Lysine 624 of the amyloid precursor protein (APP) is a critical determinant of amyloid β peptide length: support for a sequential model of γ-secretase intramembrane proteolysis and regulation by the amyloid β precursor protein (APP) juxtamembrane region.

γ-Secretase is a multiprotein intramembrane cleaving aspartyl protease (I-CLiP) that catalyzes the final cleavage of the amyloid β precursor protein (APP) to release the amyloid β peptide (Aβ). Aβ is the primary component of senile plaques in Alzheimer's disease (AD), and its mechanism of production has been studied intensely. γ-Secretase executes multiple cleavages within the transmembrane domain of APP, with cleavages producing Aβ and the APP intracellular domain (AICD), referred to as γ and ε, respectively.

Cortical blindness following a near-drowning incident.

Victims of near-drowning incidents often suffer neurologic injury with long-term sequelae secondary to hypoxic-ischemic injury. We describe a case of profound visual loss due to bilateral occipital lobe infarcts in a 23-year-old male victim of a near-drowning incident.

Risk factors associated with incident cataracts and cataract surgery in the Age-related Eye Disease Study (AREDS): AREDS report number 32.

Objective: To investigate potential risk factors associated with incident nuclear, cortical, and posterior subcapsular (PSC) cataracts and cataract surgery in participants in the Age-Related Eye Disease Study (AREDS).

Design: Clinic-based prospective cohort study.

Participants: Persons (n = 4425) 55 to 80 years of age enrolled in a controlled clinical trial of antioxidant vitamins and minerals, AREDS, for age-related macular degeneration and cataract.

Expanding indications for the Boston keratoprosthesis.

Purpose Of Review: To review emerging indications for the Boston keratoprosthesis (KPro) and to discuss current research underway to improve clinical outcomes.

Recent Findings: In addition to multiple failed corneal grafts, other ocular conditions for which the Boston KPro has been used include herpetic keratitis, aniridia, autoimmune ocular disorders, and pediatric corneal opacities. In the recent years, the KPro has been implanted for various other conditions and has also been explored as a cost-effective treatment for severe corneal diseases internationally.

Biology and pathophysiology of the amyloid precursor protein.

The amyloid precursor protein (APP) plays a central role in the pathophysiology of Alzheimer's disease in large part due to the sequential proteolytic cleavages that result in the generation of β-amyloid peptides (Aβ). Not surprisingly, the biological properties of APP have also been the subject of great interest and intense investigations. Since our 2006 review, the body of literature on APP continues to expand, thereby offering further insights into the biochemical, cellular and functional properties of this interesting molecule.

Robust, functionalizable, nanometer-thick poly(acrylic acid) films spontaneously assembled on oxidized aluminum substrates: structures and chemical properties.

Immersion of oxidized aluminum substrates in ethanol solutions of poly(acrylic acid) (PAA), followed by extensive solvent immersion, results in tenaciously chemisorbed, nanometer scale, controllable thickness films for a wide range of solution concentrations and molecular weights. Atomic force microscope images reveal isolated polymer globules from adsorption in low-concentration solutions with crossover to conformal, highly uniform, nanometer-thickness films at higher concentrations, an indication that the chemisorbing chains start to overlap and trap underlying segments to form planar chemisorbed films only two or three chains in thickness. Quantitative IR reflection spectroscopy in combination with chemical derivitization on a standard set of 1.

Anti-aβ therapeutics in Alzheimer's disease: the need for a paradigm shift.

Most current Alzheimer's disease (AD) therapies in advanced phases of development target amyloid β-peptide (Aβ) production, aggregation, or accumulation. Translational models suggest that anti-Aβ therapies may be highly effective if tested as agents to prevent or delay development of the disease or as therapies for asymptomatic patients with very early signs of AD pathology. However, anti-Aβ therapeutics are currently being tested in symptomatic patients where they are likely to be much less effective or ineffective.

Multiple psoas abscess formation after pharmacopuncture -a case report-.

Acupuncture has been widely used in alternative medicine for pain relief but may have many complications due to lack of appropriate cares. Pharmacopuncture is a sort of acupuncture that injects a herbal ingredient through a thin tube for the purpose of combining the effects of the herb and acupuncture and it has many pitfalls. The agents used in pharmacopuncture are not refined for a desired effect and not produced by sterile standard processes under strict medical surveillance.

