Biomarkers.

Background: In the context of pathological aging and Alzheimer's disease (AD), the overexpression of calcineurin has been identified as a factor linked to astrocyte reactivity, neuronal death, and inflammation. This suggests that inhibiting calcineurin or downstream nuclear factor of activated T cells (NFAT) signaling could be a promising strategy for preventing or slowing down AD pathophysiology.

Method: Baseline and annual MRI sessions including higher-order diffusion-weighted imaging was performed over four years on 43 dogs ranging from 5 to 8.

Calcineurin/NFAT inhibitors maintain cognition in a preclinical prevention study in an aging canine model of Alzheimer disease.

Brain signaling of calcineurin (CN) and nuclear factor of activated T-cells (NFAT) transcription factor increases in Alzheimer disease (AD) and is associated with synaptic loss, neurodegeneration, neuroinflammation, amyloid-β (Aβ) production, and cognitive decline. CN/NFAT inhibitors ameliorate these neuropathologies in mouse models of AD. Further, chronic use of tacrolimus in transplant patients reduces risk of AD.

Age-Related Brain Atrophy and the Positive Effects of Behavioral Enrichment in Middle-Aged Beagles.

Aging dogs serve as a valuable preclinical model for Alzheimer's disease (AD) due to their natural age-related development of β-amyloid (Aβ) plaques, human-like metabolism, and large brains that are ideal for studying structural brain aging trajectories from serial neuroimaging. Here we examined the effects of chronic treatment with the calcineurin inhibitor (CNI) tacrolimus or the nuclear factor of activated T cells (NFAT)-inhibiting compound Q134R on age-related canine brain atrophy from a longitudinal study in middle-aged beagles (36 females, 7 males) undergoing behavioral enrichment. Annual MRI was analyzed using modern, automated techniques for region-of-interest-based and voxel-based volumetric assessments.

The Effect of Preoperative Education Prior to Hip or Knee Arthroplasty on Immediate Postoperative Outcomes.

There is ample research demonstrating improved patient outcomes when using an enhanced recovery program. However, the literature reporting the impact of preoperative education alone prior to hip and knee arthroplasty is conflicting. With the number of these surgical procedures expected to increase in the next few years, the identification of strategies that positively impact outcomes is important.

Tacrolimus Protects against Age-Associated Microstructural Changes in the Beagle Brain.

The overexpression of calcineurin leads to astrocyte hyperactivation, neuronal death, and inflammation, which are characteristics often associated with pathologic aging and Alzheimer's disease. In this study, we tested the hypothesis that tacrolimus, a calcineurin inhibitor, prevents age-associated microstructural atrophy, which we measured using higher-order diffusion MRI, in the middle-aged beagle brain ( = 30, male and female). We find that tacrolimus reduces hippocampal ( = 0.

Assumptions of authority: the story of Sue the T-rex and controversy over access to fossils.

Although the buying, selling, and trading of fossils has been a principle part of paleontological practice over the centuries, the commercial collection of fossils today has re-emerged into a pervasive and lucrative industry. In the United States, the number of commercial companies driving the legal, and sometimes illegal, selling of fossils is estimated to have doubled since the 1980s, and worries from academic paleontologists over this issue has increased accordingly. Indeed, some view the commercialization of fossils as one of the greatest threats to paleontology today.

How preparation to touch or grasp alters visual size perception.

Prior studies have suggested that visually guided actions are resistant to the effects of some pictorial size illusions, e.g., the maximum grip aperture component of a grasp for an element of the Ebbinghaus illusion display.

Reliability and validity of the Jefferson scale of attitudes toward physician-nurse collaboration for nurse practitioners.

Background: The Jefferson Scale of Attitudes Toward Physician-Nurse Collaboration (JSATPNC) has been used to measure attitudes regarding nurse-physician collaboration. However, psychometric evaluation is lacking for the nurse practitioner (NP) population.

Purpose: This study details a confirmatory approach in testing the factor analytic structure of the JSATPNC against previously reported structures.

Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design.

A fragment-based screen against human immunodeficiency virus type 1 (HIV) integrase led to a number of compounds that bound to the lens epithelium derived growth factor (LEDGF) binding site of the integrase catalytic core domain. We determined the crystallographic structures of complexes of the HIV integrase catalytic core domain for 10 of these compounds and quantitated the binding by surface plasmon resonance. We demonstrate that the compounds inhibit the interaction of LEDGF with HIV integrase in a proximity AlphaScreen assay, an assay for the LEDGF enhancement of HIV integrase strand transfer and in a cell based assay.

Structural basis for a new mechanism of inhibition of HIV-1 integrase identified by fragment screening and structure-based design.

Background: HIV-1 integrase is a clinically validated therapeutic target for the treatment of HIV-1 infection, with one approved therapeutic currently on the market. This enzyme represents an attractive target for the development of new inhibitors to HIV-1 that are effective against the current resistance mutations.

Methods: A fragment-based screening method employing surface plasmon resonance and NMR was initially used to detect interactions between integrase and fragments.

Royal ruptures: Caroline of Ansbach and the politics of illness in the 1730s.

