen offenen Studien mit sorgfältiger Patientenselektion gestartet, die sehr ermutigende Ergebnisse bei zumindest einem Teil der Patienten erbrachten. In den vergangenen Jahren wurden in den USA zwei doppelblinde, kontrollierte Studien abgeschlossen, deren Resultate eher enttäuschend blieben, da die primären Endpunkte (Besserung der Parkinson-Symptomatik im Off) keine signifikanten Unterschiede zeigten. Zudem wurden in beiden Studien 12 Stunden nach L-Dopa-Einnahme Dyskinesien beobachtet. Die Ursachen dieser unterschiedlichen Ergebnisse könnten in der Variabilität des Gewebes, relevanten Immunreaktionen und ungleichmäßiger Dopaminausschüttung im Striatum liegen. Zudem legen die ethischen Probleme bei der Gewinnung des Gewebes die Notwendigkeit anderer, besser standardisierter Gewebe nahe. Derzeit scheint es möglich, dass alternativ sowohl aus embryonalen als auch neuralen Stammzellen, vielleicht sogar aus körpereigenen mesenchymalen Stammzellen dopaminerge Neurone generiert werden könnten. Diese Zellen können über einen langen Zeitraum expandiert, ausreichend standardisiert und charakterisiert werden.

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Identifizierung MTB-spezifischer Zellen in der BAL von Patienten mit mikroskopisch negativer Tuberkulose: Proof of principle

Pneumologie ◽

10.1055/s-2006-933860 ◽

2006 ◽

Vol 60 (S 1) ◽

Author(s):

C Jafari ◽

M Ernst ◽

K Marienfeld ◽

C Lange

Keyword(s):

Proof Of Principle

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Enantioselective Multi-Component Cyclopropane Synthesis Enabled by Cu-Catalyzed Cyclopropene Carbometallation with Organoboron Reagent

10.26434/chemrxiv.7011548 ◽

2018 ◽

Author(s):

Zhanyu Li ◽

Mengru Zhang ◽

Yu Zhang ◽

Shuang Liu ◽

Jinbo Zhao ◽

...

Keyword(s):

Carbon Source ◽

Stereoselective Synthesis ◽

Organometallic Reagents ◽

Preliminary Results ◽

Quaternary Center ◽

Chiral Centers ◽

Substituted Cyclopropanes ◽

Proof Of Principle

Deployment of organoboron in lieu of the strongly basic organometallic reagents as carbon source in Cu-catalyzed cyclopropene carbometallation opens unprecedented three- component reactivity for stereoselective synthesis of poly-substituted cyclopropanes. A proof-of-principle demonstration of this novel carbometallation strategy is presented herein for a highly convergent access to poly-substituted aminocyclopropane framework via carboamination. Preliminary results on asymmetric desymmetrization with commercial bisphosphine ligands attained high levels of enantioselection, offering a straightforward access to enantioenriched aminocyclopropanes bearing all-three chiral centers, including an all-carbon quaternary center. This strategy may underpin a host of novel synthetic protocols for poly-substituted cyclopropanes.

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Covalent-Fragment Screening of Brd4 Identifies a Ligandable Site Orthogonal to the Acetyl-Lysine Binding Sites

10.26434/chemrxiv.8859098 ◽

2019 ◽

Author(s):

Michael Olp ◽

Daniel Sprague ◽

Stefan Kathman ◽

Ziyang Xu ◽

Alexandar Statsyuk ◽

...

Keyword(s):

