Showing papers by "University of Iowa published in 2005"
TL;DR: In this review the different models of antimicrobial-peptide-induced pore formation and cell killing are presented and several observations suggest that translocated peptides can alter cytoplasmic membrane septum formation, inhibit cell-wall synthesis, inhibit nucleic-acid synthesis, inhibits protein synthesis or inhibit enzymatic activity.
Abstract: Antimicrobial peptides are an abundant and diverse group of molecules that are produced by many tissues and cell types in a variety of invertebrate, plant and animal species. Their amino acid composition, amphipathicity, cationic charge and size allow them to attach to and insert into membrane bilayers to form pores by 'barrel-stave', 'carpet' or 'toroidal-pore' mechanisms. Although these models are helpful for defining mechanisms of antimicrobial peptide activity, their relevance to how peptides damage and kill microorganisms still need to be clarified. Recently, there has been speculation that transmembrane pore formation is not the only mechanism of microbial killing. In fact several observations suggest that translocated peptides can alter cytoplasmic membrane septum formation, inhibit cell-wall synthesis, inhibit nucleic-acid synthesis, inhibit protein synthesis or inhibit enzymatic activity. In this review the different models of antimicrobial-peptide-induced pore formation and cell killing are presented.
5,102 citations
TL;DR: In this article, a meta-analysis investigated the relationships between person-job (PJ), person-organization (PO), person group, and person-supervisor fit with pre-entry (applicant attraction, job acceptance, intent to hire, job offer) and postentry individual-level criteria (attitudes, performance, withdrawal behaviors, strain, tenure).
Abstract: This meta-analysis investigated the relationships between person‐job (PJ), person‐organization (PO), person‐group, and person‐supervisor fit with preentry (applicant attraction, job acceptance, intent to hire, job offer) and postentry individual-level criteria (attitudes, performance, withdrawal behaviors, strain, tenure). A search of published articles, conference presentations, dissertations, and working papers yielded 172 usable studies with 836 effect sizes. Nearly all of the credibility intervals did not include 0, indicating the broad generalizability of the relationships across situations. Various ways in which fit was conceptualized and measured, as well as issues of study design, were examined as moderators to these relationships in studies of PJ and PO fit. Interrelationships between the various types of fit are also meta-analyzed. 25 studies using polynomial regression as an analytic technique are reviewed separately, because of their unique approach to assessing fit. Broad themes emerging from the results are discussed to generate the implications for future research on fit.
4,107 citations
TL;DR: It is shown that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the retinal pigmented epithelium, implicating HF1 function in the pathogenetic mechanisms underlying AMD.
Abstract: Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. Our previous studies implicated activation of complement in the formation of drusen, the hallmark lesion of AMD. Here, we show that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the retinal pigmented epithelium. Because previous linkage analyses identified chromosome 1q25-32, which harbors the factor H gene (HF1/CFH), as an AMD susceptibility locus, we analyzed HF1 for genetic variation in two independent cohorts comprised of ≈900 AMD cases and 400 matched controls. We found association of eight common HF1 SNPs with AMD; two common missense variants exhibit highly significant associations (I62V, χ2 = 26.1 and P = 3.2 × 10-7 and Y402H, χ2 = 54.4 and P = 1.6 × 10-13). Haplotype analysis reveals that multiple HF1 variants confer elevated or reduced risk of AMD. One common at-risk haplotype is present at a frequency of 50% in AMD cases and 29% in controls [odds ratio (OR) = 2.46, 95% confidence interval (1.95-3.11)]. Homozygotes for this haplotype account for 24% of cases and 8% of controls [OR = 3.51, 95% confidence interval (2.13-5.78)]. Several protective haplotypes are also identified (OR = 0.44-0.55), further implicating HF1 function in the pathogenetic mechanisms underlying AMD. We propose that genetic variation in a regulator of the alternative complement pathway, when combined with a triggering event, such as infection, underlie a major proportion of AMD in the human population.
2,012 citations
TL;DR: The first consensus-based operational criteria for symptomatic remission in schizophrenia are based on distinct thresholds for reaching and maintaining improvement, as opposed to change criteria, allowing for alignment with traditional concepts of remission in both psychiatric and nonpsychiatric illness.
