LDLR Expression and Localization Are Altered in Mouse and Human Cell Culture Models of Alzheimer's Disease

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common form of dementia. The major molecular risk factor for late-onset AD is expression of the ε-4 allele of apolipoprotein E (apoE), the major cholesterol transporter in the brain. The low-density lipoprotein receptor (LDLR) has the highest affinity for apoE and plays an important role in brain cholesterol metabolism.Using RT-PCR and western blotting techniques we found that over-expression of APP caused increases in both LDLR mRNA and protein levels in APP transfected H4 neuroglioma cells compared to H4 controls. Furthermore, immunohistochemical experiments showed aberrant localization of LDLR in H4-APP neuroglioma cells, Aβ-treated primary neurons, and in the PSAPP transgenic mouse model of AD. Finally, immunofluorescent staining of LDLR and of γ- and α-tubulin showed a change in LDLR localization preferentially away from the plasma membrane that was paralleled by and likely the result of a disruption of the microtubule-organizing center and associated microtubule network.These data suggest that increased APP expression and Aβ exposure alters microtubule function, leading to reduced transport of LDLR to the plasma membrane. Consequent deleterious effects on apoE uptake and function will have implications for AD pathogenesis and/or progression

The Tempered Polymerization of Human Neuroserpin

Neuroserpin, a member of the serpin protein superfamily, is an inhibitor of proteolytic activity that is involved in pathologies such as ischemia, Alzheimer's disease, and Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). The latter belongs to a class of conformational diseases, known as serpinopathies, which are related to the aberrant polymerization of serpin mutants. Neuroserpin is known to polymerize, even in its wild type form, under thermal stress. Here, we study the mechanism of neuroserpin polymerization over a wide range of temperatures by different techniques. Our experiments show how the onset of polymerization is dependent on the formation of an intermediate monomeric conformer, which then associates with a native monomer to yield a dimeric species. After the formation of small polymers, the aggregation proceeds via monomer addition as well as polymer-polymer association. No further secondary mechanism takes place up to very high temperatures, thus resulting in the formation of neuroserpin linear polymeric chains. Most interesting, the overall aggregation is tuned by the co-occurrence of monomer inactivation (i.e. the formation of latent neuroserpin) and by a mechanism of fragmentation. The polymerization kinetics exhibit a unique modulation of the average mass and size of polymers, which might suggest synchronization among the different processes involved. Thus, fragmentation would control and temper the aggregation process, instead of enhancing it, as typically observed (e.g.) for amyloid fibrillation

Primary cerebellar glioblastoma multiforme

Glioblastoma multiforme in adults arising in the cerebellum is a rare tumor, well documented in only 13 cases in the literature. We report a fourteenth case, an 80-year-old female, and reassess the clinical and CT aspects of this tumor based on a review of the world's literature. The median age of patients is 53 years with a median survival of three months, which is less than adult cerebral hemisphere malignant gliomas.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45390/1/11060_2004_Article_BF00151226.pd

Regulation of immune cell function and differentiation by the NKG2D receptor

NKG2D is one of the most intensively studied immune receptors of the past decade. Its unique binding and signaling properties, expression pattern, and functions have been attracting much interest within the field due to its potent antiviral and anti-tumor properties. As an activating receptor, NKG2D is expressed on cells of the innate and adaptive immune system. It recognizes stress-induced MHC class I-like ligands and acts as a molecular sensor for cells jeopardized by viral infections or DNA damage. Although the activating functions of NKG2D have been well documented, recent analysis of NKG2D-deficient mice suggests that this receptor may have a regulatory role during NK cell development. In this review, we will revisit known aspects of NKG2D functions and present new insights in the proposed influence of this molecule on hematopoietic differentiation

Indigenous use and bio-efficacy of medicinal plants in the Rasuwa District, Central Nepal

<p>Abstract</p> <p>Background</p> <p>By revealing historical and present plant use, ethnobotany contributes to drug discovery and socioeconomic development. Nepal is a natural storehouse of medicinal plants. Although several ethnobotanical studies were conducted in the country, many areas remain unexplored. Furthermore, few studies have compared indigenous plant use with reported phytochemical and pharmacological properties.</p> <p>Methods</p> <p>Ethnopharmacological data was collected in the Rasuwa district of Central Nepal by conducting interviews and focus group discussions with local people. The informant consensus factor (F_IC) was calculated in order to estimate use variability of medicinal plants. Bio-efficacy was assessed by comparing indigenous plant use with phytochemical and pharmacological properties determined from a review of the available literature. Criteria were used to identify high priority medicinal plant species.</p> <p>Results</p> <p>A total of 60 medicinal formulations from 56 plant species were documented. Medicinal plants were used to treat various diseases and disorders, with the highest number of species being used for gastro-intestinal problems, followed by fever and headache. Herbs were the primary source of medicinal plants (57% of the species), followed by trees (23%). The average F_IC value for all ailment categories was 0.82, indicating a high level of informant agreement compared to similar studies conducted elsewhere. High F_ICvalues were obtained for ophthalmological problems, tooth ache, kidney problems, and menstrual disorders, indicating that the species traditionally used to treat these ailments are worth searching for bioactive compounds: <it>Astilbe rivularis</it>, <it>Berberis asiatica</it>, <it>Hippophae salicifolia, Juniperus recurva</it>, and <it>Swertia multicaulis</it>. A 90% correspondence was found between local plant use and reported plant chemical composition and pharmacological properties for the 30 species for which information was available. Sixteen medicinal plants were ranked as priority species, 13 of which having also been prioritized in a country-wide governmental classification.</p> <p>Conclusions</p> <p>The <it>Tamang </it>people possess rich ethnopharmacological knowledge. This study allowed to identify many high value and high priority medicinal plant species, indicating high potential for economic development through sustainable collection and trade.</p