Substrate docking to γ-secretase allows access of γ-secretase modulators to an allosteric site.

γ-Secretase generates the peptides of Alzheimer's disease, Aβ(40) and Aβ(42), by cleaving the amyloid precursor protein within its transmembrane domain. γ-Secretase also cleaves numerous other substrates, raising concerns about γ-secretase inhibitor off-target effects. Another important class of drugs, γ-secretase modulators, alter the cleavage site of γ-secretase on amyloid precursor protein, changing the Aβ(42)/Aβ(40) ratio, and are thus a promising therapeutic approach for Alzheimer's disease.

Comparison of the Psoriatic Arthritis Quality of Life (PsAQoL) questionnaire, the functional status (HAQ) and utility (EQ-5D) measures in psoriatic arthritis: results from a cross-sectional survey.

Objectives: To compare the Psoriatic Arthritis Quality of Life (PsAQoL) instrument, the Health Assessment Questionnaire (HAQ) as a measure of functional status, and the generic health status (utility) measure the EuroQoL (EQ-5D) in terms of ability to assess disease severity in psoriatic arthritis (PsA).

Methods: The differences between known groups and correlations of the PsAQoL, the HAQ and the EQ-5D with clinical measures were analysed in a sample of 183 PsA patients.

Results: Different severities of PsA determined by known groups were distinguished well by all three questionnaires; more severe disease was associated with significantly worse values of the instruments.

alpha-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Abeta generation.

The Swedish mutation within the amyloid precursor protein (APP) causes early-onset Alzheimer's disease due to increased cleavage of APP by BACE1. While beta-secretase shedding of Swedish APP (APPswe) largely results from an activity localized in the late secretory pathway, cleavage of wild-type APP occurs mainly in endocytic compartments. However, we show that liberation of Abeta from APPswe is still dependent on functional internalization from the cell surface.

A fragment of the scaffolding protein RanBP9 is increased in Alzheimer's disease brains and strongly potentiates amyloid-beta peptide generation.

Increasing biochemical and genetic evidence indicates that the amyloid-beta (Abeta) peptide derived from amyloid precursor protein (APP) plays a central role in Alzheimer's disease (AD) pathogenesis. We previously reported that RanBP9 promotes Abeta generation by scaffolding APP/BACE1/LRP complexes together. Interestingly, the RanBP9-Delta1/N60 (residues 1-392) deletion mutant interacted much more strongly with APP/BACE1/LRP than full-length RanBP9.

Mechanism of cytotoxicity mediated by the C31 fragment of the amyloid precursor protein.

The cytoplasmic tail of the amyloid precursor protein (APP) contains two putatively cytotoxic peptides, Jcasp and C31, derived by caspase cleavage of APP. Jcasp is a fragment starting from the epsilon-secretase site to position 664, while C31 is a fragment from position 665 to the C-terminus. Our studies now showed that compared to C31, Jcasp appeared to play a minor role in cytotoxicity.

Inflammasome-dependent caspase-1 activation in cervical epithelial cells stimulates growth of the intracellular pathogen Chlamydia trachomatis.

Inflammasomes have been extensively characterized in monocytes and macrophages, but not in epithelial cells, which are the preferred host cells for many pathogens. Here we show that cervical epithelial cells express a functional inflammasome. Infection of the cells by Chlamydia trachomatis leads to activation of caspase-1, through a process requiring the NOD-like receptor family member NLRP3 and the inflammasome adaptor protein ASC.

Induced dimerization of the amyloid precursor protein leads to decreased amyloid-beta protein production.

The amyloid precursor protein (APP) plays a central role in Alzheimer disease (AD) pathogenesis because sequential cleavages by beta- and gamma-secretase lead to the generation of the amyloid-beta (Abeta) peptide, a key constituent in the amyloid plaques present in brains of AD individuals. In several studies APP has recently been shown to form homodimers, and this event appears to influence Abeta generation. However, these studies have relied on APP mutations within the Abeta sequence itself that may affect APP processing by interfering with secretase cleavages independent of dimerization.