Abstract: New advances in the understanding of schizophrenia etiology, course, and treatment have increased interest on the part of patients, families, advocates, and professionals in the development of consensus-defined standards for clinical status and improvement, including illness remission and recovery As demonstrated in the area of mood disorders, such standards provide greater clarity around treatment goals, as well as an improved framework for the design and comparison of investigational trials and the subsequent evaluation of the effectiveness of interventions Unlike the approach to mood disorders, however, the novel application of the concept of standard outcome criteria to schizophrenia must reflect the wide heterogeneity of its long-term course and outcome, as well as the variable effects of different treatments on schizophrenia symptoms As an initial step in developing operational criteria, an expert working group reviewed available definitions and assessment instruments to provide a conceptual framework for symptomatic, functional, and cognitive domains in schizophrenia as they relate to remission of illness The first consensus-based operational criteria for symptomatic remission in schizophrenia are based on distinct thresholds for reaching and maintaining improvement, as opposed to change criteria, allowing for alignment with traditional concepts of remission in both psychiatric and nonpsychiatric illness This innovative approach for standardizing the definition for outcome in schizophrenia will require further examination of its validity and utility, as well as future refinement, particularly in relation to psychosocial and cognitive function and dysfunction These criteria should facilitate research and support a positive, longer-term approach to studying outcome in patients with schizophrenia
1,964 citations
TL;DR: A very fast empirical method is presented for structure‐based protein pKa prediction and rationalization and unusual pKa values at buried active sites are predicted very well with the empirical method.
Abstract: A very fast empirical method is presented for structure-based protein pKa prediction and rationalization. The desolvation effects and intra-protein interactions, which cause variations in pKa values of protein ionizable groups, are empirically related to the positions and chemical nature of the groups proximate to the pKa sites. A computer program is written to automatically predict pKa values based on these empirical relationships within a couple of seconds. Unusual pKa values at buried active sites, which are among the most interesting protein pKa values, are predicted very well with the empirical method. A test on 233 carboxyl, 12 cysteine, 45 histidine, and 24 lysine pKa values in various proteins shows a root-mean-square deviation (RMSD) of 0.89 from experimental values. Removal of the 29 pKa values that are upper or lower limits results in an RMSD = 0.79 for the remaining 285 pKa values.
1,857 citations
TL;DR: A neural model for economic decision is proposed, in which emotions are a major factor in the interaction between environmental conditions and human decision processes, with these emotional systems providing valuable implicit or explicit knowledge for making fast and advantageous decisions.
1,713 citations
TL;DR: The overall diagnostic accuracy of digital and film mammography as a means of screening for breast cancer is similar, but digital mammography is more accurate in women under the age of 50 years, women with radiographically dense breasts, and premenopausal or perimenopausal women.
Abstract: background Film mammography has limited sensitivity for the detection of breast cancer in women with radiographically dense breasts. We assessed whether the use of digital mammography would avoid some of these limitations. methods A total of 49,528 asymptomatic women presenting for screening mammography at 33 sites in the United States and Canada underwent both digital and film mammography. All relevant information was available for 42,760 of these women (86.3 percent). Mammograms were interpreted independently by two radiologists. Breast-cancer status was ascertained on the basis of a breast biopsy done within 15 months after study entry or a follow-up mammogram obtained at least 10 months after study entry. Receiver-operating-characteristic (ROC) analysis was used to evaluate the results. results In the entire population, the diagnostic accuracy of digital and film mammography was similar (difference between methods in the area under the ROC curve, 0.03; 95 percent confidence interval, i0.02 to 0.08; P=0.18). However, the accuracy of digital mammography was significantly higher than that of film mammography among women under the age of 50 years (difference in the area under the curve, 0.15; 95 percent confidence interval, 0.05 to 0.25; P=0.002), women with heterogeneously dense or extremely dense breasts on mammography (difference, 0.11; 95 percent confidence interval, 0.04 to 0.18; P=0.003), and premenopausal or perimenopausal women (difference, 0.15; 95 percent confidence interval, 0.05 to 0.24; P=0.002). conclusions The overall diagnostic accuracy of digital and film mammography as a means of screening for breast cancer is similar, but digital mammography is more accurate in women under the age of 50 years, women with radiographically dense breasts, and premenopausal or perimenopausal women. (clinicaltrials.gov number, NCT00008346.)
