Alternate Day Fasting Leads to Improved Post-Stroke Motor Recovery in Mice.

Background: Caloric restriction promotes neuroplasticity and recovery after neurological injury. In mice, we tested the hypothesis that caloric restriction can act post-stroke to enhance training-associated motor recovery.

Methods: Mice were trained to perform a skilled prehension task.

Rational design of proteasome inhibitors based on the structure of the endogenous inhibitor PI31/Fub1.

Proteasome inhibitors are widely used anticancer drugs. The three clinically approved agents are modified small peptides that preferentially target one of the proteasome's three active sites (β5) at physiologic concentrations. In addition to these drugs, there is also an endogenous proteasome inhibitor, PI31/Fub1, that enters the proteasome's interior to simultaneously yet specifically inhibit all three active sites.

Squeeze-film properties of synovial fluid and hyaluronate-based viscosupplements.

The rheological properties of synovial fluid and hyaluronate (HA) solutions have been studied using a variety of viscometers and rheometers. These devices measure the viscosity of the fluid's resistance to shearing forces, which is useful when studying the lubrication and frictional properties of movable joints. Less commonly used is a squeeze-film fluid test, mechanistically similar to when two joint surfaces squeeze interposed fluid.

Enhanced Spontaneous Motor Recovery After Stroke in Mice Treated With Cerebrolysin.

Background: Motor recovery after stroke in humans and in rodent models is time sensitive. Recovery in patients is a result of biological spontaneous recovery via endogenous repair mechanisms and is likely improved by enhancing the synaptic plasticity required for endogenous repair. Cerebrolysin is a polypeptide preparation known to enhance neuroplasticity and may improve recovery in patients.

Snagfall the first decade after severe bark beetle infestation of high-elevation forests in Colorado, USA.

The persistence and fall rate of snags (standing dead trees) generated during bark beetle outbreaks have consequences for the behavior, effects, and suppression of potential wildfires, hazard tree and timber salvage operations, wildlife habitat, and numerous ecosystem processes. However, post-beetle snagfall dynamics are poorly understood in most forest types. We tagged standing live and dead lodgepole pine (Pinus contorta), subalpine fir (Abies lasiocarpa), and Engelmann spruce (Picea engelmannii), including beetle-killed pine snags following the peak of a recent mountain pine bark beetle outbreak in watersheds at the Fraser Experimental Forest in northcentral Colorado and sampled snagfall 10 and 12 years later.

Evaluating Skilled Prehension in Mice Using an Auto-Trainer.

We describe a method to introduce naïve mice to a novel prehension (reach-to-grasp) task. Mice are housed singly in cages with a frontal slot that permits the mouse to reach out of its cage and retrieve food pellets. Minimal food restriction is employed to encourage the mice to perform the food retrieval from the slot.

Evolutionary Models of Leadership : Tests and Synthesis.

This study tested four theoretical models of leadership with data from the ethnographic record. The first was a game-theoretical model of leadership in collective actions, in which followers prefer and reward a leader who monitors and sanctions free-riders as group size increases. The second was the dominance model, in which dominant leaders threaten followers with physical or social harm.

Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors.

Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, K = 160 μM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays.

Formation of A Novel Purine Metabolite through CYP3A4 Bioactivation and Glutathione Conjugation.

Background: The study of novel sites of metabolism is important in understanding new mechanisms of biotransformation of a particular moiety by metabolic enzymes. This information is valuable in designing metabolically-stable compounds with drug-like properties. It may also provide insights into the existence of active and reactive metabolites.

Paradoxical Motor Recovery From a First Stroke After Induction of a Second Stroke: Reopening a Postischemic Sensitive Period.

