Mycobacterium tuberculosis blocks crosslinking of annexin-1 and apoptotic envelope formation on infected macrophages to maintain virulence.

Macrophages infected with attenuated Mycobacterium tuberculosis strain H37Ra become apoptotic, which limits bacterial replication and facilitates antigen presentation. Here we demonstrate that cells infected with H37Ra became apoptotic after the formation of an apoptotic envelope on their surface was complete. This process required exposure of phosphatidylserine on the cell surface, followed by deposition of the phospholipid-binding protein annexin-1 and then transglutaminase-mediated crosslinking of annexin-1 through its amino-terminal domain.

Emergency hospital admissions after income-based deductibles and prescription copayments in older users of inhaled medications.

Background: Rapid growth in prescription drug costs has compelled insurers to require increased patient cost-sharing.

Objective: The aim of this study was to compare the effects of 2 recent cost-sharing policies on emergency hospitalizations due to chronic obstructive pulmonary disease, asthma, or emphysema (CAE), and on physician visits.

Methods: We analyzed data from a large-scale natural experiment in British Columbia (BC), Canada.

Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors.

A structure-activity relationship study of dorsomorphin, a previously identified inhibitor of SMAD 1/5/8 phosphorylation by bone morphogenetic protein (BMP) type 1 receptors ALK2, 3, and 6, revealed that increased inhibitory activity could be accomplished by replacing the pendent 4-pyridine ring with 4-quinoline. The activity contributions of various nitrogen atoms in the core pyrazolo[1,5-a]pyrimidine ring were also examined by preparing and evaluating pyrrolo[1,2-a]pyrimidine and pyrazolo[1,5-a]pyridine derivatives. In addition, increased mouse liver microsome stability was achieved by replacing the ether substituent on the pendent phenyl ring with piperazine.

Weight gain in older adolescent females: the internet, sleep, coffee, and alcohol.

Objectives: To examine whether excessive recreational Internet time, insufficient sleep, regular coffee consumption, or alcoholic beverages promote weight gain.

Study Design: A longitudinal cohort of >5000 girls (Growing Up Today Study), from all over the United States and aged 14 to 21 years, returned surveys in 2001 reporting typical past-year recreational Internet time, sleep, coffee (with caffeine), and alcohol consumption. We estimated correlations among these 4 exposures.

Promotion of BACE1 mRNA alternative splicing reduces amyloid beta-peptide production.

Production of the amyloid beta-peptide (Abeta) via sequential proteolytic cleavage of the amyloid precursor protein by beta- and gamma-secretases is strongly implicated in the pathogenesis of Alzheimer disease. The beta-secretase that executes the first cleavage event is a transmembrane aspartyl protease known as beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1). BACE1 pre-mRNA is alternatively spliced through the use of alternative splice sites in exons 3 and 4, although the significance of these splicing events is unclear.

Structure-activity relationship and liver microsome stability studies of pyrrole necroptosis inhibitors.

Necroptosis is a regulated caspase-independent cell death pathway resulting in morphology reminiscent of passive non-regulated necrosis. Several diverse structure classes of necroptosis inhibitors have been reported to date, including a series of [1,2,3]thiadiazole benzylamide derivatives. However, initial evaluation of mouse liver microsome stability indicated that this series of compounds was rapidly degraded.

Serum lipids regulate dendritic cell CD1 expression and function.

Dendritic cells (DCs) are highly potent antigen-presenting cells (APCs) and play a vital role in stimulating naïve T cells. Treatment of human blood monocytes with the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 stimulates them to develop into immature dendritic cells (iDCs) in vitro. DCs generated by this pathway have a high capacity to prime and activate resting T cells and prominently express CD1 antigen-presenting molecules on the cell surface.

Cerebral amyloid-beta protein accumulation with aging in cotton-top tamarins: a model of early Alzheimer's disease?

Alzheimer's disease (AD) is the most common progressive form of dementia in the elderly. Two major neuropathological hallmarks of AD include cerebral deposition of amyloid-beta protein (Abeta) into plaques and blood vessels, and the presence of neurofibrillary tangles in brain. In addition, activated microglia and reactive astrocytes are often associated with plaques and tangles.

