Phosphomimetics at Ser199/Ser202/Thr205 in Tau Impairs Axonal Transport in Rat Hippocampal Neurons.

Our understanding of the biological functions of the tau protein now includes its role as a scaffolding protein involved in signaling regulation, which also has implications for tau-mediated dysfunction and degeneration in Alzheimer's disease and other tauopathies. Recently, we found that pseudophosphorylation at sites linked to the pathology-associated AT8 phosphoepitope of tau disrupts normal fast axonal transport through a protein phosphatase 1 (PP1)-dependent pathway in squid axoplasm. Activation of the pathway and the resulting transport deficits required tau's N-terminal phosphatase-activating domain (PAD) and PP1 but the connection between tau and PP1 was not well defined.

Gene electrotransfer of FGF2 enhances collagen scaffold biocompatibility.

Tendon injuries are a common athletic injury that have been increasing in prevalence. While there are current clinical treatments for tendon injuries, they have relatively long recovery times and often do not restore native function of the tendon. In the current study, gene electrotransfer (GET) parameters for delivery to the skin were optimized with monophasic and biphasic pulses with reporter and effector genes towards optimizing underlying tendon healing.

Frontotemporal Lobar Dementia Mutant Tau Impairs Axonal Transport through a Protein Phosphatase 1γ-Dependent Mechanism.

Pathologic tau modifications are characteristic of Alzheimer's disease and related dementias, but mechanisms of tau toxicity continue to be debated. Inherited mutations in tau cause early onset frontotemporal lobar dementias (FTLD-tau) and are commonly used to model mechanisms of tau toxicity in tauopathies. Previous work in the isolated squid axoplasm model demonstrated that several pathogenic forms of tau inhibit axonal transport through a mechanism involving activation of protein phosphatase 1 (PP1).

Reference intervals for end-tidal carbon monoxide of preterm neonates.

Objectives: We constructed reference intervals for end-tidal carbon monoxide (ETCOc) levels of neonates 28 to 34 weeks gestation in order to assess hemolytic rate.

Study Design: This is a prospective four-NICU study in Bangkok, Thailand, and Utah, USA.

Results: Of 226 attempted measurements, 92% were successful.

Pathogenic MAST3 Variants in the STK Domain Are Associated with Epilepsy.

Objective: The MAST family of microtubule-associated serine-threonine kinases (STKs) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been conclusively associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum.

Methods: Using exome sequencing, we identify MAST3 missense variants in individuals with epilepsy.

cAMP-regulated phosphoproteins DARPP-32, ARPP16/19, and RCS modulate striatal signal transduction through protein kinases and phosphatases.

Decades of research led by Paul Greengard identified protein phosphorylation as a ubiquitous and vital post-translational modification involved in many neuronal signaling pathways. In particular, his discovery that second messenger-regulated protein phosphorylation plays a central role in the propagation and transduction of signals in the nervous system has been essential in understanding the molecular mechanisms of neuronal communication. The establishment of dopamine (DA) as an essential neurotransmitter in the central nervous system, combined with observations that DA activates G-protein-coupled receptors to control the production of cyclic adenosine monophosphate (cAMP) in postsynaptic neurons, has provided fundamental insight into the regulation of neurotransmission.

Phosphodiesterase PDE4D Is Decreased in Frontal Cortex of Aged Rats and Positively Correlated With Working Memory Performance and Inversely Correlated With PKA Phosphorylation of Tau.

Age is the largest risk factor for Alzheimer's disease (AD) and contributes to cognitive impairment in otherwise healthy individuals. Thus, it is critical that we better understand the risk aging presents to vulnerable regions of the brain and carefully design therapeutics to address those effects. In this study we examined age-related changes in cAMP-regulatory protein, phosphodiesterase 4D (PDE4D).

Pathogenic tau modifications occur in axons before the somatodendritic compartment in mossy fiber and Schaffer collateral pathways.