Background And Objective: Prior studies have suggested that after stroke there is a time-limited period of increased responsiveness to training as a result of heightened plasticity-a sensitive period thought to be induced by ischemia itself. Using a mouse model, we have previously shown that most training-associated recovery after a caudal forelimb area (CFA) stroke occurs in the first week and is attributable to reorganization in a medial premotor area (AGm). The existence of a stroke-induced sensitive period leads to the counterintuitive prediction that a second stroke should reopen this window and promote full recovery from the first stroke.

Fluoxetine Maintains a State of Heightened Responsiveness to Motor Training Early After Stroke in a Mouse Model.

Background And Purpose: Data from both humans and animal models suggest that most recovery from motor impairment after stroke occurs in a sensitive period that lasts only weeks and is mediated, in part, by an increased responsiveness to training. Here, we used a mouse model of focal cortical stroke to test 2 hypotheses. First, we investigated whether responsiveness to training decreases over time after stroke.

Developing lipid nanoparticle-based siRNA therapeutics for hepatocellular carcinoma using an integrated approach.

Successful siRNA therapeutics requires the optimal integration of multiple components, including an efficient delivery system, a disease indication that is appropriate for siRNA-based therapy, and a potent and nontoxic siRNA against a robust therapeutic target. Although all currently available delivery systems have limitations, it is important to recognize that a careful selection of the disease indication, therapeutic target, and siRNA molecule could partially compensate for deficiencies associated with the delivery system and makes it possible to advance a therapeutic siRNA regimen. In this study, we present the development of siRNA therapeutics for hepatocellular carcinoma using an integrated approach, including the development of an efficient lipid nanoparticle delivery system, the identification of a robust therapeutic target that does not trigger liver toxicity upon target knockdown, and the selection of potent and nonimmunogenic siRNA molecules against the target.

Links among nitrification, nitrifier communities, and edaphic properties in contrasting soils receiving dairy slurry.

Soil biotic and abiotic factors strongly influence nitrogen (N) availability and increases in nitrification rates associated with the application of manure. In this study, we examine the effects of edaphic properties and a dairy (Bos taurus) slurry amendment on N availability, nitrification rates and nitrifier communities. Soils of variable texture and clay mineralogy were collected from six USDA-ARS research sites and incubated for 28 d with and without dairy slurry applied at a rate of ~300 kg N ha(-1).

Cationic lipids percentage and processing temperature are critical in designing siRNA lipid nanoparticles.

To design a clinically viable small interfering RNA (siRNA) formulation, it is essential to understand the in vivo siRNA delivery mechanism during the product development. However, majority of reported siRNA delivery studies are based on testing only isolated factors, with ambiguous interpretation of often in vitro transfection results. Correlating physicochemical properties with in vivo transfection efficiency thus represents an important step towards rational design of siRNA delivery systems.

A robust in vivo positive-readout system for monitoring siRNA delivery to xenograft tumors.

Delivering small interfering RNA (siRNA) to tumors is the major technical hurdle that prevents the advancement of siRNA-based cancer therapy. One of the difficulties associated with the development of clinically relevant delivery systems is the lack of reliable tools for monitoring siRNA delivery to tumors in vivo. We describe here a novel, positive-readout system where siRNA-mediated target knockdown elicits a rapid and robust increase of reporter activity.

Substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as multi-targeted inhibitors of insulin-like growth factor-1 receptor (IGF1R) and members of ErbB-family receptor kinases.

This Letter describes the lead discovery, optimization, and biological characterization of a series of substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as potent inhibitors of IGF1R, EGFR, and ErbB2. The leading compound 11 showed an IGF1R IC(50) of 12 nM, an EGFR (L858R) IC(50) of 31 nM, and an ErbB2 IC(50) of 11 nM, potent activity in cellular functional and anti-proliferation assays, as well as activity in an in vivo pharmacodynamic assay.

Imidazo[2,1-b]thiazoles: multitargeted inhibitors of both the insulin-like growth factor receptor and members of the epidermal growth factor family of receptor tyrosine kinases.

The design and enzyme activities of a novel class of imidazo[2,1-b]thiazoles is presented.

