Biomedical subjects

Luis Cruz

Publications and source records attributed to Luis Cruz.

11 recordsLinked to original sources

PubMed2006

Tracheal development in the Drosophila brain is constrained by glial cells.

The Drosophila brain is tracheated by the cerebral trachea, a branch of the first segmental trachea of the embryo. During larval stages the cerebral trachea splits into several main (primary) branches that grow around the neuropile, forming a perineuropilar tracheal plexus (PNP) at the neuropile surface. Five primary tracheal branches whose spatial relationship to brain compartments is relatively invariant can be distinguished, although the exact trajectories and branching pattern of the brain tracheae are surprisingly variable. Immunohistochemical and electron microscopic studies demonstrate that all brain tracheae grow in direct contact with the glial cell processes that surround the neuropile. To investigate the effect of glia on tracheal development, embryos and larvae lacking glial cells as a result of a genetic mutation or a directed ablation were analyzed. In these animals, the tracheal branching pattern was highly abnormal. In particular, the number of secondary branches entering the central neuropile was increased. Wild-type larvae possess only two central tracheae, typically associated with the mushroom body and the antennocerebral tract. In larvae lacking glial cells, six to ten tracheal branches penetrate the neuropile in a variable pattern. This finding indicates that glia-derived signals constrained tracheal growth in the Drosophila brain and restrict the number of branches entering the neuropile.

Animals↗

PubMed2006

Ab initio discrete molecular dynamics approach to protein folding and aggregation.

Understanding the toxicity of amyloidogenic protein aggregates and designing therapeutic approaches require the knowledge of their structure at atomic resolution. Although solid-state NMR, X-ray diffraction, and other experimental techniques are capable of discerning the protein fibrillar structure, determining the structures of early aggregates, called oligomers, is a challenging experimental task. Computational studies by all-atom molecular dynamics, which provides a complete description of a protein in the solvent, are typically limited to study folding of smaller protein or aggregation of a small number of short protein fragments. We review an efficient ab initio computer simulation approach to protein folding and aggregation using discrete molecular dynamics (DMD) in combination with several coarse-grained protein models and implicit solvent. This approach involves different complexity levels in both the protein model and the interparticle interactions. Starting from the simplest protein model with minimal interactions, and gradually increasing its complexity, while guided by in vitro findings, we can systematically select the key features of the protein model and interactions that drive protein folding and aggregation. Because the method used in this DMD approach does not require any knowledge of the native or any other state of the protein, it can be applied to study degenerative disorders associated with protein misfolding and aberrant protein aggregation. The choice of the coarse-grained model depends on the complexity of the protein and specific questions to be addressed, which are mostly suggested by in vitro findings. Thus, we illustrate our approach on amyloid beta-protein (Abeta) associated with Alzheimer's disease (AD). Despite the simplifications introduced in the DMD approach, the predicted Abeta conformations are in agreement with existing experimental data. The in silico findings also provide further insights into the structure and dynamics of Abeta folding and oligomer formation that are amenable to in vitro testing.

Amyloid beta-Peptides↗

PubMed2006

Elucidating amyloid beta-protein folding and assembly: A multidisciplinary approach.

Oligomeric, neurotoxic amyloid protein assemblies are thought to be causative agents in Alzheimer's and other neurodegenerative diseases. Development of oligomer-specific therapeutic agents requires a mechanistic understanding of the oligomerization process. This is a daunting task because amyloidogenic protein oligomers often are metastable and comprise structurally heterogeneous populations in equilibrium with monomers and fibrils. A single methodological approach cannot elucidate the entire protein assembly process. An integrated multidisciplinary program is required. We discuss here the synergistic application of in hydro, in vacuo, and in silico methods to the study of the amyloid beta-protein, the key pathogenetic agent in Alzheimer's disease.

Amino Acid Sequence↗

PubMed2006

Computer simulations of Alzheimer's amyloid beta-protein folding and assembly.

Pathological folding and aggregation of the amyloid beta-protein (Abeta) are widely perceived as central to understanding Alzheimer's disease (AD) at the molecular level. Experimental approaches to study Abeta self-assembly are limited, because most relevant aggregates are quasi-stable and inhomogeneous. In contrast, simulations can provide significant insights into the problem, including specific sites in the molecule that would be attractive for drug targeting and details of the assembly pathways leading to the production of toxic assemblies. Here we review computer simulation approaches to understanding the structural biology of Abeta. We discuss the ways in which these simulations help guide experimental work, and in turn, how experimental results guide the development of theoretical and simulation approaches that may be of general utility in understanding pathologic protein folding and assembly.