The deposition of tau pathology in Alzheimer's disease (AD) may occur first in axons of neurons and then progress back into the cell bodies to form neurofibrillary tangles, however, studies have not directly analyzed this relationship in relatively discrete circuits within the human hippocampus. In the early phases of tau deposition, both AT8 phosphorylation and exposure of the amino terminus of tau occurs in tauopathies, and these modifications are linked to mechanisms of synaptic and axonal dysfunction. Here, we examined the localization of these tau pathologies in well-characterized post-mortem human tissue samples from the hippocampus of 44 cases ranging between non-demented and mild cognitively impaired to capture a time at which intrahippocampal pathways show a range in the extent of tau deposition.

Impact of moderate prenatal alcohol exposure on histaminergic neurons, histidine decarboxylase levels and histamine H receptors in adult rat offspring.

We have reported that moderate prenatal alcohol exposure (PAE) elevates histamine H receptor-mediated inhibition of glutamatergic neurotransmission in dentate gyrus (DG), and that the H receptor antagonist ABT-239 ameliorates PAE-induced deficits in DG long-term potentiation. Here, we investigated whether PAE alters other markers of histaminergic neurotransmission. Long-Evans rat dams voluntarily consumed either a 0% or a 5% ethanol solution 4 h each day throughout gestation.

Effects of printing-induced interfaces on localized strain within 3D printed hydrogel structures.

Additive manufacturing, or 3D printing, is a promising approach for the fabrication of biological structures for regenerative medicine applications using tissue-like materials such as hydrogels. Herein, inkjet printing is implemented as a model droplet-based 3D printing technology for which interfaces have been shown to form between printed lines within printed layers of hydrogel structures. Experimental samples with interfaces in two orientations are fabricated by inkjet printing and control samples with and without interfaces are fabricated by extrusion printing and casting, respectively.

In Situ Printing-then-Mixing for Biological Structure Fabrication Using Intersecting Jets.

Although traditional three-dimensional bioprinting technology is suitable for many tissue engineering applications, various biomaterials and constructs call for bioprinting innovations. There is a need for the fabrication of complex structures from reactive biomaterials as well as heterogeneous structures with controlled material compositions. In particular, during reactive material printing, reactive solutions/suspensions that undergo changes in rheological properties or cytocompatibility are not printable using traditional bioprinting approaches that require all components of bioinks to be mixed before deposition.

Promotion of Civic Engagement with the Family Leadership Training Institute.

In this efficacy study, both quantitative and qualitative data were used to gauge the effects of the Family Leadership Training Institute (FLTI) on civic knowledge and empowerment, civic engagement, and community health. The sample of 847 FLTI participants and 166 comparison adults completed pretest and posttest surveys. Medium to very large short-term effects were observed in civic literacy, empowerment, and engagement.

Axonal Degeneration in Tauopathies: Disease Relevance and Underlying Mechanisms.

Tauopathies are a diverse group of diseases featuring progressive dying-back neurodegeneration of specific neuronal populations in association with accumulation of abnormal forms of the microtubule-associated protein tau. It is well-established that the clinical symptoms characteristic of tauopathies correlate with deficits in synaptic function and neuritic connectivity early in the course of disease, but mechanisms underlying these critical pathogenic events are not fully understood. Biochemical evidence fueled the widespread notion that microtubule stabilization represents tau's primary biological role and that the marked atrophy of neurites observed in tauopathies results from loss of microtubule stability.

Inkjet Bioprinting of 3D Silk Fibroin Cellular Constructs Using Sacrificial Alginate.

Silk fibroin is a natural protein which has shown great promise for tissue engineering but is not printable due to slow gelation or harsh gelation conditions which are not cell-friendly. In this study, a two-step gelation process is proposed for the printing of silk fibroin, which utilizes alginate as a sacrificial hydrogel during an inkjetting-based process. A cell-laden blend of alginate with silk fibroin is utilized to achieve rapid gelation by calcium alginate formation during printing; it is followed by horseradish peroxidase (HRP) catalyzed covalent cross-linking of the fibroin protein at tyrosine residues after printing.

Tryptophan, kynurenine, and kynurenine metabolites: Relationship to lifetime aggression and inflammatory markers in human subjects.