Mass Spectrometry ◽

Binding Site ◽

Binding Sites ◽

Computational Prediction ◽

Chemical Probes ◽

Computational Docking ◽

Fragment Screening ◽

Covalent Inhibitors ◽

Bet Protein ◽

Proof Of Principle

Brd4, a member of the bromodomain and extraterminal domain (BET) family, has emerged as a promising epigenetic target in cancer and inflammatory disorders. All reported BET family ligands bind within the bromodomain acetyl-lysine binding sites and competitively inhibit BET protein interaction with acetylated chromatin. Alternative chemical probes that act orthogonally to the highly-conserved acetyl-lysine binding sites may exhibit selectivity within the BET family and avoid recently reported toxicity in clinical trials of BET bromodomain inhibitors. Here, we report the first identification of a ligandable site on a bromodomain outside the acetyl-lysine binding site. Inspired by our computational prediction of hotspots adjacent to non-homologous cysteine residues within the C-terminal Brd4 bromodomain (Brd4-BD2), we performed a mid-throughput mass spectrometry screen to identify cysteine-reactive fragments that covalently and selectively modify Brd4. Subsequent mass spectrometry, NMR and computational docking analyses of electrophilic fragment hits revealed a novel ligandable site near Cys356 that is unique to Brd4 among all human bromodomains. This site is orthogonal to the Brd4-BD2 acetyl-lysine binding site as Cys356 modification did not impact binding of the pan-BET bromodomain inhibitor JQ1 in fluorescence polarization assays. Finally, we tethered covalent fragments to JQ1 and performed NanoBRET assays to provide proof of principle that this orthogonal site can be covalently targeted in intact human cells. Overall, we demonstrate the potential of targeting sites orthogonal to bromodomain acetyl-lysine binding sites to develop bivalent and covalent inhibitors that displace Brd4 from chromatin.

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Faculty Opinions recommendation of Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1157905.620704 ◽

2009 ◽

Author(s):

Sumio Hoka

Keyword(s):

Cohort Study ◽

Resistant Hypertension ◽

Sympathetic Denervation ◽

Renal Sympathetic Denervation ◽

Proof Of Principle ◽

Renal Sympathetic

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Proof of Principle Study of Thickness Measurements Using Characteristic X-Ray Line Ratio Techniques

10.21236/ada221113 ◽

1990 ◽

Author(s):

Kerry W. Habiger ◽

Charles Stein

Keyword(s):

Line Ratio ◽

X Ray ◽

Thickness Measurements ◽

Proof Of Principle

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Proof of Principle for an 81-mm Nonlethal Mortar Cartridge

10.21236/ada403230 ◽

2002 ◽

Author(s):

James M. Garner ◽

Davie H. Lyon

Keyword(s):

Proof Of Principle

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Anterior Cruciate Ligament Injury Prevention Exercises: Could a Neuromuscular Warm-Up Improve Muscle Pre-Activation before a Soccer Game? A Proof-of-Principle Study on Professional Football Players

Applied Sciences ◽

10.3390/app11114958 ◽

2021 ◽

Vol 11 (11) ◽

pp. 4958

Author(s):

Alessandro de Sire ◽

Andrea Demeco ◽

Nicola Marotta ◽

Lucrezia Moggio ◽

Arrigo Palumbo ◽

...

Keyword(s):

Anterior Cruciate Ligament ◽

Cruciate Ligament ◽

Acl Injury ◽

Football Players ◽

Professional Football ◽

Activation Time ◽

Exercise Protocol ◽

Warm Up ◽

Anterior Cruciate ◽

Proof Of Principle

Neuromuscular warm-up has been shown to decrease the risk of anterior cruciate ligament (ACL) injury improving muscular firing patterns. All preventive training programs described in the literature have a duration of several weeks. To date, no studies have explored the immediate effect of a neuromuscular warm-up exercise on pre-activation time of the knee stabilizer muscles. Thus, this proof-of-principle study aimed at evaluating the acute effects of a neuromuscular warm-up exercises on the electromyographic activation of knee stabilizer muscles’ activation pattern. We included 11 professional football players, mean aged 23.2 ± 4.5 years, from a Southern Italy football team. All of them underwent a standard warm-up exercise protocol at the first day of the evaluation. At 1 week, they underwent a structured neuromuscular warm-up exercise protocol. We assessed as outcome measure the pre-activation time (ms) of rectus femoris (RF), vastus medialis (VM), biceps femoris (BF), and medial hamstrings (MH) upon landing. Outcomes were assessed before and after the standard warm-up and neuromuscular warm-up. Pre-activation time of RF, VM, BF and MH significantly improved only after neuromuscular warm-up (p < 0.05); moreover, there was a significant (p < 0.05) between-group difference in pre-activation time of all muscles after the neuromuscular warm-up compared with the standard warm-up. These findings suggested that physical exercise consisting of a structured injury prevention neuromuscular warm-up might have an immediate effect in improving the activation time of the knee stabilizer muscles, thus potentially reducing the risk of ACL injury.

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