The mitogen-activated protein kinase(MAPK) interacting protein kinases 1 and 2(Mnk1 and Mnk2) play important roles in controlling signals involved in mRNA translation. In addition to the MAPKs(p38 or Erk), multiple st...The mitogen-activated protein kinase(MAPK) interacting protein kinases 1 and 2(Mnk1 and Mnk2) play important roles in controlling signals involved in mRNA translation. In addition to the MAPKs(p38 or Erk), multiple studies suggest that the Mnk kinases can be regulated by other known kinases such as Pak2 and/or other unidentified kinases by phosphorylation of residues distinct from the sites phosphorylated by the MAPKs. Several studies have established multiple Mnk protein targets, including PSF, heterogenous nuclear ribonucleoprotein A1, Sprouty 2 and have lead to the identification of distinct biological functions and substrate specificity for the Mnk kinases. In this review we discuss the pathways regulating the Mnk kinases, their known substrates as well as the functional consequences of engagement of pathways controlled by Mnk kinases. These kinases play an important role in mRNA translation via their regulation of eukaryotic initiation factor 4E(eIF4E) and their functions have important implications in tumor biology as well as the regulation of drug resistance to anti-oncogenic therapies. Other studies have identified a role for the Mnk kinases in cap-independent mRNA translation, suggesting that the Mnk kinases can exert important functional effects independently of the phosphorylation of eIF4 E. The role of Mnk kinases in inflammation and inflammationinduced malignancies is also discussed.展开更多
Aqueous suppressants may lower IOP in eyes with XFS but do not interfere with the mechanism of the cause of progression of trabecular damage, i.e. iridolenticular friction and disruption of the iris pigment epithelial...Aqueous suppressants may lower IOP in eyes with XFS but do not interfere with the mechanism of the cause of progression of trabecular damage, i.e. iridolenticular friction and disruption of the iris pigment epithelial cells. Long term treatment with aqueous suppressants and the concomitant reduction of flow through the trabecular meshwork may have a detrimental effect on tra-展开更多
The doctrine of＇the golden mean＇ of the Confucian certainly applies at the molecular level to cell growth and migration. It is critically important for tissue architecture and homeostasis that cells stop prolifera- ...The doctrine of＇the golden mean＇ of the Confucian certainly applies at the molecular level to cell growth and migration. It is critically important for tissue architecture and homeostasis that cells stop prolifera- tion when reaching appropriate density and halt migration in a direction to avoid collision with others. This ＇red light＇ to hinder cell movement is essential for maintaining contact inhibition of locomotion （CIL）--a phe- nomenon that a cell ceases to continue moving in the same direction when it comes into contact with another cell. The concept of CIL emerged initially from the early work of Abercrombie and Heaysman in the 1950s.展开更多
We studied a large cohort of identical twin sisters, utilizing the unique properties of a twin research design to explore the relationship between obstetrical delivery mode and stress urinary incontinence. Study desig...We studied a large cohort of identical twin sisters, utilizing the unique properties of a twin research design to explore the relationship between obstetrical delivery mode and stress urinary incontinence. Study design: An anonymous 67- item survey was completed by 271 identical twin pairs (n = 542) at the world s largest annual gathering of twins. Logistic regression for repeated binary measures was used to evaluate risk factors and accounting for shared genetics within pairs. Results: The twins had a mean age of 47.1 years (range 15 to 85 years), and stress urinary incontinence was reported by 51.8% . Stress urinary incontinence was associated with age (P = .001), parity (P = .001), obesity (P = .002), and birth mode, with vaginal delivery conferring a considerable increase in stress urinary incontinence risk relative to cesarean section (odds ratio 2.28, 95% confidence interval 1.14 to 4.55, P = .019). Conclusion: Vaginal delivery mode represents a potent determinant of stress urinary incontinence, carrying more than twice the risk of cesarean section. This study of identical twins provides new insight into the epidemiology of female incontinence.展开更多
