Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies.

The accumulation of aberrantly aggregated MAPT (microtubule-associated protein Tau) defines a spectrum of tauopathies, including Alzheimer's disease. Mutations in the gene cause frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), characterized by neuronal pathological Tau inclusions in the form of neurofibrillary tangles and Pick bodies and in some cases glial Tau pathology. Increasing evidence points to the importance of prion-like seeding as a mechanism for the pathological spread in tauopathy and other neurodegenerative diseases.

A novel panel of α-synuclein antibodies reveal distinctive staining profiles in synucleinopathies.

Synucleinopathies are a spectrum of neurodegenerative diseases characterized by the intracellular deposition of the protein α-synuclein leading to multiple outcomes, including dementia and Parkinsonism. Recent findings support the notion that across the spectrum of synucleinopathies there exist diverse but specific biochemical modifications and/or structural conformations of α-synuclein, which would give rise to protein strain specific prion-like intercellular transmission, a proposed model that could explain synucleinopathies disease progression. Herein, we characterized a panel of antibodies with epitopes within both the C- and N- termini of α-synuclein.

Generation and characterization of new monoclonal antibodies targeting the PHF1 and AT8 epitopes on human tau.

Tauopathies are a group of neurodegenerative disorders, including Alzheimer's disease, defined by the presence of brain pathological inclusions comprised of abnormally aggregated and highly phosphorylated tau protein. The abundance of brain tau aggregates correlates with disease severity and select phospho-tau epitopes increase at early stages of disease. We generated and characterized a series of novel monoclonal antibodies directed to tau phosphorylated at several of these phospho-epitopes, including Ser396/Ser404, Ser404 and Thr205.

Murine Models of Sepsis and Trauma: Can We Bridge the Gap?

Sepsis and trauma are both leading causes of death in the United States and represent major public health challenges. Murine models have largely been used in sepsis and trauma research to better understand the pathophysiological changes that occur after an insult and to develop potential life-saving therapeutic agents. Mice are favorable subjects for this type of research given the variety of readily available strains including inbred, outbred, and transgenic strains.

How do stones form? Is unification of theories on stone formation possible?

There are two basic pathways for formation of calcium based kidney stones. Most idiopathic calcium oxalate (CaOx) stones are formed in association with sub-epithelial plaques of calcium phosphate (CaP), known as Randall's plaques, on renal papillary surfaces. Crystal formation and retention within the terminal collecting ducts, the ducts of Bellini, leading to the formation of Randall's plugs, is the other pathway.

One Step Forward, One Step Back: Changes in News Coverage of Medical Interventions.

During 2005-2013, the award-winning website HealthNewsReview.org offered reviews of major media outlets' news stories related to health interventions, including tests, treatments, dietary changes, and prescription drugs. The reviews offered a measure by which the public and journalists themselves could assess the completeness and usefulness of health coverage across 10 criteria for quality reporting.

Changes in Verbal Fluency in Parkinson's Disease.

Background: The test for semantic verbal fluency is quick and easy to administer. Decreases in semantic verbal fluency would suggest executive dysfunction among individuals with Parkinson's disease (PD).

Methods: The National Parkinson Foundation's Outcomes Project is a multicenter study that seeks to determine best practices in PD management.

Novel antibodies to phosphorylated α-synuclein serine 129 and NFL serine 473 demonstrate the close molecular homology of these epitopes.

Pathological inclusions containing aggregated, highly phosphorylated (at serine129) α-synuclein (αS pSer129) are characteristic of a group of neurodegenerative diseases termed synucleinopathies. Antibodies to the pSer129 epitope can be highly sensitive in detecting αS inclusions in human tissue and experimental models of synucleinopathies. However, the generation of extensively specific pSer129 antibodies has been problematic, in some cases leading to the misinterpretation of αS inclusion pathology.

Proteolysis of α-synuclein fibrils in the lysosomal pathway limits induction of inclusion pathology.

Progression of α-synuclein inclusion pathology may occur through cycles of release and uptake of α-synuclein aggregates, which induce additional intracellular α-synuclein inclusion pathology. This process may explain (i) the presence of α-synuclein inclusion pathology in grafted cells in human brains, and (ii) the slowly progressive nature of most human α-synucleinopathies. It also provides a rationale for therapeutic targeting of extracellular aggregates to limit pathology spread.

Bad for Breathing: A Pictorial of Drug-Induced Pulmonary Disease.

Drug-induced lung disease has been described with over 300 different agents, some of which are asymptomatic and may first present on imaging. These pulmonary diseases may present with variable imaging manifestations, and often overlap with other etiologies such as rejection, lymphoproliferative disorders, and infection that may be suspected in this patient population. However, there are several drugs that have classic imaging appearances, and in the proper clinical context, the radiologist should include their toxicity in the differential diagnosis, potentially expediting withdrawal of the drug and avoiding irreversible lung injury such as fibrosis.

