Synthesis and Biological Evaluation of Enantiomerically Pure () and ()[18F]OF-NB1 for Imaging the GluN2B Subunit-Containing NMDA Receptors.

GluN2B subunit-containing methyl-d-aspartate (NMDA) receptors have been implicated in various neurological disorders. Nonetheless, a validated fluorine-18 labeled positron emission tomography (PET) ligand for GluN2B imaging in the living human brain is currently lacking. The aim of this study was to develop a novel synthetic approach that allows an enantiomerically pure radiosynthesis of the previously reported PET radioligands ()[F]OF-NB1 and ()[F]OF-NB1 as well as to assess their and performance characteristics for imaging the GluN2B subunit-containing NMDA receptor in rodents.

Negative allosteric modulators of NMDA receptors with GluN2B subunit: synthesis of β-aminoalcohols by epoxide opening and subsequent rearrangement.

In order to obtain novel antagonists of GluN2B subunit containing NMDA receptors, aryloxiranes were opened with benzylpiperidines. Phenyloxiranes 6 and (indazolyl)oxirane 15 were opened regioselectively at the position bearing the aryl moiety. Reaction of the resulting β-aminoalcohols 7 and 16 with carboxylic acids under Mitsunobu conditions (DIAD, PPh) led to rearrangement and after ester hydrolysis to the regioisomeric β-aminoalcohols 9 and 18.

Synthesis and Biological Evaluation of Enantiomerically Pure ()- and ()-[F]OF-NB1 for Imaging the GluN2B Subunit-Containing NMDA receptors.

GluN2B subunit-containing -methyl-d-aspartate (NMDA) receptors have been implicated in various neurological disorders. Nonetheless, a validated fluorine-18 labeled positron emission tomography (PET) ligand for GluN2B imaging in the living human brain is currently lacking. As part of our PET ligand development program, we have recently reported on the preclinical evaluation of [F]OF-NB1 - a GluN2B PET ligand with promising attributes for potential clinical translation.

Chemical, pharmacodynamic and pharmacokinetic characterization of the GluN2B receptor antagonist 3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1-3-benzazepine-1,7-diol - starting point for PET tracer development.

GluN2B-NMDA receptors play a key role in several neurological and neurodegenerative disorders. In order to develop novel negative allosteric GluN2B-NMDA receptor modulators, the concept of conformational restriction was pursued, i.e.

Photocatalytic Isomerization of ()-Anethole to ()-Anethole.

Natural product ()-anethole was isomerized to ()-anethole in a photocatalytic reaction. For this purpose, a self-designed cheap photoreactor was constructed. Among 11 photosensitizers (organo and metal complex compounds), Ir(p-Bu-ppy) led to the highest conversion.

Interactions between SQUAMOSA and SHORT VEGETATIVE PHASE MADS-box proteins regulate meristem transitions during wheat spike development.

Inflorescence architecture is an important determinant of crop productivity. The number of spikelets produced by the wheat inflorescence meristem (IM) before its transition to a terminal spikelet (TS) influences the maximum number of grains per spike. Wheat MADS-box genes VERNALIZATION 1 (VRN1) and FRUITFULL 2 (FUL2) (in the SQUAMOSA-clade) are essential to promote the transition from IM to TS and for spikelet development.

Microscale Parallel Synthesis of Acylated Aminotriazoles Enabling the Development of Factor XIIa and Thrombin Inhibitors.

Herein we report a microscale parallel synthetic approach allowing for rapid access to libraries of N-acylated aminotriazoles and screening of their inhibitory activity against factor XIIa (FXIIa) and thrombin, which are targets for antithrombotic drugs. This approach, in combination with post-screening structure optimization, yielded a potent 7 nM inhibitor of FXIIa and a 25 nM thrombin inhibitor; both compounds showed no inhibition of the other tested serine proteases. Selected N-acylated aminotriazoles exhibited anticoagulant properties in vitro influencing the intrinsic blood coagulation pathway, but not extrinsic coagulation.

Deconstruction - Reconstruction: Analysis of the Crucial Structural Elements of GluN2B-Selective, Negative Allosteric NMDA Receptor Modulators with 3-Benzazepine Scaffold.

Background/aims: The NMDA receptor plays a key role in the pathogenesis of neurodegenerative disorders including Alzheimer's and Huntington's disease, as well as depression and drug or alcohol dependence. Due to its participation in these pathologies, the development of selective modulators for this ion channel is a promising strategy for rational drug therapy. The prototypical negative allosteric modulator ifenprodil inhibits selectively GluN2B subunit containing NMDA receptors.

Acylated 1-1,2,4-Triazol-5-amines Targeting Human Coagulation Factor XIIa and Thrombin: Conventional and Microscale Synthesis, Anticoagulant Properties, and Mechanism of Action.

We herein report the conventional and microscale parallel synthesis of selective inhibitors of human blood coagulation factor XIIa and thrombin exhibiting a 1,2,4-triazol-5-amine scaffold. Structural variations of this scaffold allowed identifying derivative , a potent 29 nM inhibitor of FXIIa, with improved selectivity over other tested serine proteases and also finding compound with 27 nM inhibitory activity toward thrombin. For the first time, acylated 1,2,4-triazol-5-amines were proved to have anticoagulant properties and the ability to affect thrombin- and cancer-cell-induced platelet aggregation.