Inflammatory proteins are thought to be causally involved in the generation of aggression, possibly due to direct effects of cytokines in the central nervous system and/or by generation of inflammatory metabolites along the tryptophan-kynurenine (TRP/KYN) pathway, including KYN and its active metabolites kynurenic acid (KA), quinolinic acid (QA), and picolinic acid (PA). We examined plasma levels of TRP, KYN, KA, QA, and PA in 172 medication-free, medically healthy, human subjects to determine if plasma levels of these substances are altered as a function of trait aggression, and if they correlate with current plasma levels of inflammatory markers. Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), and soluble interleukin-1 receptor-II (sIL-1RII) protein were also available in these subjects.

Intensive OutPatient Therapy for Clergy Burnout: How Much Difference Can a Week Make?

A pre-test and post-test quasi-experimental matched pairs design was used to assess the effectiveness of a week-long multi-therapist intensive outpatient intervention process with clergy suffering from depression and burnout. Participants (n = 23) in the "Clergy in Kairos" program of the Pastoral Institute (Muse in J Pastor Care Couns 61(3):183-195, 2007) constituted the experimental variable. Clergy surveyed from United Methodist and Presbyterian denominations (n = 121) provided a control group from which 23 respondents were selected whose pre-test scores in depression and burnout were statistically equivalent to those in the experimental group.

Freeform inkjet printing of cellular structures with bifurcations.

Organ printing offers a great potential for the freeform layer-by-layer fabrication of three-dimensional (3D) living organs using cellular spheroids or bioinks as building blocks. Vascularization is often identified as a main technological barrier for building 3D organs. As such, the fabrication of 3D biological vascular trees is of great importance for the overall feasibility of the envisioned organ printing approach.

A double-blind placebo-controlled comparison of a novel formulation of intravenous diclofenac and ketorolac for postoperative third molar extraction pain.

Dyloject is a novel formulation of diclofenac intended for intravenous (IV) administration. This formulation employs the solubilizing agent hydroxypropyl-β-cyclodextrin to permit bolus IV administration. The efficacy and safety of 5 dose levels of IV diclofenac were compared with IV ketorolac and placebo following third molar extraction.

A single-tablet fixed-dose combination of racemic ibuprofen/paracetamol in the management of moderate to severe postoperative dental pain in adult and adolescent patients: a multicenter, two-stage, randomized, double-blind, parallel-group, placebo-controlled, factorial study.

Background: The combination of ibuprofen and paracetamol may confer analgesic benefits over monotherapy with either agent. In a previous study, an ibuprofen/paracetamol combination provided significantly better analgesic efficacy than comparable doses of ibuprofen or paracetamol alone in patients experiencing moderate to severe acute postoperative pain after extraction of impacted third molars.

Objective: This study compared the efficacy and tolerability of 3 doses of a single-tablet fixed-dose combination (FDC) of ibuprofen and paracetamol (ibuprofen/paracetamol doses of 100 mg/250 mg, 200 mg/500 mg, and 400 mg/1000 mg) with comparable doses of ibuprofen (200 or 400 mg) monotherapy, paracetamol (500 or 1000 mg) monotherapy, and placebo in the 8 hours after surgical removal of 3 to 4 impacted third molars (stage 1) and with placebo over the next 72 hours (stage 2).

The analgesic efficacy and safety of a novel intranasal morphine formulation (morphine plus chitosan), immediate release oral morphine, intravenous morphine, and placebo in a postsurgical dental pain model.

Background: Opioids are standard treatment for postoperative pain. In this study, we compared the safety and efficacy of intranasal (i.n.

Valdecoxib versus rofecoxib in acute postsurgical pain: results of a randomized controlled trial.

The analgesic efficacy of the cyclooxygenase-2 specific inhibitors, valdecoxib and rofecoxib, were evaluated in patients following oral surgery. In a randomized, double-blind, controlled trial, patients experiencing moderate or severe pain received single-dose valdecoxib 40 mg (n=99), rofecoxib 50 mg (n=101), or placebo (n=50) within 4 hours after multiple third molar extraction with bone removal. Onset of action was significantly faster with valdecoxib 40 mg (30 minutes) compared with rofecoxib 50 mg (45 minutes), as measured by pain intensity difference and pain relief scores (P View Article and Find Full Text PDF