1,685 citations
Wellcome Trust Sanger Institute1, J. Craig Venter Institute2, George Washington University3, University of Glasgow4, University of Oxford5, Newcastle University6, University of Bordeaux7, University of Cambridge8, Oregon Health & Science University9, University of Dundee10, Imperial College London11, Case Western Reserve University12, Yale University13, Université catholique de Louvain14, University of Iowa15, Wellcome Trust16
TL;DR: Comparisons of the cytoskeleton and endocytic trafficking systems of Trypanosoma brucei with those of humans and other eukaryotic organisms reveal major differences.
Abstract: African trypanosomes cause human sleeping sickness and livestock trypanosomiasis in sub-Saharan Africa. We present the sequence and analysis of the 11 megabase-sized chromosomes of Trypanosoma brucei. The 26-megabase genome contains 9068 predicted genes, including ∼900 pseudogenes and ∼1700 T. brucei–specific genes. Large subtelomeric arrays contain an archive of 806 variant surface glycoprotein (VSG) genes used by the parasite to evade the mammalian immune system. Most VSG genes are pseudogenes, which may be used to generate expressed mosaic genes by ectopic recombination. Comparisons of the cytoskeleton and endocytic trafficking systems with those of humans and other eukaryotic organisms reveal major differences. A comparison of metabolic pathways encoded by the genomes of T. brucei, T. cruzi, and Leishmania major reveals the least overall metabolic capability in T. brucei and the greatest in L. major. Horizontal transfer of genes of bacterial origin has contributed to some of the metabolic differences in these parasites, and a number of novel potential drug targets have been identified.
1,631 citations
Ludwig Institute for Cancer Research1, State University of Campinas2, University of Iowa3, University of Arizona4, University of New Mexico5, University of Washington6, SINTEF7, Karolinska Institutet8, Indiana University9, Johns Hopkins University School of Medicine10, University of Virginia11, McGill University12, Dartmouth College13, United States Military Academy14
TL;DR: In this paper, a double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11).
Abstract: Summary Background A randomised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11). Methods 277 young women (mean age 20·2 years [SD 1·7]) were randomly assigned to quadrivalent HPV (20 μg type 6, 40 μg type 11, 40 μg type 16, and 20 μg type 18) L1 virus-like-particle (VLP) vaccine and 275 (mean age 20·0 years [1·7]) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, participants underwent regular gynaecological examinations, cervicovaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV 6, 11, 16, or 18, or cervical or external genital disease (ie, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia, cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol. Findings Combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 fell by 90% (95% CI 71–97, p Interpretation A vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types. Published online April 7, 2005 DOI 10.1016/S1470-2045(05)70101-7
1,627 citations
TL;DR: These studies identify TSPs as CNS synaptogenic proteins, provide evidence that astrocytes are important contributors to synaptogenesis within the developing CNS, and suggest that TSP-1 and -2 act as a permissive switch that times CNSsynaptogenesis by enabling neuronal molecules to assemble into synapses within a specific window of CNS development.
1,521 citations
TL;DR: The hypothesis that prenatal phthalate exposure at environmental levels can adversely affect male reproductive development in humans is supported.
Abstract: Prenatal phthalate exposure impairs testicular function and shortens anogenital distance (AGD) in male rodents. We present data from the first study to examine AGD and other genital measurements in relation to prenatal phthalate exposure in humans. A standardized measure of AGD was obtained in 134 boys 2–36 months of age. AGD was significantly correlated with penile volume (R = 0.27, p = 0.001) and the proportion of boys with incomplete testicular descent (R = 0.20, p = 0.02). We defined the anogenital index (AGI) as AGD divided by weight at examination [AGI = AGD/weight (mm/kg)] and calculated the age-adjusted AGI by regression analysis. We examined nine phthalate monoester metabolites, measured in prenatal urine samples, as predictors of age-adjusted AGI in regression and categorical analyses that included all participants with prenatal urine samples (n = 85). Urinary concentrations of four phthalate metabolites [monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), and monoisobutyl phthalate (MiBP)] were inversely related to AGI. After adjusting for age at examination, p-values for regression coefficients ranged from 0.007 to 0.097. Comparing boys with prenatal MBP concentration in the highest quartile with those in the lowest quartile, the odds ratio for a shorter than expected AGI was 10.2 (95% confidence interval, 2.5 to 42.2). The corresponding odds ratios for MEP, MBzP, and MiBP were 4.7, 3.8, and 9.1, respectively (all p-values < 0.05). We defined a summary phthalate score to quantify joint exposure to these four phthalate metabolites. The age-adjusted AGI decreased significantly with increasing phthalate score (p-value for slope = 0.009). The associations between male genital development and phthalate exposure seen here are consistent with the phthalate-related syndrome of incomplete virilization that has been reported in prenatally exposed rodents. The median concentrations of phthalate metabolites that are associated with short AGI and incomplete testicular descent are below those found in one-quarter of the female population of the United States, based on a nationwide sample. These data support the hypothesis that prenatal phthalate exposure at environmental levels can adversely affect male reproductive development in humans.
