Showing papers by "Saint Louis University published in 2006"

Global landscape of protein complexes in the yeast Saccharomyces cerevisiae

Abstract: Identification of protein-protein interactions often provides insight into protein function, and many cellular processes are performed by stable protein complexes. We used tandem affinity purification to process 4,562 different tagged proteins of the yeast Saccharomyces cerevisiae. Each preparation was analysed by both matrix-assisted laser desorption/ionization-time of flight mass spectrometry and liquid chromatography tandem mass spectrometry to increase coverage and accuracy. Machine learning was used to integrate the mass spectrometry scores and assign probabilities to the protein-protein interactions. Among 4,087 different proteins identified with high confidence by mass spectrometry from 2,357 successful purifications, our core data set (median precision of 0.69) comprises 7,123 protein-protein interactions involving 2,708 proteins. A Markov clustering algorithm organized these interactions into 547 protein complexes averaging 4.9 subunits per complex, about half of them absent from the MIPS database, as well as 429 additional interactions between pairs of complexes. The data (all of which are available online) will help future studies on individual proteins as well as functional genomics and systems biology.

Insights from the genome of the biotrophic fungal plant pathogen Ustilago maydis

Abstract: Ustilago maydis is a ubiquitous pathogen of maize and a well-established model organism for the study of plant-microbe interactions. This basidiomycete fungus does not use aggressive virulence strategies to kill its host. U. maydis belongs to the group of biotrophic parasites (the smuts) that depend on living tissue for proliferation and development. Here we report the genome sequence for a member of this economically important group of biotrophic fungi. The 20.5-million-base U. maydis genome assembly contains 6,902 predicted protein-encoding genes and lacks pathogenicity signatures found in the genomes of aggressive pathogenic fungi, for example a battery of cell-wall-degrading enzymes. However, we detected unexpected genomic features responsible for the pathogenicity of this organism. Specifically, we found 12 clusters of genes encoding small secreted proteins with unknown function. A significant fraction of these genes exists in small gene families. Expression analysis showed that most of the genes contained in these clusters are regulated together and induced in infected tissue. Deletion of individual clusters altered the virulence of U. maydis in five cases, ranging from a complete lack of symptoms to hypervirulence. Despite years of research into the mechanism of pathogenicity in U. maydis, no 'true' virulence factors had been previously identified. Thus, the discovery of the secreted protein gene clusters and the functional demonstration of their decisive role in the infection process illuminate previously unknown mechanisms of pathogenicity operating in biotrophic fungi. Genomic analysis is, similarly, likely to open up new avenues for the discovery of virulence determinants in other pathogens.

Chromatin Modifications by Methylation and Ubiquitination: Implications in the Regulation of Gene Expression

Abstract: It is more evident now than ever that nucleosomes can transmit epigenetic information from one cell generation to the next. It has been demonstrated during the past decade that the posttranslational modifications of histone proteins within the chromosome impact chromatin structure, gene transcription, and epigenetic information. Multiple modifications decorate each histone tail within the nucleosome, including some amino acids that can be modified in several different ways. Covalent modifications of histone tails known thus far include acetylation, phosphorylation, sumoylation, ubiquitination, and methylation. A large body of experimental evidence compiled during the past several years has demonstrated the impact of histone acetylation on transcriptional control. Although histone modification by methylation and ubiquitination was discovered long ago, it was only recently that functional roles for these modifications in transcriptional regulation began to surface. Highlighted in this review are the recent biochemical, molecular, cellular, and physiological functions of histone methylation and ubiquitination involved in the regulation of gene expression as determined by a combination of enzymological, structural, and genetic methodologies.

Neonatal-Onset Multisystem Inflammatory Disease Responsive to Interleukin-1β Inhibition

Abstract: All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events. Conclusions Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations. (ClinicalTrials.gov number, NCT00069329.)