Disease burden of psoriatic arthritis compared to rheumatoid arthritis, Hungarian experiment.

The objectives of this study were to assess the costs of psoriatic arthritis (PsA) in Hungary and to identify key cost drivers among demographic and clinical variables and to compare cost-of-illness of PsA and rheumatoid arthritis (RA). Cross-sectional retrospective survey of 183 consecutive patients from eight rheumatology centres was conducted. Mean direct medical, direct non medical, indirect and total costs were 1,876, 794, 2,904 and 5,574 euros/patient/year, respectively.

Standardization of in vitro macrophotography for assessment of cutaneous responses.

The increased popularity of commercially available three-dimensional human skin equivalents in recent years has allowed for assessment of melanogenesis modulated by compounds topically applied to the skin or directly incorporated from the medium. These skin equivalents provide a suitable model for elucidating the mechanisms of action of various factors that modulate skin pigmentation or other properties of the skin. As such, researchers need to objectively quantify cutaneous responses at the macroscopic level.

Novel role of RanBP9 in BACE1 processing of amyloid precursor protein and amyloid beta peptide generation.

Accumulation of the amyloid beta (Abeta) peptide derived from the proteolytic processing of amyloid precursor protein (APP) is the defining pathological hallmark of Alzheimer disease. We previously demonstrated that the C-terminal 37 amino acids of lipoprotein receptor-related protein (LRP) robustly promoted Abeta generation independent of FE65 and specifically interacted with Ran-binding protein 9 (RanBP9). In this study we found that RanBP9 strongly increased BACE1 cleavage of APP and Abeta generation.

Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease.

Profound neuronal dysfunction in the entorhinal cortex contributes to early loss of short-term memory in Alzheimer's disease. Here we show broad neuroprotective effects of entorhinal brain-derived neurotrophic factor (BDNF) administration in several animal models of Alzheimer's disease, with extension of therapeutic benefits into the degenerating hippocampus. In amyloid-transgenic mice, BDNF gene delivery, when administered after disease onset, reverses synapse loss, partially normalizes aberrant gene expression, improves cell signaling and restores learning and memory.

Formation of Pmel17 amyloid is regulated by juxtamembrane metalloproteinase cleavage, and the resulting C-terminal fragment is a substrate for gamma-secretase.

The formation of insoluble cross beta-sheet amyloid is pathologically associated with disorders such as Alzheimer, Parkinson, and Huntington diseases. One exception is the nonpathological amyloid derived from the protein Pmel17 within melanosomes to generate melanin pigment. Here we show that the formation of insoluble MalphaC intracellular fragments of Pmel17, which are the direct precursors to Pmel17 amyloid, depends on a novel juxtamembrane cleavage at amino acid position 583 between the furin-like proprotein convertase cleavage site and the transmembrane domain.

Biodistribution and toxicological safety of adenovirus type 5 and type 35 vectored vaccines against human immunodeficiency virus-1 (HIV-1), Ebola, or Marburg are similar despite differing adenovirus serotype vector, manufacturer's construct, or gene inserts.

The Vaccine Research Center has developed vaccine candidates for different diseases/infectious agents (including HIV-1, Ebola, and Marburg viruses) built on an adenovirus vector platform, based on adenovirus type 5 or 35. To support clinical development of each vaccine candidate, pre-clinical studies were performed in rabbits to determine where in the body they biodistribute and how rapidly they clear, and to screen for potential toxicities (intrinsic and immunotoxicities). The vaccines biodistribute only to spleen, liver (Ad5 only), and/or iliac lymph node (Ad35 only) and otherwise remain in the site of injection muscle and overlying subcutis.

Amyloid precursor protein trafficking, processing, and function.

Intracellular trafficking and proteolytic processing of amyloid precursor protein (APP) have been the focus of numerous investigations over the past two decades. APP is the precursor to the amyloid beta-protein (Abeta), the 38-43-amino acid residue peptide that is at the heart of the amyloid cascade hypothesis of Alzheimer disease (AD). Tremendous progress has been made since the initial identification of Abeta as the principal component of brain senile plaques of individuals with AD.