Caffeine consumption and the risk of primary open-angle glaucoma: a prospective cohort study.

Purpose: To investigate whether caffeine, which transiently increases intraocular pressure (IOP) is associated with the risk of primary open-angle glaucoma (POAG).

Methods: A total of 79,120 women from 1980 to 2004 and 42,052 men from 1986 to 2004, who were 40+ years of age, did not have POAG, and reported undergoing eye examinations, were observed. Information on caffeine consumption, potential confounders, and POAG diagnoses were repeatedly updated in validated follow-up questionnaires.

Functional trends in structural classes of the DNA binding domains of regulatory transcription factors.

The DNA-binding domain (DBD) structure of a regulatory transcription factor (TF) is important in determining its DNA sequence specificity, but it is unclear whether a relationship exists between DBD structure and general TF biological function or regulatory mechanism. We observed moderate enrichment of functional annotation terms among TFs of the same structural class in Escherichia coli, Saccharomyces cerevisiae, Drosophila melanogaster, or Mus musculus, suggesting some preference for TFs of similar structures in the regulation of similar processes. In yeast, we also found trends among TF structural classes in phenomena including gene expression coherence, DNA binding site motif similarity, the general or specific nature of TFs' regulatory roles, and the position of a TF in a gene regulatory network.

Structure-activity relationship study of [1,2,3]thiadiazole necroptosis inhibitors.

Necroptosis is a regulated caspase-independent cell death mechanism that results in morphological features resembling non-regulated necrosis. This form of cell death can be induced in an array of cell types in apoptotic deficient conditions with death receptor family ligands. A series of [1,2,3]thiadiazole benzylamides was found to be potent necroptosis inhibitors (called necrostatins).

Novel Abeta immunogens: is shorter better?

Active and passive Abeta immunotherapy in Alzheimer's disease (AD)-like mouse models lowers cerebral amyloid-beta protein (Abeta) levels, especially if given early in the disease process, and improves cognitive deficits. In 2002, a Phase IIa clinical trial was halted due to meningoencephalitis in approximately 6% of the AD patients. It is hypothesized that the immunogen, full-length Abeta1-42, may have led to an autoimmune response.

The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases.

The intestinal flora has long been thought to play a role either in initiating or in exacerbating the inflammatory bowel diseases (IBD). Host defenses, such as those mediated by the Toll-like receptors (TLR), are critical to the host/pathogen interaction and have been implicated in IBD pathophysiology. To explore the association of genetic variation in TLR pathways with susceptibility to IBD, we performed a replication study and pooled analyses of the putative IBD risk alleles in NFKB1 and TLR4, and we performed a haplotype-based screen for association to IBD in the TLR genes and a selection of their adaptor and signaling molecules.

Identification of tau stem loop RNA stabilizers.

Alternative splicing of tau exon 10 produces tau isoforms with either 3 (3R) or 4 (4R) repeated microtubule-binding domains. Increased ratios of 4R to 3R tau expression, above the physiological 1:1, leads to neurofibrillary tangles and causes neurodegenerative disease. An RNA stem loop structure plays a significant role in determining the ratio, with decreasing stability correlating with an increase in 4R tau mRNA expression.

Structure-activity relationship, kinetic mechanism, and selectivity for a new class of ubiquitin C-terminal hydrolase-L1 (UCH-L1) inhibitors.

3-Amino-2-keto-7H-thieno[2,3-b]pyridin-6-one derivatives were discovered as moderately potent inhibitors of ubiquitin C-terminal hydrolase-L1 (UCH-L1) utilizing an assay that measures hydrolysis of the fluorogenic substrate Ub-AMC. SAR studies revealed that both the carboxylate at the 5-position and the 6-pyridone ring were critical for inhibitory activity. Furthermore, activity was dependent on the nature of the ketone substituent at the 2-position, with 4-Me-Ph and 2-naphthyl being best.

Structure-activity relationship study of tricyclic necroptosis inhibitors.

Necroptosis is a regulated caspase-independent cell death mechanism that can be induced in multiple cell types and is characterized by morphological features resembling necrosis. Here we describe a series of tricyclic heterocycles (i.e.