Alzheimer Disease↗

PubMed2006

Tachycardia-induced elevations in cardiac troponin in the absence of coronary artery disease.

Elevations in serum cardiac troponins are used to diagnose myocardial infarction caused by ischemic heart disease. Several other conditions result in elevated cardiac makers in the absence of significant coronary artery disease. While not commonly recognized elevations of troponin I (TNI) may be seen in patients with protracted arrhythmias. We describe three patients with prolonged tachycardia, heart rates of 200-260 beats per minute, who had elevated TNI (0.81-4.6 ng/ml) but no significant coronary artery disease. Two patients presented with ventricular tachycardia and one had an atrioventricular re-entrant tachycardia. None of the patients presented with symptomatic hypotension. Coronary angiography in all three patients did not demonstrate significant coronary artery disease. The finding of an elevated TNI level may be the result of tachycardia and not myocardial infarction related to ischemic heart disease.

Administration, Oral↗

PubMed2005

Solvent and mutation effects on the nucleation of amyloid beta-protein folding.

Experimental evidence suggests that the folding and aggregation of the amyloid beta-protein (Abeta) into oligomers is a key pathogenetic event in Alzheimer's disease. Inhibiting the pathologic folding and oligomerization of Abeta could be effective in the prevention and treatment of Alzheimer's disease. Here, using all-atom molecular dynamics simulations in explicit solvent, we probe the initial stages of folding of a decapeptide segment of Abeta, Abeta(21-30), shown experimentally to nucleate the folding process. In addition, we examine the folding of a homologous decapeptide containing an amino acid substitution linked to hereditary cerebral hemorrhage with amyloidosis-Dutch type, [Gln-22]Abeta(21-30). We find that: (i) when the decapeptide is in water, hydrophobic interactions and transient salt bridges between Lys-28 and either Glu-22 or Asp-23 are important in the formation of a loop in the Val-24-Lys-28 region of the wild-type decapeptide; (ii) in the presence of salt ions, salt bridges play a more prominent role in the stabilization of the loop; (iii) in water with a reduced density, the decapeptide forms a helix, indicating the sensitivity of folding to different aqueous environments; and (iv) the "Dutch" peptide in water, in contrast to the wild-type peptide, fails to form a long-lived Val-24-Lys-28 loop, suggesting that loop stability is a critical factor in determining whether Abeta folds into pathologic structures.

Amyloid beta-Peptides↗

PubMed2005

A statistically based density map method for identification and quantification of regional differences in microcolumnarity in the monkey brain.

We present a statistical density map method derived from condensed matter physics to quantify microcolumns, the fundamental computational unit of the cerebral cortex. This method provides measures for microcolumnar strength, width, spacing, length, and periodicity. We applied this method to Nissl-stained 30 microm thick frozen sections from areas 46, TE, and TL of rhesus monkey brains, areas that differ visually in microcolumnarity and are associated with different cognitive functions. Our results indicate that microcolumns in these areas are similar in width, spacing, and periodicity, but are stronger (possess a higher neuronal density) in area TE, as compared to areas TL and 46. We modeled the effect of section orientation on microcolumnar spacing and demonstrated that this method provides an adequate estimate of spacing. We also modeled disruption of microcolumnarity by performing simulations that randomly displace neurons and demonstrated that displacements of only one neuronal diameter effectively eliminate microcolumnar organization. These results indicate that our density map method is sensitive enough to detect and quantify subtle differences in microcolumnar organization that may occur in the context of development, aging, and neuropathology, as well as between areas and species.

Animals↗

PubMed2005

Effectiveness of kukui nut oil as a topical treatment for psoriasis.