Caroline of Ansbach, wife of George II, occupied a crucial position in the public life of early 18th-century Britain. She was seen to exert considerable influence on the politics of the court and, as mother to the Hanoverian dynasty's next generation, she became an important emblem for the nation's political well-being. This paper examines how such emblematic significance was challenged and qualified when Caroline's body could no longer be portrayed as healthy and life giving.

Microwave-promoted synthesis of 3-amino-substituted 1,2-benzisoxazoles.

Background: 1,2-benzisoxazole derivatives have been the focus of numerous studies, due to their biological and chemical interest.

Results: We demonstrate an efficient synthesis of a series of 3-amino-substituted 1,2-benzisoxazoles from a 3-chloro-1,2-benzisoxazole by microwave-promoted nucleophilic aromatic substitution. The 3-amino-1,2-benzisoxazoles prepared were obtained in 1-6 h in good-to-high yields of 54-90%.

Antiviral agents 3. Discovery of a novel small molecule non-nucleoside inhibitor of hepatitis B virus (HBV).

The discovery of a small molecule non-nucleoside inhibitor of Hepatitis B Virus is described. During our work on conocurvone derived naphthoquinone 'trimers' for the treatment of HIV, we discovered a potent inhibitor 9 of Hepatitis B Virus in an antiviral screen. During attempts to resynthesis 9 for proof of concept studies, we altered the synthesis in order to attempt to reduced side reactions and difficult to remove by-products.

High content imaging-based assay to classify estrogen receptor-α ligands based on defined mechanistic outcomes.

Estrogen receptor-α (ER) is an important target both for therapeutic compounds and endocrine disrupting chemicals (EDCs); however, the mechanisms involved in chemical modulation of regulating ER transcriptional activity are inadequately understood. Here, we report the development of a high content analysis-based assay to describe ER activity that uniquely exploits a microscopically visible multi-copy integration of an ER-regulated promoter. Through automated single-cell analyses, we simultaneously quantified promoter occupancy, recruitment of transcriptional cofactors and large-scale chromatin changes in response to a panel of ER ligands and EDCs.

Design of a series of bicyclic HIV-1 integrase inhibitors. Part 2: azoles: effective metal chelators.

Synthesis of a diverse set of azoles and their utilizations as an amide isostere in the design of HIV integrase inhibitors is described. The Letter identified thiazole, oxazole, and imidazole as the most promising heterocycles. Initial SAR studies indicated that these novel series of integrase inhibitors are amenable to lead optimization.

Design of a series of bicyclic HIV-1 integrase inhibitors. Part 1: selection of the scaffold.

HIV integrase inhibitors based on a novel bicyclic pyrimidinone core is presented. Nine variations of the core scaffold are evaluated leading to optimization of the 6:6 core giving compound 48 with an EC(50) of 3 nM against wild type HIV infected T-cells.

Antiviral agents 2. Synthesis of trimeric naphthoquinone analogues of conocurvone and their antiviral evaluation against HIV.

The synthesis of a new series of conocurvone analogues is presented that explores the importance of the pyran rings of conocurvone, their degree of unsaturation as well as the role of alkoxy functionalities as pyran ring replacements, for the inhibition of the HIV-1 integrase (IN) enzyme. Difficulties in synthesising a trimeric naphthoquinone where the central quinone bears a peri-dihydropyran ring was attributed to distortion of the electrophilic dihaloquinone successfully utilised in the past. Increased electron density could also be a factor in reducing reactivity.

Discovery of potent HIV integrase inhibitors active against raltegravir resistant viruses.

A series of novel HIV integrase inhibitors active against rategravir resistant strains are reported. Initial SAR studies revealed that activities against wild-type virus were successfully maintained at single digit nanomolar level with a wide range of substitutions. However, inclusion of nitrogen-based cyclic substitutions was crucial for achieving potency against mutant viruses.

Studies on the structure-activity relationship of 1,3,3,4-tetra-substituted pyrrolidine embodied CCR5 receptor antagonists. Part 2: Discovery of highly potent anti-HIV agents.

Modification of 1,3,3,4-tetra-substituted pyrrolidine embodied CCR5 receptor antagonists revealed that introducing a fluoro group at the 3-position of the 3-phenyl group to reduce metabolism did not adversely affect the high potency against HIV infection, and that replacing the piperidine ring with a tropane ring could deliver the most potent anti-HIV agents. Stereochemistry of the substituted tropane ring is essential for maintaining the potent anti-HIV activity because only exo-isomers displayed subnanomolar whole cell activity.

Studies on the structure-activity relationship of 1,3,3,4-tetra-substituted pyrrolidine embodied CCR5 receptor antagonists. Part 1: Tuning the N-substituents.

A novel series of CCR5 antagonists has been identified, utilizing the lead, nifeviroc, which were further modified based on bioisosteric principles. Lead optimization was pursued by balancing potential toxicity and potency. Potent analogues with low toxic properties were successfully developed by formation of urea and amide bonds at the nitrogen at position 4- of the pyrrolidine ring.