The purpose of this study was to compare the cost effectiveness of empiric intravenous immunoglobulin (IVIG) with that of fetal blood sampling-indicated treatment for the antepartum care of fetal and neonatal alloimmu...The purpose of this study was to compare the cost effectiveness of empiric intravenous immunoglobulin (IVIG) with that of fetal blood sampling-indicated treatment for the antepartum care of fetal and neonatal alloimmune thrombocytopenia. Study design: We developed a decision analysis model to compare the cost effectiveness of 2 strategies for treatment of pregnancies in women with a history of fetal and neonatal alloimmune thrombocytopenia and an at-risk fetus: 1) IVIG and corticosteroids as indicated by fetal platelet levels determined by fetal blood sampling (FBS); and 2) empiric IVIG. In the first strategy, FBS is used to measure fetal platelets at 24 weeks of gestation and repeated 6 weeks later to guide pharmacotherapy. In the second strategy, weekly IVIG is empirically administered from 24 weeks’ to 37 weeks’ gestation. The main outcome measure was the marginal cost per quality-adjusted life years (QALY) gained. Results: For every 1000 women with a fetus at risk for recurrent alloimmune thrombocytopenia, empiric therapy, compared with FBS- indicated treatment, decreases perinatal deaths from 31.7 to 11.8 while increasing the number of infants with long-term neurologic deficits from 6.1 to 9.6. These health outcomes translate to 382 QALYs gained with empiric therapy and a cost effectiveness ratio of ＄ 32,747 per QALY favoring empiric therapy. In the sensitivity analysis, empiric therapy was not cost effective when the rate of perinatal ICH exceeded 28% . Conclusion: Empiric IVIG therapy is a cost-effective strategy for the treatment of women at risk for fetal and neonatal alloimmune thrombocytopenia when the rate of perinatal ICH is less than 28% .展开更多
Little is known about pre-mRNA splicing in Dictyostelium discoideum although its genome has been completely sequenced.Our analysis suggests that pre-mRNA splicing plays an important role in D.discoideum gene expressio...Little is known about pre-mRNA splicing in Dictyostelium discoideum although its genome has been completely sequenced.Our analysis suggests that pre-mRNA splicing plays an important role in D.discoideum gene expression as two thirds of its genes contain at least one intron.Ongoing curation of the genome to date has revealed 40 genes in D.discoideum with clear evidence of alternative splicing,supporting the existence of alternative splicing in this unicellular organism.We identified 160 candidate U2-type spliceosomal proteins and related factors in D.discoideum based on 264 known human genes involved in splicing.Spliceosomal small ribonucleoproteins(snRNPs),PRP19 complex proteins and late-acting proteins are highly conserved in D.discoideum and throughout the metazoa.In non-snRNP and hnRNP families,D.discoideum orthologs are closer to those in A.thaliana,D.melanogaster and H.sapiens than to their counterparts in S.cerevisiae.Several splicing regulators,including SR proteins and CUGbinding proteins,were found in D.discoideum,but not in yeast.Our comprehensive catalog of spliceosomal proteins provides useful information for future studies of splicing in D.discoideum where the efficient genetic and biochemical manipulation will also further our general understanding of pre-mRNA splicing.展开更多
Retinitis pigmentosa is a leading cause of blindness and a progressive retinal disorder,affecting millions of people worldwide.This disease is characterized by photoreceptor degeneration,eventually leading to complete...Retinitis pigmentosa is a leading cause of blindness and a progressive retinal disorder,affecting millions of people worldwide.This disease is characterized by photoreceptor degeneration,eventually leading to complete blindness.Autosomal dominant(adRP)has been associated with mutations in at least four ubiquitously expressed genes encoding pre-mRNA splicing factors—Prp3,Prp8,Prp31 and PAP1.Biological function of adRPassociated splicing factor genes and molecular mechanisms by which mutations in these genes cause cell-type specific photoreceptor degeneration in humans remain to be elucidated.To investigate the in vivo function of these adRP-associated splicing factor genes,we examined Drosophila in which expression of fly Prp31 homolog