TL;DR: The existing structural evidence establishes that the mood and anxiety disorders should be collapsed together into an overarching class of emotional disorders, which can be decomposed into 3 subclasses.
Abstract: The fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1994) groups disorders into diagnostic classes on the basis of the subjective criterion of "shared phenomenological features." There are now sufficient data to eliminate this rational system and replace it with an empirically based structure that reflects the actual similarities among disorders. The existing structural evidence establishes that the mood and anxiety disorders should be collapsed together into an overarching class of emotional disorders, which can be decomposed into 3 subclasses: the bipolar disorders (bipolar I, bipolar II, cyclothymia), the distress disorders (major depression, dysthymic disorder, generalized anxiety disorder, posttraumatic stress disorder), and the fear disorders (panic disorder, agoraphobia, social phobia, specific phobia). The optimal placement of other syndromes (e.g., obsessive-compulsive disorder) needs to be clarified in future research.
TL;DR: Using functional brain imaging, it is shown that the level of ambiguity in choices correlates positively with activation in the amygdala and orbitofrontal cortex, and negatively with the striatal system, suggesting a general neural circuit responding to degrees of uncertainty, contrary to decision theory.
Abstract: Much is known about how people make decisions under varying levels of probability (risk). Less is known about the neural basis of decision-making when probabilities are uncertain because of missing information (ambiguity). In decision theory, ambiguity about probabilities should not affect choices. Using functional brain imaging, we show that the level of ambiguity in choices correlates positively with activation in the amygdala and orbitofrontal cortex, and negatively with a striatal system. Moreover, striatal activity correlates positively with expected reward. Neurological subjects with orbitofrontal lesions were insensitive to the level of ambiguity and risk in behavioral choices. These data suggest a general neural circuit responding to degrees of uncertainty, contrary to decision theory.
TL;DR: It is concluded that sexual difficulties are relatively common among mature adults throughout the world, and tend to be more associated with physical health and aging among men than women.
Abstract: The Global Study of Sexual Attitudes and Behaviors (GSSAB) is an international survey of various aspects of sex and relationships among adults aged 40–80 y. An analysis of GSSAB data was performed to estimate the prevalence and correlates of sexual problems in 13 882 women and 13 618 men from 29 countries. The overall response rate was modest; however, the estimates of prevalence of sexual problems are comparable with published values. Several factors consistently elevated the likelihood of sexual problems. Age was an important correlate of lubrication difficulties among women and of several sexual problems, including a lack of interest in sex, the inability to reach orgasm, and erectile difficulties among men. We conclude that sexual difficulties are relatively common among mature adults throughout the world. Sexual problems tend to be more associated with physical health and aging among men than women.
TL;DR: It is shown that SM, a patient with rare bilateral amygdala damage, shows an inability to make normal use of information from the eye region of faces when judging emotions, a defect the authors trace to a lack of spontaneous fixations on the eyes during free viewing of faces.
Abstract: Ten years ago, we reported that SM, a patient with rare bilateral amygdala damage, showed an intriguing impairment in her ability to recognize fear from facial expressions. Since then, the importance of the amygdala in processing information about facial emotions has been borne out by a number of lesion and functional imaging studies. Yet the mechanism by which amygdala damage compromises fear recognition has not been identified. Returning to patient SM, we now show that her impairment stems from an inability to make normal use of information from the eye region of faces when judging emotions, a defect we trace to a lack of spontaneous fixations on the eyes during free viewing of faces. Although SM fails to look normally at the eye region in all facial expressions, her selective impairment in recognizing fear is explained by the fact that the eyes are the most important feature for identifying this emotion. Notably, SM's recognition of fearful faces became entirely normal when she was instructed explicitly to look at the eyes. This finding provides a mechanism to explain the amygdala's role in fear recognition, and points to new approaches for the possible rehabilitation of patients with defective emotion perception.