Ghrelin controls hippocampal spine synapse density and memory performance

Abstract: The gut hormone and neuropeptide ghrelin affects energy balance and growth hormone release through hypothalamic action that involves synaptic plasticity in the melanocortin system. Ghrelin binding is also present in other brain areas, including the telencephalon, where its function remains elusive. Here we report that circulating ghrelin enters the hippocampus and binds to neurons of the hippocampal formation, where it promotes dendritic spine synapse formation and generation of long-term potentiation. These ghrelin-induced synaptic changes are paralleled by enhanced spatial learning and memory. Targeted disruption of the gene that encodes ghrelin resulted in decreased numbers of spine synapses in the CA1 region and impaired performance of mice in behavioral memory testing, both of which were rapidly reversed by ghrelin administration. Our observations reveal an endogenous function of ghrelin that links metabolic control with higher brain functions and suggest novel therapeutic strategies to enhance learning and memory processes.

Comparison of the Saint Louis University Mental Status Examination and the Mini-Mental State Examination for Detecting Dementia and Mild Neurocognitive Disorder—A Pilot Study

Abstract: Context The Mini-Mental State Examination (MMSE) is commonly used as a screening tool to detect dementia. However, it performs poorly in identifying persons with mild neurocognitive disorder. The Saint Louis University Mental Status (SLUMS) examination is a 30-point screening questionnaire that tests for orientation, memory, attention, and executive functions. Objective The objective of this study was to compare SLUMS and the MMSE for detecting dementia and mild neurocognitive disorder (MNCD) using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM–IV) criteria. Methods Patients at the Veterans' Affairs Geriatric Research, Education and Clinical Center, St. Louis, MO (N = 702) were clinically classified as having normal cognitive functioning, MNCD, or dementia based on DSM–IV criteria. The SLUMS and MMSE were administered for comparison. Results Mean age was 75.3 years (standard deviation: 5.5). Regarding education, 62.4% of the sample had at least completed high school and 30.6% had not. Sensitivity and specificity were calculated and receiver operator curves (ROCs) generated for SLUMS and MMSE as a function of diagnosis (MCND versus dementia) and education. Both the SLUMS and MMSE produced acceptable ROCs for the diagnosis of dementia, but the ROCs for SLUMS were better than the MMSE for the diagnosis of MNCD in both education groups. Conclusion These results suggest that the SLUMS and MMSE have comparable sensitivities, specificities, and area under the curve in detecting dementia. Although the definition of MNCD is controversial, the authors believe that the SLUMS is possibly better at detecting mild neurocognitive disorder, which the MMSE failed to detect, but this needs to be further investigated.

Investigation, Treatment, and Monitoring of Late-Onset Hypogonadism in Males: ISA, ISSAM, EAU, EAA, and ASA Recommendations

Abstract: Demographic data clearly demonstrate that the percentage of the population in the older age group is increasing. Androgen deficiency in the aging male has become a topic of increasing interest and debate throughout the world. Cross-sectional and longitudinal data indicate that the testosterone falls progressively with age and that a significant percentage of men over the age of 60 years have serum testosterone levels that are below the lower limits of young adult (age 20–30 years) men (1–4). The principal questions raised by these observations are whether older hypogonadal men will benefit from testosterone treatment and what will be the risks associated with such intervention. The past decade has brought evidence of benefit of androgen treatment of hypogonadal men on multiple target organs and the recent studies show short-term beneficial effects of testosterone in older men that are similar to those in younger men. This has been comprehensively reviewed and summarized by the Institute of Medicine in ‘Testosterone and Aging: Clinical Research Directions’ (5). Long-term data on the effects of testosterone treatment in the older population are limited mainly to effects on body composition and bone mass (6–11). Key questions of the effects of testosterone on patient reported outcomes and functional benefits that may retard physical or mental frailty of the elderly or improve the quality of life are not yet available. Specific risk data on the prostate and cardiovascular systems are needed.

Advancing Tailored Health Communication: A Persuasion and Message Effects Perspective

Abstract: Tailored health communication (THC) is any combination of information and behavior change strategies intended to reach one specific person based on information unique to that person, related to the outcome of interest, and derived from an individual assessment. THCs have been studied as a means to facilitate behavior change by influencing some key intermediate steps that precede the behavioral outcome. These include the extent to which people attend to communications, think about them, find them relevant and salient, and intend to take action. Evidence shows that THCs have achieved modest success in changing a number of cancer-related behaviors, including smoking, diet, exercise, and cancer screening. However, it is likely that THCs could be more effective if they were developed with a greater understanding of message effects and what we refer to as the behavioral pathway. Instead of using unidimensional approaches to influence behavior change, a message effects approach would help researchers identify key leverage points for impact on such intermediate outcomes as persuasion and yielding. Such a strategy also might be used to determine when THCs are the preferred approach and when generic, targeted, or combinations of THCs and targeted communications might be appropriate. Viewing THCs from the perspective of the behavioral pathway might indicate use of different messages, sources, and formats to influence different people at different points on the pathway. We provide a brief history of THCs and suggest how integrating a broader perspective of health behavior and health communication theories could enrich THCs.