was down-regulated.Sequence analyses show that CG6876 is the likely candidate of Drosophila melanogaster Prp31 homolog(DmPrp31).Predicted peptide sequence for CG6876 shows 57%similarity to the Homo sapiens Prp31 protein(HsPrp31).Reduction of the endogenous Prp31 by RNAi-mediated knockdown speci-fically in the eye leads to reduction of eye size or complete absence of eyes with remarkable features of photoreceptor degeneration and recapitulates the bimodal expressivity of human Prp31 mutations in adRP patients.Such transgenic DmPrp31RNAi flies provide a useful tool for identifying genetic modifiers or interacting genes for Prp31.Expression of the human Prp31 in these animals leads to a partial rescue of the eye phenotype.Our results indicate that the Drosophila CG6876 is the fly ortholog of mammalian Prp31 gene.展开更多
文摘The mitogen-activated protein kinase(MAPK) interacting protein kinases 1 and 2(Mnk1 and Mnk2) play important roles in controlling signals involved in mRNA translation. In addition to the MAPKs(p38 or Erk), multiple studies suggest that the Mnk kinases can be regulated by other known kinases such as Pak2 and/or other unidentified kinases by phosphorylation of residues distinct from the sites phosphorylated by the MAPKs. Several studies have established multiple Mnk protein targets, including PSF, heterogenous nuclear ribonucleoprotein A1, Sprouty 2 and have lead to the identification of distinct biological functions and substrate specificity for the Mnk kinases. In this review we discuss the pathways regulating the Mnk kinases, their known substrates as well as the functional consequences of engagement of pathways controlled by Mnk kinases. These kinases play an important role in mRNA translation via their regulation of eukaryotic initiation factor 4E(eIF4E) and their functions have important implications in tumor biology as well as the regulation of drug resistance to anti-oncogenic therapies. Other studies have identified a role for the Mnk kinases in cap-independent mRNA translation, suggesting that the Mnk kinases can exert important functional effects independently of the phosphorylation of eIF4 E. The role of Mnk kinases in inflammation and inflammationinduced malignancies is also discussed.
文摘Aqueous suppressants may lower IOP in eyes with XFS but do not interfere with the mechanism of the cause of progression of trabecular damage, i.e. iridolenticular friction and disruption of the iris pigment epithelial cells. Long term treatment with aqueous suppressants and the concomitant reduction of flow through the trabecular meshwork may have a detrimental effect on tra-
文摘The doctrine of＇the golden mean＇ of the Confucian certainly applies at the molecular level to cell growth and migration. It is critically important for tissue architecture and homeostasis that cells stop prolifera- tion when reaching appropriate density and halt migration in a direction to avoid collision with others. This ＇red light＇ to hinder cell movement is essential for maintaining contact inhibition of locomotion （CIL）--a phe- nomenon that a cell ceases to continue moving in the same direction when it comes into contact with another cell. The concept of CIL emerged initially from the early work of Abercrombie and Heaysman in the 1950s.
文摘We studied a large cohort of identical twin sisters, utilizing the unique properties of a twin research design to explore the relationship between obstetrical delivery mode and stress urinary incontinence. Study design: An anonymous 67- item survey was completed by 271 identical twin pairs (n = 542) at the world s largest annual gathering of twins. Logistic regression for repeated binary measures was used to evaluate risk factors and accounting for shared genetics within pairs. Results: The twins had a mean age of 47.1 years (range 15 to 85 years), and stress urinary incontinence was reported by 51.8% . Stress urinary incontinence was associated with age (P = .001), parity (P = .001), obesity (P = .002), and birth mode, with vaginal delivery conferring a considerable increase in stress urinary incontinence risk relative to cesarean section (odds ratio 2.28, 95% confidence interval 1.14 to 4.55, P = .019). Conclusion: Vaginal delivery mode represents a potent determinant of stress urinary incontinence, carrying more than twice the risk of cesarean section. This study of identical twins provides new insight into the epidemiology of female incontinence.