TL;DR: The term 'sociomicrobiology' is introduced because bacteria exhibit many social activities and they represent a model for dissecting social behavior at the genetic level, and these two aspects of bacterial behavior represent a small part of the social repertoire of bacteria.
TL;DR: A constructive replication approach was used to delineate an integrative hierarchical account of the structure of normal and abnormal personality, which integrates many Big Trait models proposed in the literature and provides insight into the nature of personality hierarchy more generally.
Abstract: Increasing evidence indicates that normal and abnormal personality can be treated within a single structural framework. However, identification of a single integrated structure of normal and abnormal personality has remained elusive. Here, a constructive replication approach was used to delineate an integrative hierarchical account of the structure of normal and abnormal personality. This hierarchical structure, which integrates many Big Trait models proposed in the literature, replicated across a meta-analysis as well as an empirical study, and across samples of participants as well as measures. The proposed structure resembles previously suggested accounts of personality hierarchy and provides insight into the nature of personality hierarchy more generally. Potential directions for future research on personality and psychopathology are discussed.
TL;DR: The authors found that students report higher levels of engagement and learning at institutions where faculty members use active and collaborative learning techniques, engage students in experiences, emphasize higher-order cognitive activities in the classroom, interact with students, challenge students academically, and value enriching educational experiences.
Abstract: This study uses two national data sets to explore the relationship between faculty practices and student engagement. Our findings suggest that students report higher levels of engagement and learning at institutions where faculty members use active and collaborative learning techniques, engage students in experiences, emphasize higher-order cognitive activities in the classroom, interact with students, challenge students academically, and value enriching educational experiences. The quality and value of an undergraduate education in the past decade received, and continues to receive, scrutiny by various stakeholders associated with the higher education community. Much of the energy surrounding the undergraduate experience and student learning was placed on the two major responsibilities of faculty, teaching and research (Fairweather, 1996, 2002; Marsh and Hattie, 2002). The regulation of time allocated to these two roles was quickly becoming one of the most salient issues in higher education. Unfortunately, much of the debate about the nature of faculty work was shrouded in myth, opinion, and conjecture (Fairweather, 2002). Some of these perceptions, such as a faculty member being highly involved in teaching, engages students in the undergraduate experience resulting in greater student learning gains, were important to debunk or substantiate. As a result, assessing the impact that faculty
University of Pennsylvania1, Washington University in St. Louis2, Icahn School of Medicine at Mount Sinai3, University of North Carolina at Chapel Hill4, Duke University5, Emory University6, McGill University7, Columbia University8, National Institutes of Health9, University of California, San Diego10, University of Miami11, Rutgers University12, Rush University Medical Center13, University of Washington14, Stanford University15, Food and Drug Administration16, Johns Hopkins University17, Rockefeller University18, University of Florida19, University of Pittsburgh20, University of Iowa21, Group Health Cooperative22, American Diabetes Association23
TL;DR: A growing body of evidence suggests that biological mechanisms underlie a bidirectional link between mood disorders and many medical illnesses and there is evidence to suggest that mood disorders affect the course of medical illnesses.
TL;DR: Verbal memory and processing speed and attention are potential targets for psychosocial interventions to improve outcome in schizophrenia, and cognition appears to explain less of the variance in outcome.
Abstract: Objective: The relationship between cognition and outcome in people with schizophrenia has been established in studies that, for the most part, examined chronic patients and were cross-sectional in design. The purpose of this study was to analyze the relationships between neurocognitive variables assessed at illness onset and functional outcome in a longitudinal design. An additional area of interest was whether the severity of negative symptoms would predict outcome independently from neurocognitive variables or whether there would be an overlap in their predictive power. Method: The authors administered a comprehensive cognitive battery and clinical assessments to 99 subjects who were in their first episode of illness and analyzed the relationship of cognition and symptom severity at intake with community outcome after an average follow-up period of 7 years. Results: Verbal memory, processing speed and attention, and the severity of negative symptoms at intake were related to subsequent outcome. Global psychosocial functioning was predicted by negative symptoms and attention. Verbal memory was the significant predictor of the degree of impairment in recreational activities. Impairment in relationships was predicted by negative symptoms and memory, whereas attention and negative symptoms were predictive of work performance. There was an overlap in the variance in outcome explained by cognitive variables and negative symptoms. Conclusions: Verbal memory and processing speed and attention are potential targets for psychosocial interventions to improve outcome. Results from cross-sectional or chronic patient studies do not necessarily correspond to the findings of this prospective first-episode study in which cognition appears to explain less of the variance in outcome.