Shaping the context of health: a review of environmental and policy approaches in the prevention of chronic diseases.

Abstract: ■ Abstract Given the growing attention on how environmental and policy interventions can affect chronic disease burden, our objectives are to describe (a) effective and promising interventions to address tobacco use, physical activity, and healthy eating and (b) lessons learned from the literature and practice experience in applying environmental and policy approaches. A total of 17 interventions were reviewed, organized across 3 domains affecting the physical environment/access, economic environment, and communication environment. Many of these interventions are effective. Several lessons are important to consider, such as the need to start with environmental and policy approaches, intervene comprehensively and across multiple levels, make use of economic evaluations, make better use of existing analytic tools, understand the politics and local context, address health disparities, and conduct sound policy research.

Severe Community-acquired Pneumonia Due to Staphylococcus aureus, 2003–04 Influenza Season

Abstract: During the 2003–04 influenza season, 17 cases of Staphylococcus aureus community-acquired pneumonia (CAP) were reported from 9 states; 15 (88%) were associated with methicillin-resistant S. aureus (MRSA). The median age of patients was 21 years; 5 (29%) had underlying diseases, and 4 (24%) had risk factors for MRSA. Twelve (71%) had laboratory evidence of influenza virus infection. All but 1 patient, who died on arrival, were hospitalized. Death occurred in 5 (4 with MRSA). S. aureus isolates were available from 13 (76%) patients (11 MRSA). Toxin genes were detected in all isolates; 11 (85%) had only genes for Panton-Valentine leukocidin. All isolates had community-associated pulsed-field gel electrophoresis patterns; all MRSA isolates had the staphylococcal cassette chromosome mec type IVa. In communities with a high prevalence of MRSA, empiric therapy of severe CAP during periods of high influenza activity should include consideration for MRSA.

The path to a healthy workplace: A critical review linking healthy workplace practices, employee well-being, and organizational improvements.

Abstract: This review synthesizes much of the previousresearch since 1990 linking healthy workplacepractices in organizations to employee well-be-ing and organizational improvements Based onthe review, both a direct and an indirect linkbetween healthy workplace practices and orga-nizational improvements are proposed Fivegeneral categories of healthy workplace prac-tices were identified in the literature: work-lifebalance, employee growth and development,health and safety, recognition, and employeeinvolvement Previous research also suggeststhat the link between these practices and em-ployee and organizational outcomes is contin-gent on the effectiveness of communicationwithin the organization and the alignment ofworkplace practices with the organizationalcontext Finally, a discussion of some limita-tions of previous research and recommenda-tions for future work in the area of healthyworkplace practices are providedKeywords:

The role of race and poverty in access to foods that enable individuals to adhere to dietary guidelines.

Abstract: INTRODUCTION The increase in obesity and disparities in obesity and related chronic diseases across racial and ethnic and income groups have led researchers to focus on the social and environmental factors that influence dietary intake. The question guiding the current study was whether all communities have equal access to foods that enable individuals to make healthy dietary choices. METHODS We conducted audits of community supermarkets and fast food restaurants to assess location and availability of food choices that enable individuals to meet the dietary guidelines established by the U.S. Department of Agriculture (e.g., fruit and vegetable consumption, low-fat options). We used 2000 census data to assess the racial distribution and the percentage of individuals living below the federal poverty level in a defined area of St Louis, Mo. Spatial clustering of supermarkets and fast food restaurants was determined using a spatial scan statistic. RESULTS The spatial distribution of fast food restaurants and supermarkets that provide options for meeting recommended dietary intake differed according to racial distribution and poverty rates. Mixed-race or white high-poverty areas and all African American areas (regardless of income) were less likely than predominantly white higher-income communities to have access to foods that enable individuals to make healthy choices. CONCLUSION Without access to healthy food choices, individuals cannot make positive changes to their diets. If certain eating behaviors are required to reduce chronic disease and promote health, then some communities will continue to have disparities in critical health outcomes unless we increase access to healthy food.