文摘The purpose of this study was to compare the cost effectiveness of empiric intravenous immunoglobulin (IVIG) with that of fetal blood sampling-indicated treatment for the antepartum care of fetal and neonatal alloimmune thrombocytopenia. Study design: We developed a decision analysis model to compare the cost effectiveness of 2 strategies for treatment of pregnancies in women with a history of fetal and neonatal alloimmune thrombocytopenia and an at-risk fetus: 1) IVIG and corticosteroids as indicated by fetal platelet levels determined by fetal blood sampling (FBS); and 2) empiric IVIG. In the first strategy, FBS is used to measure fetal platelets at 24 weeks of gestation and repeated 6 weeks later to guide pharmacotherapy. In the second strategy, weekly IVIG is empirically administered from 24 weeks’ to 37 weeks’ gestation. The main outcome measure was the marginal cost per quality-adjusted life years (QALY) gained. Results: For every 1000 women with a fetus at risk for recurrent alloimmune thrombocytopenia, empiric therapy, compared with FBS- indicated treatment, decreases perinatal deaths from 31.7 to 11.8 while increasing the number of infants with long-term neurologic deficits from 6.1 to 9.6. These health outcomes translate to 382 QALYs gained with empiric therapy and a cost effectiveness ratio of ＄ 32,747 per QALY favoring empiric therapy. In the sensitivity analysis, empiric therapy was not cost effective when the rate of perinatal ICH exceeded 28% . Conclusion: Empiric IVIG therapy is a cost-effective strategy for the treatment of women at risk for fetal and neonatal alloimmune thrombocytopenia when the rate of perinatal ICH is less than 28% .
基金supported by grants to J.Y.W from NIH(EY014576 and GM070967)A.F.from NSF Career award MCB-0643542 and to R.L.C.from NIH(GM64426 and HG02273).
文摘Little is known about pre-mRNA splicing in Dictyostelium discoideum although its genome has been completely sequenced.Our analysis suggests that pre-mRNA splicing plays an important role in D.discoideum gene expression as two thirds of its genes contain at least one intron.Ongoing curation of the genome to date has revealed 40 genes in D.discoideum with clear evidence of alternative splicing,supporting the existence of alternative splicing in this unicellular organism.We identified 160 candidate U2-type spliceosomal proteins and related factors in D.discoideum based on 264 known human genes involved in splicing.Spliceosomal small ribonucleoproteins(snRNPs),PRP19 complex proteins and late-acting proteins are highly conserved in D.discoideum and throughout the metazoa.In non-snRNP and hnRNP families,D.discoideum orthologs are closer to those in A.thaliana,D.melanogaster and H.sapiens than to their counterparts in S.cerevisiae.Several splicing regulators,including SR proteins and CUGbinding proteins,were found in D.discoideum,but not in yeast.Our comprehensive catalog of spliceosomal proteins provides useful information for future studies of splicing in D.discoideum where the efficient genetic and biochemical manipulation will also further our general understanding of pre-mRNA splicing.
基金We acknowledge Ms.Tiffany Jean and members of the Wu lab for their help in preparation of the manuscript.We thank NIH(GM070967 and EY014576 to JYW)and Searle Foundation(to JYW)for grant support.
文摘Retinitis pigmentosa is a leading cause of blindness and a progressive retinal disorder,affecting millions of people worldwide.This disease is characterized by photoreceptor degeneration,eventually leading to complete blindness.Autosomal dominant(adRP)has been associated with mutations in at least four ubiquitously expressed genes encoding pre-mRNA splicing factors—Prp3,Prp8,Prp31 and PAP1.Biological function of adRPassociated splicing factor genes and molecular mechanisms by which mutations in these genes cause cell-type specific photoreceptor degeneration in humans remain to be elucidated.To investigate the in vivo function of these adRP-associated splicing factor genes,we examined Drosophila in which expression of fly Prp31 homolog was down-regulated.Sequence analyses show that CG6876 is the likely candidate of Drosophila melanogaster Prp31 homolog(DmPrp31).Predicted peptide sequence for CG6876 shows 57%similarity to the Homo sapiens Prp31 protein(HsPrp31).Reduction of the endogenous Prp31 by RNAi-mediated knockdown speci-fically in the eye leads to reduction of eye size or complete absence of eyes with remarkable features of photoreceptor degeneration and recapitulates the bimodal expressivity of human Prp31 mutations in adRP patients.Such transgenic DmPrp31RNAi flies provide a useful tool for identifying genetic modifiers or interacting genes for Prp31.Expression of the human Prp31 in these animals leads to a partial rescue of the eye phenotype.Our results indicate that the Drosophila CG6876 is the fly ortholog of mammalian Prp31 gene.