Molecular mechanisms of vaspin action: from adipose tissue to skin and bone, from blood vessels to the brain

Visceral adipose tissue derived serine protease inhibitor (vaspin) or SERPINA12 according to the serpin nomenclature was identified together with other genes and gene products that  were specifically expressed or overexpressed in the intra abdominal or visceral adipose tissue  (AT) of the Otsuka Long-Evans Tokushima fatty rat. These rats spontaneously develop visceral  obesity, insulin resistance, hyperinsulinemia and ‐glycemia, as well as hypertension and thus represent a well suited animal model of obesity and related metabolic disorders such as type  2 diabetes.  The follow-up study reporting the cloning, expression and functional characterization of  vaspin suggested the great and promising potential of this molecule to counteract obesity induced insulin resistance and inflammation and has since initiated over 300 publications, clinical and experimental, that have contributed to uncover the multifaceted functions and molecular mechanisms of vaspin action not only in the adipose, but in many different cells, tissues and organs. This review will give an update on mechanistic and structural aspects of vaspin with a focus on its serpin function, the physiology and regulation of vaspin expression, and will summarize the latest on vaspin function in various tissues such as the different adipose tissue depots as well as the vasculature, skin, bone and the brain

Managerial Mindsets Toward Corporate Social Responsibility: The Case of Auto Industry in Iran

Despite a plethora of empirical evidence on the potential role of senior management in the success of corporate social responsibility (CSR) in Western-dominated organizational contexts, little attempt has been made to document the various managerial mindsets toward CSR in organizations in Muslim-dominated countries in the Middle East region. To address this existing lacuna of theoretical and empirical research in CSR management, this paper offers a qualitative case study of CSR in three manufacturing firms operating in Iran’s auto industry. Based on an inductive analysis of the qualitative data, three types of managerial mindset toward CSR are identified: conformist, self-seeker, and satisfier. While it is evident that these different mindsets of Iranian managers seek to serve managerial ends and short-term self-interests, they fall short of core values of Islamic ethics and CSR

Manifestações cutâneo-mucosas da coccidioidomicose: estudo de trinta casos procedentes dos estados do Piauí e Maranhão Skin and mucous membrane manifestations of coccidioidomycosis: a study of thirty cases in the Brazilian states of Piauí and Maranhão

FUNDAMENTOS: A coccidioidomicose é micose sistêmica usualmente manifesta como infecção benigna de resolução espontânea; porém, uma pequena proporção dos infectados desenvolve quadros progressivos potencialmente fatais, podendo atingir a pele com lesões pleomórficas disseminadas. OBJETIVOS: Identificar e descrever as manifestações cutâneo-mucosas da coccidioidomicose, as ocupações de risco relacionadas à doença e o quadro clínico associado. MÉTODOS: Estudo realizado entre os anos 2003 e 2006 em 30 pacientes portadores de coccidioidomicose provenientes dos estados do Piauí e Maranhão e diagnosticados por exame microscópico direto, cultivo do escarro ou sorologia de triagem de imunodifusão dupla em gel de ágar, aliados à anamnese e exame físico. RESULTADOS: Identificaram-se lesões extrapulmonares em 13 casos (43,3%), com predomínio de manifestações dermatológicas de hipersensibilidade: eritema nodoso (26,6%), exantema com lesões eritemato-escamosas (26,6%) e eritema multiforme (23,3%), além de úlceras de língua (13,3%) e lábio (6,6%) e abscesso subcutâneo (3,3%). Tais manifestações foram observadas na fase aguda da doença. CONCLUSÕES: As manifestações cutâneas associadas à infecção respiratória aguda fortalecem a hipótese diagnóstica desta doença, especialmente, em caçadores de tatus ou pessoas expostas à escavação do solo.<br>BACKGROUND: Coccidioidomycosis is a systemic mycosis that usually presents as a benign infection. Patients generally recover spontaneously; however, a small proportion of infected individuals develop progressive complications that may affect the skin in the form of disseminated pleomorphic lesions and may become fatal. OBJECTIVES: To identify and describe skin and mucous membrane manifestations of coccidioidomycosis, to identify occupational hazards associated with the disease and to determine its associated clinical presentation. METHODS: A study conducted between 2003 and 2006 involving 30 patients from the Brazilian states of Piauí and Maranhão with coccidioidomycosis diagnosed by direct microscopy, sputum culture or screening serology using agar gel double immunodiffusion, in association with anamnesis and physical examination. RESULTS: Extrapulmonary lesions were found in 13 cases (43.3%), consisting predominantly of dermatological manifestations of hypersensitivity: erythema nodosum (26.6%), exanthema with erythematosquamous lesions (26.6%) and erythema multiforme (23.3%), as well as ulcerations of the tongue (13.3%), lip ulcers (6.6%) and subcutaneous abscess (3.3%). These manifestations were seen during the acute phase of the disease. CONCLUSIONS: Skin manifestations associated with an acute respiratory infection reinforce the hypothesis of a diagnosis of coccidioidomycosis, particularly in individuals who hunt armadillos or in those exposed to soil excavation