Multisite effectiveness trials of treatments for substance abuse and co-occurring problems: have we chosen the best designs?

Multisite effectiveness trials such as those carried out in the National Drug Abuse Treatment Clinical Trials Network (CTN) are a critical step in the development and dissemination of evidence-based treatments because they address how such treatments perform in real-world clinical settings. As Brigham et al. summarized in a recent article (G.

Reversal of oncogene transformation and suppression of tumor growth by the novel IGF1R kinase inhibitor A-928605.

Background: The insulin-like growth factor (IGF) axis is an important signaling pathway in the growth and survival of many cell and tissue types. This pathway has also been implicated in many aspects of cancer progression from tumorigenesis to metastasis. The multiple roles of IGF signaling in cancer suggest that inhibition of the pathway might yield clinically effective therapeutics.

Quantifying phosphorus levels in soils, plants, surface water, and shallow groundwater associated with bahiagrass-based pastures.

Background, Aim, And Scope: Recent assessments of water quality status have identified eutrophication as one of the major causes of water quality 'impairment' not only in the USA but also around the world. In most cases, eutrophication has accelerated by increased inputs of phosphorus due to intensification of crop and animal production systems since the early 1990 s. Despite substantial measurements using both laboratory and field techniques, little is known about the spatial and temporal variability of phosphorus dynamics across landscapes, especially in agricultural landscapes with cow-calf operations.

Development of multitargeted inhibitors of both the insulin-like growth factor receptor (IGF-IR) and members of the epidermal growth factor family of receptor tyrosine kinases.

Emerging clinical and pre-clinical data indicate that both insulin-like growth factor receptor (IGF-IR) and members of the epidermal growth factor (EGF) family of receptor tyrosine kinases (RTKs) exhibit significant cross-talk in human cancers. Therefore, a small molecule that successfully inhibits the signaling of both classes of oncogenic kinases might provide an attractive agent for chemotherapeutic use. Herein, we disclose the structure activity relationships that led to the synthesis and biological characterization of 14, a novel small molecule inhibitor of both IGF-IR and members of the epidermal growth factor family of RTKs.

Synthesis and evaluation of aniline headgroups for alkynyl thienopyrimidine dual EGFR/ErbB-2 kinase inhibitors.

Aniline 'headgroups' were synthesized and incorporated into an alkynyl thienopyrimidine series of EGFR and ErbB-2 inhibitors. Potent inhibition of enzyme activity and cellular proliferation was observed. In certain instances, protein binding was reduced and oral exposure was found to be somewhat improved relative to compounds containing the reference aniline.

Synthesis and stereochemical effects of pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines as EGFR and ErbB-2 inhibitors.

A novel class of pyrrolidinyl-acetyleneic thieno[3,2-d]pyrimidines has been identified which potently inhibit the EGFR and ErbB-2 receptor tyrosine kinases. Synthetic modifications of the pyrrolidine carbamate moiety result in a range of effects on enzyme and cellular potency. In addition, the impact of the absolute stereochemical configuration on cellular potency and oral mouse pharmacokinetics is described.

Dual EGFR/ErbB-2 inhibitors from novel pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines.

A novel class of substituted pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines has been identified that are potent and selective inhibitors of both EGFR/ErbB-2 receptor tyrosine kinases. The inhibitors are found to display a range of enzyme and cellular potency and also to display a varying level of covalent modification of the kinase targets. Selected molecules, including compound 15h, were found to be potent in enzymatic and cellular assays while also demonstrating exposure in the mouse from an oral dose.

A comparison of four office chairs using biomechanical measures.

Objective: The authors sought to use biomechanical measures, including motion and pressure, to compare four office chairs.

Background: The fit of a person to a chair is related to the geometric and kinematic compatibility between the two. This geometric compatibility influences the motions that are allowed or prohibited and the support pressures at the body-chair interface.