Protein binding microarrays for the characterization of DNA-protein interactions.

A number of important cellular processes, such as transcriptional regulation, recombination, replication, repair, and DNA modification, are performed by DNA binding proteins. Of particular interest are transcription factors (TFs) which, through their sequence-specific interactions with DNA binding sites, modulate gene expression in a manner required for normal cellular growth and differentiation, and also for response to environmental stimuli. Despite their importance, the DNA binding specificities of most DNA binding proteins still remain unknown, since prior technologies aimed at identifying DNA-protein interactions have been laborious, not highly scalable, or have required limiting biological reagents.

Adiposity in adolescents: change in actual BMI works better than change in BMI z score for longitudinal studies.

Purpose: Longitudinal epidemiologic studies often relate adiposity changes to suspected causal factors. In growing adolescents, this becomes complicated. Many investigators use within-child change in body mass index (BMI) z scores (Delta z) from sex- and age-specific BMI charts developed by the Centers for Disease Control and Prevention (CDC).

Lysosomal exocytosis is impaired in mucolipidosis type IV.

Mucolipidosis type IV (MLIV) is an autosomal recessive disease characterized by severe neurological impairment, ophthalmologic defects, and gastric dysfunction. MLIV cells have a deficiency in the late endosomal/lysosomal (LEL) pathway that results in the buildup of lysosomal inclusions. Using a Xenopus oocyte expression system, we previously showed that mucolipin-1 (MLN1), the protein encoded by the MCOLN1 gene is a Ca2+ -permeable non-selective cation channel that is transiently modulated by elevations in intracellular Ca2+.

A web application to support consumer health vocabulary development.

We describe a Web application that supports collaborative development of a consumer health vocabulary. It performs text analyses and enables distributed human review. It also provides on-the-fly summary reports and facilitates the generation of a final vocabulary based on the results of the review.

Amyloid-beta immunotherapy for the prevention and treatment of Alzheimer disease: lessons from mice, monkeys, and humans.

Alzheimer disease (AD), the most common form of dementia, is without an effective cure or preventive treatment. Recently, amyloid-beta protein (Abeta) has become a major therapeutic target. Many efforts are underway to either reduce the production of Abeta or enhance its clearance.

Visual search deficits in Parkinson's disease are attenuated by bottom-up target salience and top-down information.

Patients with Parkinson's disease (PD), a degenerative disorder primarily affecting the nigrostriatal dopamine system, exhibit deficits in selecting task-relevant stimuli in the presence of irrelevant stimuli, such as in visual search tasks. However, results from previous studies suggest that these deficits may vary as a function of whether selection must rely primarily on the "bottom-up" salience of the target relative to background stimuli, or whether "top-down" information about the identity of the target is available to bias selection. In the present study, moderate-to-severe medicated PD patients and age-matched controls were tested on six visual search tasks that systematically varied the relationship between bottom-up target salience (feature search, noisy feature search, conjunction search) and top-down target knowledge (Target Known versus Target Unknown).

Carotenoids and cardiovascular disease: what research gaps remain?

Purpose Of Review: Dietary and blood carotenoids, including alpha-carotene, beta-carotene, lycopene, lutein/zeaxanthin, and beta-cryptoxanthin, have been examined in a number of epidemiological studies in recent years for the risk of cardiovascular disease. This review assimilated the existing and recent literature on carotenoids and cardiovascular disease and considered what research gaps may remain.

Recent Findings: Numerous large cohort studies have been published in largely American men and women that have examined dietary intake or blood levels of total or individual carotenoids with the risk of various cardiovascular endpoints.

CD1a-, b-, and c-restricted TCRs recognize both self and foreign antigens.

Individual CD1-restricted T cells can recognize either endogenous or foreign lipid Ags, but the extent to which the same CD1-restricted TCR can react to both self and microbial lipids is unknown. In this study, we have identified CD1a-, CD1b-, and CD1c-restricted T cells from normal human donors that induce cytolysis and secrete copious IFN-gamma in response to self-CD1 expressed on monocyte-derived dendritic cells. Remarkably, microbial Ags presented by CD1 are even more potent agonists for these same T cells.