Oligomerization of the microtubule-associated protein tau is mediated by its N-terminal sequences: implications for normal and pathological tau action.

Despite extensive structure-function analyses, the molecular mechanisms of normal and pathological tau action remain poorly understood. How does the C-terminal microtubule-binding region regulate microtubule dynamics and bundling? In what biophysical form does tau transfer trans-synaptically from one neuron to another, promoting neurodegeneration and dementia? Previous biochemical/biophysical work led to the hypothesis that tau can dimerize via electrostatic interactions between two N-terminal 'projection domains' aligned in an anti-parallel fashion, generating a multivalent complex capable of interacting with multiple tubulin subunits. We sought to test this dimerization model directly.

Information without Implementation: A Practical Example for Developing a Best Practice Education Control Group.

This article considers methodology for developing an education-only control group and proposes a simple approach to designing rigorous and well-accepted control groups. This approach is demonstrated in a large randomized trial. The Lifestyles trial (n = 367) compared three group interventions: (a) cognitive-behavioral treatment (CBT) for osteoarthritis pain, (b) CBT for osteoarthritis pain and insomnia, and (c) education-only control (EOC).

Do patient-perceived pros and cons of opioids predict sustained higher-dose use?

Objectives: Chronic opioid therapy (COT) is associated with various adverse outcomes, especially at higher doses, yet little is known about predictors of sustained higher-dose COT. This study aimed to ascertain, among higher-dose COT patients, the association of patient-perceived pros and cons of opioids with continued higher-dose use 1 year later.

Methods: Patients (N=1229) in 2 large health plans prescribed ≥50 mg morphine-equivalent dose (MED) per day for chronic noncancer pain completed a survey assessing opioid benefits and harms.

Single feature polymorphism (SFP)-based selective sweep identification and association mapping of growth-related metabolic traits in Arabidopsis thaliana.

Background: Natural accessions of Arabidopsis thaliana are characterized by a high level of phenotypic variation that can be used to investigate the extent and mode of selection on the primary metabolic traits. A collection of 54 A. thaliana natural accession-derived lines were subjected to deep genotyping through Single Feature Polymorphism (SFP) detection via genomic DNA hybridization to Arabidopsis Tiling 1.

Patterns of care for depressed older adults in a large-staff model HMO.

The authors examined automated pharmacy and visit data for 502 members of a large-staff model health maintenance organization (HMO) who had been diagnosed with depression and started on antidepressants by their primary-care providers. Older patients (age >/=60; n=110) were less likely than younger adults (age 18-59, n=110) to receive adequate doses of antidepressant medications for 30 or 90 days. Older adults were also less likely than younger adults to receive more than two primary-care visits for depression in the 12 weeks after receiving a new antidepressant prescription and were less likely to receive specialty mental health care in the 6 months after receiving a new antidepressant prescription.

Chronic use of symptomatic headache medications.

Chronic use of symptomatic headache medication is believed to be a risk factor for drug-induced chronic headache. This study reports the frequency of chronic use of symptomatic headache medications implicated in drug-induced chronic headache among primary-care headache (PCH) patients and identifies predictors of chronic/frequent use. The design uses a 2-year cohort study of a sample of PCH patients in Group Health Cooperative of Puget Sound, a large health maintenance organization in Seattle, WA.

An investigation of the potential for laser nerve welding.

Suture repair of a severed peripheral nerve is cumbersome, presents a focus for infection and neuroma formation, and does not always produce adequate stump alignment. An alternative form of repair is laser nerve welding, which is attractive because it does not introduce foreign material into the anastomotic site, it forms a circumferential seal, and it can be performed in difficult-to-reach areas. Laser repair has not been widely accepted both because the effect of laser irradiation on intact nerves is not well documented, and the anastomotic strength of the weld has been inferior to suture repair.

Job satisfaction of night nurses in Germany.

In Germany research on nurses has dealt mainly with shortages, fluctuation, motivation, stress and working conditions, not on the characteristics of nursing care nor on specific groups of nurses. And as there were few research projects that touched on nurses who work night shifts, a study was designed to specifically cover this group. Below, the results of a research project that was both a teaching and a learning project initiated by nurses who wanted to learn nursing research by doing research.

[The implantation of self-expanding metal prostheses (stents) into the bronchial system in central neoplasms].

This paper reports the use of an endobronchial metallic prosthesis (wall stent) for palliative management of 6 patients with central neoplasms and life-threatening airway obstruction. In five of six patients implantation of the stent resulted in improvement of their dyspnoea. However, functional data showed only a slight amelioration.

Evoked accelerometry: a sensitive and accurate method for evaluating facial nerve function using a portable device.

A new electrodiagnostic technique has been developed which can be used to monitor facial nerve function. The technique has been termed "evoked accelerometry" (EAC) and is administered by a portable DC powered device. In performing a test, the device stimulates the facial nerve and then measures the evoked muscular response by a small accelerometer sensor affixed to the face with suction.