bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional Analysis of saxophone, the Drosophila Gene Encoding the BMP Type I Receptor Ortholog of Human ALK1/ACVRL1 and ACVR1/ALK2
Authors: Twombly Vern , Bangi Erdem , Le Viet , Malnic Bettina , Singer Matthew A , Wharton Kristi A 
Published: July 2009

Abstract
In metazoans, bone morphogenetic proteins (BMPs) direct a myriad of developmental and adult homeostatic events through their heterotetrameric type I and type II receptor complexes. We examined 3 existing and 12 newly generated mutations in the Drosophila type I receptor gene, saxophone (sax), the ortholog of the human Activin Receptor-Like Kinase1 and -2 (ALK1/ACVRL1 and ALK2/ACVR1) genes. Our genetic analyses identified two distinct classes of sax alleles. The first class consists of homozygous viable gain-of-function (GOF) alleles that exhibit (1) synthetic lethality in combination with mutations in BMP pathway components, and (2) significant maternal effect lethality that can be rescued by an increased dosage of the BMP encoding gene, dpp+. In contrast, the second class consists of alleles that are recessive lethal and do not exhibit lethality in combination with mutations in other BMP pathway components. The alleles in this second class are clearly loss-of-function (LOF) with both complete and partial loss-of-function mutations represented. We find that one allele in the second class of recessive lethals exhibits dominant-negative behavior, albeit distinct from the GOF activity of the first class of viable alleles. On the basis of the fact that the first class of viable alleles can be reverted to lethality and on our ability to independently generate recessive lethal sax mutations, our analysis demonstrates that sax is an essential gene. Consistent with this conclusion, we find that a normal sax transcript is produced by saxP, a viable allele previously reported to be null, and that this allele can be reverted to lethality. Interestingly, we determine that two mutations in the first class of sax alleles show the same amino acid substitutions as mutations in the human receptors ALK1/ACVRl-1 and ACVR1/ALK2, responsible for cases of hereditary hemorrhagic telangiectasia type 2 (HHT2) and fibrodysplasia ossificans progressiva (FOP), respectively. Finally, the data presented here identify different functional requirements for the Sax receptor, support the proposal that Sax participates in a heteromeric receptor complex, and provide a mechanistic framework for future investigations into disease states that arise from defects in BMP/TGF-β signaling.
Reproductive Value and Fluctuating Selection in an Age-Structured Population
Authors: Engen Steinar , Lande Russell , Sæther Bernt-Erik 
Published: July 2009

Abstract
Fluctuations in age structure caused by environmental stochasticity create autocorrelation and transient fluctuations in both population size and allele frequency, which complicate demographic and evolutionary analyses. Following a suggestion of Fisher, we show that weighting individuals of different age by their reproductive value serves as a filter, removing temporal autocorrelation in population demography and evolution due to stochastic age structure. Assuming weak selection, random mating, and a stationary distribution of environments with no autocorrelation, we derive a diffusion approximation for evolution of the reproductive value weighted allele frequency. The expected evolution obeys an adaptive topography defined by the long-run growth rate of the population. The expected fitness of a genotype is its Malthusian fitness in the average environment minus the covariance of its growth rate with that of the population. Simulations of the age-structured model verify the accuracy of the diffusion approximation. We develop statistical methods for measuring the expected selection on the reproductive value weighted allele frequency in a fluctuating age-structured population.
Lethal Mutagenesis in Viruses and Bacteria
Authors: Chen Peiqiu , Shakhnovich Eugene I 
Published: July 2009

Abstract
In this work we study how mutations that change physical properties of cell proteins (stability) affect population survival and growth. We present a model in which the genotype is presented as a set folding free energies of cell proteins. Mutations occur upon replication, so stabilities of some proteins in daughter cells differ from those in the parent cell by amounts deduced from the distribution of mutational effects on protein stability. The genotype–phenotype relationship posits that the cell's fitness (replication rate) is proportional to the concentration of its folded proteins and that unstable essential proteins result in lethality. Simulations reveal that lethal mutagenesis occurs at a mutation rate close to seven mutations in each replication of the genome for RNA viruses and at about half that rate for DNA-based organisms, in accord with earlier predictions from analytical theory and experimental results. This number appears somewhat dependent on the number of genes in the organisms and the organism's natural death rate. Further, our model reproduces the distribution of stabilities of natural proteins, in excellent agreement with experiments. We find that species with high mutation rates tend to have less stable proteins compared to species with low mutation rates.
Analysis of Synthetic Lethality Reveals Genetic Interactions Between the GTPase Snu114p and snRNAs in the Catalytic Core of the Saccharomyces cerevisiae Spliceosome
Authors: Frazer Lily Novak , Lovell Simon C , O'Keefe Raymond T 
Published: July 2009