TL;DR: Osteoporosis is widely viewed as a major public health concern, but the exact magnitude of the problem is uncertain and likely to depend on how the condition is defined, and the design and implementation of control programs directed at this major health problem must be given.
Abstract: Osteoporosis is widely viewed as a major public health concern, but the exact magnitude of the problem is uncertain and likely to depend on how the condition is defined. Noninvasive bone mineral measurements can be used to define a state of heightened fracture risk (osteopenia), or the ultimate clinical manifestation of fracture can be assessed (established osteoporosis). If bone mineral measurements more than 2 standard deviations below the mean of young normal women represent osteopenia, then 45% of white women aged 50 years and over have the condition at one or more sites in the hip, spine, or forearm on the basis of population-based data from Rochester, Minnesota. A smaller proportion is affected at each specific skeletal site: 32% have bone mineral values this low in the lumbar spine, 29% in either of two regions in the proximal femur, and 26% in the midradius. Although this overall estimate is substantial, some other serious chronic diseases are almost as common. More importantly, low bone mass is associated with adverse health outcomes, especially fractures. The lifetime risk of any fracture of the hip, spine, or distal forearm is almost 40% in white women and 13% in white men from age 50 years onward. If the enormous costs associated with these fractures are to be reduced, increased attention must be given to the design and implementation of control programs directed at this major health problem.
TL;DR: The construct and measurement overlap among the 3 negative affects is discussed, which requires the development of more complex affect-disease models and has implications for the interpretation of prior studies, statistical analyses, prevention, and intervention in health psychology and behavioral medicine.
Abstract: Several recent reviews have identified 3 affective dispositions--depression, anxiety, and anger-hostility--as putative risk factors for coronary heart disease. There are, however, mixed and negative results. Following a critical summary of epidemiological findings, the present article discusses the construct and measurement overlap among the 3 negative affects. Recognition of the overlap necessitates the development of more complex affect-disease models and has implications for the interpretation of prior studies, statistical analyses, prevention, and intervention in health psychology and behavioral medicine. The overlap among the 3 negative dispositions also leaves open the possibility that a general disposition toward negative affectivity may be more important for disease risk than any specific negative affect.
TL;DR: The continuing discovery of mechanisms regulating appetite and metabolism is likely to lead to new therapies for obesity-induced hypertension and better understanding of leptin signaling in the hypothalamus and the mechanisms of leptin resistance should facilitate therapeutic approaches to reverse the phenomenon of selective leptin resistance.
Abstract: Obesity is strongly associated with hypertension and cardiovascular disease. Several central and peripheral abnormalities that can explain the development or maintenance of high arterial pressure in obesity have been identified. These include activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Obesity is also associated with endothelial dysfunction and renal functional abnormalities that may play a role in the development of hypertension. The continuing discovery of mechanisms regulating appetite and metabolism is likely to lead to new therapies for obesity-induced hypertension. Better understanding of leptin signaling in the hypothalamus and the mechanisms of leptin resistance should facilitate therapeutic approaches to reverse the phenomenon of selective leptin resistance. Other hunger and satiety signals such as ghrelin and peptide YY are potentially attractive therapeutic strategies for treatment of obesity and its complications. These recent discoveries should lead to novel strategies for treatment of obesity and hypertension.
TL;DR: The results indicate that infection of human airway epithelia by SARS coronavirus correlates with the state of cell differentiation and ACE2 expression and localization, which has implications for understanding disease pathogenesis associated with SARS-CoV and NL63 infections.