Routine Clinical Mutation Profiling of Non-Small Cell Lung Cancer Using Next-Generation Sequencing.

Context: The availability of massive, parallel-sequencing technologies makes possible efficient, simultaneous detection of driver and druggable mutations in cancer.

Objective: To develop an amplicon-based, next-generation sequencing, mutation-detection assay for lung cancer using the 454 GS Junior (Roche Applied Science, Indianapolis, Indiana) platform.

Design: Fusion primers incorporating target sequence, 454 adaptors, and multiplex identifiers were designed to generate 35 amplicons (median length 246 base pairs) covering 8.

Differential Inhibition of Signal Peptide Peptidase Family Members by Established γ-Secretase Inhibitors.

The signal peptide peptidases (SPPs) are biomedically important proteases implicated as therapeutic targets for hepatitis C (human SPP, (hSPP)), plasmodium (Plasmodium SPP (pSPP)), and B-cell immunomodulation and neoplasia (signal peptide peptidase like 2a, (SPPL2a)). To date, no drug-like, selective inhibitors have been reported. We use a recombinant substrate based on the amino-terminus of BRI2 fused to amyloid β 1-25 (Aβ1-25) (FBA) to develop facile, cost-effective SPP/SPPL protease assays.

Brain injection of α-synuclein induces multiple proteinopathies, gliosis, and a neuronal injury marker.

Intracerebral injection of amyloidogenic α-synuclein (αS) has been shown to induce αS pathology in the CNS of nontransgenic mice and αS transgenic mice, albeit with varying efficiencies. In this study, using wild-type human αS transgenic mice (line M20), we demonstrate that intracerebral injection of recombinant amyloidogenic or soluble αS induces extensive αS intracellular inclusion pathology that is associated with robust gliosis. Near the injection site, a significant portion of αS inclusions are detected in neurons but also in astrocytes and microglia.

Acute hypernatremia promotes anxiolysis and attenuates stress-induced activation of the hypothalamic-pituitary-adrenal axis in male mice.

Previous investigation by our laboratory found that acute hypernatremia potentiates an oxytocinergic tone that inhibits parvocellular neurosecretory neurons in the paraventricular nucleus of the hypothalamus (PVN), attenuates restraint-induced surges in corticosterone (CORT), and reduces anxiety-like behavior in male rats. To investigate the neural mechanisms mediating these effects and extend our findings to a more versatile species, we repeated our studies using laboratory mice. In response to 2.

Intestinal microbial ecology and environmental factors affecting necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is the most devastating intestinal disease affecting preterm infants. In addition to being associated with short term mortality and morbidity, survivors are left with significant long term sequelae. The cost of caring for these infants is high.

γ-Secretase processing and effects of γ-secretase inhibitors and modulators on long Aβ peptides in cells.

Understanding how different species of Aβ are generated by γ-secretase cleavage has broad therapeutic implications, because shifts in γ-secretase processing that increase the relative production of Aβx-42/43 can initiate a pathological cascade, resulting in Alzheimer disease. We have explored the sequential stepwise γ-secretase cleavage model in cells. Eighteen BRI2-Aβ fusion protein expression constructs designed to generate peptides from Aβ1-38 to Aβ1-55 and C99 (CTFβ) were transfected into cells, and Aβ production was assessed.

Anti-tau antibodies: hitting the target.

Immunotherapies targeting tau in mouse models of human tauopathies could have disease-modifying effects. In this issue of Neuron, Yanamandra et al. (2013) use tau antibodies, which effectively block tau seeding in culture, to attenuate tauopathy and improve cognition in mutant tau mouse models.

Repeat sample intraocular pressure variance in induced and naturally ocular hypertensive monkeys.

Purpose: To compare repeat-sample means variance of laser induced ocular hypertension (OH) in rhesus monkeys with the repeat-sample mean variance of natural OH in age-range matched monkeys of similar and dissimilar pedigrees.

Materials & Methods: Multiple monocular, retrospective, intraocular pressure (IOP) measures were recorded repeatedly during a short sampling interval (SSI, 1-5 months) and a long sampling interval (LSI, 6-36 months). There were 5-13 eyes in each SSI and LSI subgroup.

Diprivan attenuates the cytotoxicity of nitric oxide in cultured human bronchial epithelial cells.

Objective: Excess nitric oxide (NO) and its reactive derivatives cause oxidative reactions that lead to cell death. Propofol, an intravenous anesthetic, exhibits antioxidant properties. Diprivan is a widely used commercial preparation of propofol that is emulsified in 10% intralipids.