Abstract
Conformational changes of snRNAs in the spliceosome required for pre-mRNA splicing are regulated by eight ATPases and one GTPase Snu114p. The Snu114p guanine state regulates U4/U6 unwinding during spliceosome activation and U2/U6 unwinding during spliceosome disassembly through the ATPase Brr2p. We investigated 618 genetic interactions to identify an extensive genetic interaction network between SNU114 and snRNAs. Snu114p G domain alleles were exacerbated by mutations that stabilize U4/U6 base pairing. G domain alleles were made worse by U2 and U6 mutations that stabilize or destabilize U2/U6 base pairing in helix I. Compensatory mutations that restored U2/U6 base pairing in helix I relieved synthetic lethality. Snu114p G domain alleles were also worsened by mutations in U6 predicted to increase 5′ splice site base pairing. Both N-terminal and G domain alleles were exacerbated by U5 loop 1 mutations at positions involved in aligning exons while C-terminus alleles were synthetically lethal with U5 internal loop 1 mutations. This suggests a spatial orientation for Snu114p with U5. We propose that the RNA base pairing state is directly or indirectly sensed by the Snu114p G domain allowing the Snu114p C-terminal domain to regulate Brr2p or other proteins to bring about RNA/RNA rearrangements required for splicing.
Bruising Frequency and Patterns in Children With Physical Disabilities
Authors: Goldberg Amy P. , Tobin Jane , Daigneau Janet , Griffith Robert T. , Reinert Steven E. , Jenny Carole 
Published: July 2009

OBJECTIVE: We obtained normative data on bruising in children with physical disability in functioning and evaluated factors associated with bruising in this population.
METHODS: We studied children with physical and/or cognitive disabilities who attend a school that provides comprehensive services. Over a 15-month period, the children had skin examinations, including external inspection of the genitalia and anus. For each child, we gathered information on demographics, medications, growth measures, medical conditions, equipment used, and muscle tone. Functional independence in basic mobility, self-care, and social communication was assessed by using the Functional Independence Measure for Children (WeeFIM). Results were compared with a previously studied nondisabled or “typical” population of children.
RESULTS: Fifty children and adolescents 4 to 20 years of age had 2 skin examinations. There was no relationship between the number of bruises and the child's age, race, or BMI. Overall, our subjects were more likely to have at least 1 bruise noted than nondisabled children from a comparable study. There was no significant relationship between the number of bruises and functional mobility, self-care, cognition, or muscle tone. The bruising locations in our study group were different from those of nondisabled children. However, in both groups bruises were rarely found on the neck, ears, chin, anterior chest, or buttocks.
CONCLUSIONS: The children in our study were different from nondisabled children in the frequency and pattern of their bruising. Areas uncommonly bruised in typical children were also uncommonly bruised in the disabled children. Although increasing age and mobility clearly make a difference in the number of bruises a typically functioning child sustains, these factors are not relevant when evaluating bruises on a child with disabilities. Other factors such as muscle tone, cognition, and equipment should be considered when evaluating a child with significant disabilities who presents with bruises.
Prenatal Airborne Polycyclic Aromatic Hydrocarbon Exposure and Child IQ at Age 5 Years
Authors: Perera Frederica P. , Li Zhigang , Whyatt Robin , Hoepner Lori , Wang Shuang , Camann David , Rauh Virginia 
Published: July 2009