Spectrum of CHD7 Mutations in 110 Individuals with CHARGE Syndrome and Genotype-Phenotype Correlation

Abstract: CHARGE syndrome is a well-established multiple-malformation syndrome with distinctive consensus diagnostic criteria. Characteristic associated anomalies include ocular coloboma, choanal atresia, cranial nerve defects, distinctive external and inner ear abnormalities, hearing loss, cardiovascular malformations, urogenital anomalies, and growth retardation. Recently, mutations of the chromodomain helicase DNA-binding protein gene CHD7 were reported to be a major cause of CHARGE syndrome. We sequenced the CHD7 gene in 110 individuals who had received the clinical diagnosis of CHARGE syndrome, and we detected mutations in 64 (58%). Mutations were distributed throughout the coding exons and conserved splice sites of CHD7. Of the 64 mutations, 47 (73%) predicted premature truncation of the protein. These included nonsense and frameshift mutations, which most likely lead to haploinsufficiency. Phenotypically, the mutation-positive group was more likely to exhibit cardiovascular malformations (54 of 59 in the mutation-positive group vs. 30 of 42 in the mutation-negative group; P=.014), coloboma of the eye (55 of 62 in the mutation-positive group vs. 30 of 43 in the mutation-negative group; P=.022), and facial asymmetry, often caused by seventh cranial nerve abnormalities (36 of 56 in the mutation-positive group vs. 13 of 39 in the mutation-negative group; P=.004). Mouse embryo whole-mount and section in situ hybridization showed the expression of Chd7 in the outflow tract of the heart, optic vesicle, facio-acoustic preganglion complex, brain, olfactory pit, and mandibular component of the first branchial arch. Microarray gene-expression analysis showed a signature pattern of gene-expression differences that distinguished the individuals with CHARGE syndrome with CHD7 mutation from the controls. We conclude that cardiovascular malformations, coloboma, and facial asymmetry are common findings in CHARGE syndrome caused by CHD7 mutation.

Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy.

Abstract: Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features. We previously assigned the locus for autosomal dominant intermediate CMT neuropathy type C (DI-CMTC) to chromosome 1p34-p35. Here we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC. Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins, and mutations in YARS, or in its yeast ortholog TYS1, reduce yeast growth. YARS localizes to axonal termini in differentiating primary motor neuron and neuroblastoma cultures. This specific distribution is significantly reduced in cells expressing mutant YARS proteins. YARS is the second aminoacyl-tRNA synthetase found to be involved in CMT, thereby linking protein-synthesizing complexes with neurodegeneration.

Tracheobronchial aspiration of gastric contents in critically ill tube-fed patients: frequency, outcomes, and risk factors.

Abstract: Tracheobronchial aspiration can be defined as the inhalation of oropharyngeal or gastric contents into the respiratory tract (1). Although aspiration from either source is important, the type of greatest concern in critically ill tube-fed patients is tracheobronchial aspiration of gastric contents. The extent to which aspiration of gastric contents occurs is difficult to determine, primarily because most clinical studies have relied on flawed detection methods (such as observing tracheal secretions for dye-stained formula or glucose) (2–7). Nonetheless, there is evidence that it is a formidable problem. For example, a recent study found that 30 of 40 critically ill patients who received enteral formula stained with yellow microscopic beads had at least one episode of aspiration (as defined by detection of a yellow color in tracheal secretions by fluorometry) (8). The mean percentage of samples containing colored beads was 22.1% (range, 0% to 94%). Aspiration of gastric contents is a recognized risk factor for ventilator-associated pneumonia in critically ill patients (9–12). However, more information is needed to determine the extent to which the frequency of tracheobronchial aspiration of gastric contents predisposes to pneumonia and other adverse outcomes. This was an analysis to determine the occurrence of aspiration as a risk factor for pneumonia and as a determinant of clinical outcomes in comparison with other factors.