BACKGROUND: No cure for psoriasis exists for the 1-3% of the American population who suffer from it; however, anecdotal reports from patients with psoriasis visiting Hawaii who purchased kukui nut oil, claim it helped reduce the severity of their lesions. OBJECTIVE: This pilot study was a double-blind, placebo-controlled clinical trial to determine the effectiveness of kukui nut oil as a topical treatment for psoriasis. METHODS: Thirty adult subjects (18-78 year) were recruited from the community for a 12-week randomized, double-blind, placebo-controlled pilot study. Subjects were previously diagnosed with mild, stable plaque psoriasis (less than 15% of total body surface area [TBSA]) and agreed to abstain from other treatments during the course of the study. Following a 4-week washout period the subjects were randomized into a treatment group (15 subjects applying kukui nut oil) or a control group (15 applying the mineral oil placebo). Patients were seen every 2 weeks (seven visits at 0, 2, 4, 6, 8, 10, and 12 weeks) by a dermatological nurse practitioner under the general supervision of a board certified dermatologist. Measurable outcomes included evaluation of one targeted lesion and of the overall severity of their psoriasis using clinical evaluation, Psoriasis Area and Sensitivity Index (PASI), Global Severity of Psoriasis Scale, and photographs. Each patient also evaluated their own lesions daily using the Global Severity of Psoriasis Scale, and noted any side-effects or other treatments used. RESULTS: Although both groups improved, we found no significant difference between the treatment (kukui nut oil) and the placebo (mineral oil) among the 24 out of 30 subjects (80%) who completed the study. No side-effects or adverse events were reported. CONCLUSION: Kukui nut oil did not significantly reduce symptoms of psoriasis; however, this was a small pilot study, and the use of this oil cannot be dismissed without using a larger study population of patients with psoriasis.

Double-Blind Method↗

PubMed2004

Age-related reduction in microcolumnar structure in area 46 of the rhesus monkey correlates with behavioral decline.

Many age-related declines in cognitive function are attributed to the prefrontal cortex, area 46 being especially critical. Yet in normal aging, studies indicate that neurons are not lost in area 46, suggesting that impairments result from more subtle processes. One cortical feature that is functionally important, but that has not been examined in normal aging because of a lack of efficient quantitative methods, is the vertical arrangement of neurons into microcolumns, a fundamental computational unit of the cortex. By using a density-map method derived from condensed-matter physics, we quantified microcolumns in area 46 of seven young and seven aged rhesus monkeys that had been cognitively tested. This analysis demonstrated that there is no age-related reduction in total neuronal density or in microcolumn width, length, or periodicity. There was, however, a statistically significant decrease in the strength of microcolumns, indicating microcolumnar disorganization. This reduction in strength was significantly correlated with age-related cognitive decline on tests of spatial working memory and recognition memory independent of the effect of age. Modeling demonstrated that random neuron displacements of approximately 30% of a neuronal diameter (<3 mum) produced the observed reduction in strength. Hence, it is possible that, with changes in dendrites and myelinated axons, subtle displacements of neurons occur that alter microcolumnar structure and correlate with age-induced dysfunction. Therefore, quantitative measurement of microcolumnar structure may provide a sensitive morphological method to assay microcolumnar function in aging and other conditions.

Aging↗

PubMed2004

Cancer in the Territory of Guam.

The purpose of this study, funded by the National Cancer Institute, was to assess cancer awareness and service needs in Guam. Guam maintains a cancer registry, and data suggest that cancer is the second-leading cause of death in Guam. A chapter of the American Cancer Society has been established on the island. Although basic cancer diagnosis and treatment services can be provided on Guam, many cancer patients must travel to Hawai'i, the U.S. continent, or to Asian countries to seek more advanced medical care. This places a severe strain on the island's limited financial resources that, in turn, affects all aspects of health care for the people of Guam. Key informants identified a number of cancer-related service needs, and an action plan was developed based on five priority areas: 1) increasing the capacity of cancer prevention and control staff; 2) increasing public awareness of cancer risk factors; 3) expanding the capacity of the Guam Cancer Registry; 4) establishing a Cancer Prevention and Control Advisory Board for the Territory; and 5) improving early detection and screening for priority cancers.

Delivery of Health Care↗

PubMed2002

Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice.

In vitro studies indicate a role for the LIM kinase family in the regulation of cofilin phosphorylation and actin dynamics. In addition, abnormal expression of LIMK-1 is associated with Williams syndrome, a mental disorder with profound deficits in visuospatial cognition. However, the in vivo function of this family of kinases remains elusive. Using LIMK-1 knockout mice, we demonstrate a significant role for LIMK-1 in vivo in regulating cofilin and the actin cytoskeleton. Furthermore, we show that the knockout mice exhibited significant abnormalities in spine morphology and in synaptic function, including enhanced hippocampal long-term potentiation. The knockout mice also showed altered fear responses and spatial learning. These results indicate that LIMK-1 plays a critical role in dendritic spine morphogenesis and brain function.

Actin Cytoskeleton↗