OBJECTIVE: This study evaluated the relationship between prenatal exposure to airborne polycyclic aromatic hydrocarbons (PAHs) and child intelligence.METHODS: Children of nonsmoking black or Dominican-American women residing in New York City were monitored from in utero to 5 years of age, with determination of prenatal PAH exposure through personal air monitoring for the mothers during pregnancy. At 5 years of age, intelligence was assessed for 249 children by using the Wechsler Preschool and Primary Scale of Intelligence-Revised. Multivariate linear regression models were used to estimate and to test the associations between prenatal PAH exposure and IQ.RESULTS: After adjustment for maternal intelligence, quality of the home caretaking environment, environmental tobacco smoke exposure, and other potentially confounding factors, high PAH levels (above the median of 2.26 ng/m3) were inversely associated with full-scale IQ (P = .007) and verbal IQ (P = .003) scores. Children in the high-exposure group had full-scale and verbal IQ scores that were 4.31 and 4.67 points lower, respectively, than those of less-exposed children (≤2.26 ng/m3). The associations between logarithmically transformed, continuous, PAH levels and these IQ measures also were significant (full-scale IQ: β = −3.00; P = .009; verbal IQ: β = −3.53; P = .002).CONCLUSION: These results provide evidence that environmental PAHs at levels encountered in New York City air can affect children's IQ adversely.
Characteristics of Infant Homicides: Findings From a U.S. Multisite Reporting System
Authors: Fujiwara Takeo , Barber Catherine , Schaechter Judy , Hemenway David 
Published: July 2009

OBJECTIVE: The purpose of this study was to describe homicides of infants (children &lt;2 years of age) in the U.S.METHODS: Cases were derived from the National Violent Injury Statistics System; 71 incidents involving 72 infant homicides were in the data set. Type 1 involved beating/shaking injuries inflicted by a caretaker; type 2 involved all other homicides (including neonaticide, intimate partner problem-related homicide, crime-related death, and other types).RESULTS: Seventy-five percent of the incidents were type 1 incidents, perpetrated mainly by men (83%; typically the infant's father or the boyfriend of the infant's mother). In 85% of the type 1 incidents, the infant was transported to the hospital, usually at the initiative of the perpetrator or another household member. In almost one half of the type 1 incidents, a false story was offered initially to explain the injuries. In contrast, the type 2 incidents (16 cases) were perpetrated mainly by women (11 of 16 cases) and involved methods such as poisoning, drowning, sharp instruments, or withdrawal of food and water; most infants were not taken to the hospital. Although 93% of incidents were perpetrated by caretakers, the large differences between the 2 incident types suggest different avenues for prevention.CONCLUSIONS: The circumstances involved in the type 1 homicides (beatings by caretakers) suggested that those attacks occurred impulsively, death was unintended, and emergency care was summoned, often with a false story. Previous abuse was suspected in more than one half of those incidents.
Health Care Disparities and Diabetes Care: Practical Considerations for Primary Care Providers
Authors: White Richard O. , Beech Bettina M. , Miller Stephania 
Published: July 2009

IN BRIEF
Disparities in diabetes care are prevalent in the United States. This article provides an overview of these disparities and discusses both potential causes and efforts to address them to date. The authors focus the discussion on aspects relevant to the patient-provider dyad and provide practical considerations for the primary care provider's role in helping to diminish and eliminate disparities in diabetes care.
Incidence of Common Transfusion Transmitted Diseases Among Blood Donors
Authors: Ahmed Musleh Uddin , Begum Hosne Ara , Hossain Tozammel , Chakraborty Prodipesh 
Published: July 2009

Transfusion transmitted diseases are one of the major health problem in Bangladesh. This study was carried out among 12,270 voluntary and directed donors in the transfusion medicine department of Khulna Medical College Hospital (KMCH), a teaching hospital of southern Bangladesh during the period from 1st July 2007 to 30th June 2008 to see the incidence of HIV, HCV, HBV, Syphilis & Malaria. All were voluntary and relative/directed donors. No professional donors had taken part in this donation system. Blood samples were collected in sterile dry plain test tube after predonation consent. Serum of each donor was collected by proper centrifugation within 6 hours of collection. Tests of all the samples were done within 24 hours of collection. The methods used were latex agglutination Immunochromatographic test (ICT) and reconfirmed by ELISA techniques. For malaria thick and thin film studies under microscope were done. On analyzing the results, 171 (1.39%) were found positive for HBsAg, 03 (0.024%) were positive for anti HCV, 01 was positive for anti HIV (0.008%). None found positive for Malarial parasite (MP) none were reactive for RPR test. Donation from professional blood donors are completely stopped in the transfusion medicine unit of KMCH. Mandatory screening of donated blood should be done for HIV, HBV, HCV, Syphilis and Malaria to reduce their transmission by transfusion. Key Words: Transfusion transmitted diseases, Blood donors. doi: 10.3329/jafmc.v5i1.2840 JAFMC Bangladesh. Vol 5, No 1 (June) 2009 pp.4-6
Caveolae Facilitate but Are Not Essential for Platelet-Activating Factor-Mediated Calcium Mobilization and Extracellular Signal-Regulated Kinase Activation
Authors: Poisson Caroline , Rollin Simon , Véronneau Steeve , Bousquet Simon M. , Larrivée Jean-François , Le Gouill Christian , Boulay Guylain , Stankova Jana , Rola-Pleszczynski Marek 
Published: July 2009