Molecular regulation of H3K4 trimethylation by ASH2L, a shared subunit of MLL complexes

Abstract: MLL complexes are homologs of yeast COMPASS capable of methylating histone H3 Lys4 (H3K4). ASH2L, RbBP5 and WDR5 are conserved subunits of MLL complexes with homology to the Cps40/Cps60, Cps50 and Cps30 subunits of COMPASS, respectively. We report that ASH2L differentially regulates MLL's catalysis of H3K4 trimethylation similarly to Cps40 and Cps60. Furthermore, WDR5 is required to maintain MLL complex integrity, including the stability of ASH2L within the complex. These findings offer insight into the molecular role of ASH2L, and by extension that of WDR5, in proper H3K4 trimethylation.

Treatment of gastroparesis: a multidisciplinary clinical review

Abstract: This clinical review on the treatment of patients with gastroparesis is a consensus document developed by the American Motility Society Task Force on Gastroparesis. It is a multidisciplinary effort with input from gastroenterologists and other specialists who are involved in the care of patients with gastroparesis. To provide practical guidelines for treatment, this document covers results of published research studies in the literature and areas developed by consensus agreement where clinical research trials remain lacking in the field of gastroparesis.

Mitogenomic evolution and interrelationships of the Cypriniformes (Actinopterygii: Ostariophysi): the first evidence toward resolution of higher-level relationships of the world's largest freshwater fish clade based on 59 whole mitogenome sequences.

Abstract: Fishes of the order Cypriniformes are almost completely restricted to freshwater bodies and number > 3400 species placed in 5 families, each with poorly defined subfamilies and/or tribes. The present study represents the first attempt toward resolution of the higher-level relationships of the world's largest freshwater-fish clade based on whole mitochondrial (mt) genome sequences from 53 cypriniforms (including 46 newly determined sequences) plus 6 outgroups. Unambiguously aligned, concatenated mt genome sequences (14,563 bp) were divided into 5 partitions (first, second, and third codon positions of the protein-coding genes, rRNA genes, and tRNA genes), and partitioned Bayesian analyses were conducted, with protein-coding genes being treated in 3 different manners (all positions included; third codon positions converted into purine [R] and pyrimidine [Y] [RY-coding]; third codon positions excluded). The resultant phylogenies strongly supported monophyly of the Cypriniformes as well as that of the families Cyprinidae, Catostomidae, and a clade comprising Balitoridae + Cobitidae, with the 2 latter loach families being reciprocally paraphyletic. Although all of the data sets yielded nearly identical tree topologies with regard to the shallower relationships, deeper relationships among the 4 major clades (the above 3 major clades plus Gyrinocheilidae, represented by a single species Gyrinocheilus aymonieri in this study), were incongruent depending on the data sets. Treatment of the rapidly saturated third codon-position transitions appeared to be a source of such incongruities, and we advocate that RY-coding, which takes only transversions into account, effectively removes this likely "noise" from the data set and avoids the apparent lack of signal by retaining all available positions in the data set.

Student–faculty Interactions: Dynamics and Determinants

Abstract: This paper documents the results of a qualitative study of student–faculty interactions The work explores the frequency and nature of interactions, sheds light on the determinants of interactions, and reveals the dynamic processes that underlie contact between faculty and students Focus group results indicate that students have minimal contact with faculty outside the classroom, and do not appear to be aware of the importance of interacting with faculty Results also illustrate key factors that deter and facilitate student–faculty interactions The findings and their implications should be beneficial to faculty, student life professionals, and administrators alike

Rhinosinusitis: developing guidance for clinical trials.

Abstract: The Rhinosinusitis Initiative was developed by 5 national societies. The current guidance document is an expansion of the 2004 publication "Rhinosinusitis: Establishing definitions for clinical research and patient care" and provides templates for clinical trials in antimicrobial, anti-inflammatory, and symptom-relieving therapies for the following: (1) acute presumed bacterial rhinosinusitis, (2) chronic rhinosinusitis (CRS) without nasal polyps, (3) CRS with nasal polyps, and (4) classic allergic fungal rhinosinusitis. In addition to the templates for clinical trials and proposed study designs, the Rhinosinusitis Initiative has developed 6 appendices, which address (1) health outcomes, (2) nasal endoscopy and staging of CRS, (3) radiologic imaging, (4) microbiology, (5) laboratory measures, and (6) biostatistical methods.