Abstract: Studies of patients with severe acute respiratory syndrome (SARS) demonstrate that the respiratory tract is a major site of SARS-coronavirus (CoV) infection and disease morbidity. We studied host-pathogen interactions using native lung tissue and a model of well-differentiated cultures of primary human airway epithelia. Angiotensin converting enzyme 2 (ACE2), the receptor for both the SARS-CoV and the related human respiratory coronavirus NL63, was expressed in human airway epithelia as well as lung parenchyma. As assessed by immunofluorescence staining and membrane biotinylation, ACE2 protein was more abundantly expressed on the apical than the basolateral surface of polarized airway epithelia. Interestingly, ACE2 expression positively correlated with the differentiation state of epithelia. Undifferentiated cells expressing little ACE2 were poorly infected with SARS-CoV, while well-differentiated cells expressing more ACE2 were readily infected. Expression of ACE2 in poorly differentiated epithelia facilitated SARS spike (S) protein-pseudotyped virus entry. Consistent with the expression pattern of ACE2, the entry of SARS-CoV or a lentivirus pseudotyped with SARS-CoV S protein in differentiated epithelia was more efficient when applied to the apical surface. Furthermore, SARS-CoV replicated in polarized epithelia and preferentially exited via the apical surface. The results indicate that infection of human airway epithelia by SARS coronavirus correlates with the state of cell differentiation and ACE2 expression and localization. These findings have implications for understanding disease pathogenesis associated with SARS-CoV and NL63 infections.
George Washington University1, University of Washington2, Seattle Biomed3, J. Craig Venter Institute4, Wellcome Trust Sanger Institute5, Karolinska Institutet6, Newcastle University7, Centre national de la recherche scientifique8, Universidade Federal de Minas Gerais9, Medical Research Council10, University of Cambridge11, University of Iowa12
TL;DR: No evidence that these species are descended from an ancestor that contained a photosynthetic endosymbiont is revealed, and a conserved core proteome of about 6200 genes in large syntenic polycistronic gene clusters is revealed.
Abstract: A comparison of gene content and genome architecture of Trypanosoma brucei, Trypanosoma cruzi, and Leishmania major, three related pathogens with different life cycles and disease pathology, revealed a conserved core proteome of about 6200 genes in large syntenic polycistronic gene clusters. Many species-specific genes, especially large surface antigen families, occur at nonsyntenic chromosome-internal and subtelomeric regions. Retroelements, structural RNAs, and gene family expansion are often associated with syntenic discontinuities that-along with gene divergence, acquisition and loss, and rearrangement within the syntenic regions-have shaped the genomes of each parasite. Contrary to recent reports, our analyses reveal no evidence that these species are descended from an ancestor that contained a photosynthetic endosymbiont.
Journal Article•
TL;DR: Investigation regarding the pathogenesis of posttraumatic osteoarthritis, the form of osteoartritis that develops following joint injury, is helping to explain the development and progression of joint degeneration.
Abstract: Articular cartilage, which makes possible the painless, low-friction movement of synovial joints, consists of a sparsely distributed population of highly specialized cells called chondrocytes that are embedded within a matrix and provide articular cartilage with remarkable mechanical properties. Chondrocytes form the tissue matrix macromolecular framework from three classes of molecules: collagens, proteoglycans, and noncollagenous proteins. The matrix protects the cells from injury resulting from normal joint use, determines the types and concentrations of molecules that reach the cells, acts as a mechanical signal transducer for the cells, and helps maintain the chondrocyte phenotype. Throughout life, articular cartilage undergoes internal remodeling as the cells replace matrix macromolecules lost through degradation. Aging decreases the ability of chondrocytes to maintain and restore articular cartilage and thereby increases the risk of degeneration of the articular cartilage surface. Progressive degeneration of articular cartilage leads to joint pain and dysfunction that is clinically identified as osteoarthritis. Investigation regarding the pathogenesis of posttraumatic osteoarthritis, the form of osteoarthritis that develops following joint injury, is helping to explain the development and progression of joint degeneration.
TL;DR: Testicular cancer survivors are at statistically significantly increased risk of solid tumors for at least 35 years after treatment, and young patients may experience high levels of risk as they reach older ages.