AbstractCertain proteins, including receptors and signaling molecules, are known to be enriched in caveolae and lipid rafts. Caveolin-1, the major structural protein of caveolae, specifically interacts with many signaling molecules and, thus, caveolae and lipid rafts are often seen as preassembled signaling platforms. A potential binding site for caveolin-1 is present in the platelet-activating factor receptor (PAFR) sequence, and many downstream signaling components of PAFR activation preferentially localize in caveolae. The aim of this study was to investigate whether the PAFR was localized in caveolae/lipid raft domains and, if so, what would be the significance of such localization for PAFR signaling. In this study, we demonstrate that PAFR localizes within membrane microdomains, in close proximity to caveolin-1 in living cells, with potential interaction through a caveolin-1-binding sequence in the PAFR C terminus. Caveolin-1, however, is not essential for PAFR localization in lipid rafts. Disruption of caveolae/lipid rafts with methyl-β-cyclodextrin markedly reduced PAF-triggered inositol phosphate production and cytosolic calcium flux, suggesting that PAFR signaling through the Gαq protein was critically dependent on integrity of lipid rafts and/or caveolae. Interestingly, whereas in caveolin-1-expressing cells lipid raft disruption markedly decreased PAFR-mediated activation of the ERK/MAPK pathway, in cells lacking caveolae, such as leukocytes, lipid raft disruption had either the same inhibitory effect (Ramos B cells) or no effect (monocytes) on PAFR capacity to signal through the ERK/MAPK pathway. In conclusion, PAFR appears to localize within caveolae or lipid rafts in different cell types, and this location may be important for specific signaling events.
Blocking TNF-α Attenuates Aneurysm Formation in a Murine Model
Authors: Xiong Wanfen , MacTaggart Jason , Knispel Rebecca , Worth Jennifer , Persidsky Yuri , Baxter B. Timothy 
Published: July 2009

Abstract
Abdominal aortic aneurysm (AAA) is one of a number of diseases associated with a prominent inflammatory cell infiltrate and local destruction of structural matrix macromolecules. This chronic infiltrate is predominately composed of macrophages and T lymphocytes. Activated macrophages produce a variety of cytokines, including TNF-α. Elevated levels of TNF-α were observed in patients with AAA, suggesting that TNF-α may play a role in the pathogenic mechanisms of AAA. In the present study, we investigated the role of TNF-α in AAA formation. By studying a murine aneurysm model, we found that both mRNA and protein levels of TNF-α were increased in aneurysm tissue compared with normal aortic tissues. Therefore, we tested the response of mice lacking expression of TNF-α. These mice were resistant to aneurysm formation. Our results show that TNF-α deficiency attenuates matrix metalloproteinase (MMP) 2 and MMP-9 expression and macrophage infiltration into the aortic tissue. These data suggest that TNF-α plays a central role in regulating matrix remodeling and inflammation in the aortic wall leading to AAA. In addition, we investigated the pharmacological inhibition of AAA. A Food and Drug Administration-approved TNF-α antagonist, infliximab, inhibited aneurysm growth. Our data also show that infliximab treatment attenuated elastic fiber disruption, macrophage infiltration, and MMP-2 and MMP-9 expression in aortic tissue. This study confirms that a strategy of TNF-α antagonism may be an important therapeutic strategy for treating AAA.
Aberrant Selection and Function of Invariant NKT Cells in the Absence of AP-1 Transcription Factor Fra-2
Authors: Lawson Victoria J. , Maurice Diane , Silk Jonathan D. , Cerundolo Vincenzo , Weston Kathleen 
Published: July 2009