Abstract: Background: Although second primary cancers are a leading cause of death among men with testicular cancer, few studies have quantifi ed risks among long-term survivors. Methods: Within 14 population-based tumor registries in Europe and North America (1943–2001), we identifi ed 40 576 1-year survivors of testicular cancer and ascertained data on any new incident solid tumors among these patients. We used Poisson regression analysis to model relative risks (RRs) and excess absolute risks (EARs) of second solid cancers. All statistical tests were two-sided. Results: A total of 2285 second solid cancers were reported in the cohort. The relative risk and EAR decreased with increasing age at testicular cancer diagnosis ( P <.001); the EAR increased with attained age ( P <.001) but the excess RR decreased. Among 10-year survivors diagnosed with testicular cancer at age 35 years, the risk of developing a second solid tumor was increased (RR = 1.9, 95% confi dence interval [CI] = 1.8 to 2.1). Risk remained statistically signifi cantly elevated for 35 years (RR = 1.7, 95% CI = 1.5 to 2.0; P <.001). We observed statistically signifi cantly elevated risks, for the fi rst time, for cancers of the pleura (malignant mesothelioma; RR = 3.4, 95% CI = 1.7 to 5.9) and esophagus (RR = 1.7, 95% CI = 1.0 to 2.6). Cancers of the lung (RR = 1.5, 95% CI = 1.2 to 1.7), colon (RR = 2.0, 95% CI = 1.7 to 2.5), bladder (RR = 2.7, 95% CI = 2.2 to 3.1), pancreas (RR = 3.6, 95% CI = 2.8 to 4.6), and stomach (RR = 4.0, 95% CI = 3.2 to 4.8) accounted for almost 60% of the total excess. Overall patterns were similar for seminoma and nonseminoma patients, with lower risks observed for nonseminoma patients treated after 1975. Statistically signifi cantly increased risks of solid cancers were observed among patients treated with radiotherapy alone (RR = 2.0, 95% CI = 1.9 to 2.2), chemotherapy alone (RR = 1.8, 95% CI = 1.3 to 2.5), and both (RR = 2.9, 95% CI = 1.9 to 4.2). For patients diagnosed with seminomas or nonseminomatous tumors at age 35 years, cumulative risks of solid cancer 40 years later (i.e., to age 75 years) were 36% and 31%, respectively, compared with 23% for the general population. Conclusions : Testicular cancer survivors are at statistically signifi cantly increased risk of solid tumors for at least 35 years after treatment. Young patients may experience high levels of risk as they reach older ages. The statistically signifi cantly increased risk of malignant mesothelioma in testicular cancer survivors has, to our knowledge, not been observed previously in a cohort of patients treated with radiotherapy. [J Natl Cancer Inst 2005;97:1354–65]
TL;DR: Whether the authors' conclusions about participants' knowledge in the Iowa Gambling Task are justified is considered.
TL;DR: In this article, the authors strengthen the chain of effects that link customer satisfaction to shareholder value by establishing the link between satisfaction and two characteristics of future cash flows that determine the value of the firm to shareholders: growth and stability.
Abstract: In this article, the authors strengthen the chain of effects that link customer satisfaction to shareholder value by establishing the link between satisfaction and two characteristics of future cash flows that determine the value of the firm to shareholders: growth and stability. Using longitudinal American Customer Satisfaction Index and COMPUSTAT data and hierarchical Bayesian estimation, the authors find that satisfaction creates shareholder value by increasing future cash flow growth and reducing its variability. They test the stability of findings across several firm and industry characteristics, and they assess the robustness of the results using multimeasure and multimethod estimation.
TL;DR: Three broad, innate temperament dimensions differentiate through both biologically and environmentally based developmental processes into a hierarchical personality trait structure and, at their extremes, are risk factors for psychopathology, especially given adverse life experiences (stress).
Abstract: Personality and psychopathology long have been viewed as related domains, but the precise nature of their relations remains unclear. Through most of the 20th century, they were studied as separate fields; within psychopathology, clinical syndromes were separated from personality disorders in 1980. This division led to the revelation of substantial overlap among disorders both within and across axes and to the joint study of normal and abnormal personality. The author reviews these literatures and proposes an integrative framework to explain personality-psychopathology relations: Three broad, innate temperament dimensions--negative affectivity, positive affectivity, and disinhibition--differentiate through both biologically and environmentally based developmental processes into a hierarchical personality trait structure and, at their extremes, are risk factors (diatheses) for psychopathology, especially given adverse life experiences (stress).