Abstract
The transcription factors mediating the development of CD1d-restricted invariant NKT (iNKT) cells remain incompletely described. Here, we show that loss of the AP-1 transcription factor Fra-2 causes a marked increase in the number of both thymic and peripheral iNKT cells, without affecting the development of other T-lineage cells. The defect is cell-autonomous and is evident in the earliest iNKT precursors. We find that iNKT cells expressing the lower affinity TCRVβ8 are proportionally overrepresented in the absence of Fra-2, indicating altered selection of iNKT cells. There is also widespread dysregulation of AP-1-directed gene expression. In the periphery, mature Fra-2-deficient iNKT cells are able to participate in an immune response, but they have an altered response to Ag, showing increased expansion and producing increased amounts of IL-2 and IL-4 compared with their wild-type counterparts. Unusually, naive Fra-2-deficient T cells also rapidly produce IL-2 and IL-4 upon activation. Taken together, these data define Fra-2 as necessary for regulation of normal iNKT cell development and function, and they demonstrate the central role played by the AP-1 family in this lineage.
Novel Generation Mycobacterial Adjuvant Based on Liposome-Encapsulated Monomycoloyl Glycerol from Mycobacterium bovis Bacillus Calmette-Guérin
Authors: Andersen Claire A. Swetman , Rosenkrands Ida , Olsen Anja W. , Nordly Pernille , Christensen Dennis , Lang Roland , Kirschning Carsten , Gomes Jessica M. , Bhowruth Veemal , Minnikin David E. , Besra Gurdyal S. , Follmann Frank , Andersen Peter , Agger Else Marie 
Published: July 2009

Abstract
The immunostimulatory activity of lipids associated with the mycobacterial cell wall has been recognized for several decades and exploited in a large variety of different adjuvant preparations. Previously, we have shown that a mycobacterial lipid extract from Mycobacterium bovis bacillus Calmette-Guérin delivered in cationic liposomes was a particular efficient Th1-inducing adjuvant formulation effective against tuberculosis. Herein, we have dissected the adjuvant activity of the bacillus Calmette-Guérin lipid extract showing that the majority of the activity was attributable to the apolar lipids and more specifically to a single lipid, monomycoloyl glycerol (MMG), previously also shown to stimulate human dendritic cells. Delivered in cationic liposomes, MMG induced the most prominent Th1-biased immune response that provided significant protection against tuberculosis. Importantly, a simple synthetic analog of MMG, based on a 32 carbon mycolic acid, was found to give rise to comparable high Th1-biased responses with a major representation of polyfunctional CD4 T cells coexpressing IFN-γ, TNF-α, and IL-2. Furthermore, comparable activity was shown by an even simpler monoacyl glycerol analog, based on octadecanoic acid. The use of these synthetic analogs of MMG represents a promising new strategy for exploiting the immunostimulatory activity and adjuvant potential of components from the mycobacterial cell wall without the associated toxicity issues observed with complex mycobacterial preparations.
Leukotriene B4 Potentiates CpG Signaling for Enhanced Cytokine Secretion by Human Leukocytes
Authors: Gaudreault Éric , Gosselin Jean 
Published: July 2009

Abstract
TLRs are known to be important in innate host defense against a variety of microbial infections. In particular, TLR9 has been associated with immune defense against different foreign organisms by recognition of unmethylated DNA sequences. In this report, we provide evidence that leukotriene B4 (LTB4) has the capacity to modulate TLR9 expression on human neutrophils. The effect of LTB4 was found to be specific, because related leukotrienes such as LTC4 and LTD4 or neutrophil agonists IL-8 and C5a failed to modulate TLR9 expression in neutrophils. Using fluorochrome-tagged CpG DNA, we observed that LTB4 treatment also increased TLR9 ligand binding in neutrophils. Moreover, LTB4 stimulation potentiates CpG-mediated signaling via an endosome-independent mechanism in human neutrophils, leading to enhanced secretion of proinflammatory cytokines. The increase in cytokine secretion by LTB4 following CpG stimulation of neutrophils was associated with the activation of TGF-β-activated kinase (TAK-1) as well as p38 and c-Jun (JNK) kinases. In contrast, in PBMC LTB4 leads to an increase in cytokine secretion following CpG stimulation but via a MyD88- and endosome-dependent mechanism. As observed in neutrophils, PBMC stimulation with LTB4 in the presence of CpG also results in enhanced TAK-1, p38, and JNK phosphorylation/activation. These data provide new evidence underlying the immunomodulatory properties of LTB4 leading to antimicrobial defense.